Synthesis and Evaluation of Lipophilic Aza-C-glycosides as Inhibitors of Glucosylceramide Metabolism

Authors


Abstract

The structure–activity relationship of lipophilic aza-C-glycosides as inhibitors of the three enzymes of glucosylceramide metabolism is investigated. A library of β-aza-C-glycosides was synthesized with variations in N-alkylation and the linker length/type to the lipophilic moiety. A cross-metathesis reaction was used to prepare a second library of α-aza-C-glycosides with D-gluco, L-ido and D-xylo iminosugar cores possessing analogous linker variations. Evaluation of both libraries did not reveal a potent or selective inhibitor of glucosylceramide synthase. However, β-aza-C-glycoside 43 was found to be a selective inhibitor of β-glucosidase 2. The α-aza-C-glycosides – especially with a D-xylo core (e.g. 80) – proved to be very potent and selective inhibitors of glucocerebrosidase.

Introduction

The first synthesis1 of carbohydrate analogues with a nitrogen atom in the ring – so-called iminosugars or azasugars – and their concurrent discovery as natural products in microorganisms2,3 were reported during the 1960s. The continuously increasing amount of research on iminosugars since then can mainly be attributed to the subsequent discovery of their ability to inhibit glycoprocessing enzymes46 combined with major advances in the field of glycobiology.7 Recently, attention has focused on their ability to stabilize certain deficient glycosidases, associated with lysosomal storage disorders, during folding and transport as so-called pharmacological chaperones.8 However, a recurring problem in the development of iminosugars as inhibitors or chaperones of these enzymes is their lack of specificity. The countless complex carbohydrate structures and conjugates involved in human physiological processes are composed of a relatively limited selection of monosaccharide building blocks. Therefore, an iminosugar inhibitor that only mimics one monosaccharide subunit of the complex substrate of the target enzyme will often inhibit additional carbohydrate-processing enzymes that also create or cleave a glycosidic bond with this monosaccharide. A way to achieve selectivity for a specific enzyme is to add structural elements to the iminosugar that resemble the anomeric substituent/aglycon of the enzyme glycoside substrate or transition state. This should result in additional interactions with the aglycon binding site and as a consequence more selective binding. However, a true iminosugar mimic of the glycoside substrate would result in a labile N,O-acetal function, making it unsuitable as a potential drug or probe in biological research. Replacing the oxygen atom of the iminosugar's pseudo-anomeric centre for a methylene group results in a stable mimic of the target glycoside or transition state. This class of iminosugars is called the aza-C-glycosides. The first piperidine-based aza-C-glycoside to be discovered was α-homonojirimycin (1) that was synthesized in 19879 and later also discovered as a natural product10 (Figure 1).

Figure 1.

α-Homonojirimycin (1) and examples of strategies (AE) for the synthesis of aza-C-glycosides.

Since then many synthetic strategies have been developed for the synthesis of aza-C-glycosides.8,11,12 Most of these can be roughly divided into two general categories depending on the disconnection(s) made in the retrosynthetic analysis. Disconnecting C1–N and C5–N results in approaches that use a final intramolecular cyclization to construct the aza-C-glycoside (Figure 1, AC). A convenient method for cyclization that uses the ability of amines to form imines with carbonyl compounds is the reductive amination. Both a double-reductive amination of a C-1/C-5 diketone (A)13,14 or a single-reductive amination of a C-1/C-5 amino ketone penultimate (B)1517 has proven to be a popular method for the preparation of aza-C-glycosides. Another method to achieve cyclization is to activate, with a suitable leaving group, the C-1 or C-5 position of an intermediate with an amine function on the opposing carbon centre (C).18,19 Alternatively, a disconnection made at C-1–CH2R results in approaches that use a cyclic electrophilic precursor (Figure 1, DE). For example, in this category organometal additions20 and Ugi multicomponent reactions21 have been used on cyclic imines to produce aza-C-glycosides (D). Carbohydrate-derived cyclic nitrones have also been used. Aza-C-glycosides were constructed from these by 1,3-dipolar cycloadditions or nucleophilic additions (E).22,23

We recently reported three β-aza-C-glycoside derivatives (35) based on lipophilic iminosugar 2 (Figure 2). Iminosugar 2 is the lead compound in an ongoing study in which we aim to develop selective inhibitors of the enzymes involved in glucosylceramide metabolism.2428 Glucosylceramide is a β-D-glucoside of the lipid ceramide and belongs to the family of glycosphingolipids (GSLs) that are membrane components in eukaryotes and involved in many (patho)physiological processes.2931 The biosynthesis of glucosylceramide occurs on the cytosolic leaflet of the Golgi apparatus by the membrane-bound enzyme glucosylceramide synthase (GCS). Catabolism of glucosylceramide occurs in the lysosomes by glucocerebrosidase (GBA1). A second catabolic pathway for glucosylceramide, the membrane-bound β-glucosidase 2 (GBA2), is located at or close to the cell surface.32,33 Selective inhibitors of these enzymes can be used to probe the diverse functions of GSLs, but also have potential as therapeutics for diseases associated with abnormal GSL metabolism such as lysosomal sphingolipidoses and type-2 diabetes.26,31,34 Lead compound 2 isa potent inhibitor of GCS (IC50 = 150 nM), GBA1 (IC50 = 200 nM) and GBA2 (IC50 = 1 nM). It also inhibits several intestinal glycosidases (IC50 = 0.4–35 μM). The β-aza-C-glycosides (35) are part of a series of derivatives of 2 that vary in the position of the hydrophobic adamant-1-ylmethoxy moiety on the 1-deoxynojirimycin ring and the functionalization of the endocyclic nitrogen atom. The main message from that library of compounds was that changing the position of the hydrophobic moiety in 2 abolished all GCS inhibitory activity except for β-aza-C-glucoside 3 (GCS: IC50 = 9 μM).28 Additionally, the N-butylated (5) derivative of 3, but not its N-methylated (4) counterpart, also inhibits GCS with modest activity. Expanding on these findings, the here reported study consisted of the synthesis and evaluation of two libraries of lipophilic aza-C-glycosides based on compound 3. This enabled the further investigation of the structure–activity relationship of this class of compounds as inhibitors of GCS, GBA1 and GBA2.

Figure 2.

Lead compound 2, β-aza-C-glycosides 35 and the here reported libraries A/B. R1 = adamant-1-ylmethoxy–spacer; R2 = H or N-alkylated.

The first library (A; Figure 2) consists of derivatives of 3 that retain the pseudo β-orientation [(S)-C-1] of the hydrophobic moiety, but vary in the length and the saturation of the pentyl spacer. The influence of the nitrogen atom on inhibition is also further investigated with C-glycoside derivatives and additional N-alkylated derivatives. For the second library (B) the C-1 stereochemistry was altered to pseudo-α [(R)-C-1)]. For this library the iminosugar core was varied to also encompass L-ido and D-xylo substitution patterns. This variation is based on our recently reported finding that epimerization of the C-5 position in 2 is a suitable strategy to obtain more selective inhibitors of GCS.26 Additionally, analogous spacer variations to library A were prepared for all three α-aza-C-glycoside cores. Both libraries were evaluated in an enzyme assay for inhibitory activity against GCS, GBA1, GBA2. The library entries were also evaluated as inhibitors of the three intestinal glycosidases (sucrase, lactase and maltase) that are not associated with glucosylceramide metabolism, but which are known to be inhibited by 2.

Results and Discussion

The entries of the first library of β-(aza)-C-glycosides with D-gluco stereochemistry could be synthesized by the route described previously28 for 35 or via synthetic intermediates from this route. Alkyne 9 was synthesized from but-3-yn-1-ol (6) by the previously reported three-step protocol (Scheme 1). The synthesis of alkyne 11 was also attempted by this route but this proved low-yielding. The intermediate triflate proved susceptible to side reactions35 and only produced approximately 30 % of the desired triethylsilyl (TES) protected intermediate of 11 upon reaction with adamantylmethanol. An alternative higher yielding route for the synthesis of 11 was found in treating known aldehyde 1025 with the Bestmann–Ohira reagent36,37 to produce 11 in 87 % yield. Alkynes 9 and 11 were deprotonated to the acetylenic anion and condensed with 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (12) to yield 13 and 14 (Scheme 2).38 Next, ketoses 13 and 14 were transformed into 15 and 16 by a tandem reduction/Swern oxidation/double reductive amination reaction sequence.28

Scheme 1.

Reagents and conditions: (a) i: BuLi, THF, –68 °C, 1 h; ii: TESCl, –68 °C to room temp., 20 h; iii: 2 M HCl, 48 h, 71 %. (b) i: Tf2O, Et3N, DCM, –40 °C, 1 h; ii: adamantylmethanol, K2CO3, DCM, reflux, 3 d, 84 %. (c) 4 equiv. NaOMe, THF/MeOH (2:1), 90 °C, 20 h, 87 %. (d) Bestmann–Ohira reagent, K2CO3, MeOH, 0 °C → room temp., 16 h, 87 %.

Scheme 2.

Reagents and conditions: (a) i: BuLi, THF, –50 °C, 1 h; ii: 12, –50 °C, 2 h, 13: 60 %, 14: 86 %. (b) i: NaBH4, MeOH/DCM (5:1), 2 h; ii: DMSO, (COCl)2, DCM, –75 °C, 2 h; iii: Et3N, –75 °C → room temp., 0.5 h; iv: NaBH3CN, NH4HCO2, 3 Å molecular sieves, MeOH/DCM (5:1), 0 °C → room temp., 20 h, 15: 53 %; 16: 59 %; 31: 67 % 3 steps. (c) Pd/C, H2, EtOH, HCl, 20 h, 17: 90 %, 18: 75 %, 27: 81 %, 28: 89 %, 29: 90 %, 32: 97 %. (d) i: Pd/C (Degussa), H2, formaldehyde, n-propanol, 1 h; ii: Pd/C, H2, EtOH, HCl, 20 h, 19: 89 %, 20: 69 %. (e) i: butyraldehyde, NaBH3CN, EtOH/AcOH (3:1), 20 h; ii: Pd/C, H2 4 bar, EtOH, HCl, 20 h, 21: 60 %, 22: 66 %. (f) BF3·Et2O, Et3SiH, CH3CN, –30 °C, 1.5 h, 24: 89 %, 25: 79 %, 26: 60 %. (g) BuLi, THF, –50 °C, 2 h, 72 %. (h) 10, NaBH3CN, Na2SO4, CH3CN/MeOH (5:1), 75 °C, 18 h, 79 %. (i) Pd/C, H2 4 bar, EtOH, HCl, 20 h, 85 %.

The double-reductive amination solely yielded the β-aza-C-D-glucoside stereoisomer in both cases. This indicates that the intramolecular cyclization probably occurs exclusively by axial hydride addition onto cyclic imines (C-1=N/C-5=N) that are in equilibrium with a bis(hemiaminal) intermediate.13,14,39 Compounds 15 and 16 were deprotected by Pd-catalyzed hydrogenolysis to produce β-aza-C-glycosides 17 and 18. Reductive amination of 15 and 16 with formaldehyde or butyraldehyde and hydrogenolysis of the crude intermediate produced the N-methylated (19 and 20) and N-butylated (21 and 22) derivatives, which together with 17 and 18 completed the butyl/hexyl spacer-length variations based on 35 (i.e. pentyl spacer length). Reductive elimination of ketoses 13, 14 and previously reported 2328 with boron trifluoride–diethyl ether/triethylsilane and subsequent Pd/C-catalyzed hydrogenolysis of the intermediates 24, 25 and 26 produced the β-C-glycosides 27, 28 and 29. The synthesis of two β-butyl-aza-C-glycoside derivatives started with the addition of butyllithium to lactone 12 and subsequent transformation of ketose 30 into iminosugar 31 (Scheme 2). Straight deprotection of 31 produced library entry 32. Reductive amination of 31 with aldehyde 10 and deprotection gave 34, which is an analogue of 5 with the C-1/N substituents inverted.

Manipulation of previously reported 3528 provided the final two classes of derivatives for the first library (Scheme 3). Reductive amination of 35 with hexanal, nonanal or aldehyde 10 and subsequent deprotection gave 36, 37 and 38, respectively. During the synthesis of 38, palladium-catalyzed hydrogenolysis of the alkyne function in the crude reductive amination product at atmospheric H2 pressure proceeded sluggishly and gave a separable approximately 1:1 mixture of 38 and (Z)-alkene 39. Alkylation of 3 with benzyl bromide under the agency of potassium carbonate at 85 °C in DMF produced the final N-alkylated derivative 40. Hydrogenolysis of 35 in the presence of Lindlar's catalyst and subsequent Birch reduction of intermediate 41 produced (Z)-alkene 42. A Birch reduction of 35 with sodium for 30 min achieved complete debenzylation but only minor reduction of the alkyne function to yield alkyne derivative 43. A Birch reduction of 35 with lithium for 3 h was able to reduce the alkyne function to give (E)-alkene derivative 44.

Scheme 3.

Reagents and conditions: (a) i: aldehyde, NaBH3CN, EtOH/AcOH (3:1), 20 h; ii: Pd/C, H2 4 bar, EtOH, HCl, 20 h, 36: 71 %, 37: 63 %, 38: 79 %. (b) i: 10, NaBH3CN, EtOH/AcOH (3:1), 20 h; ii: Pd/C, H2, EtOH, HCl, 20 h, 41 %. (c) BnBr, K2CO3, DMF, 85 °C, 18 h, 71 %. (d) Lindlar cat., H2, EtOAc, 18 h, 74 %. (e) Na, NH3, –60 °C, 1 h, 67 %. (f) Na, NH3, –60 °C, 0.5 h, 24 %. (g) Li, NH3, –60 °C, 3 h, 70 %. AMP = 5-(adamant-1-ylmethoxy)pentyl.

For the preparation of the second library, the adamant-1-ylmethoxy-functionalized α-aza-C-glycosides, a cross-metathesis reaction approach was chosen.40,41 In this way the three distinct spacer lengths can be prepared by using three appropriate adamant-1-ylmethoxy-functionalized terminal alkenes in combination with the same iminosugar cross-metathesis partner. Additionally, unsaturated spacer derivatives can be generated by a Birch reduction of the cross-metathesis products. Positioning of this alkene function at the same site as in library one entries 42 and 44 is not possible, because Compain and Martin have previously reported that α-vinyl-aza-C-glycosides are not suitable for cross-metathesis.41 Therefore D-gluco, L-ido and D-xylo α-allyl-aza-C-glycosides were selected as cross-metathesis partner (Scheme 5).

The adamant-1-ylmethoxy-functionalized alkenes 45 and 47 could be prepared by a Williamson etherification of adamantylmethanol with allyl bromide and 5-bromopent-4-ene (Scheme 4). Alkene 46 could be prepared by substitution of the triflate of 3-buten-1-ol with adamantylmethanol. The synthesis of the α-allyl-aza-C-glycosides started with a Grignard reaction of allylmagnesium bromide on the anomeric p-methoxybenzyl aminoglycoside 49, which in turn was prepared from commercially available 48 (Scheme 5). The Grignard reaction produced (R)-50, which can be rationalized by taking into account an O-2/NPMB-chelated Felkin–Anh-type intermediate (see ref.42).18,42 Selective mesylation of the 5-OH group in 50 and subsequent SN2-like cyclization with a Walden inversion at C-5 produced L-ido compound 51. Intermediate 50 could be transformed into D-gluco α-allyl-aza-C-glycoside 54 by a procedure adapted from Nicotra and co-workers. This procedure consisted of Fmoc protection of 50 to 52, oxidation of the 5-hydroxy group in 52 to 53 and finally removal of the Fmoc group and cyclization to 54 by a reductive amination.15 Compain and Martin have previously shown that the cross-metathesis reaction is incompatible with certain endocyclic tertiary amines similar to 51 and 54.41 The p-methoxybenzylamines in 51, 54 were therefore oxidatively cleaved with ammonium cerium(IV) nitrate and protected as a benzyloxy carbamate (55 and 66) to make them suitable for cross-metathesis. Starting from the D-xylose (57) derived 58, the D-xylo α-allyl-aza-C-glycoside 62 was synthesized by a similar sequence of reactions as described for 55. Except now amino alcohol 60, obtained from a stereoselective43 Grignard reaction on 59, was cyclized to 61 by an intramolecular Mitsunobu reaction.44,45

Scheme 4.

Reagents and conditions: (a) adamantylmethanol, NaH, DMF, 16 h, 45: 80 %, 47: 53 %. (b) i: Tf2O, Et3N, DCM, –40 °C → 0 °C, 1 h; ii: adamantylmethanol, K2CO3, DCM, 50 °C, 20 h, 99 %.

Scheme 5.

Reagents and conditions: (a) NH2PMB, pTsOH, Na2SO4, toluene, reflux, 18 h, used crude. (b) AllylMgBr, Et2O, 0 °C → room temp., 16 h, 93 %. (c) MsCl, pyridine, 0 °C → room temp., 4 h; ii: 90 °C, 16 h, 78 %. (d) FmocCl, aq. NaHCO3, DCM, 16 h, 91 %. (e) Dess–Martin periodinane, DCM, 0 °C, 6 h, 98 %. (f) i: piperidine, DMF, 0 °C, 0.5 h; ii: NaCNBH3, AcOH, Na2SO4, MeOH, –35 °C → –20 °C, 16 h, 81 %. (g) i: CAN, THF/H2O (5:1), 0 °C, 3 h; ii: ZCl, aq. NaHCO3, dioxane, 20 h, 55: 75 %, 56: 65 %, 62: 87 %. (h) i: BnBr, NaH, DMF, 0 °C → room temp., 20 h; ii: 1 M HCl/AcOH (1:2.2), 105 °C, 4 h, 55 %. (i) NH2PMB, CSA, Na2SO4, toluene, reflux, 2.5 h, used crude. (j) AllylMgBr, THF, 0 °C → room temp., 16 h, 97 %. (k) PPh3, DEAD, DCM, 20 h, 88 %. (l) 45, 46, 47 or non-1-ene, 25 mol-% Grubbs' 1st generation catalyst, DCM, 45 °C, 24 h, 65–88 %.

Initial attempts at cross-metathesis between α-allyl-aza-C-glycosides 55, 56, 62 and adamant-1-ylmethoxy alkenes 4547 by using Grubbs' generation 2 catalyst showed little conversion of the aza-C-glycoside metathesis partners. Cross-metathesis of 55, 56 and 62 with a threefold excess of 45, 46 and 47 under the agency of 25 mol-% of Grubbs' generation 1 catalyst proved more productive. By using these conditions, the nine penultimates (6371) were obtained in moderate to good yields (65–88 %) as (E)/(Z) mixtures varying from 2:1 to 5:1 (Scheme 5). As a reference compound in the enzyme assay the potent GBA1 inhibitor 82 (Table 1), reported by Compain and co-workers,46 was synthesized from 62 by cross-metathesis with oct-1-ene to produce 72. Deprotection of all the cross-metathesis products by Pd/C-catalyzed hydrogenation at 4 bar gave library entries 7382 (for structures see Table 1). The final entries for the second library were made by a Birch reduction of protected cross-metathesis products 64, 67, 70 and 72 to provide double-bond-containing α-aza-C-glycosides 8386. In the case of 86 this solely provided the (E) isomer, but for 83, 84 and 85 it gave an inseparable mixture of (E)/(Z) isomers. These mixtures were tested as such in the enzyme assay.47,48

Biological Evaluation

The inhibitory potency and selectivity of the two libraries of lipophilic aza-C-glycosides A (1722; 2729; 32, 34; 3640; 4244) and B (7386) were assessed by evaluating the compounds in assays for the three enzymes involved in glucosylceramide metabolism; glucosylceramide synthase (GCS), glucocerebrosidase (GBA1) and β-glucosidase 2 (GBA2). To further establish the selectivity profile of the library entries they were also tested in inhibition assays for the intestinal glycosidases sucrase, lactase and maltase. As an unwanted side-effect most 1-deoxynojirymycin-based inhibitors of glucosylceramide metabolism also inhibit these glycosidases.

Table 1. Enzyme inhibition assay results for α- and β-(aza)-C-glycosides (apparent IC50 values in μM).[a]
  • [a]

    AM = adamant-1-ylmethyl; AMP = 5-(adamant-1-ylmethoxy)pentyl.

original image

In our previous study28 the hydrophobic moiety of lead compound 2 was translocated to produce β-aza-C-glycoside 3. When comparing the structures of 2 and 3 this translocation lengthens the carbon chain connecting the endocyclic nitrogen atom and the adamant-1-ylmethoxy group from five to six atoms. The influence of this change on the SAR could be assessed with derivatives 17 and 18. The assay results for the first library show that neither shortening (17) nor lengthening (18) this carbon chain by one carbon atom improves inhibition of GCS, but instead abolishes it (Table 1). Evidently, the carbon chain length of 3 is already optimal for GCS inhibition. Altering the saturation of the pentyl spacer of 3 into the (Z)-alkene 42, alkyne 43 or (E)-alkene 44 derivatives also prevented GCS inhibition. When compared to 3, 42 is a more selective inhibitor of GBA1, and both 43 and 44 are more selective for GBA2.

The β-C-glycoside derivatives 27, 28 and 29 did not inhibit any of the tested enzymes to a significant extent. When combined with the fact24 that derivatives of 2 with an endocyclic amide are also inactive as inhibitors of glucosylceramide metabolism this strongly suggests that a basic nitrogen function is essential for inhibition. The previously reported observation, that GCS is inhibited by the N-butylated 5 and not N-methylated 4, is not reproduced for the lengthened or shortened N-alkylated derivatives 19, 20 and 21, 22. Compound 19 is a relatively selective inhibitor of GBA2. Also the synthesized derivatives of 3 with alternate/lengthened N-alkyl moieties 3640, all lost the ability to inhibit GCS and showed no improvement of GBA1 or GBA2 inhibition. These findings indicate that the secondary endocyclic nitrogen atom of 3 plays an important part in the ability of 3 to inhibit GCS, GBA1 and GBA2. The only derivative from the first library that still very modestly inhibits GCS is 34 (15 % at 10 μM) – the C-1/N-substituent-inverted derivative of 5. The related entry, 32, did not significantly inhibit any of the enzymes in the assay. Compound 32 is a β-aza-C-glycoside derivative of the known clinically used GCS inhibitor N-butyl-1-deoxynojirimycin (GCS: IC50 = 50 μM in this assay). This reconfirms the observation from our previous study28 that relocating the hydrophobic moiety from the nitrogen atom to C-1 does not lead to more potent GCS inhibitors.

Almost all the entries of the second library of lipophilic α-aza-C-glycosides showed very modest inhibition of GCS (≤20 % at 10 μM) with none being as potent as 3 (Table 1). These results corroborate an earlier study by Boucheron and co-workers that showed that N-alkylated α-aza-C-glycosides are poor inhibitors of GCS.49 The three different iminosugar cores did, however, have a distinct effect on GBA2 inhibition. The D-gluco derivatives (7678, 84) in general were >25-fold more potent GBA2 inhibitors than the L-ido (7375, 83) or D-xylo (7981, 82, 85, 86) derivatives. For GBA1 inhibition the effect of the iminosugar core was even more pronounced. The D-xylo α-aza-C-glycosides were all 1–2 nM inhibitors of GBA1 as opposed to the L-ido derivatives that were 2–6 μM inhibitors of the same enzyme. D-xylo analogue 85 is an (E)/(Z) mixture, and these isomers should be tested separately to fully elucidate their relative contributions to GBA1 inhibition. In general, the unsaturated pentyl spacer derivatives (83, 84 and 85) did not show a significantly different inhibition profile for the tested enzymes compared to their saturated counterparts (74, 77 and 80). However, introduction of an (E)-alkene into the known46 potent GBA1 inhibitor 82 to give 86 does reduce inhibition of GCS and GBA2 to make it more selective.

Conclusions

The syntheses and biological evaluation of two libraries of lipophilic aza-C-glycosides is reported. The structures of the library entries are based on the previously reported β-aza-C-glycosides 3.28 The aim was to investigate the structure–activity relationship of this class of iminosugars as inhibitors of three enzymes, GCS, GBA1 and GBA2, involved in glucosylceramide metabolism.

The first library consisted of β-aza-C-glycosides and showed that for GCS inhibition an aliphatic pentyl-spacer length between C-1 and the adamant-1-ylmethoxy group combined with a secondary endocyclic nitrogen atom is optimal in this library. β-C-Glycoside derivatives showed the importance of a basic endocyclic nitrogen atom for inhibition of the here evaluated glycosidases and the glycosyltransferase GCS. From this first library the alkyne-containing 43 was found to be a potent and selective inhibitor of GBA2 and the (Z)-alkene-containing 42 a selective inhibitor of GBA1.

The second library of α-aza-C-glycosides did not contain a potent inhibitor of GCS, which indicates that a pseudo-β orientation of the hydrophobic moiety is necessary for potent inhibition of GCS. The type of iminosugar core in the α-aza-C-glycosides proved to exert a pronounced influence on inhibition of GBA1 and GBA2. The D-gluco iminosugar core proved most suitable for GBA2 inhibition, and the D-xylo core is optimal for GBA1 inhibition. All D-xylo analogues (7981, 82, 85, 86) were very potent and selective GBA1 inhibitors. Iminosugar 82 has already been reported by Compain, Martin and co-workers. Their study showed that 82 holds potential as a pharmacological chaperone for improving the activity of a deficient variant of GBA1 in N370S fibroblasts from patients with the lysosomal storage disorder, Gaucher disease.46 Therefore, it might prove interesting to also evaluate the novel derivatives (7981, 85, 86) presented here to this end.

Experimental Section

General Methods: All solvents and reagents were obtained commercially and used as received unless stated otherwise. Reactions were executed at ambient temperatures unless stated otherwise. All moisture-sensitive reactions were performed under argon. Residual water was removed from starting compounds by repeated coevaporation. All solvents were removed by evaporation under reduced pressure. Reaction grade acetonitrile, dimethyl sulfoxide, 2-propanol and methanol were stored over 3 Å molecular sieves. Other reaction grade solvents were stored over 4 Å molecular sieves. THF was distilled prior to use from LiAlH4. Ethanol was purged of acetaldehyde contamination by distillation from zinc/KOH. DCM was distilled prior to use from P2O5. Rf values were determined from TLC analysis by using DC-Fertigfolien (Schleicher & Schuell, F1500, LS254) with detection by spraying with a solution of(NH4)6Mo7O24·4H2O (25 g/L) and (NH4)4Ce(SO4)4·2H2O (10 g/L) in 10 % sulfuric acid or a solution of phosphomolybdic acid hydrate (7.5 wt.-% in ethanol) followed by charring at ca. 150 °C. Visualization of all deprotected iminosugar compounds during TLC analysis was accomplished by exposure to iodine vapour. Column chromatography was performed on silica gel (40–63 μm). Iminosugars (43, 7386) were purified with an automated HPLC system fitted with a semi-preperative C18 column (21 mm diameter × 150 mm length, 5 μm particle size, 25 mL/min). Isocratic or gradient elution was performed with eluent A: 0.1 % aq. TFA and eluent B: CH3CN. Iminosugar samples were dissolved in a mixture of 0.1 % aq. TFA/tBuOH/CH3CN (3:1:1, v/v/v, 2 mL) with optional MeOH for full solvation of the compound. The solution was filtered through a 5 μm filter and injected onto the column in 500 μL portions for preparative runs. Compound detection was carried out by a charged aerosol detector (Esa Corona, sensitivity setting: 100 pA). Appropriate fractions were collected, concentrated, coevaporated with water (2 ×) and lyophilized. 1H and 13C APT NMR spectra were recorded with a Bruker DMX 600 (600/150 MHz), Bruker DMX 500 (500/125 MHz), Bruker AV 400 (400/100 MHz), or Bruker AC 200 (200/50 MHz) spectrometer in CDCl3 or MeOD. Chemical shifts (δ) are given in ppm relative to tetramethylsilane as internal standard (1H NMR in CDCl3) or the signal of the deuterated solvent. Coupling constants (J) are given in Hz. Where indicated, NMR peak assignments were made by using COSY and HSQC experiments. All presented 13C APT spectra are proton-decoupled. High-resolution mass spectra were recorded by direct injection (2 μL of a 2 μM solution in water/acetonitrile; 50:50; v/v and 0.1 % formic acid) with a mass spectrometer (Thermo Finnigan LTQ Orbitrap) equipped with an electrospray ion source in positive mode (source voltage 3.5 kV, sheath gas flow 10, capillary temperature 250 °C) with resolution R = 60000 at m/z = 400 (range m/z = 150–2000) and dioctyl phthalate (m/z = 391.28428) as a “lock mass”. Optical rotations were measured with a Propol automatic polarimeter (sodium D-line, λ = 589 nm). ATR-IR spectra were recorded with a Shimadzu FTIR-8300 fitted with a single-bounce Durasample IR diamond crystal ATR-element and are reported in cm–1.

Enzyme Assays: The enzyme assays used for determining the inhibition of activity of glucosylceramide synthase (GCS), glucocerebrosidase (GBA1), β-glucosidase 2 (GBA2), sucrase, lactase and maltase were carried out as described previously.28

General Procedure A. Addition of Acetylenic Anions of 9 and 11 to Gluconolactone (12): A dry solution of the acetylene in THF (0.1 M) was cooled to –50 °C, and BuLi (1.2 equiv., 1.6 M in toluene) was added slowly to the solution. After stirring at –50 °C for 1 h, a dry solution of 1238 (2 equiv.) in THF (0.33 M) was slowly added, and the reaction mixture was stirred at –50 °C for 2 h. The reaction mixture was quenched (satd. aq. NH4Cl), warmed to room temp. and poured into satd. aq. NH4Cl. The aqueous layer was extracted with Et2O (3 ×), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by silica gel column chromatography to provide the ketose product.

General Procedure B. Transformation of Ketose 13, 14 and 23 into β-C-Glycosides by Reductive Elimination: Triethylsilane (5 equiv.) and BF3·O(Et)2 (6 equiv.) were successively added to a cooled (–30 °C) solution of the ketose in anhydrous acetonitrile (0.1 M). After stirring at –30 °C for 1.5 h, TLC analysis showed complete disappearance of the starting material. The reaction mixture was quenched by addition of aq. Na2CO3 (6 × reaction volume, 10 wt.-%) and subsequently extracted with Et2O (3 ×). The combined organic phases were dried (MgSO4) and concentrated. The residue was purified by silica gel column chromatography to provide the β-C-glycoside.

