Abstract
The synthesis of substituted d-phenylalanines in high yield and excellent optical purity, starting from inexpensive cinnamic acids, has been achieved with a novel one-pot approach by coupling phenylalanine ammonia lyase (PAL) amination with a chemoenzymatic deracemization (based on stereoselective oxidation and nonselective reduction). A simple high-throughput solid-phase screening method has also been developed to identify PALs with higher rates of formation of non-natural d-phenylalanines. The best variants were exploited in the chemoenzymatic cascade, thus increasing the yield and ee value of the d-configured product. Furthermore, the system was extended to the preparation of those l-phenylalanines which are obtained with a low ee value using PAL amination.
Highlights
The synthesis of substituted d-phenylalanines in high yield and excellent optical purity, starting from inexpensive cinnamic acids, has been achieved with a novel one-pot approach by coupling phenylalanine ammonia lyase (PAL) amination with a chemoenzymatic deracemization
The system was extended to the preparation of those l-phenylalanines which are obtained with a low ee value using PAL amination
The coupling of PAL amination and l-amino acid deaminases (LAADs)/NH3:BH3 deracemization (Scheme 1) resulted in 71 % conversion of p-nitrocinnamic acid (1 a) into d-2 a with 96 % ee, and would be useful for preparative applications compared to alternative methods
Summary
Abstract: The synthesis of substituted d-phenylalanines in high yield and excellent optical purity, starting from inexpensive cinnamic acids, has been achieved with a novel one-pot approach by coupling phenylalanine ammonia lyase (PAL) amination with a chemoenzymatic deracemization (based on stereoselective oxidation and nonselective reduction). For this purpose we designed a cascade process involving the deracemization of 2 (i.e., an enantioselective conversion of l-2 into a prochiral intermediate, along with a nonspecific complementary reaction which regenerates rac2, resulting in the accumulation of d-2).[5] we selected a system involving the enzymatic oxidation of l-2 into the corresponding imino acid 3 and the nonselective chemical reduction of the latter (Scheme 1, right).
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