Synthesis of proposed aglycone of mandelalide A

Article abstract of DOI:10.1021/ol500875e

A highly convergent synthesis of the proposed mandelalide A aglycone is reported. The cornerstones of the synthetic strategy include the following: E-selective intramolecular Heck cyclization, Masamune-Roush olefination, Stork-Zhao-Wittig olefination, mod

Full text of DOI:10.1021/ol500875e

Letter
pubs.acs.org/OrgLett
Synthesis of Proposed Aglycone of Mandelalide A
Karla Mahender Reddy,† Vanipenta Yamini,† Kiran K. Singarapu,‡ and Subhash Ghosh*,†
‡
†Organic and Biomolecular Chemistry Division, Centre for NMR & Structural Chemistry, CSIR-Indian Institute of Chemical
Technology, Tarnaka, Hyderabad-500007, India
S
* Supporting Information
ABSTRACT: A highly convergent synthesis of the proposed mandelalide A
aglycone is reported. The cornerstones of the synthetic strategy include the
following: E-selective intramolecular Heck cyclization, Masamune−Roush
olefination, Stork−Zhao−Wittig olefination, modified Prins cyclization;
Sharpless asymmetric dihydroxylation followed by Williamson-type ether-
ification, Julia−Kocienski olefination, Brown crotylation, and Brown allylation
reactions.
scidians, commonly known as sea squirts, are a vital source
of marine natural products with wide ranging biological
low natural abundance. Thus, a complex architecture and
promising biological activities, along with limited availability
from natural sources, impelled us to undertake a total synthesis
of highly potent mandelalide A. While we were attempting to
communicate our results in the form of the present manuscript,
A
activities. Natural products isolated from sea squirts have a huge
potential to become drugs, and they have already provided two
important drugs in clinical use for cancer therapy.1 In 2012,
McPhail and co-workers isolated a new class of unusual
glycosylated polyketide macrolides, called mandelalides A−D2
(Figure 1), via bioassay guided fractionation of the cytotoxic
Furstner and Willwacher3 reported an elegant synthesis of
̈
mandelalide A, where they claimed that the structure of
mandelalide A, proposed by McPhail et al., does not
correspond to the originally published structure. As they
observed significant 13C NMR chemical shift variation
particularly with respect to the C25 and C11 carbons, this
prompted them to attempt a synthesis of its C11-epimer, but
this also showed spectral deviation from the reported natural
product, which led them to conclude more than one
misassignment in the originally proposed structure of
mandelalide A. This account describes the synthesis of a fully
functionalized aglycone of the originally reported structure of
mandelalide A.
The retrosynthetic analysis outlined in Scheme 1 shows that
the disconnection of 5 would lead to the phosphonate 6 and
aldehyde 7. Assembly of the 24-membered macrocyclic core 5
would proceed through Masamune−Roush olefination between
6 and 7 at C2−C3 which would be followed by E-selective
intramolecular Heck cyclization at C12−C13. The phospho-
nate 6 would be derived from aldehyde 8 via Stork−Zhao−
Wittig olefination followed by acylation with diethyl
phosphonoacetic acid, and 8 could be obtained from alcohol
9 by Sharpless asymmetric dihydroxylation followed by
Williamson-type etherification. The aldehyde 7, with a pyran
unit, could be obtained from ester 10 by utilizing segment
coupling Prins cyclization, developed by Rychnovsky and co-
Figure 1. Mandelalides A−D.
extracts of a new Lissoclinum species from Algoa Bay, South
Africa. The absolute structures were confirmed by extensive
NMR, mass spectral, and GC studies.
Biological evaluation of mandelalides A and B revealed
remarkably potent cytotoxic activity against cancer cell lines in
human lung cancer cells (NCI-H460, IC50 = 12 nM, 29 nM
respectively) and mouse neuroblastoma (Neuro-2A, IC50 = 44
nM, 84 nM respectively). This promising preliminary
cytotoxicity result against two different cancer cell lines
demands detailed biological evaluations of the Mandelalide
family. However, such biological studies are hampered by their
Received: March 24, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
modified Julia-olefination7 with the known sulfone 158 afforded
