Stereoselective Total Synthesis of Antitumor Macrolide (+)-rhizoxin D

Article abstract of DOI:10.1021/ol049701h

A convergent, stereoselective total synthesis of the macrolide antitumor agent rhizoxin D is described. (+)-DIPCI-promoted asymmetric aldol reaction, Evans-Tishchenko 1,3-diol synthesis, modified Julia coupling, and Horner-Wadsworth-Emmons reactions are featured.

Full text of DOI:10.1021/ol049701h

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1445-1448
Stereoselective Total Synthesis of
Antitumor Macrolide (+)-Rhizoxin D
Yueheng Jiang,‡ Jian Hong,§ and Steven D. Burke*
†
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706-1396
burke@chem.wisc.edu
Received February 19, 2004
ABSTRACT
A convergent, stereoselective total synthesis of the macrolide antitumor agent rhizoxin D is described. (+)-DIPCl-promoted asymmetric aldol
reaction, Evans−Tishchenko 1,3-diol synthesis, modified Julia coupling, and Horner−Wadsworth−Emmons reactions are featured.
Rhizoxin, 1, (Scheme 1) and its congeners constitute a family
of 16-membered macrolactones first isolated in 1984 from
the plant pathogenic fungus Rhizopus chinensis by Iwasaki
and co-workers.1 Rhizoxin is a tubulin-interactive antimitotic
agent that exhibits pronounced antimicrobial and antifungal
activity as well as potent in vitro cytotoxicity and in vivo
antitumor activity.2 Rhizoxin (1) has undergone extensive
clinical trials as a potential drug candidate.3 Rhizoxin D (2),
a didesepoxy analogue of rhizoxin, was isolated in 1986 and
is thought to be the biogenetic precursor of 1.4 Although
rhizoxin D is equally potent as 1, it has been less studied
due to limited natural abundance.5 Because of their significant
biological activity, potential as chemotherapeutic agents, and
unique structural features, the rhizoxins have attracted
substantial interest as synthetic targets. One total synthesis
of rhizoxin6 and six syntheses of rhizoxin D,7 along with
several partial syntheses,8 have been reported. In a culmina-
tion of our previous efforts,9 we describe herein a total
synthesis of rhizoxin D (2).
As outlined in Scheme 1, our convergent strategy breaks
rhizoxin D into segments 3-5. An asymmetric aldol reaction
and an anti-stereoselective Evans-Tishchenko 1,3-diol syn-
(3) (a) Hanauske, A.-R.; Catimel, G.; Aamdal, S.; ten Bokkel Huinink,
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Verweij, J. Br. J. Cancer 1996, 73, 397. (b) Verweij, J.; Wanders, J.; Gil,
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1996, 74, 1944.
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S. Chem. Pharm. Bull. 1986, 34, 1387. (b) Kiyoto, S.; Kawai, Y.; Kawakita,
T.; Kino, E.; Okuhara, M.; Uchida, I.; Tanaka, H.; Hashimoto, M.; Terano,
H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1986, 39, 762.
(5) Kato, Y.; Ogawa, Y.; Imada, T.; Iwasaki, S.; Shimazaki, N.;
Kobayashi, T.; Komai, T. J. Antibiot. 1991, 44, 66.
† This work was presented at the 38th National Organic Symposium,
Bloomington, IN, June 8-12, 2003.
‡ Present address: Schering-Plough Research Institute, 2015 Galloping
Hill Road, Kenilworth, NJ 07033.
§ Present address: Eli Lilly & Company, Lilly Corporate Center,
Indianapolis, IN 46285.
(1) (a) Iwasaki, S.; Kobayashi, H.; Furukawa, J.; Namikoshi, M.; Okuda,
S.; Sato, Z.; Matsuda, I.; Noda, T. J. Antibiot. 1984, 37, 354. (b) Kiyoto,
S.; Kawai, Y.; Kawakita, T.; Kino, E.; Okuhara, M.; Uchida, I.; Tanaka,
H.; Hashimoto, M.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J.
Antibiot. 1986, 39, 762. (c) Takahashi, M.; Iwasaki, S.; Kobayashi, H.;
Okuda, S.; Murai, T.; Sato, Y.; Haraguchi-Hiraoka, T.; Nagano, H. J.
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M.; Schwartsmann, G. Ann. Oncol. 1992, 3, 755.
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10.1021/ol049701h CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/31/2004

