Efficient "one-pot" synthesis of N-tritylamino acids

Abstract

A sequential procedure has been developed whereby neutral amino acids 1 were tritylated via their corresponding trimethylsilyl esters 2 to afford, after mild hydrolysis, IV-trityl amino acids 3 in high yields and purity. Hydroxy amino acids 4 were preferentially tritylated at the amino function by using either Me3SiCl or Me^iCtj (or Ph^iCy for temporary protection of the hydroxy and carboxyl groups. Finally, !Vim-tritylhistidine (9c) was prepared in 97% yield with the aid of the Me2SiCl2, whereas the use of Me3SiCl produced, after tritylation, IV"-tritylhistidine (9b) and 9c in almost equimolar amounts.It is well-known that the trityl moiety as an a-amino protecting group in peptide synthesis can be selectively removed, under extremely mild acidic conditions2, in the presence of other acid-sensitive protecting group.3 In addition, racemization during the coupling step using IV-trityl amino acids is expected to be lower in comparison to otherwise N-protected amino acids.However, the application of the trityl function in peptide synthesis is limited because of the low yields in the prep-aration2,4 of IV-trityl amino acids and their failure, with a few exceptions,2 to couple with other amino acids in acceptable yields.2 While the latter obstacle has been overcome, when dicyclohexylcarbodiimide, mediated with 1-hydroxybenzotriazole, was used as the coupling agent,5 the facile preparation of IV-trityl amino acids remains to be a serious problem.The present synthesis readily provides IV-trityl amino acids in high yields by an experimentally simple "one-pot" procedure involving tritylation of silylated esters of amino acids followed by mild cleavage of the susceptible oxygen-silicon bond.

Amino Acid-Protecting Groups

“…400,396 -N τ -Trityl (Trt): It is the usual protecting group for the Fmoc/ t Bu strategy. 20,401 It is removed with 95% TFA but is much less acid-labile than the N α -trityl group and cannot be selectively removed in the presence of t Bu groups. 402 Using N τ protection, the free N π can still catalyze racemization.…”

“…An example of the former is the use of trimethylsilyl esters of amino acids prepared in situ, 18,20 -Trityl (Trt). 28,29 It is removed with 1% TFA in DCM or 0.1M HOBt in 2,2,2-trifluoroethanol (TFE) in solution.…”

Synthesis of N-Trityl-L-homoserine

“…To a solution of N-Trt-L-methionine [15] (150 g, 383 mmol) in 100 ml ethyl acetate 100 ml (1.605 mol) of Mel were added and the mixture was refluxed with stirring for 4 h. The thus produced solid material was filtered off and washed well with ethyl acetate, Et^O and petroleum ether. The obtained light yellow powder was dried in vacuo (KOH and P205).…”

“…Moreover, the preparation of 3 in pure form was not always successful in our hands. Naturally, compound 4 can be converted smoothly to the corresponding diethylamine salt 6 in crystalline form and high yield.Already we have reported that 5 can be easily prepared in high yield [15], Treatment of 5 with excess Mel under reflux in ethyl acetate produced the quaternary salt 7 in 75% yield. Treatment of 7 with two equivalents of KOH in H20-THF followed by controlled acidification and addition of diethylamine gave finally the diethylammonium salt 6 in 74% yield [2]).…”

“…The first strategy [15] involves treatment of 1 with the * Reprint requests to Prof. D. Theodoropoulos. 0340-5087/82/0700-0886/$ 01.00/0 bifunctional protecting agent Me2SiCl2 in the presence of EtsN.…”