Synthetic organic chemistry has undergone a paradigm shift over the past 15 years with new metal-catalyzed transformations enabling bond formation in ways that chemists previously only dreamed about. Realizing the impact that new catalytic asymmetric reactions will have on the continued evolution of organic synthesis, we have focused our research on the development of new processes and on studying their utility in complex molecule synthesis. Our progress towards these goals depends upon expertise in many areas of chemistry including organometallic chemistry, physical organic chemistry, and synthetic organic chemistry. In each of the research areas described below, reaction development is intimately intertwined with efforts in total synthesis. These activities allow one to assess the strengths and limitations of new chemical transformations and often inspire efforts in new methodology development.

Catalytic Enantioselective Dimetalation. Enantioselective dimetalation of unsaturated substrates provides products with the capacity to undergo multiple bond-forming reactions and hence can provide powerful new routes to chiral organic compounds. Our group recently developed the first catalytic enantioselective alkene diboration reaction [JACS 2003, 125, 8702; JOC 2005, 70, 9538] which offers a versatile method for the conversion of simple alkene substrates to a variety of products possessing diverse functionality (Scheme 1). While oxidation provides the derived 1,2-diol, cross-coupling/oxidation provides carbohydroxylation adducts [OL 2004, 6, 131]. Diboration of prochiral allenes provides a product that contains both vinylboronate and stereogenic allylboronate functionality (Scheme 1). Our group has introduced the first enantioselective example of this reaction and has undertaken extensive mechanistic investigations to elucidate its mechanism [JACS 2004, 126, 16328; JACS 2007, 129, 8766]. The allene diboration intermediates are notable for their ability to participate in stereoselective allylation of aldehydes [OL 2005, 7, 5505] and imines [JACS 2006, 128, 74].

Scheme 1.

Currently, we are exploiting the utility of diboration-based multi-step reaction sequences for the efficient construction of natural products. In one example, we are targeting the natural product sclerophytin A, a compound with extremely potent activity against cancer cell lines. As depicted in Scheme 2, inexpensive citral (1) reacts with an allene diboration intermediate (2) and, after cross-coupling with iodomethane, provides trisubstituted alkene (3) in a single-pot reaction sequence. A subsequent stereoselective Oshima-Utimoto reaction developed in our lab [OL 2005, 7, 3367; OL 2005, 7, 3371; OL 2005, 7, 5465] provides oxacycle 4 which is primed for conversion to the natural product.

Scheme 2

New Allylation Reactions Based on Novel Reactivity of Transition-Metal Allyl Complexes. The development of new catalytic enantioselective processes that operate on inexpensive readily available reactants is an important objective in chemical research. Such processes can improve the efficiency with which target compounds can be assembled, thereby rendering both the discovery and development of new commodity chemicals more efficient. In this area of research, we focus on the development of new reactions that are enabled by the propensity for unsaturated π-allyl complexes such as 5 to undergo 3,3’ reductive elimination (Scheme 3). We have recently discovered this reactivity manifold for vinylic π-allyl complexes and initial computational experiments suggest that the activation barrier for this transformation is so low that it may be used as a driving force for the development of many unusual chemical reactions.

Scheme 3

Employing the 3,3’ reductive elimination manifold, we recently established that Pd-complexes catalyze the conjugate addition of allylboronic esters to dibenzylideneacetone [JACS 2007, 129, 2214]. We have recently rendered this reaction enantioselective (Scheme 4) and are exploring the utility of this process in natural product synthesis. Further, we are investigating mechanistic features of this reaction which may obtain for the invention of other new catalytic stereoselective process.

Scheme 4