HETEROCYCLES

Paper | Special issue | Vol. 90, No. 1, 2015, pp. 405-424
Received, 21st May, 2014, Accepted, 30th May, 2014, Published online, 13th June, 2014.
DOI: 10.3987/COM-14-S(K)32

■ Stereoselective Approach toward Ophiodilactones Based on an Intramolecular [2 + 2] Cycloaddition Reaction

Takaaki Matsubara, Jun Ishihara, and Susumi Hatakeyama*

Graduate School of Biomedical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

The highly enantio- and diastereoselective synthesis of a promising precursor of ophiodilactones A and B, tetrameric phenylpropanoids isolated from the ophiuroid Ophiocoma scolopendrina, is described. The synthesis involves an organocatalytic asymmetric Michael reaction, intramolecular [2 + 2] cycloaddition of a ketene to an alkene, Baeyer-Villiger oxidation, and construction of the C2 quaternary center as major transformations.

INTRODUCTION
Ophiodilactones A (1) and B (2) are new tetrameric phenylpropanoids isolated from Ophiocoma scolopendrina, a tropical and subtropical ophiuroid widely distributed in the Indo-Pacific, and exhibit moderate cytotoxic activity against P388 murine leukemia cells with IC50 values of 5.0 and 2.2 µgmL–1, respectively.1 These compounds possess characteristic compact structures consisting of a fused γ-lactone/δ-lactone skeleton with four phenyl groups and four or five contiguous stereogenic centers containing three quaternary centers. Their unique highly substituted dilactone structures and biological activities prompted us to investigate the synthesis of ophiodilactones,2 resulting in our recent achievement of the first total synthesis.3 During that time, we also studied an alternative approach based on intramolecular [2 + 2] cycloaddition of a ketene to an alkene.

We report here the highly stereoselective synthesis of keto lactone 3, a promising precursor of ophiodilactones.

RESULTS AND DISCUSSION
Ophiodilactone A (1) can be directly transformed to ophiodilactone B (2) by Cu(OAc)2-mediated radical cyclization.3 We therefore focused on the synthesis of 1. Based on a Baeyer-Villiger oxidation, we envisioned ketone 3 as a precursor which would be accessible from cyclobutanone 4 through another Baeyer-Villiger oxidation and stereoselective benzylation followed by hydroxylation by taking advantage of the rigid bicylic skeleton. To access 4 we considered intramolecular [2 + 2] cycloaddition of ketene 5 which could be in situ generated from 6. Although such cycloaddition reactions are well documented,4 the reactions giving products with four contiguous stereogenic centers involving two adjacent quaternary centers at junctures have been rarely investigated.5 One of key issues of this approach is therefore the feasibility and diastereoselectivity of the [2 + 2] cycloaddition step.

Scheme 2 illustrates the synthesis of the compounds corresponding to 6. Thus, organocatalytic asymmetric Michael addition6 of dimethyl malonate to cinnamaldehyde afforded aldehyde 7 of 97% ee in 98% yield. Acetalization of 7 and Krapcho decarboxylation7 of 8 gave 9, which was then benzylated in the presence of lithium diisopropylamide to provide ester 10 as a 1:1 epimeric mixture in excellent overall yield. After acidic hydrolysis of 10, the resulting aldehyde was directly subjected to Nozaki-Hiyama-Kishi reaction8 with (2-iodoallyl)benzene9 to afford alcohol 11 as an inseparable 1:1:1:1 diastereoisomeric mixture. For the next [2 + 2] cycloaddition, we then attempted to prepare TBDPS ether 13a, Bn ether 13b, and MOM ether 13c by protection of the hydroxy group followed by saponification. However, the protected compounds 15a-c turned out to be unexpectedly stable under saponification conditions and no reactions occurred. Compounds 13a-c were eventually obtained by a three-step sequence involving DIBAL-H reduction, Dess-Martin oxidation, and Pinnick-Kraus oxidation in good overall yields. On the other hand, 11 underwent saponification without difficulty to give carboxylic acid 12, which was acetylated to provide acetate 13d and δ-lactone 14 in 77% and 15% yields, respectively. The 1H NMR spectrum revealed 14 to be a single stereoisomer with all equatorial substituents.

The crucial [2 + 2] cycloaddition was then examined with four carboxylic acids 13a-d. When the acid chlorides, prepared from 13a-d using oxalyl chloride, were treated with triethylamine in boiling toluene, the desired cycloaddition products were not produced at all. On the other hand, as seen in Table 1, when 13a-d were heated in acetic anhydride10 in the presence of NaOAc at 200 °C for 12 h, cycloadditions of the ketenes, in situ generated from the corresponding mixed anhydrides, took place to provide the cyclized products.11 Among the substrates examined, acetoxy derivative 13d gave the most satisfying result and 4d was obtained as a 1.7:1 mixture in 91% yield (entry 4).

The stereochemical outcomes can be explained by assuming transition states A and B,12 the latter of which would be largely disfavored by the steric repulsion between the C4 benzyl and C5 phenyl groups. However, as OR group on the C7 position is bulkier, the energy difference between A and B becomes smaller leading to the formation of 16β as well as 4α and 4β because the steric interactions between C7 and C3 substituents become serious (entries 1 and 2).
With the desired cyclobutanone 4d in hand, we then attempted to synthesize ophiodilactone A (1) starting from the Baeyer-Villiger oxidation13 (Scheme 3). Methanolysis of 4d afforded 17α and 17β in 58% and 35% yields, respectively. Baeyer-Villiger oxidation of 17α was first examined using mCPBA under various conditions but no reaction occurred. However, we gratifyingly found that when 17α was treated with lithium tert-butyl peroxide in THF at 0 °C, γ-lactone 18α was obtained in 88% yield. This procedure again effectively worked for 17β to produce γ-lactone 18β in 98% yield, which was converted to 18α via 19 by Dess-Martin oxidation followed by NaBH4 reduction in good yield. At this stage, the stereostructure of 18α was confirmed by its X-ray crystallographic analysis.14 After protection of the hydroxy group of 18α as its TBS ether 20, the stereoselective introduction of benzyl and hydroxy groups at the C2 position was then examined.

Thus, the lithium enolate generated from 20 was reacted with benzyl iodide in THF-HMPA at 0 °C afforded benzylated compound 21 in 93% yield. Compound 21 was then converted to the potassium enolate and reacted with the Davis reagent15 in THF-HMPA at –40 °C to cleanly give alcohol 23 as a single diastereoisomer in 91% yield. The observed high stereoselectivity can be explained by the convex face attack of the Davis reagent to enolate 22. Successive desilylation of 23 and Dess-Martin oxidation of 24 gave keto lactone 3, the stereostructure of which was confirmed by the X-ray analysis of its acetate.16 The final Baeyer-Villiger oxidation was then examined using lithium tert-butyl peroxide as mentioned for the oxidation of 17α. However, ophiodilactone A (1) was not produced but cyclopentenone 25 was formed by base-promoted retro-aldol followed by E1cb elimination. After protection of the hydroxy group of 24 as its acetate and MOM ether, their Baeyer-Villiger oxidations were also examined but no reaction occurred possibly for steric reasons.
In conclusion, we have developed a highly enantio- and diastereoselective route to keto lactone 3, a promising precursor of ophiodilactones A (1) and B (2), which proceeds through an organocatalytic Michael addtion, intramolecular [2 + 2] cycloaddition, Baeyer-Villiger oxidation, and stereoselective construction of the C2 quaternary center by benzylation followed by hydroxylation. The remaining task toward the total synthesis of ophiodilactone A (1) is the only construction of the δ-lactone ring structure, which is currently under investigation.

