Research Overview:

Our goal is to apply the principles of transition metal catalysis to the asymmetric synthesis of highly functionalized, strained small molecules. Representative targets include substituted aziridines, azetidines, cyclobutanones, and cyclopropane amino acids. Such building blocks are ideal precursors for enantioselective total syntheses of new natural products. The methods and reaction sequences we will develop are the result of careful retrosynthetic planning for selected complex molecules. In essence, we seek to merge a more classic (target-inspired) approach to organic synthesis with a keen awareness of the contemporary issues of practicality, efficiency, and selectivity.

A New Synthesis of 3-Acyl Cyclobutyl Ketones.

We are developing a catalytic asymmetric synthesis of 3-acyl-substituted cyclobutanones (see box) that involves commercially available starting materials and mild reaction conditions. The mechanism of this process is a subject of current interest, because the reaction formally derives from a reactivity umpolung. The small ring products – many of which contain contiguous all-carbon-substituted quaternary centers – represent versatile intermediates for complex molecule synthesis, since both of the carbonyl groups are poised for further stereoselective C–C bond constructions in which they might serve as either electrophile (carbonyl addition) or nucleophile (enolate alkylation). An exciting strategic application of this chemistry involves intramolecular bicyclization to afford cyclobutanones of type i, in which the central C–C bond is flanked by two electron-withdrawing carbonyl groups. Facile reductive cleavage of this bond (i ii) represents an atom-efficient fragmentation approach to the synthesis of medium ring carbocycles, lactones, and lactams, where ring size is simply a function of the tether length in the starting materials.



A New Approach to Medium Ring Azacycles. Application to Naturally Occurring Alkaloids.

Aziridines are well-studied synthetic intermediates, and like epoxides, their chemistry is dominated by ring-opening reactions. Such transformations lead to molecules with valuable 1,2-heteroatom relationships, commonly found in natural products and pharmaceuticals. Nonetheless, we are confident that conceptually new ways to exploit these versatile intermediates await discovery. Merging strain release (in iii or its derivatives) with C–C bond formation would be especially powerful. In this context, we are developing modern methods to elaborate simple hydroxymethyl-substituted aziridines and azetidines to seven- ( iv) and eight-membered azacycles. The high levels of stereocontrol and generality that are expected to accompany these reactions render the products useful as scaffolds for building molecular diversity and as starting materials for total synthesis. Selected natural product targets include the Stemona alkaloid sessilifoliamide B and indole alkaloid iboxyphylline.



Identification of Catalysts for the Formal Deoxygenative Insertion of Carbonyl Compounds into Acyclic and Cyclic Ketones.

α-Substituted carbonyl compounds, especially those derived from simple aldehydes or ketones, represent an extremely important class of intermediates for the synthesis of fine chemicals and natural products. The most common synthetic approach to these structures involves, α-alkylation of the corresponding metal enolate, a process that must be repeated if a quaternary center is desired. Some of the more popular enantioselective versions of this routine C–C bond construction rely on multi-step reaction sequences and a chiral auxiliary. In an effort to improve upon the existing state of the art, our group has initiated a search for a catalyst that will formally allow for the reductive insertion of one carbonyl compound into a second with control over absolute stereochemistry (v, see below). If successful, this approach will confront the problem of efficient α-functionalization of ketone carbonyls in a unique way – by merging C–C bond formation with a synthetically useful chain extension or ring expansion.