Tandem Allylboration–Prins Reaction for the Rapid Construction of Substituted Tetrahydropyrans: Application to the Total Synthesis of (−)‐Clavosolide A

Abstract Tetrahydropyrans are common motifs in natural products and have now been constructed with high stereocontrol through a three‐component allylboration‐Prins reaction sequence. This methodology has been applied to a concise (13 steps) and efficient (14 % overall yield) synthesis of the macrolide (−)‐clavosolide A. The synthesis also features an early stage glycosidation reaction to introduce the xylose moiety and a lithiation‐borylation reaction to attach the cyclopropyl‐containing side chain.


General information
All required fine chemicals were used directly without purification unless mentioned. All air-and water-sensitive reactions were carried out in flame-dried glassware under nitrogen atmosphere using standard Schlenk manifold technique. 1 H-and 13 C-Nuclear Magnetic Resonance (NMR) spectra were acquired at various field strengths as indicated, and were referenced to CHCl 3 (7.27 and 77.0 ppm for 1 H and 13 C respectively). 1 H NMR coupling constants are reported in Hertz and refer to apparent multiplicities and not true coupling constants. Data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet, dd = doublet of doublet, etc.) and integration. 11 B-NMR spectra were recorded with complete proton decoupling using BF 3 ·Et 2 O (0.0 ppm) as an external standard.
High resolution mass spectra were recorded using Electron Spray Ionization (ESI). All IR data was obtained on a Perkin-Elmer Spectrum One FT-IR spectrometer. Optical rotations were obtained on a Perkin-Elmer 241MC polarimeter. Melting points were determined with a Boetius hot stage apparatus and were not corrected.
Analytical TLC were performed using aluminium backed plates pre-coated (0.25 mm) with Merck Silica Gel 60 F254. Compounds were visualized by exposure to UV -light or by dipping the plates in phosphomolybdic acid (PMA) or KMnO 4 followed by heating. Flash column chromatography was performed using Merck Silica Gel 60 (40-63 μm). All mixed solvent eluents are reported as v/v solutions. Chiral HPLC was performed using a Diacel Chiralpak AS-H column (4.6 × 250 mm × 5 μm) and AD-H (4.6 × 250 mm × 5 μm) fitted with guards (4 × 10 mm), and monitored by DAD (Diode Array Detector). GC was performed on Agilent Technologies 6890N Network GC system using an Agilent Technologies HP-5 column (15 m × 2.5 mm x 0.25 μm), and monitored by FID (Flame Ionisation Detector).

Materials and reagents
All reagents were used as received unless otherwise stated. Anhydrous THF, CH 2 Cl 2 , toluene, hexane and Et 2 O were dried by passing through a modified Grubbs system of alumina columns, manufactured by Anhydrous Engineering. Anhydrous Et 2 O, THF and CH 2 Cl 2 were stored over 3 Å molecular sieves. Petroleum ether refers to the fraction collected between 40-60 °C. TMEDA, DBU and Et 3 N were distilled over CaH 2 and stored in a Young's tube under N 2 . (−)-Sparteine was obtained from the commercially available sulfate pentahydrate salt (ABCR chemicals) and isolated according to literature procedure. 1 (+)-Sparteine was obtained as the free base (BOC sciences), distilled over CaH 2 or NaOH and stored in a Young's tube under N 2 . The sparteine free base readily absorbs atmospheric carbon dioxide (CO 2 ) and should be stored in a Young's tube under inert atmosphere at −20 °C. Cyclohexanecarboxaldehyde, hydrocinnamaldehyde and benzaldehyde were distilled over molecular sieves using a Hickman distillation apparatus and stored in a Young's tube under N 2 . NaH (60% oil dispersion) was washed three times with dry hexane under N 2 prior to use. Copper (I) chloride was purified by the addition of 37% aq. HCl followed by the addition of water and filtration and was dried under high vac overnight and kept under N 2 . Organolithiums were periodically titrated using N-benzylbenzamide. 2 Compounds 4, 3 4-ent, 3 10 4 and 18 5 were prepared according to the literature and all spectroscopic data match with the reported ones. 1 N. A. Nikolic, P. Beak, Org. Synth. 1997, 74, 23. 2 A. F. Burchat, J. M. Chong, N. Nielsen, J. Organomet. Chem. 1997 H. Lin, W. Pei, H. Wang, K. N. Houk, I. J. Krauss, J. Am. Chem. Soc. 2013, 135, 82. 4 X. Han, P. E. Floreancig, Angew. Chem. Int. Ed. 2014 J. L. Stymiest, G. Dutheuil, A. Mahmood, V. K. Aggarwal, Angew. Chem. Int. Ed. 2007, 46, 7491. The spectroscopic data are in accordance with the literature. 7 -Method B