EXPERIMENTAL
Where appropriate, reactions were performed in flame-dried glassware under argon atmosphere. All extracts were dried over MgSO4 and concentrated by rotary evaporation below 30 °C at 25 Torr unless otherwise noted. Commercial reagents and solvents were used as supplied with following exceptions. Benzene, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane (CH2Cl2), ethyl acetate (AcOEt), hexamethyldisilazane (HMDS), hexamethylphosphoric triamide (HMPA), hexane, toluene, and triethylamine were distilled from CaH2. Thin layer chromatography (TLC) was performed using precoated silica gel plates (0.2 or 0.5 mm thickness). Column chromatography was performed using silica gel (particle size 100-210 mm (regular), 40-50 mm (flash)). Optical rotations were recorded on a digital polarimeter at ambient temperature. Infrared spectra were measured on a Fourier transform infrared spectrometer. 1H NMR (400 and 500 MHz) and 13C NMR (100 and 125 MHz) spectra were measured using CDCl3 or CD3OD as solvent, and chemical shifts are reported as δ values in ppm based on internal CHCl3 (7.26 ppm, 1H; 77.0 ppm, 13C), MeOH (3.31 ppm, 1H; 49.2 ppm, 13C). MS and HRMS spectra were taken in EI or FAB mode.
(S)-Dimethyl 2-(3-Oxo-1-phenylpropyl)malonate (7). To an ice-cooled solution of cinnamaldehyde (264 mg, 2.0 mmol), (R)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine (32 mg, 0.10 mmol), and acetic acid (12 µL, 0.20 mmol) in H2O (0.5 mL) was added dimethyl malonate (132 mg, 1.0 mmol). After being stirred at 0 °C for 1 day, the mixture was diluted with AcOEt, washed with saturated NaHCO3 and brine, dried, and concentrated. Purification of the residue by column chromatography (SiO2 10 g, hexane/AcOEt = 5:1) gave 7 (258 mg, 98%) as a yellow oil: [α]D26 +32.1 (c 0.850, CHCl3) (lit.17 [α]D23 +29.8 (c. 0.56, CHCl3), 97% ee); 1H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 7.31-7.20 (m, 5H), 4.06-4.00 (m, 1H), 3.76-3.74 (m, 4H), 3.50 (s, 3H), 2.93-2.90 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 199.9, 168.3, 167.8, 139.7, 128.7, 127.9, 127.5, 57.2, 52.7, 52.4, 47.2, 39.4; FTIR (neat) 2954, 1755, 1740, 1725, 1435, 1254 cm-1; MS (EI) m/z 43 (100), 105, 132, 236, 264 (M+); HRMS (EI) calcd for C14H16O5 (M+) 264.0987, found 264.0998; HPLC: 97% ee, Chiralcel OJ-H, hexane/i-PrOH = 7:3, 25 °C, 5 µL, 1.0 mL/min, 210 nm, tR = 12.6 min (minor), tR = 16.3 min (major).
(S)-Dimethyl (2-(1,3-Dioxolan-2-yl)-1-phenylethyl)malonate (8). A solution of 7 (150 mg, 0.570 mmol), ethylene glycol (0.317 mL, 5.70 mmol), and p-toluenesulfonic acid (1 mg, 0.0057 mmol) in benzene (3 mL) was heated under reflux using a Dean-Stark apparatus for 7 h. The mixture was cooled to room temperature, diluted with AcOEt, washed with saturated NaHCO3 and brine, dried, and concentrated. Purification of the residue by column chromatography (SiO2 8 g, hexane/AcOEt = 4:1) gave 8 (173 mg, 99%) as a yellow oil: [α]D26 –9.1 (c 0.950, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.32-7.19 (m, 5H), 4.51 (dd, J = 7.5, 2.8 Hz, 1H), 3.95-3.87 (m, 2H), 3.76-3.64 (m, 7H), 3.44 (s, 3H), 2.12 (td, J = 12.1 Hz, 2.7 Hz, 1H), 1.97-1.91 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 168.5, 167.9, 140.0, 128.4, 128.2, 127.1, 102.4, 64.7, 64.6, 58.1, 52.6, 52.2, 41.5, 37.8; FTIR (neat) 2954, 1736, 1435, 1250, 1138 cm-1; MS (EI) m/z 73 (100), 169, 230, 308 (M+); HRMS (EI) calcd for C16H20O6 (M+) 308.1252, found 308.1244.
(S)-Methyl 4-(1,3-Dioxolan-2-yl)-3-phenylbutanoate (9). A solution of 8 (2.50 g, 8.11 mmol), LiCl (687 mg, 16.2 mmol), and H2O (0.146 mL, 8.11 mmol) in DMSO (80 mL) was heated at 150 °C for 7 h. The mixture was cooled to room temperature, diluted with Et2O, washed with saturated NH4Cl and brine, dried, and concentrated. Purification of the residue by column chromatography (SiO2 100 g, hexane/AcOEt = 4:1) gave 9 (2.00 g, 99%) as a yellow oil: [α]D26 –15.1 (c 0.600, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.31-7.18 (m, 5H), 4.62 (dd, J = 6.8, 3.4 Hz, 1H), 3.97-3.90 (m, 2H), 3.81-3.73 (m, 2H), 3.57 (s, 3H), 3.42-3.35 (m, 1H), 2.75 (dd, J = 15.4, 6.8 Hz, 1H), 2.62 (dd, J = 15.4, 8.3 Hz, 1H), 2.08-2.02 (m, 1H), 1.97-1.91 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 172.4, 143.2, 128.5, 127.4, 126.7, 102.8, 64.8, 64.7, 51.5, 41.4, 40.0, 38.0; FTIR (neat) 2952, 1738, 1140, 1030 cm-1; MS (EI) m/z 43, 73 (100), 104, 172, 250 (M+); HRMS (EI) calcd for C14H18O4 (M+) 250.1202, found 250.1205.
(2RS,3S)-Methyl 2-Benzyl-4-(1,3-dioxolan-2-yl)-3-phenylbutanoate (10) (1:1 mixture). To a solution of diisopropylamine (1.2 mL, 8.40 mmol) was added n-butyllithium (2.69 M in hexane, 3.0 mL, 8.00 mmol) at –78 °C, and the mixture was stirred at 0 °C for 15 min. HMPA (2.8 mL, 16.0 mmol) was added and the mixture was stirred at 0 °C for 15 min. This mixture was cooled to –78 °C and a solution of 9 (1.00 g, 4.00 mmol) in THF (15 mL) was added and then benzyl bromide (0.52 mL, 4.40 mmol) was added after stirring at –78 °C for 1 h. The mixture was warmed to 0 °C and stirred for 4 h. The reaction was quenched with saturated NH4Cl (4 mL) and the mixture was extracted with AcOEt. The extract was washed with brine, dried, concentrated, and chromatographed (SiO2 120 g, hexane/AcOEt = 4:1) to give 10 (1.35 g, 99%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.37-7.11 (m, 9H), 6.98-6.96 (m, 1H), 4.55 (dd, J = 6.0, 4.0 Hz, 0.5 x 1H), 4.44 (dd, J = 7.9, 2.5 Hz, 0.5 x 1H), 3.94-3.85 (m, 2H), 3.80-3.67 (m, 2H), 3.55 (s, 0.5 x 3H), 3.24 (s, 0.5 x 3H), 3.15 (td, J = 11.0, 3.2 Hz, 1H), 3.03-2.86 (m, 2H), 2.67 (dd, J = 13.4, 11.5 Hz, 0.5 x 1H), 2.49 (dd, J = 13.6, 3.8 Hz, 0.5 x 1H), 2.20-2.09 (m, 1.5H), 1.82-1.76 (m, 0.5 x 1H); 13C NMR (100 MHz, CDCl3) δ 174.9, 173.9, 141.4, 139.2, 128.8,128.5, 128.3, 128.3, 128.3, 128.2, 128.2, 127.0,126.8, 126.3, 126.2, 102.7, 102.6, 64.8, 64.7, 64.7, 64.7, 54.8, 54.3, 51.4, 51.0, 44.6, 44.3, 38.6, 37.2, 37.1, 36.3; FTIR (neat) 2950, 1732, 1139 cm-1; MS (EI) m/z 43 (100), 73, 163, 262, 340 (M+); HRMS (EI) calcd for C21H24O4 (M+) 340.1676, found 340.1677.
(2RS,3S,5RS)-Methyl 2,6-Dibenzyl-5-hydroxy-3-phenylhept-6-enoate (11) (1:1:1:1 mixture). A solution of 9 (13.5 g, 39.7 mmol) in 50% aq acetic acid (120 mL) was heated at 90 °C for 16 h. The mixture was cooled to room temperature and extracted with AcOEt. The extract was washed with saturated NaHCO3 and brine, dried, and concentrated to give the correspondingaldehyde (12.0 g), which was used for the next reaction without purification.
