Stereoselective synthesis of the C(1)-C(11) fragment of peloruside A

Article abstract of DOI:10.1021/ol0514303

(Chemical Equation Presented) A highly stereoselective synthesis of the C(1)-C(11) fragment 4 of peloruside A has been accomplished via a stereoselective double allylboration and an intramolecular epoxide opening to provide the functionally dense C(3)-C(1

Full text of DOI:10.1021/ol0514303

ORGANIC
LETTERS
2005
Vol. 7, No. 18
3941-3944
Stereoselective Synthesis of the
C(1) C(11) Fragment of Peloruside A
−
Robert M. Owen and William R. Roush*,†
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
roush@umich.edu
Received June 20, 2005
ABSTRACT
A highly stereoselective synthesis of the C(1)
and an intramolecular epoxide opening to provide the functionally dense C(3)
to introduce the remaining stereocenters at C(2) C(3).
−
C(11) fragment 4 of peloruside A has been accomplished via a stereoselective double allylboration
−C(11) segment 14. A glycolate aldol reaction was then employed
−
The cytotoxic marine natural product peloruside A (1, Figure
1),1 a microtubule-stabilizing agent, represents a recent
addition to the important class of natural products that
interacts with this validated anticancer chemotherapeutic
target.2 Peloruside A was first isolated (3 mg/170 g wet
sponge) by Northcote and co-workers from marine sponges
of the genus Mycale (Carmia) collected in the Pelorus Sound
of New Zealand.1 Determination of its structure and relative
stereochemistry indicated that 1 is comprised of a highly
oxygenated, 16-membered macrolide ring system that is
bridged by a six-membered hemiketal connecting C(5) and
C(9). In addition, the natural product contains an unsaturated,
branched side chain emanating from C(15). Initial biological
characterization demonstrated that 1 exhibits potent cyto-
static/cytotoxic activity (IC50 ) 3.7-14.9 nM) against a range
of cancer cell lines.3 Miller and co-workers have demon-
strated that this activity is tied to the ability of peloruside A
to stabilize the formation of microtubules and induce arrest
at the G2-M phase of the cell cycle.4 More recent studies
have shown that 1 does not bind to the taxoid binding site
of â-tublin and maintains acivity against paclitaxel-resistant
cell lines.5 In addition, peloruside A is more effective at
inducing cell death in ras-transformed cancer cells than in
untransformed cells.6 These results highlight the potential
utility of peloruside A as a new chemotherapeutic agent.
The significant biological properties of peloruside A
coupled with its scarcity in nature and densely functionalized
structure have prompted numerous studies directed toward
its synthesis. De Brabander and co-workers descibed the first
total synthesis of the enantiomer of 1 and thereby confirmed
the relative configuration proposed by Northcote and co-
workers.7 Recently, Taylor and co-workers have also com-
(3) Hood, K. A.; Ba¨ckstro¨m, B. T.; West, L. M.; Northcote, P. T.;
Berridge, M. V.; Miller, J. H. Anti-Cancer Drug Des. 2001, 16, 155.
(4) 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.
(5) Gaitanos, T. N.; Buey, R. M.; D´ıaz, J. F.; Northcote, P. T.; Teesdale-
Spittle, P.; Andreu, J. M.; Miller, J. H. Cancer Res. 2004, 64, 5063.
(6) Miller, J. H.; Rouwe´, B.; Gaitanos, T. N.; Hood, K. A.; Crume, K.
P.; Ba¨ckstro¨m, B. T.; La Flamme, A. C.; Berridge, M. V.; Northcote, P. T.
Apoptosis 2004, 9, 785.
† Address correspondence to this author at: Department of Medicinal
Chemistry, Scripps Florida, 5353 Parkside Drive, RF-2, Jupiter, FL 33485.
(1) West, L. M.; Northcote, P. T. J. Org. Chem. 2000, 65, 445.
(2) For recent reviews on microtubule-stabilizing agents, see: (a) Myles,
D. C. Ann. Rep. Med. Chem. 2002, 37, 125. (b) He, L.; Orr, G. A.; Horwitz,
S. B. Drug DiscoV. Today 2001, 6, 1153. (c) Altmann, K.-H. Curr. Opin.
Chem. Biol. 2001, 5, 424.
10.1021/ol0514303 CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/09/2005

