Formal total synthesis of (+)-macrosphelide A based on regioselective hydrolysis using lipase.

Article abstract of DOI:10.1248/cpb.50.692

Three kinds of seco-macrosphelide A congeners, (4R,5S,10R,11S,15S)-6, (4R,5S,9S,14R,15S)-7 and (3S,8R,9S,14R,15S)-8 were chemically synthesized, and they were exposed to the lipase OF-360 from Candida rugosa to give three hydroxy carboxylic acids, respectively. Macrolactonization of the hydroxy acid (4R,5S,10R,11S)-18 derived from (4R,5S,10R,11S,15S)-6 gave 12-membered lactone (19) in 47% overall yield from 6, while that of the seco-acid (4) derived from (4R,5S,9S,14R,15S)-7 afforded (-)-dibenzyl macrosphelide A (25) in 27% overall yield from 7. Macrolactonization of the hydrolysis product, seco-acid (5) derived from (3S,8R,9S,14R,15S)-8, provided (-)-dibenzyl macrosphelide A (25) (5% overall yield from 8) and 12-membered lactone (19) (20% overall yield from 8) concurrently.

Full text of DOI:10.1248/cpb.50.692

692
Notes
Chem. Pharm. Bull. 50(5) 692—696 (2002)
Vol. 50, No. 5
Formal Total Synthesis of (؉)-Macrosphelide A Based on Regioselective
Hydrolysis Using Lipase
Machiko ONO, Hiroshi NAKAMURA, Satoko ARAKAWA, Naoko HONDA, and Hiroyuki AKITA*
School of Pharmaceutical Sciences, Toho University; 2–2–1 Miyama, Funabashi, Chiba 274–8510, Japan.
Received January 7, 2002; accepted January 30, 2002
Three kinds of seco-macrosphelide A congeners, (4R,5S,10R,11S,15S)-6, (4R,5S,9S,14R,15S)-7 and (3S,8R,
9S,14R,15S)-8 were chemically synthesized, and they were exposed to the lipase OF-360 from Candida rugosa to
give three hydroxy carboxylic acids, respectively. Macrolactonization of the hydroxy acid (4R,5S,10R,11S)-18 de-
rived from (4R,5S,10R,11S,15S)-6 gave 12-membered lactone (19) in 47% overall yield from 6, while that of the
seco-acid (4) derived from (4R,5S,9S,14R,15S)-7 afforded (؊)-dibenzyl macrosphelide A (25) in 27% overall yield
from 7. Macrolactonization of the hydrolysis product, seco-acid (5) derived from (3S,8R,9S,14R,15S)-8, provided
(؊)-dibenzyl macrosphelide A (25) (5% overall yield from 8) and 12-membered lactone (19) (20% overall yield
from 8) concurrently.
Key words macrosphelide A; enzymatic hydrolysis; total synthesis; Keck condensation
(ϩ)-Macrosphelide A (1), isolated from the culture broth sible.
of Microsphaeropsis sp. FO-5050 by Omura and co-workers,
In addition, we reported that the enantioselective hydroly-
has been shown to strongly inhibit the adhesion of human sis of (Ϯ)-(4,5)-anti-5-acetoxy-4-benzyloxy-2(E)-hexenoate
leukemia HL-60 cells to human umbilical-vein endothelial (9) using the lipase “Amano P” from Pseudomonas sp. in
cells (HUVEC) in a dose-dependent fashion.1,2) It is the first phosphate buffer solution gave the (4R,5S)-5-acetoxy ester
16-membered ring antibiotic involving three lactone link- (9) (Ͼ99% ee, 48% yield) and the (4S,5R)-5-hydroxy ester
ages.1,2) We reported the total synthesis of (ϩ)-macrosphe- (10) (Ͼ99% ee, 44% yield), and methanolysis of (4R,5S)-9
lide A (1) involving macrolactonization of a seco-acid (2) provided the (4R,5S)-10 in 84% yield.4) Silylation (98%
derived from the corresponding 2,2,2-trichloroethyl ester yield) of (4R,5S)-10 using tert-butyldimethylsilyl chloride
(4R,5S,10R,11S,15S)-3.3) In this synthesis, a three ester moi- (TBDMSCl), followed by hydrolysis (99% yield), gave the
ety in the substrate 3 was differentiated, and a 2,2,2- desired carboxylic acid (4R,5S)-11 in 97% overall yield.3)
trichloroethyl group was deprotected in the presence of Zn in
Model Experiments for Lipase-Catalysed Hydrolysis of
acetic acid buffer solution to afford a seco-acid (2). Now we Diesters (4R,5S,10R,11S)-12, (4R,5S,9S)-13 and (3S,8R,9S)-
have examined whether the synthesis of three kinds of seco- 14 As model experiments, lipase-catalyzed hydrolyses of
acids, (2), (4) and (5), from three corresponding triesters diesters 12, 13 and 14 were carried out in order to check the
(4R,5S,10R,11S,15S)-6, (3S,8R,9S,14R,15S)-7 and (4R,5S,9S, hydrolysis site of two ester moieties in the substrate. Conden-
14R,15S)-8, respectively, under a lipase-catalysed hydrolysis sation of a secondary alcohol (4R,5S)-104) and carboxylic
condition and formal synthesis of (ϩ)-macrosphelide A (1) acid (4R,5S)-113) via the Keck procedure5) (dicyclohexylcar-
from a seco-acid (2 or 4 or 5) via macrolactonization is pos- bodiimide (DCC), 4-(dimethylamino)pyridine (DMAP), cam-
Fig. 1
Chart 1
To whom correspondence should be addressed. e-mail: akita@phar.toho-u.ac.jp
© 2002 Pharmaceutical Society of Japan

May 2002
693
Chart 2
phorsulfonic acid (CSA)) provided diester (4R,5S,10R,11S)- vided triester (4R,5S,10R,11S,15S)-23 in 70% yield, which
15 in 57% yield, which was desilylated to yield hydroxy-di- was desilylated to yield hydroxy-triester (4R,5S,10R,11S,
ester (4R,5S,10R,11S)-12 in 67% yield. A second condensa- 15S)-6 in 82% yield. A second condensation of secondary al-
tion of carboxylic acid (S)-163) and (4R,5S)-10 via the Keck cohol (4R,5S,9S)-13 and (4R,5S)-11 via the Keck procedure
procedure afforded diester (4R,5S,9S)-17 in 83% yield, which afforded triester (4R,5S,9S,14R,15S)-24 in 53% yield, which
