Synthesis of γ‐Oxo γ‐Aryl and γ‐Aryl α‐Amino Acids from Aromatic Aldehydes and Serine

Abstract

γ‐Oxo α‐amino acids and γ‐aryl α‐amino acids are compounds with very interesting biological properties and are active components of many drug molecules. Oxo amino acids are also used as synthetic precursors for a number of unnatural amino acids and amino alcohols. We report a very efficient synthesis of such compounds through the coupling of aromatic dithianes, prepared from aromatic aldehydes and an iodide derivative of serine. The dithiane groups in compounds thus obtained can be either hydrolyzed or reduced to generate 4‐oxo‐4‐aryl or 4‐aryl 2‐amino butanol derivatives, respectively, which, on further transformations, can be converted into the title compounds. Starting with L‐serine provides the corresponding D‐amino acids with complete enantiopurity. The reported method is economically viable and complements the existing methods, which rely largely on cross‐coupling reactions.

Chelation controlled reduction of N-protected β-amino ketones toward the synthesis of HPA-12 and analogues

“…We have already shown that these transformations proceed without a loss of enantiopurity and that the amino alcohols 1 retain the configuration of the serine derivative used. 17 We also synthesized three analogous derivatives 3h-j from L-threonine using the same method (Scheme 2).…”

“…17 One of the key intermediates of the synthesis is c-aryl-c-oxo-b-amino alcohols 1, which upon reduction provide 1-aryl-3-amino-1,4-diols. A syn-selective reduction of 1 would provide intermediates 2, which could be used for the synthesis of HPA-12 and its analogues (Scheme 1).…”

“…17 The iodide derivative was coupled with aryl dithianes using n-BuLi (THF, À20°C) and the resulting dithiane derivatives 3 were treated with trifluoroacetic acid (7% in CH 3 OH) to give the amino alcohol derivatives 4. Hydrolysis of the dithiane group in 4 (I 2 , NaHCO 3 ) yielded the required c-aryl-c-oxo-b-amino alcohols 1.…”

Synthesis of peptides containing oxo amino acids and their crystallographic analysis

“…The oxo amino acids were synthesized following a procedure that we had developed for the synthesis of γ‐aryl γ‐oxo α‐amino acids from 1,3‐dithiane derivatives of aromatic aldehydes and an iodide derived from serine . We assumed that a γ‐oxo group would be too close to the peptide backbone and decided to base this study on δ‐ and ε‐oxo amino acids.…”

Synthesis of stableC-linked ferrocenyl amino acids and their use in solution-phase peptide synthesis

“…We have reported the use of aromatic dithianes for the synthesis of unusual amino acids by coupling them with iodide derivatives of serine . Here, we report a very facile, high yielding and stereospecific synthesis of ferrocene‐containing amino acids from 2‐ferrocenyl‐1,3‐dithiane ( 1 ) using a similar method (Scheme ).…”