Synthesis of allylic boronic ester 6a via lithiation-borylation
To a solution of primary carbamate 18 (3.00 g, 17.3 mmol, 3 equiv.) and TMEDA (2.59 mL, 17.3 mmol, 3.0 equiv.) in Et 2 O (85 mL) at −78 o C was added s-BuLi (13.3 mL, 1.30 M in hexanes, 17.3 mmol, 3.0 equiv.) dropwise. The resulting mixture was stirred for 5 h at −78 °C and then vinyl boronic acid pinacol ester (0.97 mL, 5.7 mmol, 1.0 equiv.) was added dropwise. The reaction mixture was further stirred at −78 °C for 1 h. MgBr 2 •OEt 2 in Et 2 O, made as follows, was added to the reaction mixture and stirred for 10 min : 1,11 mmol,2 equiv.) was added to a suspension of magnesium (278 mg, 11.4 mmol, 2 equiv.) in Et 2 O (14 mL) at room temperature. The reaction flask was then placed into a water bath in order to control the exothermic reaction and was stirred for 2 h. The reaction was then warmed to room temperature and refluxed for 16 hours. The reaction mixture was allowed to cool down to room temperature, filtered through a short silica pad (using pentane as eluent) and evaporated under reduced pressure at 0 °C. The crude reaction mixture contained a mixture of 6a:vinyl boronic acid pinacol ester (9:1 by 1 H NMR). Purification was achieved by flash column chromatography (SiO 2 , pentane: Et 2 O, 97:3) to afford compound 6a (as a single compound) as a colourless oil (312 mg, 30% yield), and a mixture of 6a:vinyl boronic acid pinacol ester (290 mg, 81:19 ratio).

