Thioesters, homologation

Homologous thioesters Besides complete hydrolysis to give esters, 1,1,1-tris-(methylthio)alkanes derived from alkyl halides can also be a source of methylthio esters. The transformation is accomplished by heating the tris(methylthio)alkanes with aqueous HBF4 in DMSO at 130°C. 

Partially protected peptide thioesters that are prepared from SPPS and purified by RP-HPLC can condense with other peptide segments to form highly homologous peptides which can comprise as many as 100 amino acid residues. 9 Syntheses of peptide thioesters using Boc-SPPS have been quite successful.161214 However, the preparation of thioesters by Fmoc chemistry is difficult because the piperidine used to remove the Fmoc group attacks the carbonyl moiety of the resin-bound thioester to release the peptide from solid support. However, peptide thioesters have been prepared by SPPS using Fmoc chemistry. 9 ... 

Based on the identified homology of the cefD and cefDZ proteins with known eukaryotic enzymes, a mechanism for the A. chrysogenum two-component epimerization system which is different from the epimerization found in prokaryotes has been established <2002JBC46216>. Therefore, it was suggested that the cephalosporin biosynthesis pathway begins with the activation of the substrate isopenicillin N to its CoA, followed by an epimerization to the D-enantiomer, namely penicillinyl-CoA. Next, the required hydrolysis of the CoA-thioesters seems to occur in a nonstereoselective manner by different thioesterases. The resulting product, penicillin N, is the direct precursor of all cephalosporins and cephamycins. 

The reaction of thiol esters with lithium ynolates (equation 67) takes place by a route different than the one shown in equation 65 for alcohol esters. Thiol esters (162) undergo a two-carbon homologation to S-keto thiol esters 165 in good yield. Intermediates 163 undergo a two-step rearrangement to a S-keto thiol ester enolate (165), via elimination of lithium thiolate to yield a ketene (164), followed by the nucleophilic attack of the thiolate on 164. Finally, the homologated S-keto thioester (165 ) is obtained on acidification of the reaction mixture . ... 

In studies directed toward intermediates for the synthesis of quadrone, Livinghouse demonstrated the utility of lithiated methoxy(phenylthio)(trimethylsilyl)methane (327) for the conversion of aldehydes and ketones to ketene 0,5-acetals (328) in good to excellent yields (Scheme 46). These Peterson alkena-tions gave predominantly the ( )-double bond isomer. As the example depicted in the scheme demonstrates, this procedure may be used to homologate a carbonyl to the phenyl thioester (329) in excellent yields. 

The loading module comprises three domains. The first (CL) shows homology to ATP-dependent carboxylic acid-CoA ligases, the second is a putative enoyl reductase (ER) and the third an ACP. The probable sequence of operations starts with the enoic acid 74 derived from shikimic acid which is reduced by the ER domain. The first domain will activate the carboxylic acid to an active acyl derivative ready for transfer to the thiol residue of the ACP. The final saturated product will end up attached to the ACP as a thioester derivative ready for transfer to the KS domain of the first chain extension module. The timing of the reduction in this sequence of operations cannot be predicted. 

The first synthesis of vermiculine by Corey, outlined in Scheme 4.14, employed an isopropenyl group as a protected version of the acetone sidechain. Aldehyde 57, the Dibal reduction product of readily available dimethyl 2,2-dimethoxyglutarate, was condensed with dimethallyl cadmium and the resulting alcohol silylated to produce 58 (70%). Reduction of ester 58 to the aldehyde followed by two-carbon homologation afforded a 94% yield of a,P unsaturated ester 59. Hydrolysis of 59 to the to the acid and conversion to the 2-thiopyridyl ester (77%) set the stage for double lactonization. This transformation was accomplished by thermolysis of a diluted solution of the thioester, affording a 30% yield of the diasteromeric diolides 60a and 60b (1 1). The former was then converted by oxidation into the synthetic 56 and the latter into the meso isomer 61, both in 70% yield. 

Degradation of fatty acids proceeds via an inducible set of enzymes that catalyze the pathway of P-oxidation [18]. P-Oxidation occurs via repeated cycles of reactions that are essentially the reverse of the reactions of fatty acid synthesis (Fig. 8). However, three major differences distinguish the two pathways. First, P-oxidation utilizes acyl-CoA thioesters and not acyl-ACPs. Second, the P-hydroxy intermediates have the opposite stereochemistry (L in P-oxidation and d in synthesis). Finally, the enzymes of P-oxidation share no homology with those of synthesis. 

The only absolute requirement for N CL and EPL, other than a a-thioester, is of a cysteine residue or a homolog at the ligation site. The natural occurrence of this amino acid is low and there is the possibility that insertion of additional cysteine residues can alter the structure and function of a given protein. Therefore, different approaches have been developed to overcome this requirement [50]. 

ECH or crotonase is the prototypical member of the crotonase superfamily. As noted above, sequence homology between ECH and 3,2-enoyl-CoA isomerase as well as with dibydroxynapbtboate syntbase (MenB) and 4-chlorobenzoyl-CoA dehalogenase resulted in the initial proposal for a superfamily based on the crotonase scaffold. Since then, many more members of the superfamily have been identified. Most family members utilize substrates that are CoA thioesters, and a unifying mechanistic theme throughout the superfamily concerns the use of an oxyanion hole to stabilize carbanionic transition states. Figure 40 shows the reactions catalyzed by a subset of family members. ... 

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