Current Research Interests

 

The mitomycin family of natural products (Figure 1) has been of great interest to the scientific community since their discovery in the late 1950’s.  To the biologist, the DNA cross linking ability of these compounds acting as effective anticancer agents, is both unique and intriguing.1  Mitomycin C has been found to be highly effective against solid tumors and is widely used in chemotherapy today.  To the organic chemist, the mitomycin family of natural products presents a formidable challenge in the total synthesis of these compounds.  Danishefsky put it well when he said, “The synthesis of a mitomycin is the chemical equivalent of walking on egg shells.” 2

Figure 1. Structures of the Mitomycins

The complexity of the mitomycins is due primarily to the unstable nature of these compounds to both acidic and reductive conditions.  Under these conditions the aziridine ring is especially prone to ring opening as well as elimination of the methylaminal (Scheme 1).  Synthesis of the mitomycins is further complicated with four contiguous stereocenters packed into a densely functionalized skeleton.  Kishi completed the first total synthesis of mitomycin C in 1977 in 46 steps with a 0.19% overall yield.3  Twelve years after Kishi’s

Scheme 1. Labile methylaminal in the Mitomycins

landmark accomplishment, Fukuyama completed his own total synthesis spanning 27 total steps with an overall yield of 10%.4  It should be noted that both of these syntheses were racemic. Danishefsky has completed a total synthesis of mitomycin K, also racemic.5 Up to this date there has not been an asymmetric total synthesis of any of the mitomycins.

The focus and intent of our current research is to complete an enantioselective total synthesis of mitomycin C, as well as other members of the mitomycin family.  The total synthesis of mitomycin C is currently under progress.  We are also interested in studying the biosynthesis of the mitomycins and currently are in collaboration with other research groups in this matter.
 

References:

  1. Iyer, V. N.; Szybalski, W. A. Proc. Natl. Acad. Sci. U.S.A. 1963, 50, 355.  Iyer, V. N.; Szybalski, W. A. Science 1964, 145, 55. 
  2. Danishefsky, S. J.; Schkeryantz, J. M. Synlett 1995, 475-490.
  3. Nakatsubo, F.; Cocuzza, A. J.; Keeley, D. E.; Kishi, Y. J. Am. Chem. Soc. 1977, 99, 4835-4836.  Nakatsubo, F.; Fukuyama, T.; Cocuzza, A. J.; Kishi, Y. J. Am. Chem. Soc. 1977, 99, 8115-8116.
  4. Fukuyama, T.; yang, L. J. Am. Chem. Soc. 1989, 111, 8303.  Fukuyama, T.; Yang, L. Tetrahedron Lett. 1986, 27, 6299.
  5. Benbow, J. W.; Schulte, G. K.; Danishefsky, S. J. Angew. Chem. Int. Ed. Engl. 1992, 31, 915-916.