Synthesis of α-CF₃-proline derivatives by means of a formal (3 + 2)-cyclisation between trifluoropyruvate imines and Michael acceptors

Abstract

The first (3 + 2)-cyclisation of 3,3,3-trifluoropyruvate-derived imines and indandione-based Michael acceptors giving spirocyclic α-CF3-α-proline derivatives was developed.

Synthesis of complex unnatural fluorine-containing amino acids

“…The preparation of spirocyclic compounds has garnered considerable interest in recent years as these motifs have gained greater significance as medicinally relevant scaffolds ( Scheme 17 ) [ [76] , [77] , [78] , [79] , [80] ]. Waser and co-workers disclosed the synthesis of spirocyclic fluorinated proline derivatives in 2019 [ 81 ]. To achieve this, a (3 + 2)-cyclisation approach under phase transfer conditions was implemented.…”

“…For example, an additional fluorine was successfully incorporated to give compound 72b in 40 % yield.

Scheme 17 Synthesis of spirocyclic fluorinated amino acids, Waser and co-workers [ 81 ].

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Pd‐Catalyzed Allylation of Imines to Access α‐CF3‐Substituted α‐Amino Acid Derivatives

“…We have recently shown that preformed imines 4 undergo highly diastereoselective (3+2)‐type cyclizations with Michael acceptors to access CF 3 ‐proline derivatives 6 , with the α‐position acting as the donor site . Based on these observations, we now became interested in developing this concept further towards a more general approach to access (novel) acyclic α‐CF 3 ‐α‐amino acid derivatives in an unprecedented fashion.…”

“…In addition to using imines as acceptors for nucleophilic additions, the last years saw an increasing number of reports demonstrating that the inherent reactivity of imines can be inverted (making the imine carbon nucleophilic). Such an imine umpolung can be achieved by using a suited benzylamine protecting group that allows for the formation of ambident nucleophilic azaallyl anions under basic reaction conditions, which then preferably react with electrophiles in the α‐position (compare with Scheme B) . Accordingly, these umpolung approaches allow for the synthesis of valuable acyclic, or cyclic, products by starting from easily accessible imines.…”

“…Such an imine umpolung can be achieved by using a suited benzylamine protecting group that allows for the formation of ambident nucleophilic azaallyl anions under basic reaction conditions, which then preferably react with electrophiles in the α‐position (compare with Scheme B) . Accordingly, these umpolung approaches allow for the synthesis of valuable acyclic, or cyclic, products by starting from easily accessible imines. Interestingly however, CF 3 ‐containing benzylic imines 2 have only sparingly been reported and utilized as building blocks so far , .…”