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Total syntheses of macrosphelides (+)-A, (−)-A and (+)-E
Tetrahedron: Asymmetry 11 (2000) 2753±2764
Total syntheses of macrosphelides (+)-A, (^)-A and (+)-E Machiko Ono,* Hiroshi Nakamura, Fumi Konno and Hiroyuki Akita* School of Pharmaceutical Science, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan Received 15 May 2000; accepted 19 June 2000
Abstract Total syntheses of (+)-macrosphelide A 1 (18.5% overall yield in 11 steps) and (+)-macrosphelide E 2 (23.9% overall yield in 11 steps) have been achieved via the chemoenzymatic reaction product (4R,5S)-4benzyloxy-5-hydroxy-2(E)-hexenoate 4. The enantiomer (^)-A (1) (14.2% overall yield in 11 steps) of (+)-1 was also synthesized from the chemoenzymatic reaction product (4S,5R)-4-benzyloxy-5-hydroxy-2(E)hexenoate 4. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction (+)-Macrosphelide A 1 isolated from the culture broth of Microsphaeropsis sp. FO-5050 by Omura and co-workers has been shown to strongly inhibit the adhesion of human leukemia HL60 cells to human umbilical-vein endothelial cells (HUVEC) in dose-dependent fashion.1 It is the ®rst 16-membered ring antibiotic involving three lactone linkages.1 (+)-Macrosphelide E 2 was isolated from a strain of Periconia byssoides separated from the gastrointestinal tract of the sea hare Aplysia kurodai and was found to be the stereoisomer, in which the con®guration of C(3) was dierent from that of (+)-macrosphelide A 1.2 Recently, the absolute con®gurations of (+)macrosphelides A 1 and E 2 have been determined as depicted in 1 and 2. Total syntheses of (+)-1 have been reported by two groups.3,4 The synthesis of key compound, trans-(4R,5S)-4,5-dihydroxy2-hexenoic acid congener from the sorbic ester in the ®rst synthesis, was carried out by using the Sharpless AD reaction5 with 85% ee followed by Mitsunobu inversion6 at C(4) position.3 The key steps in the second asymmetric synthesis are the preparation of (S)-1-(2-furyl)ethanol from the corresponding racemic alcohol using the Sharpless reagents7 and diastereoselective reduction of an a,b-unsaturated ketone in the chiral substrate elaborated from the above-mentioned chiral alcohol.4 On the other hand, we reported that the enantioselective hydrolysis of (þ)-(4,5)-anti-5acetoxy-4-benzyloxy-2(E)-hexenoate 3 using the lipase `Amano P' from Pseudomonas sp. in phosphate buer solution gave the (4R,5S)-5-acetoxy ester 3 (>99% ee, 48% yield) and the *Corresponding authors. E-mail: [email protected] 0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S0957-4166(00)00245-7
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(4S,5R)-5-hydroxy ester 4 (>99% ee, 44% yield), and methanolysis of (4R,5S)-3 provided the (4R,5S)-4 in 84% yield (Scheme 1).8
Scheme 1.
2. Results and discussion The key steps of our synthetic strategy of (+)-1 and (+)-2 are the enantioselective preparation of two dierentially protected (4R,5S)-4-benzyloxy-5-hydroxy-2(E)-hexenoic acid congeners, carboxylic acid (4R,5S)-5 and alcohol (4R,5S)-6 from (4R,5S)-4, and regioselective ester formation from (4R,5S)-5 and (4R,5S)-6 (Scheme 2). The third building blocks, enantiomerically pure methyl (S)- and (R)-3-hydroxybutanoates, are commercially available. Herein, we report the total syntheses of (+)-1, (^)-1 and (+)-2 based on the above-mentioned strategy. Silylation (98% yield) of (4R,5S)-4 using tert-butyldimethylsilyl chloride (TBDMSCl) followed by hydrolysis (99% yield) gave the desired carboxylic acid (4R,5S)-5 in 97% overall yield. Ester formation (93% yield) of (4R,5S)-5 using 2,2,2-trichloroethanol followed by deprotection (87% yield) of silyl group aorded the desired alcohol (4R,5S)-6 ([ ]D ^46.1 (c 0.58, CHCl3)) in 81% overall yield. Condensation of carboxylic acid (4R,5S)-5 and alcohol (4R,5S)-6 via the Keck procedure9 (dicyclohexylcarbodiimide (DCC), 4-(dimethylamino)pyridine (DMAP), camphorsulfonic acid (CSA), CH2Cl2) provided dimer ester (^)-7 ([ ]D ^26.3 (c 0.56, CHCl3)) in 75% yield, which was desilylated to yield an alcohol (^)-8 ([ ]D ^42.3 (c 0.24, CHCl3)) in 79% yield (Scheme 2). The third fragment, TBDMS ether (S)-9, was prepared from methyl (S)-3-hydroxybutanoate and coupled with (^)-8 to give the triester (^)-10 ([ ]D ^29.5 (c 0.33, CHCl3)) in 79% yield under the Keck conditions. Removal of the silyl group of (^)-10 aorded the desilylated alcohol (^)-11 ([ ]D ^40.0 (c 0.44, CHCl3)) in 96% yield. Deprotection of (^)-11 using Zn in an acetic acid buer solution followed by subjecting to Yamaguchi macrolactonization10 (2,4,6-trichlorobenzoyl chloride, Et3N, DMAP) provided (^)-dibenzyl macrosphelide A 13 ([ ]D ^75.9 (c 0.34, CHCl3)) in 70% overall yield from (^)-11. Finally, deprotection of benzyl group in (^)-13 using AlCl3 in the presence of m-xylene8 gave (+)-synthetic macrosphelide A 1 ([ ]D +82.3 (c 0.15, MeOH), mp 142 C) in 75% yield. Physical data ([ ]D, mp, 1H and 13C NMR) of synthetic (+)-1 were identical with those ([ ]D +84.1 (c 0.59, MeOH), mp 141±142 C) of the natural (+)-1.1 The total synthesis of (+)-macrosphelide A 1 has been achieved via highly convergent strategy in 18.5% overall yield (11 steps) from the chemoenzymatic reaction product (4R,5S)-4.
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Scheme 2. (a) (1) TBDMSCl/imidazole/DMF; (2) NaOH aq./MeOH; (b) (1) TBDMSCl/imidazole/DMF; (2) NaOH aq./MeOH; (3) CCl3CH2OH/DCC/DMAP; (4) AcOH/H2O/THF; (c) DCC/DMAP/CSA/CH2Cl2; (d) AcOH:H2O:THF (2:1:1); (e) (S)-9, DCC/DMAP/CH2Cl; (f) Zn/THF/AcOH±AcONa buer; (g) 2,4,6-trichlorobenzoyl chloride/Et3N/DMAP/toluene; (h) m-xylene/AlCl3/CH2Cl2
Scheme 3.
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The synthesis of enantiomer (^)-1 of (+)-macrosphelide A 1 was achieved from the (4S,5R)-4 in the same way as for the synthesis of (+)-1 from (4R,5S)-4 as shown in Scheme 3. Condensation of (+)-8 and TBDMS ether (R)-9 gave the triester (+)-10 ([ ]D +30.6 (c 0.33, CHCl3)) which was ®nally converted to the (^)-macrosphelide A (1) ([ ]D ^79.2 (c 0.29, MeOH), mp 142 C) in 14.2% overall yield (11 steps) from the chemoenzymatic reaction product (4S,5R)-4. Next the total synthesis of (+)-macrosphelide E (2) was achieved by applying the abovementioned synthetic route of (+)-1 from (^)-8. Condensation of (^)-8 and TBDMS ether (R)-9 gave the triester (^)-14 ([ ]D ^43.0 (c 0.27, CHCl3)) in 90% yield, which was desilylated to aord (^)-alcohol 15 ([ ]D ^60.4 (c 0.54, CHCl3)) in 86% yield. Deprotection of 2,2,2-trichloroethyl group in (^)-15 provided a seco-acid 16 which was subjected to macrolactonization10 to yield (^)dibenzyl macrosphelide E 17 ([ ]D ^40.7 (c 0.77, CHCl3)) in 82% overall yield from (^)-15 (Scheme 4). Finally, deprotection of benzyl group of (^)-17 gave (+)-synthetic macrosphelide E 2 ([ ]D +78.5 (c 0.21, EtOH)) in 81% yield. Physical data ([ ]D, 1H and 13C NMR) of synthetic (+)2 were identical with those ([ ]D +56.8 (c 0.46, EtOH)) of the natural (+)-2.2
Scheme 4. (a) (R)-9, DCC/DMAP/CH2Cl2; (b) AcOH:H2O:THF (2:1:1); (c) Zn/THF/AcOH±AcONa buer; (d) 2,4,6trichlorobenzoyl chloride/Et3N/DMAP/toluene; (e) m-xylene/AlCl3/CH2Cl2
In conclusion, total syntheses of (+)-macrosphelide A 1 (18.5% overall yield in 11 steps), (^)-A 1 (14.2% overall yield in 11 steps) and (+)-macrosphelide E 2 (23.9% overall yield in 11 steps) were achieved from the chemoenzymatic reaction product (4R,5S)- and (4S,5R)-4-benzyloxy-5hydroxy-2(E)-hexenoates 4. 3. Experimental 3.1. General All melting points were measured on a Yanaco MP-3S micro melting point apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on a JEOL AL 400 spectrometer in CDCl3. Carbon substitution degrees were established by DEPT pulse sequence. The fast atom bombardment mass spectra (FAB MS) and electrospray ionization mass spectra (ESI MS) were obtained with a JEOL JMS-DX 303 spectrometer and ThermoQuest LCQ, respectively. IR spectra were recorded on a JASCO FT/IR-300 spectrometer. Optical rotations were measured with a JASCO DIP-370 digital polarimeter. All evaporations were performed under reduced pressure. For column chromatography, silica gel (Kieselgel 60) was employed.
