Stereoselective synthesis of C1-C12 fragment of amphotericin B

Article abstract of DOI:10.1016/j.tetlet.2014.10.017

An efficient synthesis of C1-C12 fragment of amphotericin B is described. The synthesis is based on asymmetric dihydroxylation and cross-metathesis reactions.

Full text of DOI:10.1016/j.tetlet.2014.10.017

Tetrahedron Letters 55 (2014) 6474–6476
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Stereoselective synthesis of C1–C12 fragment of amphotericin B
⇑
Akkapalli Rajesh , Gangavaram V. M. Sharma, Krishna Damera
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of C1–C12 fragment of amphotericin B is described. The synthesis is based on asym-
metric dihydroxylation and cross-metathesis reactions.
Received 17 July 2014
Revised 2 October 2014
Accepted 3 October 2014
Available online 13 October 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric dihydroxylation
Cross-metathesis
Stereoselective
L-malic acid
Amphotericin B is a polyene antifungal agent first isolated from
tion and dihydroxylation, while C5 and C11 are from L-malic acid.
Streptomyces nodosus in 1955 from Venezuelan soil.1 Amphotericin
B (1) has remained the cornerstone of the therapy of serious sys-
temic fungal infections,2–4 and the only complex polyene macro-
lide whose molecular structure and absolute configuration are
firmly established by X-ray crystallographic analysis.5 Due to its
biological activity and structural features (polyene and 1,3-diols,
1,4-diols and 1,2 diols system) amphotericin B and its aglycon
amphoteronolide B, generated considerable interest for the devel-
opment of both new and existing synthetic methods.6–10 The ear-
lier work by Nicolau6–8 and others9,10 reported the synthesis of
C1–C12 fragment as a crucial intermediate for the successful total
synthesis of 1. In continuation of our interest in the synthesis of
bioactive natural product synthesis,11 herein we report the stereo-
selective synthesis of C1–C12 of 1 using olefin cross-metathesis.
Fragment 3 was achieved from compounds 4 and 5 by cross-
metathesis reaction.
Synthesis of fragment 4
Accordingly, the synthesis of fragment 4 starts with known com-
pound 712 (Scheme 2), which is readily obtained from
L-malic acid.
Thus, compound 7 was treated with benzaldehyde dimethyl acetal
and pyridinium p-toluenesulfonate (PPTS) in CH2Cl2 at room tem-
perature, which to afford 8 in 86% yield. Regioselective reductive
opening of the acetal 8 from the less hindered side with DIBAL-
H13 (20% solution in toluene) in CH2Cl2 at 0 °C to room temperature
for 1 h gave the corresponding alcohol 9 exclusively in 80% yield.
Compound 9 was further treated with PPTS in MeOH to cleave ace-
tonide to afforded diol 10 in 74% yield. Diol in compound 10 was
treated with anisaldehyde dimethyl acetal and PPTS (cat.) in CH2Cl2
at room temperature to afford the PMP acetal 11 in 80% yield. Reac-
tion of alcohol 11 with tert-butyl(chloro)diphenylsilane (TBDPSCl)
and imidazole in CH2Cl2 at room temperature for 5 h gave silyl ether
12 in 77% yield. Selective opening of the PMP acetal with DIBAL-H13
via chelation resulted in the desired PMB ether 13 exclusively in
72% yield. Oxidation of the alcohol 13 with Dess–Martin period-
inane gave aldehyde 13a, which after Wittig olefination with
(methylene)triphenyl phosphonium bromide and n-BuLi in THF at
À10 °C for 10 min afforded olefin 14 in 62% yield. Finally oxidative
deprotection of PMB ether in compound 14 with 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) at room temperature for 1 h fur-
nished alcohol 4 in 70% yield (Scheme 2).
OH
OH
12
1
O
OH
HO
O
OH OH
OH OH
O
CO2H
H
O
O
Amphotericin B (1)
HO
OH
NH2
In the retrosynthetic analysis (Scheme 1) of the C1–C12 frag-
ment of amphotericin B (1), we envisioned the introduction of
the desired C3, C8 and C9 through Sharpless asymmetric epoxida-
Having successfully synthesized 4 we next aimed the synthesis
of sub fragment 5 from the same starting material L-malic acid 6.
⇑
Corresponding author. Tel.: +91 9908178304.
E-mail address: rajesh.rjsiict@gmail.com (A. Rajesh).
http://dx.doi.org/10.1016/j.tetlet.2014.10.017
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