was desilylated to yield hydroxy-diester (4R,5S,9S)-13 in was desilylated to yield a hydroxy-triester (4R,5S,9S,14R,
69% yield. In order to find the most effective lipase for the 15S)-7 in 56% yield. An exposure of (4R,5S,10R,11S,15S)-6
hydrolysis of the a,b-unsaturated ester moiety, compound with lipase OF-360, followed by subjection to Yamaguchi
(Ϯ)-10 was selected as a model substrate, and screening ex- macrolactonization, provided a 12-membered lactone (19) in
periments using several kinds of lipases were carried out. 47% overall yield from 6, of which the physical data (1H-
Among them, lipase OF-360 from Candida rugosa was NMR and [a]D) were identical with those reported for 19.7)
found to be effective. The exposure of (4R,5S,10R,11S)-12 In this case, no preparation of (S)-3-hydroxybutanoic acid
with lipase OF-360, followed by subjection to Yamaguchi was observed from the organic layer. The second substrate,
macrolactonization6) (2,4,6-trichlorobenzoyl chloride, Et3N, (4R,5S,9S,14R,15S)-7, was treated with the lipase OF-360 to
DMAP) provided a 12-membered lactone (19) in 62% over- give a mixture of seco-acid (4) , hydroxy-acid (21) and the
all yield, of which the physical data were identical with those starting material 7. No preparation of (S)-3-hydroxybutanoic
(1H-NMR) of the reported 19.7) Ester cleavage in the sub- acid was observed from the organic layer, and preparation of
strate 12 was found to occur at the outer ester moiety. The the hydroxy acid (3S,8R,9S)-22 was not clear. This mixture
second substrate, (4R,5S,9S)-13, was treated with the lipase was subjected to Yamaguchi macrolactonization to give (Ϫ)-
OF-360 to give the desired hydroxy carboxylic acid dibenzyl macrosphelide A (25) ([a]D Ϫ93.6° (cϭ0.47,
(4R,5S,9S)-20, along with hydroxy carboxylic acid (4R,5S)- CHCl3)) in 27% overall yield from (4R,5S,9S,14R,15S)-7),
21. The preparation of (S)-3-hydroxybutanoic acid was not along with starting material 7 (14% recovery). The spectral
observed from the organic layer because this acid could be data (1H-, 13C-NMR and [a]D) of (Ϫ)-25 were identical with
easily soluble in the water layer. This result showed that ester those ([a]D Ϫ75.9° (cϭ0.34, CHCl3)) reported for (Ϫ)-25.3)
cleavage occurred at both outer and inner ester moieties. The Finally, deprotection of the benzyl group in (Ϫ)-25 using
third substrate, (3S,8R,9S)-14,8) was again treated with the li- AlCl3 in the presence of m-xylene4) was reported to give (ϩ)-
pase OF-360 to afford the corresponding acid (3S,8R,9S)-22, macrosphelide A (1).3) The third substrate, (3S,8R,9S,14R,
and ester cleavage was found to occur at the outer ester 15S)-8,8) was treated with the lipase OF-360 to afford a mix-
moiety. In the case of diesters (4R,5S,10R,11S)-12 and ture of seco-acid (5) and starting material 8. This mixture
(3S,8R,9S)-14, selective hydrolysis of the methyl ester oc- was subjected to Yamaguchi macrolactonization to give 12-
curred in the presence of lipase OF-360.
membered lactone (19) (20% overall yield from 8), (Ϫ)-
Lipase-Catalysed Hydrolysis of Triesters (4R,5S,10R, dibenzyl macrosphelide A (25) ([a]D Ϫ82.9° (cϭ0.25,
11S,15S)-6, (4R,5S,9S,14R,15S)-7 and (3S,8R,9S,14R,15S)- CHCl3) in 5% overall yield from 8), along with starting ma-
8
The condensation of secondary alcohol (4R,5S,10R,11S)- terial 8 (27% recovery). The preparation of 19 could be ex-
12 and carboxylic acid (S)-16 via the Keck procedure pro- plained by the fact that chemically synthesized seco-acid (5)

694
Vol. 50, No. 5
Chart 3
evaporated to give a crude residue, which was chromatographed on silica gel
(50 g) to give (4R,5S,10R,11S)-15 (2.206 g, 57%) as a homogenous oil from
n-hexane : AcOEtϭ10 : 1 eluate, and (4R,5S)-10 (1.007 g, 40% recovery)
was subjected to Yamaguchi macrolactonization to give (Ϫ)-
dibenzyl macrosphelide A (25) (18%) and 12-membered lac-
tone (19) (63%).7)
was recovered from n-hexane : AcOEtϭ5 : 1 eluate. (4R,5S,10R,11S)-15; IR
1
In conclusion, the lipase-catalysed hydrolysis of three (neat): 2931, 1726, 1659 cmϪ1; [a]D22 Ϫ29.3° (cϭ1.41, CHCl3); H-NMR: d
0.05 (3H, s), 0.07 (3H, s), 0.89 (9H, s), 1.23 (3H, d, Jϭ6 Hz), 1.31 (3H, d,
Jϭ6 Hz), 3.76 (3H, s), 3.79 (1H, ddd, Jϭ2, 6, 6 Hz), 3.88 (1H, quintet,
Jϭ6 Hz), 4.13 (1H, ddd, Jϭ2, 4, 6 Hz), 4.47, 4.52, 4.63, 4.66 (each 1H, d,
Jϭ12 Hz), 5.16 (1H, dq, Jϭ4, 6 Hz), 6.07 (1H, dd, Jϭ2, 16 Hz), 6.15 (1H,
kinds of seco-macrosphelide A congeners, (4R,5S,10R,11S,
15S)-6, (4R,5S,9S,14R,15S)-7 and (3S,8R,9S,14R,15S)-8,
gave hydroxy carboxylic acids, respectively. The results were
different in all cases. Macrolactonization of the hydroxy acid
(4R,5S,10R,11S)-18 derived from (4R,5S,10R,11S,15S)-6
gave a 12-membered lactone (19) in 47% overall yield from
6, while that of the seco-acid (4) derived from (4R,5S,9S,
14R,15S)-7 afforded (Ϫ)-dibenzyl macrosphelide A (25) in
27% overall yield from 7. Macrolactonization of the hydroly-
sis products, seco-acid (5) derived from (3S,8R,9S,14R,15S)-
8, provided (Ϫ)-dibenzyl macrosphelide A (25) (5% overall
yield from 8) and 12-membered lactone (19) (20% overall
yield from 8), concurrently.
