LETTER
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lAetteCr onvergent and Stereoselective Total Synthesis of Phomolides G and H
Synthesis of Phomolides G and H
B. V. Subba Reddy,*a P. Sivaramakrishna Reddy,a B. Phaneendra Reddy,a,b J. S. Yadava
a
Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: basireddy@iict.res.in
b
Department of Chemistry, Yogi Vemana University, Kadapa 516003, Andhra Pradesh, India
Received: 20.09.2013; Accepted after revision: 13.11.2013
OH
OH
Abstract: A stereoselective total synthesis of phomolides G and H,
a polyketide natural products is described. The synthesis involves
organocatalytic enantioselective asymmetric epoxidation, C1-Wit-
tig olefination, and ring-closing metathesis as key steps. The use of
organocatalytic MacMillan asymmetric epoxidation for the con-
struction of two chiral centers of phomolides G and H makes this
approach more attractive.
HO
OH
HO
OMe
O
O
O
O
phomolide G
phomolide H
Key words: MacMillan asymmetric epoxidation, ring-closing me-
tathesis, decalactones
O
HO
O
OH
O
O
O
Polyhydroxy macrolides were isolated as secondary me-
tabolites of terrestrial and marine organisms, such as bac-
teria, fungi, and plants. They are found to exhibit various
biological activities such as antibacterial, antifungal, phy-
totoxic, or enzyme-inhibitory effects.1 In particular, the
ten-membered macrolides such as sonnerlactones,2 decar-
estrictines,3 modiolides,4 and stagonolides5 have received
significant attention due to their interesting biological
properties.
stagonolide A
modiolides B
O
O
OH
O
O
HO
O
HO
(3R,5R)-sonnerlactone
OH
decarestrictine J
Figure 1 Examples of ten-membered macrolides
Phomolides G (1, Figure 1) and H (2), were isolated from
the leaves of mangrove species, that is, Kandelia candel.6
Due to their interesting biological activity and natural
scarcity, these natural products have attracted immense
interest to take up their total synthesis for further biologi-
cal evaluation.7
responding aldehyde 7 in 90% yield.10 The aldehyde was
then subjected to organocatalyzed asymmetric epoxida-
tion using catalyst A to give the terminal epoxide 8 (93%
de, by HPLC analysis) in 86% yield.11 Regioselective ring
opening of epoxide 8 with ethylmagnesium bromide in the
presence of a catalytic amount of copper(I) iodide gave
the corresponding alcohol 9 in quantitative yield. Deben-
zylation of compound 9 with Li/naphthalene in THF af-
forded the primary alcohol 10 in 84% yield. Oxidation of
alcohol 10 with DMP in CH2Cl2 gave the corresponding
lactol, which upon C-1 Wittig olefination, afforded the al-
kenol 11 in 75% yield (Scheme 2).
In continuation of our efforts in the area of biologically
active natural product synthesis,8 we herein report a con-
vergent and stereoselective total synthesis of phomolides
G and H starting from a readily available dimethyl L-tar-
trate (Scheme 1).
Our retrosynthetic analysis of the target molecules 1 and
2 revealed that they could be synthesized by means of
ring-closing metathesis of 18, which could in turn be pre-
pared through the esterification of the alkenol 11 derived
from readily available dimethyl L-tartrate (3, Scheme 1).
Next, we attempted the synthesis of another key interme-
diate 17 from butane-1,4-diol (12). Monoprotection of the
diol 12 with BnBr in the presence of NaH in THF afforded
the benzyl ether 13 in 88% yield. Oxidation of alcohol 13
with IBX gave the corresponding aldehyde, which was
then subjected to organocatalyzed asymmetric epoxida-
tion using catalyst A, and resulted in the formation of ep-
oxide 14 (95% ee, by HPLC analysis) in 85% yield.11
Treatment of epoxide 14 with trimethylsulfonium iodide
in the presence of n-BuLi in THF at –20 °C gave the allyl-
ic alcohol in 88% yield,12 which was then protected as its
TBS ether 15 using TBSCl and imidazole. Debenzylation
of 15 with Li/naphthalene afforded the alcohol 16 in 85%
yield. One-pot oxidation of 16 with 2,2,6,6-tetramethylpi-
Accordingly, oxidation of alcohol 4 with tetrapropylam-
monium perruthenate (TPAP) followed by Wittig
olefination9 afforded the trans-olefinic ester 5 in 80%
overall yield. Reduction of 5 with diisobutylaluminum
hydride (DIBAL-H) afforded the allylic alcohol 6 in 85%
yield. Isomerization of 6 using 7 mol% of preactivated
Pd(OH)2/C in benzene at room temperature gave the cor-
SYNLETT 2014, 25, 0501–0504
Advanced online publication: 10.01.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340348; Art ID: ST-2013-D0895-L
© Georg Thieme Verlag Stuttgart · New York