Crude aldehyde (12.0 g) and (2-iodoallyl)benzene9 (12.6 g, 51.6 mmol) were dissolved in degassed DMF (200 mL), and NiCl2 (504 mg, 3.97 mmol) and CrCl2 (16.3 g, 159 mmol) were added at 0 °C. After being stirred at room temperature for 2 h, the mixture was diluted with AcOEt, washed with saturated NH4Cl and brine, dried, and concentrated. Purification of the residue by column chromatography (SiO2 1 kg, hexane/AcOEt = 4:1) gave 11 (15.8 g, 96%, 2 steps) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.36-7.01 (m, 12H), 6.98-6.93 (m, 3H), 5.08 (s, 0.25 x 1 H), 5.03 (s, 0.25 x 1 H), 4.93 (s, 0.5 x 1H), 4.75 (s, 0.25 x 1 H), 4.71 (s, 0.25 x 1 H), 4.67 (s, 0.5 x 1H), 3.85-3.11 (m, 6H), 2.97-2.40 (m, 4H), 2.06-1.46 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 175.4, 175.1, 174.0, 152.0, 151.8, 149.8, 149.7, 141.8, 141.5, 141.5, 141.2, 140.5, 139.3, 139.2, 139.0, 139.0, 137.4, 129.4, 129.2, 129.0, 129.0, 128.8, 128.8, 128.7, 128.7, 128.5, 128.4, 128.4, 128.4, 128.3, 128.3, 128.2, 128.2, 128.2, 128.2, 128.1, 128.0, 127.0, 126.9, 126.8, 126.7, 126.3, 126.2, 126.2, 126.2, 126.1, 126.1, 126.1, 126.0, 124.5, 119.7, 114.3, 114.1, 111.1, 110.9, 102.6, 74.8, 73.7, 73.7, 71.3, 71.1, 64.6, 64.6, 54.9, 54.8, 54.7, 54.4, 53.9, 51.3, 50.9, 50.9, 45.4, 45.2, 45.2, 45.0, 44.9, 44.6, 40.7, 40.1, 39.5, 39.4, 39.3, 37.8, 34.5, 37.4, 37.3, 37.0, 36.9, 36.4, 36.0, 13.9; FTIR (neat) 3471, 3027, 1731, 1446, 1162 cm-1; MS (EI) m/z 73 (100), 163, 278, 414 (M+); HRMS (EI) calcd for C28H30O3 (M+) 414.2185, found 414.2175.
(2RS,3S,5RS)-Methyl 2,6-Dibenzyl-5-((tert-butyldiphenylsilyl)oxy)-3-phenylhept-6-enoate (15a) (diastereoisomeric mixture). To a solution of 11 (90 mg, 0.217 mmol) in DMF (0.2 mL) were added tert-butyldiphenylchlorosilane (0.28 mL, 1.08 mmol) and imidazole (148 mg, 2.17 mmol) at room temperature. After being stirred at room temperature for 2 h, the mixture was diluted with AcOEt, washed with 1 M HCl (2 mL), saturated NaHCO3, and brine, dried, and concentrated. Purification of the residue by column chromatography (SiO2 6 g, hexane/AcOEt = 40:1) gave 15a (123 mg, 87%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.65-6.61 (m, 25H), 4.87, 4.84, 4.47, 4.44, 4.42, 4.35 (6 x s, 2H), 4.02-3.85 (m, 1H), 3.56-3.16 (m, 3H), 2.99-2.51 (m, 3H), 2.23-1.89 (m, 2H), 1.07-0.90 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 175.1, 174.9, 174.8, 173.9, 150.7, 148.8, 148.4, 142.1, 142.0, 140.6, 140.4, 139.5, 139.5, 139.4, 139.3, 138.8, 136.2, 136.2, 136.2, 136.2, 136.1, 136.1, 135.9, 135.9, 135.9, 135.8, 135.8, 134.4, 134.3, 134.2, 133.6, 133.6, 130.0, 129.7, 129.6, 129.5, 129.5, 129.4, 128.9, 128.9, 128.7, 128.7, 128.7, 128.6, 128.5, 128.5, 128.4, 128.4, 128.3, 128.2, 128.2, 128.0, 128.0, 127.9, 127.8, 127.6, 127.5, 127.4, 127.4, 127.4, 127.3, 126.5, 126.5, 126.3, 126.1, 126.1, 126.0, 125.8, 125.8, 114.6, 114.5, 112.6, 78.4, 77.2, 75.8, 75.0, 55.3, 55.2, 54.8, 51.3, 51.3, 51.2, 50.9, 44.9, 44.8, 44.8, 44.5, 44.3, 41.7, 39.0, 37.8, 37.3, 37.2, 37.0, 36.0, 35.6, 35.1, 27.1, 27.0, 27.0, 26.9, 26.5, 19.4, 19.3, 19.2, 12.8; FTIR (neat) 2947, 1734, 1108 cm-1; MS (EI) m/z 199 (100), 471, 595, 652 (M+); HRMS (EI) calcd for C44H48O3Si (M+) 652.3380, found 652.3387.
(2RS,3S,5RS)-Methyl 2,6-dibenzyl-5-(benzyloxy)-3-phenylhept-6-enoate (15b) (diastereoisomeric mixture). To a solution of 11 (90 mg, 0.217 mmol) and benzyl trichloroacetimidate (0.080 mL, 0.435 mmol) in Et2O (0.8 mL) was added trifluoromethanesulfonic acid (10 µL, 0.109 mmol) at room temperature. After stirring at room temperature for 2 h, the reaction was quenched with 1 M HCl (2 mL) and the mixture was extracted with AcOEt. The extract was washed saturated NaHCO3 and brine, dried, concentrated, and chromatographed (SiO2 6 g, hexane/AcOEt = 20:1) to give 15b (107 mg, 97%) as acolorless oil: 1H NMR (400 MHz, CDCl3) δ 7.37-6.91 (m, 20H), 5.15-4.30 (m, 4H), 4.06-3.39 (m, 5H), 3.32-3.02 (m, 3H), 2.93-2.42 (m, 2H), 2.30-1.65 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 175.3, 175.0, 174.6, 174.0, 161.9, 148.7, 141.9, 141.3, 141.2, 139.4, 139.3, 139.3, 139.2, 139.1, 138.6, 138.3, 136.3, 136.2, 131.2, 130.9, 129.8, 129.5, 129.3, 129.3, 129.2, 129.1, 128.9, 128.9, 128.8, 128.8, 128.8, 128.7, 128.6, 128.5, 128.5, 128.4, 128.4, 128.3, 128.3, 128.3, 128.2, 128.2, 128.1, 128.1, 128.0, 127.9, 127.8, 127.8, 127.7, 127.6, 127.4, 127.4, 127.3, 127.3, 126.9, 126.7, 126.6, 126.5, 126.4, 126.2, 126.2, 126.1, 126.1, 126.0, 126.0, 125.9, 116.7, 116.3, 112.6, 81.4, 81.0, 78.2, 69.9, 69.9, 69.8, 69.6, 69.5, 54.9, 54.7, 54.7, 54.3, 54.0, 52.7, 51.3, 51.2, 51.2, 50.9, 50.8, 45.2, 45.2, 45.0, 44.6, 43.0, 41.4, 40.1, 38.6, 37.5, 37.4, 36.9, 36.5, 36.3, 36.0, 35.6, 13.9; FTIR (neat) 3027, 1730, 1492 1454, 1159 cm-1; MS (EI) m/z 91 (100), 233, 396, 471, 504 (M+); HRMS (EI) calcd for C35H36O3 (M+) 504.2669, found 504.2673.
(2RS,3S,5RS)-Methyl,2,6-Dibenzyl-5-(methoxymethoxy)-3-phenylhept-6-enoate (15c) (diastereoisomeric mixture). To an ice-cooled solution of 11 (100 mg, 0.241 mmol) in CH2Cl2 (2 mL) were added N,N-diisopropylethylamine (0.21 mL, 1.21 mmol), chloromethyl methyl ether (92 µL, 1.21 mmol), and tetra-n-butylammonium iodide (446 mg, 1.21 mmol). After being stirred at room temperature for 2 h, the mixture was diluted with AcOEt, wahed with 1 M HCl, saturated NaHCO3 and brine, dried, and concentrated. Purification of the residue by column chromatography (SiO2 6 g, hexane/AcOEt = 7:1) gave 15c (108 mg, 97%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.36-6.95 (m, 15H), 4.99, 4.94, 4.84, 4.76, 4.73, 4.68 (6 x s, 2H), 4.65-4.30 (m, 2H), 3.89-3.51 (m, 3H), 3.39-3.16 (m, 6H), 3.09-2.80 (m, 2H), 2.74-2.40 (m, 1H), 2.26-1.67 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 175.2, 174.9, 174.1, 174.0, 148.8, 146.3, 141.8, 141.1, 141.0, 139.3, 139.3, 139.2, 139.1, 139.0, 129.7, 129.5, 129.2, 129.2, 129.0, 129.0, 128.9, 128.7, 128.5, 128.5, 128.5, 128.4, 128.4, 128.4, 128.3, 128.3, 128.3, 128.2, 128.2, 128.2, 128.1, 128.0, 127.4, 127.0, 126.9, 126.8, 126.8, 126.7, 126.4, 126.2, 126.2, 126.1, 126.1, 126.0, 117.1, 117.0, 113.3, 94.5, 94.5, 94.1, 93.6, 93.4, 80.1, 78.1, 78.0, 77.2, 77.1, 56.0, 55.9, 55.4, 55.2, 55.2, 55.1, 55.0, 54.5, 54.2, 51.3, 51.3, 51.0, 50.9, 45.3, 45.2, 45.1, 45.0, 44.9, 44.5, 39.8, 38.8, 38.3, 37.3, 37.2, 36.4, 36.0, 35.5, 13.1, 11.6; FTIR (neat) 2945, 1734, 1157, 1093, 1032 cm-1; MS (EI) m/z 91 (100), 163, 396, 458 (M+); HRMS (EI) calcd for C30H34O4 (M+) 458.2455, found 458.2458.
