New total syntheses of (+)-macrosphelides C, F and G

Article abstract of DOI:10.1016/S0957-4166(02)00180-5

The total synthesis of (+)-macrosphelide C 1 (25% overall yield in nine steps), (+)-macrosphelide F 2 (20% overall yield in nine steps) and (+)-macrosphelide G 3 (22% overall yield in nine steps) has been achieved from the chemoenzymatic reaction product

Full text of DOI:10.1016/S0957-4166(02)00180-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 705–713
New total syntheses of (+)-macrosphelides C, F and G
Hiroshi Nakamura, Machiko Ono, Yuki Shida and Hiroyuki Akita*
School of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
Received 27 February 2002; accepted 11 April 2002
Abstract—The total synthesis of (+)-macrosphelide C 1 (25% overall yield in nine steps), (+)-macrosphelide F 2 (20% overall yield
in nine steps) and (+)-macrosphelide G 3 (22% overall yield in nine steps) has been achieved from the chemoenzymatic reaction
product (4R,5S)-4-benzyloxy-5-hydroxy-(2E)-hexenoate 7. © 2002 Published by Elsevier Science Ltd.
1. Introduction
acids at the O(10)ꢀC(11) bond followed by reduction
and Mitsunobu inversion of the resulting hydroxyl
group,4 while asymmetric synthesis of macrosphelide G
3 has not been reported so far. On the other hand, we
reported that the enantioselective hydrolysis of ( )-
(+)-Macrosphelide C 1 was isolated from a cultured
broth of Macrosphaeropsis sp. FO-5050, and the plane
structure of (+)-1 was determined as depicted 1,1
whereas (+)-macrosphelides F 2, G 3 and C 1 were
obtained from a strain of Periconia byssoides separated
from the gastrointestinal tract of the sea hare Aplysia
kurodai as minor products (Scheme 1).2 These com-
pounds were found to strongly inhibit the adhesion of
human leukemia HL-60 cells to human umbilical-vein
endothelial cells (HUVEC).1,2 The absolute stereostruc-
tures of macrosphelides F 2 and G 3 have been eluci-
dated on the basis of spectroscopic analysis using 1D
and 2D NMR techniques and some chemical transfor-
mations.2 In addition, the absolute configuration of 1
has been established by X-ray analysis and application
of the modified Mosher method.2 Recently, syntheses of
macrosphelides (+)-A 43a,b,c and (+)-E 53c were carried
out by three groups to investigate the biological proper-
ties and determine their stereochemistry. The asymmet-
ric synthesis of macrosphelides C 1 and F 2 was
achieved by lactonization of the chiral 14-oxo seco-
(4,5)-anti-5-acetoxy-4-benzyloxy-(2E)-hexenoate
6
using the lipase ‘Amano P’ from Pseudomonas sp. in
phosphate buffer solution gave the (4R,5S)-5-acetoxy
ester 6 (>99% e.e., 48% yield) and the (4S,5R)-5-
hydroxy ester 7 (>99% e.e., 44% yield), and methanol-
ysis of (4R,5S)-6 provided (4R,5S)-7 in 84% yield
(Scheme 2).5 These enzymatic products were effectively
applied to the synthesis of macrosphelides (+)-A 4,3c
(−)-A 43c and (+)-E 53c as useful chiral synthons.
Herein, we report a new synthesis of macrosphelides
(+)-C 1, (+)-F 2 and (+)-G 3 from the above-mentioned
enzymatic products.
2. Results and discussion
We reported previously the total synthesis of (+)-
macrosphelide A 4 via paths A, B and C (Scheme 1)
Scheme 1.
* Corresponding author. E-mail: akita@phar.toho-u.ac.jp
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00180-5

706
H. Nakamura et al. / Tetrahedron: Asymmetry 13 (2002) 705–713
involving macrolactonization. The synthesis via path A
was found to give the best result from the viewpoint of
synthetic efficiency.6 The common synthetic intermedi-
ate in the synthesis of 1 and 2 via path A is considered
to be the diester (5S,10R,11S)-8, which is coupled with
(3S)-butanoic acid derivative 9 or (3R)-9 to lead to the
synthesis of C 1 or F 2, respectively. On the other hand,
the synthetic intermediate via path A in the synthesis of
macrosphelide G 3 can be regarded as the diester
(4R,5S,11S)-10, which is connected with (3R)-9 to
enable the synthesis of G 3 (Scheme 3). As a prelimi-
nary experiment, ester formation between (4R,5S,2E)-
hexenoic acid congener 11 derived from (4R,5S)-75 and
( )-5-hydroxy-(2E)-hexenoate 12 in the presence of 4-
N,N-dimethylaminopyridine (DMAP) and camphorsu-
fonic acid (CSA) in CH2Cl2 (method a) gave a
diastereomeric mixture (29%) of diester 13 and diester
14, while in the absence of CSA (method b) a
diastereomeric mixture (38%) of diester 13 and diester
14 was afforded. When 2,2,2-trichloroethyl 5-hydroxy-
(2E)-hexenoate instead of methyl ester ( )-12 was
applied to the above esterification reaction using
method a, a diastereomeric mixture (44%) of the diester
corresponding to a mixture of 13 and 14 along with
2,4-hexadienoate (12%) was produced. In order to cir-
cumvent the low yield and the undesired generation of
2,4-hexadienoate in this process, the macrolactonization
process was changed to path C from path A (Scheme
4).
First, (5S)-tert-butyldimethylsiloxy-(2E)-hexenoic acid
15 was synthesized from the enzymatic reaction product
(4R,5S)-7 (Scheme 5). Debenzylation of (4R,5S)-7 by
the reported method gave (4R,5S)-dihydroxy ester 167
which was treated with tert-butyldimethylsilyl chloride
(TBDMSCl) to provide (4R,5S)-17 (12%) and (4R,5S)-
18 (65%). In order to confirm the position of silylation,
both 17 and 18 were subjected to mesylation with
methanesulfonic anhydride (Ms2O) to afford the corre-
sponding mesylates (4R,5S)-19 (87%) and (4R,5S)-20
(96%), respectively. The structures of both (4R,5S)-19
and (4R,5S)-20 were confirmed by the fact that chemi-
cal shift due to the C(5) hydrogen of (4R,5S)-19
appeared at lower field (l 4.74, dq, J=4, 6 Hz) in
comparison with that due to C(5) hydrogen of (4R,5S)-
20 (l 4.02, dq, J=4, 6 Hz). Treatment of (4R,5S)-20
with NaBH4 in the presence of 1,1,1-tris(dibenzyl-
ideneacetone)dipalladium(0)–chloroform
adduct
(Pd2(dba)3·CHCl3) and Bu3P according to the proce-
dure of Tsuji8 gave (5S)-tert-butyldimethylsiloxy-(2E)-
hexenoate 21 in 78% yield. Alkaline hydrolysis of 21
afforded the corresponding carboxylic acid (5S)-15
(95% crude yield), which was used for the next reaction
without further purification.
OBn
OBn
OBn
lipase Amano P
phosphate buffer
Me
Me
Me
+
COOMe
COOMe
COOMe
OAc
R3
OH
(±)-6
R3 = OAc : (4R,5S)-6
R3 = OH : (4R,5S)-7
(4S,5R)-7
K2CO3 / MeOH
Scheme 2.
O
O
Me
O
Me
Macrosphelide C 1
R1
4R
3S
HO
HO
OTBDMS
(3S)-9
5S
O
or
or
R2
10R
11S
+
Macrosphelide F 2
or
Me
COOCH2CCl3
Macrosphelide G 3
Me
OH
3R OTBDMS
(3R)-9
R1 =H, R2 = OBn : (5S,10R,11S)-8
R1 =OBn, R2 = H : (4R,5S,11S)-10
TBDMS: -SiMe2But
Scheme 3.
Scheme 4. Reagents: (a) DCC/DMAP/CSA/CH2Cl2; (b) DCC/DMAP/CH2Cl2.

