Total synthesis of phorboxazole A. 1. Preparation of four subunits

Article abstract of DOI:10.1021/ol062530r

(Chemical Equation Presented) Four subunits of the potent antitumor agent phorboxazole A were constructed; fragments C20-C32 and C9-C19 containing tetrahydropyrans A and B, respectively, were assembled using palladium-catalyzed intramolecular alkoxycarbonylation.

Full text of DOI:10.1021/ol062530r

ORGANIC
LETTERS
2006
Vol. 8, No. 26
6039-6042
Total Synthesis of Phorboxazole A. 1.
Preparation of Four Subunits
James D. White,* Punlop Kuntiyong, and Tae Hee Lee
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331
james.white@oregonstate.edu
Received October 13, 2006
ABSTRACT
Four subunits of the potent antitumor agent phorboxazole A were constructed; fragments C20
−C32 and C9
−C19 containing tetrahydropyrans
A and B, respectively, were assembled using palladium-catalyzed intramolecular alkoxycarbonylation.
Phorboxazole A (1) and its C13 epimer phorboxazole B were
isolated by Molinski from a marine sponge of the genus
Phorbas sp. and are among the most potent cytotoxic natural
products yet discovered.1 Tumor cell growth is inhibited by
1 at subnanomolar concentration by a mechanism that has
been shown to arrest the cell cycle at the S phase. A more
detailed description of its mode of action awaits further study,
but it is known that 1 has no effect on tubulin polymerization
and does not interfere with the integrity of microtubules.
high potency of 1 has invited a broad array of synthetic
endeavors that includes completed syntheses of phorboxazole
A by Forsyth,3 Smith,4 Williams,5 and Pattenden,6 as well
as syntheses of its C13 epimer (phorboxazole B) by Evans7
and Lin.8 In addition, numerous publications have reported
syntheses of subunits of 1.9
A striking feature of the structure of phorboxazole A is
the presence of three tetrahydropyran units embedded in a
21-membered lactone. Two of these tetrahydropyrans, A and
(2) (a) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J.
Am. Chem. Soc. 1996, 118, 9422. (b) Molinski, T. F. Tetrahedron Lett.
1996, 37, 7879. (c) Molinski, T. F.; Brzezinski, L. J.; Leahy, J .W.
Tetrahedron: Asymmetry 2002, 13, 1013.
(3) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc.
1998, 120, 5597.
(4) Smith, A. B., III; Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M. J.
Am. Chem. Soc. 2001, 123, 4834.
(5) (a) Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.;
Berliner, M. A.; Reeves, J. T. Angew. Chem., Int. Ed. 2003, 42, 1258. (b)
Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner, M.
A.; Reeves, J. T. Proc. Natl. Acad. Sci. 2004, 101, 12058.
(6) (a) Gonzalez, M. A.; Pattenden, G. Angew. Chem., Int. Ed. 2003,
42, 1255. (b) Pattenden, G.; Gonza´lez, M. A.; Little, P. B.; Millan, D. S.;
Plowright, A. T.; Tornos, J. A.; Ye, T. Org. Biomol. Chem. 2003, 1,
4173.
The structure of phorboxazole A (1), including its absolute
configuration, was derived by a combination of spectroscopic
and degradative studies.2 The complex architecture and very
(7) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem.
Soc. 2000, 122, 10033.
(8) Li, D.-R.; Zhang, D.-H.; Sun, C.-Y.; Zhang, J.-W.; Yang, L.; Chen,
J.; Liu, B.; Su, C.; Zhou, W.-S.; Lin, G.-Q. Chem.-Eur. J. 2006, 12, 1185.
(1) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126.
10.1021/ol062530r CCC: $33.50
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Published on Web 11/22/2006