(2RS,3S,5RS)-2,6-Dibenzyl-5-((tert-butyldiphenylsilyl)oxy)-3-phenylhept-6-enoic Acid (13a) (diastereoisomeric mixture). To a solution of 15a (110 mg, 0.169 mmol) in CH2Cl2 (2 mL) was added DIBAL-H (1.02 M in hexane, 0.38 mL, 0.388 mmol) at –78 °C. After stirring at –78 °C for 3 h, the reaction was quenched with saturated Rochelle salt (2 mL) and the mixture was extracted with AcOEt. The extrct was washed with brine, dried, concentrated, and chromatographed (SiO2 6 g, hexane/AcOEt = 10:1) to give the corresponding alcohol (100 mg, 95%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.70-6.67 (m, 25H), 4.88, 4.76, 4.47, 4.42, 4.40 (5 x s, 2H), 4.14-3.93 (m, 1H), 3.52-2.87 (m, 5H), 2.53-2.33 (m, 2H), 2.17-1.76 (m, 4H), 1.06-0.90 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 150.9, 148.8, 148.6, 142.9, 142.8, 141.8, 141.7, 141.1, 141.0, 140.9, 139.8, 139.6, 139.6, 139.1, 137.9, 136.2, 136.1, 136.0, 136.0, 135.9, 134.8, 134.5, 134.4, 133.8, 133.5, 129.8, 129.6, 129.5, 129.5, 129.5, 129.4, 129.1, 129.0, 129.0, 128.9, 128.7, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.2, 128.1, 128.1, 128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 127.5, 127.5, 127.4, 127.4, 127.4, 127.3, 127.3, 127.3, 126.7, 126.2, 126.0, 126.0, 126.0, 125.9, 125.9, 125.8, 114.3, 112.8, 78.8, 76.1, 75.8, 62.2, 62.0, 61.6, 48.9, 48.6, 48.5, 48.4, 48.3, 42.4, 41.9, 41.9, 41.7, 40.2, 39.0, 37.9, 37.6, 37.5, 36.2, 36.0, 35.2, 34.9, 34.4, 34.2, 27.0, 27.0, 19.4, 19.3, 19.3, 12.7; FTIR (neat) 3457, 2932, 1107, 1045 cm-1; MS (FAB) m/z 91 (100), 135, 199, 625 (M+1); HRMS (FAB) calcd for C43H48O2Si (M+) 624.3400, found 624.3376.
To an ice-cooled solution of the alcohol (100 mg, 0.160 mmol) in CH2Cl2 (2 mL) were added NaHCO3 (70 mg, 0.801 mmol) and Dess-Martin periodinane (136 mg, 0.320 mmol). After being stirred at room temperature for 1 h, the mixture was diluted with AcOEt, washed with 50% Na2S2O3, saturated NaHCO3, and brine, dried, and concentrated to give the corresponding aldehyde as a yellow oil which was used for the next reaction without purification.
Crude aldehyde thus obtained was dissolved in tert-BuOH (1.2 mL) and H2O (0.6 mL), NaH2PO4 (77 mg, 0.641 mmol), NaClO2 (58 mg, 0.641 mmol), and 2-methyl-2-butene (0.36 mL, 3.20 mmol) were added at 0 °C. After being stirred at 0 °C for 1 h, the mixture was diluted with AcOEt, washed with saturated NaHCO3 and brine, dried, and concentrated. Purification of the residue by column chromatography (SiO2 6 g, hexane/AcOEt = 7:1) gave 13a (101 mg, 98%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.66-6.61 (m, 25H), 4.88, 4.85, 4.48, 4.46, 4.42, 4.37 (6 x s, 2H), 4.05-3.73 (m, 1H), 3.56-3.15 (m, 1H), 3.00-2.85 (m, 1H), 2.80-2.29 (m, 4H), 2.21-1.86 (m, 2H), 1.05-1.00 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 180.4, 150.8, 148.9, 148.4, 141.5, 140.3, 140.0, 139.5, 139.4, 139.2, 139.1, 138.9, 138.8, 137.6, 136.3, 136.2, 136.0, 136.0, 135.9, 135.9, 134.8, 134.4, 134.3, 134.2, 134.1, 134.1, 133.7, 133.6, 133.6, 133.6, 130.0, 129.8, 129.7, 129.5, 129.5, 129.4, 128.9, 128.9, 128.8, 128.7, 128.7, 128.5, 128.5, 128.5, 128.4, 128.3, 128.3, 128.3, 128.2, 128.1, 128.0, 128.0, 127.8, 127.7, 127.6, 127.5, 127.5, 127.4, 127.4, 127.4, 127.3, 127.3, 126.5, 126.3, 126.2, 126.1, 126.0, 125.9, 125.8, 114.6, 114.5, 112.5, 77.7, 75.7, 74.7, 54.9, 54.9, 54.4, 44.5, 43.9, 41.8, 40.5, 38.1, 36.8, 36.6, 36.0, 35.2, 34.9, 27.1, 27.0, 27.0, 27.0, 26.9, 21.0, 19.4, 19.3, 19.3, 19.2, 19.2, 14.2, 13.0, 11.4; FTIR (neat) 3060, 3030, 2933, 2848, 1706, 1107 cm-1; MS (FAB) m/z 91 (100), 135, 199, 639 (M+1); HRMS (FAB) calcd for C43H46O3Si (M+) 638.3231, found 638.3245.
(2RS,3S,5RS)-2,6-Dibenzyl-5-(benzyloxy)-3-phenylhept-6-enoic Acid (13b) (diastereoisomeric mixture). Compound 15b (100 mg, 0.198 mmol) was reduced with DIBAL-H in the same manner as described for the reduction of 15a to give the corresponding alcohol (72.4 mg, 77%) as a colorless oil after column chromatography (SiO2 6 g, hexane/AcOEt = 10:1): 1H NMR (400 MHz, CDCl3) δ 7.34-6.87 (m, 20H), 5.03-4.35 (m, 3H), 4.08-3.86 (m, 3H), 3.65-3.31 (m, 4H), 2.94-2.31 (m, 2H), 2.19-1.72 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 149.1, 148.8, 147.0, 143.7, 141.3, 141.0, 140.8, 140.7, 139.4, 139.3, 139.1, 138.4, 138.3, 138.1, 131.4, 130.6, 130.5, 129.6, 129.6, 129.3, 129.1, 129.0, 128.9, 128.9, 128.8, 128.8, 128.7, 128.6, 128.5, 128.4, 128.4, 128.3, 128.3, 128.2, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 127.4, 127.4, 126.9, 126.4, 126.3, 126.3, 126.2, 126.1, 125.9, 125.9, 125.9, 125.8, 125.7, 115.9, 112.6, 81.6, 81.0, 78.9, 70.2, 70.0, 62.1, 61.5, 60.9, 51.4, 48.3, 48.2, 47.8, 47.7, 43.0, 42.5, 42.0, 41.5, 39.3, 38.8, 38.7, 36.5, 36.3, 36.0, 35.0, 34.9, 34.4, 14.2, 14.0; FTIR (neat) 3423, 3025, 2946, 1058, 1492, 1450 cm-1; MS (EI) m/z 91 (100), 233, 368, 458, 476 (M+); HRMS (EI) calcd for C34H36O2 (M+) 476.2702, found 476.2688.
The alcohol (70 mg, 0.147 mmol) was subjected to Dess-Martin oxidation followed by Pinnick-Kraus oxidation in the same manner as described for the synthesis of 13a to give 13b (66.0 mg, 92%) as a colorless oil after column chromatography (SiO2 6 g, hexane/AcOEt = 6:1): 1H NMR (400 MHz, CDCl3) δ 7.28-6.91 (m, 20H), 5.03, 4.90, 4.83, 4.81, 4.74, 4.63 (6 x s, 2H), 4.10-3.50 (m, 3H), 3.42-2.40 (m, 6H), 2.31-1.66 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 179.8, 148.6, 147.0, 141.6, 141.0, 140.7, 139.1, 139.1, 139.0, 138.9, 138.5, 138.3, 136.8, 129.9, 129.8, 129.5, 129.4, 129.3, 129.1, 128.9, 128.8, 128.7, 128.5, 128.5, 128.4, 128.3, 128.3, 128.2, 128.2, 128.0, 127.9, 127.8, 127.8, 127.7, 127.7, 127.5, 127.4, 127.0, 126.8, 126.7, 126.3, 126.2, 126.2, 126.0, 116.1, 112.6, 80.7, 78.1, 76.8, 70.1, 70.0, 69.9, 69.9, 69.8, 54.5, 53.0, 44.9, 44.8, 44.1, 41.5, 40.0, 38.8, 38.6, 37.4, 37.1, 36.8, 35.6; FTIR (neat) 3060, 3027, 2924, 1706, 1449 cm-1; MS (EI) m/z 91 (100), 233, 382, 471, 504 (M+); HRMS (EI) calcd for C34H34O3 (M+) 490.2504, found 490.2500.
(2RS,3S,5RS)-2,6-Dibenzyl-5-(methoxymethoxy)-3-phenylhept-6-enoic acid (13c) (diastereoisomeric mixture). Compound 15c (100 mg, 0.218 mmol) was reduced with DIBAL-H in the same manner as described for the reduction of 15a to give the corresponding alcohol (86.5 mg, 92%) as a colorless oil after column chromatography (SiO2 6 g, hexane/AcOEt = 4:1): 1H NMR (400 MHz, CDCl3) δ 7.36-7.03 (m, 15H), 5.00-4.38 (m, 4H), 3.92-3.56 (m, 1H), 3.43-3.11 (m, 7H), 2.88-1.79 (m, 7H); 13C NMR (100 MHz, CDCl3) δ 148.8, 146.6, 146.4, 143.1, 142.7, 142.6, 142.4, 141.2, 141.0, 140.8, 140.7, 139.3, 139.2, 139.0, 137.2, 129.5, 129.5, 129.2, 129.1, 129.0, 129.0, 129.0, 128.9, 128.7, 128.7, 128.5, 128.4, 128.4, 128.4, 128.3, 128.3, 128.2, 128.2, 128.2, 128.1, 128.0, 127.5, 126.6, 126.5, 126.5, 126.4, 126.1, 125.9, 125.8, 125.8, 125.7, 116.7, 116.4, 113.5, 113.4, 94.3, 93.9, 93.7, 93.6, 80.5, 80.4, 78.5, 78.4, 77.7, 62.4, 62.0, 61.3, 61.1, 56.1, 56.0, 55.4, 55.3, 55.2, 48.7, 48.5, 48.4, 48.3, 48.2, 43.1, 42.6, 42.5, 41.6, 38.6, 38.4, 38.3, 37.6, 36.7, 36.4, 36.2, 35.8, 34.9, 34.8, 34.7, 34.4, 13.1, 12.2, 11.9; FTIR (neat) 3446, 2932, 1090, 1034 cm-1; MS (EI) m/z 91 (100), 368, 398, 430 (M+); HRMS (EI) calcd for C29H34O3 (M+) 430.2517, found 430.2526.
