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Keywords:

  • Alkaloids;
  • Heterocycles;
  • Lactams;
  • Asymmetric synthesis;
  • Total synthesis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results and Discussion
  5. Conclusions
  6. Experimental Section
  7. Acknowledgements

Starting from tricyclic lactam 2, which is easily accessible by cyclocondensation of δ-oxoester 1 with (R)-phenylglycinol, a three-step synthetic route to enantiopure 1-substituted tetrahydroisoquinolines, including 1-alkyl-, 1-aryl-, and 1-benzyltetrahydroisoquinoline alkaloids, as well as the tricyclic alkaloid (–)-crispine A, has been developed. The key step is a stereoselective α-amidoalkylation reaction using the appropriate Grignard reagent.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results and Discussion
  5. Conclusions
  6. Experimental Section
  7. Acknowledgements

The tetrahydroisoquinoline ring system is present in numerous structurally diverse natural products exhibiting a wide range of biological and pharmacological activities.1 In particular, simple 1-substituted tetrahydroisoquinolines are of great interest not only as alkaloids themselves but also as useful key intermediates in the synthesis of more complex alkaloids. This has stimulated the development of a number of methodologies aimed at the enantioselective synthesis of 1-substituted tetrahydroisoquinoline derivatives2 (Figure 1).

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Figure 1. Selected 1-substituted tetrahydroisoquinoline alkaloids.

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In previous work, we demonstrated that phenylglycinol-derived oxazolopiperidone lactams are versatile scaffolds that allow the regio- and stereocontrolled introduction of substituents at different positions of the piperidine ring, thus providing access to enantiopure substituted piperidines bearing virtually any type of substitution pattern, aswell as to quinolizidine, indolizidine, decahydroquinoline, and complex piperidine-containing indole alkaloids3 (Scheme 1).

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Scheme 1. Natural and bioactive products prepared from phenylglycinol-derived lactams.

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Results and Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results and Discussion
  5. Conclusions
  6. Experimental Section
  7. Acknowledgements

To further expand the synthetic potential of phenylglycinol-derived oxazolopiperidone lactams, we report here a general methodology for the enantioselective synthesis of 1-substituted tetrahydroisoquinoline alkaloids. The application of our enantiomeric scaffolding strategy4 would simply require starting from an appropriate benzo-fused oxazolopiperidone lactam and the subsequent stereocontrolled introduction of the substituent at the 1-position of the tetrahydroisoquinoline ring by an asymmetric α-amidoalkylation reaction.5

Tricyclic lactam 2 was envisaged as the pivotal intermediate of our synthesis. It was prepared in 52 % yield by cyclocondensation of aldehyde ester 16 with (R)-phenylglycinol in refluxing toluene in the presence of a catalytic amount of p-TsOH (Scheme 2). The absolute configuration of lactam 2 was unambiguously determined by X-ray crystallographic analysis.7 Minor amounts (6 %) of lactam epi-2, epimeric at the 2-position of the oxazolidine ring, were also formed.

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Scheme 2. Preparation of key tricyclic lactam 2.

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In contrast with related cis-oxazolopiperidone lactams,8 minor cis lactam epi-2 did not undergo epimerization under acidic conditions (1.2 n HCl, MeOH, r.t); isoquinolone 3 and trace amounts of dimer 4 were formed instead. This dimer was formed in 49 % yield after prolonged acidic treatment (1.2 n HCl, MeOH, reflux, 66 h) of isoquinolone 3.

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Initial attempts to carry out the α-amidoalkylation reaction with a higher order cyanocuprate [Me2Cu(CN)Li2] in the presence of BF3·Et2O9 resulted in failure, leading exclusively to isoquinolone 3. However, treatment of lactam 2 with an excess amount (3 equiv.) of methylmagnesium chloride at 5 °C stereoselectively led to the expected 1-substituted tetrahydroisoquinolone 5a in 61 % yield (Table 1).10 Isoquinolone 3 was formed as a byproduct (17 %). Higher temperatures resulted in the formation of increasing amounts of 3, whereas when the reaction was carried out at a lower temperature the starting lactam was recovered to a considerable extent.

Table 1. Enantioselective synthesis of 1-substituted tetrahydroisoquinolines.
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The observed retention of the configuration of the reactive methine carbon can be rationalized by considering that the Grignard reagent coordinates with the oxygen atom of the oxazolidine ring and that the subsequent intramolecular delivery of the alkyl group occurs on the same face of the C–O bond of the incipient acyl iminium salt (Figure 2).11

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Figure 2. Stereochemical outcome of the α-amidoalkylation reaction.

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As in related cis-substituted oxazolopiperidones,11 minor cis lactam epi-2 was more reluctant to undergo α-amidoalkylation12 than trans isomer 2 and, upon treatment with MeMgCl, led to isoquinolone 3 as the major product (50 %); 2-methyltetrahydroisoquinoline 5a was formed in low yield (35 %).

Removal of the phenylethanol moiety from lactam 5a was accomplished in excellent yield with sodium in liquid ammonia to give N-unsubstituted lactam 6a. Subsequent reduction with borane generated in situ from NaBH4 and iodine completed the enantioselective synthesis of (–)-salsolidine (7a).13 Taking into account previous correlations, this synthesis also constitutes a formal synthesis of the alkaloid (–)-carnegine.14

The above protocol provides general access to 1-alkyl-substituted tetrahydroisoquinolines. Thus, reaction of lactam 2 with ethylmagnesium bromide stereoselectively afforded (82 % yield) lactam 5b, which was then debenzylated and converted into (S)-1-ethyl-1,2,3,4-tetrahydroisoquinoline 7b in good overall yield, as in the above methyl series.

With the aim of demonstrating the potential of the methodology for the synthesis of 1-aryl-, 1-benzyl-, and 1-phenethyltetrahydroisoquinoline alkaloids, we applied the above three-step sequence from lactam 2 using a variety of aryl-, benzyl-, and phenethylmagnesium halides. The results are summarized in Table 1 (Entries c–g). In all cases the α-amidoalkylation reaction took place stereoselectively to give a single 1-substituted tetrahydroisoquinolone derivative (i.e., 5cg).15

Although the reductive cleavage of the exocyclic benzylic C–N bond of 2-phenyl derivative 5c with Na/liq. NH3 occurred with concomitant cleavage of the doubly benzylic endocyclic C–N bond to give 2-benzyl-4,5-dimethoxyphenylacetamide (8), a similar reduction from the methoxyphenyl-substituted tetrahydroisoquinolones 5d and 5e satisfactorily led to the respective N-unsubstituted lactams 6d and 6e in excellent yield. Subsequent reduction of the lactam carbonyl of 6d led to (–)-norcryptostyline II (7d), which constitutes a formal synthesis of the alkaloid (+)-cryptostyline II.16 Similarly, lactam 6e was converted into (–)-norcryptostyline III (7e), a known precursor of the alkaloid (+)-cryptostyline III.17

The same set of sequential reductions (Na/liq. NH3 and then NaBH4/I2) was used to convert 2-benzyl derivative 5f into (–)-O,O-dimethylcoclaurine (7f).18 Taking into account previous transformations, this synthesis also constitutes a formal synthesis of the alkaloids (+)-O-methylarmepavine,18a,18b zanoxyline,19 and (–)-demethylcoclaurine[(–)-higenamine].18d

Similarly, the usefulness of this methodology in the synthesis of 1-phenethyltetrahydroisoquinolines was demonstrated by the preparation of 7g20 from α-amidoalkylation product 5g.

The procedure allows the preparation of tetrahydroisoquinolines and tetrahydroisoquinolones bearing a functionalized C-1 substituent, for instance allyl21 or 2-(1,3-dioxan-2-yl)ethyl (Table 1, Entries h and i),22 which can open access to more complex tetrahydroisoquinoline alkaloids embodying an additional ring. This was exemplified with the synthesis of the pyrrolo[2,1-g]isoquinoline alkaloid crispine A. The three-carbon fragment required for the construction of the pyrrolidine ring was incorporated in the α-amidoalkylation step. Thus, reaction of lactam 2 with the Grignard reagent derived from 2-(2-bromoethyl)-1,3-dioxane (Scheme 3) gave 1-substituted tetrahydroisoquinolone. In this synthesis, the lactam carbonyl was reduced prior to debenzylation to give tetrahydroisoquinoline 9 in excellent yield. Subsequent catalytic hydrogenation under acidic conditions brought about the hydrogenolysis of the exocyclic benzylic C–N bond, deprotection of the acetal function, and closure of the pyrrolidine ring by reductive amination, directly leading to crispine A23 in 74 % yield.

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Scheme 3. Enantioselective synthesis of (–)-crispine A.

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Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results and Discussion
  5. Conclusions
  6. Experimental Section
  7. Acknowledgements

Tricyclic (R)-phenylglycinol-derived lactam 2 has proven to be a useful scaffold that provides general access to enantiopure 1-substituted tetrahydroisoquinoline derivatives, including 1-alkyl-, 1-aryl-, and 1-benzyltetrahydroisoquinoline alkaloids as well as more complex alkaloids bearing the tetrahydroisoquinoline moiety (Scheme 4). The enantioselective synthesis of 1-benzyltetrahydroisoquinolines is of particular interest because these derivatives not only play a pivotal role in the biosynthesis of numerous alkaloids with a variety of skeletal types (e.g., aporphines, cularines, protoberberines, and pavines) but have also been used as key synthetic precursors of such alkaloids.24

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Scheme 4. Enantiopure 1-substituted tetrahydroisoquinolines prepared from common scaffold 2.

