ORGANIC
LETTERS
2006
Vol. 8, No. 11
2353-2356
A Concise Stereoselective Synthesis of
Preussin, 3-epi-Preussin, and Analogues
Myra Beaudoin Bertrand and John P. Wolfe*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue,
Ann Arbor, Michigan, 48109-1055
Received March 15, 2006
ABSTRACT
A new stereoselective synthesis of the antifungal and antitumor agents Preussin and 3-epi-Preussin via a Pd-catalyzed carboamination of a
protected amino alcohol is described. The key transformation leads to simultaneous formation of the N C2 bond and the C1′−aryl bond, and
−
allows installation of the aryl group one step from the end of the sequence. This strategy permits the facile construction of a variety of
preussin analogues bearing different aromatic groups.
The natural product preussin (1) was first isolated in 1988
by Schwartz and co-workers from the fermentation extracts
of Preussia sp. and Aspergillus ochraceus.1 Initial screens
revealed that this compound had significant antifungal
activity,1,2 and more recent work has demonstrated that
preussin induces apoptosis in a number of human cancer cell
lines and is a potent (IC50 ) 500 nm) inhibitor of cyclin-E
kinase.3 Preussin has also shown antiviral activity, and is
believed to inhibit -1 ribosomal frameshifting of RNA-based
viruses.4 Interestingly, all eight stereoisomers of preussin
exhibit biological activity.5
employ phenylalanine as the source of the C1′-phenyl group,
and most other routes also install this group early in the
synthetic sequence.7,10 Thus, the previously described syn-
theses of preussin are generally not well suited to the rapid
generation of preussin analogues that differ in the nature of
the aryl substituent. A concise approach to this molecule that
involves the installation of the aryl group near the end of
(6) Kitahara has described a nonstereoselective route that affords all eight
stereoisomers of preussin in a two-step sequence. The isomers were
separated by preparative chiral HPLC. See ref 5.
(7) For a recent review, see: Basler, B.; Brandes, S.; Spiegel, A.; Bach,
T. Top. Curr. Chem. 2005, 243, 1.
Owing to its interesting biological properties, preussin has
been a popular target for total synthesis, and has been
prepared via 22 different routes ranging from 5 steps to over
23 steps.6-9 However, the large majority of these syntheses
(8) For early synthetic studies see: (a) Shimazaki, M.; Okazaki, F.;
Nakajima, F.; Ishikawa, T.; Ohta, A. Heterocycles 1993, 36, 1823. (b)
McGrane, P. L.; Livinghouse, T. J. Am. Chem. Soc. 1993, 115, 11485. (c)
Overhand, M.; Hecht, S. M. J. Org. Chem. 1994, 59, 4721. (d) Deng, W.;
Overman, L. E. J. Am. Chem. Soc. 1994, 116, 11241.
(9) For recent syntheses, see: (a) Canova, S.; Bellosta, V.; Cossy, J.
Synlett 2004, 1811. (b) Davis, F. A.; Deng, J. Tetrahedron 2004, 60, 5111.
(c) Raghavan, S.; Rasheed, M. A. Tetrahedron 2003, 59, 10307. (d) Huang,
P.-Q.; Wu, T.-J.; Ruan, Y.-P. Org. Lett. 2003, 5, 4341. (e) Dikshit, D. K.;
Goswami, L. N.; Singh, V. S. Synlett 2003, 1737.
(1) Schwartz, R. E.; Liesch, J.; Hensens, O.; Zitano, L.; Honeycutt, S.;
Garrity, G.; Fromtling, R. A.; Onishi, J.; Monaghan, R. J. Antibiot. 1988,
41, 1774.
(2) (a) Johnson, J. H.; Phillipson, D. W.; Kahle, A. D. J. Antibiot. 1989,
42, 1184. (b) Kasahara, K.; Yoshida, M.; Eishima, J.; Takesako, K.; Beppu,
T.; Horinouchi, S. J. Antibiot. 1997, 50, 267.
(3) Achenbach, T. V.; Slater, P. E.; Brummerhop, H.; Bach, T.; Mu¨ller,
R. Antimicrob. Agents Chemother. 2000, 44, 2794.
(4) Kinzy, T. G.; Harger, J. W.; Carr-Schmid, A.; Kwon, J.; Shastry,
M.; Justice, M.; Dinman, J. D. Virology 2002, 300, 60.
(5) Okue, M.; Watanabe, H.; Kasahara, K.; Yoshida, M.; Horinouchi,
S.; Kitahara, T. Biosci. Biotechnol. Biochem. 2002, 66, 1093.
(10) Two strategies allow installation of the aryl moiety within 1-3 steps
of the final target. Davis generated the C-2 benzyl group as the final step
via reaction of lithium diphenyl cuprate with a pyrrolidinylmethyl iodide
(40% yield, single diastereomer; 10 steps total, 9% overall yield). Bach
employed a Paterno`-Bu¨chi reaction of benzaldehyde with a dihydropyrrole
(4:1 dr, 53% yield after separation of diastereomers) followed by a two-
step deprotection sequence to generate the benzyl substituent (39% over 3
steps; 9 steps total, 11% overall yield). See: (a) Reference 9b. (b) Bach,
T.; Brummerhop, H. Angew. Chem., Int. Ed. 1998, 37, 3400.
10.1021/ol0606435 CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/27/2006