The alcohol (80 mg, 0.186 mmol) was subjected to Dess-Martin oxidation followed by Pinnick-Kraus oxidation in the same manner as described for the synthesis of 13a to give 13c (79.3 mg, 96%) as a colorless oil after column chromatography (SiO2 6 g, hexane/AcOEt = 1:1): 1H NMR (400 MHz, CDCl3) δ 7.35-6.94 (m, 15H), 4.97-4.33 (m, 4H), 3.89-3.60 (m, 1H), 3.35-3.04 (m, 6H), 2.86-2.48 (m, 3H), 2.24-1.78 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 180.4, 179.8, 179.1, 148.7, 148.7, 146.4, 146.3, 141.4, 140.8, 140.5, 139.1, 139.1, 139.0, 138.9, 137.4, 137.2, 134.9, 129.7, 129.5, 129.3, 129.2, 129.0, 129.0, 128.9, 128.8, 128.8, 128.7, 128.7, 128.6, 128.5, 128.5, 128.4, 128.4, 128.3, 128.3, 128.2, 128.1, 128.0, 127.5, 127.1, 127.0, 126.7, 126.4, 126.3, 126.3, 126.1, 126.0, 126.0, 117.1, 116.8, 113.4, 94.5, 94.3, 94.1, 93.6, 93.4, 78.0, 77.3, 56.0, 55.9, 55.4, 55.3, 55.3, 55.2, 54.9, 54.7, 53.4, 44.9, 44.6, 44.1, 39.7, 38.7, 38.4, 38.2, 37.2, 37.0, 36.9, 36.8, 36.5, 35.9, 35.6, 35.5, 35.4, 13.1, 11.6; FTIR (neat) 3053, 3030, 2941, 1707, 1151, 1031 cm-1; MS (EI) m/z 91 (100), 382, 412, 444 (M+); HRMS (EI) calcd for C29H32O4 (M+) 444.2294, found 444.2287.
(2RS,3S,5RS)-5-Acetoxy-2,6-dibenzyl-3-phenylhept-6-enoic Acid (13d)　and　(3R,4S,6S)-3-Benzyl-4-phenyl-6-(3-phenylprop-1-en-2-yl)tetrahydro-2H-pyran-2-one (14). A solution of 11 (3.7 g, 8.90 mmol) and LiOH (1.1 g, 26.8 mmol) in 50% aq THF (50 mL) was heated at 80 °C for 12 h. The mixture was cooled in an ice bath, acidified with 1 M HCl (30 mL), and extracted with AcOEt. The extract was washed with brine, dried, and concentrated to give hydroxy acid 12 which was used for the next reaction without purification.
To an ice-cooled solution of crude hydroxy acid 12 thus obtained in CH2Cl2 (80 mL) were added pyridine (2.66 mL, 33.0 mmol) and acetyl chloride (1.76 mL, 24.7 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was then cooled to 0 °C, and NaHCO3 (3.59 g, 41.2 mmol) and MeOH (20 mL) were added. After being stirred at room temperature for 1 h, the mixture was diluted with AcOEt and acidified with 1 M HCl (30 mL). The organic layer was washed with saturated NaHCO3 (10 mL) and brine, dried, concentrated, and chromatographed (SiO2 150 g, hexane/AcOEt = 6:1 to 1:1) to give 13d (2.81 g, 77%) and 14 (501 mg, 15%).
13d: yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.34-6.96 (m, 15H), 5.00-4.70 (m, 2H), 3.71-3.62 (m, 1H), 3.43-3.17 (m, 2H), 3.00-2.76 (m, 2H), 2.66-2.57 (m, 1H), 2.51-2.39 (m, 1H), 2.22-1.66 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 180.4, 180.2, 180.0, 171.8, 170.0, 170.0, 147.6, 147.5, 145.2, 140.6, 140.3, 140.2, 140.2, 138.8, 138.7, 138.7, 138.5, 138.4, 136.9, 133.7, 130.4, 129.3, 129.1, 129.0, 129.0, 128.9, 128.9, 128.8, 128.8, 128.7, 128.5, 128.4, 128.4, 128.3, 128.3, 128.2, 128.2, 128.1, 128.1, 128.0, 127.3, 127.2, 127.1, 126.8, 126.5, 126.4, 126.2, 126.1, 126.0, 123.9, 122.0, 116.4, 113.1, 112.7, 110.3, 109.7, 78.5, 75.7, 74.1, 73.8, 54.9, 54.7, 54.4, 53.8, 51.6, 45.1, 44.8, 44.8, 44.3, 42.5, 39.6, 39.6, 38.4, 37.6, 37.4, 37.1, 37.0, 36.9, 36.3, 35.9, 35.8, 29.9, 21.2, 21.1, 20.8, 20.7, 14.0, 12.4; FTIR (neat) 3027, 2924, 1736, 1708, 1239 cm-1; MS (EI) m/z 91 (100), 143, 233, 382, 442 (M+); HRMS (EI) calcd for C29H30O4 (M+) 442.2155, found 442.2166.
14: colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.37-7.08 (m, 15H), 5.14 (m, 1H), 4.82 (m, 1H), 4.49 (dd, J = 11.7 Hz, 2.4 Hz, 1H), 3.48 (d, J = 15.6 Hz, 1H), 3.40 (dd, J = 14.2 Hz, 3.9 Hz, 1H), 3.35 (d, J = 15.6 Hz, 1H), 3.09-3.04 (m, 1H), 2.87 (td, J = 12.2 Hz, 3.4 Hz, 1H), 2.65 (dd, J = 14.2 Hz, 5.4 Hz, 1H), 1.99 (dt, J = 14.2 Hz, 2.9 Hz, 1H), 1.91-1.81 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 173.0, 146.2, 142.2, 138.3, 138.2, 129.7, 129.2, 129.0, 128.4, 128.4, 127.3, 127.3, 126.6, 126.4, 114.0, 81.0, 48.4, 41.6, 38.4, 37.2, 34.5; FTIR (neat) 3027, 2923, 1725, 1108 cm-1; MS (EI) m/z 63 (100), 78, 234, 382 (M+); HRMS (EI) calcd for C27H26O2 (M+) 382.1938 found 382.1944.
General Procedure for [2 + 2] Cycloaddition Reactions of Compounds 13a-d. Compound 13a-d (1.0 mmol), NaOAc (82 mg, 1.0 mmol), acetic anhydride (0.47 mL, 5.0 mmol) and toluene (10 mL) were placed in a sealed tube, and the mixture was heated at 200 °C for 12 h. The mixture was cooled to room temperature and diluted with AcOEt, washed with saturated NaHCO3 and brine, dried, concentrated, and chromatographed.
Reaction of 13a. 4aα (15 mg, 15%), 4aβ (33 mg, 34%), and 16a (11 mg, 11%) were obtained from 13a (100 mg, 0.157 mmol) after column chromatography (SiO2 5 g, hexane/AcOEt = 40:1).
4aα: colorless oil; [α]D26 +4.7 (c 0.705, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.58-7.53 (m, 4H), 7.44-7.00 (m, 19H), 6.76-6.74 (m, 2H), 4.51 (dd, J = 10.4, 6.8 Hz, 1H), 3.59 (d, J = 18.6 Hz, 1H), 3.11 (d, J = 15.0 Hz, 1H), 3.03 (d, J = 15.0 Hz, 1H), 2.99 (s, 2H), 2.87 (q, J = 6.8 Hz, 1H), 2.79 (d, J = 18.6 Hz, 1H), 2.04-1.93 (m, 2H), 0.98 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 212.3, 138.1, 138.0, 136.9, 135.8, 135.8, 134.1, 133.6, 130.2, 130.2, 129.7, 128.6, 128.4, 128.0, 127.7, 127.6, 127.5, 126.6, 126.2, 77.6, 77.2, 50.4, 48.6, 48.1, 39.8, 39.3, 36.7, 27.0, 19.3; FTIR (neat) 2932, 1768, 1111 cm-1; MS (FAB) m/z 91, 135 (100), 199, 621 (M+1); HRMS (FAB) calcd for C43H44O2Si (M+) 621.3188, found 621.3188.
4aβ: colorless oil; [α]D25 +116.1 (c 1.500, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 6.8 Hz, 2H), 7.57 (d, J = 6.8 Hz, 2H), 7.44-7.19 (m, 16H), 7.07-7.06 (m, 3H), 6.63-6.62 (m, 2H), 4.42 (d, J = 2.8 Hz, 1H), 3.95 (d, J = 14.2 Hz, 1H), 3.74-3.69 (m, 1H), 3.18 (d, J = 14.8 Hz, 1H), 3.08 (d, J = 14.8 Hz, 1H), 2.81 (d, J = 18.4 Hz, 1H), 2.73 (d, J = 14.2 Hz, 1H), 2.55 (d, J = 18.4 Hz, 1H), 2.15 (dd, J = 14.0 Hz, 6.8 Hz, 1H), 2.03 (td, J = 14.0 Hz, 3.2 Hz, 1H), 1.12 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 211.1,. 139.2, 138.8, 137.2, 136.2, 135.8, 134.6, 133.0, 130.8, 129.9, 129.7, 129.6, 128.4, 128.3, 128.2, 127.8, 127.8, 127.5, 126.4, 126.3, 126.2, 79.6, 79.0, 52.4, 50.7, 50.0, 40.1, 35.8, 34.7, 27.4, 19.4; FTIR (neat) 2932, 1764, 1106, 1066 cm-1; MS (FAB) m/z 91, 135 (100), 199, 621 (M+1); HRMS (FAB) calcd for C43H44O2Si (M+) 621.3188, found 621.3188.