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Experimental Section

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results and Discussion
  5. Conclusions
  6. Experimental Section
  7. Acknowledgements

General: Flash chromatography was carried out on SiO2 (silica gel 60, SDS, 0.04–0.06 mm) or (when indicated) by using a cartridge containing amine-functionalized silica. Melting points were taken with a Büchi apparatus and are uncorrected. Optical rotations were measured with a Perkin-Elmer 241 polarimeter. High-resolution mass spectra (HMRS; LC/MSD TOF Agilent Technologies) were performed by Serveis Científico-Tècnics, Barcelona. Microanalyses (Carlo Erba 1106 analyzer) were performed by Centre d'Investigació i Desenvolupament (CSIC), Barcelona. Only noteworthy IR absorptions (Perkin-Elmer 1600) are listed. NMR spectra were recorded with either a Varian Gemini-300 (300 and 75.4 MHz for 1H and 13C, respectively) or Mercury-400 (400 and 100.6 MHz for 1H and 13C, respectively) spectrometer.

(3R,10bS)-8,9-Dimethoxy-5-oxo-3-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo[2,3-a]isoquinoline (2): To a mixture of aldehyde-ester 16 (993 mg, 4.2 mmol) and (R)-phenylglycinol (690 mg, 5.0 mmol) in anhydrous toluene (45 mL) containing 4 Å molecular sieves was added a catalytic amount of p-TsOH. The mixture was heated at reflux for 18 h with azeotropic elimination of water produced by a Dean–Stark apparatus. The resulting suspension was concentrated under reduced pressure to give a yellow foam. Flash chromatography (Et2O to EtOAc) afforded lactam 2 (710 mg, 52 %) and the 10b-epimer epi-2 (82 mg, 6 %). Data for 2: White solid; m.p. 135–137 °C (Et2O). [α]D22 = –136.6 (c = 1.0, CHCl3). IR (KBr): equation image = 1665 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 3.52 (d, J = 19.2 Hz, 1 H, 6-H), 3.73 (dd, J = 19.2, 2.2 Hz, 1 H, 6-H), 3.88 (s, 3 H, OCH3), 3.91 (s, 3 H, OCH3), 4.02 (dd, J = 9.0, 7.5 Hz, 1 H, 2-H), 4.58 (dd, J = 9.0, 7.5 Hz, 1 H, 2-H), 5.38 (t, J = 7.5 Hz, 1 H, 3-H), 6.02 (d, J = 2.2 Hz, 1 H, 10b-H), 6.66 (s, 1 H, 10-H), 6.99 (s, 1 H, 7-H), 7.35 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 36.9 (C-6), 56.0 (OCH3), 56.1 (OCH3), 58.6 (C-3), 72.7 (C-2), 87.8 (C-10b), 107.7 (C-10), 109.8 (C-7), 122.5 (C-6a), 123.1 (C-10a), 126.0 (C-o), 127.7 (C-p), 128.8 (C-m), 139.3 (C-i), 148.4 (C-8), 149.7 (C-9), 166.2 (CO) ppm. HRMS: calcd. for C19H19NO4 [M + H]+ 326.1386; found 326.1382. C19H19NO4 (325.36): calcd. C 70.14, H 5.89, N 4.31; found C 70.27, H 5.87, N 4.08. Data for epi-2: [α]D22 = +62.5 (c = 1.0, CHCl3). IR (KBr): equation image = 1667 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.45 (d, J = 18.9 Hz, 1 H, 6-H), 3.60 (dd, J = 18.9, 2.1 Hz, 1 H, 6-H), 3.90 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 4.20 (dd, J = 9.0, 0.9 Hz, 1 H, 2-H), 4.47 (dd, J = 9.0, 6.3 Hz, 1 H, 2-H), 5.10 (d, J = 6.3 Hz, 1 H, 3-H), 5.90 (d, J = 2.1 Hz, 1 H, 10b-H), 6.71 (s, 1 H, 10-H), 7.10 (s, 1 H, 7-H), 7.15–7.25 (m, 5 H, ArH) ppm. 13C NMR (75.6 MHz, CDCl3, 25 °C): δ = 38.1 (C-6), 55.9 (OCH3), 56.0 (OCH3), 58.6 (C-3), 74.8 (C-2), 87.3 (C-10b), 106.5 (C-10), 110.1 (C-7), 123.0 (C-6a), 125.0 (C-10a), 125.9 (C-o), 127.4 (C-p), 128.4 (C-m), 140.5 (C-i), 148.0 (C-8), 149.2 (C-9), 165.2 (CO) ppm. HRMS: calcd. for C19H19NO4 [M + H]+ 326.1386; found 326.1382.

Dimer 4: A solution of 1.2 M HCl in MeOH (6 mL) was added to a solution of isoquinolone 3 (96 mg, 0.3 mmol) in MeOH (1 mL). The mixture was heated at reflux for 66 h. The solvent was removed, and the resulting solid was diluted with EtOAc. The solution was washed with saturated aqueous Na2CO3. The organic phase was dried and concentrated to give a residue, which was purified by chromatography (7:3 Et2O/EtOAc to EtOAc) to afford 4 (47 mg, 49 %) as a yellow oil. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 3.48 (s, 6 H, 2 OCH3), 3.64 (s, 6 H, 2 OCH3), 4.27 (dd, J = 13.0, 2.8 Hz, 2 H, 2 CH2OH), 4.43 (d, J = 10.8 Hz, 2 H, 2 CHCO), 4.44 (dd, J = 13.0, 3.6 Hz, 2 H, 2 CH2OH), 4.79 (d, J = 11.2 Hz, 2 H, 2 CHNCO), 5.68 (s, 2 H, 2 CH3OCCH), 5.73 (t, J = 2.9 Hz, 2 H, CHAr), 6.26 (s, 2 H, 2 CH3OCCH), 7.08 (d, J = 6.4 Hz, 4 H, ArH), 7.14–7.23 (m, 6 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 55.9 (OCH3), 56.0 (OCH3), 56.9 (CHCO), 58.5 (CHNCO), 58.7 (CHAr), 62.1 (CH2OH), 108.6 (CH3OCCH), 110.3 (CH3OCCH), 127.7 (C-p), 128.4 (C-o), 128.7 (CCHCO), 128.9 (C-m), 131.5 (CCHN), 136.4 (C-i), 147.5 (CH3OC), 147.9 (CH3OC), 176.0 (CO) ppm. HRMS: calcd. for C38H38N2O8 [M + H]+ 651.2706; found 651.2697.

General Procedure for the α-Amidoalkylation Reaction: The Grignard reagent (3.0 equiv.) was added to a cooled (5 °C) solution of oxazolopiperidone 2 (1 equiv.) in THF, and the mixture was stirred at this temperature until the disappearance of the starting material was observed by TLC. The reaction was quenched by the addition of water, and the mixture was extracted with EtOAc. The combined extracts were dried and concentrated to give the 1-substituted tetrahydroisoquinolones after flash chromatography.

(1S)-2-[(1R)-2-Hydroxy-1-phenylethyl]-6,7-dimethoxy-1-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline (5a): Following the above general procedure (reaction time 1.5 h), from lactam 2 (100 mg, 0.31 mmol) and methylmagnesium chloride (3 M in THF, 0.31 mL, 0.92 mmol) in THF (12.5 mL) a brown oil was obtained. Flash chromatography (7:3 Et2O/EtOAc, increasing polarity and 9:1 EtOAc/EtOH) gave 5a (64 mg, 61 %) as a yellow oil and isoquinolone 3 (17 mg, 17 %) as a yellow-green foam. Data for 5a: [α]D22 = +23.5 (c = 1.0, CHCl3). IR (KBr): equation image = 1629, 3400 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.39 (d, J = 7.2 Hz, 3 H, CH3), 3.60 (d, J = 18.9 Hz, 1 H, 4-H), 3.76 (d, J = 18.9 Hz, 1 H, 4-H), 3.77 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 4.28 (q, J = 7.2 Hz, 1 H, 1-H), 4.29 (dd, J = 12.0, 8.4 Hz, 1 H, CH2OH), 4.30 (dd, J = 12.0, 5.2 Hz, 1 H, CH2OH), 5.70 (dd, J = 8.4, 5.2 Hz, 1 H, CHAr), 6.38 (s, 1 H, 8-H), 6.66 (s, 1 H, 5-H), 7.18–7.30 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 23.2 (CH3), 37.3 (C-4), 55.6 (OCH3), 56.0 (OCH3), 56.1 (C-1), 60.8 (CHAr), 63.3 (CH2OH), 107.7 (C-8), 110.3 (C-5), 123.1 (C-4a), 127.6 (C-o), 128.1 (C-p), 128.7 (C-m), 130.5 (C-8a), 136.8 (C-i), 148.3 (C-7), 147.8 (C-6), 171.7 (CO) ppm. HRMS: calcd. for C20H23NO4 [M + H]+ 342.1699; found 342.1695. C20H23NO4·1/4CH2Cl2 (362.64): calcd. C 67.07, H 6.53, N 3.86; found C 67.13, H 6.65, N 3.81. Data for 3: IR (KBr): equation image = 1652, 3269 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 3.82 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 4.31 (dd, J = 12.4, 7.2 Hz, 1 H, CH2OH), 4.42 (dd, J = 12.4, 4.4 Hz, 1 H, CH2OH), 6.12 (s, 1 H, 5-H), 6.26 (s, 1 H, 8-H), 6.47 (dd, J = 7.2, 4.4 Hz, 1 H, CHAr), 6.59 (s, 1 H, 4-H), 7.33 (m, 5 H, ArH), 7.95 (s, 1 H, 1-H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 55.7 (OCH3), 55.8 (OCH3), 60.7 (CHAr), 62.9 (CH2OH), 100.6 (C-7), 103.6 (C-5), 107.6 (C-4), 114.2 (C-8a), 127.9 (C-m), 128.1 (C-p), 128.9 (C-o), 135.3 (C-1), 137.4 (C-i), 140.6 (C-6), 147.7 (C-7), 155.0 (C-4a), 160.5 (CO) ppm. EM (IQ+): m/z (%) = 326 (47), 325 (5), 206 (13), 138 (27), 122 (12) 121 (100).