H. Nakamura et al. / Tetrahedron: Asymmetry 13 (2002) 705–713
707
R1
OTBDMS
R1
Me
Me
Me
a
b
+
COOMe
COOMe
COOR4
OH
R3
OTBDMS
R1 = OBn : (4R,5S)-7
R1 = OH : (4R,5S)-16
R3 = OH : (4R,5S)-17
R3 = OMs : (4R,5S)-19
R1 = OH, R4 = Me : (4R,5S)-18
b
ref. 8
R1 = OMs, R4 = Me : (4R,5S)-20
c
R1 = H, R4 = Me : (5S)-21
R1 = H, R4 = H : (5S)-15
TBDMS: -SiMe2But
d
Scheme 5. Reagents: (a) TBDMSCl/imidazole/DMF; (b) Ms2O/pyridine; (c) NaBH4/Pd2(dba)3·CHCl3/Bu3P/dioxane–H2O; (d) (1)
2 M NaOH aq./MeOH (2) 2 M HCl aq.
2.1. Synthesis of (+)-macrosphelide C 1
15S)-benzyl macrosphelide F 32 ([h]D −19.7 (c=0.16,
CHCl3)) in 79% overall yield from (−)-30 (Scheme 7).
Finally, deprotection of the benzyl group in (−)-32
using AlCl3 in the presence of m-xylene gave synthetic
(+)-macrosphelide F 2 ([h]D +42.8 (c=0.50, EtOH) in
Ester formation between the carboxylic acid (5S)-15
and the reported hydroxy-diester (4R,5S,9S)-226 via the
Steglich procedure9 gave a triester (4R,5S,9S,15S)-23 in
86% yield, which was subjected to desilylation to
provide a secondary alcohol (4R,5S,9S,15S)-24 in 88%
yield. Deprotection of (4R,5S,9S,15S)-24 using Zn in
acetic acid buffer solution followed by Yamaguchi
macrolactonization10 (2,4,6-trichlorobenzoyl chloride,
Et3N, DMAP) provided (3S,9S,14R,15S)-benzyl
macrosphelide C 26 ([h]D −43.7 (c=0.22, CHCl3)) in
69% overall yield from (−)-24. Finally, deprotection of
the benzyl group in (−)-26 using AlCl3 in the presence
of m-xylene5 gave the synthetic (+)-macrosphelide C 1
(mp 152–155°C, [h]D +53.3 (c=0.08, EtOH)) in 77%
1
89% yield. Physical data ([h]D, H and 13C NMR) of
synthetic (+)-2 were identical with those of the natural
(+)-2 ([h]D +23.3 (c=0.09, EtOH)).2
2.3. Synthesis of (+)-macrosphelide G 3
Ester formation between (5S)-15 and (4R,5S)-27 via
the Steglich procedure gave diester (4R,5S,11S)-33 in
67% yield, which was subjected to desilylation to
provide the secondary alcohol (4R,5S,11S)-10 in 93%
yield. The second ester formation between the car-
boxylic acid (3R)-9 and the alcohol (4R,5S,11S)-10 via
the Steglich procedure resulted in the recovery of the
staring material. On the other hand, the above-men-
tioned reaction via the Keck procedure11 provided a
triester (4R,5S,11S,15R)-34 in 88% yield, which was
subjected to desilylation to give a secondary alcohol
(4R,5S,11S,15R)-35 (93% yield, [h]D −37.8 (c=0.50,
CHCl3)). Deprotection of (4R,5S,11S,15R)-35 using Zn
in acetic acid buffer solution followed by Yamaguchi
macrolactonization provided (3R,8R,9S,15S)-benzyl
macrosphelide G 37 ([h]D −22.1 (c=0.35, CHCl3)) in
68% overall yield from (−)-35. Finally, deprotection of
the benzyl group of (−)-37 using AlCl3 in the presence
of m-xylene gave (+)-synthetic macrosphelide G 3 ([h]D
+51.7 (c=0.35, EtOH) in 78% yield. Physical data
1
yield. Physical data ([h]D, H and 13C NMR) of syn-
thetic (+)-1 were identical with those of the natural
(+)-1 (mp 156–158°C, [h]D +46.3 (c=0.54, EtOH))
(Scheme 6).1,2
2.2. Synthesis of (+)-macrosphelide F 2
Ester formation between the carboxylic acid (3R)-9
(>99% e.e.)3c and the reported hydroxy ester (4R,5S)-
273c via the Steglich procedure followed by desilylation
gave a diester (4R,5S,9R)-28 in 76% yield. The second
ester formation between (5S)-15 and the diester
(4R,5S,9R)-28 again via the Steglich procedure pro-
vided a triester (4R,5S,9R,15S)-29 in 55% yield, which
was subjected to desilylation to provide the secondary
alcohol (4R,5S,9R,15S)-30 (86% yield, [h]D −27.9 (c=
0.27, CHCl3)). Deprotection of (4R,5S,9R,15S)-30
using Zn in acetic acid buffer solution followed by
Yamaguchi macrolactonization provided (3S,9S,14R,
1
([h]D, H and 13C NMR) of synthetic (+)-3 were identi-
cal with those ([h]D +66.7 (c=0.48, EtOH)) of the
natural (+)-3.2 This synthetic route represents the first
synthesis of macrosphelide G 3 (Scheme 8).
Me
15S
O
O
Me
O
R6O
R5O
OCH2CCl3
Me
O
9S
a
d
BnO
BnO
R2
O
Me
O
O
Me
4R
4R
14R
5S
5S
15S
9S
Me
O
O
O
9S
3S
O
Me
O
OH
Me
O
O
(4R,5S,9S)-22
R5 = TBDMS, R6 = CH2CCl3 : (4R,5S,9S,15S)-23
R5 = H, R6 = CH2CCl3 : (4R,5S,9S,15S)-24
R2 = OBn : (3S,9S,14R,15S)-26
R2 = OH : (+)-1
b
e
c
TBDMS: -SiMe2But
R5 = R6 = H : (4R,5S,9S,15S)-25
Scheme 6. Reagents: (a) (5S)-15, DCC/DMAP/CH2Cl2; (b) AcOH:H2O:THF (2:1:1); (c) Zn/THF/AcOH–AcONa buffer; (d);
2,4,6-trichlorobenzoyl chloride/Et3N/DMAP/toluene; (e) m-xylene/AlCl3/CH2Cl2.

708
H. Nakamura et al. / Tetrahedron: Asymmetry 13 (2002) 705–713
O
O
OCH2CCl3
Me
OCH2CCl3
a
BnO
BnO
+
(3R)-9
O
4R
4R
5S
5S
9R
Me
O
OH
Me
OH
(4R,5S)-27
TBDMS: -SiMe2But
(4R,5S,9R)-28
Me
15S
O
Me
O
R6O
R5O
O
9S
e
b
BnO
R2
O
Me
O
Me
4R
14R
15S
5S
3R
Me
O
O
O
Me
O
O
O
9R
R5 = TBDMS, R6 = CH2CCl3 : (4R,5S,9R,15S)-29
R5 = H, R6 = CH2CCl3 : (4R,5S,9R,15S)-30
R2 = OBn : (3R,9S,14R,15S)-32
R2 = OH : (+)-2
c
f
d
R5 = R6 = H : (4R,5S,9R,15S)-31
Scheme 7. Reagents: (a) (1) DCC/DMAP/CH2Cl2; (2) AcOH:H2O:THF (2:1:1); (b) (5S)-15, DCC/DMAP/CH2Cl2; (c)
AcOH:H2O:THF (2:1:1); (d) Zn/THF/AcOH–AcONa buffer; (e); 2,4,6-trichlorobenzoyl chloride/Et3N/DMAP/toluene; (f) m-
xylene/AlCl3/CH2Cl2.
