Postulated biogenesis of WS9885B and progress toward an enantioselective synthesis

Article abstract of DOI:10.1021/ol990723r

(Matrix presented) WS9885B promotes the assembly of microtubules in vitro and displays cytotoxicity as potent as paclitaxel against several cancer cell lines. In this Letter, we propose a biogenesis for this architecturally complex bacterial metabolite fr

Full text of DOI:10.1021/ol990723r

ORGANIC
LETTERS
1999
Vol. 1, No. 4
645-648
Postulated Biogenesis of WS9885B and
Progress toward an Enantioselective
Synthesis
Christopher D. Vanderwal, David A. Vosburg, Sven Weiler, and Erik J. Sorensen*
The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
sorensen@scripps.edu
Received June 8, 1999
ABSTRACT
WS9885B promotes the assembly of microtubules in vitro and displays cytotoxicity as potent as paclitaxel against several cancer cell lines.
In this Letter, we propose a biogenesis for this architecturally complex bacterial metabolite from a much simpler, polyunsaturated precursor.
We also present significant progress toward a convergent, enantioselective synthesis of WS9885B. Our work features a chemoselective palladium-
catalyzed cross-coupling of two advanced building blocks and an uncommon Claisen-like cyclization.
Scientists from the Fujisawa Pharmaceutical Company
recently described the constitution, relative stereochemistry,
and pronounced cytotoxicity of WS9885B (1), a substance
isolated from the fermentation broth of Streptomyces sp.
No9885.1 This compound possesses an unprecedented hexa-
cyclic architecture, a bridgehead alkene, and 12 stereocenters.
Against several cancer cell lines in vitro, WS9885B displays
cytotoxicity as potent as paclitaxel (Taxol®), an established
drug for the treatment of ovarian and breast cancers.2 Like
paclitaxel,3 1 stabilizes cellular microtubules in Vitro and
warrants serious attention as a potential chemotherapeutic
agent for the treatment of cancer.
powerful incentive for research in organic synthesis. An
enantioselective synthesis of 1 would establish its absolute
stereochemistry and permit a systematic study of the
relationship between its constitution and microtubule-
stabilizing properties and cytotoxicity.
While the biosynthesis of 1 is not yet known, we propose
that the architecturally and stereochemically complex struc-
ture of WS9885B could eVolVe from a substantially less
complex substance by spontaneous intramolecular reorga-
nization. The essence of our biogenetic postulate and strategy
for synthesis is that a structure of type 3 (Scheme 1), which
could arise via an intramolecular Diels-Alder reaction4 of
(1) Muramatsu, H.; Miyauchi, M.; Sato, B.; Yoshimura, S. 40th
Symposium on The Chemistry of Natural Products, Fukuoka, Japan, 1998,
Paper 83, p 487.
(2) Rowinsky, E. K.; Donehower, R. C. New Engl. J. Med. 1995, 332,
1004.
(3) (a) Schiff, P. B.; Fant, J.; Horwitz, S. B. Nature 1979, 277, 665. (b)
Schiff, P. B.; Horwitz, S. B. Proc. Natl. Acad. Sci. U.S.A. 1980, 77, 1561.
(4) (a) Roush, W. R.; Gillis, H. R.; Ko, A. I. J. Am. Chem. Soc. 1982,
104, 2269. (b) Marshall, J. A.; Audia, J. E.; Grote, J.; Shearer, B. G.
Tetrahedron 1986, 42, 2893. (c) Roush, W. R.; Essenfeld, A. P.; Warmus,
J. S. Tetrahedron Lett. 1987, 28, 2447. (d) Roush, W. R. In AdVances in
Cycloaddition; JAI Press: Greenwich, CT, 1990; Vol. 2, p 91.
WS9885B combines the important elements of novel
structure with high biological activity and provides a
10.1021/ol990723r CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/07/1999

