Coupling methods, acid fluoride

As mentioned above, thiazolidine-4-carboxylic acid is characterized by an anomalously low basicity and thus difficult acylation in peptide synthesis. 189 Therefore, the incorporation of this amino acid residue into a growing peptide chain is preferentially preformed via dipeptide derivatives. 139 Suitably N-protected amino acids are coupled directly to the thiazolidine-4-carboxylic acid by the acid fluoride 139 or iV-carboxyan hydride 1392111 methods. The resulting dipeptides are used as building blocks without risk of racemization 139 and standard coupling procedures are applied as pentachlorophenyl esters prepared by the mixed anhydride procedure 121 or PyBOP. 171 ... 

Section 2.1.1.10.2). For coupling of extremely hindered systems, such as N-protected Aib or (Me)Aib to amine-free (Me)Aib derivatives, arylsulfonic-protected amino acid chlorides proved to be the method of choice, while the corresponding acid fluorides do not react at... 

Very difficult peptide syntheses are those which contain sterically hindered C -dialkylannino adds such as Aib residues, especially if these residues are found next to each other. Due to their influence on the stabilization of helical stmcturest l in small peptides, the introduction of such amino acids is of interest. Various protocols for the coupling of hindered systems using UNCAs,t l symmetric anhydrides,t HATU,b CIP/HOAt, and PyBroPl l activation have been reported. In a comparative analysis of activation methods for the synthesis of H-Aib-Aib-Aib-Aib-OH as a model peptide which included the symmetric anhydride, PyBroP, acid fluoride, and UNCA methods, the acid fluoride technique was shown to be exceptionally well suited.t 1... 

Besides coupling of adjacent Aib residuest , the incorporation of other hindered amino acids into peptides such as 1-aminocyclohexane-l-carboxylic acid (Acscjb l and 4-amino-piperidine-4-carboxylic acid,b l as well as the coupling of 0,0-(dimethylphosphoro)tyrosine to these amino acids b was achieved by the use of the corresponding acid fluorides with solid-phase methods. 

The two key catalytic intermediates have been observed by electrospray mass spectrometry [394]. Although the exact role and influence of the base remains unclear [395], the transmetallation is thought to be facilitated by base-mediated formation of the tetracoordinate boronate anion [396], which is more electrophilic than the free boronic acid (Sections 1.5.1 and 1.5.2). A useful carbonylative variant has also been developed to access benzophenones (Equation 70) [397], which can also be produced from the coupling of acid chlorides [398] or anhydrides [399], A variant of this method allows the preparation of a, 3-unsaturated esters from alkenylboronic esters [243]. In all of these reactions, one dreaded limitation with some ortho-substituted and electron-poor arylboronic acids is the possible occurrence of a competitive protolytic de-boronation, which is exacerbated by the basic conditions and the use of a transition metal catalyst (Section 1.5.1). Methods to minimize this side reaction were developed in particular the use of milder alternative bases [400] such as fluoride salts [401], and... 

A special one-pot deprotection-transacylation method involves coupling of activated Fmoc amino acids with Aloc-protected amino acid esters.The Aloc-deprotection proceeds with palladium/phenylsilane in the presence of the acylating species. Using Fmoc-Phe-F the synthesis of the sterically demanding dipeptide Fmoc-Phe-(Me)Aib-OMe was accomplished in a yield of 65% A similar one-pot approach to the acylation of the even more difficult hindered and weakly nucleophilic a-trifluoromethyl amino acid esters involves the intermediate A-Teoc protection. Thus treatment of ( )-Teoc-a-(a-CF3)Leu-OMe with Fmoc-Gly-F and a catalytic amount of tetraethylammonium fluoride in acetonitrile at 50 °C for 1-2 weeks gave ( )-Fmoc-Gly-(a-CF3)Leu-OMe (77%... 

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