The spirastrellolides: Construction of the southern C(1)-C(25) fragment exploiting anion Relay chemistry

Article abstract of DOI:10.1021/ol071282b

Effective construction of the southern C(1)-C(25) fragment of spirastrellolide A has been achieved. Central to this venture was the use of four dithiane unions, including the highly effective deployment of the anion relay chemistry (ARC) tactic recently introduced by our laboratory.

Full text of DOI:10.1021/ol071282b

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3311-3314
The Spirastrellolides: Construction of
the Southern C(1) C(25) Fragment
−
Exploiting Anion Relay Chemistry
Amos B. Smith, III* and Dae-Shik Kim
Department of Chemistry, Monell Chemical Senses Center, and Laboratory for
Research on the Structure of Matter, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received May 31, 2007
ABSTRACT
Effective construction of the southern C(1)−C(25) fragment of spirastrellolide A has been achieved. Central to this venture was the use of four
dithiane unions, including the highly effective deployment of the anion relay chemistry (ARC) tactic recently introduced by our laboratory.
Spirastrellolides A and B (1 and 2), two unique polyketide
natural products, isolated from the sponge Spirastrella
coccinea endemic to the Caribbean, were disclosed by
Andersen and co-workers in 2003 and 2007, respectively
(Figure 1).1 The relative configurations of the three major
segments of 1 (C3-C7, C9-C24, and C27-C38) were
elucidated via extensive NMR studies of the methyl ester.1b
Later, the stereochemical relationships between the segments
and the absolute configuration of the macrolide core were
assigned via X-ray diffraction of a crystalline derivative of
2.1c The absolute configuration at C(46), however, remains
unknown. Spirastrellolide A acts as a potent selective
inhibitor of protein phosphatase PP2A (IC50 ) 1 nM for
PP2A and 50 nM for PP1), resulting in premature cell entry
into mitosis and thereby mitotic arrest.1a,b The challenging
architecture, in conjunction with the novel biological profile
of 1, has attracted considerable attention.2 Herein we disclose
an effective construction of the C(1)-C(25) southern frag-
ment (3) of spirastrellolide A.
From the retrosynthetic perspective, disconnection of 1 at
the macrocyclic lactone, the C(25)-C(26) bond, and C(40)-
C(41) trans double bond yields three advanced subtargets:
ABC ring fragment 3; DEF ring fragment 4; and side chain
5 (Figure 1). Further disconnection of 3 at the C(9)-C(10)
and C(22)-C(23) bonds reveals A-ring dithiane 6, BC
spiroketal 7, and known dithiane 8.3 The BC spiroketal 7 in
(2) (a) Liu, J.; Hsung, R. P. Org. Lett. 2005, 7, 2273. (b) Liu, J.; Yang,
J. K.; Ko, C.; Hsung, R. P. Tetrahedron Lett. 2006, 47, 6121. (c) Paterson,
I.; Anderson, E. A.; Dalby, S. M.; Loiseleur, O. Org. Lett. 2005, 7, 4121.
(d) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Loiseleur, O. Org. Lett.
2005, 7, 4125. (e) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Lim, J. H.;
Maltas, P.; Moessner, C. Chem. Commun. 2006, 4186. (f) Furstner, A.;
Fenster, M. D. B.; Fasching, B.; Godbout, C.; Radkowski, K. Angew. Chem.,
Int. Ed. 2006, 45, 5506. (g) Furstner, A.; Fenster, M. D. B.; Fasching, B.;
Godbout, C.; Radkowski, K. Angew. Chem., Int. Ed. 2006, 45, 5510. (h)
Pan, Y.; De Brabander, J. K. Synlett 2006, 853. (i) Wang, C.; Forsyth, C.
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Lim, J. H.; Loiseleur, O.; Maltas, P.; Moessner, C. Pure Appl. Chem. 2007,
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(1) (a) Williams, D. E.; Roberge, M.; Van Soest, R.; Andersen, R. J. J.
Am. Chem. Soc. 2003, 125, 5296. (b) Williams, D. E.; Lapawa, M.; Feng,
X.; Tarling, T.; Roberge, M.; Andersen, R. J. Org. Lett. 2004, 6, 2607. (c)
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10.1021/ol071282b CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/18/2007

We began with a two-step construction of dithiane 13 from
known triol (-)-125 (Scheme 1). Exploiting the Schlosser
Scheme 1. Anion Relay Chemistry (ARC)
base (n-BuLi/KO-t-Bu),6 the first alkylation was achieved
at -78 °C with concomitant 1,4-Brook rearrangement,
leading in situ to dithiane anion 14,7 which upon treatment
with epoxide (-)-10 completed the three-component con-
struction to furnish (+)-15 in 77% isolated yield. Importantly,
this ARC transformation could be carried out on a 5 g scale.
Scheme 2. Synthesis of BC spiroketal (-)-7
Figure 1. Structure of spirastrellolides A (1) and B (2) and
retrosynthetic analysis of the spirastrellolides.
turn was envisioned to arise from bisketone 9 via 1,3-anti
reduction of the C(13) ketone, followed by acid-catalyzed
spiroketalization, and C(14) methylation. To construct 9, the
anion relay tactic (ARC),4 recently introduced by our
laboratory, appeared ideal to unite the commercially available
epoxide (-)-10, known linchpin (-)-11,4a and a protected
form of known dithiane (-)-125 in a single operation.
(3) Honda, Y.; Morita, E.; Ohshiro, K.; Tsuchihashi, G.-I. Chem. Lett.
1988, 21. See Supporting Information for synthesis of (-)-8.
(4) (a) Smith, A. B., III; Xian, M. J. Am. Chem. Soc. 2006, 128, 66. (b)
Smith, A. B., III; Xian, M.; Kim, W.-S.; Kim, D.-S. J. Am. Chem. Soc.
2006, 128, 12368.
(5) (a) Abel, S.; Faber, D.; Hu¨ter, O.; Giese, B. Angew. Chem., Int. Ed.
1995, 33, 2466.
(6) Schlosser, M.; Strunk, S. Tetrahedron Lett. 1984, 25, 741.
3312
Org. Lett., Vol. 9, No. 17, 2007