General Procedure C. Transformation of Ketose 13 and 14 into β-Aza-C-glycosides: Reduction of Ketal: A dry solution of the ketose in MeOH/DCM (0.1 M, 5:1, v/v) was cooled to 0 °C and NaBH4 (5 equiv.) was added. After stirring at 0 °C for 2 h, TLC analysis indicated full conversion to a slower running product. The reaction was quenched by addition of acetone and additional stirring (15 min). The reaction mixture was concentrated, transferred into satd. aq. NH4Cl and extracted with EtOAc (3 ×). The combined organic phases were dried (MgSO4) and concentrated to provide the glucitol derivative, which was used without further purification in the Swern oxidation [Rf(diol) ≈ 0.4 in EtOAc/toluene; 1:3].

Swern Oxidation of Diol: A solution of oxalyl chloride (4 equiv.) in DCM (1 M) was cooled to –78 °C. After dropwise addition of a solution of DMSO (5 equiv.) in DCM (2 M) over 10 min, the reaction mixture was stirred for 40 min, while being kept below –70 °C. Next, a dry solution of the glucitol intermediate in DCM (0.5 M) was added dropwise to the reaction mixture over a 15 min period, while keeping the reaction mixture below –70 °C. After stirring the reaction mixture below –65 °C for 2 h, Et3N (12 equiv.) was added dropwise over a 10 min period, while keeping the reaction mixture below –65 °C. After addition, the reaction mixture was warmed to –5 °C over 2 h [Rf(diketone) ≈ 0.80 in EtOAc/toluene, 1:3].

Double-Reductive Amination: The Swern reaction mixture was concentrated at a moderate temperature (ca. 30 °C) with simultaneous coevaporation of toluene (3 ×). The residue was dissolved in a mixture of MeOH/DCM (0.02 M, relative to starting compound, 5:1, v/v), and NH4HCO2 (20 equiv.) was added. The mixture was cooled to 0 °C and stirred until all NH4HCO2 had dissolved. Activated 3 Å molecular sieves (10 g/mmol) was added, and the reaction mixture was stirred for 15 min, after which NaBH3CN (4 equiv.) was added. The reaction mixture was kept at 0 °C for 1 h, after which the cooling source was removed, and the reaction mixture was stirred for an additional 20 h. After removal of the molecular sieves with the aid of a glass microfibre filter, the filtrate was concentrated, dissolved in EtOAc and washed with satd. aq. NaHCO3. The aqueous phase was back-extracted with EtOAc (3 ×), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by silica gel column chromatography to provide the β-aza-C-glycoside product (Rf ≈ 0.5 in EtOAc/toluene, 1:3).

General Method D. N-Alkylation of β-Aza-C-glycosides by Reductive Amination: A dry mixture of the tetrabenzylated iminosugar, the aldehyde (10 equiv.) and Na2SO4 (10 equiv.) in a mixture of EtOH/AcOH (0.1 M, 3:1, v/v) was charged with NaBH3CN (4 equiv.). The reaction mixture was stirred for 20 h and subsequently concentrated by coevaporation with toluene. The residue was dissolved EtOAc, poured into satd. aq. NaHCO3 and extracted with EtOAc (3 ×). The combined organic layers were dried (Na2SO4) and concentrated. The crude N-alkylated iminosugar was used in the Pd/C-catalyzed hydrogenolysis.

General Method E. Oxidative Cleavage of the PMB Group and Reprotection as Benzyloxy Carbamate: A solution of the PMB-protected amine in THF (0.5 M) was slowly added to a cooled (0 °C) solution of ammonium cerium(IV) nitrate (4 equiv.) in H2O/THF (0.05 M, 1:5, v/v). The resulting suspension was stirred at 0 °C for 3 h, after which it was diluted with EtOAc (3 × reaction volume) and washed with satd. aq. NaHCO3 (3 × reaction volume). The aqueous phase was back-extracted with EtOAc (2 ×). The combined organic phases were concentrated. The residue was suspended in a mixture of dioxane/satd. aq. NaHCO3 (0.1 M, 2:1, v/v) after which benzyloxy chloroformate (2 equiv.) was added. The reaction mixture was stirred for 20 h. The mixture was diluted with water and extracted with Et2O (2 ×). The combined organic phases were dried (Na2SO4) and concentrated. To facilitate the separation of the product from p-anisaldehyde during column chromatography, the crude benzyloxy carbamate was dissolved in MeOH (0.2 M), cooled to 0 °C and treated with sodium borohydride (3 equiv.). After 15 min, the reaction was quenched by slow addition of acetone. The mixture was acidified to pH = 2 with 1 M aq. HCl, diluted with water (3 × reaction volume) and extracted with Et2O (3 ×). The combined organic phases were dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography to afford the benzyloxy carbamate protected iminosugar.

General ProcedureF. Cross Metathesis: The iminosugar cross metathesis partner was coevaporated with DCE (3 ×). Next, the second alkene cross-metathesis partner (3 equiv.) was added, and together they were dissolved in DCM (0.067 M, relative to iminosugar). Alkenes 45, 46 and 47 are not coevaporated because 46 and 47 are volatile. The solution was degassed by sonication under an argon flow for 10 min. Grubbs' first generation catalyst (25 mol-%) was added, and the reaction mixture was refluxed at 45 °C for 24 h. The reaction mixture was concentrated and exposed to air at room temp. for 48 h. The residue was purified by by silica gel column chromatography to afford the cross-metathesis product. In cases were the product was difficult to isolate from residual iminosugar cross-metathesis partner or catalyst breakdown products, the residue was purified once and then used impure in general procedure G or general procedure H (in a Parr apparatus).

GeneralProcedureG. Birch Reduction: A dry (100 mL) three-neck roundbottom flask was cooled to –60 °C, and ammonia gas (through a CaO-filled drying column) was passed through it until 20–30 mL of ammonia had condensed. The ammonia gasflow was stopped, and sodium (50–100 mg, rinsed beforehand with heptane) was added to the liquid ammonia. After stirring the dark blue mixture at –60 °C for 1 min, a solution of the benzylated iminosugar (50–200 mg) in tBuOH/THF (0.5 mL/ 2 mL) was added. The reaction mixture was stirred at –60 °C for 1–2 h, and additional sodium was added if the blue colour of the mixture disappeared. The reaction was quenched by slow addition of satd. aq. NH4HCO2 (1 mL). The ammonia was evaporated, and the resulting residue was coevaporated with dioxane. The solid residue was redissolved in MeOH and concentrated in the presence of Celite. The Celite/compound mixture was purified by silica gel column chromatography to afford the deprotected iminosugar.

General Procedure H. Pd/C-Catalyzed Hydrogenolysis atAtmospheric H2 Pressure: A solution of the compound (ca. 50–250 μmol) in “acetaldehyde-free” EtOH (4 mL) was acidified to pH ≈ 2 with 1 M aq. HCl. Argon was passed through the solution for 5 min, after which a catalytic amount of Pd/C (ca. 50 mg, 10 wt.-% Pd on C) was added. Hydrogen was passed through the reaction mixture for 15 min, and the reaction mixture was stirred under atmospheric hydrogen pressure for 20 h. The Pd/C was removed by filtration through a glass microfibre filter, followed by thorough rinsing of the filter cake with MeOH. The filtrate was concentrated by coevaporation with toluene. In the case of incomplete reduction, hydrogenolysis was repeated after workup and coevaporation (3 ×) with “acetaldehyde-free” EtOH, at atmospheric pressure in the presence of Pd/C (ca. 50 mg) and Pd black (ca. 5 mg) or at higher H2 pressure in a Parr apparatus.

Pd/C-Catalyzed Hydrogenolysis in a Parr Apparatus: A solution of the compound (ca. 50–250 μmol) in “acetaldehyde-free” EtOH (50 mL) was acidified to pH ≈ 2 with 1 M aq. HCl. Argon was passed through the solution for 5 min, after which a catalytic amount of Pd/C (50 mg, 10 wt.-% Pd on C) was added. The reaction vessel was placed under vacuum and subsequently ventilated with hydrogen gas. This cycle was repeated one more time, after which the vessel was placed under 4 bar of hydrogen gas and mechanically shaken for 20 h. Workup was the same as described in general procedure H.

4-(Triethylsilyl)but-3-yn-1-ol (7): A dry and cooled (–68 °C) solution of but-3-yn-1-ol (6; 3.11 g, 44.3 mmol) in THF (50 mL) was charged with BuLi (60.9 mL, 97.5 mmol, 1.6 M in toluene) and stirred at –68 °C for 1 h. Triethylsilyl chloride (22.5 mL, 132.9 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at –68 °C for 1 h, after which cooling was ceased and the solution was stirred for 18 h. 2 M aq. HCl (200 mL) was added, and the reaction mixture was stirred for 48 h [Rf(intermediate disilyl compound) = 0.80 (EtOAc/PE, 1:2)]. The mixture was extracted with Et2O (2 × 200 mL), and the combined organic layers were washed with water (2 × 200 mL). The organic phase was dried (MgSO4), concentrated, and the resulting residue was purified by silica gel column chromatography (0 % → 30 % EtOAc in PE) to provide product 7 (5.82 g, 31.5 mmol) in 71 % yield as a colourless oil. Rf = 0.10 (EtOAc/PE, 1:9). 1H NMR (200 MHz, CDCl3): δ = 3.72 (t, J = 5.8 Hz, 2 H, OCH2-1 butynyl), 2.53 (t, J = 6.6 Hz, 2 H, CH2-2 butynyl), 1.82 (br. s, 1 H, OH), 0.99 (t, J = 8.0 Hz, 9 H, 3 × CH3 SiEt3), 0.58 (q, J = 8.0 Hz, 6 H, 3 × CH2SiEt3) ppm. IR (thin film): equation imagemax. = 3323, 2953, 2876, 2174, 1458, 1414, 1236, 1018, 1004, 972, 889, 721 cm–1. MS (ESI): found 185.2 [M + H]+, calcd. for [C10H2OSi + H]+ 185.1.

[4-(Adamant-1-ylmethoxy)but-1-ynyl]triethylsilane (8): A dry solution of 7 (2.21 g, 12.0 mmol) in DCM (120 mL) was cooled to –40 °C followed by addition of Et3N (1.66 mL, 12.0 mmol). Next, Tf2O (2.42 mL, 14.4 mmol) was added dropwise, and the reaction mixture was stirred at –40 °C for 1 h. Cooling was ceased, and the reaction mixture was concentrated at room temp. by means of a nitrogen flow. The residue was purified by silica gel column chromatography (isocratic 10 % EtOAc in PE), and the product-containing fractions were concentrated under a nitrogen flow at room temp. to provide the intermediate triflate. [Rf = 0.67 (EtOAc/PE, 1:9)]. The triflate (ca. 12 mmol) was dissolved in DCM (80 mL), to which adamantylmethanol (9.98 g, 60 mmol) and K2CO3 (8.17 g, 60 mmol) were successively added. The reaction mixture was refluxed (ca. 55 °C) for 3 d, after which the solids were removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0 % → 20 % EtOAc in PE) to provide 8 (3.37 g, 10.1 mmol) in 84 % yield as a colourless oil. Rf = 0.83 (EtOAc/PE, 1:9). 1H NMR (200 MHz, CDCl3): δ = 3.52 (t, J = 7.1 Hz, 2 H, OCH2-4 butynyl), 3.02 (s, 2 H, OCH2-Ada), 2.49 (t, J = 7.1 Hz, 2 H, CH2-3 butynyl), 1.95 (s, 3 H, 3 × CH Ada), 1.79-1.57 (m, 6 H, 3 × CH2 Ada), 1.53 (d, J = 2.7 Hz, 6 H, 3 × CH2 Ada), 0.98 (t, J = 7.8 Hz, 9 H, 3 × CH3 SiEt3), 0.57 (q, J = 7.7 Hz, 6 H, 3 × CH2 SiEt3) ppm. 13C NMR (50 MHz, CDCl3): δ = 105.5 (Cq-2 butynyl), 82.6 (Cq-1 butynyl), 82.2 (OCH2-Ada), 70.2 (OCH2-4 butynyl), 39.9 (CH2 Ada), 37.5 (CH2 Ada), 34.3 (Cq Ada), 28.6 (CH Ada), 21.4 (CH2-3 butynyl), 7.6 (CH3 SiEt3), 4.7 (CH2 SiEt3) ppm. IR (thin film): equation imagemax. = 2901, 2874, 2849, 2175, 1456, 1236, 1157, 1111, 1003, 723 cm–1. HRMS: found 333.2609 [M + H]+, calcd. for [C21H36OSi + H]+ 333.2608.

4-(Adamant-1-ylmethoxy)but-1-yne (9): A dry solution of 8 (3.37 g, 10.1 mmol) in a mixture of THF (50 mL) and MeOH (25 mL) was charged with NaOMe (2.86 g, 52.95 mmol) and refluxed at 90 °C for 20 h. The reaction was quenched (water, 0.5 mL) and the mixture concentrated. The residue was dissolved in EtOAc (200 mL) and washed with water (2 × 200 mL). The organic phase was dried (MgSO4) and concentrated. The residue was purified by silica gel column chromatography (2 % → 10 % acetone in PE) to provide 9 (1.92 g, 8.80 mmol) in 87 % yield as a colourless oil. Rf = 0.70 (EtOAc/PE, 1:9). 1H NMR (200 MHz, CDCl3): δ = 3.53 (t, J = 7.2 Hz, 2 H, OCH2-4 butynyl) 3.01 (s, 2 H, OCH2-Ada), 2.43 (td, J = 2.7, 7.2 Hz, 2 H, CH2-3 butynyl), 1.97 (br. s, 3 H, 3 × CH Ada), 1.94 (t, J = 2.6 Hz, 1 H, CH-1 butynyl), 1.78–1.57 (m, 6 H, 3 × CH2 Ada), 1.53 (d, J = 2.8 Hz, 6 H, 3 × CH2 Ada) ppm. 13C NMR (50 MHz, CDCl3): δ = 82.1, (OCH2-Ada), 81.6 (Cq butynyl), 69.8 (OCH2-4 butynyl), 69.2 (Cq butynyl), 39.8 (CH2 Ada), 37.3 (CH2 Ada), 34.2 (Cq Ada), 28.4 (CH Ada), 19.8 (CH2-3 butynyl) ppm. IR (thin film): equation imagemax. = 3312, 2899, 2847, 1450, 1362, 1157, 1103, 1070 cm–1. MS (ESI): found 219.9 [M + H]+, calcd. for [C15H22O + H]+ 219.2.

6-(Adamant-1-ylmethoxy)hex-1-yne (11): (1-Diazo-2-oxopropyl)-di-O-methyl phosponate (1.44 g, 7.5 mmol)50,51 and K2CO3 (1.38 g, 10.0 mmol) were added to a cooled (0 °C) solution of 1025 (1.25 g, 5.0 mmol) in methanol (25 mL). After 30 min, the reaction mixture was warmed to room temp. and stirred for an additional 16 h. The reaction mixture was transferred into satd. aq. NH4Cl (20 mL) and extracted with Et2O (4 × 50 mL). The combined organic phases were washed with satd. aq. NaCl (50 mL), dried (MgSO4) and concentrated. The crude product was purified by silica gel column chromatography (0 % → 6 % EtOAc in PE) to furnish 11 (1.07 g, 4.34 mmol) in 87 % yield as a colourless oil. Rf = 0.6 (PE/acetone, 19:1). 1H NMR (200 MHz, CDCl3): δ = 3.40 (t, J = 6.0 Hz, 2 H, OCH2-6 hex-1-yn), 2.95 (s, 2 H, OCH2-Ada), 2.28–2.17 (m, 2 H, CH2-3 hexynyl), 1.96 (br. s, 3 H, 3 × CH Ada), 1.94 (t, J = 2.6 Hz, 1 H, CH-1 hexynyl), 1.78–1.57 (m, 10 H, 3 × CH2 Ada, 2 × CH2 hexynyl), 1.53 (d, J = 2.8 Hz, 6 H, 3 × CH2 Ada) ppm. 13C NMR (50 MHz, CDCl3): δ = 84.3 (Cq hexynyl), 82.0 (OCH2-Ada), 70.9 (OCH2-6 hexynyl), 68.6 (Cq hexynyl), 39.9 (CH2 Ada), 37.4 (CH2 Ada), 34.2 (Cq Ada), 28.8 (CH2-5 hexynyl), 28.5 (CH Ada), 25.5 (CH2-4 hexynyl), 18.3 (CH2-3 hexynyl) ppm. IR (thin film): equation imagemax. = 3311, 2899, 2847, 1452, 1360, 1157, 1113, 1056, 625 cm–1. HRMS: found 247.2058 [M + H]+, calcd. for [C17H26O + H]+ 247.2056.

α/β-Mixture of 1-C-[4-(Adamant-1-ylmethoxy)but-1-ynyl]-2,3,4,6-tetra-O-benzyl-D-glucopyranose (13): Compound 9 (1.0 g, 4.58 mmol) was subjected to general procedure A to produce 13 (2.09 g, 2.76 mmol) in 60 % yield after silica gel column purification (0 % → 5 % acetone in toluene). Rf = 0.46 (toluene/acetone, 19:1). 1H NMR (300 MHz, CDCl3, α/β mixture): δ = 7.42–7.09 (m, 20 H, HAr Bn), 5.07–4.43 (m, 8 H, 4 × CH2 Bn), 4.06–3.56 (m, 6 H, 2-H, 3-H, 4-H, 5-H, CH2-6), 3.55–3.44 (m, 2 H, OCH2-4 butynyl), 3.01–2.90 (m, 2 H, OCH2-Ada), 2.56–2.43 (m, 2 H, CH2-3 butynyl), 1.91 (br. s, 3 H, 3 × CH Ada), 1.74–1.54 (m, 6 H, 3 × CH2 Ada), 1.48 (s, 6 H, 3 × CH2 Ada) ppm. 13C NMR (75 MHz, CDCl3, α/β mixture): δ = 138.5, 138.46, 138.42, 138.3, 137.93, 137.91, 137.8 (Cq Bn α/β), 128.1, 128.0, 127.86, 127.81, 127.7, 127.6, 127.5, 127.4, 127.2 (CHAr Bn α/β), 95.3, 91.4, 86.2, 84.1, 84.0, 83.5, 82.9, 82.3, 81.9, 81.8 (OCH2-Ada), 80.3, 78.0, 77.5, 77.3, 77.0, 76.8, 76.7, 76.4, 75.6, 75.5, 75.4, 74.9, 74.7, 74.4, 73.8, 73.2, 71.5, 69.2, 69.0 (OCH2-4 butynyl), 68.3, 39.4 (CH2 Ada), 36.9 (CH2 Ada), 33.8 (Cq Ada), 28.0 (CH Ada), 19.8, 19.7 (CH2-3 butynyl) ppm. IR (thin film): equation imagemax. = 3321, 3032, 2905, 2847, 1496, 1454, 1367, 1209, 1146, 1103, 1045, 1028, 1007, 986, 951, 910, 808, 754, 742 cm–1. [α]D20 = 36.1 (c = 4.6, CHCl3). HRMS: found 774.4367 [M + NH4]+, calcd. for [C49H56O7 + NH4]+ 774.4364.

α/β-Mixture of 1-C-[6-(Adamant-1-ylmethoxy)hex-1-ynyl]-2,3,4,6-tetra-O-benzyl-D-glucopyranose (14): Compound 11 (493 mg, 2.0 mmol) was subjected to general procedure A to produce 14 (1.35 g, 1.72 mmol) in 86 % yield after silica gel column purification (0 % → 5 % acetone in toluene). Rf = 0.50 (toluene/acetone, 19:1). 1H NMR (200 MHz, CDCl3, α/β mixture): δ = 7.44–7.08 (m, 20 H, HAr Bn), 5.07–4.45 (m, 8 H, 4 × CH2 Bn), 3.96–3.25 (m, 8 H, CH2-6 hexenyl, 2-H, 3-H, 4-H, 5-H, CH2-6), 2.92, 2.91 (s, 2 H, OCH2-Ada α/β), 2.36–2.21 (m, 2 H, CH2-3 hexenyl), 1.93 (br. s, 3 H, 3 × CH Ada), 1.76–1.54 (m, 10 H, 3 × CH2 Ada, 2 × CH2 hexenyl), 1.50 (d, J = 2.0 Hz, 6 H, 3 × CH2 Ada) ppm. 13C NMR (50 MHz, CDCl3, α/β mixture): δ = 138.7, 138.7, 138.6, 138.1, 138.1, 138.0, 138.0 (Cq Bn α/β), 128.3, 128.2, 128.1, 127.99, 127.97, 127.94, 127.92, 127.87, 127.85, 127.7, 127.6, 127.5, 127.4, 127.3 (CHAr Bn α/β), 95.6, 91.6 (C-1 α/β), 89.1, 84.8 (Cq hexenyl α/β), 84.4, 84.3, 83.7, 82.5, 81.8 (OCH2-Ada), 79.9, 77.8, 77.4, 77.1, 76.4, 75.6, 75.6, 75.0, 74.8, 74.4, 73.8, 73.6, 73.4, 73.2, 73.2, 71.5, 70.8, 70.7, 68.5, 39.6 (CH2 Ada), 37.1 (CH2 Ada), 34.0 (Cq Ada), 28.8, 28.7 (CH2 hexenyl α/β), 28.2 (CH Ada), 25.1, 24.9 (CH2 hexenyl α/β), 18.5 (CH2-3 hexenyl) ppm. IR (thin film): equation imagemax. = 3362, 3032, 2902, 2849, 1497, 1453, 1360, 1211, 1067, 1027, 910, 733, 695 cm–1. [α]D20 = 33.4 (c = 2.2, CHCl3). HRMS: found 802.4681 [M +NH4]+, calcd. for [C51H60O7 + NH4]+ 802.4677.

(1S)-1-C-[4-(Adamant-1-ylmethoxy)but-1-ynyl]-2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin (15): Compound 13 (371 mg, 0.49 mmol) was subjected to general procedure C to give 15 (191 mg, 0.26 mmol) as a colourless oil in 53 % yield after silica gel column chromatography (0 % → 20 % EtOAc in toluene). Rf = 0.19 (toluene/EtOAc, 9:1). 1H NMR (600 MHz, CDCl3): δ = 7.39–7.16 (m, 20 H, HAr Bn), 5.02 (d, J = 10.5 Hz, 1 H, CHH Bn), 4.91 (d, J = 10.8 Hz, 1 H, CHH Bn), 4.83 (d, J = 11.0 Hz, 1 H, CHH Bn), 4.81 (m, 2 H, 2 × CHH Bn), 4.49–4.42 (m, 3 H, CH2 Bn, CHH Bn), 3.68 (dd, J = 2.4, 9.0 Hz, 1 H, 6a-H), 3.54–3.48 (m, 4 H, 3-H, 6b-H, OCH2-4 butynyl), 3.44–3.43 (m, 2 H, 1-H, 2-H), 3.37 (dd, J = 9.4, 9.4 Hz, 1 H, 4-H), 2.95 (s, 2 H, OCH2-Ada), 2.77–2.73 (m, 1 H, 5-H), 2.47 (t, J = 7.3 Hz, 2 H, CH2-3 butynyl), 1.93 (br. s, 3 H, 3 × CH Ada), 1.65 (dd, J = 12.0, 43.7 Hz, 6 H, 3 × CH2 Ada), 1.49 (d, J = 2.4 Hz, 6 H, 3 × CH2 Ada) ppm. 13C NMR (150 MHz, CDCl3): δ = 138.9, 138.6, 138.4, 138.1 (4 × Cq Bn), 128.65, 128.62, 128.5, 128.4, 128.2, 128.17, 128.12, 128.0, 127.97, 127.95, 127.8 (CHAr Bn), 87.0 (C-3), 84.6 (C-2), 82.2 (OCH2-Ada), 81.3 (Cq butynyl), 80.1 (C-4), 76.0, 75.7, 75.3, 73.6 (4 × CH2 Bn), 70.3 (C-6), 70.0 (CH2-4 butynyl), 58.9 (C-5), 51.9 (C-1), 39.8 (CH2 Ada), 37.4 (CH2 Ada), 34.2 (Cq Ada), 28.4 (CH Ada), 20.2 (CH2-3 butynyl) ppm. IR (thin film): equation imagemax. = 2901, 2847, 1454, 1360, 1151, 1096, 1070, 1028, 1007, 735, 696 cm–1. [α]D20 = 6.8 (c = 0.8, CHCl3). HRMS: found 740.4309 [M + H]+, calcd. for [C49H57NO5 + H]+ 740.4310.

(1S)-1-C-[6-(Adamant-1-ylmethoxy)hex-1-ynyl]-2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin (16): Compound 14 (0.40 g, 0.51 mmol) was subjected to general procedure C to give 16 (234 mg, 0.30 mmol) as a colourless oil in 59 % yield after silica gel column chromatography (0 % → 20 % EtOAc in toluene). Rf = 0.6 (toluene/acetone, 9:1). 1H NMR (400 MHz, C6D6): δ = 7.23–7.05 (m, 20 H, HAr Bn), 5.20 (d, J = 11.0 Hz, 1 H, CHH Bn), 4.97–4.93 (m, 2 H, CHH Bn, CHH Bn), 4.88 (d, J = 11.4 Hz, 1 H, CHH Bn), 4.81 (d, J = 11.3 Hz, 1 H, CHH Bn), 4.47 (d, J = 11.4 Hz, 1 H, CHH Bn), 4.25 (d, J = 11.9 Hz, 1 H, CHH Bn), 4.19 (d, J = 11.9 Hz, 1 H, CHH Bn), 3.65 (dd, J = 2.4, 8.9 Hz, 1 H, 6a-H), 3.59–3.48 (m, 4 H, 1-H, 2-H, 3-H, 6b-H), 3.45 (dd, J = 9.1, 9.1 Hz, 1 H, 4-H), 3.21 (t, J = 5.9 Hz, 2 H, CH2-6 hexenyl), 2.87 (s, 2 H, OCH2-Ada), 2.76 (ddd, J = 2.4, 6.2, 9.0 Hz, 1 H, 5-H), 2.08 (t, J = 6.5 Hz, 2 H, CH2-3 hexenyl), 1.94 (s, 3 H, 3 × CH Ada), 1.73–1.50 (m, 16 H, 6 × CH2 Ada, 2 × CH2 hexenyl) ppm. 13C NMR (100 MHz, C6D6): δ = 140.2, 140.0, 139.8, 139.1 (4 × Cq Bn), 129.0, 128.8, 128.7, 128.5, 128.3, 128.2, 128.0, 127.9 (CHAr Bn), 87.9 (C-3), 85.6 (C-2), 84.2 (Cq hexenyl), 82.6 (OCH2-Ada), 80.9 (C-4), 80.9 (Cq hexenyl), 76.0, 75.8, 75.4, 73.9 (4 × CH2 Bn), 71.4 (CH2-6 hexenyl), 71.0 (C-6), 59.8 (C-5), 52.9 (C-1), 40.5 (CH2 Ada), 38.0 (CH2 Ada), 34.7 (Cq Ada), 29.7 (CH2 hexenyl), 29.2 (CH Ada), 26.3 (CH2 hexenyl), 19.3 (C-3 hexenyl) ppm. IR (thin film): equation imagemax. = 3031, 2901, 2848, 1497, 1452, 1359, 1209, 1071, 1027, 1007, 734, 696 cm–1. [α]D20 = 6.2 (c = 1.0, CHCl3). HRMS: found 768.4623 [M + H]+, calcd. for [C51H61NO5 + H]+ 768.4623.

(1S)-1-C-[4-(Adamant-1-ylmethoxy)butyl]-1-deoxynojirimycin (17): Compound 15 (66 mg, 89 μmol) was subjected to hydrogenolysis at atmospheric H2 (see general procedure H) to produce 17 (30 mg, 79 μmol) as a colourless oil in 90 % yield after purification (silica gel: 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Rf = 0.22 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 3.92 (dd, J = 3.1, 10.8 Hz, 1 H, 6a-H), 3.50 (dd, J = 7.8, 10.8 Hz, 1 H, 6b-H), 3.41 (t, J = 6.2 Hz, 2 H, OCH2-4 butyl), 3.20 (dd, J = 8.9, 8.9 Hz, 1 H, 3-H), 3.11 (dd, J = 9.3, 9.3 Hz, 1 H, 4-H), 2.99 (dd, J = 9.2, 9.2 Hz, 1 H, 2-H), 2.97 (s, 2 H, OCH2-Ada), 2.56 (ddd, J = 3.1, 7.8, 9.9 Hz, 1 H, 5-H), 2.43 (td, J = 2.8, 9.2 Hz, 1 H, 1-H), 1.94 (s, 3 H, 3 × CH Ada), 1.93–1.89 (m, 1 H, CHH-1 butyl), 1.72 (dd, J = 11.9, 44.4 Hz, 6 H, 3 × CH2 Ada), 1.65–1.52 (m, 3 H, CHH-2 butyl, CH2-3 butyl), 1.56 (d, J = 2.1 Hz, 6 H, 3 × CH2 Ada), 1.45–1.28 (m, 2 H, CHH-1 butyl, CHH-2 butyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.2 (OCH2-Ada), 80.7 (C-3), 76.7 (C-2), 73.7 (C-4), 72.6 (CH2-4 butyl), 63.7 (C-6), 62.6 (C-5), 60.9 (C-1), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 32.9 (CH2-1 butyl), 31.1 (CH2-3 butyl), 29.9 (CH Ada), 23.7 (CH2-2 butyl) ppm. IR (thin film): equation imagemax. = 3356, 2899, 2847, 1448, 1092, 999 cm–1. [α]D20 = 3.3 (c = 0.3, MeOH). HRMS: found 384.2746 [M + H]+, calcd. for [C21H37NO5 + H]+ 384.2744.