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3.2. (4R,5S)-4-Benzyloxy-5-tert-butyldimethylsiloxy-2(E)-hexenoic acid 5 (i) To a solution of (4R,5S)-4 (5.21 g, 20.8 mmol) and imidazole (5.67 g, 83.2 mmol) in dimethylformamide (DMF, 42 ml) was added TBDMSCl (7.85 g, 52.0 mmol) at 0 C and the reaction mixture was stirred for 1 h at 0 C and for 1.5 h at room temperature. The reaction mixture was diluted with H2O and extracted with ether. The ether layer was washed with saturated brine and dried over MgSO4. The ether layer was evaporated to give a crude residue, which was chromatographed on silica gel (200 g, n-hexane:AcOEt=20:1) to give methyl (4R,5S)4-benzyloxy-5-tert-butyldimethylsiloxy-2(E)-hexenoate (7.44 g, 98%) as a colorless oil. IR (neat): 1724, 1658 (sh) cm^1 (COOMe); NMR: 0.02 (3H, s), 0.04 (3H, s), 0.87 (9H, s), 1.20 (3H, d, J=6 Hz), 3.76 (3H, s), 3.77 (1H, dt, J=1, 6 Hz), 3.85 (1H, quintet, J=6 Hz), 4.44 (1H, d, J=12 Hz), 4.61 (1H, d, J=12 Hz), 6.06 (1H, dd, J=1, 16 Hz), 6.95 (1H, dd, J=6, 16 Hz), 7.27±7.35 (5H, m). Anal. found: C, 66.22; H, 9.03. Calcd for C20H32O4Si: C, 65.89; H, 8.85%. ESI MS m/z: 365 (M++1). (ii) To a solution of methyl (4R,5S)-4-benzyloxy-5-tert-butyldimethylsiloxy-2(E)hexenoate (4.19 g, 11.5 mmol) in MeOH (40 ml) was added dropwise 2 M aqueous NaOH (12 ml) at 0 C and the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was acidi®ed with 2 M aqueous HCl under ice-cooling and extracted with ether. The ether layer was washed with saturated brine and dried over MgSO4. The ether layer was evaporated to give a crude (4R,5S)-5 (3.99 g, 99%) as a colorless oil. 24 D ^22.6 (c 0.59, CHCl3); NMR: 0.03 (3H, s), 0.05 (3H, s), 0.87 (9H, s), 1.21 (3H, d, J=6 Hz), 3.82 (1H, dt, J=2, 6 Hz), 3.86 (1H, quintet, J=6 Hz), 4.47 (1H, d, J=12 Hz), 4.62 (1H, d, J=12 Hz), 6.07 (1H, dd, J=2, 16 Hz), 7.07 (1H, dd, J=6, 16 Hz), 7.27±7.37 (5H, m). 3.3. 2,2,2-Trichloroethyl (4R,5S)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 6 (i) To a mixture of DCC (2.66 g, 12.8 mmol), DMAP (2.10 g, 17.0 mmol) in CH2Cl2 (150 ml) was added a solution of (4R,5S)-5 (3.01 g, 8.5 mmol), CCl3CH2OH (1.93 g, 17.0 mmol) in CH2Cl2 (30 ml) and the reaction mixture was stirred for 3 days at room temperature. After the generated precipitate was ®ltered o, the ®ltrate was washed with 2 M aqueous HCl and 7% aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (110 g, n-hexane:AcOEt=20:1) to give 2,2,2trichloroethyl (4R,5S)-4-benzyloxy-5-tert-butyldimethylsiloxy-2(E)-hexenoate (3.85 g, 93%) as a colorless oil: IR (neat): 1739 cm^1 (ester); 31 D ^15.6 (c 0.75, CHCl3); NMR: 0.03 (3H, s), 0.05 (3H, s), 0.87 (9H, s), 1.23 (3H, d, J=6 Hz), 3.81 (1H, dt, J=2, 6 Hz), 3.86 (1H, quintet, J=6 Hz), 4.07 (1H, d, J=12 Hz), 4.63 (1H, d, J=12 Hz), 4.81 (1H, d, J=12 Hz), 4.86 (1H, d, J=12 Hz), 6.16 (1H, dd, J=2, 16 Hz), 7.12 (1H, dd, J=6, 16 Hz), 7.28±7.38 (5H, m). Anal. found: C, 52.56; H, 6.56. Calcd for C21H31O4SiCl3: C, 52.34; H, 6.48%. FAB MS m/z: 480 (M+). (ii) A mixture of 2,2,2-trichloroethyl (4R,5S)-4-benzyloxy-5-tert-butyldimethylsiloxy-2(E)-hexenoate (4.04 g, 8.4 mmol) in the mixed solvent (AcOH (10 ml), H2O (10 ml) and THF (5 ml)) was stirred for 12 h at 70 C and the whole mixture was again stirred for 3 h at 110 C after adding AcOH (4 ml). The reaction mixture was evaporated and the residue was diluted with H2O, extracted with Et2O. The organic layer was washed with 7% aqueous NaHCO3 and dried over MgSO4 then evaporated to give a crude residue, which was chromatographed on silica gel (100 g, n-hexane:AcOEt=20:1) to give (4R,5S)-6 (2.68 g, 87%) as a colorless crystal: Mp 62 C; IR (neat): 3477, 1730 cm^1; a21 D ^46.1 (c 0.58, CHCl3); NMR: 1.17 (3H, d, J=6 Hz), 3.96±4.03 (2H, m), 4.06 (1H, d, J=12 Hz), 4.67 (1H, d, J=12 Hz), 4.81 (1H, d, J=12 Hz), 4.84 (1H, d, J=12 Hz), 6.19 (1H, dd, J=1,
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16 Hz), 7.08 (1H, dd, J=6, 16 Hz), 7.28±7.40 (5H, m). 13C NMR: 163.8 (s), 146.8 (d), 137.3 (s), 128.4 (d), 127.8 (d), 127.7 (d), 122.6 (d), 94.9 (s), 81.8 (d), 74.2 (t), 71.8 (t), 69.2 (d), 18.1 (q). Anal. found: C, 49.16; H, 4.71. Calcd for C15H17O4Cl3: C,49.00; H,4.66%. FAB MS m/z: 366 (M+). 3.4. Ester formation between (4R,5S)-5 and (4R,5S)-6 To a mixture of DCC (1.21 g, 5.9 mmol), DMAP (0.95 g, 7.8 mmol) and (+)-CSA (0.91 g, 3.9 mmol) in CH2Cl2 (30 ml) was added a solution of (4R,5S)-5 (1.244 g, 3.9 mmol) and (4R,5S)-6 (1.436 g, 3.9 mmol) in CH2Cl2 (3 ml) and the reaction mixture was stirred for 2 days at room temperature. After the generated precipitate was ®ltered o, the ®ltrate was washed with 2 M aqueous HCl and 7% aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (60 g, n-hexane: AcOEt=20:1) to give (^)-7 (2.05 g, 75%) as a homogenous oil and recovery (4R,5S)-6 (171 mg, 12% recovery): IR (neat): 1732 cm^1; 27 D ^26.3 (c 0.56, CHCl3); NMR: 0.02 (3H, s), 0.05 (3H, s), 0.87 (9H, s), 1.22 (3H, d, J=6 Hz), 1.31 (3H, d, J=6 Hz), 3.78 (1H, dt, J=1, 6 Hz), 3.86 (1H, quintet, J=6 Hz), 4.20 (1H, ddd, J=1, 5, 6 Hz), 4.46, 4.56, 4.62, 4.67 (each 1H, d, J=12 Hz), 4.80, 4.84 (each 1H, d, J=12 Hz), 5.17 (1H, dq, J=5, 6 Hz), 6.05 (1H, dd, J=1, 16 Hz), 6.25 (1H, dd, J=1, 16 Hz), 6.93 (1H, dd, J=6, 16 Hz), 7.07 (1H, dd, J=6, 16 Hz), 7.27±7.39 (10H, m). 13C NMR: 164.6 (s), 163.6 (s), 146.5 (d), 144.6 (d), 137.4 (s), 137.2 (s), 128.4 (d), 128.3 (d), 127.7 (d), 127.5 (d), 127.4 (d), 127.4 (d),124.0 (d), 122.2 (d), 94.8 (s), 81.8 (d), 79.4 (d), 74.0 (t), 71.9 (t), 71.4 (d), 71.3 (t), 69.1 (d), 18.2 (q), 15.2 (q). Anal. found: C, 58.35; H, 6.44. Calcd for C34H45O7SiCl3: C, 58.32; H, 6.48%. 3.5. Desilylation of (^)-7 A mixture of (^)-7 (1.529 g, 2.2 mmol) in the mixed solvent (AcOH (10 ml), H2O (5 ml) and THF (5 ml)) was stirred for 2 days at 80 C. The reaction mixture was evaporated and the residue was diluted with H2O, extracted with Et2O. The organic layer was washed with 7% aqueous NaHCO3 and dried over MgSO4 then evaporated to give a crude residue, which was chromatographed on silica gel (40 g, n-hexane:AcOEt=4:1) to give (^)-8 (1.015 g, 79%) as a homogeneous oil: IR (neat): 3472, 1727 cm^1; 21 D ^42.3 (c 0.24, CHCl3); NMR: 1.16 (3H, d, J=6 Hz), 1.31 (3H, d, J=6 Hz), 2.20 (1H, br. d, J=5 Hz), 3.92 (1H, ddd, J=1, 5, 6 Hz), 3.97 (1H, m), 4.17 (1H, ddd, J=1, 5, 6 Hz), 4.42, 4.53, 4.65, 4.67 (each 1H, d, J=12 Hz), 4.79, 4.83 (each 1H, d, J=12 Hz), 5.15 (1H, dq, J=5, 6 Hz), 6.06 (1H, dd, J=1, 16 Hz), 6.23 (1H, dd, J=1, 16 Hz), 6.92 (1H, dd, J=6, 16 Hz), 7.05 (1H, dd, J=6, 16 Hz), 7.28±7.39 (10H, m). Anal. found: C, 57.39; H, 5.63. Calcd for C28H31O7Cl3: C, 57.40; H, 5.33%. FAB MS m/z: 585 (M++1). 3.6. (S)-3-tert-Butyldimethylsiloxy butanoic acid 9 (i) To a solution of methyl (S)-3-hydroxybutanoate (2.01 g, 17 mmol) and imidazole (5.21 g, 76.5 mmol) in DMF (20 ml) was added TBDMSCl (3.85 g, 25.5 mmol) at 0 C and the reaction mixture was stirred for 30 min at 0 C and for 30 min at room temperature. The reaction mixture was diluted with saturated brine, extracted with ether and dried over MgSO4. The ether layer was evaporated to give a crude residue, which was chromatographed on silica gel (100 g, n-hexane:
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AcOEt=40:1) to give methyl (S)-3-tert-butyldimethylsiloxy butanoate (3.217 g, 81%) as a colorless oil. 25 D +29.1 (c 0.49, CHCl3); NMR: 0.03 (3H, s), 0.07 (3H, s), 0.86 (9H, s), 1.19 (3H, d, J=6 Hz), 2.38 (1H, dd, J=5, 14 Hz), 2.47 (1H, dd, J=8, 14 Hz), 3.65 (3H, s), 4.27 (1H, ddq, J=5, 6, 8 Hz). (ii) To a solution of methyl (S)-3-tert-butyldimethylsiloxy butanoate (0.896 g, 3.9 mmol) in MeOH (8 ml) was added dropwise 2 M aqueous NaOH (4 ml) at 0 C and the reaction mixture was stirred for 2 days at room temperature. The reaction mixture was acidi®ed with 2 M aqueous HCl under ice-cooling and extracted with ether. The ether layer was washed with brine and dried over MgSO4. The ether layer was evaporated to give a crude (S)-9 (765 mg, 91%) as a colorless oil. 26 D +8.64 (c 0.22, CHCl3); NMR: 0.06 (3H, s), 0.08 (3H, s), 0.87 (9H, s), 1.22 (3H, d, J=6 Hz), 2.45 (1H, dd, J=6, 14 Hz), 2.50 (1H, dd, J=6, 14 Hz), 4.27 (1H, sixtet, J=6 Hz). 3.7. Ester formation between (^)-8 and (S)-9 To a mixture of DCC (0.35 g, 1.68 mmol), DMAP (0.27 g, 2.24 mmol) and (+)-CSA (0.26 g, 1.12 mmol) in CH2Cl2 (10 ml) was added a solution of (^)-8 (0.653 g, 1.12 mmol) and (S)-9 (0.363 g, 1.17 mmol) in CH2Cl2 (5 ml) and the reaction mixture was stirred for 2 d at room temperature. After the generated precipitate was ®ltered o, the ®ltrate was washed with 2 M aqueous HCl, 7% aqueous NaHCO3 and saturated brine. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (30 g, n-hexane:AcOEt=10:1) to give (^)-10 (0.692 g, 79%) as a homogenous oil: IR (neat): 1735, 1657 cm^1; 24 D ^29.5 (c 0.33, CHCl3); NMR: 0.04 (3H, s), 0.06 (3H, s), 0.86 (9H, s), 1.19 (3H, d, J=6 Hz), 1.23 (3H, d, J=6 Hz), 1.31 (3H, d, J=6 Hz), 2.35 (1H, dd, J=6, 15 Hz), 2.47 (1H, dd, J=6, 15 Hz), 4.09 (1H, ddd, J=2, 5, 6 Hz), 4.18 (1H, ddd, J=2, 5, 6 Hz), 4.24 (1H, sixtet, J= 6 Hz), 4.49, 4.54, 4.63, 4.68 (each 1H, d, J=12 Hz), 4.80, 4.83 (each 1H, d, J=12 Hz), 5.03 (1H, dq, J=5, 6 Hz), 5.13 (1H, dq, J=5, 6 Hz), 6.09 (1H, dd, J=2, 16 Hz), 6.23 (1H, dd, J=2, 16 Hz), 6.85 (1H, dd, J=6, 16 Hz), 7.05 (1H, dd, J=6, 16 Hz), 7.27±7.37 (10H, m). Anal. found: C, 58.27; H, 5.64. Calcd for C38H51O9SiCl3: C, 58.05; H, 5.55%. 3.8. Desilylation of (^)-10 A mixture of (^)-10 (0.408 g, 0.52 mmol) in the mixed solvent (AcOH (6 ml), H2O (3 ml) and THF (3 ml)) was stirred for 3 h at 80 C. The reaction mixture was evaporated, and the residue was diluted with H2O and extracted with Et2O. The organic layer was washed with 7% aqueous NaHCO3 and dried over MgSO4 then evaporated to give a crude residue, which was chromatographed on silica gel (20 g, n-hexane:AcOEt=5:1) to give (^)-11 (0.335 g, 96%) as a homogeneous oil: IR (neat): 1731, 1657 cm^1; 23 D ^40.0 (c 0.44, CHCl3); NMR: 1.19 (3H, d, J=6 Hz), 1.25 (3H, d, J=6 Hz), 1.31 (3H, d, J=6 Hz), 2.36 (1H, dd, J=8, 16 Hz), 2.44 (1H, dd, J=4, 16 Hz), 2.90 (1H, br. s), 4.04 (1H, ddd, J=2, 5, 6 Hz), 4.14 (1H, m), 4.17 (1H, ddd, J=2, 5, 6 Hz), 4.46, 4.53, 4.63, 4.67 (each 1H, d, J=12 Hz), 4.80, 4.83 (each 1H, d, J=12 Hz), 5.10 (1H, dq, J=5, 6 Hz), 5.15 (1H, dq, J=5, 6 Hz), 6.08 (1H, dd, J=2, 16 Hz), 6.23 (1H, dd, J=2, 16 Hz), 6.85 (1H, dd, J=6, 16 Hz), 7.05 (1H, dd, J=6, 16 Hz), 7.27±7.38 (10H, m). 13C NMR: 171.8 (s), 164.7 (s), 163.7 (s), 146.4 (d), 144.1 (d), 137.3 (s), 137.3 (s), 128.4 (d), 128.4 (d), 127.8 (d), 127.8 (d), 127.5 (d), 127.5 (d), 124.0 (d), 122.3 (d), 94.8 (s), 79.4 (d), 79.4 (d), 74.1 (t), 71.9 (t), 71.6 (d), 71.6 (t), 71.4 (d), 64.3 (d), 43.3 (t), 22.6 (q), 15.4 (q), 15.2 (q). Anal. found: C, 57.01; H, 5.64. Calcd for C32H37O9Cl3: C, 57.20; H, 5.55%. FAB MS m/z: 671 (M++1).
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3.9. Deprotection of 2,2,2-trichloroethyl group of (^)-11 To a mixture of Zn dust (0.15 g, 2.29 mmol) and AcOH±AcONa buer solution (4 ml) in THF (4 ml) was added a solution of (^)-11 (0.191 g, 0.29 mmol) in THF (2 ml) at 0 C and the whole mixture was stirred for 2.5 h at room temperature. The reaction mixture was ®ltered o, and the ®ltrate was acidi®ed with 2 M aqueous HCl and extracted with Et2O. The organic layer was dried over MgSO4 then evaporated to give crude seco-acid 12 in quantitative yield: NMR: 1.20 (3H, d, J=6 Hz), 1.25 (3H, d, J=6 Hz), 1.31 (3H, d, J=6 Hz), 2.39 (1H, dd, J=8, 12 Hz), 2.45 (1H, dd, J=5, 12 Hz), 4.02 (1H, ddd, J=2, 5, 7 Hz), 4.12 (1H, ddd, J=2, 5, 7 Hz), 4.17 (1H, ddq, J=5, 6, 8 Hz), 4.45, 4.51, 4.62, 4.66 (each 1H, d, J=12 Hz), 5.10 (1H, dq, J=5, 6 Hz), 5.13 (1H, dq, J=5, 6 Hz), 6.07 (1H, dd, J=2, 16 Hz), 6.12 (1H, dd, J=2, 16 Hz), 6.85 (1H, dd, J=7, 16 Hz), 6.97 (1H, dd, J=7, 16 Hz), 7.27±7.38 (10H, m). 3.10. Dibenzyl ether (^)-13 To a solution of 12 (0.177 g, 0.29 mmol) in toluene (2 ml) were added molecular sieves 4A (0.2 g), triethylamine (0.06 g, 0.29 mmol) and 2,4,6-trichlorobenzoyl chloride (0.07 g, 0.29 mmol) and the reaction mixture was stirred for 3 h at room temperature. To a solution of DMAP (0.21 g, 1.74 mmol) in toluene (150 ml) was added dropwise the above-mentioned reaction mixture at 60 C and the whole mixture was stirred for 24 h at 100 C. The reaction mixture was washed with 7% aqueous NaHCO3, 2 M aqueous HCl and saturated brine. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (20 g, nhexane:AcOEt=10:1) to give (^)-13 (0.104 g, 70% overall yield from (^)-11) as a colorless solid: IR (CHCl3): 1722, 1520 cm^1; 22 D ^75.9 (c 0.34, CHCl3); NMR: 1.29 (3H, d, J=6 Hz), 1.31 (3H, d, J=7 Hz), 1.40 (3H, d, J=6 Hz), 2.50 (1H, dd, J=8, 15 Hz), 2.55 (1H, dd, J=4, 15 Hz), 3.74 (1H, dt, J=1, 7 Hz), 3.85 (1H, dt, J=1, 7 Hz), 4.34, 4.37, 4.59, 4.67 (each 1H, d, J=12 Hz), 4.98 (1H, dq, J=6, 7 Hz), 5.03 (1H, dq, J=6, 7 Hz), 5.35 (1H, m), 5.95 (1H, dd, J=1, 16 Hz), 5.99 (1H, dd, J=1, 16 Hz), 6.76 (1H, dd, J=7, 16 Hz), 6.83 (1H, dd, J=7, 16 Hz), 7.27±7.38 (10H, m). Anal. found: C, 68.66; H, 6.84. Calcd for C30H34O8: C, 68.95; H, 6.56%. FAB MS m/z: 523 (M++1). 3.11. (+)-Macrosphelide A 1 To a mixture of AlCl3 (0.6 g, 0.45 mmol) in CH2Cl2 (3 ml) was added dropwise a solution of (^)-13 (47 mg, 0.09 mmol) and m-xylene (1 ml) in CH2Cl2 (0.5 ml) at ^20 C and the reaction mixture was stirred for 2 h at 0 C then diluted with saturated brine and extracted with Et2O. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (20 g, n-hexane:AcOEt=15:1) to give (+)-1 (23 mg, 75%) as colorless 1 needles: mp 142 C; IR (KBr): 3438, 1708 cm^1; 22 D +82.3 (c 0.15, MeOH); H NMR: 1.32 (3H, d, J=7 Hz), 1.35 (3H, d, J=7 Hz), 1.44 (3H, d, J=7 Hz), 2.58 (1H, dd, J=3, 16 Hz), 2.61 (1H, dd, J=7, 16 Hz), 3.03 (1H, br. s), 3.28 (1H, br. s), 4.11 (1H, br. t, J=5.5 Hz), 4.20 (1H, br. t, J=5 Hz), 4.84 (1H, dq, J=5.5, 7 Hz), 4.95 (1H, dq, J=5, 7 Hz), 5.32±5.40 (1H, m), 6.02 (1H, dd, J=2, 16 Hz), 6.03 (1H, dd, J=2, 16 Hz), 6.84 (1H, dd, J=5.5, 16 Hz), 6.87 (1H, dd, J=5, 16 Hz). 13C NMR: 169.9 (s), 165.6 (s), 164.7 (s), 146.3 (d), 145.5 (d), 122.5 (d), 122.1 (d), 74.7 (d), 74.5 (d), 73.8 (d), 73.0 (d), 67.7 (d), 41.1 (t), 19.8 (q), 18.1 (q), 17.9 (q). Anal. found: C, 55.56; H, 6.46. Calcd for C16H22O8: C, 56.13; H, 6.48%. FAB MS m/z: 343 (M++1). HRMS (FAB MS, matrix: m-nitrobenzyl alcohol (NBA)): calcd for C16H23O8 (M++1) 343.1393; found 343.1441.
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3.12. (4S,5R)-4-Benzyloxy-5-tert-butyldimethylsiloxy-2(E)-hexenoic acid 5 (4S,5R)-4-Benzyloxy-5-tert-butyldimethylsiloxy-2(E)-hexenoic acid 5 was prepared from (4S,5R)-4 in 93% overall yield in the same way as for the preparation of (4R,5S)-5. The spectral data of (4S,5R)-5 were identical with those of (4R,5S)-5. 27 D +22.1 (c 0.99, CHCl3). 3.13. 2,2,2-Trichloroethyl (4S,5R)-5-tert-butyldimethylsiloxy-4-hydroxy-2(E)-hexenoate 6 2,2,2-Trichloroethyl (4S,5R)-5-tert-butyldimethylsiloxy-4-hydroxy-2(E)-hexenoate 6 was prepared from (4S,5R)-5 in 74% overall yield in the same way as for the preparation of (4R,5S)6. The spectral data of (4S,5R)-6 were identical with those of (4R,5S)-6; mp 62 C; 22 D +51.9 (c 0.49, CHCl3). 3.14. Ester formation between (4S,5R)-5 and (4S,5R)-6 Diester (+)-7 was prepared in 66% yield in the same way as for the preparation of (^)-7. The spectral data of (+)-7 were identical to those of (^)-7. 22 D +29.0 (c 0.59, CHCl3). 3.15. Desilylation of (+)-7 Hydroxy diester (+)-8 was prepared in 90% yield in the same way as for the preparation of (±)-8. The spectral data of (+)-8 were identical with those of (^)-8. 20 D +53.0 (c 0.32, CHCl3). 3.16. (R)-3-tert-Butyldimethylsiloxy butanoic acid 9 (R)-3-tert-Butyldimethylsiloxy butanoic acid 9 was prepared from methyl (R)-3-hydroxybutanoate in 65% overall yield in the same way as for the preparation of (S)-9. The spectral data of (R)-9 were identical to those of (S)-9. 24 D ^8.6 (c 0.22, CHCl3). 3.17. Ester formation between (+)-8 and (R)-9 Triester (+)-10 was prepared in 88% yield in the same way as for the preparation of (+)-10. The spectral data of (+)-10 were identical to those of (^)-10. 22 D +30.6 (c 0.84, CHCl3). 3.18. Desilylation of (+)-10 Hydroxy triester (+)-11 was prepared in 67% yield in the same way as for the preparation of (+)-11. The spectral data of (+)-11 were identical to those of (^)-11. 24 D +37.0 (c 0.67, CHCl3). 3.19. Dibenzyl ether (+)-13 Dibenzyl ether (+)-13 was prepared in 74% overall yield from (+)-11 in the same way as for the preparation of (^)-13. The spectral data of (+)-13 were identical to those of (^)-13. 21 D +83.6 (c 0.2, CHCl3).