(1S)-1-Ethyl-2-[(1R)-2-hydroxy-1-phenylethyl]-6,7-dimethoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline (5b): Following the general procedure (reaction time 6 h), from lactam 2 (400 mg, 1.23 mmol) in THF (10 mL) and ethylmagnesium bromide (3 M in Et2O, 1.23 mL, 3.68 mmol) a residue was obtained. Flash chromatography (1:1 Et2O/EtOAc) gave 5b (354 mg, 82 %) as a yellow oil: [α]D22 = +34.4 (c = 1.0, CHCl3). IR (KBr): equation image = 1630, 3388 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.72 (t, J = 7.2 Hz, 3 H, CH3), 1.66–1.77 (m, 1 H, CH2), 1.79–1.89 (m, 1 H, CH2), 3.57 (d, J = 18.0 Hz, 1 H, 4-H), 3.77 (s, 3 H, OCH3), 3.79 (d, J = 18.0 Hz, 1 H, 4-H), 3.86 (s, 3 H, OCH3), 4.00 (dd, J = 9.6, 3.2 Hz, 1 H, 1-H), 4.23 (dd, J = 11.6, 8.4 Hz, 1 H, CH2OH), 4.29 (dd, J = 11.6, 5.2 Hz, 1 H, CH2OH), 5.66 (dd, J = 8.4, 5.2 Hz, 1 H, CHAr), 6.33 (s, 1 H, 8-H), 6.67 (s, 1 H, 5-H), 7.10–7.30 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 10.2 (CH3), 29.1 (CH2), 37.5 (C-4), 55.9 (OCH3), 56.1 (OCH3), 61.3 (C-1), 61.5 (CHAr), 63.4 (CH2OH), 109.3 (C-8), 110.3 (C-5), 123.7 (C-4a), 127.7 (C-o), 127.8 (C-p), 127.8 (C-8a), 129.9 (C-m), 136.8 (C-i), 147.2 (C-7), 148.3 (C-6), 171.9 (CO) ppm. HRMS: calcd. for C21H25NO4 [M + H]+ 356.1862; found 356.1872. C21H25NO4·1/4CHCl3 (385.28): calcd. C 66.25, H 6.61, N 3.64; found C 66.13, H 6.64, N 3.53.

(1S)-2-[(1R)-2-Hydroxy-1-phenylethyl]-6,7-dimethoxy-3-oxo-1-phenyl-1,2,3,4-tetrahydroisoquinoline (5c): Following the general procedure (reaction time 1 h), from lactam 2 (500 mg, 1.54 mmol) in THF (10 mL) and phenylmagnesium chloride (2 M in THF, 2.3 mL, 4.61 mmol) a residue was obtained. Flash chromatography (Et2O/EtOAc increasing polarity and 9:1 EtOAc/EtOH) gave 5c (415 mg, 67 %) as a yellow oil and 3 (125 mg, 25 %). Data for 5c: [α]D22 = +16.7 (c = 1.0, CHCl3). IR (KBr): equation image = 1629, 3388 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.66 (d, J = 19.8 Hz, 1 H, 4-H), 3.71 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.84 (d, J = 19.8 Hz, 1 H, 4-H), 3.88–3.91 (m, 2 H, CH2OH), 5.26 (s, 1 H, 1-H), 5.96 (t, J = 6.6 Hz, 1 H, CHAr), 6.41 (s, 1 H, 8-H), 6.58 (s, 1 H, 5-H), 7.15–7.30 (m, 10 H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 37.2 (C-4), 55.8 (OCH3), 55.9 (OCH3), 59.9 (C-1), 62.2 (CH2OH), 62.5 (CHAr), 108.6 (C-8), 110.0 (C-5), 122.3 (C-4a), 126.0 (C-o), 127.4 (C-p), 127.8 (C-p), 128.1 (C-m), 128.3 (C-o), 128.5 (C-8a), 128.8 (C-m), 136.7 (C-i), 143.0 (C-i), 147.8 (C-6), 148.0 (C-7), 171.9 (CO) ppm. HRMS: calcd. for C25H25NO4 [M + H]+ 404.1862; found 404.1875.

(1S)-1-(3,4-Dimethoxyphenyl)-2-[(1R)-2-hydroxy-1-phenylethyl]-6,7-dimethoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline (5d): Following the general procedure (reaction time 15 min), from lactam 2 (150 mg, 0.46 mmol) in THF (10 mL) and 3,4-dimethoxyphenylmagnesium bromide (0.5 M in THF, 2.8 mL, 1.4 mmol) a residue was obtained. Flash chromatography (1:1 Et2O/EtOAc, increasing polarity and 9:1 EtOAc/EtOH) gave 5d (115 mg, 54 %) as a yellow foam and 3 (50 mg, 33 %). Data for 5d: [α]D22 = +17.1 (c = 1.0, CHCl3). IR (KBr): equation image = 1634, 3406 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 3.68 (d, J = 20.0 Hz, 1 H, 4-H), 3.73 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 3.83 (s, 3 H, CH3O), 3.86 (s, 3 H, CH3O), 3.87 (d, J = 20.0 Hz, 1 H, 4-H), 3.95 (dd, J = 11.6, 8.4 Hz, 1 H, CH2OH), 4.01 (dd, J = 11.6, 5.2 Hz, 1 H, CH2OH), 5.18 (s, 1 H, 1-H), 5.93 (dd, J = 8.4, 5.2 Hz, 1 H, CHAr), 6.37 (s, 1 H, 2′-H), 6.58 (s, 1 H, 5′-H), 6.72 (s, 1 H, 6′-H), 6.75 (s, 1 H, 8-H), 6.76 (s, 1 H, 5-H), 7.12–7.15 (m, 2 H, ArH), 7.26–7.32 (m, 3 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 37.4 (C-4), 55.8 (OCH3), 55.9 (OCH3), 55.9 (OCH3), 56.0 (OCH3), 60.4 (C-1), 62.5 (CHAr), 62.6 (CH2OH), 108.1 (C-8), 109.5 (C-5), 110.1 (C-2′), 111.3 (C-5′), 118.3 (C-6′), 122.4 (C-4a), 127.9 (C-p), 128.4 (C-o), 128.6 (C-8a), 128.6 (C-m), 134.4 (C-1′), 136.2 (C-i), 147.9 (C-6), 148.5 (C-4′), 148.6 (C-7), 149.2 (C-3′), 171.6 (CO) ppm. HRMS: calcd. for C27H29NO6 [M + H]+ 464.2073; found 464.2081. C27H29NO6·1/4CHCl3 (493.37): calcd. C 66.34, H 5.98, N 2.84; found C 66.65, H 6.33, N 2.49.