(1S)-1-C-[6-(Adamant-1-ylmethoxy)hexyl]-1-deoxynojirimycin (18): Compound 16 (75 mg, 98 μmol) was subjected to hydrogenolysis at atmospheric H2 (see general procedure H) to produce 18 (30 mg, 73 μmol) as a colourless oil in 75 % yield after purification (silica gel: 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Rf = 0.24 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (400 MHz, MeOD): δ = 3.92 (dd, J = 3.0, 11.1 Hz, 1 H, 6a-H), 3.62 (dd, J = 6.8, 11.1 Hz, 1 H, 6b-H), 3.38 (t, J = 6.4 Hz, 2 H, CH2-6 hexyl), 3.28–3.20 (m, 2 H, 3-H, 4-H), 3.12–3.06 (m, 1 H, 2-H), 2.96 (s, 2 H, OCH2-Ada), 2.71–2.64 (m, 1 H, 1-H), 2.61–2.54 (m, 1 H, 5-H), 1.94 (br. s, 4 H, 3 × CH Ada, CHH-1 hexyl), 1.72 (dd, J = 12.1, 32.0 Hz, 6 H, 3 × CH2 Ada), 1.59–1.51 (m, 8 H, 3 × CH2 Ada, CH2 hexyl), 1.39 (m, 7 H, 3 × CH2 hexyl, CHH-1 hexyl) ppm. 13C NMR (100 MHz, MeOD): δ = 83.2 (OCH2-Ada), 80.2 (C-3), 75.9 (C-2), 72.8 (CH2-6 hexyl), 72.6 (C-4), 62.5 (C-5), 62.5 (C-6), 60.9 (C-1), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 32.6 (CH2-1 hexyl), 30.9 (CH2 hexyl), 30.8 (CH2-5 hexyl), 29.9 (CH Ada), 27.4 (CH2 hexyl), 26.9 (CH2 hexyl) ppm. IR (thin film): equation imagemax. = 3344, 2901, 2849, 1606, 1452, 1360, 1156, 1095, 753 cm–1. [α]D20 = –6.5 (c = 1.0, MeOH). HRMS: found 412.3056 [M + H]+, calcd. for [C23H41NO5 + H]+ 412.3057.

(1S)-1-C-[4-(Adamant-1-ylmethoxy)butyl]-1-deoxy-N-methylnojirimycin (19): Argon was passed through a solution of compound 15 (62 mg, 84 μmol) and formaldehyde (1 mL, 37 wt.-% in water) in n-propanol (4 mL) for 5 min, after which a catalytic amount of Pd/C (Degussa type, 50 mg, 5 wt.-% Pd on C) was added. Hydrogen was passed through the reaction mixture for 15 min. After stirring the reaction mixture under atmospheric hydrogen pressure for 2 h, the Pd/C was removed by filtration through a glass microfibre filter, followed by thorough rinsing with MeOH [Rf(intermediate) = 0.73 (EtOAc/PE, 1:3)]. The filtrate was concentrated, and the resulting residue was subjected to Pd/C-catalyzed hydrogenolysis at atmospheric H2 (see general procedure H). The crude product was purified by silica gel column chromatography (0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH) to give 19 (30 mg, 75 μmol) as a colourless oil in 89 % yield. Rf = 0.35 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 3.92 (dd, J = 3.0, 11.8 Hz, 1 H, 6a-H), 3.83 (dd, J = 3.9, 11.9 Hz, 1 H, 6b-H), 3.40 (t, J = 6.3 Hz, 2 H, CH2-4 butyl), 3.39 (dd, J = 9.1, 10.0 Hz, 1 H, 4-H), 3.23 (dd, J = 9.4, 9.4 Hz, 1 H, 2-H), 3.17 (dd, J = 9.1, 9.4 Hz, 1 H, 3-H), 2.98 (s, 2 H, OCH2-Ada), 2.32 (s, 3 H, NCH3), 2.12–2.07 (m, 2 H, 1-H, 5-H), 1.94 (s, 3 H, 3 × CH Ada), 1.82–1.66 (m, 8 H, 3 × CH2 Ada, CH2-1 butyl), 1.60–1.54 (m, 8 H, 3 × CH2 Ada, CH2-3 butyl), 1.51–1.43 (m, 2 H, CH2-2 butyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.2 (OCH2-Ada), 80.6 (C-3), 72.9 (C-2), 72.7 (CH2-4 butyl), 71.0 (C-4), 70.0 (C-5), 68.1 (C-1), 60.4 (C-6), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 36.3 (NCH3), 35.3 (Cq Ada), 31.2 (CH2-3 butyl), 29.9 (CH Ada), 29.7 (CH2-1 butyl), 22.5 (CH2-2 butyl) ppm. IR (thin film): equation imagemax. = 3358, 2900, 2848, 1652, 1452, 1362, 1158, 1095, 1014 cm–1. [α]D20 = 2.6 (c = 0.3, MeOH). HRMS: found 398.2898 [M + H]+, calcd. for [C22H39NO5 + H]+ 398.2901.

(1S)-1-C-[6-(Adamant-1-ylmethoxy)hexyl]-1-deoxy-N-methylnojirimycin (20): Argon was passed through a solution of compound 16 (76 mg, 99 μmol) and formaldehyde (1 mL, 37 wt.-% in water) in n-propanol (4 mL) for 5 min, after which a catalytic amount of Pd/C (Degussa type, 50 mg, 5 wt.-% Pd on C) was added. Hydrogen was passed through the reaction mixture for 15 min. After stirring the reaction mixture under atmospheric hydrogen pressure for 2 h, the Pd/C was removed by filtration through a glass microfibre filter, followed by thorough rinsing with MeOH [Rf(intermediate) = 0.75 (EtOAc/PE, 1:3)]. The filtrate was concentrated, and the resulting residue was subjected to Pd/C-catalyzed hydrogenolysis at atmospheric H2 (see general procedure H). The crude product was purified by silica gel column chromatography (0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH) to give 20 (29 mg, 68 μmol) as a colourless oil in 69 % yield. Rf = 0.36 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (400 MHz, MeOD + CDCl3): δ = 3.94 (s, 2 H, CH2-6), 3.48 (dd, J = 9.4, 9.4 Hz, 1 H, 4-H), 3.38 (t, J = 6.4 Hz, 2 H, CH2-6 hexyl), 3.34–3.25 (m, 2 H, 2-H, 3-H), 2.97 (s, 2 H, OCH2-Ada), 2.56 (s, 3 H, NCH3), 2.50–2.42 (s, 2 H, 1-H, 5-H), 1.95 (s, 3 H, 3 × CH Ada), 1.80–1.65 (m, 8 H, 3 × CH2 Ada, CH2 hexyl), 1.60–1.54 (m, 8 H, 3 × CH2 Ada, CH2-5 hexyl), 1.50–1.32 (m, 6 H, 3 × CH2 hexyl) ppm. 13C NMR (100 MHz, MeOD + CDCl3): δ = 81.1 (OCH2-Ada), 77.7 (C-3), 70.8 (CH2-6 hexyl), 70.5 (C-2), 67.9 (C-4), 67.8 (C-5), 66.3 (C-1), 57.0 (C-6), 38.9 (CH2 Ada), 36.4 (CH2 Ada), 34.3 (NCH3), 33.2 (Cq Ada), 28.9 (CH2 hexyl), 28.7 (CH2 hexyl), 27.7 (CH Ada, CH2 hexyl), 25.3 (CH2 hexyl), 24.7 (CH2 hexyl) ppm. IR (thin film): equation imagemax. = 3324, 2902, 2849, 1637, 1452, 1362, 1158, 1102, 1025, 753 cm–1. [α]D20 = –1.6 (c = 1.0, MeOH). HRMS: found 426.3212 [M + H]+, calcd. for [C24H43NO5 + H]+ 426.3214.

(1S)-1-C-[4-(Adamant-1-ylmethoxy)butyl]-N-butyl-1-deoxynojirimycin (21): Compound 15 (62 mg, 83 μmol) was N-butylated (see general procedure D), and the crude intermediate (Rf = 0.80 in EtOAc/PE, 1:3) was subjected to hydrogenolysis at 4 bar H2 (see general procedure H) to furnish 21 (22 mg, 50 μmol) as a colourless oil in 60 % yield after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Rf = 0.45 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 3.87 (dd, J = 3.1, 11.8 Hz, 1 H, 6a-H), 3.84 (dd, J = 2.7, 11.8 Hz, 1 H, 6b-H), 3.41 (t, J = 6.1 Hz, 2 H, CH2-4 butyl), 3.34 (dd, J = 9.3, 9.3 Hz, 1 H, 4-H), 3.18 (dd, J = 9.3, 9.3 Hz, 1 H, 2-H), 3.11 (dd, J = 9.1, 9.1 Hz, 1 H, 3-H), 2.98 (s, 2 H, OCH2-Ada), 2.88–2.81 (m, 1 H, NCHH butyl), 2.75–2.68 (m, 1 H, NCHH butyl), 2.39 (dt, J = 3.6, 7.6 Hz, 1 H, 1-H), 2.33 (dt, J = 2.8, 9.7 Hz, 1 H, 5-H), 1.95 (s, 3 H, 3 × CH Ada), 1.72 (dd, J = 11.6, 46.1 Hz, 8 H, 3 × CH2 Ada, CH2-1 butyl), 1.62–1.33 (m, 12 H, 3 × CH2 Ada, 2 × CH2 butyl, CH2 N-butyl), 1.30–1.24 (m, 2 H, CH2CH3 N-butyl), 0.96 (t, J = 7.3 Hz, 3 H, CH3 N-butyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.2 (OCH2-Ada), 80.6 (C-3), 73.0 (C-2), 72.7 (CH2-4 butyl), 71.6 (C-4), 65.8 (C-5), 63.7 (C-1), 60.0 (C-6), 47.3 (NCH2 butyl), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 31.5 (CH2-3 butyl), 29.9 (CH Ada), 29.0 (CH2-1 butyl), 25.4 (CH2 N-butyl), 21.8 (CH2-CH3 N-butyl), 21.6 (CH2-2 butyl), 14.6 (CH3 N-butyl) ppm. IR (thin film): equation imagemax. = 3366, 2903, 2849, 1636, 1454, 1343, 1158, 1103 cm–1. [α]D20 = –1.0 (c = 0.1, MeOH). HRMS: found 440.3368 [M + H]+, calcd. for [C25H45NO5 + H]+ 440.3370.

(1S)-1-C-[6-(Adamant-1-ylmethoxy)hexyl]-N-butyl-1-deoxynojirimycin (22): Compound 16 (77 mg, 100 μmol) was N-butylated (see general procedure D), and the crude intermediate (Rf = 0.77 in EtOAc/PE, 1:3) was subjected to hydrogenolysis at 4 bar H2 (see general procedure H) to furnish 22 (31 mg, 66 μmol) as a colourless oil in 66 % yield after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Rf = 0.45 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (400 MHz, MeOD): δ = 3.98 (d, J = 12.0 Hz, 1 H, 6a-H), 3.88 (d, J = 12.0 Hz, 1 H, 6b-H), 3.53–3.43 (m, 1 H, 4-H), 3.38 (t, J = 6.1 Hz, 2 H, CH2-5 hexyl), 3.34–3.29 (m, 1 H, 2-H), 3.28–3.20 (m, 1 H, 3-H), 3.16–3.09 (m, 1 H, NCHH butyl), 3.01–2.93 (m, 3 H, NCHH butyl, OCH2-Ada), 2.80–2.68 (m, 2H. 1-H, 5-H), 1.94 (s, 3 H, 3 × CH Ada), 1.88–1.21 (m, 26 H, 6 × CH2 Ada, 5 × CH2 hexyl, 2 × CH2 N-butyl), 0.98 (t, J = 7.2 Hz, 3 H, CH3 butyl) ppm. 13C NMR (100 MHz, MeOD): δ = 83.2 (OCH2-Ada), 79.5 (C-3), 72.7 (CH2-6 hexyl), 72.6 (C-2), 70.1 (C-4), 66.7 (C-5), 65.1 (C-1), 58.4 (C-6), 48.5 (NCH2 butyl), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 31.0 (CH2), 30.8 (2 × CH2), 29.9 (CH Ada), 29.2 (CH2), 27.4 (CH2), 26.1 (CH2), 21.4 (CH2-CH3 N-butyl), 14.3 (CH3 N-butyl) ppm. IR (thin film): equation imagemax. = 3364, 2902, 2847, 1720 1453, 1366, 1258, 1011, 926 cm–1. [α]D20 = –1.0 (c = 0.2, MeOH). HRMS: found 468.3679 [M + H]+, calcd. for [C27H50NO5 + H]+ 468.3684.

4-(Adamant-1-ylmethoxy)-1-C-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)but-1-yne (24): Compound 13 (100 mg, 132 μmol) was subjected to general procedure B to produce 24 (86 mg, 116 μmol) in 89 % yield after silica gel column purification (0 % → 5 % acetone in toluene). Rf = 0.50 (toluene/EtOAc, 9:1). 1H NMR (600 MHz, CDCl3): δ = 7.40–7.09 (m, 20 H, H, HAr Bn), 5.02 (d, J = 10.5 Hz, 1 H, CHH Bn), 4.91 (d, J = 10.9 Hz, 1 H, CHH Bn), 4.83–4.77 (m, 3 H, CH2 Bn, CHH Bn), 4.60 (d, J = 12.2 Hz, 1 H, CHH Bn), 4.54–4.49 (m, 2 H, 2 × CHH Bn), 4.03 (dt, J = 2.0, 9.0 Hz, 1 H, 1-H), 3.73 (dd, J = 1.6, 10.7 Hz, 1 H, 6a-H), 3.67 (dd, J = 4.4, 10.8 Hz, 1 H, 6b-H), 3.64–3.55 (m, 3 H, 2-H, 3-H, 4-H), 3.50 (t, J = 7.3 Hz, 2 H, CH2-4 butenyl), 3.42 (ddd, J = 1.8, 4.2, 9.1 Hz, 1 H, 5-H), 2.97-2.93 (m, 2 H, OCH2-Ada), 2.51 (td, J = 1.8, 7.3 Hz, 2 H, CH2-3 butenyl), 1.92 (s, 3 H, 3 × CH Ada), 1.65 (dd, J = 11.9, 45.5 Hz, 6 H, 3 × CH2 Ada), 1.49 (d, J = 2.4 Hz, 6 H, 3 × CH2 Ada) ppm. 13C NMR (151 MHz, CDCl3): δ = 138.7, 138.3, 138.2, 138.2 (4 × Cq Bn), 128.6, 128.6, 128.6, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8 (CHAr Bn), 86.2 (C-3), 84.1 (Cq butynyl), 82.7 (C-2), 82.2 (OCH2-Ada), 79.1 (C-5), 78.4 (Cq butynyl), 77.9 (C-4), 75.9, 75.6, 75.3, 73.7 (4 × CH2 Bn), 70.3 (C-1), 69.8 (CH2-4 butynyl), 69.0 (C-6), 39.8 (CH2 Ada), 37.4 (CH2 Ada), 34.2 (Cq Ada), 28.4 (CH Ada), 20.3 (CH2-3 butynyl) ppm. IR (thin film): equation imagemax. = 3036, 2901, 2849, 1734, 1497, 1452, 1360, 1209, 1094, 1063, 1028, 1003, 733, 696 cm–1. [α]D20 = –1.7 (c = 0.6, CHCl3). HRMS: found 758.4416 [M + NH4]+, calcd. for [C49H56O6 + NH4]+ 758.4415.

5-(Adamant-1-ylmethoxy)-1-C-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)pent-1-yne (25): Compound 23 (250 mg, 337 μmol) was subjected to general procedure B to produce 25 (201 mg, 266 μmol) in 79 % yield after silica gel column purification (0 % → 5 % acetone in toluene). Rf = 0.55 (toluene/EtOAc, 9:1). 1H NMR (200 MHz, CDCl3): δ = 7.40–7.08 (m, 20 H, HAr Bn), 5.07–4.46 (m, 8 H, 4 × CH2 Bn), 4.05 (d, J = 8.6 Hz, 1 H, 1-H), 3.78–3.53 (m, 6 H, 2-H, 3-H, 4-H, 5-H, CH2-6), 3.41 (t, J = 6.0 Hz, 2 H, CH2-5 pentenyl), 2.90 (s, 2 H, OCH2-Ada), 2.35 (td, J = 1.6, 7.1 Hz, 2 H, CH2-3 pentenyl), 1.93 (s, 3 H, 3 × H Ada), 1.84–1.55 (m, 8 H, 3 × CH2 Ada, CH2-4 pentenyl), 1.49 (d, J = 2.7 Hz, 6 H, 3 × CH2 Ada) ppm. 13C NMR (50 MHz, CDCl3): δ = 138.7, 138.3, 138.2, 138.1 (4 × Cq Bn), 128.5, 128.4, 128.29, 128.23, 128.04, 128.02, 127.9, 127.8, 127.7 (CHAr Bn), 86.7 (Cq pentynyl), 86.1 (C-3), 82.7 (C-2), 81.9 (OCH2-Ada), 79.0 (C-5), 77.8 (C-4), 77.4 (Cq pentynyl), 75.8, 75.4, 75.1, 73.6 (4 × CH2 Bn), 70.3 (C-1), 69.9 (CH2-5 pentynyl), 68.9 (C-6), 39.8 (CH2 Ada), 37.3 (CH2 Ada), 34.1 (Cq Ada), 28.7 (CH2-4 pentynyl), 28.3 (CH Ada), 15.9 (CH2-3 pentynyl) ppm. IR (thin film): equation imagemax. = 3033, 2901, 2848, 1724, 1452, 1361, 1269, 1090, 1065, 1026, 735, 696 cm–1. [α]D20 = 3.5 (c = 0.4, CHCl3). HRMS: found 772.4572 [M + NH4]+, calcd. for [C50H58O6 + NH4]+ 772.4572.

6-(Adamant-1-ylmethoxy)-1-C-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)hex-1-yne (26): Compound 14 (428 mg, 0.56 mmol) was subjected to general procedure B to produce 26 (257 mg, 0.33 mmol) in 60 % yield after silica gel column purification (0 % → 5 % acetone in toluene). Rf = 0.65 (toluene/EtOAc, 9:1). 1H NMR (300 MHz, C6D6): δ = 7.12–6.69 (m, 20 H, HAr Bn), 4.77 (d, J = 11.0 Hz, 1 H, CHH Bn), 4.62–4.41 (m, 4 H, CH2 Bn, CHH Bn, CHH Bn), 4.25 (d, J = 11.3 Hz, 1 H, CHH Bn), 4.15 (d, J = 12.1 Hz, 1 H, CHH Bn), 4.04 (d, J = 12.1 Hz, 1 H, CHH Bn), 3.76 (dt, J = 1.8, 9.3 Hz, 1 H, 1-H), 3.42 (dd, J = 8.9, 9.6 Hz, 1 H, 4-H), 3.36–3.27 (m, 3 H, 2-H, CH2-6), 3.22 (dd, J = 8.8, 8.9 Hz, 1 H, 3-H), 2.96 (dt, J = 2.7, 10.1 Hz, 1 H, 5-H), 2.86 (t, J = 5.8 Hz, 2 H, CH2-6 hexynyl), 2.52 (s, 2 H, OCH2-Ada), 1.78 (td, J = 1.4, 6.5 Hz, 2 H, CH2-3 hexynyl), 1.60 (s, 3 H, CH Ada), 1.38–1.18 (m, 16 H, 6 × CH2 Ada, 2 × CH2 hexenyl) ppm. 13C NMR (75 MHz, C6D6): δ = 139.4, 139.1, 139.0, 138.8 (4 × Cq Bn), 128.5, 128.48, 128.46, 128.42, 128.2, 128.1, 127.96, 127.93, 127.8, 127.7, 127.65, 127.62, 127.54, 127.50 (CHAr Bn), 86.4 (Cq hexynyl), 86.3 (C-3), 83.2 (C-2), 82.0 (OCH2-Ada), 79.3 (C-5), 78.6 (Cq pentynyl), 78.1 (C-4), 75.4, 75.2, 74.9, 73.5 (4 × CH2 Bn), 70.9 (CH2-6 hexynyl), 70.6 (C-1), 69.3 (C-6), 40.0 (CH2 Ada), 37.5 (CH2 Ada), 34.2 (Cq Ada), 29.1 (CH2 hexynyl), 28.6 (CH Ada), 25.6 (CH2 hexynyl), 18.8 (CH2-3 hexynyl) ppm. IR (thin film): equation imagemax. = 3031, 2901, 2848, 1497, 1453, 1360, 1294, 1210, 1155, 1091, 1064, 1027, 1005, 910, 734, 696 cm–1. [α]D20 = 2.6 (c = 1.0, CHCl3). HRMS: found 786.4730 [M + NH4]+, calcd. for [C51H60O6 + NH4]+ 786.4728.

1-(Adamant-1-ylmethoxy)-4-C-(β-D-glucopyranosyl)butane (27): Compound 24 (86 mg, 116 μmol) was subjected to Pd/C-catalyzed hydrogenolysis at atmospheric H2 (see general procedure H). The resulting residue was purified by silica gel column chromatography (0 % → 15 % MeOH in CHCl3 with 0.5 % NH4OH) to give 27 (36 mg, 94 μmol) as a colourless oil in 81 % yield. Rf = 0.29 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 3.83 (dd, J = 2.3, 11.8 Hz, 1 H, 6a-H), 3.63 (dd, J = 5.7, 11.8 Hz, 1 H, 6b-H), 3.39 (t, J = 6.3 Hz, 2 H, CH2-4 butyl), 3.30 (dd, J = 8.8, 9.2 Hz, 1 H, 3-H), 3.25 (dd, J = 9.2, 9.4 Hz, 1 H, 4-H), 3.18 (ddd, J = 2.3, 5.6, 9.4 Hz, 1 H, 5-H), 3.15–3.09 (m, 1 H, 1-H), 3.04 (dd, J = 8.8, 9.3 Hz, 1 H, 2-H), 2.97 (s, 2 H, OCH2-Ada), 1.95 (s, 3 H, 3 × CH Ada), 1.91–1.83 (m, 1 H, CHH-1 butyl), 1.72 (dd, J = 11.8, 44.2 Hz, 6 H, 3 × CH2 Ada), 1.66–1.52 (m, 9 H, 3 × CH2 Ada, CH2-3 butyl, CHH butyl), 1.48–1.39 (m, 2 H, CHH-1 butyl, CHH butyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.2 (OCH2-Ada), 81.7 (C-5), 81.0 (C-1), 80.0 (C-3), 75.6 (C-2), 72.9 (CH2-6 hexyl), 72.2 (C-4), 63.3 (C-6), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 32.9 (CH2-1 butyl), 30.9 (CH2-3 butyl), 29.9 (CH Ada), 23.3 (CH2 butyl) ppm. IR (thin film): equation imagemax. = 3365, 2901, 2848, 1593, 1453, 1342, 1092, 1013 cm–1. [α]D20 = –1.0 (c = 0.2, MeOH). HRMS: found 385.2586 [M + H]+, calcd. for [C21H36O6 + H]+ 385.2585.

1-(Adamant-1-ylmethoxy)-5-C-(β-D-glucopyranosyl)pentane (28): Compound 25 (95 mg, 126 μmol) was subjected to Pd/C-catalyzed hydrogenolysis at atmospheric H2 (see general procedure H). The resulting residue was purified by silica gel column chromatography (0 % → 15 % MeOH in CHCl3 with 0.5 % NH4OH) to give 28 (45 mg, 112 μmol) as a colourless oil in 89 % yield. Rf = 0.32 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 3.83 (dd, J = 2.3, 11.8 Hz, 1 H, 6a-H), 3.63 (dd, J = 5.7, 11.9 Hz, 1 H, 6b-H), 3.38 (t, J = 6.5 Hz, 2 H, CH2-5 pentyl), 3.31–3.28 (dd, J = 8.8, 9.1 Hz, 1 H, 3-H), 3.25 (dd, J = 9.1, 9.4 Hz, 1 H, 4-H), 3.17 (ddd, J = 2.3, 5.7, 9.4 Hz, 1 H, 5-H), 3.15–3.09 (m, 1 H, 1-H), 3.04 (dd, J = 8.8, 9.3 Hz, 1 H, 2-H), 2.97 (s, 2 H, OCH2-Ada), 1.95 (s, 3 H, 3 × CH Ada), 1.90–1.82 (m, 1 H, CHH-1 pentyl), 1.72 (dd, J = 11.7, 44.9 Hz, 6 H, 3 × CH2 Ada), 1.65–1.51 (m, 9 H, 3 × CH2 Ada, CH2-4 pentyl, CHH pentyl), 1.45–1.31 (m, 4 H, CHH-1 pentyl, CH2 pentyl, CHH pentyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.2 (OCH2-Ada), 81.7 (C-5), 81.0 (C-1), 80.0 (C-3), 75.6 (C-2), 72.8 (CH2-5 pentyl), 72.1 (C-4), 63.3 (C-6), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 33.0 (CH2-1 pentyl), 30.8 (CH2-4 pentyl), 29.9 (CH Ada), 27.6 (CH2 pentyl), 26.5 (CH2 pentyl) ppm. IR (thin film): equation imagemax. = 3362, 2902, 2849, 1453, 1362, 1091, 1016 cm–1. [α]D20 = –12.0 (c = 0.2, MeOH). HRMS: found 399.2739 [M + H]+, calcd. for [C22H38O6 + H]+ 399.2741.

1-(Adamant-1-ylmethoxy)-6-C-(β-D-glucopyranosyl)hexane (29): Compound 26 (75 mg, 97 μmol) was subjected to Pd/C-catalyzed hydrogenolysis at atmospheric H2 (see general procedure H). The resulting residue was purified by silica gel column chromatography (0 % → 15 % MeOH in CHCl3 with 0.5 % NH4OH) to give 29 (36 mg, 87 μmol) as a colourless oil in 90 % yield. Rf = 0.33 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 3.83 (dd, J = 2.4, 11.9 Hz, 1 H, 6a-H), 3.63 (dd, J = 5.7, 11.9 Hz, 1 H, 6b-H), 3.37 (t, J = 6.5 Hz, 2 H, CH2-6 hexyl), 3.32–3.28 (dd, J = 8.7, 9.2 Hz, 1 H, 3-H), 3.25 (dd, J = 9.2, 9.4 Hz, 1 H, 4-H), 3.18 (ddd, J = 2.4, 5.7, 9.4 Hz, 1 H, 5-H), 3.14–3.09 (m, 1 H, 1-H), 3.04 (dd, J = 8.7, 9.4 Hz, 1 H, 2-H), 2.96 (s, 2 H, OCH2-Ada), 1.95 (s, 3 H, 3 × CH Ada), 1.88–1.81 (m, 1 H, CHH-1 hexyl), 1.72 (dd, J = 11.7, 44.9 Hz, 6 H), 1.60–1.53 (m, 9 H, 3 × CH2 Ada, CH2-5 hexyl, CHH hexyl), 1.45–1.29 (m, 6 H, CHH-1 hexyl, 2 × CH2 hexyl, CHH hexyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.2 (OCH2-Ada), 81.7 (C-5), 81.0 (C-1), 80.0 (C-3), 75.6 (C-2), 72.9 (CH2-6 hexyl), 72.2 (C-4), 63.3 (C-6), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 33.0 (CH2-1 hexyl), 30.9 (CH2 hexyl), 30.8 (CH2-5 hexyl), 29.9 (CH Ada), 27.5 (CH2 hexyl), 26.6 (CH2 hexyl) ppm. IR (thin film): equation imagemax. = 3361, 2901, 2849, 1453, 1361, 1092, 1012 cm–1. [α]D20 = –9.2 (c = 1.0, MeOH). HRMS: found 413.2896 [M + H]+, calcd. for [C23H40O6 + H]+ 413.2898.

α/β-Mixture of 2,3,4,6-Tetra-O-benzyl-1-C-butyl-D-glucopyranose (30): A solution of 12 (1.02 g, 1.9 mmol) in THF (3 mL) was added to a cooled (–50 °C) solution of BuLi (0.59 mL, 0.95 mmol, 1.6 M in toluene) in THF (10 mL). The reaction mixture was stirred at –50 °C for 2 h. The reaction mixture was quenched (satd. aq. NH4Cl), warmed to room temp. and poured into satd. aq. NH4Cl (150 mL). The aqueous layer was extracted with Et2O (3 × 150 mL) and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by silica gel column chromatography (5 % → 20 % EtOAc in PE) to give 30 (409 mg, 0.69 mmol) in 72 % yield as colourless oil. Rf = 0.45 (EtOAc/PE, 1:3). 1H NMR (200 MHz, CDCl3, α/β mixture): δ = 7.41–7.15 (m, 20 H, HAr Bn), 4.96–4.41 (m, 9 H, 2 × CH2 Bn, 6a-H), 4.12–3.57 (m, 4 H, 3-H, 4-H, 5-H, 6b-H), 3.43 (d, J = 9.2 Hz, 1 H, 2-H), 2.57 (s, 1 H, OH-1), 1.70–1.50 (m, 2 H, CH2 butyl), 1.49–1.13 (m, 4 H, 2 × CH2 butyl), 0.86 (t, J = 6.8 Hz, 3 H, CH3 butyl) ppm. 13C NMR (50 MHz, CDCl3, α/β mixture): δ = 138.9, 138.7, 138.5, 138.2 (4 × Cq Bn), 128.6, 128.5, 128.3, 128.2, 128.14, 128.12, 127.99, 127.94, 127.8, 127.7 (CHAr Bn), 98.6 (Cq-1), 84.1, 81.6, 76.6 (C-2, C-3, C-4), 75.8, 75.6, 75.1, 73.5 (2 × CH2 Bn), 71.8 (C-5), 69.0 (C-6), 38.6 (CH2 butyl), 24.9 (CH2 butyl), 23.0 (CH2 butyl), 14.3 (CH3 butyl) ppm. IR (thin film): equation imagemax. = 3032, 2911, 2860, 1460, 1350, 1360, 1211, 1008, 736, 694 cm–1. [α]D20 = 0.7 (c = 2.9, CHCl3). HRMS: found 596.3140 [M + H]+, calcd. for [C38H44O6 + H]+ 596.3138.