Synthesis of allylic boronic ester 6b via lithiation-borylation
To a solution of primary carbamate 18 (3.00 g, 17.3 mmol, 3 equiv.) and TMEDA (2.59 mL, 17.3 mmol, 3.0 equiv.) in Et 2 O (85 mL) at −78 o C was added s-BuLi (13.3 mL, 1.3 M in hexanes, 17.3 mmol, 3.0 equiv.) dropwise. The resulting mixture was stirred for 5 hours at −78 °C and then trans-1-propenylboronic acid pinacol ester (1.09 mL, 5.71 mmol, 1.0 equiv.) was added dropwise. The reaction mixture was further stirred at −78 °C for 1 hour. MgBr 2 •OEt 2 in Et 2 O, made as follows, was added to the reaction mixture and stirred for 10 min : 1,11 mmol,2 equiv.) was added to a suspension of magnesium (278 mg, 11.4 mmol, 2 equiv.) in Et 2 O (14 mL) at room temperature. The reaction flask was then placed into a water bath in order to control the exothermic reaction and was stirred for 2 h. The reaction was then warmed to room temperature and refluxed for 16 hours. The reaction mixture was allowed to cool down to room temperature, filtered through a short silica pad (using pentane as eluent) and evaporated under reduced pressure at 0 °C. The crude reaction mixture contained a mixture of 6b and trans-1-propenylboronic acid pinacol ester (9:1 by 1 H NMR Spectroscopic data are in accordance with the literature. 8 c) General procedure for the synthesis of 4-hydroxy THPs 8a-g (Table 1).
To a stirred solution of the corresponding allylic boronic ester (0.27 mmol, 1 equiv.) in THF (2.7 mL) at −78 °C under N 2 was added n-BuLi (1.5 M in hexanes, 0.20 mL, 0.30 mmol, 1.1 equiv.) dropwise, and the solution was allowed to stir for 15 mins. To this mixture was added TFAA (46 μL, 0.33 mmol, 1.2 equiv.) dropwise and the reaction was stirred for a further 30 min at −78 °C.
The first corresponding aldehyde (0.29 mmol, 1.05 equiv.) was then added dropwise and the mixture was stirred at −78 °C for 2 h and then allowed to slowly warm up to room temperature overnight. The solvent was evaporated under high vacuum. After refilling the flask with N 2 , the reaction mixture was dissolved in DCM (2.5 mL) and the second corresponding aldehyde (0.82 mmol equiv.) was added. After 5 mins of stirring, TFA (0.8 mL) was added at 0 °C and the reaction was then stirred at room temperature for 2 h. The reaction was quenched upon dropwise addition of an aqueous NaHCO 3 sat. solution. The two layers of the resulting biphasic solution were separated and the aqueous layer was extracted with DCM (x2). The combined organic layers were dried over MgSO 4 and the solvent was removed under reduced pressure. The residue was dissolved in MeOH (1 mL) and stirred with K 2 CO 3 (57 mg, 0.41 mmol, 1.5 equiv.) for 30 mins. MeOH was then removed under reduced pressure and water (10 mL) was added. The mixture was extracted with DCM (x3), the combined organic layers were dried over MgSO 4 and the solvent was removed under reduced pressure. The resulting 4-hydroxytetrahydropyrans were purified by flash column chromatography.
Cyclohexanecarboxaldehyde (39 mg, 0.35 mmol, 1.05 equiv.) was then added dropwise and the mixture was stirred at −78 °C for 2 h and then allowed to slowly warm up to room temperature overnight. The solvent was evaporated under high vacuum. After refilling the flask with N 2 , the reaction mixture was dissolved in DCM (3.0 mL) and a 0.5 mL aliquot was removed from the reaction mixture: this aliquot was quenched with sat. NH 4 Cl and extracted with DCM (x2). The combined organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure -the E:Z ratio was determined to be 87:13 by 1 H NMR analysis of the crude aliquot mixture (see below for the spectrum). Cyclohexanecarboxaldehyde (92 mg, 0.82 mmol, 3 equiv.) was then added to the remaining 2.5 mL bulk reaction mixture. After 5 mins of stirring, TFA (1 mL) was added at 0 °C and the reaction was then stirred at room temperature for 2 h. The reaction was quenched upon dropwise addition of an aqueous NaHCO 3 sat. solution. The two layers of the resulting biphasic solution were separated and the aqueous layer was extracted with DCM (x2). The combined organic layers were dried over MgSO 4 and the solvent was removed under reduced pressure. The residue was dissolved in MeOH ( 1 mL) and stirred with K 2 CO 3 (69 mg, 0.50 mmol, 1.5 equiv.) for 30 mins. MeOH was then removed under reduced pressure and water (10 mL) was added. The mixture was extracted with DCM (x3), the combined organic layers were dried over MgSO 4 and the solvent was removed under reduced pressure.
The crude reaction mixture was purified by flash column chromatography (petroleum ether: EtOAc, 9:1) to give 8a in 80% yield (based on the removal of 1/6 of the reaction mixture) and 87:13 dr as a colourless oil (62 mg, 0.22 mmol).
After 5 mins of stirring, TFA (1 mL) was added at 0 °C and the reaction was then stirred at room temperature for 2 h. The reaction was quenched upon dropwise additi on of an aqueous NaHCO 3 sat. solution. The two layers of the resulting biphasic solution were separated and the aqueous layer was extracted with DCM (x2). The combined organic layers were dried over MgSO 4 and the solvent was removed under reduced pressure. The residue was dissolved in MeOH (1 mL) and stirred with K 2 CO 3 (69 mg, 0.50 mmol, 1.5 equiv.) for 30 mins. MeOH was then removed under reduced pressure and water (10 mL) was added. The mixture was extracted with DCM (x3), the combined organic layers were dried over MgSO 4 and the solvent was removed under reduced pressure. The crude reaction mixture was purified by flash column chromatography (petroleum ether: EtOAc, 9:1) to give 8e in 61% yield (based on the use of 0.30 mmol of 6a) and 88:12 dr as a colourless oil (60 mg, 0.19 mmol).