Scheme 1. Postulated Biogenesis of WS9885B (1)
2, may be well-suited for a Knoevenagel cyclization5 to a
of the allylic alcohol to bromide 6 was then smoothly
achieved as shown in Scheme 2.
structure of type 4. In the particular context of 4, proximity
between electron-deficient 4π and electron-rich 2π systems
is a circumstance that may well favor the occurrence of a
transannular inverse electron demand Diels-Alder reaction
to give WS9885B (1) directly or in protected form.6,7
Our goal is to test the chemical basis of the hypothesis
put forth in Scheme 1, and we set compound 2sor a
sufficiently stable surrogatesas a preliminary objective for
synthesis. In this disclosure, we describe a convergent,
enantioselective synthesis of tetraenal 15 by a pathway that
features a chemoselective palladium-catalyzed cross-coupling
of appropriately functionalized C1-C8 and C9-C20 do-
mains. We also show that a Claisen-like cyclization of an
acetate ester potassium enolate provides a reliable solution
to the problem of constructing a â-keto lactone of the type
found in 2.
In the course of our recent synthesis of fumagillol,10 we
benefited from Corey’s outstanding one-flask method for the
Scheme 2. Synthesis of Vinyl Bromide 9a
From the abundant terpene geraniol, we have established
an expeditious eight-step synthesis of vinyl bromide 9, an
advanced intermediate comprising carbons 9-20 (see Scheme
2). Although standard dihydroxylation of geraniol is not
highly site-selective, Sharpless and co-workers have shown
that triol 5 can be prepared efficiently by asymmetric
dihydroxylation of geraniol.8 Reaction of 5 with sodium
periodate supported on silica gel9 provided an aldehyde that
was immediately protected as a dioxolane acetal. Conversion
(5) For reviews of the Knoevenagel reaction, see: (a) Jones, G. Org.
React. (N.Y.) 1967, 15, 204. (b) Tietze, L. F.; Beifuss, U. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New
York, 1991; Vol. 2, p 341.
(6) For an excellent review of inverse electron demand and hetero Diels-
Alder reactions, see: Boger, D. L. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 5,
p 451.
(7) The concept of performing tandem Knoevenagel-hetero Diels-Alder
reactions derives strong precedent from the substantial studies of Tietze
and co-workers. For reviews, see: (a) Tietze, L. F. J. Heterocycl. Chem.
1990, 27, 47. (b) Tietze, L. F. Chem. ReV. 1996, 96, 115.
(8) Xu, D.; Park, C. Y.; Sharpless, K. B. Tetrahedron Lett. 1994, 35,
2495.
(9) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622.
646
Org. Lett., Vol. 1, No. 4, 1999

controlled construction of dienyl halides of type 7.11 By this
procedure and a subsequent deprotection step, large quantities
of aldehyde 7 were obtained from allylic bromide 6.
achieve an enantiospecific synthesis of this substance from
the known D-xylose-derived lactol methyl ether 1118 through
the high-yielding sequence shown in Scheme 4. Compound
While we could not transform aldehyde 7 to â-keto lactone
10 in a stereocontrolled fashion via the catalytic asymmetric
dienolate aldol chemistry of Sato,12 we found Evans’s
asymmetric aldol methodology13 to be optimal for the task
of establishing the syn C16-C17 stereorelationship in a
rigorous way. As expected, aldehyde 7 reacted efficiently
with the boron enolate derived from the known propionimide
8.14 When the reaction temperature was maintained at -78
°C, we observed a single aldol adduct, which was subse-
quently acetylated to give imide acetate 9 in excellent yield.
Our intention was to transform 9 directly to â-keto lactone
10 via a somewhat uncommon Claisen-like cyclization (see
Scheme 3).15 Gratifyingly, treatment of 9 with 4 equiv of
Scheme 4. Synthesis of Vinyl Stannane 14a
Scheme 3. Claisen-like Cyclization of Imide Acetate 9
11 is an ideal starting material for a synthesis of 14 because
it possesses the requisite stereotriad and differentiated
oxidation states at its terminal carbon atoms. Reaction of 11
with ethanethiol in the presence of a catalytic amount of HCl
gave rise to an acyclic 1,3-diol which was subsequently
protected as di-tert-butylsilylene ketal 12.19 N-Bromosuc-
cinimide-mediated hydrolysis of the dithioacetal function
proceeded smoothly, affording the corresponding aldehyde.
After treatment with elemental silver to remove residual thiol,
the benzyl ether was hydrogenolyzed to produce a mixture
of δ-lactol and hydroxy aldehyde tautomers20 that reacted
smoothly with dimethyl 1-diazo-2-oxopropylphosphonate in
basic methanol21 to give terminal alkyne 13.
After Swern oxidation of alcohol 13, application of
Pattenden’s two-stage alkyne hydrostannylation procedure22
accomplished the introduction of the desired (E)-vinylstan-
nane moiety. Our synthesis of key intermediate 14 was
completed by a Wittig reaction of the alkynyl aldehyde with
(triphenylphosphoranylidene)acetaldehyde. It is noteworthy
potassium hexamethyldisilazide16 at -78 °C led to the rapid
expulsion of the oxazolidinone auxiliary, which was recov-
ered in quantitative yield, and provided the desired compound
10 in 68% yield following mild acidic workup.17 This reliable
and easily executed intramolecular carbon-carbon bond-
forming reaction may prove generally useful for the facile
preparation of optically active γ-alkyl-â-keto-δ-lactones.
As our studies matured, vinylstannane 14 emerged as an
appropriately functionalized C1-C8 sector, and we could
(10) Vosburg, D. A.; Weiler, S.; Sorensen, E. J. Angew. Chem., Int. Ed.
1999, 38, 971.
(11) (a) Corey, E. J.; Dittami, J. P. J. Am. Chem. Soc. 1985, 107, 256.
(b) Corey, E. J.; Lee, J.; Roberts, B. E. Tetrahedron Lett. 1997, 38, 8915.
(c) Corey, E. J.; Roberts, B. E. Tetrahedron Lett. 1997, 38, 8919.
(12) (a) Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Heterocycles 1995,
41, 1435. (b) Sato, M.; Sugita, Y.; Abiko, Y.; Kaneko, C. Tetrahedron:
Asymmetry 1992, 3, 1157.
(13) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127. (b) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am.
Chem. Soc. 1981, 103, 3099. (c) Evans, D. A.; Nelson, J. V.; Taber, T. R.
Top. Stereochem. 1982, 13, 1. (d) Evans, D. A. Aldrichimica Acta 1982,
15, 23.
(14) Gage, J. R.; Evans, D. A. Organic Syntheses; Wiley: New York,
1993; Collect. Vol. VIII, p 339.
(15) (a) Branda¨nge, S.; Leijonmarck, H. Tetrahedron Lett. 1992, 33, 3025.
(b) Leijonmarck, H. K. E. Chem. Commun. (Stockholm) 1992, 3, 1.
(16) The potassium counterion is important, as lithium and sodium acetate
enolates reportedly give 11-membered rings resulting from competitive
attack on the oxazolidinone carbonyl; see ref 15.
(17) In the base-induced Claisen-like cyclization of 9, â-elimination of
the C16 acetate group was not observed. Presumably, transition state 1,3-
allylic strain discourages deprotonation at C17 (see: Evans, D. A.; Kaldor,
S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112,
7001).
(18) (a) Anderson, C. D.; Goodman, L.; Baker, B. R. J. Am. Chem. Soc.
1958, 80, 5247. (b) Ireland, R. E.; Liu, L.; Roper, T. D. Tetrahedron 1997,
53, 13221.
(19) (a) Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 4871.
(b) Trost, B. M.; Caldwell, C. G.; Murayama, E.; Heissler, D. J. Org. Chem.
1983, 48, 3252.
(20) 1H NMR analysis at 25 °C revealed a ca. 9:1 ratio of lactol:hydroxy
aldehyde tautomers.
(21) Mu¨ller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996,
521.
(22) Boden, C. D. J.; Pattenden, G.; Ye, T. J. Chem. Soc., Perkin Trans.
1 1996, 2417.
Org. Lett., Vol. 1, No. 4, 1999
647