O
Me
4R OBn
Me
4R OBn
COOH
5S
O
5S
HO
a
+
5S
11S
COOCH2CCl3
COOCH2CCl3
(4R,5S)-27
Me
OTBDMS
Me
OR7
(5S)-15
TBDMS: -SiMe2But
R7 =TBDMS (4R,5S,11S)-33
R7 =H (4R,5S,11S)-10
Me
b
O
Me
O
O
4R
8R
OBn
R1
5S
O
O
9S
e
c
O
Me
Me
15S
11S
COOR9
15R
Me
O
OR8
Me
O
O
O
3R
R8 = TBDMS, R9 =CH2CCl3 : (4R,5S,11S,15R)-34
R8 = H, R9 =CH2CCl3 : (4R,5S,11S,15R)-35
R1 = OBn : (3R,8R,9S,15S)-37
R1 = OH : (+)-3
b
d
f
R8 = R9 = H : (4R,5S,11S,15R)-36
Scheme 8. Reagents: (a) DCC/DMAP/CH2Cl2; (b) AcOH:H2O:THF (2:1:1); (c) (3R)-9, DCC/DMAP/CSA/CH2Cl2; (d) Zn/THF/
AcOH–AcONa buffer; (e) 2,4,6-trichlorobenzoyl chloride/Et3N/DMAP/toluene; (f) m-xylene/AlCl3/CH2Cl2.
3. Conclusion
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) were
obtained with a JEOL JMS-600H spectrometer. IR
spectra were recorded on a JASCO FT/IR-300 spec-
trometer. 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.
In conclusion, the total synthesis of (+)-macrosphelide
C 1 (25% overall yield in nine steps), (+)-macrosphelide
F 2 (20% overall yield in nine steps) and (+)-macro-
sphelide G 3 (22% overall yield in nine steps) has been
achieved from the chemoenzymatic reaction product
(4R,5S)-4-benzyloxy-5-hydroxy-(2E)-hexenoate 7.
4. Experimental
4.2. Silylation of (4R,5S)-4,5-dihydroxy-(2E)-
hexenoate, 16
4.1. General
All melting points were measured on a Yanaco MP-3S
micro melting point apparatus and are uncorrected. H
To a solution of (4R,5S)-168 (3.692 g, 23 mmol) and
imidazole (6.28 g, 92 mmol) in dimethylformamide
1

H. Nakamura et al. / Tetrahedron: Asymmetry 13 (2002) 705–713
709
4.4. (5S)-5-tert-Butyldimethylsiloxy-(2E)-hexenoic acid,
(DMF, 40 mL) was added TBDMSCl (4.17 g, 28
mmol) at 0°C and the reaction mixture was stirred for
1 h at 0°C and for 3 h at room temperature. The
reaction mixture was diluted with H2O and extracted
with Et2O. The organic layer was washed with satu-
rated brine and dried over MgSO4. The organic layer
was evaporated to give a crude residue, which was
chromatographed on silica gel (200 g, n-hex-
ane:AcOEt=20:1) in elution order to give the less polar
(4R,5S)-18 (4.107 g, 65%) as a colorless oil and the
more polar (4R,5S)-17 (0.783 g, 12%) as a colorless oil.
(4R,5S)-17: IR (neat): 3477, 1725, 1658 (sh) cm−1; [h]D29
15
(i) To a solution of Pd2(dba)3·CHCl3 (0.32 g, 0.31
mmol), tributylphosphine (0.062 g, 0.31 mmol) and
(4R,5S)-20 (2.176 g, 6.1 mmol) in dioxane (50 mL)
under an argon atmosphere was added a suspension of
NaBH4 (0.23 g, 6.1 mmol) in H2O (4 mL) and the
whole mixture was stirred for 2 h at room temperature.
The reaction mixture was diluted with saturated brine
and extracted with Et2O. The organic layer was dried
over MgSO4 and evaporated to give a residue, which
was chromatographed on silica gel (100 g, n-hex-
ane:AcOEt=100:1) to afford (5S)-21 as a colorless oil
(1.238 g, 78%). IR (neat): 2954, 1727 cm−1; [h]D21 +8.8
1
−14.1 (c=0.40, CHCl3); H NMR: l 0.03 (3H, s), 0.07
(3H, s), 0.90 (9H, s), 1.11 (3H, d, J=6 Hz), 2.14 (1H,
br. s), 3.72 (3H, s), 3.80 (1H, dq, J=4, 6 Hz), 4.21 (1H,
ddd, J=2, 4, 6 Hz), 6.00 (1H, dd, J=2, 16 Hz), 6.91
(1H, dd, J=6, 16 Hz). Anal. calcd for C13H26O4Si: C,
56.90; H, 9.55. Found: C, 56.85; H, 9.69%. FAB MS
m/z: 275 (M++1). (4R,5S)-18: IR (neat): 3480, 1727,
1
(c=0.51, CHCl3); H NMR: l 0.01 (3H, s), 0.02 (3H,
s), 0.86 (9H, s), 1.13 (3H, d, J=6 Hz), 2.25–2.34 (2H,
m), 3.71 (3H, s), 3.90 (1H, tq, J=6, 6 Hz), 5.82 (1H, dt,
J=2, 16 Hz), 6.93 (1H, dt, J=8, 16 Hz). Anal. calcd
for C13H26O3Si: C, 60.42; H, 10.14. Found: C, 60.54; H,
10.33%. FAB MS m/z: 259 (M++1).
1
1666 (sh) cm−1; [h]D28 +26.1 (c=0.10, CHCl3); H NMR:
l 0.04 (6H, s), 0.85 (9H, s), 1.05 (3H, d, J=6 Hz), 2.56
(1H, br. s), 3.70 (3H, s), 3.87 (1H, dq, J=4, 6 Hz),
4.16–4.20 (1H, m), 6.06 (1H, dd, J=2, 16 Hz), 6.86
(1H, dd, J=4, 16 Hz). Anal. calcd for C13H26O4Si: C,
56.90; H, 9.55. Found: C, 56.71; H, 9.60%. FAB MS
m/z: 275 (M++1).
(ii) To a solution of (5S)-21 (2.754 g, 10.6 mmol) in
MeOH (30 mL) was added dropwise 2 M aqueous
NaOH (2 mL) and the reaction mixture was stirred for
12 h at room temperature. The reaction mixture was
acidified with 2 M aqueous HCl and extracted with
Et2O. The ether layer was washed with saturated brine
and dried over MgSO4. The ether layer was evaporated
to give a crude (5S)-15 as a colorless oil (2.467 g, 95%).
The crude (5S)-15 was found to be a single product
4.3. Mesylation of (4R,5S)-17 and (4R,5S)-18
(i) To a solution of (4R,5S)-17 (0.100 g, 0.37 mmol) in
pyridine (0.15 g) and benzene (2 mL) was added Ms2O
(0.10 g, 0.57 mmol) and the mixture was heated at 50°C
for 2 h with stirring. The reaction mixture was diluted
with H2O and extracted with Et2O. The organic layer
was washed with 7% aqueous NaHCO3, saturated brine
and dried over MgSO4. The organic layer was evapo-
rated to give a crude residue, which was chro-
matographed on silica gel (20 g, n-hexane:
AcOEt=20:1) to give a colorless oil of (4R,5S)-19
(0.113 g, 87%). IR (neat): 1727, 1662 (sh) cm−1; 1H
NMR: l 0.03 (3H, s), 0.08 (3H, s), 0.89 (9H, s), 1.31
(3H, d, J=6 Hz), 2.98 (3H, s), 3.72 (3H, s), 4.46 (1H,
ddd, J=2, 4, 6 Hz), 4.74 (1H, dq, J=4, 6 Hz), 6.05
(1H, dd, J=2, 16 Hz), 6.84 (1H, dd, J=6, 16 Hz).
Anal. calcd for C14H28O6SSi: C, 47.70; H, 8.01. Found:
C, 48.00; H, 8.22%. FAB MS m/z: 353 (M++1).
1
from H NMR analysis. (5S)-15; [h]2D6 +13.7 (c=0.67,
1
CHCl3); H NMR: l 0.02 (3H, s), 0.03 (3H, s), 0.86
(9H, s), 1.15 (3H, d, J=6 Hz), 2.33 (2H, ddd, J=2, 6,
8 Hz), 3.92 (1H, qt, J=6, 6 Hz), 5.82 (1H, dt, J=2, 16
Hz), 6.97–7.15 (1H, br. s), 7.05 (1H, dt, J=8, 16 Hz).
