Spirastrellolide B: The synthesis of southern (C9-C 2S) region

Article abstract of DOI:10.1021/ol801771s

(Chemical Equation Presented) A combination of chiron and asymmetric approaches is utilized to construct the southern (C ₉-C₂₅) region of marine natural product spirastrellolide B. The key functionalities are derived from _D-glucose and Sharpless asymmetric epoxidation and dihydroxylation.

Full text of DOI:10.1021/ol801771s

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4355-4357
Spirastrellolide B: The Synthesis of
Southern (C9-C25) Region
Srivari Chandrasekhar,* Chegondi Rambabu, and Annareddy Syamprasad Reddy
Organic DiVision-I, Indian Institute of Chemical Technology, Hyderabad, India 500 007
sriVaric@iict.res.in
Received July 31, 2008
ABSTRACT
A combination of “chiron” and “asymmetric” approaches is utilized to construct the southern (C9-C25) region of marine natural product
spirastrellolide B. The key functionalities are derived from D-glucose and Sharpless asymmetric epoxidation and dihydroxylation.
Marine invertebrates have been challenging the natural
product chemist with structurally diverse and biologically
very potent new chemical entities.1 Spirastrellolides A and
B (1 and 2) were isolated from the Caribbean sponge
Spirastrella coccinea, and the structures were disclosed by
Andersen et al.2 The stereochemical conformation was also
well-established by X-ray crystallography.3 These complex
spiro natural products have shown tremendous potential in
selective inhibition of protein phosphatase PP2A, thus turning
out to be promising in cancer chemotherapy.4 Undoubtedly,
these scarce natural products have attracted top schools of
synthesis to embark on total synthesis.5-11 Our group is
engaged in the total synthesis of marine natural products12
and was attracted to the fascinating biological profile of
spirastrellolides. In this communication, we report our
preliminary studies that resulted in the synthesis of the
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R. J. J. Am. Chem. Soc. 2007, 129, 508.
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Forsyth, C. J. Heterocycles 2007, 72, 621
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C. R. Tetrahedron 2008, 64, 5174. (b) Chandrasekhar, S.; Vijeender, K.;
Chandrashekar, G.; Reddy, C. R. Tetrahedron: Asymmetry 2007, 20, 2473.
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10.1021/ol801771s CCC: $40.75
Published on Web 09/03/2008
2008 American Chemical Society

