Total synthesis of (-)-2-epi-peloruside A

Article abstract of DOI:10.1021/ol8019132

(Chemical Equation Presented) A convergent synthesis of (-)-2-epi-peloruside A has been achieved. Highlights include implementation of multicomponent type I anion relay chemistry (ARC) to unite 2-TBS-1,3-dithiane with two epoxides to construct the eastern hemisphere, a late-stage dithiane union to secure the complete, fully functionalized carbon backbone, and Yamaguchi macrolactonization, which led to (-)-2-epi-peloruside A via an unexpected epimerization at C(2).

Full text of DOI:10.1021/ol8019132

ORGANIC
LETTERS
2008
Vol. 10, No. 24
5501-5504
Total Synthesis of (-)-2-epi-Peloruside A
Amos B. Smith III,* Jason M. Cox, Noriyuki Furuichi, Craig S. Kenesky,
Junying Zheng, Onur Atasoylu, and William M. Wuest
Department of Chemistry, Monell Chemical Senses Center, and Laboratory for
Research on the Structure of Matter, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received August 15, 2008
ABSTRACT
A convergent synthesis of (-)-2-epi-peloruside A has been achieved. Highlights include implementation of multicomponent type I anion relay
chemistry (ARC) to unite 2-TBS-1,3-dithiane with two epoxides to construct the eastern hemisphere, a late-stage dithiane union to secure the
complete, fully functionalized carbon backbone, and Yamaguchi macrolactonization, which led to (-)-2-epi-peloruside A via an unexpected
epimerization at C(2).
In 2000, Northcote and co-workers reported the isolation and
relative stereochemistry of (+)-peloruside A (1),1 an archi-
tecturally complex marine metabolite produced by the sponge
Mycale (Carmia). Although a microtubule-stabilizing agent
with potency similar to Taxol,2 recent studies reveal that (+)-
peloruside A competes competitively for the laulimalide
binding site at a newly discovered microtubule site.3
Structurally, (+)-peloruside A (1) comprises 10 stereogenic
centers, a Z-trisubstituted olefin, and a six-membered hemiket-
al ring, inscribed in a 16-membered macrolactone. Not
Scheme 1. (+)-Peloruside A Retrosynthesis
Our interest in (+)-peloruside A (1, Scheme 1) emanated
from the synthetic challenge, in conjunction with the
opportunity to showcase the synthetic utility of dithiane
linchpin tactics, in particular the use of the three-component
union of trialkylsilyl dithianes with diverse electrophiles, a
synthetic tactic we now recognize as type I anion relay
chemistry(ARC).4
(1) West, L. M.; Northcote, P. T.; Battershill, C. N. J. Org. Chem. 2000,
65, 445.
(2) 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.
(3) Huzil, J. T.; Chik, J. K.; Slysz, G. W.; Freedman, H.; Tuszynski, J.;
Taylor, R. E.; Sackett, D. L.; Schriemer, D. C. J. Mol. Biol. 2008, 378,
1016.
(4) Smith, A. B., III; Kim, W.-S.; Wuest, W. M. Angew. Chem., Int.
Ed. 2008, 47, 7082. Smith, A. B., III; Wuest, W. M. Chem. Commun.
2008, in press.
10.1021/ol8019132 CCC: $40.75
Published on Web 11/14/2008
2008 American Chemical Society

