I. Studies toward the total synthesis of scytophycin C. II. Optimized synthesis of vinyl sulfonamide inhibitors of the cysteine protease cruzain.

Scytophycins A-E, which are isolated from the blue-green alga Scytonema pseudohofmanni, are a novel class of polyoxygenated, 22-membered macrolides containing a trans-dihydropyran moiety and a vinyl formamide unit. The scytophycin family exhibits broad-spectrum anti-fungal activity as well as cytotoxicity against a variety of human cancer cell lines. The potent biological activities of these compounds, along with their low natural abundance have stimulated considerable interest in their total synthesis. The C(26)--C(32) fragment of scytophycin C has been synthesized, utilizing a Curtius rearrangement to install the N-alkenyl- N-methylformamide unit. Additionally, the C(1)--C(7) aldehyde fragment has been prepared. Using a double allylboration reaction, this aldehyde has been coupled to a C(13)--C(17) aldehyde to generate a (Z )-1,5-syn-diol. Ring closure of this diol provided the C(1)--C(17) trans-dihydropyran unit of scytophycin C. In a separate project, an efficient route for the large-scale synthesis of vinyl sulfonamide protease inhibitors was developed. These vinyl sulfonamides are known to be potent inhibitors of cruzain, a parasite cysteine protease targeted in the treatment of Chagas' Disease. Using this route, gram quantities of the most potent inhibitors were synthesized for use in initial animal studies.Ph.D.Organic chemistryPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124461/2/3138203.pd