Synthesis of the A ring segment of gambieric acid

Article abstract of DOI:10.1016/S0040-4039(01)00529-9

The A ring fragment of gambieric acids was stereoselectively synthesized based on an Evans' asymmetric alkylation, Brown's asymmetric crotyl-, allylboration and an intramolecular S_N2 reaction.

Full text of DOI:10.1016/S0040-4039(01)00529-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3645–3647
Synthesis of the A ring segment of gambieric acid
Isao Kadota,a Nao Ogurob and Yoshinori Yamamotob,*
aResearch Center for Organic Resources and Material Chemistry, Institute for Chemical Reaction Science, Tohoku University,
Sendai 980-8578, Japan
bDepartment of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 13 March 2001; revised 21 March 2001; accepted 29 March 2001
Abstract—The A ring fragment of gambieric acids was stereoselectively synthesized based on an Evans’ asymmetric alkylation,
Brown’s asymmetric crotyl-, allylboration and an intramolecular SN2 reaction. © 2001 Elsevier Science Ltd. All rights reserved.
Gambieric acids A–D, potent antifungal substances
isolated from the culture medium of the marine
dinoflagellate Gambierdiscus toxicus in 1992, have
trans-fuzed polycyclic ether skeletons including five-,
six-, seven-, and nine-membered ether rings.1 Their
unprecedented antifungal activities against Aspergillus
niger were 2000 times greater than that of amphotericin
B, a widely used antifungal agent. The low toxicity of
gambieric acids against mice and cultured mammalian
cells points to the potential of the acids as antifungal
drugs. Very recently, the absolute configurations were
determined by NMR analysis.2 In this paper, we report
the stereoselective synthesis of the A ring segment of
gambieric acids.
Our synthetic strategy is illustrated in Scheme 1. The
tetrahydrofuran ring of the target molecule 2 is broken
by the intramolecular SN2 reaction leading to 3. It was
thought that the cyclization precursor 3 would be syn-
thesized by Brown’s asymmetric crotyl- and allylbora-
tion from the known starting material 4, which can be
prepared by Evans’ asymmetric alkylation.
Ozonolysis of 4,3 prepared by Evans’ stereoselective
alkylation,4 followed by the treatment of the resulting
aldehyde with 1,3-propanediol in the presence of p-
toluenesulfonic acid gave the acetal 5 in 93% yield
(Scheme 2). Removal of the chiral auxiliary was per-
formed using LiBH4 to give the alcohol 6 in 90% yield.5
Me
H
H
H
Me Me
H
F
O
O
C
H
O Me
OH
H
HO
HO
E
B
D
O
G
O
Me
H
O
H
H
O H
H
H
A
H
H O
I
O
H
H
J
H
HO2C
Me O
Me
Me
H
Me
Gambieric acid A (1)
OH
Bn
O
OH
O
N
O
O
O
H
H
O
OTBS
O
O
2
3
4
Scheme 1. Retrosynthesis of the A ring segment 2.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00529-9