Scheme 1
thesis were envisioned as key steps to establish the C15 and
O-methylation and DIBAL-H reduction, provided aldehyde
9. An aldol reaction between 9 and the enolate of methyl
ketone 10,12 prepared with (+)-chlorodiisopinocamphenyl
borane (DIP-Cl),13 afforded â-keto alcohol 11 in 65% yield
C13 stereocenters in the central C10-C20 subunit. Modified
Julia olefination (C9-C10) and intra- and intermolecular
Horner-Wadsworth-Emmons (HWE) olefinations (C2-C3
and C20-C21, respectively) were planned for subunit
coupling to establish the carbon skeleton of rhizoxin D.
Synthesis of the C10-C20 subunit 4 began from R,â-
unsaturated aldehyde 67d (Scheme 2). Evans aldol reaction
with 7 gave the corresponding syn adduct 8 exclusively.10
Conversion of imide 8 to the Weinreb amide,11 followed by
Scheme 2a
(7) (a) Kende, A. S.; Blass, B. E.; Henry, J. R. Tetrahedron Lett. 1995,
36, 4741. (b) Williams, D. R.; Werner, K. M.; Feng, B. Tetrahedron Lett.
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J. W. Tetrahedron Lett. 1999, 40, 4145. (d) Keck, G. E.; Wager, C. A.;
Wager, T. T.; Savin, K. A.; Covel, J. A.; McLaws, M. D.; Krishnamurthy,
D.; Cee, V. J. Angew. Chem., Int. Ed. 2001, 40, 231. (e) Mitchell, I. S.;
Pattenden, G.; Stonehouse, J. P. Tetrahedron Lett. 2002, 43, 493. (f) White,
J. D.; Blakemore, P. R.; Green, N. J.; Hauser, E. B.; Holoboski, M. A.;
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7750. (g) Lafontaine, J. A.; Provencal, D. P.; Gardelli, C.; Leahy, J. W. J.
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Chem. 1992, 57, 2235. (d) Keck, G. E.; Park, M.; Krishnamurthy, D. J.
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A.; Cressman, E. N. K. Tetrahedron Lett. 1996, 37, 3291. (f) Lafontaine,
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Gardelli, C.; Lafontaine, J. A.; Leahy, J. W. Tetrahedron Lett. 1995, 36,
6033. (h) White, J. D.; Nylund, C. S.; Green, N. J. Tetrahedron Lett. 1997,
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Lett. 1997, 38, 7333. (j) Davenport, R. J.; Regan, A. C. Tetrahedron Lett.
2000, 41, 7619. (k) N’Zoutani, M.-A.; Pancrazi, A.; Ardisson, J. Synlett
2001, 769. (l) Kim, I. C.; Fuchs, P. L. Book of Abstracts, 224th National
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39, 2239. (b) Burke, S. D.; Hong, J.; Lennox, J. R.; Mongin, A. P. J. Org.
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103, 2127. (b) Evans, D. A. Aldrichimica Acta 1982, 15, 23. (c) Gage, J.
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(12) Ketone 10 was prepared in two steps from the known (2E)-4-(tert-
butyldimethylsiloxy)-2-methyl-but-2-enal7c by methyl Grignard addition and
Swern oxidation.
a Conditions: (a) 7, n-Bu2BOTf, Et3N, 0 °C, then add 6, CH2Cl2,
-78 °C to room temperature, 85%; (b) AlMe3, MeNH(OMe),
CH2Cl2, 0 °C to room temperature; (c) MeI, NaH, THF-DMF (3:
1), 0 °C, 78% for two steps; (d) DIBAL-H, THF, -78 °C, 98%;
(e) 10, (+)-DIP-Cl, Et3N, then add 9, CH2Cl2, -78 °C, 65%; (f)
p-nitrobenzaldehyde, SmI2, THF, 0 °C, 86%; (g) TIPSOTf, 2,6-
lutidine, CH2Cl2, -78 to 0 °C; (h) HF/Pyridine, THF, 0 °C to room
temperature, 83% for two steps; (i) Dess-Martin periodinane,
CH2Cl2, rt, 81%.
1446
Org. Lett., Vol. 6, No. 9, 2004