dd, Jϭ2, 16 Hz), 6.91 (1H, dd, Jϭ6, 16 Hz), 6.95 (1H, dd, Jϭ6, 16 Hz),
7.25—7.42 (10H, m). Anal. Found: C, 67.84; H, 8.15. Calcd for C33H46O7Si:
C, 68.01; H, 7.96%. ESI-MS m/z; 600 (MϩϩNH4ϩ).
Desilylation of (4R,5S,10R,11S)-15 A mixture of (4R,5S,10R,11S)-15
(2.206 g, 3.79 mmol) in the mixed solvent (AcOH (10 ml), H2O (5 ml) and
tetrahydrofuran (THF, 5 ml)), was stirred for 12 h at 80 °C. The reaction mix-
ture was evaporated and the residue was diluted with H2O, then extracted
with Et2O. The organic layer was washed with 7% aqueous NaHCO3 and
dried over MgSO4. The organic layer was evaporated to give a crude residue,
which was chromatographed on silica gel (40 g, n-hexane : AcOEtϭ5 : 1) to
give (4R,5S,10R,11S)-12 (1.187 g, 67%) as a homogeneous oil. (4R,5S,
10R,11S)-12; IR (neat): 3479, 1720, 1657 (sh) cmϪ1; [a]D21 Ϫ53.7° (cϭ0.40,
CHCl3); 1H-NMR: d: 1.16 (3H, d, Jϭ6 Hz), 1.30 (3H, d, Jϭ6 Hz), 3.76 (3H,
s), 3.92 (1H, ddd, Jϭ2, 4, 6 Hz), 3.96 (1H, dq, Jϭ4, 6 Hz), 4.10 (1H, ddd,
Jϭ2, 4, 6 Hz), 4.41, 4.42, 4.63, 4.64 (each 1H, d, Jϭ12 Hz), 5.13 (1H, dq,
Jϭ4, 6 Hz), 6.07 (1H, dd, Jϭ2, 16 Hz), 6.12 (1H, dd, Jϭ2, 16 Hz), 6.88 (1H,
dd, Jϭ6, 16 Hz), 6.92 (1H, dd, Jϭ6, 16 Hz), 7.25—7.38 (10H, m). 13C-
NMR: d 15.3 (q), 18.1 (q), 51.7 (q), 69.2 (d), 71.4 (t), 71.5 (t), 71.6 (d), 79.4
(d), 81.8 (d), 123.7 (d), 124.2 (d), 127.4 (d), 127.6 (d), 127.6 (d), 127.7 (d),
128.2 (d), 128.3 (d), 137.4 (s), 137.4 (s), 143.9 (d), 144.5 (d), 164.6 (s),
165.9 (s). Anal. Found: C, 69.18; H, 7.07. Calcd for C27H32O7: C, 69.21; H,
6.88%. FAB MS m/z; 469 (Mϩϩ1).
Ester Formation between (4R,5S)-10 and (S)-16 To a mixture of DCC
(2.01 g, 9.7 mmol), DMAP (1.59 g, 13.0 mmol) and (ϩ)-CSA (1.51 g,
6.5 mmol) in CH2Cl2 (50 ml), was added a solution of (4R,5S)-10 (1.685 g,
6.7 mmol) and (S)-16 (1.68 g, 7.7 mmol) in CH2Cl2 (5 ml) and the reaction
mixture was stirred for 2 d at room temperature. Afterwards, the generated
precipitate was filtered off and the filtrate 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) to give (4R,5S,9S)-17 (2.50 g, 83%) as a homogenous oil from n-
Experimental
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 de-
grees 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 Thermo-
Quest LCQ , respectively. IR spectra were recorded on a JASCO FT/IR-300
spectrometer. Optical rotations were measured with a JASCO DIP-370 digi-
tal polarimeter. All evaporations were performed under reduced pressure.
For column chromatography, silica gel (Kieselgel 60) was employed.
Ester Formation between (4R,5S)-11 and (4R,5S)-10 To a mixture of
DCC (2.04 g, 9.9 mmol), DMAP (1.61 g, 13.2 mmol) and (ϩ)-CSA (1.53 g,
6.6 mmol) in CH2Cl2 (50 ml) was added a solution of (4R,5S)-11 (2.179 g,
6.6 mmol) and (4R,5S)-10 (2.483 g, 9.9 mmol) in CH2Cl2 (15 ml), and this
reaction mixture was stirred for 2 d at room temperature. After the generated
precipitate was filtered off and the filtrate was washed with 2 M aqueous HCl
and 7% aqueous NaHCO3. The organic layer was dried over MgSO4 and

May 2002
695
hexane : AcOEtϭ10 : 1 eluate. (4R,5S,9S)-17; IR (neat): 1733, 1660 cmϪ1
;
with saturated brine and dried over MgSO4. The ether layer was evaporated
to give a seco-acid (3S,8R,9S)-22 (0.166 g), which was subjected to NMR
analysis. (3S,8R,9S)-22; 1H-NMR d: 1.13 (3H, d, Jϭ7 Hz), 1.33 (3H, d, Jϭ6
Hz), 2.54 (1H, dd, Jϭ6, 16 Hz), 2.70 (1H, dd, Jϭ6, 16 Hz), 3.87 (1H, ddd,
Jϭ2, 4, 6 Hz), 3.92 (1H, dq, Jϭ4, 7 Hz), 4.38, 4.60 (each 1H, d, Jϭ12 Hz),
5.31 (1H, sextet, Jϭ6 Hz), 6.02 (1H, dd, Jϭ2, 16 Hz), 6.88 (1H, dd, Jϭ6, 16
Hz), 7.24—7.35 (5H, m).
