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A new amino-protecting group is analyzed wherein a Michael acceptor is added to the protectant in order that treatment with a nucleophile will cause deblocking. The analysis involves basic structure-activity relationships and applications to peptide synthesis in solution through a beta-unsubstituted analogue of the 1,1-dioxobenzo(b)thiophene-2-ylmethyloxycarbonyl residue. The results show that, like Michael acceptors, urethanes obtained from allylic alcohols bearing 2-(alkyl- or arylsulfonyl) residues are sensitive to the incorporation of secondary amines at the alpha-beta-unsaturated site.

A series of 1-hydroxy-7-azabenzotriazole (HOAt)-based coupling reagents was utilized for the cyclization reaction of all-L-pentapeptides to determine the efficiency of the reagents in increasing the reaction rate. The head-to-tail cyclization of all-L-penta- and -hexapeptides without turn-inducing amino acids was significantly improved by HOAt-derived onium and phosphonium salts. However, the reagents did not inhibit the formation of cyclodimers and C-terminal epimerization.

The use of several 1-hydroxy-7-azabenzotriazole-based onium salts in the cyclization process for thymopentin-derived pentapeptides showed azabenzotriazole-derived coupling agents to be most effective compared with traditional coupling reagents. Rapid cyclizations were observed, while monocyclic pentapeptide ring formation was favored by residual products of C-terminal D-amino acid.

A study was conducted to determine the impact of increases in the bulk of the pyridyl alpha-substituents. Four model peptides were selected for initial testing with the new bases. More efficient results were obtained whenever the 1 equiv of 7-aza-1-hydroxybenzotriazole existed as an additive during the coupling processes. The 2,6-di-tert-butyl-4-(dimethylamino)pyridine base proved more effective than collidine for rapid onium-style coupling reagent activation.

The peptide coupling properties of 1-hydroxy-7-azabentriazole (HOAt) were compared with 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HODhbt). The results showed that for segment couplings leading to tripeptides, the relative merits of HOAt and HODhbt depend on the identity of the two amino acids at which the coupling occurs. The effects of identity of coupling reagent, base and solvent on the preservation of the configuration during the peptide coupling are presented.

Fmoc amino acid fluorides act as coupling reagents in the stepwise solid phase synthesis of peptaibols, as proved by the syntheses of saturnisporin SA III, alamethicin F30 and F50 and trichotoxin A50J. The end products possess a high degree of purity in this reaction, in which several difficulties encountered in the earlier methods of synthesis, such as chain degradation and racemization, are overcome. The assembly of C-terminal peptide alcohols through O-chlorotrityl resin is the initial step of this successful method of synthesizing peptaibols.

Solid-phase approach is used to prepare medium-sized peptides with the help of Fmoc amino acid fluorides. These fluorides have the ability to couple two sterically hindered amino acid groups. Fmoc function is stable toward the base in the active acylating agent Fmoc-Aib-F. Efficiency of this method is proved by the synthesis of different peptides having hindered Aib units.

Tertiary bases cause collidine activation-induced low racemization levels in the O-benzotriazolyluronium salt-induced peptide segment coupling reaction. Collidine reduces racemization in reactions involving classic bases and in uronium salts derived from N-hydroxybenzotriazole. The most reactive reaction reagents are those derived from 1,1-carbonyldipyrrolidine.

Research has been conducted on the pyrrolidine analogues of HATU and HBTU, a guanidinium form preferred in a solid state and solution. Results indicate the reactivity differences between HATU and relative to HATU HAPyU due to the existence of the intermediates that precede the formation of the active ester/amide.

A study of a new amino protectant subject to deblocking via nucleophilic addition to a Michael acceptor has been carried out. Results demonstrate that 2-methylsulfonyl-3-phenyl-1-prop-2-enyloxycarbonyl group can be assembled from available materials.

Dipeptide esters were obtained when (BOC)2 Phe-F and its D-enantiomer were individually coupled with alanine methyl ester. None of the DL- or LL- diastereomers were developed in these coupling reactions. Care should be taken for amino acids with substituents that would increase the acidity of the alpha-hydrogen atom, although in the case of proteinogenic amino acids, the overall transformation to the chiral bis (BOC) amino acids and their flourides is natural.

The synthesis and characterization of variously protected beta- and gamma-amino acid fluorides are described, along with corrections on previously mislabeled (1991, v 56, p 2611) non-alpha-fluorides. Asparagine and glutamic acid are also converted into fluorenylmethoxycarbonyl-protected alpha-acid fluorides which prove to be soluble, highly reactive, stable acylating agents for peptide synthesis. The alpha-acid fluorides may be distinguished from their beta- and gamma-isomers by the different methylene signals adjacent to the acid fluoride and ester carbonyl functions.

The two most readily available derivatives, the [alpha]- and [beta]-Nsmoc analogues were examined as substitutes for the Bsmoc residue in cases where the latter lead to oily protected amino acids or amino acid fluorides. The [alpha]-Nsmoc amino acid derivatives were recommended over the [beta]-isomers as substitutes for the few Bsmoc amino acids which are not available in solid form due to their greater availability and the closer correspondence of their deblocking sensitivity to the simple Bsmoc derivatives.

The application of the depsipeptide technique to extremely difficult sequences is demonstrated and a serious side reaction involving diketopiperazine formation is uncovered and subsequently avoided by the appropriate use of the Bsmoc protecting group. The method is modified in order to allow the completely automated syntheses of long-chain depsipeptides without the need for any interruption by manual esterification procedures and the method's efficiency is comparable to that of the well-known pseudoproline method.

A new class of phosphorus based coupling reagents incorporating the HOAt moiety is described. The results show that the new reagents are soluble in many organic solvents including a nonpolar solvent such as DCM.

The applications and uses of the compound, 3-Hydroxy-4-oxo-3,4-dihydro-5-azabenzo-1,2,3-triazene(HODhat) are discussed. Synthesis of HODhat 5 and HODhad 6 with their structures is discussed.

Nowick and co-workers described the synthesis of 2,6-di-tert-butyl-9-fluorenemethyloxycarbonyl group as a substitute for the Fmoc function in cases where the latter led to highly insoluble derivatives. It was shown for some systems that such substitution enhanced solubilities by 1-2 orders of magnitude.

The base-sensitive amino-protecting groups such as Fmoc, react to facile beta-elimination processes. Attempts to apply Fmoc protection to an inverse Merrifield peptide segment synthesis were disappointing and the search for a different type fo amino-protecting group was undertaken. The desired result was achieved by appropriate positioning of a urethane function relative to a Michael acceptor.

The formation protective systems for carboxyl and amide is described. The protective groups were derived from a secondary system incorporating two alpha-cyclopropyl units or a tertiary system having one cyclopropyl and two methyl residues. The results showed that the dicyclopropylmethyl group can be used for protecting carboxylic acid where selective removal is required in the presence of tert-butyl-derived or N-trityl side chain protection.

Tetramethylfluoroformamidinium hexafluorophosphate (TFFH), a nonhygroscopic, cheap, easily available and stable salt, is a useful reagent best suited for conversion of Fmoc amino acids to acid fluorides. The Fmoc amino acid fluorides are used for the coupling of sterically hindered alpha, alpha-disubstituted amino acids. Fmoc amino acids are converted via TFFH to the acid fluorides in the presence of i-Pr2NEt(DIEA) thus enabling in situ conversion of acids to fluorides. Mechanisms of reactions are discussed.