Total syntheses of macrosphelides (+)-A, (-)-A and (+)-E

Article abstract of DOI:10.1016/S0957-4166(00)00245-7

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)-4-benzyloxy-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. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00245-7

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)-4-
benzyloxy-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 HL-
60 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 di€erent 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-dihydroxy-
2-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-5-
acetoxy-4-benzyloxy-2(E)-hexenoate 3 using the lipase `Amano P' from Pseudomonas sp. in
phosphate bu€er solution gave the (4R,5S)-5-acetoxy ester 3 (>99% ee, 48% yield) and the
*Corresponding authors. E-mail: akita@phar.toho-u.ac.jp
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00245-7

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M. Ono et al. / Tetrahedron: Asymmetry 11 (2000) 2753±2764
(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 di€erentially 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 a€orded 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), camphor-
sulfonic 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-hydroxy-
butanoate 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 a€orded the desilylated
alcohol (^)-11 ([ꢀ]D ^40.0 (c 0.44, CHCl3)) in 96% yield. Deprotection of (^)-11 using Zn in an
acetic acid bu€er solution followed by subjecting to Yamaguchi macrolactonization10 (2,4,6-tri-
chlorobenzoyl 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 142ꢀC) in 75% yield. Physical data ([ꢀ]D, mp, H and 13C NMR) of synthetic (+)-1
1
were identical with those ([ꢀ]D +84.1 (c 0.59, MeOH), mp 141±142ꢀC) 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.

M. Ono et al. / Tetrahedron: Asymmetry 11 (2000) 2753±2764
2755
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 bu€er; (g) 2,4,6-trichlorobenzoyl
chloride/Et3N/DMAP/toluene; (h) m-xylene/AlCl3/CH2Cl2
Scheme 3.

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M. Ono et al. / Tetrahedron: Asymmetry 11 (2000) 2753±2764
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 142ꢀC) 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 above-
mentioned 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 a€ord
(^)-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 bu€er; (d) 2,4,6-
trichlorobenzoyl 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-5-
hydroxy-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 bombard-
ment 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.

M. Ono et al. / Tetrahedron: Asymmetry 11 (2000) 2753±2764
2757
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 0ꢀC and the
reaction mixture was stirred for 1 h at 0ꢀC 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 0ꢀC 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
24
crude (4R,5S)-5 (3.99 g, 99%) as a colorless oil. ‰ꢀŠ ^22.6 (c 0.59, CHCl3); NMR: 0.03 (3H, s),
D
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 2,2,2-
trichloroethyl (4R,5S)-4-benzyloxy-5-tert-butyldimethylsiloxy-2(E)-hexenoate (3.85 g, 93%) as a
31
colorless oil: IR (neat): 1739 cm^1 (ester); ‰ꢀŠ ^15.6 (c 0.75, CHCl3); NMR: 0.03 (3H, s), 0.05
D
(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
70ꢀC and the whole mixture was again stirred for 3 h at 110ꢀC 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
21
give (4R,5S)-6 (2.68 g, 87%) as a colorless crystal: Mp 62ꢀC; IR (neat): 3477, 1730 cm^1; ‰aŠ
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,

2758
M. Ono et al. / Tetrahedron: Asymmetry 11 (2000) 2753±2764
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,
27
D
12% recovery): IR (neat): 1732 cm^1; ‰ꢀŠ ^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 80ꢀC. 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
21
D
a homogeneous oil: IR (neat): 3472, 1727 cm^1; ‰ꢀŠ ^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 0ꢀC and the reaction
mixture was stirred for 30 min at 0ꢀC 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:

M. Ono et al. / Tetrahedron: Asymmetry 11 (2000) 2753±2764
2759
AcOEt=40:1) to give methyl (S)-3-tert-butyldimethylsiloxy butanoate (3.217 g, 81%) as a
25
colorless oil. ‰ꢀŠ +29.1 (c 0.49, CHCl3); NMR: 0.03 (3H, s), 0.07 (3H, s), 0.86 (9H, s), 1.19 (3H,
D
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 0ꢀC 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
26
a colorless oil. ‰ꢀŠ +8.64 (c 0.22, CHCl3); NMR: 0.06 (3H, s), 0.08 (3H, s), 0.87 (9H, s), 1.22
D
(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 eva-
porated to give a crude residue, which was chromatographed on silica gel (30 g, n-hex-
ane:AcOEt=10:1) to give (^)-10 (0.692 g, 79%) as a homogenous oil: IR (neat): 1735, 1657 cm^1;
24
D
‰ꢀŠ ^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 80ꢀC. 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
23
D
homogeneous oil: IR (neat): 1731, 1657 cm^1; ‰ꢀŠ ^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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M. Ono et al. / Tetrahedron: Asymmetry 11 (2000) 2753±2764
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 bu€er solution (4 ml) in THF
(4 ml) was added a solution of (^)-11 (0.191 g, 0.29 mmol) in THF (2 ml) at 0ꢀC 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
60ꢀC and the whole mixture was stirred for 24 h at 100ꢀC. 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, n-
hexane:AcOEt=10:1) to give (^)-13 (0.104 g, 70% overall yield from (^)-11) as a colorless solid:
22
D
IR (CHCl3): 1722, 1520 cm^1; ‰ꢀŠ ^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 ^20ꢀC and the reaction
mixture was stirred for 2 h at 0ꢀC 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 chromato-
graphed on silica gel (20 g, n-hexane:AcOEt=15:1) to give (+)-1 (23 mg, 75%) as colorless
22
D
ꢀ
1
needles: mp 142 C; IR (KBr): 3438, 1708 cm^1; ‰ꢀŠ +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.

M. Ono et al. / Tetrahedron: Asymmetry 11 (2000) 2753±2764
2761
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
27
D
data of (4S,5R)-5 were identical with those of (4R,5S)-5. ‰ꢀŠ +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
prepared from (4S,5R)-5 in 74% overall yield in the same way as for the preparation of (4R,5S)-
6
was
22
D
6. The spectral data of (4S,5R)-6 were identical with those of (4R,5S)-6; mp 62ꢀC; ‰ꢀŠ +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
22
D
spectral data of (+)-7 were identical to those of (^)-7. ‰ꢀŠ +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
20
D
of (±)-8. The spectral data of (+)-8 were identical with those of (^)-8. ‰ꢀŠ +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-hydroxy-
butanoate in 65% overall yield in the same way as for the preparation of (S)-9. The spectral data
24
D
of (R)-9 were identical to those of (S)-9. ‰ꢀŠ ^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
22
D
spectral data of (+)-10 were identical to those of (^)-10. ‰ꢀŠ +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
24
D
of (+)-11. The spectral data of (+)-11 were identical to those of (^)-11. ‰ꢀŠ +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
21
D
preparation of (^)-13. The spectral data of (+)-13 were identical to those of (^)-13. ‰ꢀŠ +83.6 (c
0.2, CHCl3).

2762
M. Ono et al. / Tetrahedron: Asymmetry 11 (2000) 2753±2764
3.20. (^)-Macrosphelide A 1
(^)-Macrosphelide A 1 was prepared in 84% yield from (+)-13 in the same way as for the pre-
paration of (+)-1 from (^)-13. The spectral data of synthetic (^)-1 were identical to those of (+)-1.
22
D
Colorless needles; mp 141ꢀC; ‰ꢀŠ ^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
23
D
(0.787 g, 90%) as a homogenous oil: IR (neat): 1735, 1658 cm^1; ‰ꢀŠ ^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 80ꢀC. 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 chromato-
graphed on silica gel (20 g, n-hexane:AcOEt=5:1) to give (^)-15 (0.47 g, 86%) as a homogeneous
23
D
oil: IR (neat): 1734, 1658 cm^1; ‰ꢀŠ ^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 bu€er solution (2.5 ml) in
THF (2 ml) was added Zu dust (0.1 g, 1.5 mmol) at 0ꢀC and the whole mixture was stirred for

M. Ono et al. / Tetrahedron: Asymmetry 11 (2000) 2753±2764
2763
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 100ꢀC and the
whole mixture was stirred for 24 h at 100ꢀC. 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,
25
D
1657 cm^1; ‰ꢀŠ ^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 ^20ꢀC and the reaction mixture was stirred for 2 h
at 0ꢀC. 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):
22
D
1
3452, 1717, 1665 cm^1; ‰ꢀŠ +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).
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