[a]D23 Ϫ24.8° (cϭ0.71, CHCl3); 1H-NMR: d: 0.02 (3H, s), 0.04 (3H, s), 0.84
(9H, s), 1.16, 1.21 (each 3H, d, Jϭ6 Hz), 2.32, 2.45 (each 1H, dd, Jϭ6,
16 Hz), 3.74 (3H, s), 4.02 (1H, ddd, Jϭ2, 4, 6 Hz), 4.22 (1H, sextet,
Jϭ6 Hz), 4.45, 4.60 (each 1H, d, Jϭ12 Hz), 5.02 (1H, dq, Jϭ4, 6 Hz), 6.08
(1H, dd, Jϭ2, 16 Hz), 6.83 (1H, dd, Jϭ6, 16 Hz), 7.21—7.37 (5H, m). Anal.
Found: C, 63.86; H, 8.57. Calcd for C24H38O6Si: C, 63.97; H, 8.50%. FAB
MS m/z; 451 (Mϩϩ1).
Ester Formation between (4R,5S,10R,11S)-12 and (S)-16 To a mix-
ture of DCC (1.58 g, 7.7 mmol), DMAP (1.25 g, 10.2 mmol) and (ϩ)-CSA
Desilylation of (4R,5S,9S)-17 A mixture of (4R,5S,9S)-17 (2.50 g,
5.55 mmol) in the mixed solvent (AcOH (15 ml), H2O (10 ml) and THF
(10 ml)) was stirred for 1 d at 80 °C. The reaction mixture was evaporated
and the residue was diluted with H2O, then extracted with Et2O. The organic
layer was washed with 7% aqueous NaHCO3 and dried over MgSO4. The or-
ganic layer was evaporated to give a crude residue, which was chro-
matographed on silica gel (40 g, n-hexane : AcOEtϭ5 : 1) to give (4R,5S,9S)-
13 (1.28 g, 69%) as a homogeneous oil. (4R,5S,9S)-13; IR (neat): 3498,
(1.03 g, 4.4 mmol) in CH2Cl2 (50 ml) was added
a solution of
(4R,5S,10R,11S)-12 (1.570 g, 3.4 mmol) and (S)-16 (1.156 g, 7.19 mmol) in
CH2Cl2 (20 ml), and the reaction mixture was stirred for 2 d at room temper-
ature. Afterwards, the generated precipitate was filtered off and the filtrate
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 (80 g, n-hexane : AcOEtϭ10 : 1) to give
(4R,5S,10R,11S,15S)-23 (1.566 g, 70%) as a homogenous oil. (4R,5S,10R,
11S,15S)-23; IR (neat): 1729, 1658 (sh) cmϪ1; [a]D26 Ϫ36.5° (cϭ0.46,
1
1727 cmϪ1; [a]D21 Ϫ47.5° (cϭ0.30, CHCl3); H-NMR: d: 1.21, 1.25 (each
3H, d, Jϭ6 Hz), 2.38 (1H, dd, Jϭ6, 16 Hz), 2.47 (1H, dd, Jϭ4, 16 Hz), 2.93
(1H, br s), 3.77 (3H, s), 4.03 (1H, ddd, Jϭ2, 4, 6 Hz), 4.13—4.20 (1H, m),
4.45, 4.64 (each 1H, d, Jϭ12 Hz), 5.11 (1H, dq, Jϭ4, 6 Hz), 6.10 (1H, dd,
Jϭ2, 16 Hz), 6.86 (1H, dd, Jϭ6, 16 Hz), 7.26—7.41 (5H, m). 13C-NMR: d
15.4 (q), 22.6 (q), 43.2 (t), 51.8 (q), 64.4 (d), 71.4 (d), 71.5 (t), 79.3 (d),
124.0 (d), 127.5 (d), 127.6 (d), 128.3 (d), 137.3 (s), 143.6 (d), 165.9 (s),
171.8 (s). Anal. Found: C, 63.83; H, 7.33. Calcd for C18H24O6: C, 64.27; H,
7.19%. FAB MS m/z; 337 (Mϩϩ1).
1
CHCl3); H-NMR: d: 0.04 (3H, s), 0.06 (3H, s), 0.86 (9H, s), 1.18 (3H, d,
Jϭ6 Hz), 1.22 (3H, d, Jϭ6 Hz), 1.28 (3H, d, Jϭ6 Hz), 2.37 (1H, dd, Jϭ6,
15 Hz), 2.47 (1H, dd, Jϭ6, 15 Hz), 3.75 (3H, s), 4.08 (1H, ddd, Jϭ2, 4,
6 Hz), 4.10 (1H, ddd, Jϭ2, 4, 6 Hz), 4.24 (1H, sextet, Jϭ6 Hz), 4.44, 4.45,
4.61, 4.63 (each 1H, d, Jϭ12 Hz), 5.03 (1H, dq, Jϭ4, 6 Hz), 5.10 (1H, dq,
Jϭ4, 6 Hz), 6.08 (1H, dd, Jϭ2, 16 Hz), 6.12 (1H, dd, Jϭ2, 16 Hz), 6.83 (1H,
dd, Jϭ6, 16 Hz), 6.88 (1H, dd, Jϭ6, 16 Hz), 7.24—7.39 (10H, m). Anal.
