Thioesters reactions with electrophiles

F. Reactions of Magnesium Thioesters and Thioamide Enolates with Electrophiles... 

Pyridine-, pyran- and azine-thiones behave as cyclic thioamides or thioesters and show their typical reactions. Thus, they react with electrophiles at the sulfur atom [as exemplified in (i)-(iv)], and with nucleophiles including the typical ketonic reagents at the thione carbon atom [as exemplified in (vi)-(viii)]. 

As RS" is a much better electrophile and is considered to be the active species in reactions with organic substrates, better product yields are expected in CH2CI2 solutions. This was observed when disulfides were electrolyzed in the presence of terminal alkynes, in solutions containing nucleophiles, as H2O, MeOH, EtOH, and a-oxo-thioesters were obtained as major products ... 

All native chemical ligations described to date use C-terminal thioesters or thioacids for reaction with an //-terminal nucleophile or electrophile, respectively. In the original method, an A-terminal Cys reacts with a C-terminal thioester to form a thioester intermediate that rearranges spontaneously to form a natural peptide bond with a Cys incorporated (Fig. 8) [123]. This method has been extended further to allow native bond formation without the exclusive use of //-terminal Cys. To accomplish this, an oxy-ethanethiol was attached to the amino function of the iV-terminal residue. 

Intramolecular Wittig reactions can be used for the preparation of cyclic alkenes. The formation of the phosphonium ylide must be compatible with other functionality in the molecule and thus stabilized ylides are used most commonly. Wittig reactions with carbonyl groups other than aldehydes or ketones, such as carboxylic esters, are known. For example, a route to the indole or penem ring systems uses a carboxylic amide or a thioester respectively as the intramolecular electrophile (2.77). 

Acrylic esters, thioesters and A-acryloyl pyrrole have been identified by Dixon and Rigby as elfective electrophiles in the enantioselective Michael addition reaction with p-keto esters catalysed by a cinchona alkaloid bearing a bulky phenanthrene group (Scheme 1.27). High yields combined with excellent enantioselectivities of up to 96% ee were obtained in almost all cases of substrates. 

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... 

Among the electrophilic handles proposed for head-to-tail and side-chain-to-tail cyclization of peptides on solid support by intrachain aminolysis with concurrent detachment of the product from the resin in the protected form (see Section 6.8.3.1.3), generally the oxime resin (also called Kaiser resin)1364 365 and a thioester resin[363l are recommended (see Scheme 14). In addition to the classical head-to-tail cyclization,[3431 the oxime resin is used for side-chain cyclizations as well as for the synthesis of multicyclic peptides vide infra). Due to its dual functions, the oxime resin can be employed only with Boc/Bzl chemistry it is not compatible with Fmoc/tBu chemistry where the basic N -deprotection leads to free amino groups and thus to premature cyclization reactions. To avoid this premature cleavage of the... 

This reaction is quite special in that it is an aldol-type addition in which a thioester is the donor (nucleophile) and a keto acid is the acceptor (electrophile). From the discussion in Section 18-8E, you will see that reactions of this kind involving an ester as the donor and an aldehyde or ketone as the acceptor can be achieved in the laboratory only under rather special conditions. For the thioester to function as a nucleophile at the a carbon under the restraints imposed by having the reaction occur at the physiological pH, the catalyzing enzyme almost certainly must promote formation of the enol form of the thioester. The enol then could add to the ketone carbonyl with the assistance of a basic group on the enzyme. This kind of catalysis by enzymes is discussed in Section 25-9C. 

At oxidation level 3, acid chlorides occupy a key position, since they may serve as a nearly universal substrate for an isohypsic transformation into any kind of carboxylic acid derivative. Acid halides are electrophiles that are synthetically equivalent to acyl cations (RCO ). In this capacity they are used for the synthesis of such important compounds as esters, amides (and hence, nitriles), thioesters, etc. (see Scheme 2.57), and for the formation of C-C bonds in the Friedel-Crafts reaction (see above). Acid chlorides may readily lose HCl upon treatment with triethylamine. This isohypsic conversion leads to ketenes, important reagents widely employed in [2 + 2] cycloadditions, as we will see later. 

The epi-quinine urea 81b was also found by Wennemers to promote an asymmetric decarboxylation/Michael addition between thioester 143 and 124 to afford the product 144 in good yield and high enantioselectivity (up to 90% ee) (Scheme 9.49). Here, malonic acid half-thioesters serve as a thioester enolate (i.e., enolate Michael donors). This reaction mimics the polyketide synthase-catalyzed decarboxylative acylation reactions of CoA-bound malonic acid half-thiesters in the biosynthesis of fatty adds and polyketides. The authors suggested, analogously with the enzyme system, that the urea moiety is responsible for activating the deprotonated malonic add half-thioesters that, upon decarboxylation, read with the nitroolefin electrophile simultaneously activated by the protonated quinuclidine moiety (Figure 9.5) [42]. 

Apart from the true Claisen condensations discussed in the previous section in which the electrophilic reaction partner is another thioester, a number of enzymes also catalyze related Claisen-like condensations in which an acyl-CoA-based nucleophile reacts with other electrophilic carbonyl groups such as ketones, aldehydes, and the carboxylate group of carboxy-biotin. The most important examples of such enzymes are hydroxymethylglutaryl-CoA (HMG-CoA) synthase, citrate and homocitrate synthase (HCS), malate and ct-isopropylmalate synthase (ct-IPMS), and the biotin-dependent acetyl- and propionyl-CoA carboxylases. 

The reaction of 2,5-diphenyl- and 2,3,4,5-tetraphenylthiophene with ozone has been studied <85J0C1778>. At 0°C, the latter gave, after ethanolic workup, the butenedione (96) (61%) and thioester (97) (20%). No sulfone corresponding to the starting material could be detected. The butenedione obviously arises by an electrophilic attack at position 2 by ozone (Scheme 18). Similarly, 2,5-diphenylthiophene gave an 18% yield of PhCO—CH=CH—COPh. 

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