alcohol protection (TIPS), selective cleavage of the C10-
siloxy group, and Dess-Martin oxidation15 gave the desired
C10-C20 segment 4.
Scheme 3a
Synthesis of the C3-C9 subunit 5 started with the known
aldehyde 1316 (Scheme 3). An Evans aldol condensation10
of 13 with the boron enolate of 14 afforded the aldol product
as a single diastereomer, which was protected as its TES
ether 15. Ring-closing metathesis of the diene using Grubbs’
catalyst 16 gave cyclopentene 17 in 91% yield.17 Dihydroxyl-
ation of 17 afforded the cis diol with a diastereomeric ratio
of 8:1,18 which upon silylation gave 18. Reductive removal
of the chiral auxiliary using LiBH4 yielded the primary
alcohol, which was converted to the corresponding benzo-
thiazole sulfide under Mitsunobu conditions.19 Subsequent
m-CPBA oxidation provided the C3-C9 sulfone subunit 5.
Coupling of enal 4 and sulfone 5, utilizing the one-pot
modified Julia protocol,20 selectively gave 19 as the E-isomer
in 80% yield (Scheme 4). The PNB ester was reductively
removed, and the resulting alcohol was esterified with
diethylphosphonoacetyl chloride. Subsequent removal of the
three TES groups afforded the triol 20. Differentiation of
the C5 diastereotopic groups was achieved by one-pot
oxidative cleavage of the vicinal diol and TPAP oxidation
to provide lactone aldehyde 21 in 75% overall yield.21 This
tactic for establishing the C5 stereocenter is analogous to
those employed by Keck8d and Williams,7b and relies upon
thermodynamic diequatorial deployment of the side chains
in the intermediate hemiacetal. An intramolecular Horner-
Wadsworth-Emmons coupling reaction established the mac-
rolactone C2-C3 bond in 80% yield.22 Oxidative removal
of PMB group,23 followed by MnO2 allylic oxidation,24
afforded aldehyde 22. Treatment of 22 and phosphonate 39a,b
with t-BuOK in DME gave only (E,E,E)-triene via HWE
a Conditions: (a) n-Bu2BOTf, Et3N, 14, CH2Cl2, -78 to 0 °C,
88%; (b) TESOTf, 2,6-lutidine, CH2Cl2, -78 to 0 °C, 85%; (c) 16
(3.6 mol %), ClCH2CH2Cl, rt, 91%; (d) OsO4 (6 mol %), NMO,
acetone-H2O (8:1), rt, 87%; (e) TESOTf, 2,6-lutidine, CH2Cl2, -78
to 0 °C, 95%; (f) LiBH4, MeOH, THF, 0 °C to room temperature,
58%; (g) 2-mercaptobenzothiazole, Ph3P, DEAD, THF, 0 °C to
room temperature, 98%; (h) m-CPBA, NaHCO3, CH2Cl2, rt, 97%.
with a 10:1 diastereomeric ratio. An intramolecular Evans-
Tishchenko reaction with p-nitrobenzaldehyde afforded 12
with the C13 stereocenter installed and the C15 hydroxyl
protected as the p-nitrobenzoate (PNB) ester.14 Subsequent
Scheme 4a
a Conditions: (a) LHMDS, THF, -78 °C, 0.5 h, then 4, THF, -78 °C to room temperature, 80%; (b) DIBAL-H, CH2Cl2, -78 °C, 99%;
(c) diethylphosphonoacetyl chloride, pyridine, THF, 0 °C to room temperature, 90%; (d) AcOH-THF-H2O (3:2:1), rt, 88%; (e) NaIO4,
THF-H2O (1:1); TPAP, NMO, 4 Å MS, CH2Cl2, 75%; (f) DBU, LiCl, CH3CN, rt, 5 × 10-4 M, 80%; (g) DDQ, CH2Cl2-H2O (20:1), rt,
92%; (h) MnO2, CH2Cl2, rt, 71%; (i) 3, t-BuOK, DME, 0 °C, 39%; (j) HF/pyridine, THF, 0 °C to room temperature, 70%.
Org. Lett., Vol. 6, No. 9, 2004
1447

C20-C21 coupling.25,26 Final deprotection of the C13 TIPS
agreement with those reported for the natural product.4a,7f,g
A stereoselective synthesis of rhizoxin D has thus been
accomplished with the longest linear sequence requiring 19
steps.
ether afforded rhizoxin D (2), [R]23 +271.56 (c 0.41,
D
MeOH), with all data (1H NMR, 13C NMR, IR, and [R]D) in
(13) (a) Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.;
McClure, C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663. (b) Paterson,
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(15) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(16) Beckwith, A. L. J.; Moad, G. J. Chem. Soc., Perkin Trans. 2 1975,
71, 1726.
Acknowledgment. We gratefully acknowledge support
of this work provided by NIH (Grants GM 31998 and CA
74394). We also thank Schering-Plough Research Institute
for the support of this project.
(17) (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc.
1993, 115, 9856. (b) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R.
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J. Liebigs Ann. Chem. 1993, 343.
Supporting Information Available: Detailed experi-
mental procedures and spectral data for all compounds and
1H and 13C NMR spectra for selected compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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Martin, V. Synthesis 1996, 285.
OL049701H
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(26) As reported by Williams7b and Pattenden,7e we also observed some
hydrolytic opening of the δ-lactone during the reaction. In practice, the
crude product was subjected to Yamaguchi lactonization conditions
(procedure: Suzuki, K.; Tomooka, K.; Katayama, E.; Matsumoto, T.;
Tsuchihashi, G. J. Am. Chem. Soc. 1986, 108, 5221) prior to purification,
as suggested by Professor Williams.
(24) Cahiez, G.; Alami, M. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; John Wiley & Sons: Chichester, 1995; Vol.
5, pp 3229-3235 and references therein.
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