surprisingly, the structural complexity, interesting biological
activity, and scarcity have led to considerable interest from
both the chemical5 and biological communities.6
Scheme 2. Synthesis of Dithiane (-)-3
In 2003, De Brabander and co-workers7 achieved an
elegant total synthesis of unnatural (-)-peloruside A, thus
permitting assignment of the absolute configuration. Shortly
thereafter (2005), the Taylor group8 reported the first total
synthesis of natural (+)-peloruside A, followed in 2008 by
a second total synthesis from the Ghosh laboratory.9 We
report here completion of the total synthesis of (-)-2-epi-
peluroside A (28, see Scheme 5), the result of a surprising,
late-stage epimerization (vide infra) that procluded access
to (+)-peloruside A (1).
Shortly after the report by Northcote and co-workers,1 we
initiated a synthetic venture directed toward the total
synthesis of (+)-peloruside A (1).10 Our endgame strategy
called for formation of the inscribed tetrahydropyran ring
after macrocyclization (Scheme 1). Central to this scenario
was a flexible route that would permit either acid or alcohol
activation to achieve macrolactonization. Taken together,
(+)-peloruside A (1) was envisioned to arise from macrolide
2 upon removal of the dithiane and isopropylidene protecting
groups. To construct the macrolactone precursor, we would
employ union of a dithiane 3 with aldehyde 4, followed by
appropriate functional group adjustments.
step reduction/oxidation sequence, was subjected to a Brown
asymmetric allylation13 to generate alcohol (-)-10 in a highly
diastereoselective fashion (>20:1).14,15 Protection of the
resulting alcohol as the PMB ether, followed by selective
dihydroxylation16 of the terminal olefin and oxidative cleav-
age, furnished (-)-11, the requisite aldehyde for the proposed
Mukaiyama aldol.17 Toward this end, reaction of (-)-11 with
the silyl-enol ether derived from ketone 1218 led to ꢀ-hydroxy
ketone (-)-13 with >20:1 diastereoselectivity at C(13).14
Ketone (-)-13 was then subjected to a SmI2-promoted
Evans-Tishchenko reduction19 to generate (-)-14, possess-
ing the correct stereochemistry at C(11).14
Construction of dithiane (-)-3 began with known ho-
moallylic alcohol (+)-5 (Scheme 2),11 which was protected
as the BPS-ether. Ozonolysis furnished aldehyde (+)-6.
Installation of the trisubstituted Z-olefin was next achieved
via a Still-Gennari modification of the Horner-Wadsworth-
Emmons olefination12 to yield ester (-)-8 in 89% yield as a
single diastereomer. Next, enal (-)-9, available by a two-
(5) (a) Smalley, M. K.; Hoye, T. R.; Tennakoon, M. Abstracts. 221st
National Meeting of the American Chemical Society, April 2001; American
Chemical Society: Washington, DC, 2001. (b) Paterson, I.; Di Francesco,
M. E.; Ku¨hn, T. Org. Lett. 2003, 5, 599. (c) Ghosh, A. K.; Kim, J.-H.
Tetrahedron Lett. 2003, 44, 3967. (d) Ghosh, A. K.; Kim, J.-H. Tetrahedron
Lett. 2003, 44, 7659. (e) Taylor, R. E.; Jin, M. Org. Lett. 2003, 5, 4959. (f)
Vergin, J. B.; Ryba, T. D. Abstracts. 225th National Meeting of the American
Chemical Society, March 2003; American Chemical Society: Washington,
DC, 2003. (g) HeadyT. N.; Crimmins, M. T. Abstracts. 225th National
Meeting of the American Chemical Society, April 2003; American Chemical
Society: Washington, DC, 2003. (h) Liu, B.; Zhou, W.-S. Org. Lett. 2004,
6, 71. (i) Engers, D. W.; Bassindale, M. J.; Pagenkopf, B. L. Org. Lett.
2004, 6, 663. (j) Gurjar, M. K.; Pedduri, Y.; Ramana, C. V.; Puranik, V. G.;
Gonnade, R. G. Tetrahedron Lett. 2004, 45, 387. (k) Stocker, B. L.;
Teesdale-Spittle, P.; Hoberg, J. O. Eur. J. Org. Chem. 2004, 330. (l)
Roulland, E.; Ermolenko, M. S. Org. Lett. 2005, 7, 2225. (m) Owen, R. M.;
Roush, W. R. Org. Lett. 2005, 7, 3941. (n) Chen, Z.-L.; Zhou, W. S.
Tetrahedron Lett. 2006, 47, 5289.
Completion of dithiane (-)-3 entailed formation of the
MOM-ether, reductive removal of the ethyl ester with
DIBAL-H, and generation of the methyl ether. The overall
sequence to (-)-3, the dithiane coupling partner, proved
highly efficient, proceeding with a longest linear sequence
of 14 steps and in 21.4% overall yield from (+)-5.
Construction of aldehyde (+)-4 was designed specifically
to demonstrate the utility of our multicomponent type I ARC
protocol, employing epoxide (+)-16, readily prepared from
(12) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405
.
(6) (a) Hamel, E.; Day, B. W.; Miller, J. H.; Jung, M. K.; Northcote,
P. T.; Ghosh, A. K.; Curran, D. P.; Cushman, M.; Nicolaou, K. C.; Paterson,
I.; Sorensen, E. J. Mol. Pharmacol. 2006, 70, 1555. (b) 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. (c) 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.
(13) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401
.
(14) The absolute stereochemistry of alcohols (-)-10 C(15), (-)-13
C(13), and (+)-19 C(7) was established by conversion to the corresponding
Mosher’s esters and analyzed using the Kakisawa method. See the
Supporting Informationand: Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa,
H. J. Am. Chem. Soc. 1991, 113, 4092
.
(15) The stereochemistry of the C(15) hydroxyl is epimeric to that in
the natural product but is essential to set the C(13) hydroxyl stereochemistry
in the Mukaiyama aldol reaction between (-)-11 and 12.
(16) The sterically bulky ligand in AD-mix-ꢀ provides selectivity for
the terminal olefin.
(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.
(9) Ghosh, A. K.; Xu, X.; Kim, J.-H.; Xu, C.-X. Org. Lett. 2008, 10,
1001.
(17) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974,
96, 7503.
(10) Zheng, J. Ph.D. Thesis, University of Pennsylvania, 2003. Also
see: Wuest, W. M. Ph.D. Thesis, University of Pennsylvania, 2008.
(11) Xu, Z.; Johannes, C. W.; Houri, A. F.; La, D. S.; Cogan, D. A.;
Hofilena, G. E; Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 10302.
(18) Ketone 12 was readily prepared in six steps from isobutyralde-
hyde.
(19) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447.
5502
Org. Lett., Vol. 10, No. 24, 2008

