It is proposed to study stereocontrol in aldol reactions of titanium enolates.
The specific aims are: (1) to develop enhanced systems for control of diastereofacial selectivity in aldol reactions of chiral titanium enolates, and (2) to exploit chelation of chiral alkoxyketones with titanium for chemo-, regio-, and stereoselectivity in aldol reactions of titanium enolates. Aldol reactions of titanium enolates have been little studied by other groups, probably because of the relatively modest stereoselectivities observed until our recent discovery of the deleterious effect of accompanying lithium and its prevention. It now seems possible to take full advantage of the special properties of titanium, including chelation control, in developing new systems for very high stereocontrol. Our overall objectives are to answer significant mechanistic questions which are appearing in studies of stereocontrolled aldol reactions of titanium enolates; to exploit the exciting selectivities we have observed, by further exploration and by construction of analogous systems designed for higher and for different kinds of stereoselectivity; and to develop and explain mechanistically chelation control in aldol reactions. Tools such as 500-MHz NMR, X-ray structure determination, HPLC, and capillary-column GLC make the necessary structure determinations and analyses of rates and selectivities -e.g., ratios of diatereomeric products-feesible now, even for complex molecules. The significance lies in the diverse chiral molecules common in nature, making it extremely important to develop methods for preparing specific ones in the laboratory, to allow study of their reactions and properties, particularly their physiological properties. The need is very great for compounds which are rare or unstable in nature (not easily isolated directly from natural sources), as well as for closely related structures which do not occur in nature (e.g., the enantiomer frequently does not appear in nature). Stereocontrol is thus of great importance in the contruction of complex molecules, particularly physiologically active ones.