(1S)-2-[(1R)-2-Hydroxy-1-phenylethyl]-6,7-dimethoxy-3-oxo-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (5e): Following the general procedure (reaction time 20 min), from lactam 2 (500 mg, 1.54 mmol) in THF (10 mL) and 3,4,5-trimethoxyphenylmagnesium bromide (0.5 M in THF, 9.2 mL, 4.61 mmol) a residue was obtained. Flash chromatography (Et2O/EtOAc, increasing polarity and 9:1 EtOAc/EtOH) gave 5e (370 mg, 49 %) as a yellow foam and 3 (135 mg, 27 %). Data for 5e: [α]D22 = +13.1 (c = 1.0, CHCl3). IR (KBr): equation image = 1684, 2930 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.65 (d, J = 19.5 Hz, 1 H, 4-H), 3.75 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 3.80 (masked d, 4-H), 3.81 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 5.17 (s, 1 H, 1-H), 3.98–4.08 (m, 2 H, CH2OH), 5.89 (dd, J = 8.7, 5.1 Hz, 1 H, CHAr), 6.40 (s, 1 H, 2′-H), 6.46 (s, 2 H, 5-H, 8-H), 6.62 (s, 2 H, 6′-H), 7.13–7.27 (m, 2 H, ArH), 7.29–7.31 (m, 3 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 37.3 (C-4), 55.8 (OCH3), 55.9 (OCH3), 56.0 (OCH3), 56.1 (OCH3), 56.2 (OCH3), 60.8 (C-1), 62.8 (CH2OH), 63.0 (CHAr), 103.3 (C-2′, C-6′), 108.1 (C-8), 110.0 (C-5), 122.7 (C-4a), 128.1 (C-p), 128.4 (C-o), 128.6 (C-8a), 128.6 (C-m), 136.1 (C-1′), 137.0 (C-i), 137.4 (C-4′), 147.9 (C-6), 148.6 (C-7), 153.4 (C-5′, C-3′), 172.0 (CO) ppm. HRMS: calcd. for C28H31NO7 [M + H]+ 494.2179; found 494.2183. C28H31NO7·1/4CHCl3 (523.40): calcd. C 64.83, H 6.02, N 2.68; found C 64.69, H 6.26, N 2.42.

(1S)-[(R)-2-Hydroxy-1-phenylethyl]-6,7-dimethoxy-1-(p-methoxybenzyl)-3-oxo-1,2,3,4-tetrahydroisoquinoline (5f): Following the general procedure (reaction time 15 min), from lactam 2 (150 mg, 0.46 mmol) in THF (10 mL) and 4-methoxybenzylmagnesium chloride (0.25 M in THF, 5.5 mL, 1.4 mmol) a residue was obtained. Flash chromatography (3:7 hexane/EtOAc, increasing polarity and 9:1 EtOAc/EtOH) gave 5f (129 mg, 63 %) as a white foam and 3 (37 mg, 25 %). Data for 5f: [α]D22 = +41.5 (c = 1.0, CHCl3). IR (KBr): equation image = 1630, 3393 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.84 (dd, J = 13.1, 8.5 Hz, 1 H, CHCH2Ar), 3.06 (dd, J = 13.1, 3.4 Hz, 1 H, CHCH2Ar), 3.10 (d, J = 19.4 Hz, 1 H, 4-H), 3.39 (d, J = 19.4 Hz, 1 H, 4-H), 3.51 (s, 3 H, OCH3C-4′), 3.69 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 4.29 (dd, J = 8.5, 3.4 Hz, 1 H, 1-H), 4.35–4.44 (m, 2 H, CH2OH), 5.80 (s, 1 H, 5-H or 8-H), 5.85 (t, J = 6.5 Hz, 1 H, CHAr), 6.53 (s, 1 H, 5-H or 8-H), 6.62 (s, 4 H, 2′-H, 3′-H, 5′-H, 6′-H), 7.25–7.35 (m, 5 H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 37.2 (C-4), 41.9 (C-1CH2), 55.2 (OCH3), 55.8 (OCH3), 55.9 (OCH3), 61.4 (C-1), 61.6 (CHAr), 63.6 (CH2OH), 109.2 (C-8), 109.7 (C-5), 113.5 (C-2′, C-6′), 124.2 (C-4a), 127.2 (C-8a), 127.9 (C-o), 128.0 (C-p), 128.8 (C-m), 131.1 (C-m), 131.1 (C-3′, C-5′), 136.9 (C-i), 146.8 (C-6), 148.2 (C-7), 158.5 (C-4′), 172.3 (CO) ppm. HRMS: calcd. for C27H29NO5 [M + H]+ 448.2124; found 448.2130. C27H29NO5·3/4H2O (461.04): calcd. C 70.34, H 6.67, N 3.04; found C 70.03, H 6.42, N 2.87.

(1S)-2-[(1R)-2-Hydroxy-1-phenylethyl]-6,7-dimethoxy-3-oxo-1-phenethyl-1,2,3,4-tetrahydroisoquinoline (5 g): Following the general procedure (reaction time 40 min), from lactam 2 (400 mg, 1.23 mmol) in THF (10 mL) and phenethylmagnesium chloride (1 M in THF, 3.69 mL, 3.69 mmol) a residue was obtained. Flash chromatography (8:2 Et2O/EtOAc, increasing polarity and 9:1 EtOAc/EtOH) gave 5g (353 mg, 67 %) as a white foam and 3 (68 mg, 17 %). Data for 5g: [α]D22 = +72.9 (c = 1.0, CHCl3). IR (KBr): equation image = 1632, 3399 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.92–2.07 (m, 1 H, CH2), 2.10–2.18 (m, 1 H, CH2), 2.25–2.36 (m, 1 H, CH2Ar), 2.50–2.57 (m, 1 H, CH2Ar), 3.59 (d, J = 18.8 Hz, 1 H, 4-H), 3.78 (s, 3 H, OCH3), 3.81 (d, J = 18.8 Hz, 1 H, 4-H), 3.87 (s, 3 H, OCH3), 4.10 (dd, J = 9.2, 2.8 Hz, 1 H, 1-H), 4.18–4.23 (m, 2 H, CH2OH), 5.59 (dd, J = 7.6, 6.0 Hz, 1 H, CHAr), 6.34 (s, 1 H, 8-H), 6.69 (s, 1 H, 5-H), 7.01 (d, J = 13.2 Hz, 2 H, C-2′, C-6′), 7.15 (m, 1 H, 4′-H), 7.20 (br. s, 2 H, C-3′, C-5′), 7.24–7.26 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 31.5 (CH2Ar), 37.6 (C-4), 37.7 (CH2), 56.0 (OCH3), 56.1 (OCH3), 59.4 (C-1), 61.7 (CHAr), 63.3 (CH2OH), 109.1 (C-8), 110.5 (C-5), 123.9 (C-4a), 126.1 (C-4′), 127.8 (C-p), 127.8 (C-m), 128.1 (C-o), 128.3 (C-8a), 128.5 (C-2′, C-6′), 128.6 (C-3′, C-5′), 136.7 (C-i), 140.6 (C-1′), 147.3 (C-6), 148.4 (C-7), 171.9 (CO) ppm. HRMS: calcd. for C27H29NO4 [M + H]+ 432.2175; found 432.2180. C27H29NO4·3/4H2O (445.04): calcd. C 72.87, H 6.91, N 3.15; found C 72.95, H 6.87, N 2.95.

(1S)-1-Allyl-2-[(1R)-2-hydroxy-1-phenylethyl]-6,7-dimethoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline (5h): Following the general procedure (reaction time 2 h), from lactam 2 (200 mg, 0.6 mmol) in THF (10 mL) and allylmagnesium bromide (1 M in Et2O, 1.85 mL, 1.85 mmol) a yellow oil was obtained. Flash chromatography (95:5 tert-butyl methyl ether/EtOAc) gave 5h (92 mg, 42 %) as a white oil and 1-(2-allyl-2-hydroxy-4-pentenyl)-2-{1-[2-hydroxy-(1R)-phenylethylamino]-3-butenyl}-4,5-dimethoxybenzene (10; 103 mg, 39 %). Data for 5h: [α]D22 = +16.8 (c = 1.0, CHCl3). IR (KBr): equation image = 1637, 3386 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 2.18–2.33 (m, 1 H, CH2CH=), 2.39–2.60 (m, 1 H, CH2CH=), 3.54 (d, J = 19.5 Hz, 1 H, 4-H), 3.79 (d, J = 19.5 Hz, 1 H, 4-H), 3.76 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 4.26 (m, 1 H, 1-H), 4.28 (dd, J = 11.4, 7.8 Hz, 1 H, CH2OH), 4.30 (dd, J = 11.4, 5.7 Hz, 1 H, CH2OH), 4.90 (dd, J = 10.5, 1.8 Hz, 1 H, CH2=), 4.99 (td, J = 6.0, 1.8 Hz, 1 H, CH2=), 5.51 (m, 1 H, CH=), 5.68 (dd, J = 7.8, 5.7 Hz, 1 H, 1-H), 6.31 (s, 1 H, 8-H), 6.65 (s, 1 H, 5-H), 7.22–7.38 (m, 5 H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 37.6 (C-4), 40.8 (CH2CH=), 55.8 (OCH3), 56.0 (OCH3), 60.1 (C-1), 61.3 (CHAr), 63.2 (CH2OH), 109.0 (C-8), 110.0 (C-5), 118.9 (CH2=), 123.6 (C-4a), 127.6 (C-p), 127.7 (C-o), 128.4 (C-m), 128.6 (C-8a), 133.0 (CH=), 136.8 (C-i), 147.1 (C-7), 148.2 (C-6), 171.8 (CO) ppm. HRMS: calcd. for C22H25NO4 [M + H]+ 368.1862; found 368.1873. C22H25NO4·1/2H2O (411.5): calcd. C 70.05, H 7.10, N 3.40; found C 66.69, H 6.70, N 3.55. Data for 10: IR (KBr): equation image = 1638, 3073, 3324 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.10–2.19 (m, 4 H, 2 CH2CHCH2), 2.38–2.53 (m, 2 H, CHCH2CHCH2), 2.56 (d, J = 14.8 Hz, 1 H, CH2Ar), 2.66 (d, J = 14.8 Hz, 1 H, CH2Ar), 3.57 (dd, J = 10.8, 8.0 Hz, 1 H, CH2OH), 3.67 (dd, J = 10.8, 4.4 Hz, 1 H, CH2OH), 3.85 (s, 3 H, OCH3), 3.86 (dd, J = 8.0, 4.4 Hz, 1 H, CHAr), 3.89 (s, 3 H, OCH3), 4.05 (t, J = 6.4 Hz, 1 H, CHCH2CHCH2), 4.98–5.09 (m, 2 H, CHCH2CHCH2), 5.10–5.15 (m, 4 H, 2 CH2CHCH2), 5.64–5.72 (m, 1 H, CHCH2CHCH2), 5.74–5.84 (m, 2 H, 2 CH2CHCH2), 6.65 (s, 1 H, CH3OCCH), 6.85 (s, 1 H, CH3OCCH), 7.26–7.28 (m, 5 H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 40.3 (CHCH2CHCH2), 40.4 (CH2Ar), 43.7 (CH2CHCH2), 44.0 (CH2CHCH2), 55.1 (CHCH2CHCH2), 55.6 (OCH3), 55.7 (OCH3), 61.5 (CHAr), 66.3 (CH2OH), 73.3 (COH), 110.1 (C-3), 114.8 (C-6), 117.3 (CHCH2CHCH2), 118.5 (CH2CHCH2), 118.6 (CH2CHCH2), 127.0 (C-2), 127.3 (C-m), 127.4 (C-p), 128.4 (C-o), 133.8 (CH2CHCH2), 133.9 (CH2CHCH2), 135.0 (C-1), 135.2 (CHCH2CHCH2), 140.9 (C-i), 146.9 (C-4), 147.5 (C-5) ppm. HRMS: calcd. for C28H37NO4 [M + H]+ 452.2801; found 452.2784. C28H37NO4·1/2H2O (460.61): calcd. C 73.01, H 8.32, N 3.04; found C 73.24, H 8.13, N 2.75.