analysis, intermediate 2 could be assembled via the formal
three-component coupling of aldehydes 3 and 4 with al-
lylborane 7a. Further simplification of intermediate 4 sug-
gests that this fragment could be accessed from aldehydes
511 and 612 via a similar approach.
Our efforts toward the C(1)-C(11) fragment were initiated
by the synthesis of the key 1,5-diol intermediate 10 (Scheme
1). Following our previously developed methodology,10
Scheme 1. Optimization of Synthesis of Key 1,5-Diol
Fragment 10
Figure 1. Retrosynthetic analysis of peloruside A.
pleted a total synthesis of 1.8 In addition, many research
groups have reported studies directed toward the synthesis
of fragments of the peloruside A backbone.9 We report herein
our synthetic studies culminating in an efficient synthesis
of the C(1)-C(11) fragment 4 of peloruside A.
Our retrosynthetic analysis of 1 is outlined in Figure 1.
Peloruside A can be simplified into a seco-acid precursor 2
by disconnection of the macrolactone and hemiketal ring
systems. We envisioned that 2 could be assembled by using
two applications of the double allylboration methodology
recently developed in our laboratory.10 According to this
a Enantiomeric excess values calculated via the Mosher ester
method.
(7) Liao, X.; Wu, Y.; De Brabander, J. K. Angew. Chem., Int. Ed 2003,
42, 1648.
(8) Jin, M.; Taylor, R. E. Org. Lett. 2005, 7, 1303.
l
treatment of aldehyde 511 with the Ipc-derived γ-boryl-
(9) (a) Roulland, E.; Ermolenko, M. S. Org. Lett. 2005, 7, 2225. (b)
Cox, J. M.; Furuichi, N.; Zheng, C. S.; Smith, A. B. Abstracts of Papers,
228th National Meeting of the American Chemical Society, Philadelphia,
August 22-26, 2004; American Chemical Society: Washington, DC, 2004;
ORGN-378. (c) Engers, D. W.; Bassindale, M. J.; Pagenkopf, B. L. Org.
Lett. 2004, 6, 663. (d) Liu, B.; Zhou, W.-S. Org. Lett. 2004, 6, 71. (e)
Gurjar, M. K.; Pedduri, Y.; Ramana, C. V.; Puranik, V. G.; Gonnade, R.
G. Tetrahedron Lett. 2004, 45, 387. (f) Stocker, B. L.; Teesdale-Spittle, P.;
Hoberg, J. O. Eur. J. Org. Chem. 2004, 2, 330. (g) Heady, T. N.; Crimmins,
M. T. Abstracts of Papers, 225th National Meeting of the American
Chemical Society, New Orleans, March 23-27, 2003; American Chemical
Society: Washington, DC, 2004; ORGN-408. (h) Taylor, R. E.; Jin, M.
Org. Lett. 2003, 5, 4959. (i) Ghosh, A. K.; Kim, J.-H. Tetrahedron Lett.
2003, 44, 7659. (j) Paterson, I.; Di Francesco, M. E.; Ku¨hn, T. Org. Lett.
2003, 5, 599. (k) Ghosh, A. K.; Kim, J.-H. Tetrahedron Lett. 2003, 44,
3967. (l) Vergin, A. J. B.; Ryba, T. D. Abstracts of Papers, 225th National
Meeting of the American Chemical Society, New Orleans, March 23-27,
2003; American Chemical Society: Washington, DC, 2004; CHED-494.
(m) Smalley, M. K.; Hoye, T. R.; Tennakoon, M. Abstracts of Papers, 221th
National Meeting of the American Chemical Society, San Diego, April 1-5,
2001; American Chemical Society: Washington, DC, 2001; CHED-234.
substituted allylborane 7a (prepared in situ from the hy-
droboration of allene 810 with (lIpc)2BH13) followed by
introduction of aldehyde 612 provided the desired 1,5-diol
(10) as a single diastereomer in 77% yield and 85% ee (entry
1).14 Attempts to improve the enantioselectivity of the first
allylation event (5 f 9) indicated that the enantioselectivity
was essentially insensitive to the reaction solvent (entries
(10) Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644.
(11) (a) Asari, T.; Ishikawa, S.; Sasaki, T.; Katada, J.; Hayashi, Y.;
Harada, T.; Yano, M.; Yasuda, E.; Uno, I.; Ojima, I. Bioorg. Med. Chem.
Lett. 1997, 7, 2099. (b) Chiba, T.; Sakaki, J.; Takahashi, T.; Aoki, K.;
Kamiyama, A.; Kaneko, C.; Sato, M. J. Chem. Soc., Perkin Trans. 1 1987,
1, 1845.
(12) Overman, L. E.; Bell, K. L.; Ito, F. J. Am. Chem. Soc. 1984, 106,
4192.
(13) Brown, H. C.; Singaram, B. J. Org. Chem. 1984, 49, 945.
3942
Org. Lett., Vol. 7, No. 18, 2005