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3.20. (^)-Macrosphelide A 1 (^)-Macrosphelide A 1 was prepared in 84% yield from (+)-13 in the same way as for the preparation of (+)-1 from (^)-13. The spectral data of synthetic (^)-1 were identical to those of (+)-1. Colorless needles; mp 141 C; 22 D ^79.2 (c 0.29, MeOH). Anal. found: C, 56.15; H, 6.55. Calcd for C16H22O8: C, 56.13; H, 6.48%. FAB MS m/z: 343 (M++1). 3.21. Ester formation between (^)-8 and (R)-9 To a mixture of DCC (0.348 g, 1.67 mmol), DMAP (0.041 g, 0.34 mmol) in CH2Cl2 (2 ml) was added a solution of (^)-8 (0.655 g, 1.12 mmol) and (R)-9 (0.367 g, 1.68 mmol) in CH2Cl2 (2 ml) and the reaction mixture was stirred for 1 day at room temperature. After the generated precipitate was ®ltered o, the ®ltrate was washed with 2 M aqueous HCl, 7% aqueous NaHCO3 and saturated brine. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (20 g, n-hexane:AcOEt=15:1) to give (^)-14 (0.787 g, 90%) as a homogenous oil: IR (neat): 1735, 1658 cm^1; 23 D ^43.0 (c 0.27, CHCl3); NMR: 0.05 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.18 (3H, d, J=6 Hz), 1.25 (3H, d, J=7 Hz), 1.32 (3H, d, J=7 Hz), 2.32 (1H, dd, J=6, 15 Hz), 2.49 (1H, dd, J=6, 15 Hz), 4.07 (1H, br. dt, J=1, 6 Hz), 4.19 (1H, br. dt, J=1, 6 Hz), 4.25 (1H, sixtet, J=6 Hz), 4.48, 4.54, 4.63, 4.68 (each 1H, d, J=12 Hz), 4.80, 4.84 (each 1H, d, J=12 Hz), 5.05 (1H, dq, J=6, 7 Hz), 5.15 (1H, dq, J=6, 7 Hz), 6.08 (1H, br. d, J=16 Hz), 6.24 (1H, br. d, J=16 Hz), 6.85 (1H, dd, J=6, 16 Hz), 7.05 (1H, dd, J=6, 16 Hz), 7.27±7.38 (10H, m). Anal. found: C, 58.04; H, 6.41. Calcd for C38H51O9SiCl3: C, 58.05; H, 6.54%. 3.22. Desilylation of (^)-14 A mixture of (^)-14 (0.64 g, 0.81 mmol) in the mixed solvent (AcOH (3 ml), H2O (1.5 ml) and THF (1.5 ml)) was stirred for 12 h at 80 C. The reaction mixture was evaporated, and the residue was diluted with H2O and extracted with Et2O. The organic layer was washed with 7% aqueous NaHCO3 and dried over MgSO4 then evaporated to give a crude residue, which was chromatographed on silica gel (20 g, n-hexane:AcOEt=5:1) to give (^)-15 (0.47 g, 86%) as a homogeneous oil: IR (neat): 1734, 1658 cm^1; 23 D ^60.4 (c 0.54, CHCl3); NMR: 1.19 (3H, d, J=6 Hz), 1.24 (3H, d, J=7 Hz), 1.32 (3H, d, J=7 Hz), 2.38 (1H, dd, J=8, 16 Hz), 2.43 (1H, dd, J=4, 16 Hz), 2.93 (1H, br. s), 4.04 (1H, ddd, J=2, 5, 6 Hz), 4.10±4.16 (1H, m), 4.17 (1H, ddd, J=2, 5, 6 Hz), 4.45, 4.53, 4.63, 4.67 (each 1H, d, J=13 Hz), 4.80, 4.84 (each 1H, d, J=12 Hz), 5.11 (1H, dq, J=5, 7 Hz), 5.15 (1H, dq, J=5, 7 Hz), 6.08 (1H, dd, J=2, 16 Hz), 6.24 (1H, dd, J=2, 16 Hz), 6.86 (1H, dd, J=6, 16 Hz), 7.05 (1H, dd, J=6, 16 Hz), 7.28±7.38 (10H, m). 13C NMR: 171.5 (s), 164.6 (s), 163.7 (s), 146.4 (d), 144.0 (d), 137.2 (s), 137.2 (s), 128.4 (d), 128.4 (d), 127.8 (d), 127.6 (d), 127.5 (d), 127.5 (d), 124.0 (d), 122.3 (d), 94.8 (s), 79.4 (d), 79.2 (d), 74.1 (t), 71.9 (t), 71.6 (d), 71.5 (t), 71.3 (d), 64.2 (d), 43.2 (t), 22.4 (q), 15.4 (q), 15.2 (q). Anal. found: C, 56.75; H, 5.61. Calcd for C32H37O9Cl3: C, 57.20; H, 5.55%. FAB MS m/z: 671 (M++1). 3.23. Dibenzyl ether (^)-17 (i) To a mixture of (^)-15 (0.137 g, 0.2 mmol) and an AcOH±AcONa buer solution (2.5 ml) in THF (2 ml) was added Zu dust (0.1 g, 1.5 mmol) at 0 C and the whole mixture was stirred for
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2.5 h at room temperature. The reaction mixture was ®ltered o and the ®ltrate was acidi®ed with 2 M aqueous HCl, extracted with Et2O. The organic layer was dried over MgSO4 then evaporated to give crude seco-acid 16 (0.106 g). (ii) To a solution of 16 (0.106 g) and triethylamine (0.06 g, 0.42 mmol) in THF (2 ml) was added a solution of 2,4,6-trichlorobenzoyl chloride (0.096 g, 0.4 mmol) in THF (1 ml) and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with toluene (100 ml). To a solution of DMAP (0.144 g, 1.2 mmol) in toluene (20 ml) was added dropwise the above-mentioned toluene solution at 100 C and the whole mixture was stirred for 24 h at 100 C. The reaction mixture was washed with 7% aqueous NaHCO3, 2 M aqueous HCl and saturated brine. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (15 g, n-hexane:AcOEt= 4:1) to give (^)-17 (0.084 g, 82% overall yield from (^)-15) as a homogenous oil: IR (neat): 1715, 1657 cm^1; 25 D ^40.7 (c 0.77, CHCl3); NMR: 1.21 (3H, d, J=7 Hz), 1.37 (3H, d, J=7 Hz), 1.40 (3H, d, J=7 Hz), 2.55 (1H, dd, J=7, 15 Hz), 2.75 (1H, dd, J=3, 15 Hz), 3.84 (1H, dt, J=1, 6 Hz), 3.95 (1H, dt, J=1, 6 Hz), 4.40, 4.46, 4.59, 4.62 (each 1H, d, J=12 Hz), 5.09 (1H, quintet, J=7 Hz), 5.17 (1H, quintet, J=7 Hz), 5.26 (1H, ddq, J=3, 7, 7 Hz), 6.00 (1H, dd, J=1, 16 Hz), 6.13 (1H, dd, J=1, 16 Hz), 6.80 (1H, dd, J=7, 16 Hz), 6.84 (1H, dd, J=7, 16 Hz), 7.28±7.30 (10H, m). Anal. found: C, 68.67; H, 6.70. Calcd for C30H34O8: C, 68.95; H, 6.56%. FAB MS m/z: 523 (M++1). 3.24. (+)-Macrosphelide E 2 To a mixture of AlCl3 (0.12g, 0.85 mmol) in CH2Cl2 (4 ml) was added dropwise a solution of (^)-13 (88 mg, 0.17 mmol) in m-xylene (2 ml) at ^20 C and the reaction mixture was stirred for 2 h at 0 C. The reaction mixture was diluted with ice±water and extracted with Et2O. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (20 g, n-hexane:AcOEt=1:1) to give (+)-2 (47 mg, 81%) as a colorless oil: IR (neat): 1 3452, 1717, 1665 cm^1; 22 D +78.5 (c 0.21, EtOH); H NMR: 1.29 (3H, d, J=7 Hz), 1.39 (3H, d, J=7 Hz), 1.40 (3H, d, J=7 Hz), 2.58 (1H, dd, J=7, 16 Hz), 2.73 (1H, dd, J=4, 16 Hz), 3.29 (1H, br. s), 3.52 (1H, br. s), 4.13±4.18 (1H, m), 4.33±4.37 (1H, m), 4.96 (1H, dq, J=5, 7 Hz), 5.11 (1H, dq, J=2, 7 Hz), 5.29 (1H, ddq, J=4, 7, 7 Hz), 6.04 (1H, dd, J=2, 16 Hz), 6.11 (1H, dd, J=2, 16 Hz), 6.80 (1H, dd, J=5.5, 16 Hz), 7.01 (1H, dd, J=4, 16 Hz). 13C NMR: 170.5 (s), 166.3 (s), 165.1 (s), 145.3 (d), 145.0 (d), 122.9 (d), 122.3 (d), 75.7 (d), 75.0 (d), 74.9 (d), 73.6 (d), 66.8 (d), 40.5 (t), 19.7 (q), 17.8 (q), 17.5 (q). Anal. found: C, 56.17; H, 6.34. Calcd for C16H22O8: C, 56.13; H, 6.48%. FAB MS m/z: 343 (M++1). Acknowledgements This work was supported by a Grant-in-Aid for Scienti®c Research (No. 10672002) from the Ministry of Education, Science, Sports and Culture, Japan to H.A. The authors are grateful to Professor Yoshiteru Ida, School of Pharmaceutical Sciences, Showa University for measurement of high resolution mass spectra (FAB MS) of synthetic (+)-Macrosphelide A (1). References 1. (a) Hayashi, M.; Kim, Y.-P.; Hiraoka, H.; Natori, M.; Takamatsu, S.; Kawakubo, T.; Masuma, R.; Komiyama, K.; Omura, S. J. Antibiot. 1995, 48, 1435±1439. (b) Takamatsu, S.; Kim, Y.-P.; Hayashi, M.; Hiraoka, H.; Natori, M.; Komiyama, K.; Omura, S. J. Antibiot. 1996, 49, 95±98.
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2. Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.; Matsumura, E.; Yamori, T.; Tsuruo, T. Tetrahedron Lett. 1997, 38, 8215±8218. 3. Sunazuka, T.; Hirose, T.; Harigaya, Y.; Takamatsu, S.; Hayashi, M.; Komiyama, K.; Omura, S.; Sprengeler, P. A.; Smith III, A. B. J. Am. Chem. Soc. 1997, 119, 10247±10248. 4. Kobayashi, Y.; Kumar, B. G.; Kurachi, T. Tetrahedron Lett. 2000, 41, 1559±1563. 5. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768±2771. 6. Mitsunobu, O. Synthesis 1981, 1±28. 7. (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237±6240. (b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765±5780. 8. Ono, M.; Saotome, C.; Akita, H. Tetrahedron: Asymmetry 1996, 7, 2595±2602. 9. Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394±2395. 10. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989±1993.