4.5. Ester formation between (5S)-15 and (4R,5S,9S)-
22
To a mixture of DCC (0.116 g, 0.56 mmol) and DMAP
(0.021 g, 0.17 mmol) in CH2Cl2 (1 mL) was added a
solution of (5S)-15 (0.137 g, 0.56 mmol) and
(4R,5S,9S)-226 (0.18 g, 0.4 mmol) in CH2Cl2 (3 mL)
and the reaction mixture was stirred for 2 days at room
temperature. The reaction mixture was filtered and the
filtrate was evaporated to afford a residue, which was
chromatographed on silica gel (20 g, n-hex-
ane:AcOEt=19:1) to give (4R,5S,9S,15S)-23 as an oil
(0.235 g, 86%). IR (neat): 1728, 1657 cm−1; [h]D25 −17.8
(ii) To a solution of (4R,5S)-18 (3.836 g, 14 mmol) in
pyridine (5.53 g, 70 mmol) and benzene (50 mL) was
added Ms2O (4.87 g, 28 mmol) and the mixture was
heated at 50°C for 2 h with stirring. The reaction
mixture was worked up in the same way as for the
preparation of (4R,5S)-19 to give (4R,5S)-20 as a col-
orless oil (4.71 g, 96%). IR (neat): 1727, 1666 (sh) cm−1;
1
(c=0.72, CHCl3); H NMR: l 0.01 (3H, s), 0.02 (3H,
s), 0.85 (9H, s), 1.12 (3H, d, J=6 Hz), 1.20 (3H, d, J=6
Hz), 1.28 (3H, d, J=6 Hz), 2.19–2.32 (2H, m), 2.48
(1H, dd, J=7, 16 Hz), 2.62 (1H, dd, J=7, 16 Hz), 3.88
(1H, qt, J=6, 6 Hz), 4.08 (1H, ddd, J=2, 4, 6 Hz),
4.48, 4.61 (each 1H, d, J=13 Hz), 4.80 (2H, s), 5.04
(1H, qd, J=4, 6 Hz), 5.28 (1H, qt, J=6, 7 Hz), 5.75
(1H, dt, J=1, 16 Hz), 6.19 (1H, dd, J=2, 16 Hz), 6.90
(1H, dt, J=8, 16 Hz), 6.99 (1H, dd, J=6, 16 Hz),
7.25–7.36 (5H, m). Anal. calcd for C31H45O8Cl3Si: C,
54.74; H, 6.67. Found: C, 54.60; H, 6.85%.
1
[h]2D1 −17.7 (c=0.91, CHCl3); H NMR: l 0.05 (3H, s),
0.06 (3H, s), 0.86 (9H, s), 1.15 (3H, d, J=6 Hz), 3.03
(3H, s), 3.74 (3H, s), 4.02 (1H, qd, J=4, 6 Hz), 5.02
(1H, ddd, J=2, 4, 6 Hz), 6.12 (1H, dd, J=2, 16 Hz),
6.88 (1H, dd, J=6, 16 Hz). Anal. calcd for
C14H28O6SSi: C, 47.70; H, 8.01. Found: C, 47.95; H,
8.05%. FAB MS m/z: 353 (M++1).

710
H. Nakamura et al. / Tetrahedron: Asymmetry 13 (2002) 705–713
4.6. Desilylation of (4R,5S,9S,15S)-23
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-hex-
ane:AcOEt=5:1) to give (3S,9S,14R,15S)-26 as a color-
less oil (0.073 g, 69% overall yield from
(4R,5S,9S,15S)-24). IR (CHCl3): 1720, 1521 cm−1; [h]D19
A mixture of (4R,5S,9S,15S)-23 (0.235 g, 0.35 mmol) in
a mixed solvent of AcOH (4 mL), H2O (2 mL) and
THF (2 mL) was stirred for 2.5 h at 80°C. The reaction
mixture was evaporated to give a residue, which was
diluted with ether. The organic layer was washed with
7% aqueous NaHCO3 and dried over MgSO4. Evapora-
tion of the organic solvent gave a residue, which was
chromatographed on silica gel (25 g, n-hex-
ane:AcOEt=3:1) to give (4R,5S,9S,15S)-24 as an oil
(0.172 g, 88%). IR (neat): 3455, 1729, 1656 cm−1; [h]D22
1
−43.7 (c=0.22, CHCl3); H NMR: l 1.28 (3H, d, J=6
Hz), 1.28 (3H, d, J=6 Hz), 1.35 (3H, d, J=6 Hz), 2.30
(1H, ddd, J=10, 10. 14 Hz), 2.47–2.52 (1H, m), 2.47
(1H, dd, J=8, 16 Hz), 2.52 (1H, dd, J=4, 16 Hz), 3.77
(1H, ddd, J=2, 6, 6 Hz), 4.34, 4.59 (each 1H, d, J=11
Hz), 4.99 (1H, qd, J=6, 6 Hz), 5.11 (1H, qdd, J=4, 6,
10 Hz), 5.28 (1H, qdd, J=4, 6, 8 Hz), 5.74 (1H, dt,
J=2, 16 Hz), 6.01 (1H, dd, J=2, 16 Hz), 6.78 (1H, dd,
J=6, 16 Hz), 6.82 (1H, ddd, J=7, 10, 16 Hz), 7.25–
7.35 (5H, m). 13C NMR: l 18.0 (q), 19.9 (q), 20.7 (q),
39.0 (t), 41.2 (t), 67.5 (d), 69.0 (d), 71.3 (t), 72.1 (d),
79.4 (d), 124.2 (d), 124.6 (d), 127.8 (d), 127.8 (d), 128.3
(d), 137.1 (s), 143.4 (d), 144.2 (d), 164.5 (s), 164.7 (s),
169.3 (s). Anal. calcd for C23H28O7: C, 66.33; H, 6.78.
Found: C, 66.83; H, 6.84%. FAB MS m/z; 417 (M++1).
1
−23.4 (c=0.35, CHCl3); H NMR: l 1.19 (3H, d, J=6
Hz), 1.20 (3H, d, J=6 Hz), 1.28 (3H, d, J=6 Hz),
1.74–1.87 (1H, br. s), 2.30 (2H, dd, J=7.5, 7.5 Hz),
2.49 (2H, dd, J=6, 16 Hz), 2.61 (1H, dd, J=8, 16 Hz),
3.90 (1H, qt, J=6, 6 Hz), 4.07 (1H, ddd, J=2, 4, 6 Hz),
4.48, 4.60 (each 1H, d, J=13 Hz), 4.80 (2H, s), 5.05
(1H, qd, J=4, 6 Hz), 5.28 (1H, qdd, J=6, 6, 8 Hz),
5.81 (1H, dt, J=2, 16 Hz), 6.19 (1H, dd, J=2, 16 Hz),
6.91 (1H, dt, J=8, 16 Hz), 6.99 (1H, dd, J=6, 16 Hz),
7.25–7.36 (5H, m). 13C NMR: l 15.3 (q), 20.0 (q), 23.4
(q), 41.1 (t), 41.9 (t), 66.6 (d), 67.1 (d), 71.5 (d), 71.9 (t),
74.1 (t), 79.4 (d), 94.8 (s), 122.3 (d), 123.6 (d), 127.6 (d),
127.8 (d), 128.3 (s), 137.2 (s), 145.2 (d), 146.4 (d), 163.7
(s), 165.0 (s), 169.1 (s). Anal. calcd for C25H31O8Cl3: C,
53.06; H, 5.52. Found: C, 53.34; H, 5.78%. FAB MS
m/z; 565, 567 (M++1).