Total synthesis of (−)-clavosolide A
To a solution of primary carbamate 18 (1.00 g, 5.78 mmol, 1 equiv.) and (−)-sparteine (1.6 mL, 6.9 mmol, 1.2 equiv.) in Et 2 O (29 mL) at −78 o C was added s-BuLi (1.3 M in hexanes, 4.9 mL, 6.4 mmol, 1.1 equiv.) dropwise. The resulting mixture was stirred for 5 h at −78 °C and then vinyl boronic acid pinacol ester (1.08 mL, 6.36 mmol, 1.1 equiv.) was added. The reaction mixture was further stirred at −78 °C for 1 hour. MgBr 2 •OEt 2 in Et 2 O, made as follows, was added to the reaction mixture and stirred for 10 min: 1,2-Dibromoethane (0.96 mL, 12 mmol, 2 equiv.) was added to a suspension of magnesium (277 mg, 11.6 mmol, 2 equiv.) in Et 2 O (14 mL) at room temperature. The reaction flask was then placed into a water bath in order to control the exothermic reaction and was stirred for 2 h. The reaction was then warmed to room temperature and refluxed overnight. The reaction mixture was allowed to cool down to room temperature, filtered through a short silica pad (using pentane as eluent) and evaporated under reduced pressure at 0 °C. The crude reaction mixture was purified by flash column chromatography (SiO 2 , pentane: Et 2 O, 20:1) to afford compound (R)-6a (915 mg, 87% yield) as a colourless oil. e.r.=

96:4 9
Note 1: In order to obtain the compound in good yield, the chromatography should be completed within 10 min., since the allylboronic ester decomposes readily on silica gel.
Note 2: Occasionally up to 10% of vinyl boronic ester can be obtained together with the allyl boronic ester.

Synthesis of aldehydes 7a and 7b
To a solution of N,N-diisopropylcarbamoyl chloride (4.91 g, 30.0 mmol, 1 equiv.) and Et 3 N (4.60 mL, 33.0 mmol, 1.05 equiv.) in CH 2 Cl 2 (30 mL) was added 1,3-propanediol (6.85 g, 90.0 mmol, 3 equiv.). This mixture was then heated to reflux and stirred for 24 h. The reaction was cooled to room temperature and H 2 O was added. The aqueous layer was extracted with CH 2 Cl 2 (x3) and the combined organic layers were dried over MgSO 4 and evaporated under reduced pressure.
Note 3: An 80% yield was considered to conduct the next reaction.

Lewis-base mediated allylboration
To a solution of allylic boronic ester (R)-6a (1 equiv.) in THF (0.1 M) at −78 °C under N 2 was added n-BuLi (1.52 M in hexane, 1.1 equiv.) dropwise and the solution allowed to stir for 15 min. To this mixture was added TFAA (1.2 equiv.) dropwise and the reaction was stirred for a further 30 min at −78 °C. The mixture was cooled down to −100 °C. A 0.5M solution of freshly prepared aldehyde 7a/7b (1.5 equiv.) in THF was pre-cooled to −78 °C and added to the reaction dropwise.