the chromatographically pure E-olefin 16 in 80% yield (two
steps). Cleavage of the PMB ether with buffered DDQ9
afforded the alcohol 9 in 95% yield. The secondary alcohol 9
was converted to its mesylate by MsCl and Et3N, which upon
Sharpless asymmetric dihydroxylation10 with AD-mix-β
afforded diol, which underwent in situ Williamson-type
etherification11 to provide exclusively THF alcohol 17 with
excellent diastereoselectivity (79% yield, two steps). The
rigorous five-membered-ring selectivity in Williamson-type
etherification can be explained in terms of extended Baldwin
rules12 where the 5-exo-tet cyclization is favored over the 6-exo-
tet cyclization. Alcohol 17 upon silylation with TBSOTf,
followed by selective desilylation of the primary TBS with HF-
Py, furnished primary alcohol 18 in 80% yield over two steps.
Dess-Martin periodinane oxidation of primary alcohol 18
afforded aldehyde, which was eventually converted to terminal
Z-vinyl iodide 19 by Stork−Zhao−Wittig olefination protocol13
with (iodomethyl)triphenylphosphonium iodide in 75% yield
(Z/E = 96:4). Selective hydrolysis of the acetonide of 1914
followed by chemoselective TBS protection of the primary
alcohol provided 20 (84% yield, over two steps) which, upon
esterification with diethyl phosphonoacetic acid under EDCI,
DMAP conditions, afforded phosphonate 6 in 94% yield.
The synthesis of pyran segment 7 commenced from known
compound 1115(Scheme 3). Ozonolysis of 11 furnished an
Scheme 1. Retrosynthesis of Mandelalide A Aglycone
workers. The ester 10 was expected to be prepared from alkene
11 by Brown allylation followed by acylation.
Scheme 3. Synthesis of Pyran Aldehyde 7
The synthesis of phosphonate 6 commenced from known
compound 134 (Scheme 2), which was readily obtained from
12 by Brown crotylation followed by protection of the hydroxyl
group as a PMB ether. Hydroboration5 of 13 with BH3·Me2S
followed by oxidation gave primary alcohol 14 in 85% yield
which, on Dess-Martin periodinane6 oxidation, followed by
Scheme 2. Synthesis of Phosphonate Fragment 6
aldehyde, which was subjected to Brown asymmetric
allylation16 with (−)-Ipc2BOMe and allyl magnesium bromide
at −78 °C to give alcohol 21 in 70% yield as a single
diastereomer (dr > 20:1). Acylation of 21 with acid 22 under
DCC−DMAP conditions provided compound 10 in 95% yield.
Careful reduction of compound 10 followed by acetyl
protection of the resulting lactol gave α-acetoxy ether17
which, on segment coupling Prins cyclization18 with BF3·OEt2
B
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Organic Letters
Letter
and acetic acid in hexanes at 0 °C, followed by C4-OAc
deprotection of the resulting pyran ring, afforded the desired
pyran alcohol 23 in 40% yield (three steps). This, upon TBS
protection with TBSOTf, followed by selective deprotection of
TBDPS under basic conditions,19 furnished primary alcohol 24
in 77% yield over two steps. Alcohol 24 was oxidized with
Dess-Martin periodinane to give an aldehyde which was
subjected to Julia−Kocienski olefination with known sulfone
25,20 to give olefin 26 in 80% yield. Finally DDQ mediated
PMB deprotection followed by oxidation of the resulting
primary alcohol completed the synthesis of the aldehyde
fragment 7.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: subhash@iict.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
K.M.R. and V.Y. thank CSIR, New Delhi for a research
fellowship. S.G. is thankful to the Council of Scientific and
Industrial Research for a CSIR-Young Scientist Research Grant.
We are also thankful to Dr. A. C. Kunwar for useful suggestions.
The end game for the construction of the aglycone is
depicted in Scheme 4. The Horner−Wadsworth−Emmons
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̈
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ASSOCIATED CONTENT
■
1
(23) A detailed comparison of H and 13C chemical shifts between
S
* Supporting Information
mandelalide A (isolation), mandelalide A (synthetic), and compound
5 is available in the Supporting Information.
Experimental procedures and full spectroscopic data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
C
dx.doi.org/10.1021/ol500875e | Org. Lett. XXXX, XXX, XXX−XXX