Thioesters alkylation

Another indole/oxindole synthesis achieves the critical ortho-substitution by Sommelet-Hauser rearrangement of an anilinosiilfonium ion intermediate. Use of P-thioketones (G = R, an alkyl group) generates 2-substituted indoles, whereas P-thioesters (G = OR) lead to oxindoles. In each case, a 3-thio substituent must be removed by desulfuri2ation. 

Both thermooxidation and photooxidation of polyolefins can be prevented by using the same antioxidants as those employed for the stabilization of polypropylene, ie, alkylated phenols, polyphenols, thioesters, and organic phosphites in the amount of 0.2—0.5% (22,25). 

The same diamine, when treated with carbon disulfide in alkaline medium, yielded 2-mercapto- l//-imidazo[4,5-/]quinoline (88PS267,88SC973,86IJC264), which, on treatment with alkyl, aralkyl, and acid halides, gave the corresponding thioethers and thioesters 111, respectively (88PS267, 86IJC264). 

Unlike regular aziridine-2-carboxylic esters, aziridine-2-carboxylic thioester 174 (Scheme 3.62) forms stable carbanions at the 2-position upon treatment with base [13b, 122]. Thus, electrophilic alkylations of aziridine 174 afforded products 175. The reactions were highly diastereoselective, affording 175 in moderate to good... 

Reaction of an alkyl halide with (MeS)3C—Li followed by aqueous HBF4 leads to a thioester. ... 

The stable P-unsubstituted phosphinous amide H2PN(SiMe3)2 has been shown to suffer the nucleophilic displacement of the disilazane moiety by the action of thiols R-SH giving the phosphinous thioesters R-S-PH2 [13]. For the sake of brevity we shall not comment on other relevant reactions of AT-silyl phosphinous amides, such as the anionic P-silylation [115] and P-alkylation [22], the consecutive dialkylation of PH derivatives [18] and the fluorodesily-lation of P-fluoro-JV-silyl derivatives [140]. 

Cysteine sulfhydryls and cystine disulfides may undergo a variety of reactions, including alkylation to form stable thioether derivatives, acylation to form relatively unstable thioesters, and a number of oxidation and reduction processes (Figure 1.10). Derivatization of the side chain sulfhydryl of cysteine is one of the most important reactions of modification and conjugation techniques for proteins. 

The protocol for using isobaric tags differs from that described previously for the ICAT or ECAT type reagents. In the following method, the proteins are denatured and the disulfides reduced and then alkylated to block them permanently. This eliminates disulfide re-association and also prevents the isobaric tags from forming thioester modification with cysteine thiols. Next, the proteins are digested with trypsin and then modified with an isobaric tag. Each sample is labeled with a different isobaric compound so that the samples can be differentiated upon MS/MS analysis. 

Peptides typically are prepared for this ligation process using a-alkyl thioesters, because they are simple to make at the time of peptide synthesis. However, due to the relatively slow reaction kinetics of alkyl thioesters, most native chemical ligation processes have been catalyzed through the use of thiol compound additives, such as benzyl mercaptan or thiophenol (Dawson et al., 1997). These compounds react with the initial a-alkyl thioester to form another intermediate, an aryl thioester, which is more reactive toward the N-terminal cysteine on the other peptide to be coupled. A study... 

The preparation of thiadiazoles 180 from 1-cyanoformamide 177 (2-nitrilo-acetimidic acid), or its alkyl esters 178, using disulfur dichloride under mild conditions was previously reviewed in CHEC(1984) and CHEC-II(1996). The synthesis of thiadiazoles from the thioesters 179, formed by the addition of alkylthiols to cyanogens, was more recently investigated (Equation 36) <1998JME379>. In several cases, the esters 178 or thioesters 179 prepared from cyanogen were not isolated but added directly to disulfur dichloride <1996W038431, 1998JME379>. 

Mammalian esterases have been classified into three groups according to specificity for substates and inhibitors (110). In terms of overall hydrolytic activity in mammals, the most important class of esterases is that of the B-esterases, which are principally active with aliphatic esters and amides. A-Esterases are important for aromatic esters and organophosphorus esters, and C-esterases are active with acetyl esters. In general, the specificity of mammalian esterases is determined by the nature of substituent groups (acetyl, alkyl, or aryl) rather than the heteroatom (O, N, or S) that is adjacent to the carboxy group. That is, the same esterase would likely catalyze hydrolysis of an ester, amide, or thioester as long as the substituents were identical except for the heteroatom (110). 