16a: colorless oil; [α]D26 -43.8 (c 0.540, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.53-7.00 (m, 21H), 6.78-6.75 (m, 2H), 6.55-6.53 (m, 2H), 4.73 (dd, J = 9.2 Hz, 6.4 Hz, 1H), 3.59 (d, J = 18.0 Hz, 1H), 3.24 (dd, J = 7.6 Hz, 3.2 Hz, 1H), 3.15 (d, J = 14.4 Hz, 1H), 2.98 (d, J = 14.4 Hz, 1H), 2.95 (d, J = 18.0 Hz, 1H), 2.82 (d, J = 14.4 Hz, 1H), 2.76 (d, J = 14.4 Hz, 1H), 1.98-1.88 (m, 1H), 1.81-1.75 (m, 1H), 0.99 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 214.6, 141.2, 137.9, 136.8, 135.9, 135.8, 134.1, 133.3, 130.5, 130.0, 129.7, 129.6, 128.8 128.4, 128.1, 127.6, 127.4, 126.4, 126.2, 126.1, 77.6, 76.9, 50.4, 49.3, 47.6, 40.5, 40.1, 34.5, 26.9, 19.2; FTIR (neat) 2932, 1771, 1107 cm-1; MS (EI) m/z 69 (100), 199, 397, 421, 620 (M+); HRMS (FAB) calcd for C43H44O2Si (M+) 620.3125, found 620.3139.
Reaction of 13b. 4bα (7.6 mg, 13%), 4bβ (13.2 mg, 23%), and 16b (4.0 mg, 7%) were obtained from 13b (60 mg, 0.122 mmol) after column chromatography (SiO2 5 g, hexane/AcOEt = 20:1).
4bα: colorless oil; [α]D24 +11.2 (c 0.425, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.27-7.16 (m, 16H), 7.00-6.98 (m, 2H), 6.91-6.89 (m, 2H), 4.28 (d, J = 11.4 Hz, 1H), 4.14-4.09 (m, 1H), 4.13 (d, J = 11.4 Hz, 1H), 3.46 (d, J = 18.6 Hz, 1H), 3.15-3.02 (m, 5H), 2.83 (d, J = 18.6 Hz, 1H), 2.48-2.41 (m, 1H), 2.04-1.95 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 212.6, 138.5, 138.2, 137.0, 130.6, 129.7, 128.8, 128.2, 128.1, 128.0, 127.9, 127.4, 127.3, 126.8, 126.4, 126.3, 83.4, 71.4, 51.2, 48.8, 47.3, 41.8, 37.0, 36.6, 30.9; FTIR (neat) 3028, 1767, 1111 cm-1; MS (FAB) m/z 91 (100), 274, 339, 472 (M+); HRMS (FAB) calcd for C34H32O2 (M+) 472.2404, found 472.2403.
4bβ: colorless oil; [α]D25 +54.3 (c 0.700, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.45-7.16 (m, 18H), 6.84-6.82 (m, 2H), 4.63 (d, J = 11.6 Hz, 1H), 4.42 (d, J = 11.6 Hz, 1H), 3.91 (d, J = 3.3 Hz, 1H), 3.74-3.69 (m, 1H), 3.73 (d, J = 13.0 Hz, 1H), 3.14 (d, J = 15.6 Hz, 1H), 3.08 (d, J = 15.6 Hz, 1H), 3.07 (d, J = 19.0 Hz, 1H), 2.67 (d, J = 19.0 Hz, 1H), 2.62 (d, J = 13.0 Hz, 1H), 2.44 (dd, J = 14.0 Hz, 6.7 Hz, 1H), 2.17 (td, J = 14.0 Hz, 3.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 211.1, 138.9, 138.7, 138.4, 137.1, 130.7, 129.8, 128.6, 128.5, 128.4, 128.1, 127.9, 127.6, 127.4, 126.8, 126.3, 126.3, 83.5, 78.9, 70.3, 53.1, 50.5, 49.8, 35.7, 34.9, 34.3, 30.9; FTIR (neat) 3028, 1767, 1500, 1455 cm-1; MS (FAB) m/z 91 (100), 256, 339, 472 (M+); HRMS (FAB) calcd for C34H32O2 (M+) 472.2387, found 472.2403.
16b: colorless oil; [α]D24 -45.4 (c 0.200, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.32-6.85 (m, 20H), 4.49 (dd, J = 9.8 Hz, 7.0 Hz, 1H), 4.19 (d, J = 11.4 Hz, 1H), 4.04 (d, J = 11.4 Hz, 1H), 3.52 (d, J = 18.0 Hz, 1H), 3.36 (d, J = 6.0 Hz, 1H), 3.26 (d, J = 13.6 Hz, 1H), 3.16 (d, J = 13.6 Hz, 1H), 3.02 (d, J = 18.0 Hz, 1H), 2.87, 2.24-2.18 (m, 1H), 2.00-1.92 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 214.6, 142.0, 138.4, 138.3, 136.7, 130.2, 129.8, 129.2, 129.0, 128.8, 128.7, 128.5, 128.4, 128.2, 128.1, 128.1, 128.0, 128.0, 127.8, 127.8, 127.4, 127.3, 126.6, 126.5, 83.5, 77.6, 77.2, 71.4, 51.7, 48.2, 48.2, 42.0, 37.9, 34.2; FTIR (neat) 3028, 1769, 1096 cm-1; MS (FAB) m/z 91 (100), 303, 381, 472 (M+); HRMS (FAB) calcd for C34H32O2 (M+) 472.2404, found 472.2403.
Reaction of 13c. A 1:2 inseparable mixture of 4cα and 4cβ (44.6 mg, 66%) was obtained from 13c (70 mg, 0.158 mmol) after column chromatography (SiO2 5 g, hexane/AcOEt = 10:1): 1H NMR (400 MHz, CDCl3) δ 7.33-7.15 (m, 13 x 2/3H + 13 x 1/3H), 7.02-7.00 (m, 2 x 1/3H), 6.85-6.82 (m, 2 x 2/3H), 4.79 (d, J = 6.8 Hz, 1 x 2/3H), 4.55 (d, J = 6.8 Hz, 1x 2/3H), 4.11 (s, 2 x 1/3H), 4.07 (dd, J = 10.4 Hz, 6.7 Hz, 1 x 1/3H), 4.01 (d, J = 2.9 Hz, 1 x 2/3H), 3.62 (dd, J = 13.4 Hz, 6.6 Hz, 1 x 2/3H), 3.60 (d, J = 13.7 Hz, 1 x 2/3H), 3.43 (d, J = 18.6 Hz, 1 x 1/3H), 3.32 (s, 3 x 2/3H), 3.14 (s, 3 x 1/3H), 3.11-3.00 (m, 2 x 2/3H + 5 x 1/3H), 3.03 (d, J = 18.4 Hz, 1 x 2/3H), 2.86 (d, J = 18.6 Hz, 1 x 1/3H), 2.71 (d, J = 18.4 Hz, 1 x 2/3H), 2.65 (d, J = 13.7 Hz, 1 x 2/3H), 2.50-2.45 (m, 1 x 1/3H), 2.43 (dd, J = 14.0 Hz, 6.6 Hz, 1 x 2/3H), 2.22 (td, J = 14.0 Hz, 3.2 Hz, 1 x 2/3H), 2.10-2.01 (m, 1 x 1/3H); 13C NMR (100 MHz, CDCl3) δ 212.4, 210.9, 139.0, 138.7, 138.3, 138.1, 137.2, 136.9, 130.7, 130.5, 129.6, 129.5, 128.7, 128.5, 128.4, 128.1, 128.0, 127.9, 127.9, 126.8, 126.7, 126.4, 126.4, 126.3, 126.2, 96.8, 96.4, 83.5, 83.1, 79.4, 78.4, 56.0, 55.5, 53.3, 51.3, 50.6, 49.9, 48.9, 47.2, 41.7, 38.6, 36.8, 36.4, 35.6, 35.6; FTIR (neat) 2933, 1766, 1044 cm-1; MS (FAB) m/z 91, 231, 322 (100), 426 (M+); HRMS (FAB) calcd for C29H30O3 (M+) 426.2190, found 426.2195.
Reaction of 13d. A 1.7:1 mixture of 4dα and 4dβ (2.44 g, 91%) was obtained from 13d (2.80 g, 6.33 mmol) after column chromatography (SiO2 200 g, hexane/AcOEt = 6:1). Pure 4dα and 4dβ were obtained for data collection by preparative TLC (hexane/AcOEt = 4:1).
4dα: colorless oil; [α]D23 +28.7 (c 0.880, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.28-7.13 (m, 13H), 7.00-6.96 (m, 2H), 5.34 (dd, J = 10.2 Hz, 6.6 Hz, 1H), 3.23 (d, J = 18.8 Hz, 1H), 3.21-3.16 (m, 1H), 3.14 (d, J = 15.2 Hz, 1H), 3.05-2.96 (m, 1H), 3.04 (d, J = 15.2 Hz, 1H), 2.57-2.50 (m, 1H), 1.98-1.91 (m, 1H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 211.1, 170.3, 137.6, 137.4, 136.6, 130.6, 129.3, 128.7, 128.3, 128.2, 128.0, 127.0, 126.6, 126.5, 78.6, 77.8, 51.1, 48.4, 46.0, 41.8, 36.3, 36.2, 20.4; FTIR (neat) 3030, 1768, 1734, 1243, 1044 cm-1; MS (EI) m/z 91, 231, 322 (100), 382, 424 (M+); HRMS (EI) calcd for C29H28O3 (M+) 424.2048, found 424.2038.
4dβ: colorless oil; [α]D23 +108.1 (c 0.860, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.35-7.18 (m, 11H), 7.10-7.08 (m, 2H), 6.89-6.86 (m, 2H), 5.12 (d, J = 3.6 Hz, 1H), 3.56 (dd, J = 13.4 Hz, 7.0 Hz), 3.48 (d, J = 13.8 Hz, 1H), 3.16 (d, J = 15.4 Hz, 1H), 3.10 (d, J = 15.4 Hz, 1H), 3.08 (d, J = 18.6 Hz, 1H), 2.76 (d, J = 18.6 Hz, 1H), 2.73 (d, J = 13.8 Hz, 1H), 2.38 (td, J = 14.0 Hz, 3.6 Hz, 1H), 2.25 (dd, J = 15.0 Hz, 7.0 Hz, 1H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 209.8, 169.8, 137.9, 137.8, 136.9, 130.8, 129.2, 128.7, 128.5, 128.1, 128.0, 127.0, 126.8, 126.5, 79.8, 79.1, 53.2, 50.1, 49.2, 37.3, 36.0, 35.3, 21.4; FTIR (neat) 3031, 1766, 1738, 1242 cm-1; MS (EI) m/z 91, 231, 322 (100), 424 (M+); HRMS (EI) calcd for C29H28O3 (M+) 424.2047, found 424.2039.