Three-component Lewis base mediated allylboration-Prins cyclisation
To a stirred solution of allylic boronic ester 6a (199 mg, 1.09 mmol, 1 equiv.) in THF (1.1 mL) at −78 °C under N 2 was added n-BuLi (1.6 M in hexanes, 0.75 mL, 1.1 equiv.) dropwise and the solution was allowed to stir for 15 min. To this mixture was added TFAA (0.18 mL, 1.3 mmol, 1.2 equiv.) dropwise and the reaction was stirred for further 30 min at −78 °C. A 0.5 M solution of freshly prepared aldehyde 7a (329 mg, 1.63 mmol, 1.5 equiv.) in THF was added to the reaction dropwise. The mixture was kept at −78 °C for 2 h and allowed to slowly warm up to room temperature overnight. The solvent was then evaporated under high vacuum and dry DCM was added and subsequently evaporated (x2). After refilling the flask with N 2 , the reaction mixture was dissolved in DCM (7.2 mL) and 10 (4 equiv.) was added. After 5 mins of stirring, TFA (1.8 mL) was added at 0 °C and the reaction was then stirred at room temperature for 2 h. The reaction was quenched upon dropwise addition of an aqueous NaHCO 3 solution. The two layers of the resulting biphasic solution were separated and the aqueous layer was extracted with DCM (x2).
The combined organic layers were dried over MgSO 4 and the solvent was removed under reduced pressure. The residue was dissolved in MeOH (3.6 mL) and stirred with K 2 CO 3 (226 mg, 1.63 mmol, 1.5 equiv.) for 30 mins. MeOH was then removed under reduced pressure and water (10 mL) was added. The mixture was extracted with DCM (x3), the combined organic layers were dried over MgSO 4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , petroleum ether: EtOAc, 1:9) to give compound 11 as a colourless oil in 39% yield and 88:12 dr (141 mg, 0.425 mmol).
The spectroscopic data are in accordance with the literature. 11 Hydrogen bromide in acetic acid (33%, 3.3 mL) was added under N 2 to a solution of compound 20 (2.64 g, 4.65 mmol, 1 equiv.) in dry DCM (14 mL). After 2.5 h of stirring at room temperature, the reaction was quenched with sat. aq. NaHCO 3 . The organic phase was washed with sat. aq. NaHCO 3 (x2) and brine (x1), dried over MgSO 4 and evaporated under reduced pressure. The crude reaction mixture was re-dissolved in acetone (24 mL), water (1 mL) and DCM (2.2 mL) and Ag 2 CO 3 (2.23 g, 8.08 mmol, 1.75 equiv.) was added portionwise. The reaction was stirred for 1 h at room temperature and then filtered through celite and anhydrous MgSO 4 . The filtrate was evaporated under reduced pressure and purified by flash column chromatography (SiO 2 , petroleum ether: EtOAc, 7:3). The corresponding compound 21 was obtained in 90% yield (1.93 g, 4.18 mmol) as a white solid. R f : 0.37 (petroleum ether: EtOAc, 7:3).
Data of the major isomer are reported:  The spectroscopic data are in accordance with the literature. 13 A mixture of 12a/12b (1 equiv.), 13 (1.5 equiv.) and 4 Å powder molecular sieves (0.5n equiv. g) were dissolved in DCM (0.05 M) and stirred under N 2 for 30 min at room temperature. TMSOTf (0.3 equiv.) was added at −20 °C. The reaction was stirred at this temperature for 30 min and allowed to slowly reach room temperature over 2 h. The reaction was quenched upon addition of Et 3 N (3.3 equiv.), the solution was filtered through celite and the solvent was removed under reduced pressure. The crude reaction mixture was purified by flash column chromatography.
To a stirred solution of 22a or 22b (1 equiv.) in dry MeOH (0.09M) was added NaOMe (3.4 equiv.) and the reaction was stirred for 1 h at room temperature. The reaction mixture was acidified (pH=5) with Amberlite (H + ) IR-120 resin. After filtering the resin, the solvent was evaporated and the crude reaction mixture was dissolved in dry DMF (0.07 M) under N 2 . NaH (60% dispersion in mineral oil, 8 equiv.) was added at 0 °C and the reaction was stirred 30 min at this temperature and for a further 30 min at room temperature. MeI (8 equiv.) was added and the reaction was stirred overnight. H 2 O was added, the aqueous phase was extracted with EtOAc (x3) and the combined organic layers were washed with brine (x2), dried over MgSO 4 , filtered and evaporated under reduced pressure. The crude reaction mixture was purified by flash column chromatography.

