Asymmetric Alkylation of Cyclic Ketones with Dehydroalanine via H‐Bond‐Directing Enamine Catalysis: Straightforward Access to Enantiopure Unnatural α‐Amino Acids

Abstract

The growing importance of structurally diverse and functionalized enantiomerically pure unnatural amino acids in the design of drugs, including peptides, has stimulated the development of new synthetic methods. This study reports the challenging direct asymmetric alkylation of cyclic ketones with dehydroalanine derivatives via a conjugate addition reaction for the synthesis of enantiopure ketone‐based α‐unnatural amino acids. The key to success was the design of a bifunctional primary amine‐thiourea catalyst that combines H‐bond‐directing activation and enamine catalysis. The simultaneous dual activation of the two relatively unreactive partners, confirmed by mass spectrometry studies, results in high reactivity while securing high levels of stereocontrol. A broad substrate scope is accompanied by versatile downstream chemical modifications. The mild reaction conditions and consistently excellent enantioselectivities (>95 % ee in most cases) render this protocol highly practical for the rapid construction of valuable noncanonical enantiopure α‐amino‐acid building blocks.

Enantioselective organocatalytic strategies to access noncanonical α-amino acids

“…Conversely, Chen and Xiao reported the addition of 3-substituted oxindoles catalyzed by thiourea 36 ( Scheme 48 , top), 132 and, more recently, our group developed the addition of cyclic ketones with the use of the chiral bifunctional primary amine/thiourea catalyst 48, which is capable of activating the ketone via a transient enamine intermediate and the DHA via H-bonding ( Scheme 48 , bottom). 133 …”

“…Conversely, Chen and Xiao reported the addition of 3substituted oxindoles catalyzed by thiourea 36 (Scheme 48, top), 132 and, more recently, our group developed the addition of cyclic ketones with the use of the chiral bifunctional primary amine/thiourea catalyst 48, which is capable of activating the ketone via a transient enamine intermediate and the DHA via Hbonding (Scheme 48, bottom). 133 The unique electronic structure of DHA offers a plethora of chemical transformations for its modication. In fact, depending on the reaction conditions, polar nucleophilic additions can be performed with aor b-selectivity.…”