B, bear substituents in a cis orientation at the C2 and C6
positions, whereas the third tetrahydropyran (C) has a trans
2,6-substitution pattern. This analysis pointed us toward a
synthesis strategy for 1 which foresaw two major subunits,
2 and 3, comprising C20-C32 and C9-C19, respectively,
emerging via a pathway that established the cis-2,6-disub-
stitution in each of the tetrahydropyrans A and B (Scheme
1). Specifically, we envisioned a reaction first described by
yielding and completely stereoselective synthesis of the
C20-C32 subunit from 2-methyloxazole-4-carboxaldehyde13
via hydroxy alkene 4 (Scheme 2). However, an excess of
Scheme 2. Synthesis of the C20-C32 Domain of 1 via
Palladium(II)-Mediated Alkoxycarbonylation
Scheme 1. Two of the Principal Subunits for Assembly into
Phorboxazole A
palladium(II) acetate was needed for complete conversion
of 4 to 5. Furthermore, the same conditions, when applied
to the synthesis of subunit 3, resulted in a low yield of the
tetrahydropyran.
A problem associated with alkoxycarbonylation of 4 and
6 is reduction of the palladium(II) reagent by carbon
monoxide to inactive palladium(0) during the course of the
reaction. To prevent this process, we investigated a variety
of conditions using a stoichiometric oxidant in the presence
of a catalytic quantity of a palladium(II) species. These
experiments carried out on 6 prepared from methyl 2-chloro-
methyloxazole-4-carboxylate14 showed that exposure of 6 to
catalytic palladium dichloride bis(acetonitrile) and excess
p-benzoquinone15 in methanol-acetonitrile under an atmo-
sphere of carbon monoxide afforded tetrahydropyran 7 in
58% isolated yield along with 15-20% of recoverable 6
(Scheme 3). The successful conversion of 6 to 7 by this
Semmelhack for the synthesis of tetrahydrofurans that em-
ployed palladium-mediated intramolecular alkoxycarbonyl-
ation of a hydroxy alkene.10
Our initial study of palladium(II)-mediated alkoxycarbonyl-
ation of a series of 6-hydroxy-1-octenes in methanol
demonstrated that cis-2,6-disubstituted tetrahydropyrans could
be prepared by this process but that yields were highly
dependent upon the orientation of substituents in the octene
chain.11 A subsequent investigation of palladium-mediated
intramolecular alkoxycarbonylation12 resulted in a high-
Scheme 3. Synthesis of the C9-C19 Portion of 1 via
Palladium(II)-Catalyzed Alkoxycarbonylation
(9) (a) Paterson, I.; Arnott, E. A. Tetrahedron Lett. 1998, 39, 7185. (b)
Paterson, I.; Luckhurst, C. A. Tetrahedron Lett. 2003, 44, 3749. (c) Paterson,
I.; Steven, A.; Luckhurst, C. A. Org. Biomol. Chem. 2004, 2, 3026. (d)
Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2, 1217. (e) Vitale, J.
P.; Wolckenhauer, S. A.; Do, N. M.; Rychnovsky, S. D. Org. Lett. 2005,
7, 3255. (f) Schaus, J. V.; Panek, J. S. Org. Lett. 2000, 2, 469. (g) Huang,
H.; Panek, J. S. Org. Lett. 2001, 3, 1693. (h) Wolbers, P.; Hoffmann, H.
M. R. Tetrahedron 1999, 55, 1905. (i) Wolbers, P.; Misske, A. M.;
Hoffmann, H. M. R. Tetrahedron Lett. 1999, 40, 4527. (j) Misske, A. M.;
Hoffmann, H. M. R. Tetrahedron 1999, 55, 4315. (k) Wolbers, P.;
Hoffmann, H. M. R. Synthesis 1999, 2291. (l) Wolbers, P.; Hoffmann, H.
M. R. Synlett 1999, 11, 1808. (m) Greer, P. B.; Donaldson, W. A.
Tetrahedron Lett. 2000, 41, 3801. (n) Greer, P. B.; Donaldson, W. A.
Tetrahedron 2002, 58, 6009. (o) Lucas, B. S.; Burke, S. D. Org. Lett. 2003,
5, 3915. (p) Lucas, B. S.; Luther, L. M.; Burke, S. D. Org. Lett. 2004, 6,
2965. (q) Lucas, B. S.; Luther, L. M.; Burke, S. D. J. Org. Chem. 2005,
70, 3757. (r) Brinkmann, Y.; Carreno, M. C.; Urbano, A.; Colobert, F.;
Solladie, G. Org. Lett. 2004, 6, 4335. (s) Chakraborty, T. K.; Reddy, V.
R.; Reddy, T. J. Tetrahedron 2003, 59, 8613. (t) Yadav, J. S.; Rajaiah, G.
Synlett 2004, 1537. (u) Yadav, J. S.; Prakash, S. J.; Gangadhar, Y.
Tetrahedron: Asymmetry 2005, 16, 2722.
means enabled us to employ this tetrahydropyran subunit in
a continuation of our route toward 1.
Construction of tetrahydropyran C of 1 required a subunit
which, when reacted with 7, would afford a masked 1,5-
diol that could be cyclized to the 2,6-trans configuration of
(11) White, J. D.; Hong, J.; Robarge, L. A. Tetrahedron Lett. 1999, 40,
1463.
(12) White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org. Lett. 2001, 3,
4003.
(13) White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org. Synth. 2002,
79, 244.
(14) Cardwell, K. S.; Hermitage, S. A.; Sjolin, A. Tetrahedron Lett. 2000,
41, 4239.
(15) Marshall, J. A.; Yanik, M. M. Tetrahedron Lett. 2000, 41, 4717.
(10) Semmelhack, M. F.; Zhang, N. J. Org. Chem. 1989, 54, 4483.
6040
Org. Lett., Vol. 8, No. 26, 2006

