Thioesters, reductive cleavage

Fig. 7.8 Two examples of important reactions in the thioester world a the phosphorolysis of thioesters leads to acylphosphates and b a-ketoadds are formed in the reductive cleavage of thioesters with accompanying carbonylation (de Duve, 1991)...

In the solid phase, Sc(OTf)3 also effectively catalyzed Mannich-type three-component reactions of aldehydes, amines, and PSSEEs to afford polymer-supported /3-amino thioesters (Eq. 22). Reductive cleavage from the supports gave the amino alcohols in good to high yields [85b]. /3-Amino acid and /3-lactam libraries are also constructed according by this method (Eq. 23). 

Camarero et al. [108] used the hydrazine safety-catch linker to prepare peptide thioesters. After assembling the peptide using standard Fmoc protocols, the fully protected peptide resin was activated by mild oxidation with N-bromosuc-cinimide (NB S) in the presence of pyridine, forming a reactive acyl diazene that was then deaved with an a-amino add S-alkyl thioester such as H-AA-SEt, where AA is Gly or Ala. After TFA deprotection, peptide thioesters were obtained in good yields. Although the oxidation step did produce racemization, and other sensitive amino acids such as Tyr(tBu) and Trp(Boc) were not affected, Met and Cys presented some problems. Met was completely oxidized, and a reductive cleavage was required. For Cys, the Cys(Trt) derivative should be avoided and use of Cys(Npys) or Cys(S-StBu) is recommended instead. 

A further method for reduction of carboxylic esters is the reductive cleavage of thioesters, which can be carried out under mild conditions and affords a thiol and the alcohol related to the carboxylic acid.526... 

Intramolecular addition of thiolate, dithiocarboxylate, and enedithiolate sulfurs to unsaturated carbon-carbon bonds also provides a convenient way to thiophenes. Thus, reductive cleavage of the thioester group of the compound (11) followed by intramolecular addition of the thiolate sulfur to the triple bond affords the thiophene (12) directly (Equation (2)) <93SL209>. In this way, a number of alkyl-substituted and six-membered ring annelated thiophenes were synthesized in good overall yields. 

Racemic acyldiiron complexes bearing an olefin moiety can be kinetically resolved in the [3+2] cycloaddition reaction with enantiopure nitrones. The recovered starting material is highly enantiomerically enriched. The cycloaddition product can be oxidatively demetalated using CAN. After reductive cleavage of the N-0 bond with zinc in acetic acid and thioester cleavage with mercury(II) acetate, spontaneous cyclization to the P-lactams occurs. This procedure was applied to the synthesis of carbapeneme precursors (Scheme 4-50). 

According to de Duve, thioesters on the young Earth were capable of a broad spectrum of chemical reactions for example, of phosphorolysis leading to acylphos-phates (Fig. 7.8a) or of reductive thioester cleavage, which (after carbonylation) made possible the synthesis of ketoacids (Fig. 7.8b). 

The crude peptide thioester H-Cys-Ser-Cys-Lys-Ser-Lys-Val-Cys(Acm)-Tyr-Lys-Gln-Ser-Ile-Pro-Cys-Gly-Glu-Ser-Cys-Val-Phe-Ile-Pro-Cys(Acm)-Thr-Val-Thr-Ala-Leu-Leu-Gly-COS(CH2)2CONH2 (50-80mg), obtained after cleavage from the resin support by HF (HF/PhOMe 9 1), was extracted into a 8M urea soln (150 mL) at pH 7.6 in a highly reductive environment containing 5- to 10-fold excess of TCEP and then dialyzed against 8 M urea (2000 mL) to allow cyclization in a descending concentration... 

Conversion to the Aldehyde. This transformation is accomplished through a two-step procedure. One such variant requires reduction to the alcohol (e.g. LiAllTt, H2O) and subsequent oxidation (e.g. Swem conditions). Alternatively, Wein-reb transamination " followed by Diisobutylaluminum Hydride or conversion to the thioester (see below) and subsequent Triethylsilane reduction, afford the desired aldehyde in excellent yields. Weinreb transamination proceeds with minimal endocyclic cleavage when there is a p-hydroxy moiety free for internal direction of the aluminum species. 

When the last condensation reaction has occurred, the linear precursor needs to be released from the enzyme. For this important last step, several mechanisms are known simple hydrolysis of the thioester (balhimycin, vancomycin), intramolecular cyclization leading to a lactam (tyrocidine, bacitracin) or a lactone (surfactin), or even reductive thioester cleavage (linear gramicidin). In some cases, the linear precursor is dimerized (gramicidin S) or even trimerized (bacillibactin, enterobactin) before cyclization (Fig. 2). Even though these reactions are critical for the compound s bioactivity, the catalytic domains responsible for the release are not found in all NRPS systems and will therefore be called modifying domains. 

Aromatic compounds can also be degraded anaerobically, via reductive pathways, which have been reviewed. The best-characterized example is the degradation of benzoic acid in Rhodopseudomonas palustris and Thauera aromatica via the pathway shown in Figure 8. Benzoyl-CoA is formed, and then a reductase enzyme is able to reduce the aromatic ring to a cyclohexadiene. Following two consecutive additions of water, and oxidation to a /3-keto ester, hydrolytic cleavage gives a linear 7-carbon CoA thioester, which can then be broken down via fatty acid /3-oxidation. 

Thiomethyl-PS 6b, prepared from Merrifield s resin la by reaction with thioacetate followed by reduction, can be acylated to give thioesters [263]. The resin-bound thioesters have been converted to silyl enol ethers, which were shown to form aldol products that could be released from the resin by three methods [264], Thus, reduction with lithium borohydride or diisobutylaluminum hydride (DIBAL) gave diols and aldehydes, respectively alternatively, base hydrolysis afforded carboxylic acids. Resin 6b thereby extends the range of functional groups available compared with cleavage of related molecules from an ester anchor. 

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