1-3). However, on the basis of the work of Brown and co-
workers,15 we anticipated that the replacement of (lIpc)2B-
in 7a with (2-dIcr)2B- (derived from (+)-2-carene) in 7b
might improve the enantioselectivity of this transformation.
Indeed, use of reagent 7b in the sequence provided diol 10
with excellent enantioselectivity (>95% ee16) albeit in low
yield (36%) due a sluggish reaction between intermediate
9b and aldehyde 6 (entry 4). Although extended reaction
times provided a moderate improvement in the isolated yield
of 10 (entry 6), we chose to utilize material obtained by using
reagent 7a for the remainder of the studies described herein.
Selective protection of the C(5)-hydroxyl group of diol
10 with triethylsilyl chloride followed by m-CPBA oxidation
of the olefin and protection of the C(9)-hydroxyl group as a
PMB ether provided epoxide 12 as a 15:1 mixture of
diastereomers (Scheme 2). While the stereochemistry of the
Scheme 3. Completion of C(1)-C(11) Fragment via an
Asymmetric Glycolate Aldol Reaction
Scheme 2. Synthesis of the C(3)-C(11) Fragment
epoxide 12 would lead to a single lactone 13 via a 5-exo
cyclization upon exposure to ZnCl2. Gratifyingly, treatment
of 12 with anhydrous ZnCl2 provided lactone 13 in 85%
yield. The relative C(5)-C(7) stereochemistry was confirmed
via formation of the 1,3-acetonide and 13C NMR analysis
via the Rychnovsky method.19 Subsequent methylation of
13 with Meerwein’s salt (Me3OBF4) provided intermediate
14 in excellent yield. The C(8) stereochemistry was verified
by Mosher ester analysis20 of 15, obtained by reduction of
lactone 14 with LiBH4,21 thereby demonstrating that com-
pound 14 contains the correct C(7)-C(8) stereochemistry
for peloruside A. The independent verification of the C(7)
and C(8) stereochemistry also provides clear evidence that
the stereochemistry of epoxide 12 must be as shown.
With the key intermediate 14 in hand, we turned our
attention to installation of the remaining C(2)-C(3) stereo-
centers (Scheme 3). Half-reduction of lactone 14 by treatment
with DIBAL-H at -78 °C gave the lactol as a 2:1 mixture
of anomers. Treatment of this mixture with an excess of
methylidene(triphenyl)phosporane at 65 °C for 16 h followed
epoxide was not determined at this stage, the threo-
configuration shown is consistent with an epoxidation
transition state in which A1,3 strain in minimized.17 Although
acyclic trans-olefins generally react with a low degree of
stereoinduction in these transformations, the neighboring
quaternary center may play a significant role in influencing
the diastereoselectivity of the epoxidation of 11.
On the basis of the analysis of Gorrichon and co-workers,18
we anticipated that the proposed threo-configuration of
(14) Enantioselectivities and absolute stereochemical assignments were
determined by 1H NMR anlaysis of the bis-Mosher ester prepared from the
1,5-diol: Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092. See Supporting Information for details.
(15) (a) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401. (b)
Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racherla, U. S.
J. Org. Chem. 1990, 55, 2389.
(19) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9. See Supporting Information for details.
(16) Only a trace (e2%) of the minor enantiomer could be detected in
1
the H NMR spectra of the bis-Mosher esters.
(17) (a) Rossiter, B. E.; Verhoeven, T. R.; Sharpless, K. B. Tetrahedron
Lett. 1979, 20, 4733. (b) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
(18) (a) Nacro, K.; Gorrichon, L.; Escudier, J.-M.; Baltas, M. Eur. J.
Org. Chem. 2001, 22, 4247. (b) Devianne, G.; Escudier, J.-M.; Baltas, M.;
Gorrichon, L. J. Org. Chem. 1995, 60, 7343.
(20) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092. See Supporting Information for details.
(21) See Supporting Information for details.
Org. Lett., Vol. 7, No. 18, 2005
3943