4.9. (+)-Macrosphelide C, 1
To a mixture of AlCl3 (0.058 g, 0.43 mmol) in CH2Cl2
(3 mL) was added dropwise
a
solution of
(3S,9S,14R,15S)-26 (0.059 g, 0.14 mmol) and m-xylene
(1.5 mL) in CH2Cl2 (3 mL) at −10°C and the reaction
mixture was stirred for 3 h at room temperature. The
reaction mixture was 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 (5 g, n-hex-
ane:AcOEt=2:1) to give (+)-1 (0.035 g, 77%) as color-
4.7. Deprotection of 2,2,2-trichloroethyl group of
(4R,5S,9S,15S)-24
To a solution of (4R,5S,9S,15S)-24 (0.143 g, 0.25
mmol) and AcOH–AcONa buffer solution (3 mL) in
THF (3 mL) at 0°C was added Zn dust (0.099 g, 1.5
mmol) and the mixture was stirred for 8 h at room
temperature. The reaction mixture was filtered and the
filtrate was acidified with 2 M aqueous HCl and
extracted with Et2O. The organic layer was dried over
MgSO4 and evaporated to give crude seco-acid
(4R,5S,9S,15S)-25 (0.109 g, quantitative yield).
less
solid.
Recrystallization
of
(+)-1
from
n-hexane–CH2Cl2 gave colorless needles (+)-1. (+)-1;
mp 152–155°C, IR (CHCl3): 3456, 1718 cm−1; [h]D26
+53.3 (c=0.08, EtOH). The NMR spectra (1H and 13C
NMR) of the synthetic (+)-1 were identical with those
of natural (+)-1.1 Anal. calcd for C16H22O7: C, 58.89;
H, 6.80. Found: C, 58.61; H, 6.81%. FAB MS m/z; 327
(M++1).
1
(4R,5S,9S,15S)-25; H NMR: l 1.21 (3H, d, J=6 Hz),
1.22 (3H, d, J=6 Hz), 1.28 (3H, d, J=6 Hz), 2.33 (2H,
dd, J=7, 7 Hz), 2.50 (1H, dd, J=5, 16 Hz), 2.60 (1H,
dd, J=8, 16 Hz), 3.96 (1H, ddd, J=2, 4, 7 Hz), 4.00
(1H, qt, J=6, 6 Hz), 4.42, 4.60 (each 1H, d, J=12 Hz),
5.04 (1H, qd, J=4, 6 Hz), 5.30 (1H, qdd, J=5, 6, 8
Hz), 5.83 (1H, dt, J=2, 16 Hz), 6.06 (1H, dd, J=2, 16
Hz), 6.80 (1H, br. s), 6.89 (1H, dd, J=7, 16 Hz), 6.92
(1H, dt, J=7, 16 Hz), 7.25–7.35 (5H, m).
4.10. Ester formation between (3R)-9 and (4R,5S)-27
(i) To a mixture of DCC (0.56 g, 2.71 mmol) and
DMAP (0.10 g, 0.82 mmol) in CH2Cl2 (10 mL) was
added a solution of (3R)-9 (0.59 g, 2.7 mmol) and
(4R,5S)-273c (0.50 g, 1.36 mmol) in CH2Cl2 (3 mL) and
the reaction mixture was stirred for 1 day at room
temperature. The reaction mixture was worked up in
the same way as for the preparation of (4R,5S,9S,15S)-
23 to give 2,2,2-trichloroethyl (4R,5S,9R)-4-benzyloxy-
9-tert-butyldimethylsiloxy-5-methyl-7-oxo-6-oxadeca-
(2E)-enoate as an oil (0.638 g, 82%). IR (neat): 1741,
4.8. Benzyl ether (3S,9S,14R,15S)-26
A solution of (4R,5S,9S,15S)-25 (0.109 g, 0.26 mmol),
Et3N (0.065 g, 0.64 mmol) and 2,4,6-trichlorobenzoyl
chloride (0.156 g, 0.64 mmol) in THF (3.5 mL) was
stirred for 2 h at room temperature under an argon
atmosphere and the mixture was diluted with toluene
(160 mL). The resulting reaction mixture was added
dropwise to a solution of DMAP (0.234 g, 1.91 mmol)
in toluene (20 mL) at 100°C over 2 h and the mixture
was stirred for 1 h at 100°C. The reaction mixture was
washed with saturated aqueous citric acid solution and
1
1658 cm−1; [h]D23 −43.8 (c=0.78, CHCl3); H NMR: l
0.02 (3H, s), 0.04 (3H, s), 0.84 (9H, s), 1.15 (3H, d, J=6
Hz), 1.24 (3H, d, J=6 Hz), 2.30 (1H, dd, J=6, 15 Hz),
2.46 (1H, dd, J=7, 15 Hz), 4.08 (1H, ddd, J=2, 4, 6
Hz), 4.23 (1H, qdd, J=6, 6, 7 Hz), 4.49, 4.63 (each 1H,
d, J=12 Hz), 4.80 (2H, s), 5.05 (1H, dq, J=4, 6 Hz),
6.19 (1H, dd, J=2, 16 Hz), 7.01 (1H, dd, J=6, 16 Hz),
7.26–7.37 (5H, m). Anal. calcd for C25H37O6 Cl3Si: C,

H. Nakamura et al. / Tetrahedron: Asymmetry 13 (2002) 705–713
711
52.68; H, 6.57. Found: C, 52.92; H, 6.66%. FAB MS
Hz), 4.08 (1H, ddd, J=2, 4, 6 Hz), 4.48, 4.60 (each 1H,
d, J=12 Hz), 4.78, 4.81 (each 1H, d, J=12 Hz), 5.05
(1H, qd, J=4, 7 Hz), 5.27 (1H, qdd, J=6, 7, 7 Hz),
5.82 (1H, dt, J=2, 16 Hz), 6.18 (1H, dd, J=2, 16 Hz),
6.92 (1H, dt, J=7, 16 Hz), 6.98 (1H, dd, J=6, 16 Hz),
7.26–7.37 (5H, m). 13C NMR: l 15.2 (q), 20.2 (q), 23.4
(q), 41.1 (t), 41.9 (t), 66.7 (d), 67.2 (d), 71.5 (d), 71.9 (t),
74.1 (t), 79.4 (d), 94.8 (s), 122.3 (d), 123.6 (d), 127.6 (d),
127.8 (d), 128.3 (d), 137.3 (s), 145.2 (d), 146.4 (d), 163.7
(s), 165.1 (s), 169.2 (s). Anal. calcd for C25H31O8Cl3: C,
53.06; H, 5.52. Found: C, 53.02; H, 5.67%. FAB MS
m/z; 565, 567 (M++1).
m/z; 567, 569 (M++1).
(ii) A mixture of 2,2,2-trichloroethyl (4R,5S,9R)-4-ben-
zyloxy-9-tert-butyldimethylsiloxy-5-methyl-7-oxo-6-oxa-
deca-(2E)-enoate (0.577 g, 1.02 mmol) in a mixed sol-
vent of AcOH (5 mL), H2O (2.5 mL) and THF (2.5
mL) was stirred for 12 h at 80°C. The reaction mixture
was worked up in the same way as for the preparation
of (4R,5S,9S,15S)-24 to give (4R,5S,9R)-28 (0.431 g,
93%) as an oil. IR (neat): 3444, 1731 cm−1; [h]D26 −63.5
1
(c=0.15, CHCl3); H NMR: l 1.18 (3H, d, J=6 Hz),
1.24 (3H, d, J=6 Hz), 2.38 (1H, dd, J=9, 16 Hz), 2.42
(1H, dd, J=5, 16 Hz), 2.86 (1H, br. s), 4.07 (1H, ddd,
J=2, 4, 6 Hz), 4.12 (1H, qdd, J=5, 6, 9 Hz), 4.47, 4.64
(each 1H, d, J=12 Hz), 4.81 (2H, s), 5.11 (1H, qd,
J=4, 6 Hz), 6.20 (1H, dd, J=2, 16 Hz), 7.00 (1H, dd,
J=6, 16 Hz), 7.27–7.37 (5H, m). 13C NMR: l 15.5 (q),
22.5 (q), 43.3 (t), 64.3 (d), 71.3 (d), 71.8 (t), 74.1 (t),
79.3 (d), 94.8 (s), 122.5 (d), 127.7 (d), 127.9 (d), 128.4
(d), 137.1 (s), 146.2 (d), 163.7 (s), 171.6 (s). Anal. calcd
for C19H23O6Cl3: C, 50.29; H, 5.11. Found: C, 50.24; H,
5.22%. FAB MS m/z; 453, 455 (M++1).