(1S)-2,3,4,6-Tetra-O-benzyl-1-C-butyl-1-deoxynojirimycin (31): Compound 30 (600 mg, 1.0 mmol) was subjected to general procedure procedure C to give 31 (387 mg, 0.67 mmol) as a colourless oil in 67 % yield after silica gel column chromatography (0 % → 20 % EtOAc in toluene). Rf(diol) = 0.33, Rf(diketone) = 0.77, Rf(aza-C-glycoside) = 0.56 (toluene/EtOAc, 3:1). 1H NMR (600 MHz, CDCl3): δ = 7.40–7.16 (m, 20 H, HAr Bn), 4.93–4.88 (m, 3 H, CHH Bn, CH2 Bn), 4.84 (d, J = 10.9 Hz, 1 H, CHH Bn), 4.64 (d, J = 10.9 Hz, 1 H, CHH Bn), 4.52–4.45 (m, 3 H, CHH Bn, CH2 Bn), 3.71 (dd, J = 2.4, 9.0 Hz, 1 H, 6a-H), 3.60 (dd, J = 9.1, 9.3 Hz, 1 H, 3-H), 3.45 (dd, J = 7.1, 9.0 Hz, 1 H, 6b-H), 3.35 (dd, J = 9.1, 9.4 Hz, 1 H, 4-H), 3.14 (dd, J = 9.1, 9.3 Hz, 1 H, 2-H), 2.78 (ddd, J = 2.4, 7.1, 9.4 Hz, 1 H, 5-H), 2.57–2.53 (m, 1 H, 1-H), 1.88–1.81 (m, 1 H, CHH-2 butyl), 1.41–1.24 (m, 4 H, CH2-1 butyl, CHH-2 butyl, CH2-3 butyl), 0.89 (t, J = 6.9 Hz, 3 H, CH3-4 butyl) ppm. 13C NMR (150 MHz, CDCl3): δ = 138.9, 138.6, 138.4, 138.2 (4 × Cq Bn), 128.6, 128.4, 128.28, 128.24, 128.0, 127.98, 127.95, 127.91, 127.7, 127.3 (CHAr Bn), 88.5 (C-3), 84.4 (C-2), 80.9 (C-4), 75.8, 75.6, 75.2, 73.5 (4 × CH2 Bn), 70.7 (C-6), 59.2, 59.2 (C-1, C-5), 31.8 (CH2-2 butyl), 28.2, 23.1 (CH2-1 butyl, CH2-3 butyl), 14.2 (CH3-4 butyl) ppm. IR (thin film): equation imagemax. = 3032, 2924,2862, 1458, 1358, 1312, 1211, 1072, 1026, 1003, 741, 694 cm–1.[α]D20 = 11.9 (c = 2.2, CHCl3). HRMS: found 580.3417 [M + H]+, calcd. for [C38H45NO4 + H]+ 580.3421.

(1S)-1-C-Butyl-1-deoxynojirimycin (32): Compound 31 (60 mg, 104 μmol) was subjected to hydrogenolysis at atmospheric H2 (see general procedure H) to furnish 32 (23 mg, 100 μmol) as a colourless oil in 97 % yield after purification (silica gel, 10 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Rf = 0.12 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (400 MHz, MeOD): δ = 4.00–3.86 (m, 2 H, CH2-6), 3.60–3.51 (m, 1 H, 4-H), 3.42–3.33 (m, 2 H, 2-H, 3-H), 3.09–3.00 (m, 1 H, 5-H), 3.00–2.94 (m, 1 H, 1-H), 2.05–1.95 (m, 1 H, CHH-1 butyl), 1.72–1.61 (m, 1 H, CHH-1 butyl), 1.60–1.46 (m, 2 H, CH2-2 butyl), 1.46–1.33 (m, 2 H, CH2-3 butyl), 0.97 (t, J = 7.0 Hz, 3 H, CH3-4 butyl) ppm. 13C NMR (100 MHz, MeOD): δ = 78.7 (C-3), 73.6 (C-2), 69.4 (C-4), 62.3 (C-5), 60.9 (C-1), 59.0 (C-6), 31.1 (CH2-1 butyl), 29.1 (CH2-2 butyl), 24.0 (CH2-3 butyl), 14.3 (CH3-4 butyl) ppm. IR (thin film): equation imagemax. = 3331, 2959, 2932, 2870, 1636, 1436, 1380, 1098, 1014 cm–1. [α]D20 = –6.1 (c = 0.5, MeOH). HRMS: found 220.1545 [M + H]+, calcd. for [C10H21NO4 + H]+ 220.1543.

(1S)-N-[5-(Adamant-1-ylmethoxy)pentyl]-2,3,4,6-tetra-O-benzyl-1-C-butyl-1-deoxynojirimycin (33): A solution of 31 (210 mg, 360 mmol) and 1025 (900 mg, 3.6 mmol) in acetonitrile/MeOH (1.8 mL, 5:1, v/v) was acidified to pH = 5–6 with AcOH (10 μL). Sodium sulfate (100 mg) and sodium cyanoborohydride (90 mg, 1.44 mmol) were added, and the reaction mixture was heated at 75 °C for 18 h. The mixture was diluted with satd. aq. NaHCO3 (20 mL) and extracted with Et2O (3 × 20 mL). The combined organic phases were dried (MgSO4) and concentrated. Purification by silica gel column chromatography (0 % → 10 % MeOH in CHCl3 with 0.5 % NH4OH) gave 33 (230 mg, 283 mmol) as a colourless oil in 79 % yield. Rf = 0.75 (EtOAc/PE, 1:3). 1H NMR (200 MHz, CDCl3): δ = 7.36–7.15 (m, 20 H, HAr Bn), 4.95–4.79 (m, 4 H, 2 × CH2 Bn), 4.67–4.39 (m, 4 H, 2 × CH2 Bn), 4.01–3.26 (m, 8 H, 2-H, 3-H, 4-H, CH2-6, CH2-5 pentyl), 2.94 (m, 2 H, OCH2-Ada), 2.78-2.45 (m, 4 H, NCH2-1 pentyl, 1-H, 5-H), 1.95 (s, 3 H, 3 × CH Ada), 1.78–1.07 (m, 24 H, 6 × CH2 Ada, 3 × CH2 butyl, 3 × CH2 pentyl), 0.89 (t, J = 6.9 Hz, 3 H) ppm. NMR (50 MHz, CDCl3): δ = 139.1, 138.8, 138.2 (Cq Bn), 128.5, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6 (CHAr Bn), 88.7 (C-3), 82.1 (OCH2-Ada), 80.6 (C2), 78.8 (C4), 75.3, 75.1, 73.5, 71.7 (4 × CH2 Bn), 67.7, 65.0 (C-6, CH2-5 pentyl), 63.2, 62.5 (C1, C-5), 46.9 (NCH2-1 pentyl), 39.9 (CH2 Ada), 37.4 (CH2 Ada), 34.3 (Cq Ada), 29.7, 29.6 (CH2 pentyl/butyl), 28.5 (CH Ada), 27.2, 24.0, 23.5 (CH2 pentyl/butyl), 14.5 (CH3-4 butyl) ppm. IR (thin film): equation imagemax. = 2900, 2847, 1450, 1358, 1065, 941, 841, 733, 694 cm–1. [α]D20 = –2.3 (c = 1.2, CHCl3). HRMS: found 814.5406 [M + H]+, calcd. for [C54H71NO5 + H]+ 814.5405.

(1S)-N-[5-(Adamant-1-ylmethoxy)pentyl]-1-C-butyl-1-deoxynojirimycin (34): Compound 33 (76 mg, 93 μmol) was subjected to hydrogenolysis at 4 bar H2 (see general procedure H) to furnish 34 (36 mg, 79 μmol) as a colourless oil in 85 % yield after purification (silica gel, 0 % → 15 % MeOH in CHCl3 with 0.5 % NH4OH). Rf = 0.44 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 3.92 (dd, J = 2.7, 11.9 Hz, 1 H, 6a-H), 3.86 (dd, J = 2.5, 11.9 Hz, 1 H, 6b-H), 3.41–3.34 (m, 3 H, 4-H, CH2-5 pentyl), 3.23 (dd, J = 9.4, 9.4 Hz, 1 H, 2-H), 3.16 (dd, J = 9.1, 9.1 Hz, 1 H, 3-H), 2.98–2.92 (m, 3 H, OCH2-Ada, NCHH-1 pentyl), 2.83–2.73 (m, 1 H, NCHH-1 pentyl), 2.52 (d, J = 4.8 Hz, 1 H, 1-H), 2.47 (d, J = 8.1 Hz, 1 H, 5-H), 1.95 (s, 3 H, 3 × CH Ada), 1.84–1.66 (m, 7 H, 3 × CH2 Ada, CHH-1 butyl), 1.62–1.53 (m, 9 H, 3 × CH2 Ada, CHH-1 butyl, CH2-4 pentyl), 1.45–1.29 (m, 8 H, CH2-2 butyl, CH2-3 butyl, CH2-2 pentyl, CH2-3 pentyl), 0.95 (t, J = 7.2 Hz, 3 H, CH3-4 butyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.2 (OCH2-Ada), 80.2 (C-3), 72.9 (C-2), 72.4 (CH2-5 pentyl), 71.1 (C-4), 66.1 (C-5), 64.2 (C-1), 59.4 (C-6), 48.0 (NCH2-1 pentyl), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 30.6 (CH2-4 pentyl), 29.9 (CH Ada), 28.9 (CH2-1 butyl), 27.4 (CH2-2 pentyl), 25.1, 24.5, 23.2 (3 × CH2 butyl, CH2-3 pentyl), 14.6 (CH3-4 butyl) ppm. IR (thin film): equation imagemax. = 3348, 2901, 2847, 1450, 1366, 1234, 1096, 1003, 833 cm–1. [α]D20 = –1.5 (c = 0.2, MeOH). HRMS: found 454.3523 [M + H]+, calcd. for [C26H48NO5 + H]+ 454.3527.

(1S)-1-C-[5-(Adamant-1-ylmethoxy)pentyl]-1-deoxy-N-hexylnojirimycin (36): Compound 3528 (292 mg, 220 μmol) was N-alkylated (see general procedure D), and the crude intermediate was subjected to hydrogenolysis at 4 bar H2 (see general procedure H) to furnish 36 (75 mg, 156 μmol) as a colourless oil in 71 % yield after purification (silica gel, 0 % → 10 % MeOH in CHCl3 with 0.5 % NH4OH). Rf = 0.49 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 3.88 (dd, J = 3.1, 11.8 Hz, 1 H, 6a-H), 3.84 (dd, J = 2.8, 11.7 Hz, 1 H, 6b-H), 3.39 (t, J = 6.5 Hz, 2 H, CH2-5 pentyl), 3.34 (dd, J = 9.3, 9.6 Hz, 1 H, 4-H), 3.18 (dd, J = 9.0, 9.2 Hz, 1 H, 2-H), 3.11 (dd, J = 9.0, 9.3 Hz, 1 H, 3-H), 2.97 (s, 2 H, OCH2-Ada), 2.88–2.79 (m, 1 H, NCHH hexyl), 2.73–2.64 (m, 1 H, NCHH hexyl), 2.39 (dt, J = 3.5, 9.2 Hz, 1 H, 1-H), 2.33 (dt, J = 2.9, 9.6 Hz, 1 H, 5-H), 1.95 (s, 3 H, 3 × CH Ada), 1.83–1.67 (m, 7 H, 3 × CH2 Ada, CHH-1 pentyl), 1.66–1.51 (m, 9 H, 3 × CH2 Ada, CHH-1 pentyl, CH2-4 pentyl), 1.41–1.18 (m, 14 H, CH2-2 pentyl, CH2-3 pentyl, CH2-4 pentyl, 4 × CH2 hexyl), 0.91 (t, J = 7.0 Hz, 3 H, CH3 hexyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.1 (OCH2-Ada), 80.6 (C-3), 73.1 (C-2), 72.6 (CH2-5 pentyl), 71.7 (C-4), 65.9 (C-5), 63.8 (C-1), 60.1 (C-1), 47.7 (NCH2 hexyl), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 33.1 (CH2 hexyl), 30.8 (CH2-4 pentyl), 29.9 (CH Ada), 29.2 (CH2-1 pentyl), 28.4, 28.0, 24.6, 24.0, 23.4 (2 × CH2 pentyl, 3 × CH2 hexyl), 14.6 (CH3 hexyl) ppm. IR (thin film): equation imagemax. = 3366, 2903, 2849, 1592, 1454, 1358, 1157, 1098, 1012 cm–1. [α]D20 = –2.3 (c = 0.3, MeOH). HRMS: found 482.3835 [M + H]+, calcd. for [C28H51NO5 + H]+ 482.3840.

(1S)-1-C-[5-(Adamant-1-ylmethoxy)pentyl]-1-deoxy-N-nonylnojirimycin (37): Compound 3528 (35 mg, 46 μmol) was N-alkylated (see general procedure D), and the crude intermediate was subjected to hydrogenolysis at 4 bar H2 (see general procedure H) to furnish 37 (15 mg, 29 μmol) as a colourless oil in 63 % yield after purification (silica gel, 0 % → 10 % MeOH in CHCl3 with 0.5 % NH4OH). Rf = 0.53 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 3.88 (dd, J = 3.2, 11.8 Hz, 1 H, 6a-H), 3.84 (dd, J = 2.9, 11.8 Hz, 1 H, 6b-H), 3.39 (t, J = 6.4 Hz, 2 H, CH2-5 pentyl), 3.35 (dd, J = 9.3, 9.3 Hz, 1 H, 4-H), 3.19 (dd, J = 9.3, 9.3 Hz, 1 H, 2-H), 3.13 (dd, J = 9.0, 9.0 Hz, 1 H, 3-H), 2.97 (s, 2 H, OCH2-Ada), 2.89–2.80 (m, 1 H, NCHH nonyl), 2.74–2.66 (m, 1 H, NCHH nonyl), 2.42 (dt, J = 3.6, 7.6 Hz, 1 H, 1-H), 2.37 (dt, J = 2.8, 9.7 Hz, 1 H, 5-H), 1.95 (s, 3 H, 3 × CH Ada), 1.83–1.66 (m, 7 H, 3 × CH2 Ada, CHH-1 pentyl), 1.66–1.55 (m, 9 H, 3 × CH2 Ada, CHH-1 pentyl, CH2-4 pentyl), 1.49-1.36 (m, 6 H, 2 × CH2 pentyl, NCH2CH2 nonyl), 1.36–1.18 (m, 12 H, 6 × CH2 nonyl), 0.90 (t, J = 7.0 Hz, 3 H, CH3 nonyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.2, 80.5 (C-3), 73.1 (C-2), 72.6 (CH2-5 pentyl), 71.6 (C-4), 66.0 (C-5), 64.0 (C-1), 60.1 (C-6), 47.8 (NCH2 nonyl), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 33.2 (CH2 nonyl), 30.9 (CH2 nonyl), 30.8 (CH2-4 pentyl), 30.7, 30.6 (2 × CH2 nonyl), 29.9 (CH Ada), 29.3 (CH2-1 pentyl), 28.6, 28.0, 24.8, 23.9, 23.6 (2 × CH2 pentyl, 3 × CH2 nonyl), 14.6 (CH3 nonyl) ppm. IR (thin film): equation imagemax. = 3395, 2903, 2850, 1622, 1456, 1361, 1259, 1110, 1037 cm–1. [α]D20 = –3.0 (c = 0.2, MeOH). HRMS: found 524.4304 [M + H]+, calcd. for [C31H58NO5 + H]+ 524.4310.

(1S)-1-C,N-Bis[5-(adamant-1-ylmethoxy)pentyl]-1-deoxynojirimycin (38): A solution of 3528 (271 mg, 0.36 mmol) and 1025 (900 mg, 3.6 mmol) in acetonitrile/MeOH (1.8 mL, 5:1, v/v) was acidified to pH = 5–6 with AcOH (10 μL). Sodium sulfate (100 mg) and sodium cyanoborohydride (90 mg, 1.44 mmol) were added, and the reaction mixture was heated at 75 °C for 18 h. The mixture was diluted with satd. aq. NaHCO3 (20 mL) and extracted with Et2O (3 × 20 mL). The combined organic phases were dried (MgSO4) and concentrated. Half of the resulting crude residue was subjected to Pd/C-catalyzed hydrogenolysis at 4 bar H2 (see general procedure H). The resulting crude product was purified by silica gel column chromatography (0 % → 10 % MeOH in CHCl3 with 0.5 % NH4OH) to give 38 (90 mg, 142 mmol) as a colourless oil in 79 % yield. Rf = 0.57 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 3.89 (dd, J = 2.9, 11.9 Hz, 1 H, 6a-H), 3.85 (dd, J = 2.5, 11.8 Hz, 1 H, 6b-H), 3.41–3.37 (m, 4 H, 2 × CH2-5 pentyl), 3.35 (dd, J = 8.8, 10.2 Hz, 1 H, 4-H), 3.19 (t, J = 9.3 Hz, 1 H, 2-H), 3.12 (t, J = 9.0 Hz, 1 H, 3-H), 2.97 (s, 4 H), 2.92–2.85 (m, 1 H, NCHH-1 pentyl), 2.75–2.66 (m, 1 H, NCHH-1 pentyl), 2.45–2.40 (m, 1 H, 1-H), 2.38–2.32 (m, 1 H, 5-H), 1.95 (s, 6 H, 6 × CH Ada), 1.87–1.66 (m, 14 H, 6 × CH2 Ada, 2 × CHH-1 pentyl), 1.66–1.53 (m, 18 H, 6 × CH2 Ada, 2 × CHH-1 pentyl, 2 × CH2-4 pentyl), 1.52–1.26 (m, 8 H, 4 × CH2 pentyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.2, 83.1 (2 × OCH2-Ada), 80.5 (C-3), 73.0 (C-2), 72.5, 72.4 (2 × CH2-5 pentyl), 71.4 (C-4), 65.9 (C-5), 63.7 (C-1), 59.8 (C-6), 47.8 (NCH2-1 pentyl), 41.1, 41.0 (2 × CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 30.8, 30.6 (2 × CH2-4 pentyl), 29.9 (CH Ada), 29.1 (CH2 pentyl), 28.1 (CH2 pentyl), 25.2 (CH2 pentyl) ppm. IR (thin film): equation imagemax. = 3368, 2902, 2848, 1452, 1157, 1111 cm–1. [α]D20 = 0.9 (c = 0.2, MeOH). HRMS: found 632.4881 [M + H]+, calcd. for [C38H65NO6 + H]+ 632.4885.

(1S)-1-C-[(Z)-5-(Adamant-1-ylmethoxy)pent-1-enyl]-N-[5-(adamant-1-ylmethoxy)pentyl]-1-deoxynojirimycin (39): The other half of the crude product residue from the reductive amination was subjected to Pd/C-catalyzed hydrogenolysis at atmospheric H2 pressure (see general procedure H). This resulted in a product mixture of 38 and 39. Purification by silica gel column chromatography produced 38 (60 mg, 95 mmol) in 53 % and (Z)-alkene 39 (47 mg, 74 mmol) in 41 % yield. Rf = 0.43 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 5.72 (dt, J = 7.5, 11.0 Hz, 1 H, =CH-2 pentenyl), 5.24 (dd, J = 9.9, 11.0 Hz, 1 H, =CH-1 pentenyl), 3.93 (dd, J = 2.2, 11.9 Hz, 1 H, 6a-H), 3.82 (dd, J = 2.4, 11.9 Hz, 1 H, 6b-H), 3.47–3.34 (m, 6 H, CH2-5 pentyl, CH2-5 pentenyl), 3.27 (t, J = 9.5 Hz, 1 H), 3.21 (t, J = 9.2 Hz, 1 H), 3.05 (t, J = 9.1 Hz, 1 H), 2.99–2.94 (m, 5 H, 2 × OCH2-Ada), 2.90–2.79 (m, 2 H, NCH2-1 pentyl), 2.34 (dt, J = 2.4, 9.2 Hz, 1 H, 5-H), 2.32–2.27 (m, 1 H, CHH-3 pentenyl), 2.25–2.17 (m, 1 H, CHH-3 pentenyl), 1.95 (s, 6 H, 6 × CH Ada), 1.73 (dd, J = 12.3, 46.5 Hz, 12 H, 6 × CH2 Ada), 1.66–1.52 (m, 16 H, 6 × CH2 Ada, CH2-4 pentyl, CH2-4 pentenyl), 1.48–1.17 (m, 4 H, CH2-2 pentyl, CH2-3 pentyl) ppm. 13C NMR (150 MHz, MeOD): δ = 135.6 (=CH-2 pentenyl), 130.1 (=CH-1 pentenyl), 83.1, 83.1 (2 × OCH2-Ada), 79.5 (C-3), 74.9 (C-2), 72.6, 72.3 (CH2-5 pentenyl/pentyl), 71.7 (C-4), 64.9 (C-5), 63.0 (C-1), 59.3 (C-6), 49.0 (NCH2-1 pentyl), 41.1, 41.1 (CH2-Ada), 38.5 (CH2-Ada), 35.3 (Cq Ada), 31.0 (CH2-4 pentyl), 30.8 (CH2-4 pentenyl), 29.9 (CH Ada), 26.6 (CH2-3 pentenyl), 25.3 (C-3), 22.0 (C-2) ppm. IR (thin film): equation imagemax. = 3362, 2901, 2848, 1452, 1157, 1109, 1011 cm–1. [α]D20 = 23.7 (c = 0.4, MeOH). HRMS: found 630.4725 [M + H]+, calcd. for [C38H63NO6 + H]+ 630.4728.

(1S)-1-C-[5-(Adamant-1-ylmethoxy)pentyl]-N-benzyl-1-deoxynojirimycin (40): A suspension of 328 (40 mg, 101 μmol), benzyl bromide (25 μL, 211 μmol) and K2CO3 (42 mg, 303 μmol) in DMF (0.5 mL) was heated at 85 °C for 18 h. The reaction mixture was filtered through a glass fibre filter and concentrated. The residue was purified by silica gel column chromatography (0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH) to give 40 (35 mg, 72 μmol) as a colourless oil in 71 % yield. Rf = 0.67 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 7.43 (d, J = 7.4 Hz, 2 H, o-CHAr Bn), 7.30 (t, J = 7.7 Hz, 2 H, m-CHAr Bn), 7.20 (t, J = 7.4 Hz, 1 H, p-CHAr Bn), 3.95–3.87 (m, 3 H, 6a-H, CH2 Bn), 3.82 (dd, J = 4.5, 11.6 Hz, 1 H, 6b-H), 3.53 (dd, J = 9.1, 9.8 Hz, 1 H, 4-H), 3.35 (dd, J = 9.0, 9.7 Hz, 1 H, 2-H), 3.26 (t, J = 6.6 Hz, 2 H,CH2-5 pentyl), 3.24 (dd, J = 9.0, 9.1 Hz, 1 H, 3-H), 2.93 (s, 2 H, OCH2-Ada), 2.61 (ddd, J = 4.0, 4.5, 9.8 Hz, 1 H, 5-H), 2.56 (ddd, J = 3.5, 6.3, 9.7 Hz, 1 H, 1-H), 1.96 (s, 3 H, 3 × CH Ada), 1.80–1.67 (m, 7 H, 3 × CH2 Ada, CHH-1 pentyl), 1.60–1.54 (m, 7 H, 3 × CH2 Ada, CHH-1 pentyl), 1.45–1.28 (m, 4 H, CH2-2, CH2-4 pentyl), 1.10–1.02 (m, 2 H, CH2-3 pentyl) ppm. 13C NMR (151 MHz, MeOD): δ = 143.1 (Cq Bn), 129.3 (m-CHAr Bn), 129.0 (o-CHAr Bn), 127.6 (p-CHAr Bn), 83.1 (OCH2-Ada), 80.8 (C-3), 73.1 (C-2), 72.8 (CH2-5 pentyl), 72.1 (C-4), 68.2 (C-5), 67.1 (C-1), 62.4 (C-6), 52.4 (CH2 Bn), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 30.7 (CH2-4 pentyl), 30.1 (CH2-1 pentyl), 29.9 (CH Ada), 27.6 (CH2-2 pentyl), 26.4 (CH2-3 pentyl) ppm. IR (thin film): equation imagemax. = 3368, 2901, 2848, 1700, 1454, 1285, 1094, 729, 699 cm–1.[α]D20 = –4.0 (c = 0.5, MeOH). HRMS: found 488.3365 [M + H]+, calcd. for [C29H45NO5 + H]+ 488.3370.

(1S)-1-C-[(Z)-5-(Adamant-1-ylmethoxy)pent-1-enyl]-2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin (41): A solution of 3528 (151 mg, 0.2 mmol) in EtOAc (2 mL) was charged with Lindlar catalyst (25 mg). Argon was passed through the reaction mixture for 5 min, and the mixture was subsequently exposed to atmospheric hydrogen pressure for 18 h. After 18 h, the conversion was ca. 80 % of a single slower running product. Longer or repeated exposure to hydrogen led to overreduction [Rf(starting material) = 0.57;Rf(overreduced product) = 0.49 (EtOAc/PE, 1:2)]. The reaction mixture was passed through a glass fibre filter and concentrated. The residue was purified by silica gel column chromatography (0 % → 5 % acetone in toluene) to furnish 41 (112 mg, 0.15 mmol) in 74 % yield as a colourless oil (20 % starting material recovered). Rf = 0.52 (EtOAc/PE, 1:2). 1H NMR (600 MHz, CDCl3): δ = 7.36–7.16 (m, 20 H, HAr Bn), 5.62 (dt, J = 7.4, 10.8 Hz, 1 H, =CH-2 pentenyl), 5.35 (dd, J = 9.2, 10.8 Hz, 1 H, =CH-1 pentenyl), 4.91 (d, J = 10.8 Hz, 1 H, CHH Bn), 4.84 (m, 2 H, CHH Bn, CHH Bn), 4.73 (d, J = 10.7 Hz, 1 H, CHH Bn), 4.69 (d, J = 10.7 Hz, 1 H, CHH Bn), 4.50 (d, J = 11.0 Hz, 1 H, CHH Bn), 4.46 (s, 2 H, CH2 Bn), 3.72 (dd, J = 2.6, 9.0 Hz, 1 H, 6a-H), 3.61 (dd, J = 9.0, 9.0 Hz, 1 H, 3-H), 3.50 (dd, J = 9.2, 9.2 Hz 1 H, 1-H), 3.38 (dd, J = 7.7, 8.9 Hz, 1 H, 6b-H), 3.34–3.31 (m, 3 H, 4-H, CH2-5 pentenyl), 3.25 (dd, J = 9.2, 9.2 Hz 1 H, 2-H), 2.93–2.86 (m, 3 H, 5-H, OCH2-Ada), 2.28–2.20 (m, 1 H, CHH-3 pentenyl), 2.20–2.12 (m, 1 H, CHH-3 pentenyl), 1.95 (s, 3 H, 3 × CH Ada), 1.77 (s, 1 H, NH), 1.67 (dd, J = 11.7, 36.7 Hz, 6 H, 3 × CH2 Ada), 1.62–1.54 (m, 2 H, CH2-4 pentenyl), 1.52 (d, J = 2.5 Hz, 6 H, 3 × CH2 Ada) ppm. 13C NMR (150 MHz, CDCl3): δ = 139.0, 138.7, 138.5, 138.1 (4 × Cq Bn), 134.3 (=CH-2 pentenyl), 129.5 (=CH-1 pentenyl), 128.68, 128.63, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.96, 127.91, 127.8, 127.7 (CHAr Bn), 87.9 (C-3), 84.6 (C-2), 82.0 (OCH2-Ada), 80.6 (C-4), 75.9, 75.4, 75.2, 73.6 (4 × CH2 Bn), 70.9 (CH2-5 pentenyl), 71.0 (C-6), 59.1 (C-5), 56.9 (C-1), 39.9 (CH2 Ada), 37.5 (CH2 Ada), 34.3 (Cq Ada), 29.7 (CH2-4 pentenyl), 28.5 (CH Ada), 25.1 (CH2-3 pentenyl) ppm. IR (thin film): equation imagemax. = 3031, 2900, 2848, 1497, 1453, 1360, 1209, 1152, 1096, 1072, 1027, 734, 697 cm–1. [α]D20 = 49.4 (c = 1.0, CHCl3). HRMS: found 756.4622 [M + H]+, calcd. for [C50H61NO5 + H]+ 756.4623.

(1S)-1-C-[(Z)-5-(Adamant-1-ylmethoxy)pent-1-enyl]-1-deoxynojirimycin (42): Compound 41 (45 mg, 60 μmol) was subjected to a Birch reduction (see general procedure G) to produce 42 (16 mg, 40 μmol) as a colourless oil in 67 % yield after purification (silica gel: 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Rf = 0.34 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 5.69 (dt, J = 7.6, 10.8 Hz, 1 H, =CH-2 pentenyl), 5.32 (dd, J = 9.2, 10.8 Hz, 1 H, =CH-1 pentenyl), 3.91 (dd, J = 3.1, 10.9 Hz, 1 H, 6a-H), 3.48 (dd, J = 7.9, 10.9 Hz, 1 H, 6b-H), 3.41 (t, J = 6.3 Hz, 2 H, CH2-5 pentenyl), 3.36 (dd, J = 9.2, 9.2 Hz 1 H, 1-H), 3.28 (dd, J = 8.9, 9.1 Hz, 1 H, 3-H), 3.14 (dd, J = 8.9, 9.6 Hz, 1 H, 4-H), 3.09 (d, J = 9.1, 9.2 Hz 1 H, 2-H), 3.01–2.96 (m, 2 H, OCH2-Ada), 2.64 (ddd, J = 3.1, 7.9, 9.6 Hz, 1 H, 5-H), 2.28–2.18 (m, 2 H, CH2-3 pentenyl), 1.95 (s, 3 H, 3 × CH Ada), 1.73 (dd, J = 11.5, 41.9 Hz, 6 H, 3 × CH2 Ada), 1.67–1.59 (m, 2 H, CH2-4 pentenyl), 1.58 (d, J = 2.4 Hz, 6 H, 3 × CH2 Ada) ppm. 13C NMR (150 MHz, MeOD): δ = 135.7 (=CH-2 pentenyl), 130.4 (=CH-1 pentenyl), 83.1 (OCH2-Ada), 80.3 (C-3), 76.5 (C-2), 73.8 (C-4), 72.0 (CH2-5 pentenyl), 63.8 (C-6), 62.5 (C-5), 58.5 (C-1), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 30.8 (CH2-4 pentenyl), 29.9 (CH Ada), 25.9 (CH2-3 pentenyl) ppm. IR (thin film): equation imagemax. = 3319, 2900, 2848, 1661, 1448, 1344, 1096, 1005 cm–1. [α]D20 = 10.5 (c = 0.3, MeOH). HRMS: found 396.2742 [M + H]+, calcd. for [C22H37NO5 + H]+ 396.2744.