Removal of both dithianes in (+)-15 employing Hg(ClO4)8
next furnished 1,5-bisketone (+)-9 in 75% yield
(Scheme 2). Selective 1,3-directed anti-reduction of the
â-hydroxyl ketone via the Gribble-Evans protocol9 followed
by treatment with p-TsOH in acetone led to hemiketal (+)-
16. Without purification, (+)-16 was treated with 3.5% aq
HClO4 to afford spiroketal (+)-17 in 62% yield (three steps).
After selective protection of the primary hydroxyl as tert-
butyldiphenylsilyl (BPS) ether and benzylation of the
remaining secondary hydroxyl, allylic oxidation (SeO2) using
microwave radiation led to allylic alcohol (-)-18 in 45%
yield along with 9% yield of the R-isomer. Introduction of
the requisite C(14) methyl group was next achieved via
Mitsunobu alkylation with bis(phenylsulfonyl)methane,10
followed by reduction with excess LiDBB,11 employing
t-BuOH as the proton source, to furnish diol (+)-19 in 65%
yield (two steps). Fraser-Reid epoxidation12 completed
construction of epoxide (-)-7.
overall yield was 40%). Union with (-)-7 employing the
Schlosser base (n-BuLi/KO-t-Bu)6 led to (-)-21 in 87%
yield. Removal of dithiane with Hg(ClO4), followed in turn
by 1,3-anti-reduction,9 selective removal of TBS group, and
protection of the resulting alcohol as a pivalate ester then
furnished diol (-)-23 as a crystalline solid. X-ray analysis
established both the structure and relative stereochemistry.
To introduce the final four-carbon side chain, we called
upon the Honda protocol, fully expecting dithiane (-)-8
(Scheme 4) to deliver the correct stereogenicity at C(22).3
Scheme 4. Installation of the C(23)-C(25) Fragment
Dithiane (-)-6 (Scheme 3) required for union with epoxide
(-)-7 was prepared from known pyran (-)-20,2h via a four-
step sequence involving reduction with LiAlH4, TBS protec-
tion, oxidative cleavage of the terminal double bond,13 and
dithiane formation employing MgBr2 as Lewis acid;14 the
Scheme 3. Fragment Union of A-Ring Dithiane (-)-6 and BC
Spiroketal (-)-7
Toward this end, aldehyde (+)-24 was generated via a three-
(7) Product of 14 was obtained in 85% yield by quenching with a
saturated aqueous NH4Cl solution.
(8) Fujita, E.; Nagao, Y.; Kaneko, K. Chem. Pharm. Bull. 1978, 26, 3743.
(9) (a) Nutaitis, C. F.; Gribble, G. W. Tetrahedron Lett. 1983, 24, 4287.
(b) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988,
110, 3560.
(10) Yu, J.; Cho, H.-S.; Falck, J. R. J. Org. Chem. 1993, 58, 5892.
(11) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924.
(12) (a) Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 203. (b) Cink, R.
D.; Forsyth, C. J. J. Org. Chem. 1995, 60, 8122.
(13) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217.
(14) Park, J. H.; Kim, S. Chem. Lett. 1989, 18, 629.
Org. Lett., Vol. 9, No. 17, 2007
3313

step sequence involving diol protection, removal of the BPS
group, and Dess-Martin oxidation15. Treatment of (+)-24
with the lithium anion derived from (-)-8 led to a mixture
of adducts (6.5:1) in 57% yield. Surprisingly, the minor
product proved to be the desired alcohol [(+)-26] as
established by Kakisawa modified Mosher ester analyses of
both isomers.16 The desired diastereomer could, however,
be obtained via a three-step sequence: Dess-Martin oxida-
tion, DIBAL-H reduction, and selective protection of the
resulting primary alcohol as a pivalate ester. Pleasingly, the
reduction proceeded to furnish a single isomer (NMR).
Removal of the dithiane employing the Corey conditions17
furnished R-hydroxy ketone (+)-27, which was then sub-
jected to 1,2-chelation-controlled anti-reduction with Zn-
(BH4)2.18 Acetonide formation of the resulting 1,2-diol
completed construction of the C(1)-C(25) fragment of
spirastrellolide A (1).
In summary, synthesis of the C(1)-C(25) southern frag-
ment of spirastrellolide A (1) has been achieved via four
dithiane unions. Particularly attractive, the anion relay tactic
(ARC) proceeded both with high efficiency and effective
union of three components. Further studies toward the total
synthesis of the spirastrellolides and applications of the ARC
tactic continue in our laboratory.
Acknowledgment. Financial support was provided by the
National Institutes of Health through Grant GM-29028. We
are also grateful to Eli Lilly and Company for a graduate
fellowship to D.-S.K. Finally we thank Drs. G. T. Furst, R.
Kohli, and P. Carroll at the University of Pennsylvania for
assistance in obtaining NMR, high-resolution mass spectra,
and X-ray analysis, respectively.
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.
(15) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(16) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092. See Supporting Information.
(17) Corey, E. J.; Erickson, B. W. J. Org. Chem. 1971, 36, 3553.
(18) Nakata, T.; Tanaka, T.; Oishi, T. Tetrahedron Lett. 1983, 24, 2653.
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