4.13. Deprotection of 2,2,2-trichloroethyl group of
(4R,5S,9R,15S)-30
To a solution of (4R,5S,9R,15S)-30 (0.114 g, 0.2 mmol)
and AcOH–AcONa buffer solution (2 mL) in THF (2
mL) at 0°C was added Zn dust (0.08 g, 1.22 mmol) and
the mixture was stirred for 3 h at room temperature.
The reaction mixture was worked up in the same way
as for the preparation of (4R,5S,9S,15S)-25 to give the
crude seco-acid (4R,5S,9R,15S)-31 (0.088 g, quantita-
1
tive yield). (4R,5S,9R,15S)-31; H NMR: l 1.20 (3H, d,
4.11. Ester formation between (5S)-15 and (4R,5S,9R)-
28
J=7 Hz), 1.21 (3H, d, J=7 Hz), 1.28 (3H, d, J=7 Hz),
2.31 (2H, t, J=7 Hz), 2.48 (1H, dd, J=6, 16 Hz), 2.63
(1H, dd, J=8, 16 Hz), 3.93 (1H, qt, J=7, 7 Hz), 4.00
(1H, ddd, J=2, 4, 6 Hz), 4.44, 4.59 (each 1H, d, J=12
Hz), 5.05 (1H, qd, J=4, 7 Hz), 5.26 (1H, qdd, J=7, 7,
8 Hz), 5.83 (1H, dt, J=2, 16 Hz), 6.07 (1H, dd, J=2,
16 Hz), 6.35 (2H, br. s), 6.89 (1H, dd, J=6, 16 Hz),
6.92 (1H, dt, J=7, 16 Hz), 7.26–7.36 (5H, m).
To a mixture of DCC (0.267 g, 1.29 mmol) and DMAP
(0.03 g, 0.25 mmol) in CH2Cl2 (7 mL) was added a
solution of (5S)-15 (0.316 g, 1.29 mmol) and
(4R,5S,9R)-28 (0.414 g, 0.91 mmol) in CH2Cl2 (3 mL)
and the reaction mixture was stirred for 1 day at room
temperature. The reaction mixture was worked up in
the same way as for the preparation of (4R,5S,9S,15S)-
23 to give (4R,5S,9R,15S)-29 as an oil (0.34 g, 55%). IR
(neat): 1741, 1656 cm−1; [h]D24 −22.3 (c=0.78, CHCl3);
1H NMR: l 0.01 (3H, s), 0.02 (3H, s), 0.85 (9H, s), 1.12
(3H, d, J=7 Hz), 1.22 (3H, d, J=7 Hz), 1.27 (3H, d,
J=7 Hz), 2.23 (1H, dddd, J=2, 7, 7, 14 Hz), 2.28 (1H,
dddd, J=2, 7, 7, 14 Hz), 2.43 (1H, dd, J=6, 15 Hz),
2.64 (1H, dd, J=7, 15 Hz), 3.87 (1H, ddd, J=7, 7, 7
Hz), 4.09 (1H, ddd, J=2, 4, 6 Hz), 4.48, 4.61 (each 1H,
d, J=12 Hz), 4.78 (1H, d, J=12 Hz), 4.81 (1H, d,
J=12 Hz), 5.05 (1H, qd, J=4, 7 Hz), 5.27 (1H, qdd,
J=6, 7, 7 Hz), 5.76 (1H, dt, J=2, 16 Hz), 6.19 (1H, dd,
J=2, 16 Hz), 6.91 (1H, dt, J=7, 16 Hz), 6.98 (1H, dd,
J=6, 16 Hz), 7.25–7.36 (5H, m). Anal. calcd for
C31H45O8 Cl3Si: C, 54.74; H, 6.67. Found: C, 54.46; H,
6.74%.
4.14. Benzyl ether (3R,9S,14R,15S)-32
A solution of (4R,5S,9R,15S)-31 (0.088 g, 0.2 mmol),
Et3N (0.043 g, 0.43 mmol) and 2,4,6-trichlorobenzoyl
chloride (0.104 g, 0.43 mmol) in THF (2 mL) was
stirred for 2 h at room temperature under argon atmo-
sphere and the mixture was diluted with toluene (110
mL). The above-mentioned reaction mixture was added
dropwise to a solution of DMAP (0.156 g, 1.28 mmol)
in toluene (15 mL) at 100°C over 2 h and the mixture
was stirred for 1.5 h at 100°C. The reaction mixture
was worked up in the same way as for the preparation
of (3S,9S,14R,15S)-26 to give (3R,9S,14R,15S)-32 as a
colorless oil (0.067 g, 79% overall yield from
(4R,5S,9R,15S)-30). (3R,9S,14R,15S)-32; IR (neat):
1712, 1666 cm−1; [h]D24 –19.7 (c=0.16, CHCl3); 1H
NMR: l 1.22 (3H, d, J=7 Hz), 1.37 (3H, d, J=7 Hz),
1.38 (3H, d, J=7 Hz), 2.36 (1H, dddd, J=2, 7, 7, 15
Hz), 2.49 (1H, dd, J=7, 14 Hz), 2.65 (1H, dd, J=4, 14
Hz), 2.68 (1H, dddd, J=2, 7, 7, 15 Hz), 3.83 (1H, ddd,
J=2, 7, 7 Hz), 4.39, 4.58 (each 1H, d, J=12 Hz), 4.98
(1H, qd, J=7, 7 Hz), 5.12 (1H, qdd, J=7, 7, 7 Hz),
5.21 (1H, qdd, J=4, 7, 7 Hz), 5.78 (1H, dt, J=2, 16
Hz), 6.03 (1H, dd, J=2, 16 Hz), 6.78 (1H, dd, J=7, 16
Hz), 6.85 (1H, dt, J=7, 16 Hz), 7.25–7.36 (5H, m). 13C
NMR: l 17.6 (q), 19.4 (q), 20.0 (q), 37.9 (t), 40.5 (t),
67.0 (d), 69.0 (d), 71.4 (t), 72.4 (d), 79.3 (d), 124.2 (d),
124.8 (d), 127.7 (d), 127.8 (d), 128.3 (d), 137.2 (s), 143.2
(d), 143.7 (d), 164.9 (s), 164.9 (s), 169.1 (s). Anal. calcd
4.12. Desilylation of (4R,5S,9R,15S)-29
A solution of (4R,5S,9R,15S)-29 (0.186 g, 0.27 mmol)
in a mixed solvent of AcOH (2 mL), H2O (1 mL) and
THF (1 mL) was stirred for 12 h at 80°C. The reaction
mixture was worked up in the same way as for the
preparation
of
(4R,5S,9S,15S)-24
to
give
(4R,5S,9R,15S)-30 (0.133 g, 86%) as an oil.
(4R,5S,9R,15S)-30; IR (neat): 3432, 1728 cm−1; [h]D23
1
−27.9 (c=0.27, CHCl3); H NMR: l 1.19 (3H, d, J=7
Hz), 1.21 (3H, d, J=7 Hz), 1.28 (3H, d, J=7 Hz), 1.85
(1H, br s), 2.30 (2H, t, J=7 Hz), 2.45 (1H, dd, J=6, 16
Hz), 2.63 (1H, dd, J=7, 16 Hz), 3.90 (1H, qt, J=7, 7

712
H. Nakamura et al. / Tetrahedron: Asymmetry 13 (2002) 705–713
for C23H28O7: C, 66.33; H, 6.78. Found: C, 66.44; H,
4.18. Ester formation between (4R,5S,11S)-10 and
(3R)-9
6.77%. FAB MS m/z; 417 (M++1).
