CHAPTER 5
 HIGHLY DIASTEREOSELECTIVE PEPTIDE CHAIN EXTENSIONS OF
UNPROTECTED AMINO ACIDS WITH N-(Z-a-AMINOACYL)BENZOTRIAZOLES

 5.1 Introduction

 The many coupling reagents [79Peptide] [01SPP] developed for the formation of

amide bonds in the synthesis of biologically active peptides and their analogs

[95CR2115] [97CR2243] [98CR763] include: (i) carbodiimides in combination with

additives such as 1-hydroxybenzotriazole (HOBt), [02T7851] [030L2793] 1-hydroxy-7-

azabenzotriazole (HOAt) and analogs [010L2793] or N-hydroxysuccinimide (HOSu);

[64JACS1839] (ii) phosphonium [75TL1219] [90TL205] and uronium salts [84S572]

[01S1811] of HOBt or HOAt; (iii) N-acylazoles such as 1,1'-carbonylbis(1H-imidazole)

(CDI); [00HCA2607] (iv) mixed anhydrides; [51JACS5553] or (v) carboxylic acid

fluorides. [90JACS9651] [91JOC2611]

 A commonly encountered problem in peptide synthesis is epimerization of the

amino acid component during activation of the carboxylic acid group. Many of the

coupling reagents require prior protection and subsequent deprotection of various amino

acid functional groups. [91CSP] Coupling reactions with such reagents are frequently

moisture sensitive. Furthermore, isolation and purification processes often involve

column chromatography due to the formation of by-products from the coupling reagents.

 The literature reveals that the reactions of N-protected C-activated amino acids

with unprotected amino acids have been less explored than their reactions with C-

protected amino acids. In 1980 Hegarty et al. reported peptide coupling of unprotected