(1S)-1-C-[5-(Adamant-1-ylmethoxy)pent-1-ynyl]-1-deoxynojirimycin (43): Compound 3528 (149 mg, 198 μmol) was subjected to a Birch reduction for 30 min (see general procedure G) to produce a ca. 4:1 mixture of 43 and 44 after silica gel column purification (0 % → 10 % MeOH in CHCl3 with 0.5 % NH4OH), from which 43 (19 mg, 48 μmol) could be obtained in 24 % yield as a colourless oil after HPLC purification [1 min: isocratic 30 % B → 11.5 min: 45 % B → 12.5 min: 100 % B, 20 min: isocratic 100 % B; tR(43) = 6.0 min; tR(44) = 8.2 min]. Rf = 0.37 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 3.92–3.87 (m, 2 H, 1-H, 6a-H), 3.84 (dd, J = 4.9, 11.9 Hz, 1 H, 6b-H), 3.56–3.51 (m, 2 H, 2-H, 4-H), 3.48 (t, J = 6.0 Hz, 2 H, CH2-5 pentynyl), 3.35 (dd, J = 9.1 Hz, 1 H, 3-H), 3.07 (ddd, J = 3.3, 4.9, 10.6 Hz, 1 H, 5-H), 2.98 (s, 2 H, OCH2-Ada), 2.39 (td, J = 1.6, 7.2 Hz, 2 H, CH2-3 pentynyl), 1.94 (s, 3 H, 3 × CH Ada), 1.84–1.64 (m, 8 H, 3 × CH2 Ada, CH2-4 pentynyl), 1.56 (d, J = 2.4 Hz, 6 H, 3 × CH2 Ada) ppm. 13C NMR (150 MHz, MeOD): δ = 90.2 (Cq pentynyl), 83.1 (OCH2-Ada), 77.9 (C-3), 73.8 (Cq pentynyl), 73.3 (C-2), 70.9 (CH2-5 pentynyl), 69.2 (C-4), 61.5 (C-5), 59.0 (C-6), 52.4 (C-1), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 29.9 (CH Ada), 29.6 (CH2-4 pentynyl), 16.4 (CH2-3 pentynyl) ppm. IR (thin film): equation imagemax. = 3366, 2902, 2849, 1444, 1201, 1141, 1114, 1078, 1024 cm–1. [α]D20 = –3.3 (c = 0.2, MeOH). HRMS: found 394.2586 [M + H]+, calcd. for [C22H35NO5 + H]+ 394.2588.

(1S)-1-C-[(E)-5-(Adamant-1-ylmethoxy)pent-1-enyl]-1-deoxynojirimycin (44): Compound 3528 (100 mg, 133 μmol) was subjected to a Birch reduction for 3 h with lithium instead of sodium (see general procedure G) to produce 44 (36 mg, 92 μmol) in 70 % yield as a colourless oil after purification (0 % → 10 % MeOH in CHCl3 with 0.5 % NH4OH). Rf = 0.35 (MeOH/CHCl3, 1:4 + 0.5 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 6.03 (dt, J = 6.9, 15.4 Hz, 1 H, =CH-2 pentenyl), 5.47 (dd, J = 8.7, 15.4 Hz, 1 H, =CH-1 pentenyl), 3.92 (dd, J = 3.9, 11.9 Hz, 1 H, 6a-H), 3.86 (dd, J = 2.9, 11.9 Hz, 1 H, 6b-H), 3.60–3.52 (m, 2 H, 1-H, 4-H), 3.44–3.35 (m, 7 H, 2-H, 3-H, CH2-5 pentenyl), 3.08 (dt, J = 3.3, 10.7 Hz, 1 H, 5-H), 2.98 (s, 2 H, OCH2-Ada), 2.23 (dd, J = 6.7, 14.4 Hz, 2 H, CH2-3 pentenyl), 1.95 (s, 3 H, 3 × CH Ada), 1.83-1.65 (m, 8 H, 3 × CH2 Ada, CH2-4 pentenyl), 1.57 (d, J = 2.4 Hz, 6 H, 3 × CH2 Ada) ppm. 13C NMR (150 MHz, MeOD): δ = 142.3 (=CH-2 pentenyl), 123.9 (=CH-1 pentenyl), 83.1 (OCH2-Ada), 78.3 (C-3), 72.5 (C-2), 71.7 (CH2-5 pentenyl), 69.1 (C-4), 62.9 (C-1), 61.6 (C-5), 58.6 (C-6), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 30.4 (C-3), 29.9 (CH Ada), 29.8 (C-4) ppm. IR (thin film): equation imagemax. = 3366, 2904, 2850, 1440, 1203, 1140 cm–1. [α]D20 = –3.4 (c = 0.1, MeOH). HRMS: found 396.2743 [M + H]+, calcd. for [C22H37NO5 + H]+ 396.2744.

3-(Adamant-1-ylmethoxy)prop-2-ene (45): A stirred solution of adamantylmethanol (1.38 g, 8.3 mmol) in DMF (25 mL) was cooled to 0 °C, and sodium hydride (60 % in mineral oil, 0.5 g, 12.5 mmol) was added. After stirring at 0 °C for 1 h, allyl bromide (1.46 mL, 16.8 mmol) was added. The resulting mixture was warmed to ambient temperature and stirred at ambient temperature for an additional 16 h. The reaction mixture was cooled to 0 °C and quenched by addition of water. The mixture was diluted with Et2O (200 mL) and washed with water (3 × 200 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (0 % → 5 % EtOAc in PE) to produce 45 (1.359 g, 6.59 mmol) in 80 % yield as a colourless liquid. Rf = 0.67 (100 % toluene). 1H NMR (400 MHz, CDCl3): δ = 5.94–5.80 (m, 1 H, =CH-2 propenyl), 5.25 (d, J = 17.3 Hz, 1 H, =CHH-1 propenyl), 5.12 (d, J = 10.4 Hz, 1 H, =CHH-1 propenyl), 3.92 (d, J = 5.0 Hz, 2 H, CH2-3 propenyl), 2.98 (s, 2 H, OCH2-Ada), 1.96 (s, 3 H), 1.68 (dd, J = 12.1, 26.0 Hz, 6 H), 1.55 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 135.5 (=CH-2 propenyl), 116.1 (=CH2-1 propenyl), 81.4 (OCH2-Ada), 72.3 (CH2-3 propenyl), 39.8 (CH2 Ada), 37.4 (CH2 Ada), 34.1 (Cq Ada), 28.4 (CH Ada) ppm. IR (thin film): equation imagemax. = 2902, 2849, 1733, 1453, 1378, 1258, 1158, 1090, 989, 919 cm–1. MS (ESI): found 207.2 [M + H]+, calcd. for [C14H22O + H]+ 207.2.

4-(Adamant-1-ylmethoxy)but-2-ene (46): A solution of 3-buten-1-ol (0.35 mL, 4.0 mmol) and Et3N (0.55 mL, 4.0 mmol) in DCM (40 mL) was cooled to –40 °C, and Tf2O (0.73 mL, 4.4 mmol) was slowly added over 30 s. The mixture was warmed to 0 °C over a period of 1 h, after which TLC analysis indicated complete conversion to the volatile intermediate triflate [Rf(triflate) = 0.80 (EtOAc/PE, 1:2)]. The crude reaction mixture was poured into a stirred suspension of anhydrous K2CO3 (2.76 g, 10 mmol) and adamantylmethanol (3.32 g, 20 mmol) in DCM (80 mL). The resulting mixture was refluxed at 50 °C for 20 h. The suspension was cooled to ambient temperature and filtered. The solid residue was rinsed, and the combined filtrates were concentrated. The concentrate was purified by silica gel column chromatography (2 % → 5 % EtOAc in PE) to afforded 46 (875 mg, 3.97 mmol) in 99 % yield as a volatile colourless liquid. Rf = 0.85 (EtOAc/PE, 1:9). 1H NMR (400 MHz, CDCl3): δ = 5.89–5.76 (m, 1 H, =CH-2 butenyl), 5.06 (d, J = 17.2 Hz, 1 H, =CHH-1 butenyl), 5.00 (d, J = 10.2 Hz, 1 H, =CHH-1 butenyl), 3.42 (t, J = 6.8 Hz, 2 H, CH2-4 butenyl), 2.97 (s, 2 H, OCH2-Ada), 2.36–2.26 (m, 2 H, CH2-3 butenyl), 1.95 (s, 3 H, 3 × CH Ada), 1.68 (dd, J = 12.1, 26.2 Hz, 7 H, 3 × CH2 Ada), 1.54 (s, 6 H, 3 × CH2 Ada) ppm. 13C NMR (100 MHz, CDCl3): δ = 135.6 (=CH-2 butenyl), 116.1 (=CH2-1 butenyl), 82.0 (OCH2-Ada), 71.0 (CH2-4 butenyl), 39.9 (CH2 Ada), 37.4 (CH2 Ada), 34.3 (CH2-3 butenyl), 34.2 (Cq Ada), 28.5 (CH Ada) ppm. IR (thin film): equation imagemax. = 2899, 2848, 1641, 1451, 1359, 1157, 1109, 992, 911 cm–1. MS (ESI): found 221.4 [M + H]+, calcd. for [C15H24O + H]+ 221.2.

5-(Adamant-1-ylmethoxy)pent-2-ene (47): A stirred solution of adamantylmethanol (1.38 g, 8.3 mmol) in DMF (25 mL) was cooled to 0 °C, and sodium hydride (60 % in mineral oil, 0.5 g, 12.5 mmol) was added. After stirring at 0 °C for 1 h, 5-bromopent-1-ene (2.5 g, 16.8 mmol) was added. The resulting mixture was warmed to ambient temperature and stirred at ambient temperature for an additional 16 h. The reaction mixture was cooled to 0 °C and quenched by addition of water. The mixture was diluted with Et2O (200 mL) and washed with water (3 × 200 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (0 % → 5 % EtOAc in PE) to produce 47 (1.036 g, 4.42 mmol) in 53 % yield as a volatile colourless liquid. Rf = 0.73 (100 % toluene). 1H NMR (200 MHz, CDCl3): δ = 5.82 (ddt, J = 6.6, 10.1, 16.9 Hz, 1 H, =CH-2 pentenyl), 5.09–4.88 (m, 2 H, =CH2-1 pentenyl), 3.38 (t, J = 6.4 Hz, 2 H, CH2-5 pentenyl), 2.95 (s, 2 H, OCH2-Ada), 2.20–2.05 (m, 2 H, CH2-3 pentenyl), 1.95 (s, 3 H, 3 × CH Ada), 1.64 (m, 8 H, CH2-4 pentenyl, 3 × CH2 Ada), 1.53 (d, J = 2.8 Hz, 6 H, 3 × CH2 Ada) ppm. 13C NMR (50 MHz, CDCl3): δ = 138.7 (=CH-2 pentenyl), 114.7 (=CH2-1 pentenyl), 82.1 (OCH2-Ada), 71.0 (CH2-5 pentenyl), 40.0 (CH2 Ada), 37.5 (CH2 Ada), 34.3 (Cq Ada), 30.5, 29.1 (CH2-3, CH2-4 pentenyl), 28.5 (CH Ada) ppm. IR (thin film): equation imagemax. = 2899, 2848, 1641, 1451, 1361, 1157, 1111, 1050, 990, 910 cm–1. MS (ESI): found 235.3 [M + H]+, calcd. for [C16H26O + H]+ 235.2.

α/β-Mixture of 2,3,4,6-tetra-O-benzyl-N-(4-methoxybenzyl)-D-glucopyranosylamine (49): A suspension of commercially availabe 2,3,4,6-tetra-O-benzyl-D-glucopyranose (48, 21.6 g, 40 mmol), (p-methoxybenzyl)amine (15.7 mL, 200 mmol), p-toluenesulfonic acid (200 mg, 1 mmol) and Na2SO4 (17 g, 120 mmol) in toluene (400 mL) was refluxed for 18 h. The reaction mixture was cooled to room temp., diluted with EtOAc (300 mL) and successively washed with aq. 1 M HCl (2 × 300 mL), satd. aq. NaHCO3 (2 × 200 mL) and satd. aq. NaCl (200 mL). The organic phase was dried (Na2SO4) and concentrated to provide 49 as a white solid that was used crude in the subsequent reaction. A small sample of crude 49 was purified by silica gel column chromatography (0 % → 10 % EtOAc in PE) for characterization. Rf = 0.75 (EtOAc/PE, 1:2). 1H NMR (400 MHz, CDCl3): δ = 7.52–7.10 (m, 44 H, HAr-α/β Bn/PMB), 6.83 (d, J = 7.7 Hz, 4 H, HAr-α/β PMB), 5.06–4.43 (m, 17 H, CH2-α/β Bn, 1α-H), 4.14–4.05 (m, 2 H, CHH-6, CHH PMB), 4.03 (d, J = 8.8 Hz, 1 H, 1β-H), 3.94–3.54 (m, 20 H, OMe-α/β PMB, CH2-α/β PMB), 3.40 (d, J = 7.2 Hz, 1 H), 3.30 (dd, J = 8.1, 8.8 Hz, 1 H, 2β-H), 2.21 (br. s, 2 H, NHPMB) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.8, 158.7 (p-Cq-α/β PMB), 139.1, 138.9, 138.64, 138.62, 138.4, 138.3, 138.2 (Cq-α/β Bn), 132.5, 132.4 (Cq-α/β PMB), 129.6, 129.5, 128.6, 128.58, 128.55, 128.51, 128.4, 128.1, 128.06, 128.02, 127.84, 127.81, 127.78, 127.73 (CHAr-α/β Bn/PMB), 113.9, 113.9 (CHAr-α/β PMB), 90.2 (C-1β), 84.1 (C-1α), 86.1, 82.7, 82.7, 80.4, 78.4, 78.3 (C-2, C-3, C-4 α/β), 75.8 (C-5β), 75.9, 75.7, 75.1, 75.1, 75.0, 73.7, 73.6, 73.0 (CH2-α/β Bn), 69.0 (C-5α), 69.1, 68.9 (C-6α/β), 55.4, 55.3 (OMe-α/β PMB), 49.4, 49.3 (CH2-α/β PMB) ppm. IR (thin film): equation imagemax. = 3318, 3030, 2864, 1611, 1514, 1454, 1354, 1244, 1121, 1058, 1028, 1011, 971, 748, 732, 693 cm–1. [α]D20 = 25.7 (c = 1.8, CHCl3). HRMS: found 660.3317 [M + H]+, calcd. for [C42H45NO6 + H]+ 660.3320.

(1R/S)-2,3,4,6-Tetra-O-benzyl-1-deoxy-1-[(4-methoxybenzyl)amino]-1-C-(prop-2-enyl)-D-glucitol (50): Allylmagnesium bromide (1 M in Et2O, 350 mL, 350 mmol) was slowly added over a period of 30 min to a dry and cooled (0 °C) solution of 49 (23.1 g, 35 mmol) in Et2O (50 mL). The reaction mixture was stirred for an additional 16 h and warmed to room temp. The reaction was quenched with satd. aq. NH4Cl, poured into Et2O (200 mL), and washed with satd. aq. NH4Cl (2 × 200 mL). The organic phase was dried (Na2SO4), concentrated and purified by silica gel column chromatography (0 % → 40 % EtOAc in PE) to provide 50 [2.28 g, 32.5 mmol, inseparable (R)/(S) = 9:1 isomer mixture] in 93 % yield as a colourless oil. Rf = 0.40 (EtOAc/PE, 1:2). 1H NMR (400 MHz, CDCl3): δ = 7.39–7.17 (m, 22 H, HAr Bn, HAr PMB), 6.81 (d, J = 8.5 Hz, 2 H, HAr PMB), 5.65–5.53 (m, 1 H, =CH propenyl), 5.01–4.93 (m, 2 H, =CH2 propenyl), 4.85 (d, J = 11.4 Hz, 1 H, CHH Bn), 4.78 (d, J = 11.3 Hz, 1 H, CHH Bn), 4.69 (d, J = 11.3 Hz, 1 H, CHH Bn), 4.60–4.49 (m, 5 H, CHH Bn, CHH Bn, CH2 Bn), 4.40 (d, J = 11.4 Hz, 1 H, CHH Bn), 4.27 (dd, J = 2.8, 7.5 Hz, 1 H, 3-H), 4.09–4.04 (m, 1 H, 5-H), 3.87–3.78 (m, 2 H, 2-H, CHH PMB), 3.76 (s, 3 H, OMe PMB), 3.66–3.51 (m, 2 H, 4-H, CH2-6, CHH PMB), 2.62 (t, J = 5.1 Hz, 1 H, 1-H), 2.46–2.33 (m, 1 H, CHH propenyl), 2.33–2.19 (m, 1 H, CHH propenyl) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.8 (p-Cq PMB), 139.1, 138.6, 138.35, 138.31 (Cq Bn/PMB), 136.30 (=CH propenyl), 129.8, 128.6, 128.5, 128.3, 128.0, 127.97, 127.92, 127.6 (CHAr Bn/PMB), 117.3 (=CH2 propenyl), 113.9 (CHAr PMB), 80.3 (C-2), 79.6 (C-3), 77.9 (C-4), 74.7, 73.6, 73.0 (4 × CH2 Bn), 71.8 (C-6), 70.8 (C-5), 57.0 (C-1), 55.5 (OMe PMB), 50.5 (CH2 PMB), 35.2 (CH2 propenyl) ppm. IR (thin film): equation imagemax. = 3031, 2863, 1610, 1513, 1454, 1245, 1067, 1028, 912, 825, 733, 696 cm–1. [α]D20 = –0.4 (c = 2.6, CHCl3). HRMS: found 702.3786 [M + H]+, calcd. for [C45H51NO6 + H]+ 702.3789.

(1R)-2,3,4,6-Tetra-O-benzyl-N-[(4-methoxybenzyl)amino]-1-C-(prop-2-enyl)-L-ido-1-deoxynojirimycin (51): Methanesulfonyl chloride (0.56 mL, 7.2 mmol) was added to a cooled (0 °C) solution of 50 (4.21 g, 6.0 mmol) in pyridine (77 mL). The mixture was stirred for 4 h, warmed to room temp., and subsequently heated at 90 °C for 16 h [Rf(mesylate) = 0.73 (EtOAc/PE, 1:2)]. The reaction mixture was concentrated, redissolved in EtOAc (100 mL) and washed extensively with aq. satd. CuSO4 (5 × 50 mL). The organic phase was dried (MgSO4), concentrated and purified by silica gel column chromatography (0 % → 10 % EtOAc in PE) to provide 51 (3.21 g, 4.68 mmol) in 78 % yield as a yellow oil. Rf = 0.70 (EtOAc/PE, 1:6.5). 1H NMR (500 MHz, CDCl3): δ = 7.34–7.20 (m, 20 H, HAr Bn), 7.16 (d, J = 8.6 Hz, 2 H, HAr PMB), 6.81 (d, J = 8.7 Hz, 2 H, HAr PMB), 5.91–5.82 (m, 1 H, =CH propenyl), 5.00–4.90 (m, 2 H, =CH2 propenyl), 4.81 (d, J = 10.9 Hz, 1 H, CHH Bn), 4.79 (d, J = 10.9 Hz, 1 H, CHH Bn), 4.60 (d, J = 11.3 Hz, 1 H, CHH Bn), 4.57–4.51 (m, 3 H, CHH Bn, CH2 Bn), 4.49–4.45 (m, 2 H, CH2 Bn), 4.03 (d, J = 14.5 Hz, 1 H, CHH PMB), 3.98 (d, J = 14.5 Hz, 1 H, CHH PMB), 3.83–3.67 (m, 7 H, 3-H, 5-H, CH2-6, OMe PMB), 3.60 (dd, J = 5.8, 8.2 Hz, 1 H, 2-H), 3.49 (dd, J = 5.6, 11.6 Hz, 1 H, 4-H), 3.20–3.16 (m, 1 H, 1-H), 2.51–2.43 (m, 1 H, CHH propenyl), 2.37–2.29 (m, 1 H, CHH propenyl) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.7 (p-Cq PMB), 139.3 (Cq Bn), 138.9 (=CH propenyl), 138.8 (Cq Bn), 132.8 (Cq PMB), 129.8, 129.3, 128.5, 128.4, 128.2, 128.0, 127.9, 127.8, 127.6 (CHAr Bn/PMB), 115.6 (=CH2 propenyl), 113.8 (CHAr PMB), 81.0 (C-2), 80.2 (C-3), 78.8 (C-5), 75.3, 73.4, 72.8, 72.7 (CH2 Bn), 70.6 (C-6), 59.6 (C-1), 58.9 (C-4), 57.4 (CH2 PMB), 55.4 (OMe PMB) 33.8 (CH2 propenyl) ppm. IR (thin film): equation imagemax. = 3030, 2865, 1609, 1511, 1454, 1364, 1243, 1072, 1029, 908, 825, 733, 695 cm–1. [α]D20 = 0.5 (c = 3.8, CHCl3). HRMS: found 684.3680 [M + H]+, calcd. for [C45H49NO5 + H]+ 684.3684.

(1R)-2,3,4,6-Tetra-O-benzyl-1-deoxy-1-{[(9H-fluoren-9-ylmethoxy)carbonyl](4-methoxybenzyl)amino}-1-C-(prop-2-enyl)-D-glucitol (52): Aqueous NaHCO3 (10 wt.-%, 6.3 mL, 15 mmol) was added to a solution of 50 (2.1 g, 3.0 mmol) in DCM (9 mL) and (9H-fluoren-9-ylmethoxy)carbonyl chloride (0.93 g, 3.6 mmol). The mixture was stirred vigorously for 16 h. The mixture was diluted with EtOAc (100 mL) and washed with water (2 × 100 mL). The organic layer was dried (MgSO4), concentrated and purified by silica gel column chromatography (0 % → 20 %, EtOAc in PE) to afford 52 (2.602 g, 2.75 mmol) in 91 % yield as a white foam. Rf = 0.50 (EtOAc/PE, 1:2). 1H NMR (500 MHz, C6D6, 343 K): δ = 7.61–6.66 (m, 32 H, CHAr Bn/PMB/Fmoc), 5.56–5.29 (m, 1 H, =CH propenyl), 4.97–3.64 (m, 21 H, 6 × CH2 Bn/PMB/Fmoc, CH Fmoc, =CH propenyl, =CH2, propenyl, 1-H, H2, 3-H, 4-H, CH2-6), 3.45–3.36 (m, 3 H, OMe PMB), 2.71–2.12 (m, 2 H, CH2 propenyl) ppm. 13C NMR (125 MHz, C6D6, 343 K): δ = 159.5, 145.6, 144.9, 142.1, 141.5, 139.7, 139.4, 139.0, 136.6, 135.9, 134.6, 134.1, 133.1, 130.5, 129.8, 129.6, 129.3, 129.1, 128.8, 128.7, 128.4, 128.26, 128.21, 128.0, 127.9, 127.8, 127.5, 127.3, 125.5, 125.4, 124.6, 120.4, 120.3, 117.3, 114.4, 114.2, 81.0, 79.7, 78.0, 76.0, 75.4, 74.6, 74.3, 74.2, 73.9, 72.3, 67.5, 65.6, 55.2, 51.1, 48.3, 35.4 ppm. [α]D20 = 14.5 (c = 4.9, CHCl3).IR (thin film): equation imagemax. = 3065, 3031, 2866, 1685, 1611, 1513, 1453, 1412, 1301, 1244, 1177, 1089, 1065, 1029, 916, 735, 696 cm–1. HRMS: found 946.4292 [M + Na]+, calcd. for [C45H51NO6 + Na]+ 946.4289.

(1R)-2,3,4,6-Tetra-O-benzyl-1-deoxy-1-{[(9H-fluoren-9-ylmethoxy)carbonyl](4-methoxybenzyl)amino}-1-C-(prop-2-enyl)-D-arabino-hex-5-ulose (53): Dess–Martin periodinane (0.73 g, 1.7 mmol) was added to a solution of 52 (1.0 g, 1.43 mmol) in DCM (17 mL). After the reaction mixture had been stirred for 6 h, satd. aq. Na2S2O3 (5 mL) and satd. aq. NaHCO3 (5 mL) were added and vigorously mixed for 10 min. The mixture was diluted with EtOAc (50 mL) and washed with water (2 × 15 mL). The organic phase was dried (MgSO4), concentrated and purified by silica gel column chromatography (0 % → 20 % EtOAc in PE) to afforded 53 (1.32 g, 1.4 mmol) in 98 % yield as a white foam. Rf = 0.55 (EtOAc/PE, 1:2). 1H NMR (500 MHz, C6D6): δ = 7.96–6.69 (m, 32 H, CHAr Bn/PMB/Fmoc), 5.87–3.53 (m, 21 H, 6 × CH2 Bn/PMB/Fmoc, CH Fmoc, =CH propenyl, =CH2, propenyl, 1-H, H2, 3-H, 4-H, CH2-6), 3.43 (s, 3 H, OMe PMB), 2.88–2.03 (m, 2 H, CH2 propenyl) ppm. 13C NMR (125 MHz, C6D6): δ = 207.1, 159.6, 144.9, 142.24, 142.21, 139.3, 138.8, 138.4, 135.8, 129.5, 129.2, 129.1, 128.98, 128.92, 128.7, 128.6, 127.8, 127.7, 127.3, 125.6, 120.6, 118.0, 114.2, 114.1, 75.4, 73.6, 55.1, 48.1 ppm. IR (thin film): equation imagemax. = 2934, 1728, 1693, 1611, 1513, 1453, 1412, 1301, 1246, 1177, 1106, 1029, 917, 738, 698 cm–1. HRMS: found 944.4140 [M + Na]+, calcd. for [C60H59NO8 + Na]+ 944.4133.

(1R)-2,3,4,6-Tetra-O-benzyl-N-[(4-methoxybenzyl)amino]-1-C-(prop-2-enyl)-1-deoxynojirimycin (54): Piperidine (75 μL, 0.76 mmol) was added to a cooled (0 °C) solution of 53 (0.5 g, 0.725 mmol) in DMF (5 mL). The resulting mixture was stirred at 0 °C for 30 min. The mixture was diluted with Et2O (50 mL) and washed with water (2 × 50 mL). The organic layer was dried (MgSO4) and concentrated. The residue was dissolved in MeOH (15 mL), and the mixture was cooled to –35 °C. The mixture was acidified to pH = 5 with AcOH followed by the successive addition of Na2SO4 (280 mg, 2 mmol) and NaCNBH3 (160 mg, 2.53 mmol). The reaction mixture was stirred at –20 °C under argon for 16 h. The mixture was diluted with EtOAc (50 mL) and washed with satd. aq. NaHCO3 (2 × 50 mL). The organic layer was dried (MgSO4), concentrated and purified by silica gel column chromatography (0 % → 10 % EtOAc in PE) to provide 54 (403 mg, 0.59 mmol) in 81 % yield as a colourless oil. Rf = 0.30 (EtOAc/PE, 1:6.5). 1H NMR (600 MHz, CDCl3): δ = 7.38–7.15 (m, 22 H, HAr Bn/PMB), 6.80 (d, J = 8.7 Hz, 2 H, HAr PMB), 5.76–5.67 (m, 1 H, =CH propenyl), 5.02–4.92 (m, 3 H, =CH2 propenyl, CHH Bn), 4.90 (d, J = 10.7 Hz, 1 H, CHH Bn), 4.80 (d, J = 10.9 Hz, 1 H, CHH Bn), 4.58 (d, J = 10.7 Hz, 1 H, CHH Bn), 4.51–4.46 (m, 2 H, CH2 Bn), 4.38–4.34 (m, 2 H, CH2 Bn), 3.95 (d, J = 13.9 Hz, 1 H, CHH PMB), 3.84 (dd, J = 4.9, 10.4 Hz, 1 H, 6a-H), 3.81–3.69 (m, 8 H, 6b-H, 4-H, 3-H, 2-H, CHH PMB, OMe PMB), 3.07–3.04 (m, 2 H, 1-H, 5-H), 2.42–2.33 (m, 2 H, CH2 propenyl) ppm. 13C NMR (150 MHz, CDCl3): δ = 158.5 (p-Cq PMB), 139.2, 138.8, 138.6, 138.3 (4 × Cq Bn), 137.9 (=CH propenyl), 132.7 (Cq PMB), 129.6 (=CH propenyl), 128.5, 128.5, 128.4, 128.1, 128.0, 128.0, 127.7, 127.6, 127.6, 127.6 (CHAr Bn/PMB), 115.4 (=CH2 propenyl), 113.6 (CHAr PMB), 84.2, 79.3, 78.8 (C-2, C-3, C-4), 75.6, 75.3, 73.0, 72.2 (4 × CH2 Bn), 68.5 (C-6), 57.5, 56.6 (C-5, C-1), 55.3 (OMe PMB), 52.2 (CH2 PMB), 29.1 (CH2 propenyl) ppm. IR (thin film): equation imagemax. = 3031, 2862, 1610, 1511, 1454, 1362, 1301, 1244, 1171, 1091, 1066, 1028, 908, 827, 733, 696 cm–1. [α]D20 = 21.5 (c = 3.7, CHCl3). HRMS: found 684.3679 [M + H]+, calcd. for [C45H49NO5 + H]+ 684.3684.

(1R)-2,3,4,6-Tetra-O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxy-1-C-(prop-2-enyl)-L-ido-nojirimycin (55): Compound 51 (3.02 g, 4.41 mmol) was subjected to general procedure E to provide 55 (2.32 g, 3.31 mmol) in 75 % yield as a colourless oil after purification (0 % → 5 % EtOAc in toluene). Rf(intermediate amine) = 0.60 (EtOAc/PE, 2:1); Rf(55) = 0.53 (EtOAc/PE, 1:4). 1H NMR (500 MHz, C6D6, 343 K, major rotamer): δ = 7.38–6.96 (m, 25 H), 6.17–5.93 (m, 1 H, =CH propenyl), 5.25–4.80 (m, 7 H, 5-H, CH2 Z, CH2 Bn, =CH2 propenyl), 4.66–4.28 (m, 7 H, 1-H, 3 × CH2 Bn), 3.95–3.89 (m, 2 H, 3-H, 6a-H), 3.74 (dd, J = 6.1, 10.1, 1 Hz, 6b-H), 3.54 (dd, J = 7.3, 9.3 Hz, 1 H, 4-H), 3.47 (dd, J = 6.7, 9.2 Hz, 1 H, 2-H), 2.82-2.71 (m, 1 H, CHH propenyl), 2.54–2.40 (m, 1 H, CHH propenyl) ppm. 13C NMR (125 MHz, C6D6, 343 K, major rotamer): δ = 156.6 (C=O Z), 140.1, 139.2, 139.1, 137.6 (Cq Bn/Z), 137.4 (=CH propenyl), 128.8, 128.7, 128.6, 128.4, 128.3, 128.28, 128.22, 128.1, 128.0, 127.9, 127.8, 127.7 (CHAr Bn/Z), 116.5 (=CH2 propenyl), 80.7 (C-2), 80.0 (C-4), 79.2 (C-3), 75.7, 73.7, 73.5, 73.4 (CH2 Bn), 70.3 (C-6), 68.1 (CH2 Z), 54.4 (C-1), 53.8 (C-5), 34.7 (CH2 propenyl) ppm. IR (thin film): equation imagemax. = 3065, 3031, 2868, 1696, 1496, 1453, 1416, 1364, 1308, 1210, 1092, 1026, 995, 911, 733, 695 cm–1. [α]D20 = –9.9 (c = 5.5, CHCl3). HRMS: found 698.3476 [M + H]+, calcd. for [C45H48NO6 + H]+ 698.3476.

