Convenient Peptide Synthesis without Protection of C-Terminals

Abstract

Condensation of carboxylic acids 1 and 5 with unprotected α-amino acids 2 via activation by ethyl chloroformate and triethylamine proceeded effectively to afford the corresponding amides in 50–99% yields. Tripeptide 7c was obtained in 42% yield from the dipeptide 6c in a similar manner.

α‐N‐Protected dipeptide acids: a simple and efficient synthesis via the easily accessible mixed anhydride method using free amino acids in DMSO and tetrabutylammonium hydroxide

“…Although this method (Method A) provided better yields compared with those obtained with the protocol of Noguchi et al . , some tripeptide Z‐Phe‐Ala‐Ala‐OH ( 5Zfaa ) was still present (Table , entry 5), and the reaction with the high water‐soluble aspartic ( 3d ) and glutamic acid ( 3e ) gave the corresponding dipeptide 4 in low yield (Table ). The observation that DMSO was able to dissolve a mixture of H‐Phe‐OH ( 3f , 1.2 mmol) and 55% aqueous TBA–OH (1.1 mmol) allowed to carry out the reaction in the presence of a large amount of 3f in the organic phase (THF–DMSO) favoring the coupling mechanism leading to 4Zff (reaction time 30 min, 82% yield) over the hydrolysis of the mixed anhydride 2Zf (3% yield; Table , entry 6).…”

“…It is worth to point out that when we attempted to synthesize 4Eba following the method proposed by Noguchi et al . , the HPLC–ESI–MS analysis of the crude product evidenced the presence of a mixture of Eoc‐ l ‐Phg‐Ala‐OH ( 4Eba ) and Eoc‐ d ‐Phg‐Ala‐OH ( epi‐4Eba ) in the approximate ratio 80 : 20.…”

“…The first approach to this study was the synthesis of Z-Phe-Phe-OH (4Zff) according to the method proposed by Noguchi et al [72]: a mixture of Z-Phe-OH (1Zf, 1.0 mmol), ethyl chloroformate (1.4 mmol), and TEA (3.0 mmol) in THF (20 ml) was stirred for 30 min at 0 C. After this time, a solution of H-Phe-OH (3f, 1.5 mmol) in H 2 O (20 ml) was added to the resulted suspension and the stirring was continued for 30 min at 0 C. After suitable work-up [72], the crude product (0.457 g) was crystallized [72] to afford only 0.281 g (63% yield) of 4Zff. 1 H NMR analysis of the concentrated crystallization mother liquor (0.175 g) evidenced the presence of Z-Phe-OH (1Zf), N-ethoxycarbonylphenylalanine, and 4Zff in 63%, 32%, and 5% yields, respectively.…”

“…It is noteworthy that the easily accessible mixed carbonic carboxylic anhydride method has received little attention in recent years. In fact, the few entries found in literature report the reaction of basic aqueous solutions of amino acids only with N ‐protected proline (low yields) and, more recently, with N ‐protected phenylalanine . The last one seemed the most appealing for our purposes, but we have encountered some problems (shown in later text) to reproduce the yields reported for some of the reactions described and to extend the protocol to other N ‐protected amino acids.…”

Peptide‐Chain Elongation Using Unprotected Amino Acids in a Micro‐Flow Reactor

“…Moreover, generated CO 2 and alcohol can be removed easily. Imai et al . reported an in situ preparation of mixed carbonic anhydride using ClCO 2 Et, Et 3 N, in THF, and aqueous NaHCO 3 and its use in amidation with free amino acids.…”