(1S)-1-[2-(1,3-Dioxan-2-yl)ethyl]-2-[(1R)-2-hydroxy-1-phenylethyl]-6,7-dimethoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline (5i): Following the general procedure (reaction time 2.5 h), from lactam 2 (400 mg, 1.23 mmol) in THF (20 mL) and 2-(1,3-dioxan-2-yl)ethylmagnesium bromide (0.5 M in THF, 7.4 mL, 3.69 mmol) a yellow solid was obtained. Flash chromatography (1:1 Et2O/EtOAc, increasing polarity and 9:1 EtOAc/EtOH) gave 5i (246 mg, 45 %) as a yellow foam and 3 (121 mg, 30 %). Data for 5i: [α]D22 = +38.5 (c = 1.0, CHCl3). IR (KBr): equation image = 1632, 3399 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.31 (dt, J = 13.6, 1.2 Hz, 2 H, 1′-H), 1.41–1.46 (m, 2 H, OCH2CH2), 1.72–1.81 (m, 1 H, 2′-H), 1.92–2.06 (m, 1 H, 2′-H), 3.56 (d, J = 19.0 Hz, 1 H, 4-H), 3.68 (ddd, J = 15.2, 12.0, 3.6 Hz, 2 H, CH2CH2O), 3.75 (s, 3 H, OCH3), 3.79 (d, J = 19.0 Hz, 1 H, 4-H), 3.85 (s, 3 H, OCH3), 4.03 (m, 2 H, CH2CH2O), 4.40 (t, J = 4.8 Hz, 1 H, CHO2), 4.15 (dd, J = 10.0, 3.2 Hz, 1 H, 1-H), 4.23–4.32 (m, 2 H, CH2OH), 5.76 (dd, J = 8.0, 5.6 Hz, 1 H, CHAr), 6.34 (s, 1 H, 8-H), 6.65 (s, 1 H, 5-H), 7.16 (d, J = 1.6 Hz, 1 H, ArH), 7.18 (d, J = 2.0 Hz, 1 H, ArH), 7.25–7.30 (m, 3 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 25.6 (C-1′), 30.3 (C-2′), 31.1 (CH2CH2O), 37.6 (C-4), 55.9 (OCH3), 56.0 (OCH3), 58.9 (C-1), 60.3 (CHAr), 63.1 (CH2OH), 66.7 (2 CH2CH2O), 101.6 (CHO2), 109.4 (C-8), 110.4 (C-5), 123.8 (C-4a), 127.7 (C-p), 127.8 (C-o), 128.1 (C-8a), 128.5 (C-m), 136.8 (C-i), 147.2 (C-6), 148.3 (C-7), 171.9 (CO) ppm. HRMS: calcd. for C25H31NO6 [M + H]+ 442.2223; found 442.2219.

General Procedure for Na/liquid NH3 Reaction: Into a three-necked, round-bottomed flask equipped with a cold-finger condenser charged with dry ice/acetone was condensed NH3 at –78 °C. The temperature was raised to –33 °C, and a solution of lactam 5 in THF was added. Then, sodium metal was added in small portions until the blue color persisted. After the mixture was stirred at –33 °C for 1 min, the reaction was quenched by the addition of solid NH4Cl until the blue color disappeared. The mixture was stirred at room temperature for 4 h, poured into water, and extracted with Et2O. The combined organic extracts were dried and concentrated to give a residue, which was purified by chromatography.

(1S)-6,7-Dimethoxy-1-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline (6a): Operating as described in the general procedure, from 5a (200 mg, 0.59 mmol) in THF (7 mL) and NH3 (50 mL) a clear maroon residue was obtained. Flash chromatography (9:1 EtOAc/EtOH) afforded 6a (110 mg, 85 %) as a white solid. [α]D22 = +10.0 (c = 1.0, CHCl3). IR (KBr): equation image = 1668, 3217 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.51 (d, J = 6.4 Hz, 3 H, CH3), 3.48 (d, J = 20.0 Hz, 1 H, 4-H), 3.60 (d, J = 20.0 Hz, 1 H, 4-H), 3.87 (s, 6 H, 2 OCH3), 4.60 (m, 1 H, 1-H), 6.60 (s, 1 H, 8-H), 6.61 (s, 1 H, 5-H), 6.90 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 24.4 (CH3), 35.4 (C-4), 51.3 (C-1), 56.0 (OCH3), 56.1 (OCH3), 108.2 (C-8), 110.4 (C-5), 122.8 (C-4a), 127.8 (C-8a), 148.0 (C-6), 148.4 (C-7), 171.5 (CO) ppm. HRMS: calcd. for C12H15NO3 [M + H]+ 222.1124; found 222.1122. C12H15NO3 (221.25): calcd. C 65.14, H 6.83, N 6.33; found C 64.89, H 6.76, N 6.16.

(1S)-1-Ethyl-6,7-dimethoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline (6b): Operating as described in the general procedure, from 5b (230 mg, 0.65 mmol) in THF (4 mL) and NH3 (30 mL) a residue was obtained. Flash chromatography (EtOAc) afforded 6b (140 mg, 92 %) as a white oil. [α]D22 = +21.7 (c = 0.57, CHCl3). IR (KBr): equation image = 1654, 2972 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.92 (t, J = 8.0 Hz, 3 H, CH3), 1.81 (m, 2 H, CH2), 3.46 (d, J = 20.0 Hz, 1 H, 4-H), 3.62 (d, J = 20.0 Hz, 1 H, 4-H), 3.87 (s, 6 H, 2 OCH3), 4.44 (m, 1 H, 1-H), 6.60 (s, 1 H, 8-H), 6.62 (s, 1 H, 5-H), 7.70 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 9.1 (CH3), 31.7 (CH2), 35.2 (C-4), 55.9 (OCH3), 56.0 (OCH3), 57.2 (C-1), 108.8 (C-8), 110.3 (C-5), 123.2 (C-4a), 126.2 (C-8a), 147.8 (C-7), 148.4 (C-6), 171.9 (CO) ppm. HRMS: calcd. for C13H17NO3 [M + H]+ 236.1286; found 236.1280.

(1S)-1-[3,4-(Dimethoxyphenyl)]-6,7-dimethoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline (6d): Operating as described in the general procedure, from 5d (215 mg, 0.46 mmol) in THF (3 mL) and NH3 (35 mL) a residue was obtained. Flash chromatography (2:8 to 1:9 hexane/EtOAc) afforded 6d (121 mg, 77 %) as a yellow foam. IR (KBr): equation image = 1647, 2920 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 3.52 (d, J = 24.0 Hz, 1 H, 4-H), 3.66 (d, J = 24.0 Hz, 1 H, 4-H), 3.71 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 5.54 (s, 1 H, 1-H), 6.37 (s, 1 H, 2′-H), 6.65 (s, 1 H, 5′-H), 6.72 (s, 1 H, 6′-H), 6.83 (s, 1 H, 8-H), 6.84 (s, 1 H, 5-H), 7.05 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 35.5 (C-4), 55.6 (OCH3), 55.7 (OCH3), 55.8 (OCH3), 59.6 (C-1), 109.5 (C-8), 110.0 (C-5), 110.1 (C-2′), 110.9 (C-5′), 119.7 (C-6′), 123.0 (C-4a), 126.1 (C-8a), 134.2 (C-1′), 147.7 (C-6), 148.5 (C-4′), 148.8 (C-7), 149.3 (C-3′), 170.8 (CO) ppm. HRMS: calcd. for C19H21NO5 [M + H]+ 344.1498; found 344.1491.

