Tantalum pentachloride as a coupling agent for stereohindered amide bond formation

Metal Complexes of Biologically Important Ligands, CLXXVI.[1] Formation of Peptides within the Coordination Sphere of Metal Ions and of Classical and Organometallic Complexes and Some Aspects of Prebiotic Chemistry

“…Goldman and Kohn 118–120 considered metal carboxylates as activated esters and argued that metal centres with a high positive charge should promote the nucleophilic attack of amines or amino acid esters at the carbonyl group of carboxylates. It was shown that (amino‐protected) aminocarboxylates Cp 2 Ti(O 2 CC(H)(Me)NHC(O) R ) 2 118 and CpTaCl 3 (O 2 CC(H)(Me)NHC(O) R )119 react with α‐amino acid esters to give dipeptides (Scheme ).…”

“…Particularly TaCl 5 proved to be very active to mediate the coupling of chiral N‐protected amino acids (e.g. Ac(H)N‐AlaOH) with N ‐methyl‐amino acid esters in high yields and without significant racemization (Scheme , Equation (16)) which otherwise is difficult to achieve 120…”

Evolution of amide bond formation

“…When chiral carboxylates were bound to CpTa(V)Cl 3 , their reactions with chiral amines at low temperature resulted in no racemization. 77 As N-methylated amino acids represent one of the most difficult substrates in coupling reactions, the high reactivity of Ta(V) carboxylate might mediate substitution with hindered nucleophiles or hindered carboxylates under moderate conditions such as in toluene at room temperature. TaCl 5 appears to have significant promise as an acylating agent for the synthesis of bulky amides.…”

A protocol for amide bond formation with electron deficient amines and sterically hindered substrates

“…The coupling of diphenylacetic acid with diisopropylamine has been reported in 20% yield by a TaCl 5 -based method especially developed for coupling of hindered substrates, whereas no product was observed by DCC-mediated coupling. 18 Since the diphenylacetyl fluoride intermediate and the product co-eluted on silica, an excess of the amine was used in this case, giving full conversion to 11 and 71% isolated yield. Coupling of the hindered triphenylacetic acid with propargylamine, 4-aminopyridine and tert-butylamine, by DCC or TaCl 5 or via the acid chloride catalysed by DMAP are reported with low to moderate yields in the literature.…”