southern (C9-C25) domain of spirastrellolide B, which is also
a part of the structure in another similar family of polyketides
including spirastrellolide C.13
Scheme 1
asymmetric dihydroxylation on 9 was highly diastereo- and
enantioselective in furnishing the diol 10 in 92% yield
(Scheme 2).16 The camphorsulphonic acid catalyzed keta-
Scheme 2
Figure 1. Structure of spirastrellolides A (1) and B (2) and
retrosynthetic analysis of the spirastrellolides.
lization of 1,2-diol of 10 was rather routine to furnish 11
(96% yield). A high yielding LiAlH4 reduction of ester 11
to alcohol 12 (98% yield) followed by IBX oxidation and
diastereoselective allylation17 (Zn, allylbromide, sat. NH4Cl)
yielded 13 as an unseparable mixture of syn and anti isomers
(20:80 by HPLC). The silylation of homoallyl alcohol 13
allowed us to separate the mixture by a simple chromatog-
raphy to get 14a and 14b in over 94% collective yield
(Scheme 2). The stereochemistry at the newly generated
hydroxyl group during allylation was confirmed by NMR
studies (C-20 of the target molecule).18
The major diastereomer 14a was desilylated in quantita-
tive yield to 13a which was methylated (NaH, MeI) to 15
(Scheme 3). The hydroboration of the terminal olefin was
accomplished with 9-BBN to get 16 which was further
oxidized to get the subtarget 4.
As shown in Figure 1, our overall strategy for the target
fragment 3 involves disconnection at the C8-C9 and the
C25-C26 bonds, affording two subtargets 4 and 5, respec-
tively. The subtarget 4 as represented was derived from
D-glucose, whereas subtarget 5 was realized from known
chiral epoxide 6,14 obtainable by Jacobsen epoxidation.
The first requirement was the preparation of the C17 to
C25 fragment, which was conceived from D-glucose. The
known furanose 715 on selective hydrolysis yielded the diol
8 which underwent a smooth periodate cleavage and two
carbon Wittig olefination to get the R,ꢀ-unsaturated ester 9
in 95% overall yield in two steps (Scheme 1). The Sharpless
The journey toward the synthesis of subtarget 5 began
from known epoxide 6 which was opened with propargyl
ether 17 using n-BuLi as base and BF3·OEt2 as Lewis acid
(13) Williams, D. E.; Keyzers, R. A.; Warabi, K.; Desjardine, K.; Riffell,
J. L.; Roberge, M.; Andersen, R. J. J. Org. Chem. 2007, 72, 9842.
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K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. J. Am. Chem. Soc. 2002,
124, 1307.
(15) Kinoshita, M.; Mariyama, S. Bull. Chem. Soc. Jpn. 1975, 48, 2081.
(16) Kolb, H. C.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483.
(17) Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104.
(18) (a) See the Supporting Information. (b) Hoye, T. R.; Jeffrey, C. S.;
Shao, F. Nat. Protocols 2007, 2, 2451.
(19) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974. (b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(20) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873.
(21) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
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Org. Lett., Vol. 10, No. 19, 2008

The union of the two subtargets 4 and 5 was established
through the acetylenic anion of 5 and the aldehyde func-
tionality of 4 using n-BuLi to generate the targeted carbon
framework 26 as a diastereomeric mixture (Scheme 5). The
Scheme 3
Scheme 5
catalyst to generate homopropargyl alcohol 18 (Scheme
4). The benzylation of alcohol in 18 was realized using
Scheme 4
newly created diastereomeric hydroxyl group was oxidized
to 27, which becomes the common precursor of spiras-
trellolides. The saturation of acetylenic functionality to 28
was followed by the in situ hydrolysis (0.8% H2SO4) which
transformed the acyclic synthon to spiro framework 3 in
reasonable yields. Slight amount of over hydrolysis was
noticed as evidence in the isolation of 29a and 29b. The
diol 29a can be converted back to 3 in the presence of 2,2-
DMP and CSA.
Thus, a stereoconvergent approach allowed us to complete
the southern portion of the rather complex natural product,
spirastrellolide B. Both chiron and Sharpless reactions were
effectively combined to yield the target. Progress toward the
total synthesis will be reported in due course.
NaH as base and benzyl bromide which on further
hydrolysis with p-TSA in MeOH provided 19. The LiAlH4
reduction of propargyl alcohol to allyl alcohol 20 set the
platform for introducing two more chiral centers via
Sharpless asymmetric epoxidation.19 Thus the allyl alcohol
20 on treatment with (-)-DET, Ti(OiPr)4, and TBHP
yielded epoxy alcohol 21, which was regioselectively
opened with Gillman cuprate20 generated from MeLi and
CuI at -40 °C, albeit in moderate yields thus obtaining
1,3-diol 22. Excess exposure to TBDMSCl and imidazole
provided the fully protected (dibenzyl disilyl tetrol) 23.
The selective deprotection of primary silyl ether with
p-TSA at -15 °C in MeOH furnished primary alcohol
25. The liberated 1° alcohol functionality in 24 was
oxidized (IBX) and subjected to Corey-Fuchs protocol21
to get dibromide 25. The reaction with EtMgBr in THF
provided the subtarget 5.
Acknowledgment. C.R. and A.S.P. thank CSIR-New
Delhi for the award of research fellowships.
Supporting Information Available: Spectroscopic and
analytical data and experimental details. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL801771S
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