4.15. (+)-Macrosphelide F, 2
To a mixture of DCC (0.266 g, 1.29 mmol), DMAP
(0.024 g, 0.2 mmol) and (+)-CSA (0.046 g, 0.2 mmol) in
CH2Cl2 (5 mL) was added a solution of (4R,5S,11S)-10
(0.31 g, 0.65 mmol) and (3R)-9 (0.298 g, 1.37 mmol) in
CH2Cl2 (1 mL) and the reaction mixture was stirred for
1 day at room temperature. The reaction mixture was
worked up in the same way as for the preparation of
(4R,5S,9S,15S)-23 to give (4R,5S,11S,15R)-34 as an oil
(0.385 g, 88%). IR (neat): 1734, 1656 (sh) cm−1; [h]D27
To a mixture of AlCl3 (0.063 g, 0.47 mmol) in CH2Cl2
(3 mL) was added dropwise
a
solution of
(4R,5S,9R,15S)-32 (0.067 g, 0.16 mmol) and m-xylene
(1.5 mL) in CH2Cl2 (3 mL) at −0°C and the reaction
mixture was stirred for 3 h at room temperature. The
reaction mixture was worked up in the same way as for
the preparation of macrosphelide C 1 to give (+)-2
(0.046 g, 89%) as a colorless oil. IR (neat): 3440, 1712
cm−1; [h]2D7 +42.8 (c=0.50, EtOH). The NMR spectra
(1H and 13C NMR) of the synthetic (+)-2 were identical
with those of natural (+)-2.2 Anal. calcd for C16H22O7:
C, 58.89; H, 6.80. Found: C, 58.61; H, 6.99%. FAB MS
m/z; 327 (M++1).
1
−35.6 (c=0.55, CHCl3); H NMR: l 0.02 (3H, s), 0.04
(3H, s), 0.84 (9H, s), 1.15 (3H, d, J=7 Hz), 1.22 (3H, d,
J=7 Hz), 1.26 (3H, d, J=7 Hz), 2.31 (1H, dd, J=6, 15
Hz), 2.44 (1H, dd, J=8, 15 Hz), 2.36–2.51 (2H, m),
4.13 (1H, ddd, J=2, 4, 6 Hz), 4.23 (1H, ddd, J=6, 7, 8
Hz), 4.51, 4.63 (each 1H, d, J=12 Hz), 4.78, 4.81 (each
1H, d, J=12 Hz), 4.99 (1H, tq, J=7, 7 Hz), 5.09 (1H,
dq, J=4, 7 Hz), 5.83 (1H, dt, J=1, 16 Hz), 6.20 (1H,
dd, J=2, 16 Hz), 6.85 (1H, dt, J=7, 16 Hz), 7.01 (1H,
dd, J=7, 16 Hz), 7.25–7.35 (5H, m). Anal. calcd for
C31H45O8SiCl3: C, 54.70; H, 6.67. Found: C, 54.76; H,
6.89%.
4.16. Ester formation between (5S)-15 and (4R,5S)-27
To a mixture of DCC (0.42 g, 2 mmol) and DMAP (0.1
g, 0.82 mmol) in CH2Cl2 (10 mL) was added a solution
of (5S)-15 (500 mg, 2.05 mmol) and (4R,5S)-273c (0.5 g,
1.36 mmol) in CH2Cl2 (3 mL) and the reaction mixture
was stirred for 1 day at room temperature. The reaction
mixture was worked up in the same way as for the
preparation of (4R,5S,9S,15S)-23 to give (4R,5S,11S)-
33 (0.543 g, 67%) as an oil. IR (neat): 1727, 1452 cm−1;
4.19. Desilylation of (4R,5S,11S,15R)-34
A mixture of (4R,5S,11S,15R)-34 (0.319 g, 0.47 mmol)
in a mixed solvent of AcOH (4 mL), H2O (2 mL) and
THF (2 mL) was stirred for 3 h at 80°C. The reaction
mixture was worked up in the same way as for the
1
[h]2D3 +2.8 (c=0.18, CHCl3); H NMR: l 0.02 (3H, s),
0.03 (3H, s), 0.85 (9H, s), 1.14 (3H, d, J=6 Hz), 1.26
(3H, d, J=6 Hz), 2.24–2.36 (2H, m), 3.91 (1H, tq, J=6,
6 Hz), 4.15 (1H, ddd, J=2, 4, 6 Hz), 4.52, 4.63 (each
1H, d, J=12 Hz), 4.78, 4.82 (each 1H, d, J=13 Hz),
5.11 (1H, dq, J=4, 6 Hz), 5.81 (1H, dt, J=2, 16 Hz),
6.21 (1H, dd, J=2, 16 Hz), 6.92 (1H, dt, J=7, 16 Hz),
7.03 (1H, dd, J=6, 16 Hz), 7.26–7.36 (5H, m). Anal.
calcd for C27H39O6SiCl3: C, 54.59; H, 6.62. Found: C,
54.88; H, 6.67%.
preparation
of
(4R,5S,9S,15S)-24
to
give
(4R,5S,11S,15R)-35 as a an oil (0.247 g, 93%). IR
(neat): 3465, 1722, 1656 (sh) cm−1; [h]D28 −37.8 (c=0.50,
1
CHCl3); H NMR: l 1.19 (3H, d, J=7 Hz), 1.24 (3H,
d, J=7 Hz), 1.25 (3H, d, J=7 Hz), 2.37 (1H, dd, J=9,
16 Hz), 2.43 (1H, dd, J=4, 16 Hz), 2.43–2.48 (2H, m),
2.88 (1H, br. s), 4.13 (1H, ddd, J=2, 4, 6 Hz), 4.12–
4.20 (1H, m), 4.51, 4.63 (each 1H, d, J=12 Hz), 4.78,
4.81 (each 1H, d, J=12 Hz), 5.04 (1H, qt, J=7, 7 Hz),
5.10 (1H, dq, J=4, 7 Hz), 5.84 (1H, dt, J=1, 16 Hz),
6.19 (1H, dd, J=2, 16 Hz), 6.84 (1H, dt, J=7, 16 Hz),
7.02 (1H, dd, J=6, 16 Hz), 7.26–7.36 (5H, m). 13C
NMR: l 15.3 (q), 19.8 (q), 22.6 (q), 38.4 (t), 43.1 (t),
64.2 (d), 69.4 (d), 71.3 (d), 71.9 (t), 74.0 (t), 79.5 (d),
94.8 (s), 122.1 (d), 123.8 (d), 127.6 (d), 127.8 (d), 128.3
(d), 137.2 (s), 143.9 (d), 146.5 (d), 163.7 (s), 165.0 (s),
171.9 (s). Anal. calcd for C25H31O8Cl3: C, 53.06; H,
5.52. Found: C, 52.78; H, 5.66%. FAB MS m/z; 565,
567 (M++1).
4.17. Desilylation of (4R,5S,11S)-33
A mixture of (4R,5S,11S)-33 (0.494 g, 0.83 mmol) in a
mixed solvent of AcOH (4 mL), H2O (2 mL) and THF
(2 mL) was stirred for 5 h at 80°C. The reaction
mixture was worked up in the same way as for the
preparation of (4R,5S,9S,15S)-24 to give (4R,5S,11S)-
10 (370 mg, 93%) as an oil. IR (neat): 3455, 1727, 1656
(sh) cm−1; [h]D25 −14.0 (c=0.56, CHCl3); H NMR: l
1
1.22 (3H, d, J=7 Hz), 1.27 (3H, d, J=7 Hz), 1.83 (1H,
br s), 2.34 (2H, ddd, J=1, 7, 7 Hz), 3.94 (1H, qt, J=7,
7 Hz), 4.13 (1H, ddd, J=2, 5, 6 Hz), 4.51, 4.63 (each
1H, d, J=12 Hz), 4.78, 4.82 (each 1H, d, J=12 Hz),
5.10 (1H, dq, J=5, 7 Hz), 5.86 (1H, dt, J=1, 16 Hz),
6.20 (1H, dd, J=2, 16 Hz), 6.93 (1H, dt, J=7, 16 Hz),
7.02 (1H, dd, J=6, 16 Hz), 7.26–7.35 (5H, m). 13C
NMR: l 15.4 (q), 23.4 (q), 41.9 (t), 66.7 (d), 71.2 (d),
72.0 (t), 74.1 (t), 79.5 (d), 94.8 (s), 122.1 (d), 123.5 (d),
127.6 (d), 127.7 (d), 128.3 (d), 137.3 (s), 145.5 (d), 146.7
(d), 163.8 (s), 165.1 (s). Anal. calcd for C21H25O6Cl3: C,
52.57; H, 5.25. Found: C, 52.86; H, 5.54%. FAB MS
m/z; 479, 481 (M++1).
