Amino acid thioesters

Arthur L. Weber (1998), now working at the Seti Institute of the Ames Research Center at Moffett Field, reports the successful synthesis of amino acid thioesters from formose substrates (formaldehyde and glycolaldehyde) and ammonia synthesis of alanine and homoserine was possible when thiol catalysts were added to the reaction mixture. On the basis of his experimental results, Weber (1998) suggests the process shown in Fig. 7.10 to be a general prebiotic route to amino acid thioesters. 

Fig. 7.10 A general prebiotic synthetic route to amino acid thioesters (Weber, 1998)...

Scheme 30 Synthesis of 1-Oxoethylene Peptides using an a-Amino Acid Thioester and a Grignard Reagent1651...

Boc amino acid thioesters 7 used in Boc-SPPS are prepared by reaction of Boc amino acid active esters such as the 4-nitrophenyl ester (ONp) or succinimide ester 6 (OSu) with thiols containing a carboxy group that can link to a resin (Scheme 3, Table 2). 1314 Amino acid thioesters 7 can also be prepared by reaction of Boc amino thiol acids 8 with a chloro, bromo, or hydroxy compound that also contains a carboxy group (Scheme 3, Table 2). 1516 ... 

Scheme 3 Amino Acid Thioesters by Active Ester Coupling or from Thiocarboxylic Acids113-161 rl — ...------- R1...

Similarly, enantiopure 3-substitutcd-/V-rnc thy I benzyl /3-sultams have been converted into A -methylbenzyl-a-amino acid thioesters via sulfenylation and Pummerer rearrangement with high or complete retention of configuration. Chiral sulfoxides were prepared by sulfenylation followed by oxidation of trans-isomers as two separable A and B stereoisomers. Treatment with TFAA gave chiral cr-amino acid thioesters in high yields with a de > 90%. Slight epimerization of the cr-chiral center of the cr-phenyl thioesters has been observed under the reaction conditions whereas no epimerization was observed in the case of -/-butyl thioesters (Scheme 28) <1998JOC8355>. 

The possibilities of amino acid thioesters in peptide synthesis have been demonstrated very early as well as the effect of carbon dioxide supporting the involvement of N-carboxyanhydrides in the hydrolysis and polymerization pathways [127,176,177]. Aminothioacids can also be converted into NCAs [152,178,179] but they can, in addition, be activated by oxidation into disulfides which are much more reactive [151]. 

Scheme 13.16 Enzymatic kinetic resolution of N-Boc-amino acid thioesters coupled with base-catalyzed racemization.

Enzymatic Kinetic Resolution of N-Boc-Amino Add-Thioesters Coupled with Base-catalyzed Racemization Recently, a new method leading to the preparation of a number of aryl-glycines of the L-configuration has been published. The method is based on the hydrolysis of N-Boc-amino acid thioesters 15 catalyzed by an industrial preparation of the protease subtilisin (Scheme 13.16) [43]. 

Many processes have been proposed for the formation of prebiotic peptides. Peptide bond formation from free amino acids can become thermodynamically favorable using physical or chemical means for dehydration (6, 36). Alternatively, activated amino acid derivatives are capable of polymerizing into oligopeptides in aqueous solution. A pathway for the formation of a-amino acid thioesters starting from sugar precursors has been discussed (37). a-Amino acid A-carboxyanhydrides (NCAs) correspond to... 

Weber AL. Prebiotic amino acid thioester synthesis thiol-dependent amino acid synthesis from formose substrates (formaldehyde and glycolaldehyde) and ammonia. Orig. Life Evol. Biosph. 1998 28 259-270. 

Recently, the author s group developed another aminoacylation method using PNA [18] as a tRNA-recognizing molecule (Fig. 5.1-5) [19]. An amino acid thioester was linked through a spacer to a 9-mer PNA that is complementary to the 3 region of a tRNA. When the PNA was hybridized with the tRNA, the amino acid thioester comes dose to the 3 OH group of the tRNA, provided the... 

M. Nishimura, M. Sisido, In situ chemical aminoacylation with amino acid thioesters linked to a peptide nucleic acid,/. Am. Chem. Soc. 2004, 126,15984-15989. 

Brack, A., Barbier, B., Bertrand, M, Chabin, A., and Westall, F. (2002) Polimerization of amino acids, thioesters on mineral surfaces in diluted solutions, in Lacoste H. (ed.) Proc. Second European Workshop on exo / astrobiology, Graz, Austria, 16-19 Sept., Publ. ESA Div., p.435 436. Kawabata, S., Iwata, N. and Yoneyama, H. (2000) Asymmetric electrosynthesis of amino acids using an electrode modified with amino acid oxidase and electron mediator, Chem. Lett. 110-111. 

Figure 8.3 Broensted plot for N-protected-amino acid thioesters experimental kinetic constants versus calculated basicity.

Because ofthe presence ofalarge amount of water appears to considerably narrow the field of the previously illustrated resolution system, experiments were started with immobilized enzymes in organic solvents, in which the water concentration was considerably reduced. This proved to be quite an effective strategy, permitting to carry out a nicely working DKR on a representative array of aliphatic N-Boc-amino acid thioesters [62], which could be resolved in high yield and with excellent optical purity. Moreover, the choice of an immobilized form of the enzyme (Alcalase -CLEA ) permitted recovery and reuse of the catalyst for several consecutive batches [63]. The solvent of choice proved to be tert-butanol, which was able to dissolve the hydrophobic substrates, the organic base, and the strictly necessary amount of water (Table 8.6). 

Table 8.6 Results obtained with the hydrolysis of N-Boc-amino acid thioesters under DKR conditions.

D. (2007) Chemo-enzymatic dynamic kinetic resolution of amino acid thioesters. Adv. Synth. Catal, 349 (8-9), 1345-1348. 

Moreover, the same authors employed a closely related organocatalyst and the corresponding urea derivative to promote the enantioselective dynamic kinetic resolution of azalactones with allylic alcohol. In this case of substrates, the urea derivatives proved to be superior to their thiourea analogues and, most usefully, these catalysts were insensitive to the steric bulk of the amino acid residue, allowing alanine-, methionine- and phenylalanine-derived azalactones to undergo dynamic kinetic resolution with unprecedented levels of enantioselectivity, as shown in Scheme 9.4. Furthermore, the compatibility of these catalysts with thiol nucleophiles was exploited in the first enantioselective catalytic dynamic kinetic resolution of azalactones by thiolysis to furnish enantioenriched amino acid thioesters of potential use with moderate enantioselectivities (<64% ee). 

DKR of Thioesters The acidity of the H in the a-position of a thioester is higher than the acidity of the same positioned H in esters, amides, or acids. This fact and the ability of subtUisin Carslberg to hydrolyze a-amino acid thioesters have been the keys to the successful DKR of several N-Boc-a-amino thioesters rac-118 developed by Servi et al. Reactions were carried out in a biphasic system of TBME/-water, at 37°C and pH = 8.0, with trioctylamine as the base to remove the acidic a-H of the substrates (Scheme 57.34). pH was kept constant at 8.0 throughout each process, which was stopped when all the starting substrate had been consumed. Finally, the L-Af-Boc-a-amino acids 119 were easily... 

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