Found: C, 66.03; H, 8.12. Calcd for C37H52O9Si: C, 66.44; H, 7.84%. ESI-
MS m/z; 669 (Mϩϩ1), 691 (MϩϩNa).
Lipase-Catalysed Hydrolysis of (4R,5S,10R,11S)-12 Followed by
Macrolactonization A suspension of (4R,5S,10R,11S)-12 (0.198 g, 0.42
mmol) and lipase OF-360 (400 mg) in 0.1 M phosphate buffer solution
(20 ml) was stirred for 10 d at 35 °C, and the reaction mixture was filtered
off with the aid of celite. The filtrate was acidified with 2 M aqueous HCl 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 seco-acid
(4R,5S,10R,11S)-18 (0.181 g), which was subjected to NMR analysis.
(4R,5S,10R,11S)-18; 1H-NMR: d: 1.17 (3H, d, Jϭ7 Hz), 1.30 (3H, d,
Jϭ7 Hz), 3.93 (1H, ddd, Jϭ2, 4, 6 Hz), 3.97 (1H, dq, Jϭ4, 7 Hz), 4.13 (1H,
ddd, Jϭ2, 4, 6 Hz), 4.41, 4.51, 4.64, 4.66 (each 1H, d, Jϭ12 Hz), 5.14 (1H,
dq, Jϭ4, 7 Hz), 6.07 (1H, dd, Jϭ2, 16 Hz), 6.13 (1H, dd, Jϭ2, 16 Hz), 6.92
(1H, dd, Jϭ6, 16 Hz), 6.99 (1H, dd, Jϭ6, 16 Hz), 7.27—7.39 (10H, m). To a
solution of (4R,5S,10R,11S)-18 (0.181 g, 0.4 mmol) in toluene (2 ml) was
added triethylamine (0.05 g, 0.48 mmol) and 2,4,6-trichlorobenzoyl chloride
(0.097 g, 0.4 mmol), and the reaction mixture was stirred for 3 h at room
temperature. To a solution of DMAP (0.29 g, 2.39 mmol) in toluene (150 ml)
was added dropwise a solution of the above-mentioned reaction mixture in
toluene (20 ml) at 60 °C with stirring, and the whole mixture was stirred for
2 d at 60 °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, n-hexane : AcOEtϭ20 : 1) to give (Ϫ)-19 (0.11 g, 62%
overall yield from (4R,5S,10R,11S)-12) as a colorless solid. (Ϫ)-19; IR
(neat): 1726, 1647 cmϪ1; [a]D27 Ϫ161.0° (cϭ0.36, CHCl3); 1H-NMR: d: 1.43
(6H, d, Jϭ6 Hz), 3.69 (2H, t, Jϭ9 Hz), 4.35, 4.62 (each 2H, d, Jϭ12 Hz),
5.11 (2H, qd, Jϭ6, 9 Hz), 5.94 (2H, d, Jϭ16 Hz), 6.52 (2H, dd, Jϭ9, 16 Hz),
7.26—7.37 (10H, m). Anal. Found: C, 71.49; H, 6.57. Calcd for C26H28O6:
C, 71.54; H, 6.47%. FAB MS m/z; 437 (Mϩϩ1).
Desilylation of (4R,5S,10R,11S,15S)-23 A mixture of (4R,5S,10R,11S,
15S)-23 (1.566 g, 2.39 mmol) in the mixed solvent (AcOH (7.5 ml), H2O
(5 ml) and THF (5 ml)) was stirred for 12 h at 80 °C. The reaction mixture
was evaporated and the residue was diluted with H2O, then extracted with
Et2O. The organic layer was washed with 7% aqueous NaHCO3 and dried
over MgSO4. The organic layer was evaporated to give a crude residue,
which was chromatographed on silica gel (30 g, n-hexane : AcOEtϭ4 : 1) to
give (4R,5S,10R,11S,15S)-6 (1.063 g, 82%) as a homogeneous oil. (4R,5S,
10R,11S,15S)-6; IR (neat): 3515, 1723, 1658 (sh) cmϪ1; [a]D22 Ϫ53.7°
(cϭ0.40, CHCl3); 1H-NMR: d: 1.18 (3H, d, Jϭ6 Hz), 1.22 (3H, d, Jϭ6 Hz),
1.27 (3H, d, Jϭ6 Hz), 2.35 (1H, dd, Jϭ8, 16 Hz), 2.42 (1H, dd, Jϭ4, 16 Hz),
2.93 (1H, br s), 3.73 (3H, s), 4.01 (1H, ddd, Jϭ2, 4, 6 Hz), 4.08 (1H, ddd,
Jϭ2, 4, 6 Hz), 4.12 (1H, m), 4.43, 4.46, 4.61, 4.63 (each 1H, d, Jϭ12 Hz),
5.07 (1H, dq, Jϭ4, 6 Hz), 5.10 (1H, dq, Jϭ4, 6 Hz), 6.06 (1H, dd, Jϭ2,
16 Hz), 6.11 (1H, dd, Jϭ2, 16 Hz), 6.82 (1H, dd, Jϭ6, 16 Hz), 6.87 (1H, dd,
Jϭ6, 16 Hz), 7.24—7.38 (10H, m). 13C-NMR: d 15.3 (q), 15.4 (q), 22.6 (q),
43.2 (t), 51.7 (q), 64.3 (d), 71.4 (d), 71.5 (t), 71.6 (t), 71.7 (d), 79.3 (d), 79.3
(d), 123.8 (d), 124.2 (d), 127.4 (d), 127.5 (d), 127.6 (d), 127.7 (d), 128.2 (d),
128.2 (d), 137.2 (d), 137.4 (d), 143.7 (d), 143.9 (d), 164.6 (s), 165.8 (s),
171.5 (s). Anal. Found: C, 67.20; H, 7.84. Calcd for C31H38O9: C, 67.13; H,
6.91%. FAB MS m/z; 555 (Mϩϩ1).