(1S)-6,7-Dimethoxy-3-oxo-1-[3,4,5-(trimethoxyphenyl)]-1,2,3,4-tetrahydroisoquinoline (6e): Operating as described in the general procedure, from 5e (150 mg, 0.30 mmol) in THF (2 mL) and NH3 (30 mL) a residue was obtained. Flash chromatography (EtOAc) afforded 6e (98 mg, 87 %) as a yellow foam. IR (KBr): equation image = 1663, 2926 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.56 (d, J = 18.0 Hz, 1 H, 4-H), 3.71 (d, J = 18.0 Hz, 1 H, 4-H), 3.72 (s, 3 H, OCH3), 3.76 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 5.25 (s, 1 H, 1-H), 6.41 (s, 2 H, 2′-H, 6′-H), 6.66 (s, 1 H, 8-H), 6.73 (s, 1 H, 5-H), 7.25 (br. s, 1 H, NH) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 38.8 (C-4), 55.8 (OCH3), 55.9 (OCH3), 56.0 (OCH3), 56.1 (OCH3), 60.0 (C-1), 60.1 (OCH3), 104.3 (C-8), 105.4 (C-2′, C-6′), 113.9 (C-5), 125.4 (C-4a), 131.2 (C-4′), 131.3 (C-8a), 133.4 (C-1′), 147.7 (C-6), 148.1 (C-7), 153.1 (C-3′, C-5′), 173.7 (CO) ppm. HRMS: calcd. for C20H23NO6 [M + H]+ 374.1603; found 374.1592.

(1S)-6,7-Dimethoxy-1-(p-methoxybenzyl)-3-oxo-1,2,3,4-tetrahydroisoquinoline (6f): Operating as described in the general procedure, from 5f (95 mg, 0.21 mmol) in THF (2 mL) and NH3 (30 mL) a residue was obtained. Flash chromatography (EtOAc to 95:5 EtOAc/EtOH) afforded 6f (58 mg, 85 %) as a yellow foam. [α]D22 = –61.2 (c = 0.5, CHCl3). IR (KBr): equation image = 1630, 2934 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.87 (d, J = 20.0 Hz, 1 H, 4-H), 2.91 (dd, J = 13.5, 6.0 Hz, 1 H, CH2), 3.03 (dd, J = 13.5, 4.0 Hz, 1 H, CH2), 3.23 (d, J = 20.0 Hz, 1 H, 4-H), 3.77 (s, 1 H, OCH3), 3.83 (s, 1 H, OCH3), 3.86 (s, 1 H, OCH3), 4.68 (m, 1 H, 1-H), 6.49 (s, 1 H, 8-H), 6.55 (s, 1 H, 5-H), 6.76 (d, J = 8.2 Hz, 2 H, 2′-H), 6.86 (d, J = 8.2 Hz, 2 H, 3′-H), 6.95 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 35.0 (C-4), 44.5 (CH2), 55.2 (OCH3), 55.9 (C-1), 56.0 (OCH3), 57.3 (OCH3), 108.9 (C-8), 110.1 (C-5), 113.8 (C-3′), 123.9 (C-4a), 125.2 (C-2′), 127.8 (C-8a), 131.8 (C-1′), 147.7 (C-6), 148.4 (C-7), 158.5 (C-4′), 172.3 (CO) ppm. HRMS: calcd. for C19H21NO4 [M + H]+ 328.1549; found 328.1532.

(1S)-6,7-Dimethoxy-3-oxo-1-phenethyl-1,2,3,4-tetrahydroisoquinoline (6g): Operating as described in the general procedure, from 5g (100 mg, 0.23 mmol) in THF (2 mL) and NH3 (25 mL) a residue was obtained. Flash chromatography (EtOAc) afforded 6g (56 mg, 79 %) as a white foam. [α]D22 = +16.0 (c = 1.0, CHCl3). IR (KBr): equation image = 1674 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.03–2.09 (m, 2 H, CH2), 2.62–2.70 (m, 2 H, CH2Ar), 3.48 (d, J = 20.0 Hz, 1 H, 4-H), 3.64 (d, J = 20.0 Hz, 1 H, 4-H), 3.86 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 4.60 (m, 1 H, 1-H), 6.60 (s, 2 H, 5-H, 8-H), 7.14–7.19 (m, 3 H, ArH), 7.25–7.28 (m, 2 H, ArH), 7.43 (m, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 31.2 (CH2Ar), 35.4 (C-4), 40.5 (CH2), 55.7 (C-1), 56.0 (OCH3), 56.1 (OCH3), 108.7 (C-8), 110.5 (C-5), 123.2 (C-4a), 126.1 (C-8a), 126.3 (C-4′), 128.3 (C-3′), 128.5 (C-2′), 140.9 (C-1′), 147.9 (C-6), 148.5 (C-7), 171.7 (CO) ppm. HRMS: calcd. for C19H21NO3 [M + H]+ 312.1599; found 312.1598.

(1S)-1-Allyl-6,7-dimethoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline (6h): Operating as described in the general procedure, from 5h (80 mg, 0.22 mmol) in THF (2 mL) and NH3 (25 mL) a residue was obtained. Flash chromatography (EtOAc) afforded 6h (48.3 mg, 90 %) as a yellow foam. [α]D22 = –10.5 (c = 0.6, CHCl3). IR (KBr): equation image = 1667, 2918 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.45 (ddd, J = 14.0, 7.2, 7.2 Hz, 1 H, CH2), 2.57–2.61 (m, 1 H, CH2), 3.47 (d, J = 20.0 Hz, 1 H, 4-H), 3.60 (d, J = 20.0 Hz, 1 H, 4-H), 3.88 (s, 6 H, 2 OCH3), 4.52 (m, 1 H, 1-H), 5.12–5.17 (m, 2 H, =CH2), 5.69–5.79 (m, 1 H, CH=), 6.60 (s, 1 H, 8-H), 6.65 (s, 1 H, 5-H), 6.80 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 35.4 (C-4), 43.2 (CH2), 55.5 (C-1), 55.9 (OCH3), 56.0 (OCH3), 108.6 (C-8), 110.4 (C-5), 119.9 (=CH2), 123.3 (C-4a), 125.6 (C-8a), 132.7 (CH=), 147.9 (C-6), 148.5 (C-7), 171.2 (CO) ppm. HRMS: calcd. for C14H17NO3 [M + H]+ 248.1288; found 248.1278.

(1S)-1-[2-(1,3-Dioxan-2-yl)ethyl]-6,7-dimethoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline (6i): Operating as described in the general procedure, from 5i (114 mg, 0.26 mmol) in THF (2 mL) and NH3 (30 mL) a residue was obtained. Flash chromatography (9:1 EtOAc/EtOH) afforded 6i (78.5 mg, 92 %) as a white solid. [α]D22 = +2.3 (c = 0.53, CHCl3). IR (KBr): equation image = 1674, 3217 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.33 (dm, J = 13.2 Hz, 2 H, 2′-H), 1.61–1.84 (m, 2 H, 1′-H), 1.87–1.94 (m, 1 H, CH2CH2O), 1.91–2.11 (m, 1 H, CH2CH2O), 3.56 (d, J = 19.5 Hz, 1 H, 4-H), 3.60 (d, J = 19.5 Hz, 1 H, 4-H), 3.74 (td, J = 11.6, 0.8 Hz, 2 H, CH2CH2O), 3.86 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 4.09 (ddd, J = 11.6, 4.8, 1.2 Hz, 2 H, CH2CH2O), 4.48–4.52 (br. m, 1 H, 1-H), 4.56 (t, J = 4.8 Hz, 1 H, CHO2), 6.59 (s, 1 H, 8-H), 6.65 (s, 1 H, 5-H), 7.18 (s.a., 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 25.7 (CH2CH2O), 30.5 (C-1′), 33.0 (C-2′), 35.3 (C-4), 55.6 (C-1), 55.9 (OCH3), 56.0 (OCH3), 66.8 (CH2O), 101.6 (CHO2), 108.8 (C-8), 110.4 (C-5), 123.1 (C-4a), 126.6 (C-8a), 147.8 (C-6), 148.3 (C-7), 171.4 (CO) ppm. HRMS: calcd. for C17H23NO5 [M + H]+ 322.1655; found 322.1650.

