Radical Functionalization of Unsaturated Amino Acids: Synthesis of Side-Chain-Fluorinated, Azido-Substituted, and Hydroxylated Amino Acids

Abstract

A range of enantiomerically pure protected side-chain-fluorinated amino acids has been prepared (13 examples) by treatment of protected amino acids containing unsaturated side chains with a combination of Fe(III)/NaBH 4 and Selectfluor. The modification of the conditions by replacement of Selectfluor with NaN 3 allowed the preparation of side-chain azido-substituted amino acids (five examples), which upon catalytic hydrogenation gave the corresponding amines, isolated as lactams (four examples). Radical hydration of the unsaturated side chains leading to side-chain-hydroxylated protected amino acids has also been demonstrated.

Synthesis of complex unnatural fluorine-containing amino acids

“…It was found that treating the cyclopentene containing amino acid 73 with HF.pyridine led to the successful formation of the fluorine-containing amino acid 74 ( Scheme 18 ). The Jackson group would build upon this work, and in 2019 they showed that through the use of radical functionalisation, fluoro, azido and hydroxyl moieties could be installed across olefins to access unnatural amino acids ( Scheme 19 ) [ 83 ]. Using a combination of an Fe(III) source with NaBH 4 and Selectfluor, fluorine atoms were successfully added across a range of cyclic and linear alkenes ( 75 ).…”

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Scheme 18 Fluorinated cyclopentane amino acid, Jackson and co-workers [ 82 ].

Scheme 19 Radical functionalisation of amino acids, Jackson and co-workers [ 83 ].

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Advances in Asymmetric Amino Acid Synthesis Enabled by Radical Chemistry

“…Radicals Generated from AA Derivatives in Conjugate Additions Another promising approach for the synthesis of nonproteinogenic AAs are based on generating the αcarbon radicals from glycine equivalents [184,185] and a side-chain modification of AAs, [63,65,66] for example, Laspartic and glutamic acid derivatives via radical decarboxylation, [186] leucine and valine derivatives via radical CÀ H activation [187,188] or vinyl-and allylglycine derivatives via radical conjugate additions. [189,190] In this paragraph, we will discuss the fascinating works having a deal with these topics.…”

“…[187] The alternative mechanism for the hydroxylated product 171 involved a SET from Ru(II) catalyst cannot be ruled out. [188] Recently, another alternative protocol for the radical azidation, fluorination and hydroxylation of enantiomerically pure protected AAs was described by Jackson et al [190] Accordingly, treatment of the fully protected α-AAs (S)-172 containing unsaturated side chains with a combination of Fe(III)/NaBH 4 and Selectfluor or NaN 3 provided the preparation of sidechain fluoro-and azido-substituted α-AA derivatives (S)-173 and (S)-174 in a range of 54-91% yields with no erosion of enantioselectivity (Scheme 67). The radical hydration of the unsaturated side chain of (S)-172 was conducted in the presence of air as a radical trap furnishing the side chain-hydroxylated protected α-AA derivative (S)-175 in a 62% yield (Scheme 67).…”

“…The radical hydration of the unsaturated side chain of (S)-172 was conducted in the presence of air as a radical trap furnishing the side chain-hydroxylated protected α-AA derivative (S)-175 in a 62% yield (Scheme 67). [190]…”