3646
I. Kadota et al. / Tetrahedron Letters 42 (2001) 3645–3647
Bn
Bn
O
a
b
O
e
N
O
N
O
OH
O
O
O
O
O
O
O
O
4
5
6
d
c
O
O
OH
OTBS
7
8
O
O
OR
g
h
f
O
OH
O
OTBS
OTBS
3: R = H
9
10: R = Ms
O
O
+
O
H
O
H
O
OR
11: R = TBS (68%)
12: R = H (14%)
2 (7%)
Scheme 2. (a) (i) O3, MeOH, −78°C; Me2S, −78°C to rt; (ii) 1,3-propanediol, p-TsOH, benzene, reflux, 93%; (b) LiBH4, H2O,
ether, 0°C to rt, 90%; (c) (i) (COCl)2, DMSO, CH2Cl2, −78°C; Et3N, −78°C to rt; (ii) dIpc2B-(Z)-crotyl, THF, −78°C; H2O2,
NaOH, 65°C, 72%; (d) TBSCl, 2,6-lutidine, CH2Cl2, 0°C to rt, 100%; (e) 9-BBN, THF, rt; H2O2, NaOH, rt, 91%; (f) (i)
Dess–Martin periodinane, NaHCO3, CH2Cl2, rt, 84%; (ii) dIpc2B-allyl, ether, −78°C; H2O2, NaOH, rt, 88%; (g) MsCl, Et3N,
CH2Cl2, 0°C to rt, 100%; (h) TBAF, THF, rt.
Swern oxidation of 6 gave the corresponding aldehyde,
which was subsequently treated with (Z)-crotyldiiso-
pinocamphenylborane derived from (+)-pinene, to
afford the homoallylic alcohol 7 in 72% yield with high
diastereoselectivity.6 No other stereoisomers were
detected in this reaction. Protection of the hydroxy
group with TBSCl and subsequent hydroboration of
the resulting TBS ether 8 using 9-BBN gave the pri-
mary alcohol 9 (91% from 7). Dess–Martin oxidation of
9 followed by Brown’s asymmetric allylboration gave
the alcohol 3 in 80% yield with high diastereoselectivity
(16:1).7 The secondary alcohol 3 was converted to the
mesylate 10, which was then subjected to a one-pot
desilylation–cyclization reaction.8 Unfortunately, treat-
ment of 10 with TBAF at room temperature gave the
cyclization product 2 in only 7% yield along with large
amounts (82%) of the dienes 11 and 12. Elimination of
the homoallylic mesylate 10 giving the conjugated diene
would appear to be faster than desilylation under these
basic conditions.
Since several attempts at improving the yield of 2
resulted in failure,9 we next examined the preparation
of the cyclization substrate 15 which has a protected
hydroxy group, instead of an olefin, at the terminus of
the carbon chain (Scheme 3). Ozonolysis of 3, a reduc-
tive workup with Me2S, and treatment of the resulting
aldehyde with NaBH4 gave the diol 13 in 82% yield.
Selective protection of the primary hydroxy group with
PvCl/pyridine gave 14 in 71% yield. The secondary
alcohol of 14 was converted to the mesylate 15 in
quantitative yield. The cyclization precursor 15 was
treated with TBAF to give 16 in 11% yield. A mixture
of olefins 17 was obtained as the major product. The
O
OMs
O
OH
a
c
3
O
OPv
O
OR
OTBS
OTBS
13: R = H
15
b
14: R = Pv
O
d
O
+
OPv
O
H
H
O
OPv
17 (55%)
O
OTBS
16 (11%)
Scheme 3. (a) O3, MeOH, −78°C; Me2S, −78 to 0°C; NaBH4, 0°C to rt, 82%; (b) PvCl, pyridine, CH2Cl2, 0°C to rt, 71%; (c)
MsCl, Et3N, CH2Cl2, 0°C to rt, 89%; (d) TBAF, THF, rt to 65°C.

I. Kadota et al. / Tetrahedron Letters 42 (2001) 3645–3647
3647
O
O
a
b
c
7
O
OH
O
OTES
OTES
19
18
O
O
OH
O
O
OH
e
d
f
O
O
O
OR
OTES
OTES
OTES
21: R = H
20
22: R = Pv
OMs
g
OPv
O
H
OPv
H
O
16
23
Scheme 4. (a) TESCl, 2,6-lutidine, CH2Cl2, 0°C to rt, 100%; (b) 9-BBN, THF, rt; H2O2, NaOH, rt, 86%; (c) (i) Dess–Martin
d
periodinane, NaHCO3, CH2Cl2, rt, 84%; (ii) Ipc2B-allyl, ether, −78°C; H2O2, NaOH, rt, 95%; (d) O3, MeOH, −78°C; Me2S, −78
to 0°C; NaBH4, 0°C to rt, 71%; (e) PvCl, pyridine, CH2Cl2, 0°C to rt, 56%; (f) MsCl, Et3N, CH2Cl2, 0°C to rt, 100%; (g) TBAF,
THF, rt, 84%.
Acknowledgements
4.4%
2.23
Hb
3.40
Ha
This work was financially supported by the Grant-in-
Aid for Scientific Research from the Ministry of Educa-
tion, Science and Culture of Japan.
OPv
O
O
Me
Hc
4.13
0.91
Me
H
O
References
4.6%
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Figure 1. NOE experiments on 16.
above trials indicated that the TBS ether having two
methyl groups on neighboring carbons was quite stable
under the usual deprotection conditions.
Scheme 4 shows our final synthetic approach using a
TES ether as the protective group instead of TBS. The
alcohol 7 was converted to the cyclization precursor 23
in good yield by similar procedures to those described
in Schemes 2 and 3. Treatment of 23 with TBAF at
room temperature promoted the cleavage of the TES
ether smoothly and the subsequent intramolecular SN2
reaction to give the tetrahydrofuran 16 as the sole
product in 84% yield.
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Soc. 1982, 104, 1737–1738.
5. Conversion to the corresponding Weinreb amide failed.
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conditions.
MeNHOMe·HCl
AlMe3
O
N
5
O
OMe
CH2Cl2, -10 ˚C
O
6. (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986,
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position of the starting material.
1
The stereochemistry of 16 was confirmed by H NMR
analysis and NOE experiments as shown in Fig. 1. The
observed NOE (4.4%) between Ha (3.40 ppm) and Hb
(2.23 ppm) indicates the cis relationship of these pro-
tons. Irradiation of the methyl protons (0.91 ppm) gave
a significant enhancement (4.6%) of the resonance of
the Hc proton (4.13 ppm). No NOE was observed
between the Ha and Hc protons.
.
.