Total synthesis of (+)-peloruside A

Article abstract of DOI:10.1021/ol050070g

(Chemical Equation Presented) A total synthesis of (+)-peloruside A has been successfully achieved. The strategy was highlighted by a late stage aldol coupling of two complex fragments followed by an intramolecular hemi-ketal cyclization, a MOM group part

Full text of DOI:10.1021/ol050070g

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1303-1305
Total Synthesis of (+)-Peloruside A
Meizhong Jin and Richard E. Taylor*
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 January 13, 2005
ABSTRACT
A total synthesis of (+)-peloruside A has been successfully achieved. The strategy was highlighted by a late stage aldol coupling of two
complex fragments followed by an intramolecular hemi-ketal cyclization, a MOM group participated epoxide ring fragmentation reaction, and
a highly selective methylation. This convergent route allows access to rationally designed analogues.
Peloruside A, isolated from a marine sponge, mycale, was
reported by Northcote in 2000.1 More recently, Miller and
co-workers reported a study that established peloruside A
as a potent cytotoxic agent with paclitaxel-like microtubule-
stabilizing activity.2 Peloruside A was shown to induce the
formation of multiple asters, micronuclei, microtubule bundles,
and rodlike fibers in a similar manner as paclitaxel. In
addition, both compounds induce cell-cycle arrest in the
G2-M phase and, ultimately, apoptosis.
In 2004, key biological experiments concluded that
peloruside A appears not to bind to the taxol binding site on
tubulin.3 In fact, the polyketide laulimalide was able to
displace peloruside A, and thus these compounds appear to
have related binding sites. Although the early solution NMR
studies1 provided the relative stereochemistry of the com-
pound’s 10 stereogenic centers, the absolute stereochemistry
remained unknown until recently when the De Brabander
group at the UTSW Medical Center reported an elegant total
synthesis.4,5
As a crucial aspect of a program designed to determine
the structural and conformational constraints of peloruside’s
biological activity, the development of a total synthesis
became an initial goal. We hoped to develop a practical and
stereoselective route that not only would lead to the natural
product but also could provide a variety of rationally
designed analogues. We considered a convergent strategy
based on an aldol coupling of two complex fragments. Those
fragments are a C8-C19 methyl ketone and a C1-C7
aldehyde as shown in Figure 1.
(5) For additional synthetic efforts towards peloruside A see ref 6 and
(a) Cox, J. M.; Furichi, N.; Kenesky, C. S.; Zheng, J. Y.; Smith A. B.
Abstracts of Papers, 228th ACS National Meeting, Philadelphia, August
22-26, 2004; American Chemical Society: Washington, DC, 2004; ORGN-
378. (b) Jin, M. Z.; Nicholson, C.; Taylor, R. E. Abstracts of Papers, 228th
ACS National Meeting, Philadelphia, August 22-26, 2004; American
Chemical Society: Washington, DC, 2004; ORGN-382. (c) Owen, R. M.;
Roush, W. R. Abstracts of Papers, 228th ACS National Meeting, Phila-
delphia, August 22-26, 2004; American Chemical Society: Washington,
DC, 2004; ORGN-707. (d) Vergin, A. J. B.; Ryba, T. D. Abstracts of Papers,
225th ACS National Meeting, New Orleans, March 23-27, 2003; American
Chemical Society: Washington, DC, 2003; CHED-494. (e) Engers, D. W.;
Bassindale, M. J.; Pagenkopf, B. L. Org. Lett. 2004, 6, 663-666. (f) Stocker,
B. L.; Teesdale-Spittle, P.; Hoberg, J. O. Eur. J. Org. Chem. 2004, 330-
336. (g) Gurjar, M. K.; Pedduri, Y.; Ramana, C. V.; Puranik, V. G.;
Gonnade, R. G. Tetrahedron Lett. 2004, 45, 387-390. (h) Liu, B.; Zhou,
W. S. Org. Lett. 2004, 6, 71-74. (i) Ghosh, A. K.; Kim, J. H. Tetrahedron
Lett. 2003, 44, 7659-7661. (j) Heady, T. N.; Crimmins, M. T. Abstracts
of Papers, 225th ACS National Meeting, New Orleans, March 23-27, 2003;
American Chemical Society: Washington, DC, 2003; ORGN-408. (k)
Paterson, I.; Di Francesco, M. E. and Kuhn, T. Org. Lett. 2003, 5, 599. (l)
Ghosh, A. K.; Kim, J.-H. Tetrahedron Lett. 2003, 44, 3967. (m) Hoye, T.
R.; Hu, M. 38th National Organic Chemistry Symposium, Bloomington,
IN, June 8-12, 2003, Abstract A22.
(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.
(3) (a) Gaitanos, T. N.; Buey, R. M.; Diaz, J. F.; Northcote, P. T.;
Teesdale-Spittle, P.; Andreu, J. M.; Miller, J. H. Cancer Res. 2004, 64,
5063. (b) Miller, J. H.; Rouwe, B.; Gaitanos, T. N.; Hood, K. A.; Crume,
K. P.; Backstrom, B. T.; La Flamme, A. C.; Berridge, M. V.; Northcote, P.
T. Apoptosis 2004, 9, 785.
(4) Liao, X.; Wu, Y.; De Brabander, J. K. Angew. Chem., Int. Ed. 2003,
42, 1648.
10.1021/ol050070g CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/11/2005