Total syntheses of macrosphelides (+)-A, (^)-A and (+)-E Machiko Ono,* Hiroshi Nakamura, Fumi Konno and Hiroyuki Akita* School of Pharmaceutical Science, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan Received 15 May 2000; accepted 19 June 2000
Abstract Total syntheses of (+)-macrosphelide A 1 (18.5% overall yield in 11 steps) and (+)-macrosphelide E 2 (23.9% overall yield in 11 steps) have been achieved via the chemoenzymatic reaction product (4R,5S)-4benzyloxy-5-hydroxy-2(E)-hexenoate 4. The enantiomer (^)-A (1) (14.2% overall yield in 11 steps) of (+)-1 was also synthesized from the chemoenzymatic reaction product (4S,5R)-4-benzyloxy-5-hydroxy-2(E)hexenoate 4. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction (+)-Macrosphelide A 1 isolated from the culture broth of Microsphaeropsis sp. FO-5050 by Omura and co-workers has been shown to strongly inhibit the adhesion of human leukemia HL60 cells to human umbilical-vein endothelial cells (HUVEC) in dose-dependent fashion.1 It is the ®rst 16-membered ring antibiotic involving three lactone linkages.1 (+)-Macrosphelide E 2 was isolated from a strain of Periconia byssoides separated from the gastrointestinal tract of the sea hare Aplysia kurodai and was found to be the stereoisomer, in which the con®guration of C(3) was dierent from that of (+)-macrosphelide A 1.2 Recently, the absolute con®gurations of (+)macrosphelides A 1 and E 2 have been determined as depicted in 1 and 2. Total syntheses of (+)-1 have been reported by two groups.3,4 The synthesis of key compound, trans-(4R,5S)-4,5-dihydroxy2-hexenoic acid congener from the sorbic ester in the ®rst synthesis, was carried out by using the Sharpless AD reaction5 with 85% ee followed by Mitsunobu inversion6 at C(4) position.3 The key steps in the second asymmetric synthesis are the preparation of (S)-1-(2-furyl)ethanol from the corresponding racemic alcohol using the Sharpless reagents7 and diastereoselective reduction of an a,b-unsaturated ketone in the chiral substrate elaborated from the above-mentioned chiral alcohol.4 On the other hand, we reported that the enantioselective hydrolysis of (þ)-(4,5)-anti-5acetoxy-4-benzyloxy-2(E)-hexenoate 3 using the lipase `Amano P' from Pseudomonas sp. in phosphate buer solution gave the (4R,5S)-5-acetoxy ester 3 (>99% ee, 48% yield) and the *Corresponding authors. E-mail: [email protected] 0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S0957-4166(00)00245-7
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(4S,5R)-5-hydroxy ester 4 (>99% ee, 44% yield), and methanolysis of (4R,5S)-3 provided the (4R,5S)-4 in 84% yield (Scheme 1).8
Scheme 1.
2. Results and discussion The key steps of our synthetic strategy of (+)-1 and (+)-2 are the enantioselective preparation of two dierentially protected (4R,5S)-4-benzyloxy-5-hydroxy-2(E)-hexenoic acid congeners, carboxylic acid (4R,5S)-5 and alcohol (4R,5S)-6 from (4R,5S)-4, and regioselective ester formation from (4R,5S)-5 and (4R,5S)-6 (Scheme 2). The third building blocks, enantiomerically pure methyl (S)- and (R)-3-hydroxybutanoates, are commercially available. Herein, we report the total syntheses of (+)-1, (^)-1 and (+)-2 based on the above-mentioned strategy. Silylation (98% yield) of (4R,5S)-4 using tert-butyldimethylsilyl chloride (TBDMSCl) followed by hydrolysis (99% yield) gave the desired carboxylic acid (4R,5S)-5 in 97% overall yield. Ester formation (93% yield) of (4R,5S)-5 using 2,2,2-trichloroethanol followed by deprotection (87% yield) of silyl group aorded the desired alcohol (4R,5S)-6 ([ ]D ^46.1 (c 0.58, CHCl3)) in 81% overall yield. Condensation of carboxylic acid (4R,5S)-5 and alcohol (4R,5S)-6 via the Keck procedure9 (dicyclohexylcarbodiimide (DCC), 4-(dimethylamino)pyridine (DMAP), camphorsulfonic acid (CSA), CH2Cl2) provided dimer ester (^)-7 ([ ]D ^26.3 (c 0.56, CHCl3)) in 75% yield, which was desilylated to yield an alcohol (^)-8 ([ ]D ^42.3 (c 0.24, CHCl3)) in 79% yield (Scheme 2). The third fragment, TBDMS ether (S)-9, was prepared from methyl (S)-3-hydroxybutanoate and coupled with (^)-8 to give the triester (^)-10 ([ ]D ^29.5 (c 0.33, CHCl3)) in 79% yield under the Keck conditions. Removal of the silyl group of (^)-10 aorded the desilylated alcohol (^)-11 ([ ]D ^40.0 (c 0.44, CHCl3)) in 96% yield. Deprotection of (^)-11 using Zn in an acetic acid buer solution followed by subjecting to Yamaguchi macrolactonization10 (2,4,6-trichlorobenzoyl chloride, Et3N, DMAP) provided (^)-dibenzyl macrosphelide A 13 ([ ]D ^75.9 (c 0.34, CHCl3)) in 70% overall yield from (^)-11. Finally, deprotection of benzyl group in (^)-13 using AlCl3 in the presence of m-xylene8 gave (+)-synthetic macrosphelide A 1 ([ ]D +82.3 (c 0.15, MeOH), mp 142 C) in 75% yield. Physical data ([ ]D, mp, 1H and 13C NMR) of synthetic (+)-1 were identical with those ([ ]D +84.1 (c 0.59, MeOH), mp 141±142 C) of the natural (+)-1.1 The total synthesis of (+)-macrosphelide A 1 has been achieved via highly convergent strategy in 18.5% overall yield (11 steps) from the chemoenzymatic reaction product (4R,5S)-4.
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Scheme 2. (a) (1) TBDMSCl/imidazole/DMF; (2) NaOH aq./MeOH; (b) (1) TBDMSCl/imidazole/DMF; (2) NaOH aq./MeOH; (3) CCl3CH2OH/DCC/DMAP; (4) AcOH/H2O/THF; (c) DCC/DMAP/CSA/CH2Cl2; (d) AcOH:H2O:THF (2:1:1); (e) (S)-9, DCC/DMAP/CH2Cl; (f) Zn/THF/AcOH±AcONa buer; (g) 2,4,6-trichlorobenzoyl chloride/Et3N/DMAP/toluene; (h) m-xylene/AlCl3/CH2Cl2
Scheme 3.
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The synthesis of enantiomer (^)-1 of (+)-macrosphelide A 1 was achieved from the (4S,5R)-4 in the same way as for the synthesis of (+)-1 from (4R,5S)-4 as shown in Scheme 3. Condensation of (+)-8 and TBDMS ether (R)-9 gave the triester (+)-10 ([ ]D +30.6 (c 0.33, CHCl3)) which was ®nally converted to the (^)-macrosphelide A (1) ([ ]D ^79.2 (c 0.29, MeOH), mp 142 C) in 14.2% overall yield (11 steps) from the chemoenzymatic reaction product (4S,5R)-4. Next the total synthesis of (+)-macrosphelide E (2) was achieved by applying the abovementioned synthetic route of (+)-1 from (^)-8. Condensation of (^)-8 and TBDMS ether (R)-9 gave the triester (^)-14 ([ ]D ^43.0 (c 0.27, CHCl3)) in 90% yield, which was desilylated to aord (^)-alcohol 15 ([ ]D ^60.4 (c 0.54, CHCl3)) in 86% yield. Deprotection of 2,2,2-trichloroethyl group in (^)-15 provided a seco-acid 16 which was subjected to macrolactonization10 to yield (^)dibenzyl macrosphelide E 17 ([ ]D ^40.7 (c 0.77, CHCl3)) in 82% overall yield from (^)-15 (Scheme 4). Finally, deprotection of benzyl group of (^)-17 gave (+)-synthetic macrosphelide E 2 ([ ]D +78.5 (c 0.21, EtOH)) in 81% yield. Physical data ([ ]D, 1H and 13C NMR) of synthetic (+)2 were identical with those ([ ]D +56.8 (c 0.46, EtOH)) of the natural (+)-2.2
Scheme 4. (a) (R)-9, DCC/DMAP/CH2Cl2; (b) AcOH:H2O:THF (2:1:1); (c) Zn/THF/AcOH±AcONa buer; (d) 2,4,6trichlorobenzoyl chloride/Et3N/DMAP/toluene; (e) m-xylene/AlCl3/CH2Cl2
In conclusion, total syntheses of (+)-macrosphelide A 1 (18.5% overall yield in 11 steps), (^)-A 1 (14.2% overall yield in 11 steps) and (+)-macrosphelide E 2 (23.9% overall yield in 11 steps) were achieved from the chemoenzymatic reaction product (4R,5S)- and (4S,5R)-4-benzyloxy-5hydroxy-2(E)-hexenoates 4. 3. Experimental 3.1. General All melting points were measured on a Yanaco MP-3S micro melting point apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on a JEOL AL 400 spectrometer in CDCl3. Carbon substitution degrees were established by DEPT pulse sequence. The fast atom bombardment mass spectra (FAB MS) and electrospray ionization mass spectra (ESI MS) were obtained with a JEOL JMS-DX 303 spectrometer and ThermoQuest LCQ, respectively. IR spectra were recorded on a JASCO FT/IR-300 spectrometer. Optical rotations were measured with a JASCO DIP-370 digital polarimeter. All evaporations were performed under reduced pressure. For column chromatography, silica gel (Kieselgel 60) was employed.
