Synthesis of naturally occurring antitumor agents: Stereocontrolled synthesis of the azabicyclic ring system of the azinomycins

Full details of the synthesis of the fully elaborated aziridino[1,2-a]pyrro lidine substructure 2 of the antitumor agents azinomycins A and B are repor ted. Stereoselective bromination of dehydroamino acid 4 provided control of olefin configuration in the final product, as a consequence of a stereospe cific cyclization of aziridine 3 onto the proximal beta-bromoacrylate, whic h effected pyrrolidine ring introduction. Dehydroamino acid 4 was construct ed by olefination of aldehyde 5 with a glycine-based phosphonate. Two compl ementary synthetic routes to 2 are presented. In the first route, the selec tively protected C12/C13 diol system of the targets was introduced into sta rting structure 6 in a stereocontrolled manner using Brown's (gamma-alkoxya llyl)-diisopinocampheylborane reagent system. Transient protection of the C 12 hydroxyl group of 48 as the trimethylsilyl ether was used to prevent C13 acetate migration prior to cyclization. Deprotection of the C12 hydroxyl f ollowing cyclization to the azabicyclic system afforded the extremely unsta ble core substructure 41, which could not be isolated, but was characterize d in situ. In the second route, the racemic gamma-alkoxystannane 8 was adde d in a chelation-controlled manner to serinal derivative 9 under conditions of kinetic resolution for introduction of the C12 and C13 stereogenic cent ers of the target. Phenylacetate and methoxyacetate esters were used for C1 2 hydroxyl protection. This work represents the first synthesis of the inta ct core substructure 44 of this novel class of natural products.