(1R)-2,3,4,6-Tetra-O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxy-1-C-(prop-2-enyl)nojirimycin (56): Compound 54 (2.07 g, 3.03 mmol) was subjected to general procedure E to provide 56 (1.38 g, 1.98 mmol) in 65 % yield as a colourless oil after purification (0 % → 5 % EtOAc in toluene). Rf(intermediate amine) = 0.65 (EtOAc/PE, 2:1); Rf(56) = 0.56 (EtOAc/PE, 1:4). 1H NMR (600 MHz, CDCl3, major rotamer): δ = 7.44–7.16 (m, 25 H, CHAr Bn Z), 5.85 (s, 1 H, =CH propenyl), 5.14–5.09 (m, 2 H, CH2 Z), 4.98–4.88 (m, 2 H, =CH2 propenyl), 4.68–4.33 (m, 9 H, 1-H, 4 × CH2 Bn), 4.28–4.23 (m, 1 H, 5-H), 3.98 (dd, J = 2.0, 3.6 Hz, 1 H, 4-H), 3.88 (d, J = 8.3 Hz, 1 H, 3-H), 3.75 (dd, J = 5.5, 8.1 Hz, 1 H, 2-H), 3.66 (s, 1 H, 6a-H), 3.56 (s, 1 H, 6b-H), 2.65–2.59 (m, 1 H, CHH propenyl), 2.59–2.52 (m, 1 H, CHH propenyl) ppm. 13C NMR (150 MHz, CDCl3): δ = 156.0 (C=O Z), 138.4, 138.3, 138.3, 137.9 (Cq Bn), 136.7 (=CH propenyl), 136.5 (Cq Z), 128.6, 128.57, 128.52, 128.45, 128.41, 128.3, 128.2, 128.17, 128.12, 128.05, 128.02, 127.98, 127.95, 127.86, 127.82, 127.79, 127.74, 127.5, 127.3 (CHAr Bn/Z), 116.1 (=CH2 propenyl), 81.5 (C-3), 80.6 (C-2), 77.0 (C-4), 73.0, 72.5, 72.3, 71.7 (4 × CH2 Bn), 69.9 (C-6), 67.3 (CH2 Z), 54.6 (C-5), 52.8 (C-1), 34.1 (CH2 propenyl) ppm. IR (thin film): equation imagemax. = 3032, 2871, 1698, 1495, 1453, 1417, 1270, 1206, 1093, 1026, 995, 913, 734, 694 cm–1. [α]D20 = 9.2 (c = 4.6, CHCl3). HRMS: found 698.3477 [M + H]+, calcd. for [C45H48NO6 + H]+ 698.3476.

α/β-Mixture of 2,3,4-Tri-O-benzyl-D-xylopyranose (58): A dry and cooled (0 °C) solution of D-xylose (57; 10 g, 66.6 mmol) in DMF (333 mL) was charged with sodium hydride (60 % in mineral oil, 11.72 g, 293 mmol) and stirred at 0 °C for 1 h. Next, benzyl bromide (34 mL, 286 mmol) was added to the suspension over a period of 5 min. The reaction mixture was stirred for 20 h and warmed to room temp. The reaction mixture was quenched with water and concentrated. The residue was dissolved in Et2O (400 mL) and washed successively with water (300 mL) and satd. aq. NaCl (200 mL). The organic phase was dried (Na2SO4) and concentrated to provide a yellow oil that was used crude in the next reaction [Rf(tetrabenzylated intermediate) = 0.69 (EtOAc/PE, 1:3)]. The crude intermediate was suspended in a mixture of AcOH (210 mL) and aq. 1 M HCl (93 mL) and refluxed at 105 °C for 4 h, after which TLC analysis indicated complete consumption of the starting material. The reaction mixture was concentrated and coevaporated with toluene (2 × 200 mL). The residue was transferred into aq. satd. NaHCO3 (400 mL) and extracted with EtOAc (3 × 300 mL). The combined organic phases were dried (Na2SO4) and concentrated. The product was precipitated from PE/EtOAc to provide 58 (11.34 g, 27 mmol) as a white fluffy solid after drying at 50 °C for 20 h. The mother liquor was concentrated and purified by silica gel column chromatography (10 % → 33 % EtOAc in PE) to provide additional 49 (4.10 g, 9.76 mmol) and an overall yield of 55 %. Rf = 0.20 (EtOAc/PE, 1:3). 1H NMR (400 MHz, CDCl3, major α-anomer): δ = 7.40–7.25 (m, 15 H, HAr Bn), 5.08 (d, J = 2.1 Hz, 1 H, 1α-H), 4.90–4.82 (m, 2 H, CH2 Bn), 4.76–4.60 (m, 4 H, 2 × CH2 Bn), 3.87 (dd, J = 9.1 Hz, 1 H, 3-H), 3.79 (dd, J = 10.6 Hz, 1 H, 5a-H), 3.65 (dd, J = 4.8, 11.8 Hz, 1 H, 5b-H), 3.59–3.50 (m, 1 H, 4-H), 3.47 (d, J = 8.9 Hz, 1 H, 2-H), 3.29 (s, 1 H, OH-1) ppm. 13C NMR (100 MHz, CDCl3, α/β-mixture): δ = 138.8, 138.4, 138.0 (Cq Bn), 128.7, 128.6, 128.5, 128.2, 127.9, 127.8 (CHAr Bn), 97.9 (C-1β), 91.6 (C-1α), 83.4 (C-3β), 82.6 (C-2β), 80.7 (C-3α), 79.6 (C-2α), 77.8 (C-4β), 77.7 (C-4α), 75.7 (CH2 Bn α), 75.6 (CH2 Bn β), 74.9 (CH2 Bn β), 73.5 (CH2 Bn α), 73.4 (CH2 Bn β), 73.3 (CH2 Bn α), 63.9 (C-5β), 60.4 (C-5α) ppm. IR (thin film): equation imagemax. = 3040, 2870, 1599, 1454, 1357, 1071, 1060, 747, 693 cm–1. [α]D20 = +16.3 (c = 0.6, CHCl3). MS (ESI): found 421.3 [M + H]+, calcd. for [C26H28O5 + H]+ 421.2.

α/β-Mixture of 2,3,4-Tri-O-benzyl-N-(4-methoxybenzyl)-D-xylopyranosylamine (59): A suspension of 58 (2.1 g, 5 mmol), (p-methoxybenzyl)amine (6.5 mL, 50 mmol), (±)-camphor-10-sulfonic acid (1.162 g, 5 mmol) and Na2SO4 (2.8 g, 20 mmol) in toluene (50 mL) was refluxed for 2.5 h, after which TLC analysis indicated complete consumption of 58 (Rf = 0.20 in EtOAc/PE, 1:3). The reaction mixture was cooled to room temp., diluted with EtOAc (200 mL) and successively washed with aq. 1 M HCl (2 × 200 mL), satd. aq. NaHCO3 (2 × 100 mL) and satd. aq. NaCl (100 mL). The organic phase was dried (Na2SO4) and concentrated to provide 59 as a white solid that was used crude in the subsequent reaction. A small sample of crude 59 was purified by silica gel column chromatography (10 % → 25 % EtOAc in PE) for characterization. Rf = 0.55 (EtOAc/PE, 1:3). 1H NMR (400 MHz, CDCl3): δ = 7.44–7.20 (m, 34 H, HAr-α/β Bn/PMB), 6.90–6.80 (m, 4 H, HAr-α/β PMB), 4.99–4.58 (m, 11 H, CH2-α/β Bn), 4.50–4.44 (m, 2 H, 1α-H, CHH-α Bn), 4.03–3.75 (m, 14 H, 1β-H, OMe-α/β PMB, CH2-α/β PMB), 3.63–3.56 (m, 4 H), 3.56–3.44 (m, 4 H), 3.24–3.13 (m, 2 H), 2.05–1.79 (m, 1 H, NHPMB), 1.75–1.48 (m, 1 H, NHPMB) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.8, 158.8 (p-Cq-α/β PMB), 138.9, 138.7, 138.7, 138.5, 138.3 (Cq-α/β Bn), 132.5, 132.4 (Cq-α/β PMB), 129.6, 129.5, 128.7, 128.6, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8 (CHAr-α/β Bn/PMB), 114.0, 113.9 (CHAr-α/β PMB), 90.7 (C-1β), 84.2 (C-1α), 85.2, 82.3, 80.2, 79.3, 78.6, 77.7 (H-2, H-3, H-4 α/β), 75.9, 75.3, 75.2, 73.5, 73.2, 73.1 (CH2-α/β Bn), 65.2 (C-5β), 60.3 (C-5α), 55.5, 55.5 (OMe-α/β PMB), 49.5 (CH2-β PMB), 49.1 (CH2-α PMB) ppm. IR (thin film): equation imagemax. = 3302, 3030, 2861, 1611, 1514, 1455, 1358, 1242, 1179, 1071, 1030, 933, 894, 814, 748, 693 cm–1. [α]D20 = 0.8 (c = 0.5, CHCl3). MS (ESI): found 540.4 [M + H]+, calcd. for [C34H37NO5 + H]+ 540.3.

(1R/S)-2,3,4-Tri-O-benzyl-1-deoxy-1-[(4-methoxybenzyl)amino]-1-C-(prop-2-enyl)-D-xylitol (60): Allylmagnesium bromide (1 M in Et2O, 23 mL, 23 mmol) was slowly added over a period of 2 min to a dry and cooled (0 °C) solution of 59 (2.14 g, 2.3 mmol) in THF (23 mL). The reaction mixture was stirred at 0 °C for an additional 5 min and then warmed to room temp. After stirring at room temp. for 1 h, the reaction was quenched with satd. aq. NH4Cl. The mixture was poured into additional satd. aq. NH4Cl (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic phases were dried (Na2SO4), concentrated and purified by silica gel column chromatography (10 % → 50 % EtOAc in PE) to provide 60 [1.31 g, 2.25 mmol, inseparable (R)/(S) = 5:1 isomer mixture] in 97 % yield as a colourless oil. Rf = 0.11 (EtOAc/PE, 1:3). 1H NMR (300 MHz, CDCl3): δ = 7.38–7.18 (m, 15 H, HAr Bn), 7.16 (d, J = 8.6 Hz, 2 H, HAr PMB), 6.79 (d, J = 8.7 Hz, 2 H, HAr PMB), 5.71–5.51 (m, 1 H, =CH propenyl), 5.01–4.91 (m, 2 H, =CH2 propenyl), 4.80 (d, J = 11.4 Hz, 1 H, CHH Bn), 4.75 (d, J = 11.4 Hz, 1 H, CHH Bn), 4.67 (d, J = 11.4 Hz, 1 H, CHH Bn), 4.58–4.50 (m, 2 H, CHH Bn, CHH Bn), 4.37 (d, J = 11.7 Hz, 1 H, CHH Bn), 4.07 (dd, J = 4.1, 7.0 Hz, 1 H, 3-H), 3.81–3.60 (m, 7 H, 2-H, CH2-5, CHH PMB, OMe PMB), 3.51 (d, J = 12.7 Hz, 1 H, CHH PMB), 3.44–3.35 (m, 1 H, 4-H), 2.64–2.57 (m, 1 H, 1-H), 2.48–2.31 (m, 2 H, CH2 propenyl) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.5 (p-Cq PMB), 138.7, 138.3, 138.2 (Cq Bn), 136.0 (=CH propenyl), 132.5 (Cq PMB), 129.6, 129.2, 128.2, 127.9, 127.8, 127.6, 127.5, 127.3 (CHAr Bn/PMB), 116.9 (=CH2 propenyl), 113.5 (CHAr PMB), 79.9, 79.8, 78.5 (C-2, C-3, C-4), 74.5, 74.1, 71.9 (CH2 Bn), 61.5 (C-5), 56.0 (C-1), 55.0 (OMe PMB), 50.2 (CH2 PMB), 35.1 (CH2 propenyl) ppm. IR (thin film): equation imagemax. = 2868, 1610, 1513, 1454, 1245, 1028, 913, 824, 733, 696 cm–1. [α]D20 = –17.7 (c = 3.3, CHCl3). HRMS: found 582.3209 [M + H]+, calcd. for [C37H44NO5 + H]+ 582.3214.

(1R)-2,3,4-Tri-O-benzyl-1,5-dideoxy-1,5-imino-N-[(4-methoxybenzyl)amino]-1-C-(prop-2-enyl)-D-xylitol (61): Diethyl azodicarboxylate (1.8 mL, 3.92 mmol, 2.2 M in toluene) was added over a period of 1 min to a dry solution of 60 (1.14 g, 1.96 mmol) and PPh3 (1.03 g, 3.92 mmol) in DCM (10 mL). The reaction mixture was stirred for 20 h and subsequently quenched by addition of water. The mixture was concentrated and purified by silica gel column chromatography (0 % → 20 % EtOAc in toluene) to produce 61 (976 mg, 1.73 mmol) in 88 % yield as a colourless oil.45Rf = 0.60 (EtOAc/PE, 1:4). 1H NMR (400 MHz, CDCl3): δ = 7.40–7.08 (m, 17 H, HAr Bn/PMB), 6.78 (d, J = 8.7 Hz, 2 H, HAr PMB), 5.92–5.79 (m, 1 H, =CH propenyl), 5.14–4.37 (m, 8 H, =CH2 propenyl, 3 × CH2 Bn), 3.73–3.46 (m, 8 H, 2-H, 3-H, 4-H, OMe PMB, CH2 PMB), 3.13 (dt, J = 4.9, 7.6 Hz, 1 H, 1-H), 2.78 (dd, J = 5.2, 12.3 Hz, 1 H, 5a-H), 2.53 (dd, J = 10.5, 11.9 Hz, 1 H, 5b-H), 2.49–2.32 (m, 2 H, CH2 propenyl) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.6 (p-Cq PMB), 139.2, 138.6, 138.5 (3 × Cq Bn), 138.2 (=CH propenyl), 131.0 (Cq PMB), 129.2, 128.1, 128.0, 127.7, 127.6, 127.5, 127.3, 127.2 (CHAr Bn/PMB), 115.3 (=CH2 propenyl), 113.5 (CHAr PMB), 82.6, 80.3, 78.2 (C2, C-3, C-4), 75.2, 72.5, 72.2 (3 × CH2 Bn), 59.5 (C-2), 58.0 (CH2 PMB), 54.8 (OMe PMB), 47.7 (C-5), 27.6 (CH2 propenyl) ppm. IR (thin film): equation imagemax. = 3031, 2904, 1610, 1512, 1455, 1364, 1244, 1069, 1029, 908, 822, 734, 696 cm–1. [α]D20 = 27.1 (c = 2.8, CHCl3). HRMS: found 564.3103 [M + H]+, calcd. for [C37H41NO4 + H]+ 544.3108.

(1R)-2,3,4-Tri-O-benzyl-N-[(benzyloxy)carbonyl]-1,5-dideoxy-1,5-imino-1-C-(prop-2-enyl)-D-xylitol (62): Compound 61 (1.42 g, 2.52 mmol) was subjected to general procedure E to provide 62 (1.27 g, 2.20 mmol) in 87 % yield as a colourless oil after purification (0 % → 5 % EtOAc in toluene). Rf(intermediate amine) = 0.11 (EtOAc/PE, 1:1 + 2 % Et3N); Rf(62) = 0.50 (EtOAc/PE, 1:4). 1H NMR (400 MHz, CDCl3, mixture of rotamers, a/b ≈ 1:1): δ = 7.41–7.20 (m, 40 H, HAra/b Bn Z), 5.78–5.65 (m, 1 H, =CHa propenyl), 5.62–5.50 (m, 1 H, =CHb propenyl), 5.16–4.90 (m, 8 H, CH2a/b Z, =CH2a/b propenyl), 4.89–4.81 (m, 4 H, CH2a/b Bn), 4.77–4.72 (m, 1 H, 1a-H), 4.72–4.59 (m, 8 H, 2 × CH2a/b Bn), 4.45–4.39 (m, 2 H, 1b-H, CHH-5a), 4.17 (dd, J = 5.7, 13.7 Hz, 1 H, CHH-5a), 3.68 (dd, J = 8.6, 8.6 Hz, 2 H, 3a/b-H), 3.60–3.37 (m, 4 H, 2a/b-H, 4a/b-H), 2.80–2.70 (m, 2 H, CH2-5b), 2.64–2.50 (dd, 2 H, CHHa/b propenyl), 2.35–2.25 (dt, 2 H, CHHa/b propenyl) ppm. 13C NMR (100 MHz, CDCl3, mixture of rotamers, a/b ≈ 1:1): δ = 155.7, 155.6 (C=Oa/b Z), 138.9, 138.2, 138.2 (3 × Cqa/b Bn), 136.7, 136.6 (Cqa/b Z), 134.5, 134.4 (=CHa/b propenyl), 128.65, 128.61, 128.5, 128.4, 128.27, 128.22, 128.1, 128.08, 128.03, 127.96, 127.92, 127.8, 127.7 (CHAra/b Bn Z), 117.6, 117.4 (=CH2a/b propenyl), 82.2, 82.0(C-3a/b), 79.8 (C-2a/b), 78.4, 78.3 (C-4a/b), 75.8 (CH2a/b Bn), 73.3 (CH2a Bn), 73.2 (CH2a/b Bn), 72.8 (CH2b Bn), 67.6, 67.5 (CH2a/b Z), 53.0, 52.3 (C-1a/b), 41.1, 40.8 (C-5a/b), 29.8, 29.7 (CH2a/b propenyl) ppm. IR (thin film): equation imagemax. = 3032, 2872, 1698, 1495, 1453, 1423, 1349, 1314, 1209, 1095, 1026, 991, 913, 734, 695 cm–1. [α]D20 = 13.8 (c = 3.4, CHCl3). HRMS: found 578.2899 [M + H]+, calcd. for [C37H39NO5 + H]+ 578.2801.

(1R)-1-C-[(E/Z)-4-(Adamant-1-ylmethoxy)but-2-enyl]-2,3,4,6-tetra-O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxy-L-ido-nojirimycin (63): Compound 55 (275 mg, 395 μmol) underwent a cross-metathesis reaction (see general procedure F) with alkene 45 to produce 63 (306 mg, 349 μmol) in 88 % yield as a mixture of (E)/(Z) isomers in an unassignable ca. 2:1 ratio after purification (0 % → 10 % EtOAc in PE). Rf = 0.47 (EtOAc/PE, 1:5). 1H NMR [400 MHz, CDCl3, (E)/(Z) isomers]: δ = 7.45–7.19 (m, 25 H, HAr Bn Z H), 5.83–5.40 (m, 2 H, =CH-2 butenyl, =CH-3 butenyl), 5.23–4.93 (m, 3 H, 5-H, CH2 Z), 4.93–4.39 (m, 9 H, 1-H, 4 × CH2 Bn), 3.99–3.45 (m, 7 H, 2-H, 3-H, 4-H, CH2-6, CH2-4 butenyl), 2.98–2.84 (m, 2 H, OCH2-Ada), 2.75–2.52 (m, 2 H, CH2-4 butenyl), 2.42–2.24 (m, 2 H, CH2-1 butenyl), 2.06–1.84 (m, 3 H, 3 × CH Ada), 1.83–1.43 (m, 12 H, 6 × CH2 Ada) ppm. 13C NMR [100 MHz, CDCl3, (E)/(Z) isomers]: δ = 156.4 (C=O Z), 139.0, 138.4 (Cq Bn), 131.3, 131.1, 129.9, 129.3 [=CH (E)/(Z) butenyl], 128.6, 128.5, 128.5, 128.2, 128.1, 127.9, 127.7, 127.5 [=CH (E)/(Z) butenyl, CHAr Bn/Z], 81.3 (OCH2-Ada), 80.2 (C-2), 79.6 (C-4), 78.7 (C-3), 75.9, 74.1, 73.6, 73.4, 73.1 (CH2 Bn), 72.2 (CH2-4 butenyl), 69.6 (C-6), 67.8 (CH2 Z), 54.1, 53.5, 53.2, 52.7 (C-1, C-5), 40.0 (CH2 Ada), 37.4 (CH2 Ada), 34.2 (Cq Ada), 33.0, 33.0 (CH2-1 butenyl), 28.5 (CH Ada) ppm. IR (thin film): equation imagemax. = 3032, 2900, 2848, 1698, 1453, 1403, 1360, 1302, 1209, 1069, 1026, 734, 695 cm–1. [α]D20 = –6.0 (c = 0.6, CHCl3). HRMS: found 876.4840 [M + H]+, calcd. for [C57H65NO7 + H]+ 876.4834.

(1R)-1-C-[(E/Z)-5-(Adamant-1-ylmethoxy)pent-2-enyl]-2,3,4,6-tetra-O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxy-L-ido-nojirimycin (64): Compound 55 (275 mg, 395 μmol) underwent a cross-metathesis reaction (see general procedure F) with alkene 46 to produce 64 (260 mg, 292 μmol) in 74 % yield as a mixture of (E)/(Z) isomers in an unassignable ca. 2:1 ratio after purification (0 % → 10 % EtOAc in PE). Rf = 0.50 (EtOAc/PE, 1:5). 1H NMR [400 MHz, CDCl3, (E)/(Z) isomers]: δ = 7.48–7.14 (m, 25 H, HAr Bn Z H H), 5.87–5.23 (m, 2 H, =CH-2 pentenyl, =CH-3 pentenyl), 5.23–4.92 (m, 3 H, 5-H, CH2 Z), 4.92–4.36 (m, 9 H, 1-H, 4 × CH2 B), 3.97–3.44 (m, 5 H, 2-H, 3-H, 4-H, CH2-6), 3.40–3.17 (m, 2 H, CH2-5 pentenyl), 2.99–2.86 (m, 2 H, OCH2-Ada), 2.77–2.47 (m, 1 H, CHH-1 pentenyl), 2.40–2.09 (m, 3 H, CHH-1 pentenyl, CH2-4 pentenyl), 2.09–1.87 (m, 3 H, 3 × CH Ada), 1.81–1.43 (m, 12 H, 6 × CH2 Ada) ppm. 13C NMR [100 MHz, CDCl3, (E)/(Z) isomers]: δ = 156.4 (C=O Z), 138.9, 138.5, 138.2, 138.1 (Cq Bn), 136.6 (Cq Z), 131.2, 130.9 [=CH (E)/(Z) pentenyl], 128.5, 128.4, 128.3, 128.1, 128.07, 128.03, 127.99, 127.92, 127.7, 127.6, 127.3 (CHAr Bn Z), 126.9, 126.7, 125.6 [=CH (E)/(Z) pentenyl], 81.9 (OCH2-Ada), 80.1, 79.5, 79.4, 79.2, 78.9, 78.8, 78.7, 78.6 (C-2, C-3, C-4), 75.8, 75.7, 73.9, 73.4, 73.1, 72.9, 72.5, 72.2, 72.0, 71.9, 71.4 (CH2 Bn, CH2-5 pentenyl), 69.1 (C-6), 67.7 (CH2 Z), 54.6, 53.9, 53.6, 53.2, 52.5 (C-1, C-5), 39.8, 39.6, 39.1 (CH2 Ada), 37.3, 37.2, 37.2 (CH2 Ada), 34.5, 34.1, 33.7 (Cq Ada), 32.7 (CH2-1 pentenyl), 28.4, 28.2, 28.1 (CH Ada, CH2-4 pentenyl) ppm. IR (thin film): equation imagemax. = 2902, 2849, 1698, 1453, 1416, 1271, 1093, 1026, 734, 695 cm–1. [α]D20 = –7.8 (c = 1.0, CHCl3). HRMS: found 890.4996 [M + H]+, calcd. for [C58H67NO7 + H]+ 890.4990.

(1R)-1-C-[(E/Z)-6-(Adamant-1-ylmethoxy)hex-2-enyl]-2,3,4,6-tetra-O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxy-L-ido-nojirimycin (65): Compound 55 (275 mg, 395 μmol) underwent a cross-metathesis reaction (see general procedure F) with alkene 47 to produce 65 (312 mg, 345 μmol) in 87 % yield as a mixture of (E)/(Z) isomers in an unassignable ca. 2:1 ratio after purification (0 % → 10 % EtOAc in PE). Rf = 0.52 (EtOAc/PE, 1:5). 1H NMR [400 MHz, CDCl3, (E)/(Z) isomers]: δ = 7.45–7.14 (m, 25 H, HAr Bn Z H), 5.58–5.24 (m, 2 H, =CH-2 hexenyl, =CH-3 hexenyl), 5.23–4.98 (m, 3 H, 5-H, CH2 Z), 4.94–4.37 (m, 9 H, 1-H, 4 × CH2 Bn), 3.95–3.45 (m, 5 H, 2-H, 3-H, 4-H, CH2-6), 3.38–3.26 (m, 2 H, CH2-6 hexenyl), 2.93 (s, 2 H, OCH2-Ada), 2.79–2.51 (m, 1 H, CHH-1 hexenyl), 2.32–2.18 (m, 1 H, CHH-1 hexenyl), 2.09–1.80 (m, 5 H, CH2-4 hexenyl, 3 × CH Ada), 1.77–1.40 (m, 16 H, CH2-5 hexenyl, 6 × CH2 Ada) ppm. 13C NMR [100 MHz, CDCl3, (E)/(Z) isomers]: δ = 156.5 (C=O Z), 139.0, 138.5, 138.4, 138.3, 137.9 (Cq Bn), 136.8, 136.6 (Cq Z), 132.4, 132.3, 130.9 [=CH (E)/(Z) hexenyl], 128.6, 128.5, 128.4, 128.3, 128.2, 128.2, 128.1, 127.9, 127.8, 127.7, 127.5, 127.4 [=CH (E)/(Z) hexenyl, CHAr Bn Z], 127.1, 127.0 [=CH(E)/(Z) hexenyl], 82.0 (OCH2-Ada), 80.3, 80.2 (C-2), 79.5 (C-4), 78.7, 78.7 (C-3), 75.9, 75.8, 73.6, 73.4, 73.3, 73.1 (CH2 Bn), 71.3, 71.2, 71.1 (CH2-6 hexenyl), 69.9, 69.7 (C-6), 67.8, 67.7 (CH2 Z), 55.5, 54.3, 53.8, 53.4, 53.2, 52.7 (C-1, C-5), 39.9 (CH2 Ada), 37.4 (CH2 Ada), 34.3 (Cq Ada), 33.2, 32.8 (CH2-1 hexenyl), 29.6, 29.3 (CH2 hexenyl), 28.5 (CH Ada), 27.6, 27.2 (CH2 hexenyl), 24.3, 24.2 (CH2 hexenyl) ppm. IR (thin film): equation imagemax. = 3031, 2901, 2848, 1698, 1453, 1416, 1364, 1273, 1094, 1026, 734, 695 cm–1. [α]D20 = –10.5 (c = 2.0, CHCl3). HRMS: found 904.5153 [M + H]+, calcd. for [C59H69NO7 + H]+ 904.5147.

(1R)-1-C-[(E/Z)-4-(Adamant-1-ylmethoxy)but-2-enyl]-2,3,4,6-tetra-O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxynojirimycin (66): Compound 56 (275 mg, 395 μmol) underwent a cross-metathesis reaction (see general procedure F) with alkene 45 to produce 66 (303 mg, 346 μmol) in 87 % yield as a 3.3:1 mixture of (E)/(Z) isomers after purification (0 % → 10 % EtOAc in PE). Rf = 0.51 (EtOAc/PE, 1:5). 1H NMR [400 MHz, CDCl3, (E) isomer]: δ = 7.45–7.19 (m, 25 H, HAr Bn Z), 5.74–5.40 (m, 2 H, =CH-2 butenyl, =CH-3 butenyl), 5.21–5.06 (m, 2 H, CH2 Z), 4.72–4.38 (m, 8 H, 4 × CH2 Bn), 4.33 (s, 1 H, 1-H), 4.22 (s, 1 H, 5-H), 4.00–3.70 (m, 5 H, 2-H, 3-H, 4-H, CH2-4 butenyl), 3.68–3.51 (m, 2 H, CH2-6), 2.89 (s, 2 H, OCH2-Ada), 2.66–2.47 (m, 2 H, CH2-1 butenyl), 1.93 (s, 3 H, 3 × CH Ada), 1.73–1.45 (m, 12 H, 6 × CH2 Ada) ppm. 13C NMR [100 MHz, CDCl3, (E) isomer]: δ = 156.0 (C=O Z), 138.5, 138.4, 138.4, 138.0 (4 × Cq Bn), 136.7 (Cq Z), 131.4 [=CH-2 (E) isomer butenyl], 130.3 [=CH-2 (Z) isomer butenyl], 128.8, 128.77, 128.74, 128.69, 128.64, 128.58, 128.52, 128.51, 128.36, 128.33, 128.28, 128.24, 128.05, 128.02, 127.9, 127.8, 127.6, 127.4 [=CH-3 (E)/(Z) butenyl, CHAr Bn Z], 81.6 (C-3), 81.2 (OCH2-Ada), 80.8 (C-2), 77.2 (C-4), 73.1, 72.7, 72.4, 72.3, 71.8 (CH2 Bn, CH2-4 butenyl), 70.0 (C-6), 67.4 (CH2 Z), 54.7 (C-5), 53.1 (C-1), 39.9 (CH2 Ada), 37.4 (CH2 Ada), 34.2 (Cq Ada), 32.8 (CH2-1 butenyl), 28.5 (CH Ada) ppm. IR (thin film): equation imagemax. = 3032, 2900, 2848, 1698, 1453, 1403, 1302, 1209, 1069, 1026, 734, 695 cm–1. [α]D20 = 6.5 (c = 2.8, CHCl3). HRMS: found 876.4840 [M + H]+, calcd. for [C57H65NO7 + H]+ 876.4834.

