Complexity-building reaction development and the total synthesis of pactamycin

The diastereoselective synthesis of β-hydroxy ketones via quaternary Claisen condensation is described. This was accomplished via three-component coupling technology incorporating a Reformatsky reagent, silyl glyoxylates, and enantioenriched β-lactones. An unusual case of 1,4-stereoinduction was observed, transmitting the β-lactone stereochemistry to the developing fully-substituted stereocenter. The product scaffold was designed for quick access to the common leustroducsin family core subunit and applied to the formal synthesis of leustroducsin B.;Several approaches for the construction of the pactamycin core are presented. A prevailing strategy includes the rapid formation of the fully-substituted C1 stereocenter with a pendant ketone functional handle for which to test nucleophilic addition. Highly diastereoselective additions were permitted by the use of cerium trichloride, leading to a chelation-controlled stereochemical hypothesis. Four of the five core stereocenters were completed, but a challenging C2 amination could not be completed. The results of various strategies for the amino incorporation are discussed, and an optimized route to an advanced intermediate is described.;The amination problem faced in the pactamycin core synthesis led to the invention and development of a novel a-amination protocol employing nitrones and imidoyl chlorides. Upon combination of the two reaction partners, spontaneous [3,3]-rearrangement occurred generating α-carbamoyl enamides, or enediamide products based upon the availability of enolizable protons. Treatment of the products with sodium phenylthiolate induced hydrolysis to give protected α-amino ketones in moderate yield.;The enantioselective total synthesis of pactamycin is detailed. A de novo approach to this target was pursued using an asymmetric Mannich addition to install the C2 amino functionality early in the route. A symmetry-breaking diketone monoreduction occurred with high selectivity allowing for rapid core construction. Several unanticipated stereochemical complexities allowing for the ultimate target completion were discovered ex post facto leading to a serendipitous, concise route to pactamycin. The molecule was completed in fifteen steps, less than half that of the single reported synthesis known to date. The flexibility and efficiency afforded by this route allow for derivitization toward analogue synthesis. These structural manipulations may attenuate pactamycin's cytotoxicity which currently precludes its medicinal application.