Ester Formation between (4R,5S,9S)-13 and (4R,5S)-11 To a mixture
of DCC (1.18 g, 5.7 mmol), DMAP (0.93 g, 7.6 mmol) and (ϩ)-CSA (0.88 g,
3.8 mmol) in CH2Cl2 (45 ml) was added a solution of (4R,5S)-11 (1.601 g,
4.57 mmol) and (4R,5S,9S)-13 (1.280 g, 3.81 mmol) in CH2Cl2 (10 ml), and
the reaction mixture was stirred for 2 d at room temperature. Afterwards, the
generated precipitate was filtered off and the filtrate 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 (50 g, n-hexane : AcOEtϭ10 : 1) to give (4R,5S,9S,14R,15S)-24
(1.355 g, 53%) as a homogenous oil. (4R,5S,9S,14R,15S)-24; IR (neat):
1735, 1650 cmϪ1; [a]D27 Ϫ33.8° (cϭ1.07, CHCl3); 1H-NMR: d: 0.02 (3H, s),
0.04 (3H, s), 0.86 (9H, s), 1.18 (3H, d, Jϭ6 Hz), 1.21 (3H, d, Jϭ6 Hz), 1.32
(3H, d, Jϭ6 Hz), 2.50, 2.67 (each 1H, dd, Jϭ6, 14 Hz), 3.74 (3H, s), 3.75
(1H, ddd, Jϭ2, 6, 6 Hz), 3.82 (1H, dq, Jϭ6, 6 Hz), 4.03 (1H, ddd, Jϭ2, 4,
6 Hz), 4.41, 4.46, 4.58, 4.61 (each 1H, d, Jϭ12 Hz), 5.04 (1H, dq, Jϭ4,
6 Hz), 5.32 (1H, sextet, Jϭ6 Hz), 5.99 (1H, dd, Jϭ2, 16 Hz), 6.10 (1H, dd,
Jϭ2, 16 Hz), 6.84 (1H, dd, Jϭ6, 16 Hz), 6.90 (1H, dd, Jϭ6, 16 Hz), 7.32—
7.40 (10H, m). Anal. Found: C, 66.63; H, 7.90. Calcd for C37H52O9Si: C,
66.44; H, 7.84%.
Lipase-Catalysed Hydrolysis of (4R,5S,9S)-13
A suspension of
(4R,5S,9S)-13 (0.217 g, 0.64 mmol) and lipase OF-360 (400 mg) in 0.1 M
phosphate buffer solution (20 ml) was stirred for 7 d at 35 °C, and the reac-
tion mixture was filtered off with the aid of celite. The filtrate was acidified
with 2 M aqueous HCl and extracted with ether. The ether layer was washed
with saturated brine and dried over MgSO4. The ether layer was evaporated
to give a 1 : 1.4 mixture (0.202 g) of seco-acid (4R,5S,9S)-20 and (4R,5S)-
acid 21, which was subjected to NMR analysis. (4R,5S,9S)-20; 1H-NMR: d:
1.22 (3H, d, Jϭ6 Hz), 1.25 (3H, d, Jϭ6 Hz), 2.40 (1H, dd, Jϭ8, 16 Hz), 2.46
(1H, dd, Jϭ4, 16 Hz), 4.04 (1H, ddd, Jϭ2, 4, 6 Hz), 4.18 (1H, ddq, Jϭ4, 6,
8 Hz), 4.47, 4.64 (each 1H, d, Jϭ12 Hz), 5.12 (1H, dq, Jϭ4, 6 Hz), 6.10 (1H,
1
dd, Jϭ2, 16 Hz), 6.94 (1H, dd, Jϭ6, 16 Hz), 7.28—7.37 (5H, m). 21; H-
NMR: d 1.15 (3H, d, Jϭ7 Hz), 3.93 (1H, ddd, Jϭ2, 4, 6 Hz), 3.97 (1H, dq,
Jϭ4, 6 Hz), 4.42, 4.64 (each 1H, d, Jϭ12 Hz), 6.08 (1H, dd, Jϭ2, 16 Hz),
7.01 (1H, dd, Jϭ6, 16 Hz), 7.28—7.37 (5H, m).
Desilylation of (4R,5S,9S,14R,15S)-24 A mixture of (4R,5S,9S,14R,
15S)-24 (1.100 g, 1.56 mmol) in the mixed solvent (AcOH (8 ml), H2O
(5 ml) and THF (5 ml)) was stirred for 12 h at 80 °C. The reaction mixture
was evaporated and the residue was diluted with H2O, then extracted with
Et2O. The organic layer was washed with 7% aqueous NaHCO3 and dried
over MgSO4. The organic layer was evaporated to give a crude residue,
which was chromatographed on silica gel (20 g, n-hexane : AcOEtϭ5 : 1) to
Lipase-Catalysed Hydrolysis of (3S,8R,9S)-14
A suspension of
(3S,8R,9S)-148) (0.194 g, 0.57 mmol) and lipase OF-360 (300 mg) in 0.1 M
phosphate buffer solution (20 ml) was stirred for 3 d at 35 °C, and the reac-
tion mixture was filtered off with the aid of celite. The filtrate was acidified
with 2 M aqueous HCl and extracted with ether. The ether layer was washed

696
Vol. 50, No. 5
give (4R,5S,9S,14R,15S)-7 (0.473 g, 56%) as a homogeneous oil. (4R,5S,9S,
14R,15S)-7; IR (neat): 3475, 1735 cmϪ1; [a]D24 Ϫ55.7° (cϭ0.38, CHCl3); 1H-
NMR: d: 1.12 (3H, d, Jϭ6 Hz), 1.19 (3H, d, Jϭ6 Hz), 1.32 (3H, d, Jϭ6 Hz),
2.28 (1H, br s), 2.52, 2.65 (each 1H, dd, Jϭ6, 16 Hz), 3.74 (3H, s), 3.86 (1H,
ddd, Jϭ2, 4, 6 Hz), 3.91 (1H, dq, Jϭ4, 6 Hz), 4.01 (1H, ddd, Jϭ2, 4, 6 Hz),
4.37, 4.43, 4.59, 4.60 (each 1H, d, Jϭ12 Hz), 5.03 (1H, dq, Jϭ4, 6 Hz), 5.31
(1H, sextet, Jϭ6 Hz), 6.00 (1H, dd, Jϭ2, 16 Hz), 6.08 (1H, dd, Jϭ2, 16 Hz),
6.82 (1H, dd, Jϭ6, 16 Hz), 6.87 (1H, dd, Jϭ6, 16 Hz), 7.24—7.38 (10H, m).