(1S,2R,4R,5S)-1,5-Dibenzyl-2-hydroxy-4-phenylbicyclo[3.2.0]heptan-6-one (17α) and (1S,2S,4R,5S)-1,5-Dibenzyl-2-hydroxy-4-phenylbicyclo[3.2.0]heptan-6-one (17β). Compound 4d (2.5 g, 5.89 mmol) was dissolved in CH2Cl2 (20 mL), and MeOH (40 mL) and K2CO3 (669 mg, 6,48 mmol) were added at room temperature. After being heated at 60 °C for 2 h, the mixture was cooled to room temperature, diluted with AcOEt, washed with brine, dried, and concentrated. Purification of the residue by column chromatography (SiO2 200g, CHCl3) gave 17α (1.31 g, 58%) and 17β (779 mg, 35%).
17α: yellow oil; [α]D28 +67.1 (c 3.000, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37-7.17 (m, 13H), 7.00-6.99 (m, 2H), 4.53-4.50 (m, 1H), 3.35 (d, J = 18.4 Hz, 1H), 3.13 (d, J = 15.0 Hz, 1H), 3.13-3.09 (m, 1H), 3.04 (d, J = 13.2 Hz, 1H), 3.01 (d, J = 15.0 Hz, 1H), 2.96 (d, J = 13.2 Hz, 1H), 2.36-2.31 (m, 1H), 2.05 (dd, J = 13.2 Hz, 12.0 Hz, 1H), 0.63 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 211.7, 138.0, 137.8, 137.0, 130.5, 129.3, 128.8, 128.7, 128.1, 127.9, 127.2, 127.0, 126.4, 79.6, 77.1, 49.9, 48.1, 47.5, 41.8, 38.2, 36.5; FTIR (neat) 3552, 3029, 1757, 1492, 1454 cm-1; MS (EI) m/z 91, 249 (100), 291, 340, 382 (M+); HRMS (EI) calcd for C27H26O2 (M+) 382.1942, found 382.1933.
17β: colorless oil; [α]D28 +55.2 (c 1.800, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.35-7.14 (m, 13H), 6.85-6.83 (m, 2H), 4.20 (s, 1H), 3.72 (dd, J = 13.6 Hz, 6.7 Hz, 1H), 3.59 (d, J = 13.6 Hz, 1H), 3.11 (s, 2H), 3.00 (d, J = 18.2 Hz, 1H), 2.65 (d, J = 18.2 Hz, 1H), 2.62 (d, J = 13.6 Hz, 1H), 2.35 (td, J = 13.6 Hz, 3.6 Hz, 1H), 2.11 (dd, J = 14.2 Hz, 6.7 Hz, 1H), 1.68 (d, J = 3.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 210.9, 138.7, 138.6, 137.2, 130.7, 130.1, 129.7, 128.5, 128.1, 127.9, 126.7, 126.5, 126.3, 79.3, 76.4, 53.0, 50.8, 50.5, 40.4, 35.8, 35.8; FTIR (neat) 3500, 3028, 1761, 1500, 1446 cm-1; MS (EI) m/z 91, 249 (100), 340, 382 (M+); HRMS (EI) calcd for C27H26O2 (M+) 382.1942, found 382.1033.
(3aR,4R,6R,6aS)-3a,6a-Dibenzyl-4-hydroxy-6-phenylhexahydro-2H-cyclopenta[b]furan-2-one (18α). To a solution of tert-butyl hydroperoxide (4.07 M in toluene, 0.71 mL, 2.88 mmol) in THF (5 mL) was added n-butyllithium (2.69 M in hexane, 0.97 mL, 2.62 mmol) at –78 °C, and the mixture was stirred at –78 °C for 30 min. The resulting solution of lithium tert-butyl peroxide was then added to a solution of 17α (500 mg, 1.31 mmol) in THF (7 mL) at 0 °C, and the mixture was stirred at 0 °C for 4 h. The mixture was diluted with AcOEt, washed with 1 M HCl, NaHCO3, and brine, dried, concentrated, and chromatographed (SiO2 10 g, hexane/AcOEt = 4:1) to give 18α (461 mg, 88%) as colorless needles: [α]D27 -44.3 (c 0.900, CHCl3); mp 172-173 °C; 1H NMR (400 MHz, CDCl3) δ 7.40-7.19 (m, 13H), 7.09 (d, J = 6.4 Hz, 1H), 4.32-4.27 (m, 1H), 3.30 (d, J = 12.8 Hz, 1H), 3.16 (d, J = 15.0 Hz, 1H), 3.05 (dd, J = 13.7 Hz, 5.8 Hz, 1H), 2.90 (d, J = 15.0 Hz, 1H), 2.73 (d, J = 12.8 Hz, 1H), 2.72 (d, J = 17.4 Hz, 1H), 2.39-2.33 (m, 1H), 2.07 (td, J = 13.2 Hz, 9.8 Hz, 1H), 1.84 (d, J = 17.4 Hz, 1H), 0.95 (d, J = 4.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 175.6, 136.8, 135.0, 130.9, 129.8, 129.3, 128.9, 128.4, 128.3, 127.4, 127.2, 127.0, 96.7, 75.0, 54.8, 50.4, 42.1, 39.2, 37.5, 36.1; FTIR (neat) 3464, 3027, 1766, 1182, 1083 cm-1; MS (EI) m/z 91 (100), 149, 264, 398 (M+); HRMS (EI) calcd for C27H26O3 (M+) 398.1881, found 398.1880.
(3aR,4S,6R,6aS)-3a,6a-Dibenzyl-4-hydroxy-6-phenylhexahydro-2H-cyclopenta[b]furan-2-one (18β). Compound 17β (500 mg, 1.31 mmol) was subjected to Baeyer-Villiger oxidation in the same manner as described for the reaction of 17α to give 18β (510 mg, 98%) as a white powder: [α]D24 +11.3 (c 0.770, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.36-7.10 (m, 13H), 6.77-6.75 (m, 2H), 4.08 (s, 1H), 3.68 (dd, J = 13.1 Hz, 6.9 Hz, 1H), 3.58 (d, J = 13.4 Hz, 1H), 3.23 (s, 2H), 2.72 (d, J = 18.6 Hz, 1H), 2.71 (d, J = 14.2 Hz, 1H), 2.28-2.20 (m, 2H), 2.04 (dd, J = 14.0 Hz, 7.2 Hz, 1H), 1.86 (d, J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 175.4, 137.8, 137.7, 135.9, 131.0, 130.2, 129.6, 128.6, 128.1, 127.8, 126.8, 126.6, 96.8, 75.7, 57.6, 51.8, 42.3, 39.8, 39.4, 36.2; FTIR (neat) 3465, 3028, 1754, 1257, 1204, 1015 cm-1; MS (EI) m/z 91 (100), 264, 382, 398 (M+); HRMS (EI) calcd for C27H26O3 (M+) 398.1872, found 398.1762.
(3aS,6R,6aS)-3a,6a-Dibenzyl-6-phenyltetrahydro-2H-cyclopenta[b]furan-2,4(5H)-dione (19). To a solution of 18β (450 mg, 1.13 mmol) in CH2Cl2 (12 mL) were added NaHCO3 (492 mg, 5.65 mmol) and Dess-Martin periodinane (958 mg, 2.26 mmol) at room temperature. After stirring at room temperature for 1 h, the reaction was quenched with 50% Na2S2O3 (10 mL) and the mixture was extracted with AcOEt. The extract was was washed with saturated NaHCO3 and brine, dried, concentrated, and chromatographed (SiO2 20 g, hexane/AcOEt = 10:1) to give 19 (443 mg, 99%) as a white powder: [α]D24 +1.8 (c 2.040, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.39-7.21 (m, 15H), 3.31 (d, J = 13.9 Hz, 1H), 3.25 (d, J = 14.8 Hz, 1H), 3.19 (d, J = 14.8 Hz, 1H), 3.12 (d, J = 13.9 Hz, 1H), 2.93 (dd, J = 11.6 Hz, 9.7 Hz, 1H), 2.73-2.56 (m, 2H), 2.49 (d, J = 17.3 Hz, 1H), 1.60 (d, J = 17.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 217.7, 173.4, 136.0, 135.2, 133.9, 130.8, 129.7, 129.6, 128.8, 128.7, 128.5, 127.8, 127.7, 127.6, 94.9, 62.2, 48.5, 42.6, 39.0, 38.8, 36.1; FTIR (neat) 3029, 1785, 1745, 1166 cm-1; MS (EI) m/z 91 (100), 264, 305, 382 (M+); HRMS (EI) calcd for C27H24O3 (M+) 396.1725, found 396.1725.
Reduction of Compound 19. To an ice-cooled solution of 19 (400 mg, 1.01 mmol) in CH2Cl2 (5 mL) were added EtOH (5 mL) and NaBH4 (29 mg, 0.757 mmol). After stirring at 0 °C for 12 h, the reaction was quenched with saturated NH4Cl (10 mL) and the mixture was extracted with AcOEt. The extraxt was washed with saturated NaHCO3 and brine, dried, concentrated, and chromatographed (SiO2 50 g, hexane/AcOEt = 4:1) to give 18α (351 mg, 87%) and 18β (50 mg, 12%).