by silylation of the C(8)-hydroxyl group with triethylsilyl
triflate provided compound 16 in excellent yield. Elevated
temperatures for olefination of the lactol were required to
obtain reasonable reaction rates, presumably due to the
influence of the gem-dimethyl group on the lactol f
δ-hydroxy aldehyde equilibrium. Subsequent reductive re-
moval of the benzyl protecting group of 16 with lithium 4,4′-
di-tert-butylbiphenyl (LiDBB)22 proceeded cleanly to give
alcohol 17. Oxidation of the primary alcohol unit of 17
followed by an asymmetric glycolate aldol reaction23 with
MOM-protected glycolate imide 2024 provided alcohol 19
as a 13:1 mixture of diastereomers, which corresponds to
the % ee of the starting aldehyde.25 The stereochemistry at
C(3) of 19 was assigned via application of the Rychnovsky
method for 1,3-diol configurational assignment.26 O-Methy-
lation of 19 by using Meerwein’s salt followed by ozonolysis
of the terminal alkene of 21 provided 4, the fully ellaborated
C(1)-C(11) fragment of peloruside A.
In summary, we have accomplished an efficient and highly
stereoselective synthesis of 4 corresponding to the C(1)-
C(11) fragment of peloruside A (14 steps, 24% overall yield).
Key transformations in the sequence include construction of
the C(5)-C(9) 1,5-diol unit via double allylboration with
allylboronate 7, followed by an intramolecular epoxide
opening to complete the C(3)-C(11) fragment. The final two
stereocenters were simultaneously introduced via an asym-
metric glycolate aldol reaction. Continued advancement of
these intermediates toward peloruside A (1) will be reported
in due course.
Acknowledgment. This work was supported by the
National Institues of Health (GM 38436). R.M.O. gratefully
acknowledges the American Cancer Society for a postdoc-
toral fellowship (PF-04-013-01-CDD).
Supporting Information Available: Experimental pro-
cedure and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0514303
(22) (a) Evans, D. A.; Connell, B. T. J. Am. Chem. Soc. 2003, 125, 10899.
(b) Ireland, R. E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110, 854.
(23) Evans, D. A.; Bender, S. L. Tetrahedron Lett. 1986, 27, 799.
(24) Acyloxazolidinone 20 is avalible in two steps from known R-ben-
zyloxy-protected glycolate oxazolidinone: Haigh, D.; Birrell, H. C.;
Cantello, B. C. C.; Eggleston, D. S.; Haltiwanger, R. C.; Hindley, R. M.;
Ramaswamy, A.; Stevens, N. C. Tetrahedron: Asymmetry 1999, 10, 1353.
See Supporting Information for details.
(26) The relative C(3)-C(5) stereochemistry of 19 was confirmed via
the Rychnovsky method. See Supporting Information for details.
(25) We presume that the minor aldol product derives from the minor
enantiomer of 18 since the % ee of the major diastereomer (determined for
compound 21) was >95% by Mosher ester analysis. See Supporting
Information for details.
3944
Org. Lett., Vol. 7, No. 18, 2005