that the latter two reactions afforded the desired products as
single geometrical isomers.
affords a substance possessing all of the carbon atoms of
WS9885B (1). Incidentally, â-keto lactone 10 and its derived
tert-butyldimethylsilyl enol ether are less stable than acetate
imide 9 and were found to be unsuitable as substrates in
Stille reactions with vinylstannane 14.
In summary, we propose a biogenesis for WS9885B (1),
a structurally complex natural product that stabilizes cellular
microtubules and displays pronounced cytotoxicity. On the
basis of our biogenetic proposal and the convergent strategy
described herein, we are seeking an enantioselective labora-
tory synthesis of 1. WS9885B is an ideal objective for
research in organic synthesis because significant questions
about the relationship between its constitution and cytotox-
icity persist.
Having defined enantiocontrolled pathways to key inter-
mediates 9 and 14, we addressed the task of joining them
through a Stille reaction.23 Despite the proven utility of the
Stille reaction, we approached the problem of joining 9 and
14 through this process with some trepidation because 14, a
substance bearing vinylstannane and electron-deficient enal
moieties, could conceivably react with a transitory organo-
palladium(II) intermediate via a Stille and/or a Heck reac-
tion.24 In practice, however, exposure of a solution of
compounds 9 and 14 in THF to Pd2(dba)3 (5 mol %) and
triphenylarsine (20 mol %) at reflux25 afforded the desired
compound 15 in 58% yield (see Scheme 5); a Heck reaction,
Acknowledgment. We are very grateful to Dr. Seiji
Yoshimura from the Fujisawa Pharmaceutical Co. for NMR
spectra of natural WS9885B (1). We thank Drs. D. H. Huang
and L. B. Pasternack for NMR spectroscopic assistance and
Dr. G. Siuzdak for mass spectrometric assistance. This work
was supported by The Skaggs Institute for Chemical Biology
and by predoctoral fellowships from the National Science
and Engineering Research Council of Canada (C.D.V.) and
the National Science Foundation (D.A.V.).
Scheme 5. Chemoselective Cross-Coupling of 9 and 14
Supporting Information Available: Characterization
data for compounds 9, 14, and 15. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL990723R
(23) For reviews of the Stille reaction, see: (a) Stille, J. K. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 508. (b) Farina, V.; Krishnamurthy, V.; Scott, W.
J. Org. React. (N.Y.) 1997, 50, 1.
(24) For a review of the Heck reaction, see: de Meijere, A.; Meyer, F.
E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379.
(25) The reagents and reaction conditions that we employed for this Stille
coupling were reported to be effective in the following disclosure (see entry
17 of Table 1): Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind,
L. S. J. Org. Chem. 1994, 59, 5905.
which would have created a bond between C9 of 9 and C3
of 14, was not observed. The chemoselective palladium-
mediated union of compounds 9 and 14 is most gratifying
because it establishes a crucial carbon-carbon bond and
648
Org. Lett., Vol. 1, No. 4, 1999