Fmoc amino acid fluorides in peptide synthesis — Extension of the method to extremely hindered amino acids

Amide bond formation using amino acid fluorides

“…18,20 Furthermore, an even more effective approach involves the prior treatment of the amino component of the coupling system with a silylating agent such as N,O-bis(trimethylsilyl) acetamide (BSA). 18 Amide bonds can be formed readily under mild conditions by reaction of Nsilylamines with acyl fluorides, 18,21 even in the case of sterically hindered secondary amines. 18,22 By treating the free amine portion of resulting peptide with BSA overnight in CH 2 Cl 2 prior to adding the amino acid fluoride one is able to effectively couple to highly hindered residues.…”

“…16,18 However, their most impressive application is the coupling of adjacent sterically-hindered amino acids such as Aib as demonstrated by the first successful solid-phase synthesis of the peptaibols, 17 naturally occurring peptides containing a high content (up to 60%) of Aib residues. 18 The couplings of acid fluorides derived from Aib and NMe-Gly have been shown to proceed without difficulty, although problems arose when more hindered substrates were used such a Iva, NMeVal, Deg, and NMe-Aib. [Conditions: 0.5 mmol HCl·AibOMe, 0.55 mmol Fmoc amino acid fluoride, 1.05 mmol DIEA, 5 mL DMF] 18 When the coupling rates were low, premature deblocking of the Fmoc group was observed as a prominent side reaction.…”

“…[Conditions: 0.5 mmol HCl·AibOMe, 0.55 mmol Fmoc amino acid fluoride, 1.05 mmol DIEA, 5 mL DMF] 18 When the coupling rates were low, premature deblocking of the Fmoc group was observed as a prominent side reaction. 18 In addition, IR studies revealed that Fmoc-amino acid fluorides derived from α,α-dialkylated species are converted slowly into the corresponding oxazolones 9 (Scheme 3) when tertiary amines are present.…”

“…18 The couplings of acid fluorides derived from Aib and NMe-Gly have been shown to proceed without difficulty, although problems arose when more hindered substrates were used such a Iva, NMeVal, Deg, and NMe-Aib. [Conditions: 0.5 mmol HCl·AibOMe, 0.55 mmol Fmoc amino acid fluoride, 1.05 mmol DIEA, 5 mL DMF] 18 When the coupling rates were low, premature deblocking of the Fmoc group was observed as a prominent side reaction. 18 In addition, IR studies revealed that Fmoc-amino acid fluorides derived from α,α-dialkylated species are converted slowly into the corresponding oxazolones 9 (Scheme 3) when tertiary amines are present.…”

N‐Silylation of Amines and Amino Acid Esters under Neutral Conditions Employing TMS‐Cl in the Presence of Zinc Dust.

“…10 Whenever the situation requires the use of an organic base to be avoided, N,O-bis(trimethylsilyl)acetamide (BSA) has been preferred. 11 One such example recently was illustrated by the use of BSA for silylation of amino acid esters and the demonstration of the use of the resulting N-trimethylsilyl amino acid esters for the incorporation of sterically hindered amino acids into peptide sequences 12 by Carpino and BayermannÕs groups. However, the acetamide that resulted from the reaction was difficult to remove from the reaction medium and BSA is an expensive reagent.…”