The aim of this project is to develop new chemical principles that evolve into unprecedented strategies to solve problems of creating molecular architecture of compounds of importance as antitumor agents, tumor promoters and antiviral agents. The imposition of reactivity control by transition metals, especially Pd, on pi-allyl systems may have vast implications in diverse classes of compounds. The first targets will be nucleosides and their carbocyclic analogues. A new concept for hydroxymethylation using a double metal system may introduce the almost omnipresent hydroxymethyl side chain. Practical asymmetric syntheses of carbocyclic systems will include neplanocin, carbovir, BCA and cyclaradine. extrapolation of this concept to nucleosides can target a broad array illustrated by AZT, DDI, DDDC, d4A, mizoribine, fazarabine, chryscandin and mikkomycin Z, each of which is chosen to highlight a different feature of this novel chemistry. A new thrust explores the applicability of forming cyclic peptides possessing unusual amino acids to capitalize on the efficiency of macrocyclizations as illustrated by the antitumor agents, the glidobactins. Preferences for formation of unusual ring sizes will be explored directed towards the mitomycin mimic FR900482. A strategy for the taxane family may emerge from the ease of Pd catalyzed maorocyclization followed by transannular cyclization. A new Pd catalyzed macrocyclization process may create a novel strategy toward neocarzinostatin. A new concept for cycloisomerization invokes the Pd catalyzed cyclization of alpha, omega-enynes. Testing its chemoselectivity and its opportunity for asymmetric induction targets the alkaloids castanaspermine and mitomycins and the lignans highlighted by epipodophyllotoxin. An incredibly short synthesis to the latter may emerge from the creation of a companion process - Pd catalyzed alkylative enyne cyclization. Cycloisomerization and a related Pd catalyzed cycloreduction of enynes opens the strategy to a novel class of terpenoid antitumor agents including phenazinomycin, saponaceolide, and FR111142 which examine important aspects of regio- and enantioselectivity of this new process. The development of a Pd(O) catalyzed enyne metatheses opens an avenue for the synthesis of large ring bridge bicycles possessing bridgehead double bonds. Testing the versatility of the juxtaposition of functionality may lead to effective strategies for diverse members represented, in order of increasing complexity, by roseophilin, shikodomedin and taxol. The true mettle of synthetic methods cannot be judged until it is tested in "the field of battle" - a complex synthetic target. The diversity of the challenges posed by antiviral and antitumor agents represent highly meaningful tests of their use.
NIH ExPorter
NIH ExPorter