Toward a Total Synthesis of Peloruside A: Enantioselective Preparation of the C8-C19 Region

Article abstract of DOI:10.1021/ol0358814

(Equation Presented) An efficient synthetic sequence toward the C8-C19 region of peloruside A has been developed. The route is highlighted by a selective electrophilic cyclization reaction, a single-step epoxide ring-opening/methylation sequence, and a stereoselective Mukaiyama aldol reaction.

Full text of DOI:10.1021/ol0358814

ORGANIC
LETTERS
2003
Vol. 5, No. 26
4959-4961
Toward a Total Synthesis of Peloruside
A: Enantioselective Preparation of the
C8−C19 Region
Richard E. Taylor* and Meizhong Jin
Department of Chemistry and Biochemistry and the Walther Cancer Research Center,
UniVersity of Notre Dame, 251 Nieuwland Science Hall,
Notre Dame, Indiana 46556-5670
taylor.61@nd.edu
Received September 26, 2003
ABSTRACT
An efficient synthetic sequence toward the C8−C19 region of peloruside A has been developed. The route is highlighted by a selective
electrophilic cyclization reaction, a single-step epoxide ring-opening/methylation sequence, and a stereoselective Mukaiyama aldol reaction.
Peloruside A is a cytotoxic macrolide isolated from a New
Zealand sponge, Mycale hentschi.1 The structure was orig-
inally determined by extensive NMR solution studies. More
recently, Miller and co-workers reported a study that
established peloruside A as a potent cytotoxic agent with
epothilone-like microtubule-stabilizing activity.2 This report
noted interesting structural similarities between the two
biologically related polyketides peloruside A and the
epothilones (i.e., contiguous hydroxyl, gem-dimethyl, car-
bonyl; C11-C9 peloruside, C3-C5 epothilone). This pro-
posal implied that the C15-stereogenic center of peloruside
A was of opposite configuration to the corresponding center
in epothilone. More recently, the absolute stereochemistry
of natural peloruside A was unambiguously determined to
have the identical C15 stereochemistry as epothilone by the
De Brabander group through an elegant total synthesis
effort.3,4
in Figure 1. Although there is no direct experimental
evidence, peloruside A and the epothilones may have
Our previous experience with the conformation-activity
relationships of epothilone5 revealed interesting shape and
size similarities to peloruside A, and a comparison is shown
Figure 1. Structural and conformational comparison of peloruside
A and epothilone B derived from NMR and computer modeling
analysis.
(1) West, L. M.; Northcote, P. T. J. Org. Chem. 2000, 65, 445.
(2) Hood, K. A.; West, L. M.; Rouwe, B.; Northcote, P. T.; Berridge,
M. V.; Wakefield, S. J.; Miller, J. H. Cancer Res. 2002, 62, 3356.
10.1021/ol0358814 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/25/2003