this heterocycle. The operative species chosen for this was
allylsilane 8 (Scheme 4). Asymmetric allylboration16 of
Scheme 5
Scheme 4. Synthesis of the C3-C8 Segment of 1
aldehyde 9 followed by silylation of the resultant homoallylic
alcohol and then ozonolysis gave aldehyde 10. Exposure of
10 to diazophosphonate 1117 produced alkyne 12, but
bromoboration of this material with 9-bromo-9-borabicyclo-
[3.3.1]nonane (13) gave an intractable mixture. A cleaner
result was obtained with the secondary alcohol from selective
cleavage of the TES ether, and the product from reaction
with 13 was then resilylated before treating vinyl bromide
14 with trimethylsilylmethylmagnesium chloride in the
presence of a nickel(II) catalyst18 to give 8.
Our initial plan for assembling the C20-C46 portion of
phorboxazole A envisioned capture of the anion derived from
deprotonation of the methyl substituent of oxazole 2 by a
δ-lactone 15 bearing the complete C38-C46 side chain,
including the terminal (E)-bromoalkene. Toward this end, a
route to 15 was devised starting from aldehyde 16 prepared
from diethyl (S,S)-tartrate (Scheme 5). Asymmetric allyl-
ation19 of 16 gave homoallylic alcohol 17 which was
converted to its methyl ether 18 before ozonolytic cleavage
to aldehyde 19. Acidic methanolysis of 19 cleaved both the
acetonide and the silyl ether and led directly to ketal 20, but
to attach a robust protecting group selectively at the C38
hydroxyl group, it was first necessary to reprotect the primary
alcohol of 20. After masking the secondary alcohol of 21
and releasing the primary alcohol, it was discovered that
subsequent hydrolysis of the methyl acetal and oxidation of
the resulting hemiacetal to a δ-lactone compromised the
integrity of the structure due to silyl group migration.
A solution to this problem was found in conversion of
the methyl acetal to its phenylthio acetal 22,20 so that Swern
(16) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988,
110, 1535.
(17) Mu¨ller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996,
521.
(18) Hayashi, T.; Fujiwa, T.; Okamoto, Y.; Katsuro, Y.; Kumada, M.
Synthesis 1981, 1001.
(19) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
oxidation of 22 followed by Wittig olefination of the resulting
aldehyde with ylide 23 afforded (E)-R,â-unsaturated ester
24 in excellent yield. Reduction of this ester followed by
Swern oxidation yielded R,â-unsaturated aldehyde 25 which
Org. Lett., Vol. 8, No. 26, 2006
6041

hemiacetal with Ley’s reagent.21 The terminal alkene of
lactone 31 was cleaved oxidatively to an aldehyde which
underwent a Takai reaction22 with bromoform to yield (E)-
bromotriene 15. The use of chromous chloride in this Takai
reaction was found to give a mixture of 1-chloro and 1-bromo
alkenes that was difficult to separate, and to avoid this
problem, chromium(II) bromide was prepared and used in
situ by reduction of chromium(III) bromide with lithium
aluminum hydride.
Scheme 6. Attempted Coupling of the C19-C32 Unit 3c with
C33-C46 Fragment 15
Unfortunately, attempts to use 15 in coupling reactions
with an anion prepared from 2 under a variety of conditions
led to a mixture of the desired product 32 and terminal alkyne
33 resulting from elimination of HBr (Scheme 6). In most
instances, 33 was the major product. Separation of 32 from
the mixture was tedious, and furthermore, we were unable
to convert 33 to 32.
The difficulties experienced in our attempts to forge the
C32-C33 linkage of 1 using lactone 15 as an electrophile
caused us to reevaluate our coupling strategy. As a result, a
modified assembly plan was devised employing a truncated
version of 15. This and further steps leading to the complete
synthesis of phorboxazole A are described in the Letter that
follows.
Acknowledgment. Financial support from the National
Institute of General Medical Science through grants GM-
50574 and GM-58889 is gratefully acknowledged.
underwent condensation with phosphonate 26 to afford (E,E)-
dienyl ester 27. Asymmetric allylation19 of aldehyde 28
derived from 27 furnished pure triene 29. After O-methyl-
ation of 29, the phenylthio substituent of 30 was returned to
a carbonyl function by treatment with silver nitrate in
aqueous THF20b followed by oxidation of the intermediate
Supporting Information Available: Detailed experi-
mental procedures and characterization data for new com-
pounds; 1H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL062530R
(20) (a) Hanessian, S.; Guindon, Y. Carbohydr. Res. 1980, 86, C3. (b)
White, J. D.; Blakemore, P. R.; Green, N. J.; Hauser, E. B.; Holoboski, M.
A.; Keown, L. E.; Nylund Kolz, C. S.; Phillips, B. W. J. Org. Chem. 2002,
67, 7750.
(21) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(22) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
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Org. Lett., Vol. 8, No. 26, 2006