2-Benzyl-4,5-dimethoxyphenylacetamide (8): Operating as described in the general procedure, from 5c (100 mg, 1.17 mmol) in THF (2 mL) and NH3 (30 mL) a residue was obtained. Flash chromatography (EtOAc) afforded 8 (20 mg, 28 %). IR (KBr): equation image = 1629, 2933 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 3.44 (s, 2 H, CH2CO), 3.81 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.93 (s, 2 H, CH2Ar), 5.20 (s, 1 H, NH2), 5.90 (s, 1 H, NH2), 6.70 (s, 1 H, 3-H), 6.75 (s, 1 H, 6-H), 7.10–7.25 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 38.8 (CH2Ar), 40.2 (CH2CO), 55.9 (OCH3), 56.0 (OCH3), 113.8 (C-3), 114.2 (C-6), 125.5 (C-1), 126.3 (C-p), 128.5 (C-m), 128.6 (C-o), 131.6 (C-2), 140.3 (C-i), 147.8 (C-4), 148.3 (C-5), 173.9 (CO) ppm. HRMS: calcd. for C17H19NO3 [M + H]+ 286.1443; found 286.1437.

General Procedure for the NaBH4–I2 Reduction Reactions: A solution of iodine (1 equiv.) in THF was slowly added to a cooled (0 °C) suspension of NaBH4 (2.5 equiv.) in anhydrous THF, and the mixture was stirred at this temperature for 30 min. Then, a solution of lactam 6 (1 equiv.) in THF was added to the solution (0 °C). The resulting mixture was heated at reflux for 16 h and cooled to 0 °C. MeOH (4 mL) was slowly added, and the stirring was continued at room temperature for 30 min. The solvent was evaporated, and the resulting solid was digested with 2 n NaOH (30 min). The resulting suspension was extracted with CH2Cl2, the combined organic extracts were dried and concentrated, and the residue was purified by chromatography.

(–)-Salsolidine (7a): Following the above general procedure, from lactam 6a (100 mg, 0.45 mmol) in THF (5 mL), NaBH4 (42.6 mg, 1.13 mmol) in THF (5 mL), and I2 (114 mg, 0.45 mmol) in THF (4 mL), tetrahydroisoquinoline 7a (65 mg, 70 %) was obtained as an oil after flash chromatography (9:1 EtOAc/EtOH). [α]D22 = –58.5 (c = 0.50, EtOH) {lit.1b [α]D24 = –62.5 (c = 0.1, EtOH)}. IR (KBr): equation image = 3217 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.43 (d, J = 6.5 Hz, 3 H, CH3), 1.78 (br. s, 1 H, NH), 2.60–2.68 (dt, J = 16.0, 4.8 Hz, 1 H, 4-H), 2.74–2.84 (ddd, J = 16.0, 8.4, 5.4 Hz, 1 H, 4-H), 2.99 (ddd, J = 13.0, 8.4, 4.8 Hz, 1 H, 3-H), 3.24 (ddd, J = 13.0, 4.8 Hz, 1 H, 3-H), 3.87 (s, 6 H, 2 OCH3), 4.04 (q, J = 6.5 Hz, 1 H, 1-H), 6.57 (s, 1 H, 8-H), 6.62 (s, 1 H, 5-H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 22.8 (CH3), 29.5 (C-4), 41.8 (C-3), 51.2 (C-1), 55.8 (OCH3), 55.9 (OCH3), 109.0 (C-8), 111.7 (C-5), 126.8 (C-4a), 132.5 (C-8a), 147.2 (C-7), 147.3 (C-6) ppm.

(1S)-1-Ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (7b): Following the above general procedure, from lactam 6b (91 mg, 0.39 mmol) in THF (10 mL), NaBH4 (36 mg, 1.1 mmol) in THF (4 mL), and I2 (99 mg, 0.39 mmol) in THF (4 mL), tetrahydroisoquinoline 7b (52 mg, 60 %) was obtained as an oil after flash chromatography by using a cartridge containing amine-functionalized silica (7:3 hexane/EtOAc to EtOAc). [α]D22 = –47.4 (c = 0.3, CH2Cl2) {ref.25 [α]D22 = –51.9 (c = 2.1, CH2Cl2)}. IR (KBr): equation image = 2930 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.02 (t, J = 7.6 Hz, 3 H, CH3), 1.67–1.78 (m, 1 H, CH2), 1.90 (dddd, J = 14.4, 7.2, 7.2, 3.2 Hz, 1 H, CH2), 2.40 (s, 1 H, NH), 2.67 (dt, J = 16.2, 5.2 Hz, 1 H, 3-H), 2.77 (dt, J = 16.2, 6.0 Hz, 1 H, 3-H), 2.98 (ddd, J = 12.4, 7.6, 4.8 Hz, 1 H, 4-H), 3.24 (dt, J = 12.4, 5.2 Hz, 1 H, 4-H), 3.85 (s, 6 H, 2 OCH3), 3.85 (m, 1 H, 1-H), 6.57 (s, 1 H, 8-H), 6.62 (s, 1 H, 5-H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 10.9 (CH3), 29.0 (CH2), 29.4 (C-4), 41.1 (C-3), 55.8 (OCH3), 56.0 (OCH3), 56.7 (C-1), 109.2 (C-8), 111.7 (C-5), 127.1 (C-4a), 131.0 (C-8a), 147.2 (C-7), 147.3 (C-6) ppm. HRMS: calcd. for C13H19NO2 [M + H]+ 222.1494; found 222.1488.

(–)-Norcryptostyline II (7d): Following the above general procedure, from lactam 6d (90 mg, 0.26 mmol) in THF (3 mL), NaBH4 (24.8 mg, 0.66 mmol) in THF (4 mL), and I2 (66.5 mg, 0.26 mmol) in THF (3 mL), tetrahydroisoquinoline 7d (58 mg, 69 %) was obtained as a yellow oil after flash chromatography by using a cartridge containing amine-functionalized silica (1:1 hexane/EtOAc). [α]D22 = –33.8 (c = 0.36, CHCl3) {ref.5a [α]D18 = –37 (c = 0.26, CHCl3)}. IR (KBr): equation image = 2923 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.75 (dt, J = 15.2, 4.4 Hz, 1 H, 4-H), 2.96 (ddd, J = 15.2, 4.8, 4.8 Hz, 1 H, 4-H), 3.06 (ddd, J = 13.2, 8.8, 4.8 Hz, 1 H, 3-H), 3.24 (ddd, J = 13.2, 4.8 Hz, 1 H, 3-H), 3.65 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.87 (s, 6 H, OCH3), 5.00 (s, 1 H, 1-H), 6.27 (s, 1 H, 8-H), 6.62 (s, 1 H, 5-H), 6.79 (s, 1 H, 2′-H), 6.80 (s, 1 H, 6′-H), 6.82 (s, 1 H, 5′-H) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 29.1 (C-4), 42.1 (C-3), 55.8 (OCH3), 55.9 (OCH3), 56.0 (OCH3), 61.3 (C-1), 110.7 (C-2′), 110.9 (C-5′), 111.4 (C-8), 111.8 (C-5), 121.3 (C-6′), 127.4 (C-4a), 129.8 (C-8a), 136.9 (C-i), 147.0 (C-6), 147.7 (C-4′), 148.4 (C-7), 149.0 (C-3′) ppm. HRMS: calcd. for C19H23NO4 [M + H]+ 330.1705; found 330.1691.

(–)-Norcryptostyline III (7e): Following the above general procedure, from lactam 6e (92 mg, 0.25 mmol) in THF (3 mL), NaBH4 (23.3 mg, 0.62 mmol) in THF (4 mL), and I2 (70.8 mg, 0.25 mmol) in THF (3 mL), tetrahydroisoquinoline 7e (52 mg, 58 %) was obtained as a yellow oil after flash chromatography by using a cartridge containing amine-functionalized silica (7:3 Et2O/EtOAc).[α]D22 = –45.7 (c = 0.11, CHCl3) {ref.16a [α]D = –37.0 (CHCl3)}. IR (KBr): equation image = 2919 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 2.74 (dt, J = 15.6, 4.5, 3.9 Hz, 1 H, 4-H), 2.90–3.00 (m, 1 H, 4-H), 3.07 (ddd, J = 11.7, 7.8, 3.9 Hz, 1 H, 3-H), 3.26 (dt, J = 11.7, 5.1, 4.5 Hz, 1 H, 3-H), 3.68 (s, 3 H, OCH3), 3.81 (s, 6 H, 2 CH3O), 3.85 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 5.01 (s, 1 H, 1-H), 6.26 (s, 1 H, 8-H), 6.47 (s, 2 H, 2′-H, 6′-H), 6.63 (s, 1 H, 5-H) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 27.9 (C-4), 41.5 (C-3), 55.8 (OCH3), 56.0 (OCH3), 56.2 (OCH3), 60.8 (OCH3), 61.2 (C-1), 106.4 (C-2′, C-6′), 110.8 (C-8), 111.3 (C-5), 126.7 (C-4a), 129.8 (C-8a), 137.7 (C-1′), 147.4 (C-6), 148.2 (C-7), 153.2 (C-3′, C-4′, C-5′) ppm. HRMS: calcd. for C20H25NO5 [M + H]+ 360.1809; found 360.1809.