13C-NMR: d: 15.2 (q), 18.2 (q), 19.8 (q), 41.0 (t), 51.8 (q), 67.6 (d), 69.0
(d), 71.2 (d), 71.4 (t), 71.6 (t), 79.3 (d), 81.9 (d), 123.8 (d), 124.2 (d), 127.5
(d), 127.5 (d), 127.6 (d), 127.7 (d), 128.2 (d), 128.3 (d), 137.3 (s), 137.4 (s),
143.6 (d), 144.2 (d), 164.6 (s), 165.8 (s), 169.0 (s). Anal. Found: C, 67.25;
H, 7.04. Calcd for C31H38O9: C, 67.13; H, 6.91%. FAB MS m/z; 555
(Mϩϩ1).
Lipase-Catalysed Hydrolysis of (4R,5S,10R,11S,15S)-6 Followed by
Macrolactonization A suspension of (4R,5S,10R,11S,15S)-6 (0.171 g, 0.3
mmol) and lipase OF-360 (300 mg) in 0.1 M phosphate buffer solution (40
ml) was stirred for 8 d at 35 °C, and the reaction mixture was filtered off
with the aid of celite. The filtrate was acidified with 2 M aqueous HCl 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 seco-acid
(4R,5S,10R,11S)-18 (0.14 g), which was subjected to NMR analysis. (4R,5S,
10R,11S)-18; 1H-NMR: d: 1.17 (3H, d, Jϭ7 Hz), 1.30 (3H, d, Jϭ7 Hz), 3.93
(1H, ddd, Jϭ2, 4, 6 Hz), 3.97 (1H, dq, Jϭ4, 7 Hz), 4.13 (1H, ddd, Jϭ2, 4, 6
Hz), 4.41, 4.51, 4.64, 4.66 (each 1H, d, Jϭ12 Hz), 5.14 (1H, dq, Jϭ4, 7 Hz),
6.07 (1H, dd, Jϭ2, 16 Hz), 6.13 (1H, dd, Jϭ2, 16 Hz), 6.92 (1H, dd, Jϭ6,
16 Hz), 6.99 (1H, dd, Jϭ6, 16 Hz), 7.27—7.39 (10H, m).
To a solution of crude (4R,5S,10R,11S)-18 (0.14 g, 0.31 mmol) in toluene
(2 ml) was added triethylamine (0.03 g, 0.37 mmol) and 2,4,6-trichloroben-
zoyl chloride (0.075 g, 0.31 mmol), and the reaction mixture was stirred for
2 h at room temperature under argon atmosphere. To a solution of DMAP
(0.23 g, 1.85 mmol) in toluene (200 ml) was added dropwise a solution of the
above-mentioned reaction mixture in toluene (30 ml) at 60 °C with stirring,
and the whole mixture was stirred for 3 d at 60 °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, n-hexane : AcOEtϭ
10 : 1) to give (Ϫ)-19 (0.063 g, 47% overall yield from (4R,5S,10R,11S,15S)-
6, [a]D25 Ϫ165.1° (cϭ0.24, CHCl3)). The spectral data (1H-NMR and [a]D)
were identical with those of above-mentioned (Ϫ)-19.
was chromatographed on silica gel (20 g, n-hexane : AcOEtϭ10 : 1) to give
macrosphelide A dibenzyl ether (25) (0.042 g, 27% overall yield from
(4R,5S,9S,14R,15S)-7, [a]D22 Ϫ93.6° (cϭ0.47, CHCl3)) from n-hexane :
AcOEtϭ10 : 1 eluate and recovery (4R,5S,9S,14R,15S)-7 (0.023 g, 14% re-
covery) from n-hexane : AcOEtϭ1 : 1 eluate. The spectral data (1H-NMR
and [a]D) of macrosphelide A dibenzyl ether (25) were identical with those
([a]D22 Ϫ75.9° (cϭ0.34, CHCl3)) of the reported (Ϫ)-25.2)
Lipase-Catalysed Hydrolysis of (3S,8R,9S,14R,15S)-8 Followed by
Macrolactonization A suspension of (3S,8R,9S,14R,15S)-8 (0.205 g, 0.37
mmol) and lipase OF-360 (400 mg) in 0.1 M phosphate buffer solution (40
ml) was stirred for 10 d at 35 °C, and the reaction mixture was filtered off
with the aid of celite. The filtrate was acidified with 2 M aqueous HCl and
extracted with ether. The ether layer was washed with saturated brine and
dried over MgSO4. The ether layer was evaporated to give a mixture
(0.185 g) of seco-acid (3S,8R,9S,14R,15S)-5 and starting material (3S,8R,9S,
14R,15S)-8, which was subjected to NMR analysis. 5 : 8ϭ2.5 : 1 (3S,8R,9S,
1
14R,15S)-5; H-NMR d: 1.15 (3H, d, Jϭ6 Hz), 1.29 (3H, d, Jϭ6 Hz), 1.32
(3H, d, Jϭ6 Hz), 2.54 (1H, dd, Jϭ6, 16 Hz), 2.66 (1H, dd, Jϭ6, 16 Hz), 3.85
(1H, ddd, Jϭ2, 4, 6 Hz), 3.95 (1H, dq, Jϭ4, 6 Hz), 4.02 (1H, ddd, Jϭ2, 5, 6
Hz), 4.39, 4.44, 4.61, 4.62 (each 1H, d, Jϭ12 Hz), 5.06 (1H, dq, Jϭ5, 6 Hz),
5.32 (1H, sextet, Jϭ6 Hz), 6.01 (1H, dd, Jϭ2, 16 Hz), 6.05 (1H, dd, Jϭ2,
16 Hz), 6.84 (1H, dd, Jϭ6, 16 Hz), 6.85 (1H, dd, Jϭ6, 16 Hz), 7.23—7.35
(10H, m). (3S,8R,9S,14R,15S)-8; 1H-NMR d 1.15 (3H, d, Jϭ6 Hz), 1.30
(3H, d, Jϭ6 Hz), 1.34 (3H, d, Jϭ6 Hz), 2.28 (1H, br s, OH), 2.54, 2.70 (each