attempts to use a MOM-protected glycolate enolate in the
preceding aldol coupling, failed. After this exchange of
protecting groups, the terminal olefin was oxidatively cleaved
by ozone to give the C1-C7 fragment B as aldehyde 7.
When we reported the synthesis of C8-C19 ketone
fragment A,6 the C11 hydroxy group was left unprotected
because we envisioned the need to explore different protect-
ing groups at this position for the following crucial aldol
coupling reaction. Previous studies in this area10 had
demonstrated that the protecting group at C11 could affect
the construction of the highly oxidized pyran unit. After
model reaction studies, we decided to protect alcohol 8 as
its MOM ether because (1) it does not generate significant
steric hindrance (vide infra) and (2) it could be removed in
a final global deprotection along with the C2-MOM group
and the primary TIPS ether.
Figure 1. Connectivity Analysis for the Synthesis of Peloruside
A
With both fragments in hand, we proceeded with the key
aldol coupling and the construction of the pyran, Scheme 2.
We have previously published an efficient route to the
ketone fragment A.6 The route to fragment B is outlined in
Scheme 1. Treatment of commercially available (S)-glycidyl
Scheme 2
Scheme 1
tosylate 1 with lithiated 1,3-dithiane followed by a copper-
catalyzed Grignard addition afforded a secondary alcohol.7
Protection of this hydroxyl group as its triethylsilyl (TES)
ether and removal of the 1,3-dithiane provided the aldehyde
2. The aldehyde was then used directly in the coupling
reaction with easily prepared oxazolidinone 38 to provide
aldol adduct 4 as a single diastereomer. The relative
stereochemistry of the aldol coupling was confirmed by the
synthesis of acetonide 5 and NMR analysis.9
Ketone 8, after protection of C11, was treated with LDA,
and the resulting enolate was then reacted with aldehyde 7.
The resulting mixture of diastereomeric aldol adducts was
subjected to Dess-Martin periodinane oxidation11 to give
â-diketone 9, which existed as an enol tautomer in solution.
The next synthetic hurdle was the removal of the C5-TES
group under acidic conditions and the generation of the
corresponding pyranone through an intramolecular condensa-
tion. Treatment of diketone 9 with catalytic protic acid in
toluene at room temperature quickly removed the C5-TES
ether; however, the following intramolecular cyclization that
would provide pyranone 10 proved to be a very slow
reaction. The conversion was <50% even after stirring for
24 h at room temperature. Moreover, the starting material
After the C3-methyl ether was generated from 4, the PMB
ether at C2 was exchanged for a MOM ether. Unfortunately,
(6) Taylor, R. E.; Jin, M. Z. Org. Lett. 2003, 5, 4959.
(7) Yokokawa, F.; Asano, T.; Shioiri, T. Tetrahedron 2001, 57, 6311.
(8) (a) Jones, T. K.; Reamer, R. A.; Desmond, R.; Mills, S. G. J. Am.
Chem. Soc. 1990, 112, 2998. (b) Crimmins, M. T.; Emmitte, K. A.; Katz,
J. D. Org. Lett. 2000, 2, 2165.
(9) (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945. (b) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990,
31, 7099.
(10) De Brabander, J. K. (UTSW) Personal communication; also see ref
4.
(11) Dess, D. B., Martin, J. C. J. Org. Chem. 1983, 48, 4155.
1304
Org. Lett., Vol. 7, No. 7, 2005