(–)-O,O-Dimethylcoclaurine (7f): Following the above general procedure, from lactam 6f (200 mg, 0.6 mmol) in THF (3 mL), NaBH4 (58 mg, 1.5 mmol) in THF (4 mL), and I2 (152 mg, 0.8 mmol) in THF (3 mL), tetrahydroisoquinoline 7f (111 mg, 59 %) was obtained as a yellow oil after flash chromatography by using a cartridge containing amine-functionalized silica (8:2 to 1:1 hexane/EtOAc). [α]D22 = –11.8 (c = 0.5, CHCl3) {ref.18c [α]D22 = –19.9 (c = 1, CHCl3)}. IR (KBr): equation image = 2932 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.64–2.79 (m, 1 H, 3-H), 2.73 (ddd, J = 11.6, 6.0, 6.0 Hz, 1 H, 4-H), 2.86 (dd, J = 14.0, 9.5 Hz, 1 H, CH2Ar), 2.91 (ddd, J = 12.0, 6.0, 5.6 Hz, 1 H, 3-H), 3.15 (dd, J = 14.0, 4.5 Hz, 1 H, CH2Ar), 3.20 (ddd, J = 11.6, 11.6, 5.6 Hz, 1 H, 4-H), 3.80 (s, 1 H, OCH3), 3.82 (s, 1 H, OCH3), 3.86 (s, 1 H, OCH3), 4.11 (dd, J = 9.5, 4.5 Hz, 1 H, 1-H), 6.59 (s, 1 H, 8-H), 6.63 (s, 1 H, 5-H), 6.86 (d, J = 8.5 Hz, 2 H, 3′-H), 7.16 (d, J = 8.5 Hz, 2 H, 5′-H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 29.5 (C-4), 40.7 (CH2Ar), 41.5 (C-3), 55.3 (OCH3), 55.8 (OCH3), 55.9 (OCH3), 56.9 (C-1), 109.4 (C-8), 111.8 (C-5), 114.0 (C-3′), 127.3 (C-4a), 130.3 (C-2′), 130.5 (C-1′), 131.0 (C-8a), 147.0 (C-7), 147.4 (C-6), 158.3 (C-4′) ppm. HRMS: calcd. for C19H23NO3 [M + H]+ 314.1756; found 314.1743.

(1S)-6,7-Dimethoxy-1-phenylethyl-1,2,3,4-tetrahydroisoquinoline (7g): Following the above general procedure, from lactam 6g (250 mg, 0.8 mmol) in THF (3 mL), NaBH4 (76 mg, 2.0 mmol) in THF (4 mL), and I2 (203 mg, 0.8 mmol) in THF (3 mL), tetrahydroisoquinoline 7g (183 mg, 77 %) was obtained as a colorless oil after flash chromatography (SiO2 previously washed with 8:2 Et3N/EtOAc; 8:2 to 1:1 Et2O/EtOAc as eluent). [α]D22 = –23.4 (c = 0.25, CHCl3). IR (KBr): equation image = 2955 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.04–2.17 (m, 2 H, CH2), 2.66–2.89 (m, 4 H, CH2Ar, 4-H), 3.02 (ddd, J = 12.0, 7.2, 5.6 Hz, 1 H, 3-H), 3.27 (ddd, J = 12.0, 5.6, 5.6 Hz, 1 H, 3-H), 3.82 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 4.00 (dd, J = 8.0, 2.8 Hz, 1 H, 1-H), 6.57 (s, 2 H, 5-H, 8-H), 7.17–7.31 (m, 5 H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 29.1 (CH2Ar), 32.4 (C-4), 38.1 (CH2), 40.9 (C-3), 55.1 (C-1), 55.8 (OCH3), 56.0 (OCH3), 109.2 (C-8), 111.8 (C-5), 125.9 (C-4′), 127.0 (C-4a), 128.4 (C-2′, C-3′), 128.5 (C-8a), 142.2 (C-4′), 147.3 (C-6), 147.4 (C-7) ppm. HRMS: calcd. for C19H23NO2 [M + H]+ 298.1807; found 298.1802.

(1S)-1-[2-(1,3-Dioxan-2-yl)ethyl]-2-[(1R)-2-hydroxy-1-phenylethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9): LiAlH4 (96 mg, 2.54 mmol) was slowly added to a suspension of AlCl3 (113 mg, 0.85 mmol) in THF (6 mL) at –78 °C and the mixture was stirred for 2 h. Then, a solution of tetrahydroisoquinolone 5i (170 mg, 0.39 mmol) in anhydrous THF (6 mL) was slowly added. The stirring was continued at –78 °C for 20 h, and the reaction was quenched with water. The aqueous layer was extracted with CH2Cl2, and the combined organic extracts were dried and concentrated to give a residue, which was purified by chromatography (Et2O to 1:1 Et2O/EtOAc) to afford tetrahydroisoquinoline 9 (144 mg, 87 %). [α]D22 = –37.1 (c = 1.03, CHCl3). IR (KBr): equation image = 3399 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.26–1.31 (m, 1 H, C1CH2), 1.49–1.52 (m, 1 H, OCH2CH2), 1.53–1.62 (m, 1 H, CH2CHO2), 1.76–1.82 (m, 1 H, CH2CHO2), 1.83–1.93 (m, 1 H, OCH2CH2), 1.97–2.09 (m, 1 H, C1CH2), 2.27 (s, 1 H, OH), 2.43 (dd, J = 17.0, 5.0 Hz, 1 H, 4-H), 2.97 (ddd, J = 17.0, 12.0, 6.0 Hz, 1 H, 4-H), 3.20 (dd, J = 13.5, 6.0 Hz, 1 H, 3-H), 3.31 (dd, J = 13.5, 5.0 Hz, 1 H, 3-H), 3.37 (dd, J = 9.6, 4.4 Hz, 1 H, 1-H), 3.64–3.67 (m, 2 H, 2 OCH2CH2), 3.68–3.73 (m, 1 H, CHAr), 3.75 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.81–3.86 (m, 2 H, 2 OCH2CH2), 3.95 (dd, J = 10.8, 6.0 Hz, 1 H, CH2OH), 4.05 (dd, J = 10.8, 4.8 Hz, 1 H, CH2OH), 4.40 (t, J = 4.8 Hz, 1 H, CHO2), 6.28 (s, 1 H, 8-H), 6.55 (s, 1 H, 5-H), 7.28–7.29 (m, 5 H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 22.5 (CH2CH2O), 25.6 (C-4), 30.7 (C-1′), 32.1 (C-2′), 39.0 (C-3), 55.6 (OCH3), 55.7 (OCH3), 57.6 (C-1), 64.0 (CH2OH), 64.5 (CHAr), 66.6 (OCH2CH2), 102.1 (CHO2), 110.5 (C-8), 111.3 (C-5), 125.4 (C-4a), 127.4 (C-p), 128.2 (C-o), 128.6 (C-m), 130.3 (C-8a), 140.9 (C-i), 146.9 (C-6), 147.1 (C-7) ppm. HRMS: calcd. for C25H33NO5 [M + H]+ 428.2437; found 428.2424.

(S)-(–)-Crispine A: A solution of tetrahydroisoquinoline 9 (110 mg, 0.26 mmol) in EtOH (12 mL) and 1.0 M aqueous HCl (0.5 mL) containing 10 % Pd/C (15 mg) was hydrogenated with vigorous stirring at room temperature and atmospheric pressure for 3 d. The catalyst was removed by filtration, the solvent was concentrated under vacuum, and the resulting oil was purified by chromatography with a cartridge containing amine-functionalized silica (1:1 hexane/EtOAc) to give crispine A (45 mg, 74 %). [α]D22 = –100.1 (c = 0.32, CHCl3) {ref.26 [α]D22 = –96 (c = 0.25, CHCl3)}. IR (KBr): equation image = 2922 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.69–1.78 (m, 1 H, 1-H), 1.82–1.99 (m, 2 H, 2-H), 2.30–2.38 (m, 1 H, 1-H), 2.63 (ddd, J = 17.0, 8.0, 8.0 Hz, 1 H, 6-H), 2.69 (m, 1 H, 5-H), 2.74 (m, 1 H, 3-H), 3.00 (ddd, J = 12.4, 9.6, 5.6 Hz, 1 H, 3-H), 3.07 (ddd, J = 17.0, 8.0, 4.0 Hz, 1 H, 6-H), 3.18 (dddd, J = 17.2, 11.2, 6.4, 2.8 Hz, 1 H, 5-H), 3.49 (m, 1 H, 10b-H), 3.85 (s, 6 H, OCH3), 6.57 (s, 1 H, 10-H), 6.61 (s, 1 H, 7-H) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 22.3 (C-2), 27.9 (C-6), 30.6 (C-3), 48.2 (C-3), 53.1 (C-5), 55.9 (OCH3), 56.0 (OCH3), 62.8 (C-10b), 108.8 (C-10), 111.3 (C-7), 126.1 (C-6a), 130.5 (C-10a), 147.3 (C-8), 147.4 (C-9) ppm. HRMS: calcd. for C14H19NO2 [M + H]+ 234.1494; found 234.1486.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results and Discussion
  5. Conclusions
  6. Experimental Section
  7. Acknowledgements

Financial support from the Ministry of Science and Innovation, Spain (Project CTQ2009-07021/BQU) and the AGAUR, Generalitat de Catalunya (Grant 2009-SGR-111) is gratefully acknowledged.

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