overlapping pharmacophores. Toward our interest in the
structural and conformational constraints of peloruside’s
biological activity, we have begun a program where total
synthesis is an initial goal. Herein we report our preliminary
efforts toward that aim.
Scheme 2
The synthesis commenced with readily available oxazo-
lidinone 1 (Scheme 1), which was stereoselectively alkylated
Scheme 1
The next stage of the plan was to build the 1,3-syn
relationship between C13 and C15. Iodine-induced carbonate
cyclization methodology originally published by Bartlett10a
and later improved by Smith10b was first considered, Scheme
3. This is a particularly interesting substrate for this elec-
Scheme 3
with BOMCl in the presence of titanium tetrachloride.6 After
an exchange of protecting groups, the chiral auxiliary was
reductively removed with LiBH4. Oxidation of 2 with Dess-
Martin periodinane7 followed by a Still-Gennari olefination8
provided exclusively the (Z)-trisubstituted alkene 3. Then, a
two-step conversion of the methyl ester to the corresponding
aldehyde allowed for a Brown asymmetric allylation to set
the C15 stereogenic center and provide 4 (dr ) 97:3, 77%
for two steps).
The nonpolar physical properties of alcohol 4 made
purification difficult, a common problem with this allylation
method due to reaction byproducts. However, a diastereo-
random allylation with inexpensive allylmagnesium bromide
followed by chromatographic separation and processing of
the undesired 4-15R isomer through Mitsunobu inversion9
proved to be a practical alternative for large-scale work. As
shown in Scheme 2, simple Grignard allylation proceeded
in good yield to provide a 1:1 mixture of diastereomers that
were easily separable by column chromatography. The two-
step conversion of the undesired isomer proceeded efficiently
to provide diastereomerically pure 4-15S. The 16,17-(Z)-
olefin geometry was maintained through this sequence as
proven by NOE studies (see Supporting Information).
trophilic cyclization reaction because of the presence of two
potential sites for reactivity. One could envision electrophilic
activation of the more electron-rich trisubstituted olefin to
provide a five-membered cyclic carbonate11 or the sterically
accessible terminal olefin to provide the desired six-
membered cyclic carbonate. In fact, treatment of the mixed
carbonate with either I2 or IBr, at low temperature, provided
complex mixtures of products. However, the use of N-
iodosuccinimide proved to be selective for the formation of
a single compound, carbonate 7, in 92% yield. As expected,
this material, upon exposure to basic methanol solution and
protection, efficiently provided the syn-epoxy ether 8.
Generation of the polyacetate syn-diol would then be
unveiled by epoxide ring opening with an acyl anion synthon.
(3) Liao, X.; Wu, Y.; De Brabander, J. K. Angew. Chem., Int. Ed. 2003,
42, 1648.
(4) For additional synthetic efforts towards peloruside A, see: (a)
Paterson, I.; Di Francesco, M. E.; Kuhn, T. Org. Lett. 2003, 5, 599. (b)
Ghosh, A. K.; Kim, J.-H. Tetrahedron Lett. 2003, 44, 3967. (c) Hoye, T.
R.; Hu, M. 38th National Organic Chemistry Symposium, Bloomington,
IN, June 8-12, 2003; Abstract A22. (d) Ghosh, A. K.; Kim, J.-H.
Tetrahedron Lett. 2003, 44, 7659.
(5) (a) Yoshimura, F.; Rivkin, A.; Gabarda, A. E.; Chou, T.-C.; Dong,
H.; Sukenick, G.; Morel, F. F.; Taylor, R. E.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2003, 42, 2518. (b) Taylor, R. E.; Chen, Y.; Beatty, A.;
Myles, D. C.; Zhou, Y. J. Am. Chem. Soc. 2003, 125, 26. (c) Taylor, R. E.;
Zajicek, J. J. Org. Chem. 1999, 64, 7224.
The lithium anion of dithiane was used to fragment the
epoxide and proceeded in 85% yield as shown in Scheme 3.
Formation of C13-methyl ether was accomplished with
(6) Ihara, M.; Katsumata, A.; Setsu, F.; Tokunaga, Y.; Fukumoto, K. J.
Org. Chem. 1996, 61, 677.
(7) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(8) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(9) Mitsunobu, O. Synthesis 1981, 1.
(10) (a) Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.;
Jernstedt, K. K. J. Org. Chem. 1982, 47, 4013. (b) Duan, J. J-W.; Smith,
A. B., III. J. Org. Chem. 1993, 58, 3703.
(11) Bongini, A.; Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S. J. Org.
Chem. 1982, 47, 4626.
4960
Org. Lett., Vol. 5, No. 26, 2003

methyl iodide in the presence of KOtBu in 78% yield. This
was followed by hydrolysis of the dithiane to provide
aldehyde 9. A more efficient generation of the C13-methyl
ether was accomplished by in situ alkylation of the inter-
mediate alkoxide resulting from epoxide ring opening. As
shown in Scheme 4, exposure of epoxide 8 to the lithiated
Scheme 5
Scheme 4
In summary, we have developed an efficient, enantiose-
lective route to a protected C8-C19 fragment of peloruside
A. The route is highlighted by a selective electrophilic
cyclization reaction, a single-step epoxide ring-opening/
methyl ether formation, and an anti stereoselective Mu-
kaiyama aldol reaction. Conversion of this advanced inter-
mediate to peloruside A and analogues is currently underway
in our laboratories, and results along these lines will be
reported in due course.
dithiane followed by the addition of an HMPA solution of
dimethyl sulfate led to direct isolation of methyl ether 10 in
85% yield.
Mukaiyama aldol12 reaction of the â-methoxy aldehyde 9
provided methyl ketone 11 in 91% yield as shown in Scheme
5. Mosher ester analysis13 of the major isomer, obtained in
an 8:1 mixture, proved to have the desired absolute stereo-
chemistry at C11 and thus a 1,3-anti stereochemical relation-
ship between C11 and C13.
Acknowledgment. This work was partially supported by
the National Cancer Institute and National Institutes of Health
(CA84599). R.E.T. thanks Eli Lilly for a Grantee Award.
This work was done in collaboration with the Walther Cancer
Research Institute of Indianapolis, Indiana.
Supporting Information Available: Full experimental
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Reetz, M. T.; Kesseler, K.; Jung, A. Tetrahedron Lett. 1984,
25, 729. (b) Trieselmann, T.; Hoffmann, R. W. Org. Lett. 2000, 2, 1209.
(c) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc.
1996, 118, 4322. (d) Willson, T. M.; Kocrenski, P.; Jarowicki, K.; Isaac,
K.; Hitchcock, P. M.; Faller, A.; Campbell, S. F. Tetrahedron 1990, 46,
1767.
(13) Dale, J. S.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
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