Asymmetric Mannich Reaction of Fluorinated Ketoesters with a Tryptophan‐Derived Bifunctional Thiourea Catalyst

Abstract

Small organic molecules capable of hydrogen-bonding interactions with substrates have found widespread application in asymmetric catalysis. In particular, thiourea-based organic molecules have become the most prominent hydrogen-bonddonor catalysts in a wide variety of organic reactions. In this context, bifunctional organic molecules containing a tertiary amino functionality and a thiourea moiety are remarkably useful organic catalysts. Despite their tremendous utility, these bifunctional catalysts are derived from a very limited range of chiral structural scaffolds, including cyclohexane-1,2diamine, 1,1’-binaphthyl-2,2’-diamine, and cinchona alkaloids. The development of readily accessible novel bifunctional catalysts of this nature would be highly desirable. As part of our research program towards the development of practical organocatalysts based on primary amino acids, we were intrigued by the possibility of designing novel tertiary amine– thiourea catalysts on the basis of simple amino acids. The facile conversion of natural amino acids into 1,2-diamines and the availability of structurally diverse side chains make this method very attractive. To investigate the validity of this approach, we selected l-tryptophan as the chiral precursor. We reasoned that the indole moiety would be capable of engaging in aromatic and hydrogen-bonding interactions with substrates, and these effects may result in efficient chiral induction (Scheme 1). Fluorinated molecules are of high importance in the pharmaceutical industry, and their asymmetric preparation has drawn great attention. The catalytic construction of fluorinated quaternary carbon stereocenters is a formidable synthetic challenge. A number of excellent methods based on metal catalysis have been reported; however, organocatalytic approaches for the creation of fluorinated quaternary centers are rather limited. Recently, organocatalytic synthetic methods with fluorinated substrates have become an alternative and viable option for accessing chiral fluorinated molecules. In such approaches, racemic fluorinated nucleophiles are used as substrates. A C C bond is formed rather than a C F bond, and full advantage is taken of the high electronegativity and small molecular radius of the fluorine atom. We and others have used fluorinated substrates in this way in organocatalytic Michael and alkylation reactions for the construction of fluorinated chiral molecules. To assess the utility of tryptophan-based bifunctional catalysts, we chose to focus on the direct asymmetric Mannich reaction of a-fluorinated b-ketoesters, as such reactions yield structurally demanding and biologically important a-fluorob-amino acids. Organocatalytic asymmetric Mannich reactions of b-ketoesters and malonates were reported recently by the research groups of Schaus, Deng, and Dixon, all of whom employed organic catalysts derived from cinchona alkaloids. Herein, we report that tryptophan-based bifunctional thiourea derivatives promote the asymmetric Mannich reaction of fluorinated substrates to afford highly optically enriched fluorine-containing molecules containing adjacent quaternary and tertiary stereocenters. We selected the Mannich reaction of a-fluoro-b-ketoester 1a with N-Boc imine 2a as a model reaction and examined the catalytic effects of various bifunctional catalysts (Table 1). Quinidine-derived thioureas and a quinidine-derived sulfonamide gave disappointing results (Table 1, entries 1–3). On the other hand, the tryptophan-based thiourea derivatives Trp-1–Trp-3 were found to be good catalysts. They afforded the Mannich product 3a in quantitative yield and with good diastereoselectivity and enantioselectivity (Table 1, entries 4– 6). Under optimized reaction conditions, the fluorinated product containing adjacent quaternary and tertiary stereoScheme 1. Thiourea catalyst based on a primary amino acid (tryptophan).