Synthesis of Highly Functionalized Diazoacetoacetates and Their Synthetic Applications

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Kundu, Kousik
Doyle, Michael P
ABSTRACT Title of dissertation: SYNTHESIS OF HIGHLY FUNCTIONALIZED DIAZOACETOACETATES AND THEIR SYNTHETIC APPLICATIONS Kousik Kundu, Doctor of Philosophy, 2006 Dissertation directed by: Professor Michael P. Doyle Department of Chemistry University of Maryland, College Park, MD 20742 I. Catalytic Addition Methods for the Synthesis of Functionalized Diazoacetoacetates We have developed efficient Mukaiyama aldol and Mannich addition reactions of readily accessible vinyldiazoacetates with aldehydes and imines using low catalytic amounts of commercially available Lewis acids. During the reaction the diazo functionality remained intact. The products are synthetically interesting as they are set to undergo a Rh(II)-catalyzed carbene reactions to form various complex carbocycles with multiple stereogenic centers. II. Constructing Chiral Diazoacetoacetates by Catalytic Highly Enantioselective Mukaiyama Aldol Addition Reactions Silver(I)-BINAP catalyzed highly enantioselective Mukaiyama aldol addition methodology has been developed for efficient synthesis of chiral diazoacetoacetates. Furthermore, in order to make this approach more practical as far as product yields and enantioselections are concerned, a novel Sc(III)-mixed ligands (heterochiral) catalyst has been developed. III. Synthetic Applications of Diazoacetoacetates Prepared by Mukaiyama Aldol Addition Reactions Diazoacetoacetate addition products from reactions with aromatic aldehydes undergo rhodium(II)-catalyzed ring closure to cyclobutanones with high diastereocontrol. TMS-protected Mukaiyama aldol adducts on the other hand go through similar ylide-derived pathway, but lead to dihydrofurans in excellent chemical yield. Diazoacetoacetates derived from aliphatic aldehydes form cyclopentanone by C--H insertion, but leads to dihydrofurans with TMS-protected adducts.