(1R)-1-C-[(E/Z)-5-(Adamant-1-ylmethoxy)pent-2-enyl]-2,3,4,6-tetra-O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxynojirimycin (67): Compound 56 (275 mg, 395 μmol) underwent a cross-metathesis reaction (see general procedure F) with alkene 46 to produce 67 (289 mg, 325 μmol) in 82 % yield as a 2.5:1 mixture of (E)/(Z) isomers after purification (0 % → 10 % EtOAc in PE). Rf = 0.53 (EtOAc/PE, 1:5). 1H NMR [400 MHz, CDCl3, (E) isomer]: δ = 7.47–7.15 (m, 25 H, HAr Bn Z), 5.55–5.29 (m, 2 H, =CH-2 pentenyl, =CH-3 pentenyl), 5.19–5.07 (m, 2 H, CH2 Z), 4.74–4.39 (m, 8 H, 4 × CH2 Bn), 4.39–4.27 (m, 1 H, 1-H), 4.27–4.16 (m, 1 H, 5-H), 3.99–3.91 (m, 1 H, 4-H), 3.88–3.76 (m, 1 H, 3-H), 3.73 (dd, J = 5.5, 9.0 Hz, 1 H, 2-H), 3.71–3.50 (m, 2 H, CH2-6), 3.26 (t, J = 7.1 Hz, 2 H, CH2-5 pentenyl), 2.90 (s, 2 H, OCH2-Ada), 2.62–2.48 (m, 2 H, CH2-1 pentenyl), 2.29–2.09 (m, 2 H, CH2-4 pentenyl), 1.93 (s, 3 H, 3 × CH Ada), 1.77–1.45 (m, 12 H, 6 × CH2 Ada) ppm. 13C NMR [100 MHz, CDCl3, (E) isomer]: δ = 156.2 (C=O Z), 138.5 (Cq Bn), 129.8, 129.5, 129.0, 128.78, 128.74, 128.6, 128.59, 128.54, 128.47, 128.44, 128.3, 128.2, 128.0, 127.9, 127.85, 127.82, 127.7, 127.5, 127.1 [=CH-2, =CH-3 (E)/(Z) pentenyl, CHAr Bn Z], 82.1 (OCH2-Ada), 81.8 (C-3), 80.8 (C-2), 77.3 (C-4), 73.1, 72.7, 72.4, 71.9, 71.7 (CH2 Bn, CH2-5 pentenyl), 70.1 (C-6), 67.4 (CH2 Z), 54.7 (C-5), 53.0 (C-1), 39.9 (CH2 Ada), 37.5 (CH2 Ada), 34.3 (Cq Ada), 33.2 (CH2-1 pentenyl), 28.5 (CH Ada), 28.0 (CH2-4 pentenyl) ppm. IR (thin film): equation imagemax. = 2902, 2849, 1698, 1453, 1404, 1268, 1090, 1069, 1026, 734, 695 cm–1. [α]D20 = 3.4 (c = 1.1, CHCl3). HRMS: found 890.4996 [M + H]+, calcd. for [C58H67NO7 + H]+ 890.4990.

(1R)-1-C-[(E/Z)-6-(Adamant-1-ylmethoxy)hex-2-enyl]-2,3,4,6-tetra-O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxynojirimycin (68): Compound 56 (275 mg, 395 μmol) underwent a cross-metathesis reaction (see general procedure F) with alkene 47 to produce 68 (305 mg, 338 μmol) in 85 % yield as a 2:1 mixture of (E)/(Z) isomers after purification (0 % → 10 % EtOAc in PE). Rf = 0.55 (EtOAc/PE, 1:5). 1H NMR [400 MHz, CDCl3, (E) isomer]: δ = 7.41–7.12 (m, 25 H, HAr Bn Z H), 5.52–5.27 (m, 2 H, =CH-2 hexenyl, =CH-3 hexenyl), 5.16–5.06 (m, 2 H, CH2 Z), 4.68–4.38 (m, 8 H, 4 × CH2 Bn), 4.38–4.28 (m, 1 H, 1-H), 4.24–4.14 (m, 1 H, 5-H), 3.98–3.91 (m, 1 H, 4-H), 3.90–3.83 (m, 1 H, 3-H), 3.77–3.69 (m, 1 H, 2-H), 3.69–3.50 (m, 2 H, CH2-6), 3.36–3.21 (m, 2 H, CH2-6 hexenyl), 2.97–2.87 (m, 2 H, OCH2-Ada), 2.61–2.39 (m, 2 H, CH2-1 hexenyl), 2.07–1.88 (m, 5 H, CH2-4 hexenyl, 3 × CH Ada), 1.77–1.45 (m, 14 H, CH2-5 hexenyl, 6 × CH2 Ada) ppm. 13C NMR [100 MHz, CDCl3, (E) isomer]: δ = 156.1 (C=O Z), 138.5, 138.5, 138.4, 138.1 (Cq Bn), 136.7 (Cq Z), 131.9 [=CH-3 (E) hexenyl], 130.5 [=CH-3 (Z) hexenyl], 128.78, 128.72, 128.54, 128.52, 128.4, 128.36, 128.32, 128.29, 128.24, 128.06, 128.02, 127.97, 127.95, 127.7, 127.68, 127.64, 127.4 [=CH-2 (E)/(Z) hexenyl, CHAr Bn Z], 82.0 (OCH2-Ada), 81.8 (C-3), 80.8 (C-2), 77.4 (C-4), 73.1, 72.8, 72.4, 72.0, 71.3 (CH2 Bn, CH2-6 hexenyl), 70.0 (C-6), 67.4 (CH2 Z), 54.7 (C-5), 53.4 (C-1), 39.9 (CH2 Ada), 37.5 (CH2 Ada), 34.3 (Cq Ada), 32.8 (CH2-1 hexenyl), 29.3 (CH2-5 hexenyl), 28.5 (CH Ada), 23.9 (CH2-4 hexenyl) ppm. IR (thin film): equation imagemax. = 3031, 2901, 2848, 1698, 1453, 1403, 1361, 1267, 1210, 1089, 1070, 1026, 734, 695 cm–1.[α]D20 = 4.8 (c = 2.8, CHCl3). HRMS: found 904.5152 [M + H]+, calcd. for [C59H69NO7 + H]+ 904.5147.

(1R)-1-C-[(E/Z)-4-(Adamant-1-ylmethoxy)but-2-enyl]-2,3,4-tri-O-benzyl-N-[(benzyloxy)carbonyl]-1,5-dideoxy-1,5-imino-D-xylitol (69): Compound 62 (200 mg, 346 μmol) underwent a cross-metathesis reaction (see general procedure F) with alkene 45 to produce 69 (170 mg, 225 μmol) in 65 % yield as a 5:1 mixture of (E)/(Z) isomers after purification (0 % → 10 % EtOAc in PE). Rf = 0.51 (EtOAc/PE, 1:4). 1H NMR [500 MHz, CDCl3, (E) isomer rotamers, a/b ≈ 1:1]: δ = 7.39–7.21 (m, 40 H, HAra/b Bn Z), 5.61–5.51 (m, 3 H, =CH-3a/b butenyl, =CH-2a butenyl), 5.49–5.39 (m, 1 H, =CH-2b butenyl), 5.16–5.02 (m, 4 H, CH2a/b Z), 4.91–4.81 (m, 4 H, CH2a/b Bn), δ = 4.75–4.57 (m, 9 H, 2 × CH2a/b Bn, 1a-H), 4.48–4.38 (m, 2 H, 1b-H, CHH-5a), 4.16 (dd, J = 5.7, 13.6 Hz, 1 H, CHH-5a), 4.00–3.71 (m, 4 H, CH2-4a/b butenyl), 3.68 (dd, J = 9.2, 9.4 Hz, 2 H, 3a/b-H), 3.56 (dd, J = 5.9, 9.4 Hz, 1 H, 2a-H), 3.53–3.35 (m, 3 H, 2b-H, 4a/b-H), 2.98–2.85 (m, 4 H, OCH2-Adaa/b), 2.79–2.69 (m, 2 H, CH2-5b), 2.63–2.51 (m, 2 H, CHH-1a/b butenyl), 2.36–2.26 (m, 2 H, CHH-1a/b butenyl), 1.94 (s, 6 H, 6 × CHAdaa/b) 1.67 (dd, J = 11.7, 30.7 Hz, 12 H, 6 × CH2 Adaa/b), 1.51 (s, 12 H, 6 × CH2 Adaa/b) ppm. 13C NMR [125 MHz, CDCl3, (E) isomer rotamers, a/b ≈ 1:1]: δ = 155.5, 155.5 (C=Oa/b Z), 138.9, 138.3, 138.2, 138.1, 138.0 (3 × Cqa/b Bn), 136.7, 136.6 (Cqa/b Z), 130.3, 130.1 (=CH-3a/b butenyl), 128.9 (=CH-2a butenyl), 128.65, 128.62, 128.57, 128.55, 128.52, 128.4, 128.27, 128.23, 128.06, 128.02, 127.98, 127.96 (=CH-2b butenyl, CHAra/b Bn/Z), 82.1, 82.0 (C-3a/b), 81.1, 81.0 (OCH2-Adaa/b), 79.7 (C-2a/b), 78.3, 78.2(C-4a/b), 75.8, 75.8, 73.3, 73.2, 72.8 (CH2a/b Bn), 71.8, 71.7(CH2-4a/b butenyl), 67.5, 67.5 (CH2a/b Z), 53.1, 52.3 (C-1a/b), 41.1, 40.8 (C-5a/b), 39.8 (CH2a/b Ada), 37.3 (CH2a/b Ada), 34.1, 34.1(Cqa/b Ada), 28.4 (CH a/b Ada), 28.3, 28.2 (CH-1a/b butenyl). IR (thin film): equation imagemax. = 2901, 2848, 1700, 1452, 1423, 1352, 1314, 1238, 1199, 1158, 1097, 970, 734, 696 cm–1. [α]D20 = –7.8 (c = 1.6, CHCl3). HRMS: found 778.4076 [M + Na]+, calcd. for [C49H57NO6 +Na]+ 778.4078.

(1R)-1-C-[(E/Z)-5-(Adamant-1-ylmethoxy)pent-2-enyl]-2,3,4-tri-O-benzyl-N-[(benzyloxy)carbonyl]-1,5-dideoxy-1,5-imino-D-xylitol (70): Compound 62 (200 mg, 346 μmol) underwent a cross-metathesis reaction (see general procedure F) with alkene 46 to produce 70 (190 mg, 247 μmol) in 71 % yield as a 2:1 mixture of (E)/(Z) isomers after purification (0 % → 10 % EtOAc in PE). Rf = 0.53 (EtOAc/PE, 1:4). 1H NMR [500 MHz, CDCl3, (E)/(Z) isomers, Z rotamers, a/b ≈ 1:1]: δ = 7.38–7.21 (m, 40 H, HAra/b Bn Z), 5.53–5.42 (m, 2 H, =CH-3a/b pentenyl), 5.42–5.34 (m, 1 H, =CH-2a pentenyl), 5.28–5.20 (m, 1 H, =CH-2b pentenyl), 5.17–4.99 (m, 4 H, CH2a/b Z), 4.91–4.80 (m, 4 H, CH2a/b Bn), 4.76–4.60 (m, 9 H, 2 × CH2a/b Bn, 1a-H), 4.45–4.36 (m, 2 H, 1b-H, CHH-5a), 4.22–4.13 (m, 1 H, CHH-5a), 3.73–3.64 (m, 2 H, 3a/b-H), 3.56 (dd, J = 5.9, 9.4 Hz, 1 H, 2a-H), 3.53–3.25 (m, 7 H, 2b-H, 4a/b-H, CH2-5a/b pentenyl), 2.98–2.88 (m, 4 H, OCH2-Adaa/b), 2.77–2.70 (m, 2 H, CH2-5b), 2.59–2.10 (m, 8 H, CH2-1a/b, CH2-4a/b pentenyl), 1.95 (s, 6 H, 6 × CH Adaa/b), 1.67 (dd, J = 11.7, 29.8 Hz, 12 H, 6 × CH2Adaa/b), 1.56–1.50 (m, 12 H, 6 × CH2 Adaa/b) ppm. 13C NMR [125 MHz, CDCl3, (E)/(Z) isomers, Z rotamers, a/b ≈ 1:1]: δ = 155.63, 155.61, 155.57, 155.53 [C=Oa/b (E)/(Z) Z], 138.9, 138.3, 138.27, 138.25, 138.23, 138.21 [3 × Cqa/b (E)/(Z) Bn], 136.76, 136.72, 136.68, 136.61 [Cqa/b (E)/(Z) Z] 130.1, 129.8 [=CH-3a/b (E) pentenyl], 128.8, 128.7, 128.66, 128.62, 128.61, 128.5, 128.4, 128.26, 128.22, 128.06, 128.05, 128.02, 127.98, 127.95, 127.93, 127.8, 127.7 [=CH-3a/b (Z) pentenyl, CHAra/b (E)/(Z) Bn Z], 127.4, 127.3 [=CH-2a/b (E) pentenyl], 126.8, 126.7 [=CH-2a/b (Z) pentenyl], 82.3, 82.2, 82.14, 82.11 [C-3a/b (E)/(Z)], 82.1, 82.07, 82.0, 82.02 [OCH2-Adaa/b (E)/(Z)], 79.95, 79.92, 79.85, 79.82 [C-2a/b (E)/(Z)], 78.4, 78.38, 78.33 [C-4a/b (E)/(Z)], 75.96, 75.94, 75.87, 75.82, 73.37, 73.34, 73.22, 73.20, 73.1, 72.9, 72.7 [CH2a/b (E)/(Z) Bn], 71.6, 71.4, 71.2, 71.1 [CH2-5a/b (E)/(Z) pentenyl], 67.6, 67.59, 67.54, 67.4 [CH2a/b (E)/(Z) Z], 53.5, 53.2, 53.0, 52.9 [C-1a/b (E)/(Z)], 41.15, 41.12, 40.9, 40.8 [C-5a/b (E)/(Z)], 39.9 [CH2a/b (E)/(Z) Ada], 37.4 [CH2a/b (E)/(Z) Ada], 34.2 [Cqa/b (E)/(Z) Ada], 33.1, 33.0 [CH2-4a/b (E)/(Z) pentenyl], 28.6, 28.5, 28.2 [CH2-1a/b (E)/(Z) pentenyl], 28.4 (CHa/b Ada), 23.2 [CH2-1a/b (E)/(Z) pentenyl]. IR (thin film) ppm. equation imagemax. = 2901, 2848, 1700, 1453, 1423, 1360, 1314, 1237, 1198, 1158, 1098, 970, 734, 696 cm–1. [α]D20 = –11.6 (c = 1.7, CHCl3).HRMS: found 770.4416 [M + H]+, calcd. for [C50H59NO6 + H]+ 770.4415.

(1R)-1-C-[(E/Z)-6-(Adamant-1-ylmethoxy)hex-2-enyl]-2,3,4-tri-O-benzyl-N-[(benzyloxy)carbonyl]-1,5-dideoxy-1,5-imino-D-xylitol (71): Compound 62 (200 mg, 346 μmol) underwent a cross-metathesis reaction (see general procedure F) with alkene 47 to produce 71 (222 mg, 280 μmol) in 82 % yield as a 3:1 mixture of (E)/(Z) isomers after purification (0 % → 10 % EtOAc in PE). Rf = 0.55 (EtOAc/PE, 1:4). 1H NMR [500 MHz, CDCl3, (E)/(Z) isomers, Z rotamers, a/b ≈ 1:1]: δ = 7.39–7.19 (m, 40 H, HAra/b Bn/Z), 5.52–5.39 (m, 2 H, =CH-3a/b hexenyl), 5.37–5.29 (m, 1 H, =CH-2a hexenyl), 5.25–5.18 (m, 1 H, =CH-2b hexenyl), 5.15–5.01 (m, 4 H, CH2a/b Z), 4.90–4.80 (m, 4 H, CH2a/b Bn), 4.73–4.59 (m, 9 H, 2 × CH2a/b Bn, 1a-H), 4.45–4.36 (m, 2 H, 1b-H, CHH-5a), 4.20–4.13 (m, 1 H, CHH-5a), 3.71–3.65 (m, 2 H, 3a/b-H), 3.59–3.53 (m, 1 H, 2a-H), 3.53–3.43 (m, 2 H, 2b-H, 4a-H), 3.43–3.37 (m, 1 H, 4b-H), 3.36–3.29 (m, 4 H, CH2-6a/b hexenyl), 2.97–2.92 (m, 4 H, OCH2-Adaa/b), 2.79–2.70 (m, 2 H, CH2-5b), 2.57–1.93 (m, 14 H, CH2-1a/b, CH2-4a/b hexenyl, 6 × CH Adaa/b), 1.74–1.48 (m, 28 H, CH2-5a/b hexenyl, 12 × CH2 Adaa/b) ppm. 13C NMR [125 MHz, CDCl3, (E)/(Z) isomers, Z rotamers, a/b ≈ 1:1]: δ = 155.7, 155.6, 155.57, 155.55 [C=Oa/b (E)/(Z) Z], 139.0, 138.9, 138.3, 138.28, 138.23, 138.21, 138.20 [3 × Cqa/b (E)/(Z) Bn], 136.75, 136.72, 136.66, 136.63 [Cqa/b (E)/(Z) Z], 133.3, 133.0 [=CH-3a/b (E) hexenyl], 132.1, 131.9 [=CH-3a/b (Z) hexenyl], 128.68, 128.63, 128.59, 128.55, 128.4, 128.2, 128.06, 128.02, 128.01, 127.97, 127.95, 127.93, 127.92, 127.87, 127.85, 127.6 [HAra/b (E)/(Z) Bn Z], 125.9, 125.7 [=CH-2a/b (E) hexenyl], 125.6, 125.4 [=CH-2a/b (Z) hexenyl], 82.4, 82.26, 82.25 [C-3a/b (E)/(Z)], 82.1, 82.05, 82.03 [OCH2-Adaa/b (E)/(Z)], 79.9, 79.8 [C-2a/b (E)/(Z)], 78.4, 78.3, 78.2 [C-4a/b (E)/(Z)], 75.9, 75.84, 75.83, 75.82, 73.34, 73.33, 73.2, 73.1, 72.9, 72.7 [CH2a/b(E)/(Z) Bn], 71.03, 71.01, 70.8 [CH2-6a/b (E)/(Z) hexenyl], 67.54, 67.51, 67.50, 67.4 [CH2a/b (E)/(Z) Z], 53.6, 53.3, 53.0, 52.4 [C-1a/b (E)/(Z)], 41.1, 41.1, 40.9, 40.8 [C-5a/b (E)/(Z)], 39.9 [CH2a/b (E)/(Z) Ada], 37.4, 37.4 [CH2a/b (E)/(Z) Ada], 34.2 [Cqa/b (E)/(Z) Ada], 29.6, 29.54, 29.51, 29.3, 29.2, 28.9, 28.52, 28.51 [CH2a/b (E)/(Z) hexenyl], 28.42, 28.41 (CHa/b Ada), 24.21, 24.20, 23.0, 22.9[CH2a/b (E)/(Z) hexenyl] ppm. IR (thin film): equation imagemax. = 2901, 2848, 1700, 1452, 1423, 1360, 1314, 1239, 1206, 1157, 1098, 969, 734, 696 cm–1. [α]D20 = –10.4 (c = 2.0, CHCl3). HRMS: found 784.4572 [M + H]+, calcd. for [C51H61NO6 + H]+ 784.4572.

(1R)-2,3,4-Tri-O-benzyl-N-[(benzyloxy)carbonyl]-1,5-dideoxy-1,5-imino-1-C-[(E/Z)-non-2-enyl]-D-xylitol (72): Compound 62 (200 mg, 346 μmol) underwent a cross-metathesis reaction (see general procedure F) with oct-1-ene to produce 72 (197 mg, 297 μmol) in 86 % yield as a 5:1 mixture of (E)/(Z) isomers after purification (0 % → 10 % EtOAc in PE). Rf = 0.61 (EtOAc/PE, 1:4). 1H NMR [500 MHz, CDCl3, (E) isomer rotamers, a/b ≈ 1:1]: δ = 7.41–7.03 (m, 40 H, HAra/b Bn Z), 5.39–5.30 (m, 2 H, =CH-3a/b nonenyl), 5.24–5.17 (m, 1 H, =CH-2a nonenyl), 5.13–5.06 (m, 1 H, =CH-2b nonenyl), 5.06–4.93 (m, 4 H, CH2a/b Z), 4.82–4.72 (m, 4 H,CH2a/b Bn), 4.65–4.50 (m, 9 H, 2 × CH2a/b Bn, 1a-H), 4.35–4.27 (m, 2 H, 1b-H, CHH-5a), 4.07 (dd, J = 5.7, 13.7 Hz, 1 H, CHH-5a), 3.63–3.55 (m, 2 H, 3a/b-H), 3.47 (dd, J = 5.9, 9.5 Hz, 1 H, 2a-H), 3.44–3.36 (m, 2 H, 2b-H, 4a-H), 3.32 (ddd, J = 5.9, 8.8, 11.2 Hz, 1 H, 4b-H), 2.68–2.62 (m, 2 H, CH2-5b), 2.50–2.34 (m, 2 H, CHH-1a/b nonenyl), 2.19–2.09 (m, 2 H, CHH-1a/b nonenyl), 1.87–1.74 (m, 4 H, CH2-4a/b nonenyl), 1.29–1.11 (m, 16 H, 4 × CH2a/b nonenyl), 0.83–0.75 (m, 6 H, CH3-9a/b nonenyl) ppm. 13C NMR [125 MHz, CDCl3, (E) isomer rotamers, a/b ≈ 1:1]: δ = 155.8, 155.6 (C=Oa/b Z), 139.0, 138.4, 138.33, 138.31, 138.2 (3 × Cqa/b Bn), 136.8, 136.7 (Cqa/b Z), 134.0, 133.7 (=CH-3a/b nonenyl), 128.7, 128.67, 128.62, 128.61, 128.5, 128.2, 128.16, 128.12, 128.07, 128.03, 128.02, 127.96, 127.92, 127.7 (CHAra/b Bn/Z), 125.5, 125.3 (=CH-2a/b nonenyl), 82.3, 82.1 (C-3a/b), 80.0 (C-2a/b), 78.5, 78.4 (C-4a/b), 75.9, 75.9, 73.4, 73.3, 73.2, 72.8 (CH2a/b Bn), 67.54, 67.53 (CH2a/b Z), 53.3, 52.5 (C-1a/b), 41.1, 40.8 (C-5a/b), 32.8, 32.7 (CH2-4a/b nonenyl), 31.9(CH2a/b nonenyl), 29.6, 29.5 (CH2a/b nonenyl), 29.1, 29.0 (CH2a/b nonenyl), 28.6, 28.5 (CH2-1a/b nonenyl), 22.8 (CH2a/b nonenyl), 14.3 (CH3-9 nonenyl) ppm. IR (thin film): equation imagemax. = 2926, 2855, 1700, 1454, 1423, 1359, 1313, 1203, 1096, 968, 734, 696 cm–1. [α]D20 = –11.9 (c = 1.7, CHCl3). HRMS: found 662.3839 [M + H]+, calcd. for [C43H51NO5 + H]+ 662.3840.

(1R)-1-C-[4-(Adamant-1-ylmethoxy)butyl]-1-deoxy-L-ido-nojirimycin (73): Compound 63 (141 mg, 161 μmol) was subjected to hydrogenolysis at 4 bar H2 (see general procedure H) to furnish 73 (33 mg, 86 μmol) as a colourless oil in 53 % yield after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Additional HPLC purification was required for removal of minor 5–10 % impurities (1 min: isocratic 25 % B → 11.5 min: 45 % B → 12.5 min: 100 % B, 15 min: isocratic 100 % B; tR = 9.0 min). Rf = 0.49 (MeOH/CHCl3, 1:3 + 2 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 4.02 (dd, J = 3.5, 3.5 Hz, 1 H, 3-H), 3.93–3.90 (m, 1 H, 4-H), 3.90–3.88 (m, 1 H, 2-H), 3.87–3.81 (m, 2 H, CH2-6), 3.54–3.50 (m, 1 H, 5-H), 3.44–3.39 (m, 3 H, 1-H, CH2-4 butyl), 2.98 (s, 2 H, OCH2-Ada), 2.00–1.92 (m, 4 H, CHH-1 butyl, 3 × CH Ada), 1.79–1.66 (m, 7 H, CHH-1 butyl, 3 × CH2 Ada), 1.66–1.58 (m, 2 H, CH2-3 butyl), 1.58–1.50 (m, 7 H, 3 × CH2 Ada, CHH-2 butyl), 1.46–1.38 (m, 1 H, CHH-2 butyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.3 (OCH2-Ada), 72.3 (CH2-4 butyl), 69.2 (C-4), 69.0 (C-2), 68.2 (C-3), 60.6 (C-6), 58.8 (C-5), 56.9 (C-5), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 30.6 (CH2-3 butyl), 29.9 (CH Ada), 28.9 (CH2-1 butyl), 22.9 (CH2-2 butyl) ppm. IR (thin film): equation imagemax. = 3328, 2902, 2848, 1451, 1068, 996 cm–1. [α]D20 = –14.0 (c = 0.2, MeOH). HRMS: found 384.2747 [M + H]+, calcd. for [C21H37NO5 + H]+ 384.2744.

(1R)-1-C-[5-(Adamant-1-ylmethoxy)pentyl]-1-deoxy-L-ido-nojirimycin (74): Compound 64 (139 mg, 156 μmol) was subjected to hydrogenolysis at 4 bar H2 (see general procedure H) to furnish 74 (46 mg, 116 μmol) as a colourless oil in 73 % yield after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Additional HPLC purification was required for removal of minor 5–10 % impurities (1 min: isocratic 10 % B → 12 min: 100 % B → 12 min: 100 % B, 15 min: isocratic 100 % B; tR = 7.4 min). Rf = 0.50 (MeOH/CHCl3, 1:3 + 2 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 4.02 (t, J = 3.5 Hz, 1 H, 3-H), 3.93–3.91 (m, 1 H, 4-H), 3.91–3.88 (m, 1 H, 2-H), 3.86–3.80 (m, 2 H, CH2-6), 3.54–3.50 (m, 1 H, 5-H), 3.43–3.38 (m, 3 H, 1-H, CH2-5 pentyl), 2.97 (s, 2 H, OCH2-Ada), 2.00–1.91 (m, 4 H, CHH-1 pentyl, 3 × CH Ada), 1.79–1.65 (m, 7 H, CHH-1 pentyl, 3 × CH2 Ada), 1.64–1.57 (m, 2 H, CH2-4 pentyl), 1.56 (d, J = 2.2 Hz, 6 H, 3 × CH2 Ada), 1.53–1.41 (m, 3 H, CHH-2 pentyl, CH2-3 pentyl), 1.41–1.33 (m, 1 H, CHH-2 pentyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.2 (OCH2-Ada), 72.5 (CH2-5 pentyl), 69.2 (C-4), 69.0 (C-2), 68.2 (C-3), 60.6 (C-6), 58.8 (C-5), 56.9 (C-1), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 30.6 (CH2-4 pentyl), 29.9 (CH Ada), 29.0 (CH2-1 pentyl), 27.3 (CH2-3 pentyl), 25.9 (CH2-2 pentyl) ppm. IR (thin film): equation imagemax. = 3331, 2902, 2849, 1590, 1451, 1259, 1068, 998 cm–1. [α]D20 = –14.3 (c = 0.3, MeOH). HRMS: found 398.2897 [M + H]+, calcd. for [C22H39NO5 + H]+ 398.2901.

(1R)-1-C-[6-(Adamant-1-ylmethoxy)hexyl]-1-deoxy-L-ido-nojirimycin (75): Compound 65 (154 mg, 170 μmol) was subjected to hydrogenolysis at 4 bar H2 (see general procedure H) to furnish 75 (51 mg, 124 μmol) as a colourless oil in 73 % yield after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Additional HPLC purification was required for removal of minor 5–10 % impurities (1 min: isocratic 10 % B → 12 min: 100 % B → 12 min: 100 % B, 15 min: isocratic 100 % B; tR = 7.8 min). Rf = 0.53 (MeOH/CHCl3, 1:3 + 2 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 4.02 (dd, J = 3.5 Hz, 1 H, 3-H), 3.92–3.90 (m, 1 H, 4-H), 3.90–3.87 (m, 1 H, 2-H), 3.86–3.80 (m, 2 H, CH2-6), 3.53–3.49 (m, 1 H, 5-H), 3.43–3.37 (m, 3 H, 1-H, CH2-6 hexyl), 2.97 (s, 2 H, OCH2-Ada), 1.99–1.91 (m, 4 H, CHH-1 hexyl, 3 × CH Ada), 1.79–1.65 (m, 7 H, CHH-1 hexyl, 3 × CH2 Ada), 1.60–1.54 (m, 8 H, CH2-5 hexyl, 3 × CH2 Ada), 1.51–1.31 (m, 6 H, 3 × CH2 hexyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.2 (OCH2-Ada), 72.7 (CH2-6 hexyl), 69.2 (C-4), 69.0 (C-2), 68.2 (C-3), 60.6 (C-6), 58.8 (C-5), 57.0 (C-1), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 30.7 (CH2-5 hexyl), 30.5 (CH2 hexyl), 29.9 (CH Ada), 29.0 (CH2-1 hexyl), 27.3 (CH2 hexyl), 26.1 (CH2 hexyl) ppm. IR (thin film): equation imagemax. = 3327, 2901, 2848, 1590, 1451, 1203, 1111, 1068, 999 cm–1. [α]D20 = –11.0 (c = 0.3, MeOH). HRMS: found 412.3055 [M + H]+, calcd. for [C23H41NO5 + H]+ 412.3057.

(1R)-1-C-[4-(Adamant-1-ylmethoxy)butyl]-1-deoxynojirimycin (76): Compound 66 (155 mg, 177 μmol) was subjected to hydrogenolysis at 4 bar H2 (see general procedure H) to furnish 76 (38 mg, 99 μmol) as a colourless oil in 56 % yield after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Additional HPLC purification was required for removal of minor 5–10 % impurities (1 min: isocratic 25 % B → 11.5 min: 45 % B → 12.5 min: 100 % B, 15 min: isocratic 100 % B; tR = 8.3 min). Rf = 0.32 (MeOH/CHCl3, 1:3 + 2 % NH4OH). 1H NMR (500 MHz, MeOD): δ = 3.90–3.80 (m, 2 H, CH2-6), 3.73 (dd, J = 4.1, 7.1 Hz, 1 H, 2-H), 3.64 (dd, J = 7.0, 7.1 Hz, 1 H, 3-H), 3.49 (dd, J = 7.0, 7.0 Hz, 1 H, 4-H), 3.41 (t, J = 6.2 Hz, 2 H, CH2-4 butyl), 3.38–3.32 (m, 1 H, 1-H), 3.22–3.14 (m, 1 H, 5-H), 2.97 (s, 2 H, OCH2-Ada), 1.94 (s, 3 H, 3 × CH Ada), 1.91–1.85 (m, 1 H, CHH-1 butyl), 1.71 (dd, J = 12.1, 39.6 Hz, 7 H, 3 × CH2 Ada), 1.65–1.58 (m, 3 H, CHH-1 butyl, CH2-3 butyl), 1.58–1.54 (m, 7 H, 3 × CH2 Ada), 1.54–1.44 (m, 2 H, CH2-2 butyl) ppm. 13C NMR (100 MHz, MeOD): δ = 83.3 (OCH2-Ada), 74.1 (C-3), 72.4 (CH2-4 butyl), 72.0 (C-2), 71.5 (C-4), 60.7 (C-6), 58.3 (C-5), 56.2 (C-1), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 30.7 (CH2-3 butyl), 29.9 (CH Ada), 26.8 (CH2-1 butyl), 24.1 (CH2-2 butyl) ppm. IR (thin film): equation imagemax. = 3326, 2902, 2848, 1594, 1452, 1362, 1157, 1094 cm–1. [α]D20 = 10.9 (c = 0.2, MeOH). HRMS: found 384.2746 [M + H]+, calcd. for [C21H37NO5 + H]+ 384.2744.

