Cross‐Claisen Condensation of N‐Fmoc‐Amino Acids – A Short Route to Heterocyclic γ‐Amino Acids

Abstract

4‐Amino(methyl)‐1,3‐thiazole‐5‐carboxylic acids (ATCs) are a new class of constrained heterocyclic γ‐amino acids built around a thiazole ring; these compounds are valuable as design mimics of the secondary structures of proteins such as helices, β‐sheets, turns, and β‐hairpins. We report herein a short and versatile chemical route to orthogonally protected ATCs. The synthesis is centered on cross‐Claisen condensations between N‐Fmoc‐amino acids and sterically hindered 1,1‐dimethylallyl acetate. The optimized conditions are compatible with aliphatic, aromatic, acidic, and basic amino acids. The resulting N‐Fmoc‐β‐keto ester intermediates were engaged in a two‐step process to give ATCs in 45–90 % yields. The synthetic protocol provides a highly flexible method for the introduction of a wide variety of lateral chains either on the γ‐carbon atom or on the thiazole core of the γ‐amino acids.

C9/12 Ribbon‐Like Structures in Hybrid Peptides Alternating α‐ and Thiazole‐Based γ‐Amino Acids

“…[14] Their structures were solved by NMR spectroscopy in solution in CDCl 3 and CD 3 OH (Figure 1a;a lso see Figures S14 and S16 in the Supporting Information) and X-ray crystallography (Figure 1b). Thet wo diastereomers of Z-(2-Br)-(S/R)-ATC-Phe-NH-iPr, 1 and 2,w hich differed by the absolute stereochemistry of the g-aminoa cid( Scheme 1), were prepared according to ap reviously reported procedure.…”

“…We first explored the intrinsic conformational behavior of the γ/α‐dipeptide subunit. The two diastereomers of Z ‐(2‐Br)‐( S / R )‐ATC‐Phe‐NH‐ i Pr, 1 and 2 , which differed by the absolute stereochemistry of the γ‐amino acid (Scheme ), were prepared according to a previously reported procedure . Their structures were solved by NMR spectroscopy in solution in CDCl 3 and CD 3 OH (Figure a; also see Figures S14 and S16 in the Supporting Information) and X‐ray crystallography (Figure b).…”

“…Method f Vz y (S,S)-1 XRD À69 AE 31 23 AE 21 0 AE 1 À44 AE 1 NMR (CDCl 3 ) À85 AE 2115 AE 7 À8 AE 3 À24 AE 5 NMR (CD 3 OH) À103 AE 25 110 AE 25 À6 AE 2 À19 AE 7 (R,S)-2 XRD 83 À115029 NMR (CDCl 3 )7 1 AE 6 À118 AE 27 AE 22 4 AE 2 NMR (CD 3 OH) 64 AE 2 À118 AE 11 1 AE12 6 AE 1 (R,S)-5 NMR (CDCl 3 )7 6 AE 20 À109 AE 12 4 AE 51 7 AE 9 NMR (CD 3 OH) 91 AE 39 À112 AE 23 6 AE 61 5 AE 13 poly-(S)-ATC [12][13][14][15][16] XRD À78 AE 3127 AE 14 0 AE 3 À41 AE 4 NMR (CDCl 3 ) À76 AE 16 128 AE 12 À6 AE 5 À28 AE 6 Gopi [a] XRD À119 AE 41 00 AE 50 AE 3 À78 AE 4…”

“…[14] The synthesis of peptides 1-9 is described in the Supporting Information. [14] The synthesis of peptides 1-9 is described in the Supporting Information.…”

Design and Synthesis of Arf1-Targeting γ-Dipeptides as Potential Agents against Head and Neck Squamous Cell Carcinoma

“…Fmoc-ATC-OH were prepared according to the reported procedures (Fmoc = 9-fluorenylmethoxycarbonyl) [27,28]. The synthesis of compounds 8a-d, 9a-c, 10a-d is described in the Supporting Information.…”