(3aR,4R,6R,6aS)-3a,6a-Dibenzyl-4-((tert-butyldimethylsilyl)oxy)-6-phenylhexahydro-2H-cyclopenta-[b]furan-2-one (20). A solution of 18α (1.0 g, 2.51 mmol), tert-butyldimethylchlorosilane (757 mg, 5.02 mmol), imidazole (683 mg, 10.4 mmol) in DMF (5 mL) was heated at 80 °C for 22 h. The mixture was cooled to room temperature, diluted with AcOEt, washed with 1 M HCl (15 mL), saturated NaHCO3, and brine, dried, and concentrated. Purification of the residue by flash column chromatography (SiO2 50 g, hexane/AcOEt = 9:1) gave 20 (1.25 g, 97%) as a colorless oil: [α]D24 +1.8 (c 0.750, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 6.8 Hz, 2H), 7.37-7.20 (m, 11H), 7.03 (d, J = 6.4 Hz, 2H), 4.17 (t, J = 7.3 Hz, 1H), 3.41 (d, J = 13.3 Hz, 1H), 3.11-3.06 (m, 2H), 2.85 (d, J = 14.9 Hz, 1H), 2.67 (d, J = 16.4 Hz, 1H), 2.63 (d, J = 13.3 Hz, 1H), 2.50-2.43 (m, 1H), 2.06-1.98 (m, 1H), 1.67 (d, J = 16.4 Hz, 1H), 0.63 (s, 9H), -0.16 (s, 3H), -0.53 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.9, 137.6, 136.8, 135.1, 130.9, 129.8, 129.7, 128.6, 128.4, 128.3, 127.3, 126.9, 126.9, 96.5, 74.4, 56.2, 50.8, 41.2, 40.9, 39.1, 37.0, 25.5, 17.7, -4.3, -6.1; FTIR (neat) 2930, 1776, 1109 cm-1; MS (FAB) m/z 91 (100), 135, 382, 512 (M+); HRMS (FAB) calcd for C33H40O3Si (M+) 512.2720, found 512.2698.
(3aR,4R,6R,6aS)-3,3a,6a-Tribenzyl-4-((tert-butyldimethylsilyl)oxy)-6-phenylhexahydro-2H-cyclopenta[b]furan-2-one (21). To a degassed solution of 20 (1.2 g, 2.34 mmol) in THF (15 mL) was added lithium hexamethyldisilazide (1.0 M in THF, 7.0 mL, 7.0 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 h. HMPA (2.45 mL, 14.1 mmol) was added and the mixture was stirred for 30 min at 0 °C. Benzyl iodide (0.440 mL, 3.51 mmol) was then added and stirring was continued at 0 °C for 1.5 h. The reaction was quenched with 1 M HCl (10 mL) and the mixture was extracted with AcOEt. The extract was washed with saturated NaHCO3 and brine, dried, concentrated, purified by flash column chromatography (SiO2 50 g, hexane/AcOEt = 10:1) to give 21 (1.31 g, 93%) as a colorless oil: [α]D26 –61.9 (c 1.000, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.8 Hz, 2H), 7.33-7.11 (m, 11H), 6.91 (d, J = 7.6 Hz, 2H), 4.14 (dd, J = 7.1 Hz, 4.2 Hz, 1H), 3.78 (dd, J = 11.1 Hz, 3.8 Hz, 1H), 3.59 (d, J = 15.9 Hz, 1H), 3.14 (d, J = 14.9 Hz, 1H), 3.02-2.07 (m, 1H), 2.96 (d, J = 14.9 Hz, 1H), 2.90 (d, J = 15.9 Hz, 1H), 2.35 (dd, J = 14.4 Hz, 3.9 Hz, 1H), 2.32-2.26 (m, 1H), 2.02-1.93 (m, 1H), 1.29-1.22 (m, 1H), 0.83 (s, 9H), -0.11 (s, 3H), -0.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.4, 139.5, 137.5, 136.7, 135.9, 131.4, 129.9, 129.6, 128.8, 128.6, 128.5, 128.3, 128.0, 127.3, 127.1, 126.6, 126.1, 96.0, 75.7, 57.3, 50.7, 43.5, 40.2, 39.4, 38.4, 32.3, 25.9, 17.9, -3.5, -5.9; FTIR (neat) 2952, 1766, 1111 cm-1; MS (EI) m/z 91 (100), 231, 321, 545, 602 (M+); HRMS (EI) calcd for C40H46O3Si (M+) 602.3212, found 602.3207.
(3S,3aS,4R,6R,6aS)-3,3a,6a-Tribenzyl-4-((tert-butyldimethylsilyl)oxy)-3-hydroxy-6-phenylhexahydro-2H-cyclopenta[b]furan-2-one (23). To a solution of 21 (1.30 g, 2.16 mmol) in THF (10 mL) was added potassium hexamethyldisilazide (0.5 M in toluene, 8.6 mL, 4.3 mmol) at 0 °C, the mixture was stirred at 0 °C for 1 h. HMPA (1.5 mL, 8.63 mmol) was added and the mixture was stirred for 30 min at 0 °C and cooled to –78 °C. Phenyl-2-(phenylsulfonyl)oxaziridine (Davis reagent) (1.70 g, 6.47 mmol) was then added and stirring was continued at –40 °C for 9 h. The reaction was quenched with 1 M HCl (10 mL) and the mixture was extracted with AcOEt. The extract was washed with saturated NaHCO3 and brine, dried, concentrated, chromatographed (SiO2 50 g, hexane/AcOEt = 20:1) to give 23 (1.21 g, 91%) as a colorless oil: [α]D25 –53.2 (c 1.800, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.2 Hz, 2H), 7.49-7.26 (m, 8H), 7.10 (d, J = 6.8 Hz, 2H), 7.09-6.92 (m, 8H), 4.81 (d, J = 4.4 Hz, 1H), 3.90 (d, J = 14.4 Hz, 1H), 3.71 (d, J = 13.6 Hz, 1H), 3.62 (d, J = 14.0 Hz, 1H), 3.45 (dd, J = 11.8 Hz, 4.4 Hz, 1H), 2.96 (d, J = 14.4 Hz, 1H), 2.86 (td, J = 12.2 Hz, 5.2 Hz, 1H), 2.63 (d, J = 13.6 Hz, 1H), 2.46 (d, J = 14.0 Hz, 1H), 2.36 (s, 1H), 1.99 (dd, J = 14.8 Hz, 4.4 Hz, 1H), 0.97 (s, 9H), 0.05(s, 3H), -0.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 176.0, 140.7, 136.8, 136.4, 134.2, 132.3, 131.6, 130.8, 130.4, 128.6, 128.4, 127.6, 127.4, 127.3, 127.0, 126.3, 125.3, 97.6, 65.2, 51.5, 43.7, 43.6, 37.6, 33.7, 26.3, 18.3, 0.00, -3.0, -5.4; FTIR (neat) 3534, 2934, 1773, 1500, 1455, 1265, 1182, 1000 cm-1; MS (FAB) m/z 91 (100), 247, 323, 619 (M++1), HRMS (EI) calcd for C40H46O4Si (M+) 618.3233, found 618.3281.
(3S,3aS,6R,6aS)-3,3a,6a-Tribenzyl-3-hydroxy-6-phenyltetrahydro-2H-cyclopenta[b]furan-2,4(5H)-dione (3). To an ice-cooled solution of 23 (50 mg, 0.081 mmol) in THF (1 mL) was added tetra-n-butylammonium fluoride (1.0 M in THF, 0.12 mL, 0.12 mmol). After being stirred at room temperature for 3 h, the mixture was diluted with AcOEt, washed with 1 M HCl, saturated NaHCO3, and brine, dried, and concentrated to give 24 (40.2 mg).
To a solution of 24 (40 mg) in CH2Cl2 (2 mL) were added NaHCO3 (41 mg, 0.476 mmol) and Dess-Martin periodinane (135 mg, 0.317 mmol) at room temperature. The mixture was heated under reflux for 3.3 h, cooled to room temperature, diluted with AcOEt, washed with saturated Na2S2O3, saturated NaHCO3 and brine, dried, and concentrated. Purification by flash column chromatography (SiO2 5 g, hexane/AcOEt = 8:1) to give 3 (34.3 mg, 85%) as a white powder: [α]D25 +51.7 (c 2.25 CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.1 Hz, 2H), 7.42-7.30 (m, 8H), 7.08-7.01 (m, 3H), 6.95-6.86 (m, 5H), 6.72 (d, J = 6.8 Hz, 1H), 3.87 (d, J = 14.4 Hz, 1H), 3.44 (d, J = 14.7 Hz, 1H), 3.39 (d, J = 14.2 Hz, 1H), 3.31 (d, J = 14.2 Hz, 1H), 3.19 (d, J = 14.4 Hz, 1H), 3.08 (d, J = 14.7 Hz, 1H), 2.63 (dd, J = 17.0 Hz, 12.4 Hz, 1H), 2.54-2.42 (m, 2H), 2.40 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 215.3, 174.6, 136.4, 135.3, 134.5, 132.1, 130.8, 130.7, 129.5, 128.7, 128.5, 128.4, 127.6, 127.4, 127.2, 126.2, 94.0, 68.3, 48.9, 45.9, 40.1, 38.2, 33.0; FTIR (neat) 3520, 3030, 1779, 1742, 1500, 1455, 1258, 1197, 1167, 1000 cm-1; MS (EI) m/z 91, 131, 339 (100), 411, 502 (M+); HRMS (EI) calcd for C34H30O4 (M+) 502.2134, found 502.2133.

ACKNOWLEDGEMENTS
This work was supported by the Grant-in-Aid for Scientific Research (A) (22249001) from JSPS and the Grant-in-Aid for Scientific Research on Innovative Areas “Advanced Molecular Transformations by Organocatalysis” (No. 2304) (24105526) from MEXT.

SUPPORTING INFORMATION
X-Ray crystallographic data of 18α and the acetate of 3, and 1H and 13C NMR spectra for all new compounds are available.

References

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