4.20. Deprotection of 2,2,2-trichloroethyl group of
(4R,5S,11S,15R)-35
To a solution of (4R,5S,11S,15R)-35 (0.212 g, 0.38
mmol) and AcOH–AcONa buffer solution (4 mL) in
THF (4 mL) at 0°C was added Zn dust (240 mg, 3.7
mmol) and the whole mixture was stirred for 3 h at
room temperature. The reaction mixture was worked
up in the same way as for the preparation of
(4R,5S,9S,15S)-25 to give the crude seco-acid
1
(4R,5S,11S,15R)-36 (0.147 g, 90%). H NMR: l 1.19
(3H, d, J=7 Hz), 1.23 (3H, d, J=7 Hz), 1.24 (3H, d,

H. Nakamura et al. / Tetrahedron: Asymmetry 13 (2002) 705–713
713
J=7 Hz), 2.39 (1H, dd, J=7, 16 Hz), 2.42 (1H, dd,
J=4, 16 Hz), 2.45 (2H, ddd, J=1, 7, 7 Hz), 4.07 (1H,
ddd, J=2, 4, 6 Hz), 4.12–4.19 (1H, m), 4.47, 4.61 (each
1H, d, J=12 Hz), 5.04 (1H, qt, J=7, 7 Hz), 5.08 (1H,
dq, J=4, 7 Hz), 5.80–6.00 (2H, br s), 5.84 (1H, dt,
J=1, 16 Hz), 6.08 (1H, dd, J=2, 16 Hz), 6.84 (1H, dt,
J=7, 16 Hz), 6.94 (1H, dd, J=6, 16 Hz), 7.25–7.35
(5H, m).
13C NMR) of the synthetic (+)-32 were identical with
those of natural (+)-3.2 Anal. calcd for C16H22O7: C,
58.89; H, 6.80. Found: C, 59.01; H, 6.94%. FAB MS
m/z; 327 (M++1).
Acknowledgements
4.21. Benzyl ether (3R,8R,9S,15S)-37
The authors are grateful to Professor A. Numata at
Osaka University of Pharmaceutical Sciences, for gen-
erously providing the spectral data (1H and 13C NMR)
of natural products (+)-1, (+)-2 and (+)-3.
To a solution of (4R,5S,11S,15R)-36 (0.146 g, 0.33
mmol) and Et3N (0.068 g, 0.68 mmol) in THF (3 mL)
were added a solution of 2,4,6-trichlorobenzoyl chloride
(0.165 g, 0.67 mmol) in THF (3 mL) and the reaction
mixture was stirred for 1.5 h at room temperature. To
a solution of DMAP (0.248 g, 2.03 mmol) in toluene
(20 mL) at 100°C was added dropwise the above-men-
tioned reaction mixture diluted with toluene (170 mL)
over 2 h and the whole mixture was stirred for 1 h at
100°C. The reaction mixture was worked up in the
same way as for the preparation of (3S,9S,14R,15S)-26
to give (3R,8R,9S,15S)-37 as a colorless oil (0.107 g,
76%). IR (CHCl3): 1716, 1660 (sh) cm−1; [h]D29 −22.1
References
1. Takamatsu, S.; Hiraoka, H.; Kim, Y.-P.; Hayashi, M.;
Matori, M.; Komiyama, K.; Omura, S. J. Antibiot. 1997,
50, 878–880.
2. (a) Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.;
Matsumura, E.; Yamori, T.; Tsuruo, T. Tetrahedron Lett.
1997, 38, 8215–8218; (b) Yamada, T.; Iritani, M.; Doi,
M.; Minoura, K.; Ito, T.; Numata, A. J. Chem. Soc.,
Perkin Trans. 1 2001, 3046–3053.
3. (a) Sunazuka, T.; Hirose, T.; Harigaya, Y.; Takamatsu,
S.; Hayashi, M.; Komiyama, K.; Omura, S.; Sprengeler,
P. A.; Smith, A. B., III J. Am. Chem. Soc. 1997, 119,
10247–10248; (b) Kobayashi, Y.; Kumar, B. G.; Kurachi,
T.; Acharya, H. P.; Yamazaki, T.; Kitazume, T. J. Org.
Chem. 2001, 66, 2011–2018; (c) Ono, M.; Nakamura, H.;
Konno, F.; Akita, H. Tetrahedron: Asymmetry 2000, 11,
2753–2764.
1
(c=0.35, CHCl3); H NMR: l 1.20 (3H, d, J=7 Hz),
1.29 (3H, d, J=7 Hz), 1.43 (3H, d, J=7 Hz), 2.32 (1H,
ddt, J=1, 8, 16 Hz), 2.50–2.57 (1H, m), 2.51 (1H, dd,
J=7, 16 Hz), 2.76 (1H, dd, J=4, 16 Hz), 3.95 (1H,
ddd, J=2, 4, 6 Hz), 4.47, 4.58 (each 1H, d, J=12 Hz),
4.96–5.02 (1H, m), 5.18 (1H, dq, J=4, 7 Hz), 5.25 (1H,
ddq, J=4, 7, 7 Hz), 5.75 (1H, dt, J=1, 16 Hz), 6.14
(1H, dd, J=2, 16 Hz), 6.75 (1H, dt, J=7, 16 Hz), 6.90
(1H, dd, J=6, 16 Hz), 7.25–7.35 (5H, m). 13C NMR: l
17.6 (q), 19.4 (q), 20.0 (q), 37.9 (t), 40.2 (t), 67.4 (d),
70.2 (d), 70.5 (d), 70.9 (t), 80.5 (s), 124.0 (d), 124.3 (d),
127.5 (d), 127.7 (d), 128.3 (d), 137.2 (s), 143.5 (d), 143.7
(d), 164.3 (s), 164.9 (s), 169.1 (s). Anal. calcd for
C23H28O7: C, 66.33; H, 6.78. Found: C, 66.40; H,
6.79%. FAB MS m/z; 417 (M++1).
4. Kobayashi, Y.; Acharya, H. P. Tetrahedron Lett. 2001,
42, 2817–2820.
5. Ono, M.; Saotome, C.; Akita, H. Tetrahedron: Asymme-
try 1996, 7, 2595–2602.
6. Nakamura, H.; Ono, M.; Makino, M.; Akita, H. Hetero-
cycles 2002, 57, 327–336.
7. Saotome, C.; Ono, M.; Akita, H. Tetrahedron: Asymme-
try 2000, 11, 4137–4151.
4.22. (+)-Macrosphelide G, 3
8. Oshima, M.; Yamazaki, H.; Shimizu, I.; Nisar, M.; Tsuji,
J. J. Am. Chem. Soc. 1989, 111, 6280–6287.
9. Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl.
1978, 17, 522–524.
10. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–
1993.
To a mixture of AlCl3 (0.043 g, 0.32 mmol) in CH2Cl2
(3 mL) was added dropwise
a
solution of
(3R,8R,9S,15S)-37 (0.066 g, 0.16 mmol) and m-xylene
(1.5 mL) in CH2Cl2 (3 mL) at −5°C and the reaction
mixture was stirred for 2 h at 0°C. The reaction mixture
was worked up in the same way as for the preparation
of macrosphelide C 1 to give (+)-3 as a colorless oil
(0.040 g, 78%). (+)-3; IR (CHCl3): 3465, 1714 cm−1;
[h]2D6 +51.7 (c=0.35, EtOH). The NMR spectra (1H and
11. Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50,
2394–2395.