A. Rajesh et al. / Tetrahedron Letters 55 (2014) 6474–6476
6475
O
O
12
1
TBDPSO
TBDPSO
O
OBn
OBn
OH
O
O
OH
O
OH
3
2
O
O
OH
CO2H
TBDPSO
O
HO
O
O
OBn OH
6 L-malic acid
4
5
Scheme 1. Retrosynthetic strategy of amphotericin B (1).
Ph
O
OBn
OH
O
O
O
O
O
b
c
a
O
O
OH
OH
86%
80%
74%
9
7
8
PMP
PMP
O
OH OBn
O
OBn
O
OBn
e
HO
d
80%
O
OH
OTBDPS
77%
OH
10
12
11
OBn
OBn
PMBO
HO
PMBO
O
f
g
b
72%
OTBDPS
OTBDPS
62%
13
13a
OBn
HO
OBn
14
PMBO
h
70%
OTBDPS
OTBDPS
4
Scheme 2. Reagents and conditions: (a) benzaldehyde dimethyl acetal, pyridinium p-toluenesulfonate (PPTS), CH2Cl2, 0 °C to rt, 3 h, 86%, (b) DIBAL-H, CH2Cl2, 0 °C to rt, 1 h,
80%, (c) pyridinium p-toluenesulfonate (PPTS), MeOH, 0 °C to rt, 30 min, 74%, (d) p-anisaldehyde dimethyl acetal, pyridinium p-toluenesulfonate (PPTS), CH2Cl2, 0 °C to rt, 3 h,
80%, (e) tert-butyl(chloro)diphenylsilane (TBDPSCl), imidazole, CH2Cl2, 0 °C to rt, 5 h, 77%, (f) Dess–Martin periodinane, CH2Cl2, 0 °C to rt, 30 min, (g) CH3Ph3P+BrÀ, n-BuLi, THF,
0 °C, 30 min, 62%, (h) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), CH2Cl2/H2O (19:1), 0 °C to rt, 1 h, 70%.
O
O
O
O
O
O
O
O
O
OH
O
c
b
a
O
O
O
O
O
O
O
72%
77%
75%
15
16
O
17
OH
O
e
d
O
O
O
66%
O
OH
O
O
18
O
5
O
19
Scheme 3. Reagents and conditions: (a) ADmix-b, tBuOH/H2O (1:1), 0 °C, 24 h, 75%, (b) 2,2-DMP, PPTS, CH2Cl2, 0 °C to rt, 3 h, 72%, (c) DIBAL-H, CH2Cl2, 0 °C, 1 h, 77%, (d)
(COCl)2, DMSO, Et3N, À78 °C, 1 h, (e) CH+3PPh3IÀ, K+ÀOtBu, THF, À10 °C, 30 min, 66%.
N
Cl
N
Mes
Mes
Ph
Ru
Cl
PCy3
O
Gr-II
Gr-II, CH2Cl2, rt,
O
TBDPSO
TBDPSO
O
+
O
OBn OH
O
O
6 h, 63%
OBn OH
O
O
3
4
5
Scheme 4.
Whereas the stereocentre in 6 is retained as C11 stereocentre, the
C8/C9 stereocentres were introduced by asymmetric dihydroxyla-
tion. Accordingly, Sharpless asymmetric dihydroxylation of known
oxidation conditions and the resulting aldehyde was subjected to
Wittig reaction using (methylene)triphenyl phosphonium iodide
to provide the desired product with terminal olefin compound 5
in 66% yield.
t
compound 1513 with AD-mix-b14,15 in BuOH/H2O (1:1) at 0 °C for
24 h furnished compound 16 as a major isomer (Scheme 3) in 75%
yield. The resulted 1,2-diol in compound 16 was protected with
acetonide on treatment with 2,2-dimethoxy propane and pyridini-
um p-toluenesulfonate (PPTS) in CH2Cl2 at 0 °C to room tempera-
ture for 3 h to afford compound 17 in 72% yield. Reduction of
ester 17 with DIBAL-H in CH2Cl2 at 0 °C for 1 h furnished alcohol
18 in 77%. Alcohol 18 further oxidized to aldehyde 19 under Swern
Synthesis of fragment 3
Having synthesized 4 and 5 with five stereocentres, it was next
proposed to couple them by a C–C bond formation. Accordingly, a
mixture of olefins 4 and 5 in CH2Cl2 in the presence of Grubbs 2nd
generation16 catalyst furnished 3 in 63% yield (Scheme 4).

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A. Rajesh et al. / Tetrahedron Letters 55 (2014) 6474–6476
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5. Mechlinski, W.; Schaffner, C. P.; Ganis, P.; Avitabile, G. Tetrahedron Lett. 1970,
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T. K. J. Am. Chem. Soc. 1988, 110, 4672–4685.
In conclusion, we have established a stereoselective strategy for
the synthesis of the key intermediate C1–C12 of amphotericin B.
This work features synthesis of the two sub-fragments from com-
mon starting material
L-malic acid and installation of C8/C9
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1988, 110, 4685–4696.
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hydroxy groups by Sharpless asymmetric dihydroxylation and
finally olefin cross-metathesis to complete the synthesis.
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Acknowledgements
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All the authors are thankful for the financial support from MLP-
0008 of CSIR, New Delhi India. A.R. is thankful to CSIR, New Delhi
for the fellowship.
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