Total synthesis of (+)-superstolide A

Article abstract of DOI:10.1021/ja710238h

A convergent and highly stereocontrolled synthesis of (+)-superstolide A (1) has been accomplished. Key steps of this synthesis include the intramolecular Suzuki reaction of 26 and the highly diastereoselective transannular Diels-Alder cyclization of macr

Full text of DOI:10.1021/ja710238h

Published on Web 02/07/2008
Total Synthesis of (+)-Superstolide A
Mariola Tortosa,† Neal A. Yakelis,‡ and William R. Roush*,†
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458, and
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
Received November 12, 2007; E-mail: roush@scripps.edu
Superstolides A (1) and B (2) are structurally novel macrolides
isolated from the New Caledonian sponge Neosiphonia superstes
(Figure 1).1 The superstolides are highly cytotoxic toward several
cancer cell lines including murine P388 leukemia cells (IC50 ) 3
ng/mL for 1 and 2), human nasopharyngeal cells (IC50 ) 5 ng/mL
for 2), and non-small-cell lung carcinoma cells (IC50 ) 4 ng/mL
for 1 and 2). Consequently, they have attracted attention as targets
for synthesis and further biological evaluation.2,3 We report herein a
highlystereoselectivetotalsynthesisof(+)-superstolideA(1)byaroute
that is likely biomimetic in nature,4,5 and which proceeds via the
transannular Diels-Alder reaction of the 24-membered octaene 3.6
We intended from the outset that the cis-fused bicyclic octahy-
dronaphthalene unit of 1 would be established by a Diels-Alder
reaction performed either in the intramolecular2a or transannular
manifolds.2b Among the attractive features of a plan to pursue a
transannular Diels-Alder reaction of the 24-membered octaene 3
is that certain TDA reactions are known to be much more
stereoselective than analogous IMDA reactions.6-8 However,
counter balancing this potential advantage is the chemical sensitivity
of the two conjugated tetraene units of 3. Therefore, the synthesis
was designed to proceed from the four building blocks 4-7 such
that the timing of the Diels-Alder reaction relative to the
macrocyclization event (cf., use of 3 vs 8 as key intermediates)
could be adjusted late in the synthesis. In practice, the synthesis
that proceeds by way of macrocyclic octaene 3 has proven
successful and is described herein.
Figure 1. Superstolides A and B; retrosynthetic analysis.
Scheme 1. Synthesis of Phosphonium Salt 4
The synthesis of phosphonium salt 4 commenced with the
asymmetric allylation (96:4 d.r.) of aldehyde 99 (Scheme 1).
O-Methylation of the resulting secondary alcohol followed by ketal
hydrolysis then provided diol 10. After differential protection of
the two hydroxyl groups of 10, the derived triether 11 was subjected
to ozonolysis and Horner-Wadsworth-Emmons olefination ac-
cording to the Still-Gennari procedure10 to give the (Z)-enoate 12
in 76% yield over four steps. Deprotection of the trityl ether and
oxidation of the resulting hydroxyl group with SO3-pyridine-
DMSO11 provided aldehyde 13 (90%), which was then elaborated
to 14 (79% yield) via Takai olefination (CHI3, CrCl2)12 and
DIBAL-H reduction. Finally, conversion of 14 to the corresponding
allylic bromide 15 (98%), and then treatment of 15 with Bu3P in
CH3CN, provided phosphonium salt 4 (89%).
Horner-Wadsworth-Emmons olefination of hydroxybutenolide
1613 with the â-phosphonoester 1714 provided 18 in 76% yield
(Scheme 2). Reduction of the carboxylic acid via the mixed
anhydride and then oxidation of the primary alcohol by using the
Dess-Martin procedure15 provided 6 in 85% yield. This aldehyde
(1.2 equiv) was then coupled with phosphonium salt 4 (NaHDMS,
THF, -78 °C, 87% yield) and the â-trimethylsilylethyl ester was
deprotected by treatment with TASF in DMF (75% yield)16 to give
the isomerically pure C(1)-C(15) pentaene fragment 20.
The bimetallic diene linchpin 5 was synthesized starting from
vinylstannane 2117 as outlined in Scheme 3.18,19 Alkynylation of
21 by treatment with lithiotrimethylsilyldiazomethane20 followed
by hydroboration of 22 according to Snieckus’ procedure21 provided
5 in good yield (50-67% from 22). All other methods studied for
conversion of 22 to 5 were unsuccessful.22
The C(16)-C(29) fragment 25 was synthesized starting from
alcohol 232c (Scheme 4). Temporary protection of C(25)-OH as a
TES ether followed by ozonolysis of the alkene, treatment of the
resulting aldehyde with CrCl2-CHI3,23 and deprotection of C(25)-
OH provided 24 in 79% yield. Treatment of a mixture of 24 and
† Scripps Florida.
‡ University of Michigan.
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J. AM. CHEM. SOC. 2008, 130, 2722-2723
10.1021/ja710238h CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
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Scheme 2. Synthesis of Aldehyde 6 and Wittig Coupling with 4
formed 16-membered ring, as evidenced by doubling of the H
resonance for many protons including H(3) and H(6) and confirmed
by variable temperature NMR studies. Finally, sequential treatment
of 27 with TBAF (to remove the TBDPS ether), trichloroacetyl
isocyanate,29 TFA in CH2Cl2 (to remove the Boc and acetonide
protecting groups) and then Ac2O and Et3N provided synthetic (+)-
superstolide A (1) in 42% yield from 3. The spectroscopic properties
of synthetic 1 were in complete agreement with data previously
published for the natural product.1
In summary, a convergent and highly stereocontrolled synthesis
of superstolide A has been accomplished via the highly diastereo-
selective transannular Diels-Alder cyclization of macrocyclic
octaene 3 which constitutes another example of a transannular
Diels-Alder reaction that displays much higher diastereoselectivity
than corresponding IMDA counterparts.2a,7,8
Acknowledgment. This work was supported by the National
Institutes of Health (GM026782), and a postdoctoral fellowship to
M.T. from the Ministerio de Educacio´n y Ciencia, Spain.
Supporting Information Available: Experimental procedures and
spectroscopic data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Scheme 3. Synthesis of Bimetallic Diene Linchpin 5
Scheme 4. Synthesis of the C(16)-C(29) Fragment 25
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