Scheme 1. Retrosynthetic Analysis of Spirastrellolide A
itself contains a cis-fused tetrahydropyran (A ring), a [6,6]-
Our proposed retrosynthesis of spirastrellolide is outlined
in Scheme 1. Simplification of the diastereomer problem
might be achieved through a late-stage attachment of the C46
hydroxyl-containing side chain, as in 4, after macrolacton-
ization of an appropriate seco-acid precursor. The DEF-bis-
spiroacetal subunit may then be isolated as a single region
of known relative stereochemistry through disconnection
across the C25-C26 bond. This bis-spiroacetal 3 was envis-
aged to arise from a thermodynamically controlled spiroac-
etalization of the open-chain precursor 6, following acetonide
deprotection. This ketone 6 could itself be derived from the
Horner-Wadsworth-Emmons olefination of the aldehyde
7 with phosphonate 8, followed by olefin reduction. Alde-
hyde 7 may, in turn, be constructed by acetalization of the
ketone 9, while phosphonate 8 could arise from a dihydroxyl-
ation of the allylic chloride 10, followed by the installation
of the dimethyl phosphonate moiety.
The synthesis of the C33-C40 aldehyde 7 commenced with
the cross-metathesis of buten-3-ol benzyl ether 11 with
methyl vinyl acetate 12, using the Grubbs second-generation
catalyst (Scheme 2).4 The â,γ-unsaturated ester 13 was
obtained in 82% yield as a 4:1 mixture of (E)- and
(Z)-isomers, which were further submitted to a Sharpless
asymmetric dihydroxylation,5a with concurrent hydroxyl-
differentiating lactonization.5b A subsequent recrystallization
efficiently removed the minor dihydroxylation byproduct,
originating from the (Z)-isomer of 13, while increasing the
enantiomeric purity of the desired lactone 145b from 91 to
>99% ee. TES protection of alcohol 14, followed by
debenzylation and Dess-Martin oxidation, delivered the
spiroacetal (BC rings), and an intriguing chlorinated [5,6,6]-
bis-spiroacetal (DEF rings). Significantly, both spiroacetal
motifs appear to benefit from stabilization by a double ano-
meric effect, with all substituents equatorially disposed. The
remaining C46 stereocenter appears as part of a nine-carbon
side chain, also featuring a (Z,E)-1,4-diene, appended to C38.
While the atomic connectivity of spirastrellolide and its
methyl ester derivative 2 has been determined, several stereo-
chemical uncertainties remain. In addition to the remote,
unassigned C46 stereocenter, the absolute configuration of
the natural product remains undetermined. More significantly
from a synthetic viewpoint,3 the relatiVe stereochemistry
between the three stereoclusters (C3-C7, C9-C24, and
C27-C38) within the macrolide core is also unknown.
The initial aim of any synthetic effort directed toward
spirastrellolide must be the elucidation of the stereochemical
relationship between these subunits. A flexible, modular
strategy was envisaged in which each region of known
relative stereochemistry could be independently constructed.
Subsequent union of these subunits, followed by detailed
NMR comparisons with spirastrellolide, may then enable the
determination of the stereochemical interconnection between
these regions. Toward this end, we report herein an asym-
metric synthesis of the C26-C40 segment 3 (Scheme 1),
containing the complete [5,6,6]-bis-spiroacetal DEF-ring
system of the northern hemisphere.
(2) (a) Le, L. H.; Erlichman, C.; Pillon, L.; Thiessen, J. J.; Day, A.;
Wainman, N.; Eisenhauer, E. A.; Moore, M. J. InVest. New Drugs 2004,
22, 159. (b) Honkanen, R. E.; Golden, T. Curr. Med. Chem. 2002, 9, 2055.
(3) For other synthetic studies, see: (a) Liu, J.; Hsung, R. P. Org. Lett.
2005, 7, 2273. (b) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Loiseleur,
O.; Abstracts of Papers, 229th National Meeting of the American Chemical
Society, San Diego, Mar 13-17, 2005; American Chemical Society:
Washington, DC, 2005; ORGN-331. (c) Wang, C.; Forsyth, C. J. Abstracts
of Papers, 229th National Meeting of the American Chemical Society, San
Diego, Mar 13-17, 2005; American Chemical Society: Washington, DC,
2005; ORGN-414.
(4) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360. For an example of cross-metathesis using
ester 28, see: Vasbinder, M. M.; Miller, S. J. J. Org. Chem. 2002, 67,
6240.
(5) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483. (b) The enantiomer of 14 has previously been reported;
see: Garcia, C.; Martin, T.; Martin, V. S. J. Org. Chem. 2001, 66, 1420.
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Org. Lett., Vol. 7, No. 19, 2005