and product were both unstable to these conditions, and thus
the yield of 10 was low. Fortunately, the conditions reported
by De Brabander, in a simpler system, solved the problem.4
Thus, catalytic quantities of PTSA (p-toluenesulfonic acid)
in toluene shortened the reaction time to 3 h and provided
10 in 60% yield.
Scheme 4
For the next stage, we chose to perform the macrolacton-
ization prior to modification of the pyran region in order to
minimize the use of protecting groups, Scheme 3. Thus
Scheme 3
MOM group is a result of an intramolecular glycal epoxide
ring fragmentation, through a six-membered transition state,
followed by hydrolysis of the intermediate oxo-carbenium
ion. Presumably, the resulting methyl glycoside is unstable
to the workup.
Completion of the total synthesis was accomplished by a
highly selective methylation of less hindered equatorial
hydroxyl at C7. Finally, global deprotection provided mate-
rial spectroscopically and chromatographically consistent
with (+)-peloruside A.
In conclusion, we have successfully achieved a total
synthesis of (+)-peloruside A. The convergent route is
highlighted by an aldol coupling of two complex fragments
and an interesting MOM group participated epoxide ring
fragmentation. These studies represent our initial contribution
to the study of peloruside A. Exploitation of the chemistry
for the preparation of rationally designed analogues is
currently under investigation in our laboratory.
pyranone 10 was subjected to excess pyridine/HF complex
to remove the silyl protecting groups at C15 and C19. The
primary hydroxy of the resulting diol was then selectively
reprotected as a triisopropylsilyl ether (TIPS). This com-
pound, upon exposure to aqueous LiOH, provided the
corresponding seco-acid, which after activation as a mixed
anhydride under Yamaguchi’s protocol12 provided the mac-
rocyclic lactone 11.
With advanced intermediate lactone 11 in hand, comple-
tion of peloruside A required elaboration of the pyran unit
and global deprotection. As shown in Scheme 4, ketone 11
was stereoselectively reduced under Luche reduction condi-
tions13 at low temperature. The resulting unstable allylic
alcohol, when treated with mCPBA in methylene chloride,
yielded a triol 12 with complete and selective loss of the
C11-MOM protecting group. Interestingly, running the
reaction in a mixed solvent of methylene chloride/methanol
provided a mixture of products retaining the C11-MOM
group even with identical workup and purification proce-
dures. Thus, we propose that the selective loss of the C11-
Acknowledgment. Support of this work by the National
Cancer Institute and the National Institutes of Health is
gratefully acknowledged (CA85499). We sincerely thank
Professor Jef De Brabander for a sample of peloruside A
and helpful suggestions.
Supporting Information Available: Full experimental
and characterization data for key compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) Inanaga, J.; Hirata, K.; Saeki, H.; Kastuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(13) Luche, J. L.; Rodriguez-Hahn, L.; Crabbe, P. J. Chem. Soc., Chem.
Commun. 1978, 601.
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