Stereoselective α-Deuteration of Serine, Cysteine, Selenocysteine, and 2,3-Diaminopropanoic Acid Derivatives

Abstract

Efficient methodologies for synthesizing enantiopure α-deuterated derivatives of serine, cysteine, selenocysteine, and 2,3-diaminopropanoic acid have been developed. H/D exchange was achieved by deprotonation of a chiral bicyclic serine equivalent followed by selective deuteration. Additionally, diastereoselective additions of thiols, selenols, and amines to a chiral bicyclic dehydroalanine in deuterated alcohols allowed siteselective deuteration at the Cα atom of cysteine, selenocysteine, and 2,3-diaminopropanoic acid derivatives. A deuterated analogue of carbocysteine, a drug for the treatment of bronchiectasis, was synthesized.

Stereoselective Biocatalytic α‐Deuteration of L‐Amino Acids by a Pyridoxal 5’‐Phosphate‐Dependent Mannich Cyclase

“…It is noteworthy to mention that developing a general approach for synthesizing enantiopure α-deuterated derivatives of serine 21, cysteine 17, and Dap 5 was considered a challenging task, and only a few chemical methodologies have been reported to access α-deuterated β-X-α-amino acids (X = N, O, S, or Se). [20] Our findings here demonstrate that LolT can efficiently deuterate these amino acids stereoselectively, which prompted us to further investigate whether LolT can deuterate their derivatives. Interestingly, when L-cystine 36 was incubated with LolT in D 2 O, enzymatic transformations in addition to αdeuteration took place (Figure 4a), as indicated by the unexpected loss of Cβ proton on the 1 H-NMR spectra (Figure 4b).…”

“…It is noteworthy to mention that developing a general approach for synthesizing enantiopure α‐deuterated derivatives of serine 21 , cysteine 17 , and Dap 5 was considered a challenging task, and only a few chemical methodologies have been reported to access α‐deuterated β‐ X ‐α‐amino acids ( X=N, O, S, or Se ) [20] . Our findings here demonstrate that LolT can efficiently deuterate these amino acids stereoselectively, which prompted us to further investigate whether LolT can deuterate their derivatives.…”

Photoredox Catalytic Installation of an Alkyl/Aryl Side Chain and Deuterium into (S)-Methyleneoxazolidinone: Synthesis of Enantioenriched α-Deuterated α-Amino Acid Derivatives

“…The widely used methods for the synthesis of α-deuterated α-amino acid derivatives employ the asymmetric alkylation of glycine-derived imines followed by deuteration with D 2 O (Scheme A1) − or H/D exchange of amino acid derivatives (Scheme A2). − Although these methods provide viable approaches to α-deuterated amino acids, in many cases, the polar bond connection modes carry the limitations of achieving a moderate level of deuteration and accessing highly sterically demanding amino acids. The bulky side chain amino acids, capable of restricting the conformations, and thus improving the potency and/or selectivity, lipophilicity, and metabolic stability, have found broad applications in peptides and peptidomimetics drug discovery. , …”