Our research is directed at the development of new stereoselective carbon-carbon bond-forming processes and employing these methods in organic synthesis.  The reactions that particularly interest us are those that proceed by unique reaction mechanisms and display useful stereoselectivities. 

Silacyclopropanes as Intermediates for Organic Synthesis

Although silacyclopropanes have received little attention from the synthetic chemistry community, we have explored the use of these compounds in stereoselective synthesis.  We discovered the first metal-catalyzed silylene transfer reaction for the synthesis of silacyclopropanes (eq 1).  These transformations convert chiral alkenes such as 1 into silacyclopropanes, which can be converted efficiently to highly functionalized products such as 4 (eq 1).  

Because the metal-catalyzed silylene transfer reaction allows silylene transfer under exceptionally mild conditions, we have begun to explore silylene transfer to various functional groups.  When the a,b-unsaturated ester 5 was treated under the silylene transfer conditions, a silylketene acetal was formed cleanly (eq 2). This intermediate can be used to incorporate additional molecular complexity (eq 2).  Transfer to enynes leads to dienes, which undergo highly diastereoselective Diels-Alder reactions.

New [3 + 2] Annulation Reactions of Allylic Silanes

We have developed the reactions of a-substituted allylic silanes for the synthesis of heterocycles, and we have applied these reactions to the synthesis of natural products.  For example, the allylic silane 11, which can be prepared in one step, underwent annulation to provide the tetrahydrofuran 12 as a single diastereomer (eq 4).  Simple functional-group manipulations allow us to convert this compound to the highly substituted acyclic product 13.  After we oxidized the tertiary silyl group to a tertiary hydroxyl group, we employed this fragment twice (as the C3-C8 and C9-C13 fragments) in our total synthesis of the antibiotic erythronolide A. 

We have recently demonstrated that a-oxygenated allylic silanes, which can be prepared in one step, are powerful reagents for heterocycle synthesis.  These compounds can be employed to prepare functionalized tetrahydrofurans and lactams with high diastereoselectivity (eqs 5 and 6). 

Stereoselective Reactions of Oxocarbenium Ions

We have observed that reactions proceeding via oxocarbenium ion intermediates can exhibit selectivities that are counterintuitive.  For example, the sense of stereoselectivity observed upon nucleophilic substitution on six-membered ring acetals depends upon the electronic nature of the substituents (eq 7).  Other ring systems show unusual and unprecedented selectivities (eqs 8 and 9).  Our studies of oxocarbenium ions have provided stereoelectronic models to understand and predict outcomes such as these.  We are also currently developing new models and using them to devise stereoselective syntheses of natural products such as vincarodine and laurefucin.

Synthesis of Biological Active Peroxides

While numerous biologically active natural products contain the peroxide functionality, peroxide natural products remain formidable synthetic challenges.  We recently devised a method for the generation of cyclic peroxides in high yields (eq 10).  This reaction can be applied to peroxides that are flanked by two quaternary carbon atoms, as would be required for the synthesis of the antitumor compounds such as the plakinic acids (eq 11).

Updated 2.27.04