ORGANIC
LETTERS
2006
Vol. 8, No. 26
6047-6049
Synthesis of an Advanced Intermediate
en Route to the Mitomycin Natural
Products
Amie L. Williams,† Jayasree M. Srinivasan,† and Jeffrey N. Johnston*
Department of Chemistry, Vanderbilt UniVersity, NashVille, Tennessee 37235-1822
jeffrey.n.johnston@Vanderbilt.edu
Received October 6, 2006
ABSTRACT
An advanced intermediate in our planned synthesis of mitomycin C has been acquired in nine steps from tert-butyl glyoxylate. The aziridinyl
pyrrolidine and quinone subunits are coupled regioselectively to arrive at an enamine that is prepared for C10 homologation.
The mitomycin natural products have attracted the attention
of medicinal and synthetic chemists for nearly a half
century.1,2 This interest results from several factors, including
the continued clinical use of mitomycin C (1) for treatment
of various forms of cancer. The unique pyrroloquinone
backbone presents a high degree and density of oxidation,
and this functional group array is the source of mitomycin
C’s unique ability to cross-link DNA.3 Consequently, a
substantial challenge for chemical synthesis is presented.
Indeed, there have been many reports detailing synthetic
efforts toward this class of natural products, and although
interest has not waned with the passing of time, only two
total syntheses of the title compound4 and two syntheses of
another member of the class, mitomycin K (3),5 have been
logged.
† Indiana University, Bloomington, IN 47405.
(1) Isolation and initial structure determination: (a) Webb, J. S.; Cosulich,
D. B.; Mowat, J. H.; Patrick, J. B.; Broschard, R. W.; Meyer, W. E.;
Williams, R. P.; Wolf, C. F.; Fulmor, W.; Pidacks, C.; Lancaster, J. E. J.
Am. Chem. Soc. 1962, 84, 3185. (b) Webb, J. S.; Cosulich, D. B.; Mowat,
J. H.; Patrick, J. B.; Broschard, R. W.; Meyer, W. E.; Williams, R. P.;
Wolf, C. F.; Fulmor, W.; Pidacks, C.; Lancaster, J. E. J. Am. Chem. Soc.
1962, 84, 3187. (c) Tulinsky, A. J. Am. Chem. Soc. 1962, 84, 3188.
(2) Selected recent leading references: (a) Coleman, R. S.; Felpin, F.-
X.; Chen, W. J. Org. Chem. 2004, 69, 7309. (b) Vedejs, E.; Little, J. J.
Am. Chem. Soc. 2002, 124, 748. (c) Papaioannou, N.; Evans, C. A.; Blank,
J. T.; Miller, S. J. Org. Lett. 2001, 3, 2879. (d) Ziegler, F. E.; Berlin, M.
Y.; Lee, K.; Looker, A. R. Org. Lett. 2000, 2, 3619. (e) Ban, Y.; Nakajima,
S.; Yoshida, K.; Mori, M.; Shibasaki, M. Heterocycles 1994, 39, 657. (f)
Lee, J.; Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1997, 119, 8127. (g) Luly,
J. R.; Rapoport, H. J. Org. Chem. 1984, 49, 1671.
(3) (a) Tomasz, M. Chem. Biol. 1995, 2, 575. Sheldon, P. J.; Johnson,
D. A.; August, P. R.; Liu, H.-W.; Sherman, D. H. DeV. Ind. Microbiol.
1997, 34, 123. (b) Gargiulo, D.; Musser, S. S.; Yang, L.; Fukuyama, T.;
Tomasz, M. J. Am. Chem. Soc. 1995, 117, 9388. (c) Verweij, J.; Sparreboom,
A.; Nooter, K. In Cancer Chemotherapy and Biological Response Modifiers
Annual; Pinedo, H. M., Longo, D. L., Chabner, B. A., Eds.; Elsevier: New
York, 1999; Chapter 3. (d) Crown, J. P. Anti-Cancer Drugs 1999, 10, S19.
A successful synthesis, particularly one amenable to
derivative formation, might further improve the therapeutic
profile for this natural product class,6 and rejuvenate efforts
to use contemporary biochemical techniques to similarly
improve efficacy.
To achieve a high degree of convergency, our retrosyn-
thesis disconnects the aziridinopyrrolidine and quinone across
the central dihydropyrrole ring (Figure 1). On the basis of
our previous studies of regioselective enamine additions to
(4) rac-1,2: (a) Kishi, Y.; Fukuyama, T. J. Nat. Prod. 1979, 42, 549.
(b) Fukuyama, T.; Yang, L. J. Am. Chem. Soc. 1989, 111, 8303.
(5) rac-3: (a) Benbow, J. W.; Schulte, G. K.; Danishefsky, S. J. Angew.
Chem., Int. Ed. Engl. 1992, 31, 915. See also: (b) Danishefsky, S. J.;
Schkeryantz, J. M. Synlett 1995, 475. (c) Wang, Z.; Jiminez, L. S.
Tetrahedron Lett. 1996, 37, 6049.
(6) Kasai, M.; Kono, M. Synlett 1992, 778.
10.1021/ol0624676 CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/29/2006