Lithiation-borylation reaction
From compound 14a: To a solution of primary carbamate 14a (80 mg, 0.13 mmol, 1 equiv.) and (+)-sparteine (36 mg, 0.16 mmol, 1.2 equiv.) in Et 2 O (0.7 mL) at -78 °C under N 2 was added s-BuLi (1.3 M in 92:8 cyclohexane/hexane, 0.14 mmol, 1.1 equiv.) dropwise. The resulting yellow mixture was stirred for 5 h at -78 °C before boronic ester 4 (28 mg, 0.16 mmol, 1.2 equiv.) was added as a 1 M Et 2 O solution. The reaction mixture was further stirred at -78 °C for 1 h, before being allowed to warm to room temperature. The reaction mixture was refluxed for 16 h. The reaction mixture was cooled to 0 °C and a solution of NaOH (2 M)/H 2 O 2 (30%) (2:1 v/v, 0.54 mL) was added dropwise and allowed to stir at room temperature for 2 h. After this time the layers were separated and the aqueous phase was extracted with Et 2 O (x3). The combined organic layers were dried over MgSO 4 , filtered and evaporated under reduced pressure. The crude reaction mixture was purified by flash column chromatography (petroleum ether: EtOAc, 6:4) to give 15a in 48% yield (34 mg, 0.06 mmol)as a pale yellow oil.
Note: Some problems on reproducibility were found when the reaction was repeated and/or the scale increased (23-48%). was added dropwise and allowed to stir at room temperature for 2 h. After this time the layers were separated and the aqueous phase was extracted with Et 2 O (x3). The combined organic layers were dried over MgSO 4 , filtered and evaporated under reduced pressure. The crude reaction mixture was purified by flash column chromatography (SiO 2 , petroleum ether: EtOAc, 6:4) to give 15a in 73% yield (120 mg, 0.22 mmol) as a pale yellow oil.  [α] D 22 = -18.0 (c 1, CHCl 3 ).

General procedure for the synthesis of diasteroisomers of 15a
To a solution of triisopropylbenzoate 14a (50 mg, 0.069 mmol, 1 equiv.) and chiral diamine (+) or (-)-sp (20 µL, 0.083 mmol, 1.2 equiv.) in Et 2 O (0.5 mL) at -78 °C under N 2 was added s-BuLi (1.3 M in 92:8 cyclohexane/hexane, 61 µL, 0.076 mmol, 1.1 equiv.) dropwise. The resulting yellow mixture was stirred for 1 h at -78 °C and boronic ester 4 or ent-4 (15 mg, 0.083 mmol, 1.2 equiv) was added as a 1 M Et 2 O solution. The reaction mixture was stirred at -78 °C for a further 1 h, before being allowed to warm to room temperature and refluxed for 2 h. The reaction mixture was cooled to 0 °C and a solution of NaOH (2 M)/H 2 O 2 (30%) (2:1 v/v, 0.34 mL) was added dropwise and the mixture was stirred at room temperature for 2 h. After this time the layers were separated and the aqueous phase was extracted with Et 2 O (x3). The combined organic layers were dried over MgSO 4 , filtered and evaporated under reduced pressure. The crude reaction mixture was purified by flash chromatography (SiO 2 , petroleum ether: EtOAc, 6:4).

End game: deprotection, oxidation and dimerization
To a solution of silyl ether 15a (120 mg, 0.220 mmol, 1 equiv.) in EtOH (7.7 mL) was added 1% aq. HCl solution (2.3 mL). The reaction was stirred at room temperature for 20 min and quenched with sat. NaHCO 3 and extracted with EtOAc (x4). The combined organic layers were dried over MgSO 4 , evaporated under reduced pressure and purified by flash chromatography (SiO 2 , petroleum ether: EtOAc, 6:4 and then EtOAc) to give compound 23 as a colourless oil in 84% yield (80 mg, 0.18 mmol).