known epoxide (-)-1520 and epoxide (+)-1821 (Scheme 3).
Toward this end, addition of the lithium anion of TBS-1,3-
dithiane (17) to epoxide (+)-16, followed by a solvent-
controlled Brook rearrangement (HMPA) and addition of
epoxide (+)-18, furnished alcohol (+)-1914 in 65% yield.
Methyl ether formation, followed by removal of both the
TBS and 1,3-dithiane moieties, led to ketone (+)-20. We
next called upon a hydroxyl-directed 1,3-syn reduction,22
followed in turn by acetonide formation23 and removal of
the benzyl ether via hydrogenolysis, to generate alcohol (+)-
21. Completion of (+)-4, the aldehyde coupling partner, was
achieved in five steps. First, alcohol (+)-21 was converted
via a three-step sequence to the corresponding methyl ester,
and then subjected to oxidative removal of the PMB moiety
to provide (-)-22. Parikh-Doering oxidation24 of the
resultant terminal hydroxyl then furnished aldehyde (+)-4
in 87% yield. The synthesis of (+)-4 also proved efficient,
proceeding with a longest linear sequence of 13 steps and
in 12.9% overall yield from (-)-15.
achieve macrolactonization26 via the Mitsunobu protocol proved
unsuccessful; only recovery of starting material or complete
decomposition occurred.
Scheme 4. Efforts toward (+)-Peloruside A
Scheme 3. Synthesis of Aldehyde (+)-4
Undeterred, and with acid activation for macrolactonization
as a backup, we inverted the C(15) hydroxyl (Scheme 5).
The inversion required three steps, deprotection of the PMB-
ether, oxidation of the derived secondary hydroxyl, and CBS
reduction,27 to provide the requisite C(15) stereogenicity.
Saponification then furnished seco-acid (-)-25, setting the
stage for macrolactonization. Here, we encountered what
proved to be an unexpected result. Execution of the
Yamaguchi protocol28 involving acid activation and cycliza-
tion generated a macrolide in 71% yield, albeit with
epimerization at C(2) to furnish (-)-26, a result that went
undetected until after global deprotection.
To understand after the fact (vide infra) this result, we
initiated a series of computational studies of (-)-26 and the
corresponding desired C2-epimer. Initial conformational
searches were preformed using Macromodel 7.2 software.29
The resulting low energy conformers were then clustered
according to the macrocyclic ring torsions with the repre-
sentative structures subjected to full geometry optimization
at the B3LYP/6-31G(d,p) level of theory. The undesired,
albeit observed, epimer (-)-26 was found to be more stable
by 1.8 kcal/mol. Not surprisingly, the lowest energy con-
formations of the two compounds possess different macro-
cyclic ring conformations with the major torsional differences
residing in the C1-C2 bond. As seen in Figure 1, the C2
hydrogen of (-)-26 adopts a favorable eclipsed conformation
With advanced coupling fragments (-)-3 and (+)-4 in hand,
we turned to their union (Scheme 4). Reaction of the lithium
anion derived from dithiane (-)-3, with aldehyde (+)-4, in the
presence of HMPA, led to alcohol (-)-23 as a mixture at C(8)
favoring the desired isomer (ca. 9:1) presumably under
Felkin-Anh control.25 Importantly, union of (-)-3 and (+)-4
furnished the complete carbon backbone of (+)-peloruside A.
Formation of seco-acid (-)-24 was next readily achieved, in
two steps, by removal of the PMB ether (DDQ) and saponifica-
tion of the methyl ester (LiOH). Unfortunately, all attempts to
(20) Hungerbu¨hler, E.; Seebach, D. HelV. Chim. Acta 1981, 64, 687.
(21) Smith, A. B., III; Pitram, S. M.; Boldi, A. M.; Gaunt, M. J.;
Sfouggatakis, C.; Moser, W. H. J. Am. Chem. Soc. 2003, 125, 14435.
(22) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155.
(25) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199. (b) Anh, N. T.; Eisenstein, O. NouV. J. Chem. 1977, 1, 61. (c) Anh,
N. T. Top. Curr. Chem. 1980, 88, 145. (cc) For assignment of the C(8)
hydroxyl stereochemistry, see ref 32.
(26) Hungerbu¨hler, E.; Seebach, D. HelV. Chim. Acta 1981, 64, 687.
(27) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(28) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(23) (a) Rychnovsky, S. D.; Skalitsky, D. J. Tetrahedron Lett. 1990,
31, 945. (b) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993,
58, 3511. (c) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett.
1990, 31, 7099.
(29) MacroMod, Schro¨dinger, LLC 1500 S.W. First Ave, Suite 1180,
Portland, OR 97201-5815.
(24) Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505.
Org. Lett., Vol. 10, No. 24, 2008
5503