1H, dd, Jϭ6, 16 Hz), 3.67 (3H, s), 3.93 (1H, ddd, Jϭ2, 4, 6 Hz), 3.94—3.99
(1H, m), 4.11 (1H, ddd, Jϭ2, 4, 6 Hz), 4.42, 4.49, 4.65, 4.65 (each 1H, d,
Jϭ12 Hz), 5.11 (1H, dq, Jϭ4, 6 Hz), 5.35 (1H, sextet, Jϭ6 Hz), 6.06 (1H,
dd, Jϭ2, 16 Hz), 6.08 (1H, dd, Jϭ2, 16 Hz), 6.86 (1H, dd, Jϭ6, 16 Hz), 6.91
(1H, dd, Jϭ6, 16 Hz), 7.23—7.35 (10H, m). To a solution of the above-men-
tioned mixture (0.1851 g) in THF (1 ml) was added triethylamine (0.07 g,
0.67 mmol) and 2,4,6-trichlorobenzoyl chloride (0.17 g, 0.67 mmol), and the
reaction mixture was stirred for 2 h at room temperature under argon atmos-
phere. To a solution of DMAP (0.25 g, 2.0 mmol) in toluene (35 ml) was
added dropwise a solution of the above-mentioned reaction mixture in
toluene (100 ml) at 100 °C with stirring, and the whole mixture was stirred
for 12 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 chro-
matographed on silica gel (20 g, n-hexane : AcOEtϭ10 : 1) to give (Ϫ)-19
(0.032 g 20% yield from (3S,8R,9S,14R,15S)-8, [a]D22 Ϫ156.6° (cϭ0.30,
CHCl3)), macrosphelide A dibenzyl ether (25) (0.01 g, 5% overall yield,
from (3S,8R,9S,14R,15S)-8, [a]D20 Ϫ82.9° (cϭ0.25, CHCl3)) from n-
hexane : AcOEtϭ10 : 1 eluate, and the recovery of (3S,8R,9S,14R,15S)-8
(0.057 g, 27% recovery) from n-hexane : AcOEtϭ1 : 1 eluate. The spectral
data (1H-NMR and [a]D) of (Ϫ)-19 and macrosphelide A dibenzyl ether
(25) were identical with those of the above-mentioned (Ϫ)-19 and the re-
ported (Ϫ)-25,2) respectively.
Lipase-Catalysed Hydrolysis of (4R,5S,9S,14R,15S)-7 Followed by
Macrolactonization A suspension of (4R,5S,9S,14R,15S)-7 (0.165 g, 0.3
mmol) and lipase OF-360 (200 mg) in 0.1 M phosphate buffer solution (40
ml) was stirred for 14 d at 35 °C, and the reaction mixture was filtered off
with the aid of celite. The filtrate was acidified with 2 M aqueous HCl and
extracted with ether. The ether layer was washed with saturated brine and
dried over MgSO4. The ether layer was evaporated to give a mixture (0.148
g) of seco-acid (4R,5S,9S,14R,15S)-4, a small amount of starting material
(4R,5S,9S,14R,15S)-7 and 21, which was subjected to NMR analysis.
References
1
(4R,5S,9S,14R,15S)-4; H-NMR d: 1.13 (3H, d, Jϭ6 Hz), 1.20 (3H, d, Jϭ7
1) Hayashi M., Kim Y.-P., Hiraoka H., Natori M., Takamatsu S.,
Kawakubo T., Masuma R., Komiyama K., Omura S., J. Antibiot., 48,
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2602 (1996).
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Hz), 1.32 (3H, d, Jϭ6 Hz), 2.52 (1H, dd, Jϭ6, 16 Hz), 2.65 (1H, dd, Jϭ6,
16 Hz), 3.85 (1H, ddd, Jϭ2, 4, 6 Hz), 3.92 (1H, dq, Jϭ4, 6 Hz), 4.00 (1H,
ddd, Jϭ2, 4, 6 Hz), 4.37, 4.43, 4.59, 4.60 (each 1H, d, Jϭ12 Hz), 5.05 (1H,
dq, Jϭ4, 6 Hz), 5.32 (1H, sextet, Jϭ6 Hz), 6.00 (1H, dd, Jϭ2, 16 Hz), 6.07
(1H, dd, Jϭ2, 16 Hz), 6.88 (1H, dd, Jϭ6, 16 Hz), 6.89 (1H, dd, Jϭ6, 16 Hz),
7.23—7.35 (10H, m). Other signals due to 7 (d 3.75, 3H, s) and 21 (d 7.01,
1H, dd, Jϭ6, 16 Hz) were observed separately. To a solution of the above-
mentioned mixture (0.148 g, 0.275 mmol) in THF (1 ml) was added triethyl-
amine (0.06 g, 0.549 mmol) and 2,4,6-trichlorobenzoyl chloride (0.13 g,
0.549 mmol), and the reaction mixture was stirred for 2 h at room tempera-
ture under argon atmosphere. To a solution of DMAP (0.20 g, 1.65 mmol) in
toluene (30 ml) was added dropwise a solution of the above-mentioned reac-
tion mixture in toluene (110 ml) at 100 °C with stirring, and the whole mix-
ture was stirred for 12 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
7) Nakamura H., Ono M., Makino M., Akita H., Heterocycles, 57, 327—
336 (2002).
8) Nakamura H., Ono M., Yamada T., Numata A., Akita H., Chem.
Pharm. Bull., 50, 303—306 (2002).