(1R)-1-C-[5-(Adamant-1-ylmethoxy)pentyl]-1-deoxynojirimycin (77): Compound 67 (148 mg, 155 μmol) was subjected to hydrogenolysis at 4 bar H2 (see general procedure H) to furnish 77 (54 mg, 136 μmol) as a colourless oil in 82 % yield after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Additional HPLC purification was required for removal of minor 5–10 % impurities (1 min: isocratic 10 % B → 12 min: 100 % B → 12 min: 100 % B, 15 min: isocratic 100 % B; tR = 7.2 min). Rf = 0.33 (MeOH/CHCl3, 1:3 + 2 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 4.00 (dd, J = 7.1, 12.0 Hz, 1 H, 6a-H), 3.83 (dd, J = 3.8, 12.0 Hz, 1 H, 6b-H), 3.78 (dd, J = 3.6, 6.5 Hz, 1 H, 2-H), 3.72 (t, J = 6.5, 6.6 Hz, 1 H, 3-H), 3.63 (t, J = 6.6, 6.6 Hz, 1 H, 4-H), 3.47 (td, J = 3.6, 6.9 Hz, 1 H, 1-H), 3.40 (t, J = 6.3 Hz, 2 H, CH2-5 pentyl), 3.36–3.32 (m, 1 H, 5-H), 2.97 (s, 2 H, OCH2-Ada), 1.98–1.91 (m, 4 H, CHH-1 pentyl, 3 × CH Ada), 1.72 (dd, J = 11.9, 48.4 Hz, 6 H, 3 × CH2 Ada), 1.66–1.57 (m, 3 H, CHH-1 pentyl, CH2-4 pentyl), 1.56 (d, J = 2.5 Hz, 6 H, 3 × CH2 Ada), 1.52–1.41 (m, 4 H, CH2-2, CH2-3 pentyl) ppm. 13C NMR (150 MHz, MeOD): δ = 81.7 (OCH2-Ada), 71.2 (C-3), 71.0 (CH2-5 pentyl), 68.8 (C-2), 68.0 (C-4), 58.0 (C-5), 57.0 (C-6), 53.5 (C-1), 48.0 (C-6), 39.4 (CH2 Ada), 36.9 (CH2 Ada), 33.8 (Cq Ada), 29.0 (CH2-4 pentyl), 28.4 (CH Ada), 26.0, 25.8, 25.5 (3 × CH2 pentyl) ppm. IR (thin film): equation imagemax. = 3328, 2901, 2849, 1454, 1363, 1087 cm–1. [α]D20 = 7.6 (c = 0.6, MeOH). HRMS: found 398.2898 [M + H]+, calcd. for [C22H39NO5 + H]+ 398.2901.

(1R)-1-C-[6-(Adamant-1-ylmethoxy)hexyl]-1-deoxynojirimycin (78): Compound 68 (158 mg, 175 μmol) was subjected to hydrogenolysis at 4 bar H2 (see general procedure H) to furnish 78 (58 mg, 141 μmol) as a colourless oil in 81 % yield after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Additional HPLC purification was required for removal of minor 5–10 % impurities (1 min: isocratic 10 % B → 12 min: 100 % B → 12 min: 100 % B, 15 min: isocratic 100 % B; tR = 7.8 min). Rf = 0.35 (MeOH/CHCl3, 1:3 + 2 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 4.00 (dd, J = 7.1, 12.0 Hz, 1 H, 6a-H), 3.83 (dd, J = 3.8, 12.0 Hz, 1 H, 6b-H), 3.78 (dd, J = 3.6, 6.6 Hz, 1 H, 2-H), 3.71 (dd, J = 6.6, 6.7 Hz, 1 H, 3-H), 3.62 (dd, J = 6.7, 6.7 Hz, 1 H, 4-H), 3.46 (td, J = 3.6, 6.9 Hz, 1 H, 1-H), 3.38 (t, J = 6.4 Hz, 2 H, CH2-6 hexyl), 3.34–3.32 (m, 1 H, 5-H), 2.97 (s, 2 H, OCH2-Ada), 1.98–1.90 (m, 4 H, CHH-1 hexyl, 3 × CH Ada), 1.72 (dd, J = 11.8, 48.2 Hz, 6 H, 3 × CH2 Ada), 1.65–1.60 (m, 1 H, CHH-1 hexyl), 1.59–1.54 (m, 8 H, CH2-5 hexyl, 3 × CH2 Ada), 1.50–1.44 (m, 2 H, CH2-2 hexyl), 1.44–1.39 (m, 4 H, 2 × CH2 hexyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.2 (OCH2-Ada), 72.8 (C-3), 72.7 (CH2-6 hexyl), 70.4 (C-2), 69.5 (C-4), 59.5 (C-5), 58.6 (C-6), 55.3 (C-1), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 30.7 (CH2-5 hexyl), 30.5 (CH2 hexyl), 29.9 (CH Ada), 27.6 (CH2-1 hexyl), 27.3 (CH2 hexyl), 27.2 (CH2-2 hexyl) ppm. IR (thin film): equation imagemax. = 3328, 2901, 2848, 1593, 1452, 1361, 1096, 1046 cm–1. [α]D20 = 9.2 (c = 0.7, MeOH). HRMS: found 412.3055 [M + H]+, calcd. for [C23H41NO5 + H]+ 412.3057.

(1R)-1-C-[4-(Adamant-1-ylmethoxy)butyl]-1,5-dideoxy-1,5-imino-D-xylitol (79): Compound 69 (111 mg, 147 μmol) was subjected to hydrogenolysis at 4 bar H2 (see general procedure H) to furnish 79 (41 mg, 116 μmol) as a colourless oil in 79 % yield after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Additional HPLC purification was required for removal of minor 5–10 % impurities (1 min: isocratic 25 % B → 11.5 min: 45 % B → 12.5 min: 100 % B, 15 min: isocratic 100 % B; tR = 9.2 min). Rf = 0.30 (MeOH/CHCl3, 1:4 + 2 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 3.96 (dd, J = 3.3 Hz, 1 H, 3-H), 3.92–3.89 (m, 1 H, 4-H), 3.86–3.83 (m, 1 H, 2-H), 3.44–3.38 (m, 4 H, 1-H, CHH-5, CH2-4 butyl), 3.19 (d, J = 13.1 Hz, 1 H, CHH-5), 2.98 (s, 2 H, OCH2-Ada), 1.95 (s, 3 H, 3 × CH Ada), 1.91–1.84 (m, 1 H, CHH-1 butyl), 1.72 (dd, J = 11.6, 49.2 Hz, 6 H, 3 × CH2 Ada), 1.66–1.59 (m, 3 H, CHH-1 butyl, CH2-3 butyl), 1.56 (d, J = 2.3 Hz, 6 H, 3 × CH2 Ada), 1.55–1.49 (m, 1 H, CHH-2 butyl), 1.49–1.42 (m, 1 H, CHH-2 butyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.3 (OCH2-Ada), 72.2 (CH2-4 butyl), 69.6 (C-2), 68.3 (C-4), 68.0 (C-3), 56.5 (C-1), 47.5 (C-5), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 30.6 (CH2-3 butyl), 29.9 (CH Ada), 29.6 (CH2-1 butyl), 22.9 (CH2-2 butyl) ppm. IR (thin film): equation imagemax. = 3368, 2903, 2849, 1451, 1203, 1139, 1060 cm–1. [α]D20 = –13.4 (c = 0.2, MeOH). HRMS: found 354.2639 [M + H]+, calcd. for [C20H35NO4 + H]+ 354.2639.

(1R)-1-C-[5-(Adamant-1-ylmethoxy)pentyl]-1,5-dideoxy-1,5-imino-D-xylitol (80): Compound 70 (140 mg, 182 μmol) was subjected to hydrogenolysis at 4 bar H2 (see general procedure H) to furnish 80 (62 mg, 169 μmol) as a colourless oil in 93 % yield after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Additional HPLC purification was required for removal of minor 5–10 % impurities (1 min: isocratic 30 % B → 11.5 min: 50 % B → 12.5 min: 100 % B, 15 min: isocratic 100 % B; tR = 6.5 min). Rf = 0.31 (MeOH/CHCl3, 1:4 + 2 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 3.96 (dd, J = 3.2 Hz, 1 H, 3-H), 3.92–3.89 (m, 1 H, 4-H), 3.86–3.83 (m, 1 H, 2-H), 3.43–3.37 (m, 4 H, 1-H, CHH-5, CH2-5 pentyl), 3.19 (d, J = 13.1 Hz, 1 H, CHH-5), 2.97 (s, 2 H, OCH2-Ada), 1.94 (s, 3 H, 3 × CH Ada), 1.90–1.83 (m, 1 H, CHH-1 pentyl), 1.72 (dd, J = 11.9, 49.3 Hz, 6 H, 3 × CH2 Ada), 1.66–1.57 (m, 3 H, CHH-1 pentyl, CH2-4 pentyl), 1.56 (d, J = 2.3 Hz, 6 H, 3 × CH2 Ada), 1.52–1.38 (m, 4 H, 2 × CH2 pentyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.2 (OCH2-Ada), 72.5 (CH2-5 pentyl), 69.6 (C-2), 68.4 (C-4), 68.0 (C-3), 56.4 (C-1), 47.4 (C-5), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 30.5 (CH2-4 pentyl), 29.9 (CH Ada), 29.8 (CH2-1 pentyl), 27.3 (CH2 pentyl), 25.8 (CH2 pentyl) ppm. IR (thin film): equation imagemax. = 3367, 2903, 2849, 1450, 1202, 1139, 1060 cm–1. [α]D20 = –15.8 (c = 0.3, MeOH). HRMS: found 368.2796 [M + H]+, calcd. for [C21H37NO4 + H]+ 368.2795.

(1R)-1-C-[6-(Adamant-1-ylmethoxy)hexyl]-1,5-dideoxy-1,5-imino-D-xylitol (81): Compound 71 (173 mg, 221 μmol) was subjected to hydrogenolysis at 4 bar H2 (see general procedure H) to furnish 81 (75 mg, 197 μmol) as a colourless oil in 89 % yield after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Additional HPLC purification was required for removal of minor 5–10 % impurities (1 min: isocratic 10 % B → 12 min: 100 % B → 12 min: 100 % B, 15 min: isocratic 100 % B; tR = 7.9 min). Rf = 0.33 (MeOH/CHCl3, 1:4 + 2 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 3.96 (dd, J = 3.3 Hz, 1 H, 3-H), 3.92–3.90 (m, 1 H, 4-H), 3.85–3.83 (m, 1 H, 2-H), 3.43–3.36 (m, 4 H, 1-H, CHH-5, CH2-6 hexyl), 3.19 (d, J = 13.1 Hz, 1 H, CHH-5), 2.97 (s, 2 H, OCH2-Ada), 1.94 (s, 3 H, 3 × CH Ada), 1.89–1.82 (m, 1 H, CHH-1 hexyl), 1.79–1.61 (m, 7 H, CHH-1 hexyl, 3 × CH2 Ada), 1.61–1.53 (m, 8 H, CH2-5 hexyl, 3 × CH2 Ada), 1.50–1.43 (m, 1 H, CHH-2 hexyl), 1.43–1.37 (m, 5 H, CHH-2 hexyl, 2 × CH2 hexyl) ppm. 13C NMR (150 MHz, MeOD): δ = 83.2 (OCH2-Ada), 72.7 (CH2-6 hexyl), 69.6 (C-2), 68.3 (C-4), 68.0 (C-3), 56.4 (C-1), 47.4 (C-5), 41.0 (CH2 Ada), 38.5 (CH2 Ada), 35.3 (Cq Ada), 30.7 (CH2-5 hexyl), 30.4 (CH2 hexyl), 29.9 (CH Ada), 29.7 (CH2-1 hexyl), 27.3 (CH2 hexyl), 26.0 (CH2 hexyl) ppm. IR (thin film): equation imagemax. = 3370, 2902, 2849, 1449, 1202, 1139, 1061 cm–1. [α]D20 = –13.7 (c = 0.6, MeOH). HRMS: found 382.2954 [M + H]+, calcd. for [C22H39NO4 + H]+ 382.2952.

(1R)-1,5-Dideoxy-1,5-imino-1-C-nonyl-D-xylitol (82): Compound 72 (305 mg, 461 μmol) was subjected to hydrogenolysis at 4 bar H2 (see general procedure H) to furnish 82 (113 mg, 438 μmol) as a colourless oil in 95 % yield after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Additional HPLC purification was required for removal of minor 5–10 % impurities (1 min: isocratic 10 % B → 12 min: 100 % B → 12 min: 100 % B, 15 min: isocratic 100 % B; tR = 6.7 min). Rf = 0.25 (MeOH/CHCl3, 1:4 + 2 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 3.97–3.96 (m, 1 H, 3-H), 3.93–3.89 (m, 1 H, 4-H), 3.85–3.82 (m, 1 H, 2-H), 3.41 (dd, J = 1.7, 13.1 Hz, 1 H, 5a-H), 3.37 (d, J = 7.4 Hz, 1 H, 1-H), 3.19 (d, J = 13.1 Hz, 1 H, 5b-H), 1.88–1.81 (m, 1 H, CHH-1 nonyl), 1.63 (ddd, J = 5.0, 10.5, 18.5 Hz, 1 H, CHH-1 nonyl), 1.48–1.41 (m, 1 H, CHH-2), 1.41–1.25 (m, 13 H, CHH-2 nonyl, 6 × CH2 nonyl), 0.90 (t, J = 7.0 Hz, 3 H, CH3-9 nonyl) ppm. 13C NMR (150 MHz, MeOD): δ = 69.6 (C-2), 68.3 (C-4), 68.0 (C-3), 56.5 (C-1), 47.4 (C-6), 33.2, 30.7, 30.6, 30.5, 30.4 (5 × CH2 nonyl), 29.8 (CH2-1 nonyl), 26.0 (CH2-1 nonyl), 23.9 (CH2 nonyl), 14.6 (CH3-9 nonyl) ppm. IR (thin film): equation imagemax. = 3367, 2927, 2857, 1438, 1200, 1139, 1061 cm–1. [α]D20 = –19.6 (c = 0.4, MeOH). HRMS: found 260.2222 [M + H]+, calcd. for [C14H29NO3 + H]+ 260.2220.

(1R)-1-C-[(E/Z)-5-(Adamant-1-ylmethoxy)pent-2-enyl]-1-deoxy-L-ido-nojirimycin (83): Compound 64 (95 mg, 107 μmol) was subjected to a Birch reduction (see general procedure G) to furnish 83 (30 mg, 75 μmol) as a colourless oil in 70 % yield as a 1.3:2 mixture of (E)/(Z) isomers after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Additional HPLC purification was required for removal of minor 5–10 % impurities (30 % B → 11 min: 100 % B, 15 min: isocratic 100 % B; tR = 3.8 min). Rf = 0.41/0.45 (MeOH/CHCl3, 1:4 + 2 % NH4OH). 1H NMR [600 MHz, MeOD, (E)/(Z) isomers, integrals for (Z) isomer]: δ = 5.72 [dt, J = 6.7, 15.4 Hz, =CH-3 (E) pentenyl], 5.67 [dt, J = 7.3, 10.9 Hz, 1 H, =CH-3 (Z) pentenyl], 5.52–5.39 [m, 1 H, =CH-2 (E)/(Z) pentenyl], 4.01 [dd, J = 3.3 Hz, 1 H, 3-H (E)/(Z)], 3.93–3.89 [m, 1 H, 4-H(E)/(Z)], 3.89–3.81 [m, 5 H, 2-H (E)/(Z), CH2-6 (E)/(Z)], 3.55–3.50 [m, 1 H, 5-H (E)/(Z)], 3.47–3.39 [m, 5 H, 1-H (E)/(Z), CH2-5(E)/(Z) pentenyl], 3.00 [s, 2 H, OCH2-Ada (Z)], 2.99 [s, OCH2-Ada (E)], 2.80–2.74 [m, 1 H, CHH-1 (Z) pentenyl], 2.64–2.58 [m, CHH-1 (E) pentenyl], 2.50–2.43 [m, 1 H, CHH-1 (Z) pentenyl, CHH-1 (E) pentenyl], 2.43–2.37 [m, 2 H, CH2-4 (Z) pentenyl], 2.31–2.28 [m, CH2-4 (E) pentenyl], 1.94 (s, 3 H, 3 × CH Ada), 1.72 (dd, J = 11.9, 47.0 Hz, 6 H, 3 × CH2 Ada), 1.56 (d, J = 1.8 Hz, 6 H, 3 × CH2 Ada) ppm. 13C NMR (150 MHz, MeOD): δ = 134.0 [=CH-3 (E) pentenyl], 132.5 [=CH-3 (Z) pentenyl], 126.0 [=CH-2 (E) pentenyl], 124.9 [=CH-2 (Z) pentenyl], 83.3 [OCH2-Ada (Z)], 83.2 [OCH2-Ada (E)], 72.3 [CH2-5 (E) pentenyl], 72.2 [CH2-5 (Z) pentenyl], 69.3 [C-4 (E)], 69.2 [C-4 (Z)], 69.1 [C-2 (Z)], 69.0 [C-2 (E)], 68.2 [C-3 (E)/(Z)], 60.7 [C-6 (Z)], 60.6 [C-6 (E)], 58.9 [C-5 (Z)], 58.8 [C-5 (E)], 56.8 [C-1 (E)], 56.7 [C-1 (Z)], 41.0 [CH2 Ada (E)], 40.9 [CH2 Ada (Z)], 38.5 [CH2 Ada (E)], 38.4 [CH2 Ada (Z)], 35.3 [Cq Ada (Z)], 35.2 [Cq Ada (E)], 34.1 [CH2-4 (E) pentenyl], 32.5 [CH2-1 (E) pentenyl], 29.9 [CH Ada (E)], 29.8 [CH Ada (Z)], 29.2 [CH2-4 (Z) pentenyl], 27.3 [CH2-1 (Z) pentenyl] ppm. 432IR (thin film): equation imagemax. = 3365, 2903, 2849, 1444, 1203, 1140, 1075, 1011 cm–1. [α]D20 = –10.1 (c = 0.3, MeOH). HRMS: found 396.2741 [M + H]+, calcd. for [C22H37NO5 + H]+ 396.2744.

(1R)-1-C-[(E/Z)-5-(Adamant-1-ylmethoxy)pent-2-enyl]-1-deoxynojirimycin (84): Compound 67 (105 mg, 118 μmol) was subjected to a Birch reduction (see general procedure G) to furnish 84 (34 mg, 85 μmol) as a colourless oil in 72 % yield as a 3:1 mixture of(E)/(Z) isomers after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Additional HPLC purification was required for removal of minor 5–10 % impurities (1 min: isocratic 30 % B → 12 min: 100 % B → 12 min: 100 % B, 15 min: isocratic 100 % B; tR = 4.5 min). Rf = 0.30 (MeOH/CHCl3, 1:4 + 2 % NH4OH). 1H NMR [600 MHz, MeOD, (E)/(Z) isomers, integrals for (E) isomer]: δ = 5.74 [dt, J = 6.8, 15.4 Hz, 1 H, =CH-3 (E) pentenyl], 5.73–5.71 [m, =CH-3 (E) pentenyl], 5.52–5.44 [m, 1 H, =CH-2 (E)/(Z) pentenyl], 4.02 [dd, J = 7.3, 11.9 Hz, 6a-H (Z)], 3.97 [dd, J = 7.4, 11.9 Hz, 1 H, 6a-H (E)], 3.84–3.78 [m, 2 H, 6b-H(E)/(Z), 2-H (E)/(Z)], 3.76 [t, J = 6.0 Hz, 3-H (Z)], 3.73 [t, J = 6.5 Hz, 1 H, 3-H (E)], 3.65 [t, J = 6.1 Hz, 4-H (Z)], 3.62 [t, J = 6.6 Hz, 1 H, 4-H (E)], 3.54–3.48 [m, 1 H, 1-H (E)/(Z)], 3.44 [t, J = 6.6 Hz, 2 H, CH2-5 (E)/(Z) pentenyl], 3.38–3.33 [m, 1 H, 5-H(E)/(Z)], 3.00 [s, OCH2-Ada (Z)], 2.99 [s, 2 H, OCH2-Ada (E)], 2.77–2.71 [m, CHH-1 (Z) pentenyl], 2.70–2.64 [m, 1 H, CHH-1 (E) pentenyl], 2.51–2.45 [m, CHH-1 (Z) pentenyl], 2.43–2.36 [m, 1 H, CHH-1 (E) pentenyl], 2.34–2.28 [m, 2 H, CH2-4 (E)/(Z) pentenyl], 1.95 [s, 3 H, 3 × CH Ada (E)/(Z)], 1.72 [dd, J = 11.9, 47.7 Hz, 6 H, 3 × CH2 Ada (E)/(Z)], 1.56 [d, J = 2.4 Hz, 6 H, 3 × CH2 Ada (E)/(Z)] ppm. 13C NMR [150 MHz, MeOD, (E)/(Z) isomer]: δ = 134.3 [=CH-3 (E) pentenyl], 132.6 [=CH-3 (Z) pentenyl], 126.4 [=CH-2 (E) pentenyl], 125.4 [=CH-2 (Z) pentenyl], 83.3 [OCH2-Ada (Z)], 83.2 [OCH2-Ada (E)], 72.7 [C-3 (E)], 72.5 [C-3 (Z)], 72.3 [CH2-5 pentenyl (Z)], 72.1 [CH2-5 pentenyl (E)], 70.1 [C-2 (E)], 70.1 [C-2 (Z)], 69.6 [C-4 (E)], 69.4 [C-4 (Z)], 59.5 [C-5 (E)/(Z)], 58.6 [C-6 (E)], 58.5 [C-6 (Z)], 54.7 [C-1 (E)/(Z)], 41.0 (CH2 Ada), 38.4 (CH2 Ada), 35.3 [Cq Ada (E)/(Z)], 34.1 [CH2-4 pentenyl (E)], 30.7 [CH2-1 pentenyl (E)], 29.9 (CH Ada), 29.2 [CH2-4 pentenyl (Z)], 25.8 [CH2-1 pentenyl (Z)] ppm. IR (thin film): equation imagemax. = 3351, 2903, 2849, 1443, 1203, 1139, 1050 cm–1. [α]D20 = 5.5 (c = 0.3, MeOH). HRMS: found 396.2741 [M + H]+, calcd. for [C22H37NO5 + H]+ 396.2744.

(1R)-1-C-[(E/Z)-5-(Adamant-1-ylmethoxy)pent-2-enyl]-1,5-dideoxy-1,5-imino-D-xylitol (85): Compound 70 (110 mg, 143 μmol) was subjected to a Birch reduction (see general procedure G) to furnish 85 (34 mg, 93 μmol) as a colourless oil in 65 % yield as a 1.2:1 mixture of (E)/(Z) isomers after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Additional HPLC purification was required for removal of minor 5–10 % impurities (1 min: isocratic 10 % B → 12 min: 100 % B → 12 min: 100 % B, 15 min: isocratic 100 % B; tR = 7.3 min). Rf = 0.39/0.45 (MeOH/CHCl3, 1:4 + 2 % NH4OH). 1H NMR [600 MHz, MeOD, (E)/(Z) isomers, integrals for (E) isomer]: δ = 5.75–5.67 [m, 2 H, =CH-3 (E)/(Z) pentenyl], 5.52–5.42 [m, 2 H, =CH-2 (E)/(Z) pentenyl], 3.96 (dd, J = 3.6 Hz, 2 H, 3-H), 3.93–3.90 (m, 2 H, 4-H), 3.84–3.82 [m, 1 H, 2-H (E)], 3.82–3.80 [m, 2-H (Z)], 3.46–3.37 [m, 4 H, 1-H (E)/(Z), CHH-5 (E)/(Z), CH2-5 pentenyl (E)/(Z)], 3.23–3.21 [m, 1 H, CHH-5 (E)], 3.21–3.19 [m, CHH-5 (Z)], 3.00 [s, OCH2-Ada (Z)], 2.99 [s, 2 H, OCH2-Ada (E)], 2.67–2.61 [m, CHH-1 (Z) pentenyl], 2.56–2.49 [m, 1 H, CHH-1 (E) pentenyl], 2.49–2.43 [m, CHH-1 (Z) pentenyl], 2.43–2.35 [m, 1 H, CHH-1 (E) pentenyl, CH2-4 (Z) pentenyl], 2.35–2.28 [m, 2 H, CH2-4 (E) pentenyl], 1.94 [s, 3 H, 3 × CH Ada (E)/(Z)], 1.72 [dd, J = 11.8, 47.5 Hz, 6 H, 3 × CH2 Ada (E)/(Z)], 1.56 [d, J = 2.6 Hz, 6 H, 3 × CH2 Ada (E)/(Z)] ppm. 13C NMR [150 MHz, MeOD, (E)/(Z) isomers]: δ = 134.2 [=CH-3(E)/(Z) pentenyl], 132.8 [=CH-3 (Z) pentenyl], 125.9 [=CH-2 (E) pentenyl], 124.9 [=CH-2 (Z) pentenyl], 83.3 [OCH2-Ada (Z)], 83.2 [OCH2-Ada (E)], 72.2 [CH2-5 (E) pentenyl], 72.1 [CH2-5 (Z) pentenyl], 69.7 [C-2 (E)], 69.7 [C-2 (Z)], 68.4 [C-4 (E)], 68.3 [C-4 (Z)], 68.0 [C-3 (E)/(Z)], 56.4 [C-1 (Z)], 56.4 [C-1 (E)], 47.5 [C-5 (E)/(Z)], 40.9 [CH2 Ada (E)/(Z)], 38.4 [CH2 Ada (E)/(Z)], 35.3 [Cq Ada (Z)], 35.2 [Cq Ada (E)], 34.1 [CH2-4 (E) pentenyl], 33.3 [CH2-1 (E) pentenyl], 29.9 [CH Ada (E)/(Z)], 29.2 [CH2-4 (Z) pentenyl], 28.0 [CH2-1 (Z) pentenyl] ppm. IR (thin film): equation imagemax. = 3367, 2902, 2849, 1444, 1200, 1137, 1064, 1012, 940 cm–1. [α]D20 = 12.0 (c = 0.5, MeOH). HRMS: found 366.2639 [M + H]+, calcd. for [C21H35NO4 + H]+ 366.2639.

(1R)-1,5-Dideoxy-1,5-imino-1-C-[(E)-non-2-enyl]-D-xylitol (86): Compound 72 (110 mg, 166 μmol) was subjected to a Birch reduction (see general procedure G) to furnish 86 (30 mg, 115 μmol) as a colourless oil in 69 % yield after purification (silica gel, 0 % → 20 % MeOH in CHCl3 with 0.5 % NH4OH). Additional HPLC purification was required for removal of minor 5–10 % impurities (1 min: isocratic 20 % B → 11.5 min: 40 % B → 12.5 min: 100 % B, 20 min: isocratic 100 % B; tR = 7.6 min). Rf = 0.32 (MeOH/CHCl3, 1:4 + 2 % NH4OH). 1H NMR (600 MHz, MeOD): δ = 5.69 (dt, J = 6.8, 15.2 Hz, 1 H, =CH-2 nonenyl), 5.40 (dt, J = 7.2, 15.2 Hz, 1 H, =CH-3 nonenyl), 3.97–3.93 (m, 1 H, 3-H), 3.93–3.89 (m, 1 H, 4-H), 3.84–3.80 (m, 1 H, 2-H), 3.42–3.36 (m, 2 H, 1-H, 5a-H), 3.20 (d, J = 13.2 Hz, 1 H, 5b-H), 2.55–2.48 (m, 1 H, CHH-1 nonenyl), 2.38 (dt, J = 6.8, 13.7 Hz, 1 H, CHH-1 nonenyl), 2.09–2.02 (m, 2 H, CH2-4 nonenyl), 1.43–1.36 (m, 2 H, CH2-5 nonenyl), 1.36–1.26 (m, 6 H, 3 × CH2 nonenyl), 0.90 (t, J = 7.0 Hz, 3 H, CH3-9 nonenyl) ppm. 13C NMR (150 MHz, MeOD): δ = 137.7 (=CH-3 nonenyl), 124.0 (=CH-2 nonenyl), 69.7 (C-2), 68.4 (C-4), 68.0 (C-3), 56.4 (C-1), 47.5 (C-6), 33.8 (CH2-4 nonenyl), 33.2 (CH2-1 nonenyl), 33.0 (CH2 nonenyl), 30.4 (CH2-5 nonenyl), 30.1 (CH2 nonenyl), 23.8 (CH2 nonenyl), 14.6 (CH3-9 nonenyl) ppm. IR (thin film): equation imagemax. = 3366, 2928, 2857, 1436, 1199, 1139, 1062, 1007, 971 cm–1. [α]D20 = 13.2 (c = 0.4, MeOH). HRMS: found 258.2065 [M + H]+, calcd. for [C14H27NO3 + H]+ 258.2064.

Supporting Information (see footnote on the first page of this article): Copies of 1H and 13C APT NMR spectra for all synthetic intermediates and iminosugars reported in the Experimental Section.

Acknowledgements

The authors thank Hans van den Elst for assistance with the HPLC purifications. This work was supported by the Academic Medical Center and the Chemical Sciences Division of the Netherlands Organisation for Scientific Research (NWO-CW) (governmental TOP grant 700.57.304).

Footnotes

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