FIGURE 7.17 Synthesis of a peptide by construction of a peptide alkyl thioester on a solid support, detachment of the assembled molecule that includes the spacer and transesterfication of the ester into an activated ester which is aminolyzed as it is formed. [Aimoto et al., 1991]. Dhbt = 4-oxo-3,4-dihydrobenzotriazin-3-yl. 

A superior and relatively versatile procedure for the synthesis of unsymmetrical dialkyl thioethers, which avoids the unattractive direct use of thiols, utilizes the stable l-alkylthioethaniminium halides, which are readily obtained from thioacet-amidc [32] (Scheme 4.4). The reaction has also been used for the synthesis of alkyl aryl thioethers from activated aryl halides [33], but it cannot be used for the synthesis of cyclic thioethers, as polymeric sulphides are formed from a,co-dihaloalkanes. A similar sequence to that which leads to the thioethers has been used for the synthesis of S-alkyl thioesters [34] (see 4.1.26). 

A procedure, which has been used successfully for the synthesis of dialkyl thioethers from thioacetamide has been extended to the preparation of a range of 5-alkyl thiocarboxylic esters [35] (Table 4.20). The intermediate 5-acyl ethaniminium salt (Scheme 4.14) is not stable and is converted directly into the 5-alkyl thioester. The choice of catalyst affects the yield of the thioesters. Thus, 5-n-octyl thiobenzoate... 

The reverse reaction in which thioacetamide is initially alkylated and then reacted under phase-transfer catalytic conditions with the acyl halide results in the formation of A-acylthioamidates (Scheme 4.15), with only trace amounts of the S-alkyl thioesters [35], S-Alkyl thioacetates have also been obtained from trifluoro-methylsulphonyloxy compounds upon reaction with potassium thioacetate in the presence of TDA-1 [61]. It is probable that tetraalkylammonium salts would be equally good catalysts. 

Simple alkyl or aryl thioesters are commonly assayed as substrates of hydrolases, witness the hydrolysis of phenyl thioesters by horse serum carbox-ylesterase [150], For most substrates investigated, e.g., phenyl thioacetate, phenyl thiopropionate, and phenyl thiobutyrate (7.66, R = Me, Et, and Bu, respectively), kcat values were found, which were a few times larger than those of corresponding nitrophenyl esters, whereas the affinities were lower by approximately one order of magnitude. Methyl and phenyl esters of various linear thioacids were also found to be good substrates of mammalian liver carboxylesterases and serum cholinesterases [151]. 

These ideas will be discussed in the following subsections, where most of the attention will be devoted to the mechanistic smdies with aromatic esters, which have been the subject of an overwhelming majority of the research efforts. Nevertheless, the same reaction mechanism has been shown to be valid for the PFR of anilides, thioesters, sulfonates, and so forth. Furthermore, it is also applicable to the photo-Claisen rearrangement [i.e. the migration of alkyl (or allyl, benzyl, aryl,)] groups of aromatic ethers to the ortho and para positions of the aromatic ring [21,22]. 

Reactive substrates are those with a good leaving group, such as halide (in acyl halides), hydrosulfide (in thioadds), alkyl thiolate or alkyl mercap-tide (in thioesters), and carboxylate (in anhydrides). 

A wide range of a,P-unsaturated acceptors work well under standard reaction conditions with pre-catalyst 75c (Table 7). Acceptors include a,P-unsaturated esters, amides, alkyl ketones, and phosphine oxides, many of which provide the products in greater than 90% ee [68, 69], a,P-Unsaturated phenyl ketones, nitriles, and thioesters also work, albeit with lower enantioselectivity. The scope has been extended to include a variety of vinyl phosphonate precursors providing good chemical yields and moderate to high enantioselectivity (entries 9 and 10). 

Whereas carbenoid character is definitely present in metalated alkyl vinyl ethers, lithiated alkyl and aryl vinyl sulfides and thioesters, which are easily available by hydrogen-lithium exchange, do not display carbenoid-typical reactions . They rather behave like nucleophilic reagents, so that their discussion is beyond the scope of this overview despite their utility in synthesis The same appiies to various derivatives of enamines, deprotonated in the vinyiic a-nitrogen position - . 

Selective alkylation of 6-keto esters via either anions or dianions is an important synthetic transformation. Equally, thioesters may be trans-esterified in the presence of thiophilic metal cations. These two features... 

Transesterification of the resulting alkylated B-keto thioesters to the (orresponding oxo esters is readily achieved using alcohols under various iiM-tal catalysis. ... 

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