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3.2. (4R,5S)-4-Benzyloxy-5-tert-butyldimethylsiloxy-2(E)-hexenoic acid 5 (i) To a solution of (4R,5S)-4 (5.21 g, 20.8 mmol) and imidazole (5.67 g, 83.2 mmol) in dimethylformamide (DMF, 42 ml) was added TBDMSCl (7.85 g, 52.0 mmol) at 0 C and the reaction mixture was stirred for 1 h at 0 C and for 1.5 h at room temperature. The reaction mixture was diluted with H2O and extracted with ether. The ether layer was washed with saturated brine and dried over MgSO4. The ether layer was evaporated to give a crude residue, which was chromatographed on silica gel (200 g, n-hexane:AcOEt=20:1) to give methyl (4R,5S)4-benzyloxy-5-tert-butyldimethylsiloxy-2(E)-hexenoate (7.44 g, 98%) as a colorless oil. IR (neat): 1724, 1658 (sh) cm^1 (COOMe); NMR: 0.02 (3H, s), 0.04 (3H, s), 0.87 (9H, s), 1.20 (3H, d, J=6 Hz), 3.76 (3H, s), 3.77 (1H, dt, J=1, 6 Hz), 3.85 (1H, quintet, J=6 Hz), 4.44 (1H, d, J=12 Hz), 4.61 (1H, d, J=12 Hz), 6.06 (1H, dd, J=1, 16 Hz), 6.95 (1H, dd, J=6, 16 Hz), 7.27±7.35 (5H, m). Anal. found: C, 66.22; H, 9.03. Calcd for C20H32O4Si: C, 65.89; H, 8.85%. ESI MS m/z: 365 (M++1). (ii) To a solution of methyl (4R,5S)-4-benzyloxy-5-tert-butyldimethylsiloxy-2(E)hexenoate (4.19 g, 11.5 mmol) in MeOH (40 ml) was added dropwise 2 M aqueous NaOH (12 ml) at 0 C and the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was acidi®ed with 2 M aqueous HCl under ice-cooling and extracted with ether. The ether layer was washed with saturated brine and dried over MgSO4. The ether layer was evaporated to give a crude (4R,5S)-5 (3.99 g, 99%) as a colorless oil. 24 D ^22.6 (c 0.59, CHCl3); NMR: 0.03 (3H, s), 0.05 (3H, s), 0.87 (9H, s), 1.21 (3H, d, J=6 Hz), 3.82 (1H, dt, J=2, 6 Hz), 3.86 (1H, quintet, J=6 Hz), 4.47 (1H, d, J=12 Hz), 4.62 (1H, d, J=12 Hz), 6.07 (1H, dd, J=2, 16 Hz), 7.07 (1H, dd, J=6, 16 Hz), 7.27±7.37 (5H, m). 3.3. 2,2,2-Trichloroethyl (4R,5S)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 6 (i) To a mixture of DCC (2.66 g, 12.8 mmol), DMAP (2.10 g, 17.0 mmol) in CH2Cl2 (150 ml) was added a solution of (4R,5S)-5 (3.01 g, 8.5 mmol), CCl3CH2OH (1.93 g, 17.0 mmol) in CH2Cl2 (30 ml) and the reaction mixture was stirred for 3 days at room temperature. After the generated precipitate was ®ltered o, the ®ltrate was washed with 2 M aqueous HCl and 7% aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (110 g, n-hexane:AcOEt=20:1) to give 2,2,2trichloroethyl (4R,5S)-4-benzyloxy-5-tert-butyldimethylsiloxy-2(E)-hexenoate (3.85 g, 93%) as a colorless oil: IR (neat): 1739 cm^1 (ester); 31 D ^15.6 (c 0.75, CHCl3); NMR: 0.03 (3H, s), 0.05 (3H, s), 0.87 (9H, s), 1.23 (3H, d, J=6 Hz), 3.81 (1H, dt, J=2, 6 Hz), 3.86 (1H, quintet, J=6 Hz), 4.07 (1H, d, J=12 Hz), 4.63 (1H, d, J=12 Hz), 4.81 (1H, d, J=12 Hz), 4.86 (1H, d, J=12 Hz), 6.16 (1H, dd, J=2, 16 Hz), 7.12 (1H, dd, J=6, 16 Hz), 7.28±7.38 (5H, m). Anal. found: C, 52.56; H, 6.56. Calcd for C21H31O4SiCl3: C, 52.34; H, 6.48%. FAB MS m/z: 480 (M+). (ii) A mixture of 2,2,2-trichloroethyl (4R,5S)-4-benzyloxy-5-tert-butyldimethylsiloxy-2(E)-hexenoate (4.04 g, 8.4 mmol) in the mixed solvent (AcOH (10 ml), H2O (10 ml) and THF (5 ml)) was stirred for 12 h at 70 C and the whole mixture was again stirred for 3 h at 110 C after adding AcOH (4 ml). The reaction mixture was evaporated and the residue was diluted with H2O, extracted with Et2O. The organic layer was washed with 7% aqueous NaHCO3 and dried over MgSO4 then evaporated to give a crude residue, which was chromatographed on silica gel (100 g, n-hexane:AcOEt=20:1) to give (4R,5S)-6 (2.68 g, 87%) as a colorless crystal: Mp 62 C; IR (neat): 3477, 1730 cm^1; a21 D ^46.1 (c 0.58, CHCl3); NMR: 1.17 (3H, d, J=6 Hz), 3.96±4.03 (2H, m), 4.06 (1H, d, J=12 Hz), 4.67 (1H, d, J=12 Hz), 4.81 (1H, d, J=12 Hz), 4.84 (1H, d, J=12 Hz), 6.19 (1H, dd, J=1,
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16 Hz), 7.08 (1H, dd, J=6, 16 Hz), 7.28±7.40 (5H, m). 13C NMR: 163.8 (s), 146.8 (d), 137.3 (s), 128.4 (d), 127.8 (d), 127.7 (d), 122.6 (d), 94.9 (s), 81.8 (d), 74.2 (t), 71.8 (t), 69.2 (d), 18.1 (q). Anal. found: C, 49.16; H, 4.71. Calcd for C15H17O4Cl3: C,49.00; H,4.66%. FAB MS m/z: 366 (M+). 3.4. Ester formation between (4R,5S)-5 and (4R,5S)-6 To a mixture of DCC (1.21 g, 5.9 mmol), DMAP (0.95 g, 7.8 mmol) and (+)-CSA (0.91 g, 3.9 mmol) in CH2Cl2 (30 ml) was added a solution of (4R,5S)-5 (1.244 g, 3.9 mmol) and (4R,5S)-6 (1.436 g, 3.9 mmol) in CH2Cl2 (3 ml) and the reaction mixture was stirred for 2 days at room temperature. After the generated precipitate was ®ltered o, the ®ltrate was washed with 2 M aqueous HCl and 7% aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (60 g, n-hexane: AcOEt=20:1) to give (^)-7 (2.05 g, 75%) as a homogenous oil and recovery (4R,5S)-6 (171 mg, 12% recovery): IR (neat): 1732 cm^1; 27 D ^26.3 (c 0.56, CHCl3); NMR: 0.02 (3H, s), 0.05 (3H, s), 0.87 (9H, s), 1.22 (3H, d, J=6 Hz), 1.31 (3H, d, J=6 Hz), 3.78 (1H, dt, J=1, 6 Hz), 3.86 (1H, quintet, J=6 Hz), 4.20 (1H, ddd, J=1, 5, 6 Hz), 4.46, 4.56, 4.62, 4.67 (each 1H, d, J=12 Hz), 4.80, 4.84 (each 1H, d, J=12 Hz), 5.17 (1H, dq, J=5, 6 Hz), 6.05 (1H, dd, J=1, 16 Hz), 6.25 (1H, dd, J=1, 16 Hz), 6.93 (1H, dd, J=6, 16 Hz), 7.07 (1H, dd, J=6, 16 Hz), 7.27±7.39 (10H, m). 13C NMR: 164.6 (s), 163.6 (s), 146.5 (d), 144.6 (d), 137.4 (s), 137.2 (s), 128.4 (d), 128.3 (d), 127.7 (d), 127.5 (d), 127.4 (d), 127.4 (d),124.0 (d), 122.2 (d), 94.8 (s), 81.8 (d), 79.4 (d), 74.0 (t), 71.9 (t), 71.4 (d), 71.3 (t), 69.1 (d), 18.2 (q), 15.2 (q). Anal. found: C, 58.35; H, 6.44. Calcd for C34H45O7SiCl3: C, 58.32; H, 6.48%. 3.5. Desilylation of (^)-7 A mixture of (^)-7 (1.529 g, 2.2 mmol) in the mixed solvent (AcOH (10 ml), H2O (5 ml) and THF (5 ml)) was stirred for 2 days at 80 C. The reaction mixture was evaporated and the residue was diluted with H2O, extracted with Et2O. The organic layer was washed with 7% aqueous NaHCO3 and dried over MgSO4 then evaporated to give a crude residue, which was chromatographed on silica gel (40 g, n-hexane:AcOEt=4:1) to give (^)-8 (1.015 g, 79%) as a homogeneous oil: IR (neat): 3472, 1727 cm^1; 21 D ^42.3 (c 0.24, CHCl3); NMR: 1.16 (3H, d, J=6 Hz), 1.31 (3H, d, J=6 Hz), 2.20 (1H, br. d, J=5 Hz), 3.92 (1H, ddd, J=1, 5, 6 Hz), 3.97 (1H, m), 4.17 (1H, ddd, J=1, 5, 6 Hz), 4.42, 4.53, 4.65, 4.67 (each 1H, d, J=12 Hz), 4.79, 4.83 (each 1H, d, J=12 Hz), 5.15 (1H, dq, J=5, 6 Hz), 6.06 (1H, dd, J=1, 16 Hz), 6.23 (1H, dd, J=1, 16 Hz), 6.92 (1H, dd, J=6, 16 Hz), 7.05 (1H, dd, J=6, 16 Hz), 7.28±7.39 (10H, m). Anal. found: C, 57.39; H, 5.63. Calcd for C28H31O7Cl3: C, 57.40; H, 5.33%. FAB MS m/z: 585 (M++1). 3.6. (S)-3-tert-Butyldimethylsiloxy butanoic acid 9 (i) To a solution of methyl (S)-3-hydroxybutanoate (2.01 g, 17 mmol) and imidazole (5.21 g, 76.5 mmol) in DMF (20 ml) was added TBDMSCl (3.85 g, 25.5 mmol) at 0 C and the reaction mixture was stirred for 30 min at 0 C and for 30 min at room temperature. The reaction mixture was diluted with saturated brine, extracted with ether and dried over MgSO4. The ether layer was evaporated to give a crude residue, which was chromatographed on silica gel (100 g, n-hexane:
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AcOEt=40:1) to give methyl (S)-3-tert-butyldimethylsiloxy butanoate (3.217 g, 81%) as a colorless oil. 25 D +29.1 (c 0.49, CHCl3); NMR: 0.03 (3H, s), 0.07 (3H, s), 0.86 (9H, s), 1.19 (3H, d, J=6 Hz), 2.38 (1H, dd, J=5, 14 Hz), 2.47 (1H, dd, J=8, 14 Hz), 3.65 (3H, s), 4.27 (1H, ddq, J=5, 6, 8 Hz). (ii) To a solution of methyl (S)-3-tert-butyldimethylsiloxy butanoate (0.896 g, 3.9 mmol) in MeOH (8 ml) was added dropwise 2 M aqueous NaOH (4 ml) at 0 C and the reaction mixture was stirred for 2 days at room temperature. The reaction mixture was acidi®ed with 2 M aqueous HCl under ice-cooling and extracted with ether. The ether layer was washed with brine and dried over MgSO4. The ether layer was evaporated to give a crude (S)-9 (765 mg, 91%) as a colorless oil. 26 D +8.64 (c 0.22, CHCl3); NMR: 0.06 (3H, s), 0.08 (3H, s), 0.87 (9H, s), 1.22 (3H, d, J=6 Hz), 2.45 (1H, dd, J=6, 14 Hz), 2.50 (1H, dd, J=6, 14 Hz), 4.27 (1H, sixtet, J=6 Hz). 3.7. Ester formation between (^)-8 and (S)-9 To a mixture of DCC (0.35 g, 1.68 mmol), DMAP (0.27 g, 2.24 mmol) and (+)-CSA (0.26 g, 1.12 mmol) in CH2Cl2 (10 ml) was added a solution of (^)-8 (0.653 g, 1.12 mmol) and (S)-9 (0.363 g, 1.17 mmol) in CH2Cl2 (5 ml) and the reaction mixture was stirred for 2 d at room temperature. After the generated precipitate was ®ltered o, the ®ltrate was washed with 2 M aqueous HCl, 7% aqueous NaHCO3 and saturated brine. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (30 g, n-hexane:AcOEt=10:1) to give (^)-10 (0.692 g, 79%) as a homogenous oil: IR (neat): 1735, 1657 cm^1; 24 D ^29.5 (c 0.33, CHCl3); NMR: 0.04 (3H, s), 0.06 (3H, s), 0.86 (9H, s), 1.19 (3H, d, J=6 Hz), 1.23 (3H, d, J=6 Hz), 1.31 (3H, d, J=6 Hz), 2.35 (1H, dd, J=6, 15 Hz), 2.47 (1H, dd, J=6, 15 Hz), 4.09 (1H, ddd, J=2, 5, 6 Hz), 4.18 (1H, ddd, J=2, 5, 6 Hz), 4.24 (1H, sixtet, J= 6 Hz), 4.49, 4.54, 4.63, 4.68 (each 1H, d, J=12 Hz), 4.80, 4.83 (each 1H, d, J=12 Hz), 5.03 (1H, dq, J=5, 6 Hz), 5.13 (1H, dq, J=5, 6 Hz), 6.09 (1H, dd, J=2, 16 Hz), 6.23 (1H, dd, J=2, 16 Hz), 6.85 (1H, dd, J=6, 16 Hz), 7.05 (1H, dd, J=6, 16 Hz), 7.27±7.37 (10H, m). Anal. found: C, 58.27; H, 5.64. Calcd for C38H51O9SiCl3: C, 58.05; H, 5.55%. 3.8. Desilylation of (^)-10 A mixture of (^)-10 (0.408 g, 0.52 mmol) in the mixed solvent (AcOH (6 ml), H2O (3 ml) and THF (3 ml)) was stirred for 3 h at 80 C. The reaction mixture was evaporated, and the residue was diluted with H2O and extracted with Et2O. The organic layer was washed with 7% aqueous NaHCO3 and dried over MgSO4 then evaporated to give a crude residue, which was chromatographed on silica gel (20 g, n-hexane:AcOEt=5:1) to give (^)-11 (0.335 g, 96%) as a homogeneous oil: IR (neat): 1731, 1657 cm^1; 23 D ^40.0 (c 0.44, CHCl3); NMR: 1.19 (3H, d, J=6 Hz), 1.25 (3H, d, J=6 Hz), 1.31 (3H, d, J=6 Hz), 2.36 (1H, dd, J=8, 16 Hz), 2.44 (1H, dd, J=4, 16 Hz), 2.90 (1H, br. s), 4.04 (1H, ddd, J=2, 5, 6 Hz), 4.14 (1H, m), 4.17 (1H, ddd, J=2, 5, 6 Hz), 4.46, 4.53, 4.63, 4.67 (each 1H, d, J=12 Hz), 4.80, 4.83 (each 1H, d, J=12 Hz), 5.10 (1H, dq, J=5, 6 Hz), 5.15 (1H, dq, J=5, 6 Hz), 6.08 (1H, dd, J=2, 16 Hz), 6.23 (1H, dd, J=2, 16 Hz), 6.85 (1H, dd, J=6, 16 Hz), 7.05 (1H, dd, J=6, 16 Hz), 7.27±7.38 (10H, m). 13C NMR: 171.8 (s), 164.7 (s), 163.7 (s), 146.4 (d), 144.1 (d), 137.3 (s), 137.3 (s), 128.4 (d), 128.4 (d), 127.8 (d), 127.8 (d), 127.5 (d), 127.5 (d), 124.0 (d), 122.3 (d), 94.8 (s), 79.4 (d), 79.4 (d), 74.1 (t), 71.9 (t), 71.6 (d), 71.6 (t), 71.4 (d), 64.3 (d), 43.3 (t), 22.6 (q), 15.4 (q), 15.2 (q). Anal. found: C, 57.01; H, 5.64. Calcd for C32H37O9Cl3: C, 57.20; H, 5.55%. FAB MS m/z: 671 (M++1).
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3.9. Deprotection of 2,2,2-trichloroethyl group of (^)-11 To a mixture of Zn dust (0.15 g, 2.29 mmol) and AcOH±AcONa buer solution (4 ml) in THF (4 ml) was added a solution of (^)-11 (0.191 g, 0.29 mmol) in THF (2 ml) at 0 C and the whole mixture was stirred for 2.5 h at room temperature. The reaction mixture was ®ltered o, and the ®ltrate was acidi®ed with 2 M aqueous HCl and extracted with Et2O. The organic layer was dried over MgSO4 then evaporated to give crude seco-acid 12 in quantitative yield: NMR: 1.20 (3H, d, J=6 Hz), 1.25 (3H, d, J=6 Hz), 1.31 (3H, d, J=6 Hz), 2.39 (1H, dd, J=8, 12 Hz), 2.45 (1H, dd, J=5, 12 Hz), 4.02 (1H, ddd, J=2, 5, 7 Hz), 4.12 (1H, ddd, J=2, 5, 7 Hz), 4.17 (1H, ddq, J=5, 6, 8 Hz), 4.45, 4.51, 4.62, 4.66 (each 1H, d, J=12 Hz), 5.10 (1H, dq, J=5, 6 Hz), 5.13 (1H, dq, J=5, 6 Hz), 6.07 (1H, dd, J=2, 16 Hz), 6.12 (1H, dd, J=2, 16 Hz), 6.85 (1H, dd, J=7, 16 Hz), 6.97 (1H, dd, J=7, 16 Hz), 7.27±7.38 (10H, m). 3.10. Dibenzyl ether (^)-13 To a solution of 12 (0.177 g, 0.29 mmol) in toluene (2 ml) were added molecular sieves 4A (0.2 g), triethylamine (0.06 g, 0.29 mmol) and 2,4,6-trichlorobenzoyl chloride (0.07 g, 0.29 mmol) and the reaction mixture was stirred for 3 h at room temperature. To a solution of DMAP (0.21 g, 1.74 mmol) in toluene (150 ml) was added dropwise the above-mentioned reaction mixture at 60 C and the whole mixture was stirred for 24 h at 100 C. The reaction mixture was washed with 7% aqueous NaHCO3, 2 M aqueous HCl and saturated brine. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (20 g, nhexane:AcOEt=10:1) to give (^)-13 (0.104 g, 70% overall yield from (^)-11) as a colorless solid: IR (CHCl3): 1722, 1520 cm^1; 22 D ^75.9 (c 0.34, CHCl3); NMR: 1.29 (3H, d, J=6 Hz), 1.31 (3H, d, J=7 Hz), 1.40 (3H, d, J=6 Hz), 2.50 (1H, dd, J=8, 15 Hz), 2.55 (1H, dd, J=4, 15 Hz), 3.74 (1H, dt, J=1, 7 Hz), 3.85 (1H, dt, J=1, 7 Hz), 4.34, 4.37, 4.59, 4.67 (each 1H, d, J=12 Hz), 4.98 (1H, dq, J=6, 7 Hz), 5.03 (1H, dq, J=6, 7 Hz), 5.35 (1H, m), 5.95 (1H, dd, J=1, 16 Hz), 5.99 (1H, dd, J=1, 16 Hz), 6.76 (1H, dd, J=7, 16 Hz), 6.83 (1H, dd, J=7, 16 Hz), 7.27±7.38 (10H, m). Anal. found: C, 68.66; H, 6.84. Calcd for C30H34O8: C, 68.95; H, 6.56%. FAB MS m/z: 523 (M++1). 3.11. (+)-Macrosphelide A 1 To a mixture of AlCl3 (0.6 g, 0.45 mmol) in CH2Cl2 (3 ml) was added dropwise a solution of (^)-13 (47 mg, 0.09 mmol) and m-xylene (1 ml) in CH2Cl2 (0.5 ml) at ^20 C and the reaction mixture was stirred for 2 h at 0 C then diluted with saturated brine and extracted with Et2O. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (20 g, n-hexane:AcOEt=15:1) to give (+)-1 (23 mg, 75%) as colorless 1 needles: mp 142 C; IR (KBr): 3438, 1708 cm^1; 22 D +82.3 (c 0.15, MeOH); H NMR: 1.32 (3H, d, J=7 Hz), 1.35 (3H, d, J=7 Hz), 1.44 (3H, d, J=7 Hz), 2.58 (1H, dd, J=3, 16 Hz), 2.61 (1H, dd, J=7, 16 Hz), 3.03 (1H, br. s), 3.28 (1H, br. s), 4.11 (1H, br. t, J=5.5 Hz), 4.20 (1H, br. t, J=5 Hz), 4.84 (1H, dq, J=5.5, 7 Hz), 4.95 (1H, dq, J=5, 7 Hz), 5.32±5.40 (1H, m), 6.02 (1H, dd, J=2, 16 Hz), 6.03 (1H, dd, J=2, 16 Hz), 6.84 (1H, dd, J=5.5, 16 Hz), 6.87 (1H, dd, J=5, 16 Hz). 13C NMR: 169.9 (s), 165.6 (s), 164.7 (s), 146.3 (d), 145.5 (d), 122.5 (d), 122.1 (d), 74.7 (d), 74.5 (d), 73.8 (d), 73.0 (d), 67.7 (d), 41.1 (t), 19.8 (q), 18.1 (q), 17.9 (q). Anal. found: C, 55.56; H, 6.46. Calcd for C16H22O8: C, 56.13; H, 6.48%. FAB MS m/z: 343 (M++1). HRMS (FAB MS, matrix: m-nitrobenzyl alcohol (NBA)): calcd for C16H23O8 (M++1) 343.1393; found 343.1441.
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3.12. (4S,5R)-4-Benzyloxy-5-tert-butyldimethylsiloxy-2(E)-hexenoic acid 5 (4S,5R)-4-Benzyloxy-5-tert-butyldimethylsiloxy-2(E)-hexenoic acid 5 was prepared from (4S,5R)-4 in 93% overall yield in the same way as for the preparation of (4R,5S)-5. The spectral data of (4S,5R)-5 were identical with those of (4R,5S)-5. 27 D +22.1 (c 0.99, CHCl3). 3.13. 2,2,2-Trichloroethyl (4S,5R)-5-tert-butyldimethylsiloxy-4-hydroxy-2(E)-hexenoate 6 2,2,2-Trichloroethyl (4S,5R)-5-tert-butyldimethylsiloxy-4-hydroxy-2(E)-hexenoate 6 was prepared from (4S,5R)-5 in 74% overall yield in the same way as for the preparation of (4R,5S)6. The spectral data of (4S,5R)-6 were identical with those of (4R,5S)-6; mp 62 C; 22 D +51.9 (c 0.49, CHCl3). 3.14. Ester formation between (4S,5R)-5 and (4S,5R)-6 Diester (+)-7 was prepared in 66% yield in the same way as for the preparation of (^)-7. The spectral data of (+)-7 were identical to those of (^)-7. 22 D +29.0 (c 0.59, CHCl3). 3.15. Desilylation of (+)-7 Hydroxy diester (+)-8 was prepared in 90% yield in the same way as for the preparation of (±)-8. The spectral data of (+)-8 were identical with those of (^)-8. 20 D +53.0 (c 0.32, CHCl3). 3.16. (R)-3-tert-Butyldimethylsiloxy butanoic acid 9 (R)-3-tert-Butyldimethylsiloxy butanoic acid 9 was prepared from methyl (R)-3-hydroxybutanoate in 65% overall yield in the same way as for the preparation of (S)-9. The spectral data of (R)-9 were identical to those of (S)-9. 24 D ^8.6 (c 0.22, CHCl3). 3.17. Ester formation between (+)-8 and (R)-9 Triester (+)-10 was prepared in 88% yield in the same way as for the preparation of (+)-10. The spectral data of (+)-10 were identical to those of (^)-10. 22 D +30.6 (c 0.84, CHCl3). 3.18. Desilylation of (+)-10 Hydroxy triester (+)-11 was prepared in 67% yield in the same way as for the preparation of (+)-11. The spectral data of (+)-11 were identical to those of (^)-11. 24 D +37.0 (c 0.67, CHCl3). 3.19. Dibenzyl ether (+)-13 Dibenzyl ether (+)-13 was prepared in 74% overall yield from (+)-11 in the same way as for the preparation of (^)-13. The spectral data of (+)-13 were identical to those of (^)-13. 21 D +83.6 (c 0.2, CHCl3).