Scheme 5. Synthesis of (-)-2-epi-Peloruside A
Figure 1. Observed (-)-26 epimer in green and the desired C2-
epimer in gray, with the hydrogen at C2 shown in black. The C15
side chain has been omitted for better view.
MeOH, then delivered what was revealed by extensive 1-D
and 2-D NMR analyses to be (-)-2-epi-peloruside A (28).
In summary, the synthesis of 2-epi-peloruside A (28) has
been achieved with a longest linear sequence of 25 steps
and in 0.56% overall yield. Pleasingly, this synthetic venture
demonstrates the utility of both dithiane linchpins and the
multicomponent type I ARC tactic.
with the C1 carbonyl due to A(1,3) strain,30 while the
remainder of the macrocyclic ring does not show additional
eclipsed interactions. The epimer, epi-26, on the other hand,
takes up a bisected rather than an eclipsed conformation at
C2, resulting in different C2-C3 and C5-C6 bond torsions
around the protected 1,3-diol. In addition, the lowest energy
macrocyclic ring conformer has one eclipsing interaction
between the C7 methoxy and the C8 hydroxyl groups.
Unaware at the time of the C(2) epimerization, treatment
of macrolide (-)-26 with the Stork reagent [PhI(O2CCF3)2]31
resulted in concomitant hydrolysis of the 1,3-dithiane,
removal of the isopropylidene protecting group, and hemiket-
al formation to yield (-)-27.32 Selective methylation of the
C(3) hydroxyl group with Meerwein’s reagent (Me3OBF4),33
followed by global deprotection employing 4 N HCl in
Acknowledgment. Support was provided by the National
Institutes of Health (National Cancer Institute) through Grant
No. CA-19033, American Cancer Society for a Postdoctoral
Fellowship (J.M.C.), partially funded by the National Fisher-
ies Institute (PF-03-005-01-CDD), the Japanese Society for
the Promotion of Science for a Postdoctoral fellowship
(N.F.), and the University of Pennsylvania for a graduate
fellowship (W.M.W.). Computational studies were supported
by the National Science Foundation under Grant No.
0131132.
Supporting Information Available: Spectroscopic and
analytical data for compounds 6-28 and selected experi-
mental and computational procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
(30) (a) Hoffman, R. Chem. ReV. 1989, 89, 1841. (b) Allinger, N. L.
J. Am. Chem. Soc. 1969, 91, 337.
(31) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(32) Bis-MOM ether formation of (-)-27 permitted confirmation of the
relative stereochemistry of C(5,7,8,9) by NOESY experiments. See the
Supporting Information.
(33) Schaper, U. A. Synthesis 1981, 794.
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