Design of Novel Titanium(IV) Schiff Base Complexes for Catalytic, Enantioselective Aldol Additions to Aldehydes

Citation

Singer, Robert Alan (1997) Design of Novel Titanium(IV) Schiff Base Complexes for Catalytic, Enantioselective Aldol Additions to Aldehydes. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/w287-z238. https://resolver.caltech.edu/CaltechTHESIS:07162025-181821401

Abstract

A novel chiral Schiff base ligand derived from 2-amino-2'-hydroxy-1, 1'-binaphthyl and 3-bromo-5-^tbutylsalicylaldehyde has been prepared. When binding the chiral ligand to titanium(IV) with 3,5-di-fbutylsalicylic acid, the complex formed functions as an efficient catalyst for the Mukaiyama aldol addition reaction. Using only 1-2 mol% of the catalyst, silyl ketene acetal additions to aldehydes were carried out in good chemical yield and in excellent levels of enantioselectivity. Unsaturated aldehydes tended to produce adducts in 95-99% ee, while aliphatic aldehyde products were typically obtained in 94-95% ee.

The methodology was extended to include dienolate additions to aldehydes by utilizing silyl enol ethers of dioxinones. Optimal selectivities in the dienolate additions were obtained with unsaturated, unbranched aldehydes (90-94% ee). Aromatic and aliphatic aldehydes were usually isolated in 80-84% ee. Since many of the adducts were crystalline solids, the optical purity was enhanced by recrystallization. By heating the dioxinone adduct in the presence of an alcohol or amine, the products were transformed to more useful β-ketoesters or β-ketoamides.

To demonstrate the utility of the methodology developed, the asymmetric addition reactions have been applied to the total synthesis of (R)-epinephrine and macrolactin A. After carrying out an enantioselective acetate addition to 3,4-dimethoxybenzaldehyde in 95% ee, the β-hydroxyester was converted to the amino-alcohol by a Hoffman rearrangement and a reduction. After deprotecting the catechol, (R)-epinephrine was obtained in 5 steps overall. Dienolate additions to β-stannylpropenal were employed to prepare two key fragments of macrolactin A. The convergent route involved stitching together three fragments with a Stille coupling and a Horner-Emmons olefination. Macrocyclization was accomplished by an intramolecular Stille coupling.

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