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3.20. (^)-Macrosphelide A 1 (^)-Macrosphelide A 1 was prepared in 84% yield from (+)-13 in the same way as for the preparation of (+)-1 from (^)-13. The spectral data of synthetic (^)-1 were identical to those of (+)-1. Colorless needles; mp 141 C; 22 D ^79.2 (c 0.29, MeOH). Anal. found: C, 56.15; H, 6.55. Calcd for C16H22O8: C, 56.13; H, 6.48%. FAB MS m/z: 343 (M++1). 3.21. Ester formation between (^)-8 and (R)-9 To a mixture of DCC (0.348 g, 1.67 mmol), DMAP (0.041 g, 0.34 mmol) in CH2Cl2 (2 ml) was added a solution of (^)-8 (0.655 g, 1.12 mmol) and (R)-9 (0.367 g, 1.68 mmol) in CH2Cl2 (2 ml) and the reaction mixture was stirred for 1 day at room temperature. After the generated precipitate was ®ltered o, the ®ltrate was washed with 2 M aqueous HCl, 7% aqueous NaHCO3 and saturated brine. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (20 g, n-hexane:AcOEt=15:1) to give (^)-14 (0.787 g, 90%) as a homogenous oil: IR (neat): 1735, 1658 cm^1; 23 D ^43.0 (c 0.27, CHCl3); NMR: 0.05 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.18 (3H, d, J=6 Hz), 1.25 (3H, d, J=7 Hz), 1.32 (3H, d, J=7 Hz), 2.32 (1H, dd, J=6, 15 Hz), 2.49 (1H, dd, J=6, 15 Hz), 4.07 (1H, br. dt, J=1, 6 Hz), 4.19 (1H, br. dt, J=1, 6 Hz), 4.25 (1H, sixtet, J=6 Hz), 4.48, 4.54, 4.63, 4.68 (each 1H, d, J=12 Hz), 4.80, 4.84 (each 1H, d, J=12 Hz), 5.05 (1H, dq, J=6, 7 Hz), 5.15 (1H, dq, J=6, 7 Hz), 6.08 (1H, br. d, J=16 Hz), 6.24 (1H, br. d, J=16 Hz), 6.85 (1H, dd, J=6, 16 Hz), 7.05 (1H, dd, J=6, 16 Hz), 7.27±7.38 (10H, m). Anal. found: C, 58.04; H, 6.41. Calcd for C38H51O9SiCl3: C, 58.05; H, 6.54%. 3.22. Desilylation of (^)-14 A mixture of (^)-14 (0.64 g, 0.81 mmol) in the mixed solvent (AcOH (3 ml), H2O (1.5 ml) and THF (1.5 ml)) was stirred for 12 h at 80 C. The reaction mixture was evaporated, and the residue was diluted with H2O and extracted with Et2O. The organic layer was washed with 7% aqueous NaHCO3 and dried over MgSO4 then evaporated to give a crude residue, which was chromatographed on silica gel (20 g, n-hexane:AcOEt=5:1) to give (^)-15 (0.47 g, 86%) as a homogeneous oil: IR (neat): 1734, 1658 cm^1; 23 D ^60.4 (c 0.54, CHCl3); NMR: 1.19 (3H, d, J=6 Hz), 1.24 (3H, d, J=7 Hz), 1.32 (3H, d, J=7 Hz), 2.38 (1H, dd, J=8, 16 Hz), 2.43 (1H, dd, J=4, 16 Hz), 2.93 (1H, br. s), 4.04 (1H, ddd, J=2, 5, 6 Hz), 4.10±4.16 (1H, m), 4.17 (1H, ddd, J=2, 5, 6 Hz), 4.45, 4.53, 4.63, 4.67 (each 1H, d, J=13 Hz), 4.80, 4.84 (each 1H, d, J=12 Hz), 5.11 (1H, dq, J=5, 7 Hz), 5.15 (1H, dq, J=5, 7 Hz), 6.08 (1H, dd, J=2, 16 Hz), 6.24 (1H, dd, J=2, 16 Hz), 6.86 (1H, dd, J=6, 16 Hz), 7.05 (1H, dd, J=6, 16 Hz), 7.28±7.38 (10H, m). 13C NMR: 171.5 (s), 164.6 (s), 163.7 (s), 146.4 (d), 144.0 (d), 137.2 (s), 137.2 (s), 128.4 (d), 128.4 (d), 127.8 (d), 127.6 (d), 127.5 (d), 127.5 (d), 124.0 (d), 122.3 (d), 94.8 (s), 79.4 (d), 79.2 (d), 74.1 (t), 71.9 (t), 71.6 (d), 71.5 (t), 71.3 (d), 64.2 (d), 43.2 (t), 22.4 (q), 15.4 (q), 15.2 (q). Anal. found: C, 56.75; H, 5.61. Calcd for C32H37O9Cl3: C, 57.20; H, 5.55%. FAB MS m/z: 671 (M++1). 3.23. Dibenzyl ether (^)-17 (i) To a mixture of (^)-15 (0.137 g, 0.2 mmol) and an AcOH±AcONa buer solution (2.5 ml) in THF (2 ml) was added Zu dust (0.1 g, 1.5 mmol) at 0 C and the whole mixture was stirred for
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2.5 h at room temperature. The reaction mixture was ®ltered o and the ®ltrate was acidi®ed with 2 M aqueous HCl, extracted with Et2O. The organic layer was dried over MgSO4 then evaporated to give crude seco-acid 16 (0.106 g). (ii) To a solution of 16 (0.106 g) and triethylamine (0.06 g, 0.42 mmol) in THF (2 ml) was added a solution of 2,4,6-trichlorobenzoyl chloride (0.096 g, 0.4 mmol) in THF (1 ml) and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with toluene (100 ml). To a solution of DMAP (0.144 g, 1.2 mmol) in toluene (20 ml) was added dropwise the above-mentioned toluene solution at 100 C and the whole mixture was stirred for 24 h at 100 C. The reaction mixture was washed with 7% aqueous NaHCO3, 2 M aqueous HCl and saturated brine. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (15 g, n-hexane:AcOEt= 4:1) to give (^)-17 (0.084 g, 82% overall yield from (^)-15) as a homogenous oil: IR (neat): 1715, 1657 cm^1; 25 D ^40.7 (c 0.77, CHCl3); NMR: 1.21 (3H, d, J=7 Hz), 1.37 (3H, d, J=7 Hz), 1.40 (3H, d, J=7 Hz), 2.55 (1H, dd, J=7, 15 Hz), 2.75 (1H, dd, J=3, 15 Hz), 3.84 (1H, dt, J=1, 6 Hz), 3.95 (1H, dt, J=1, 6 Hz), 4.40, 4.46, 4.59, 4.62 (each 1H, d, J=12 Hz), 5.09 (1H, quintet, J=7 Hz), 5.17 (1H, quintet, J=7 Hz), 5.26 (1H, ddq, J=3, 7, 7 Hz), 6.00 (1H, dd, J=1, 16 Hz), 6.13 (1H, dd, J=1, 16 Hz), 6.80 (1H, dd, J=7, 16 Hz), 6.84 (1H, dd, J=7, 16 Hz), 7.28±7.30 (10H, m). Anal. found: C, 68.67; H, 6.70. Calcd for C30H34O8: C, 68.95; H, 6.56%. FAB MS m/z: 523 (M++1). 3.24. (+)-Macrosphelide E 2 To a mixture of AlCl3 (0.12g, 0.85 mmol) in CH2Cl2 (4 ml) was added dropwise a solution of (^)-13 (88 mg, 0.17 mmol) in m-xylene (2 ml) at ^20 C and the reaction mixture was stirred for 2 h at 0 C. The reaction mixture was diluted with ice±water and extracted with Et2O. The organic layer was dried over MgSO4 and evaporated to give a crude residue, which was chromatographed on silica gel (20 g, n-hexane:AcOEt=1:1) to give (+)-2 (47 mg, 81%) as a colorless oil: IR (neat): 1 3452, 1717, 1665 cm^1; 22 D +78.5 (c 0.21, EtOH); H NMR: 1.29 (3H, d, J=7 Hz), 1.39 (3H, d, J=7 Hz), 1.40 (3H, d, J=7 Hz), 2.58 (1H, dd, J=7, 16 Hz), 2.73 (1H, dd, J=4, 16 Hz), 3.29 (1H, br. s), 3.52 (1H, br. s), 4.13±4.18 (1H, m), 4.33±4.37 (1H, m), 4.96 (1H, dq, J=5, 7 Hz), 5.11 (1H, dq, J=2, 7 Hz), 5.29 (1H, ddq, J=4, 7, 7 Hz), 6.04 (1H, dd, J=2, 16 Hz), 6.11 (1H, dd, J=2, 16 Hz), 6.80 (1H, dd, J=5.5, 16 Hz), 7.01 (1H, dd, J=4, 16 Hz). 13C NMR: 170.5 (s), 166.3 (s), 165.1 (s), 145.3 (d), 145.0 (d), 122.9 (d), 122.3 (d), 75.7 (d), 75.0 (d), 74.9 (d), 73.6 (d), 66.8 (d), 40.5 (t), 19.7 (q), 17.8 (q), 17.5 (q). Anal. found: C, 56.17; H, 6.34. Calcd for C16H22O8: C, 56.13; H, 6.48%. FAB MS m/z: 343 (M++1). Acknowledgements This work was supported by a Grant-in-Aid for Scienti®c Research (No. 10672002) from the Ministry of Education, Science, Sports and Culture, Japan to H.A. The authors are grateful to Professor Yoshiteru Ida, School of Pharmaceutical Sciences, Showa University for measurement of high resolution mass spectra (FAB MS) of synthetic (+)-Macrosphelide A (1). References 1. (a) Hayashi, M.; Kim, Y.-P.; Hiraoka, H.; Natori, M.; Takamatsu, S.; Kawakubo, T.; Masuma, R.; Komiyama, K.; Omura, S. J. Antibiot. 1995, 48, 1435±1439. (b) Takamatsu, S.; Kim, Y.-P.; Hayashi, M.; Hiraoka, H.; Natori, M.; Komiyama, K.; Omura, S. J. Antibiot. 1996, 49, 95±98.
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2. Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.; Matsumura, E.; Yamori, T.; Tsuruo, T. Tetrahedron Lett. 1997, 38, 8215±8218. 3. Sunazuka, T.; Hirose, T.; Harigaya, Y.; Takamatsu, S.; Hayashi, M.; Komiyama, K.; Omura, S.; Sprengeler, P. A.; Smith III, A. B. J. Am. Chem. Soc. 1997, 119, 10247±10248. 4. Kobayashi, Y.; Kumar, B. G.; Kurachi, T. Tetrahedron Lett. 2000, 41, 1559±1563. 5. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768±2771. 6. Mitsunobu, O. Synthesis 1981, 1±28. 7. (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237±6240. (b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765±5780. 8. Ono, M.; Saotome, C.; Akita, H. Tetrahedron: Asymmetry 1996, 7, 2595±2602. 9. Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394±2395. 10. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989±1993.