Thioesters enolates

I.3.4.2.2. Chiral Ulster Enolates, Silylketene Acetals, and Thioester Enolates... 

In contrast to the usual anti selectivity a remarkably high syn selectivity is observed in the addition of thioester enolates to 2-alkylidenealkanones297. The syn selectivity is probably due to a stereoselective internal autoprotonation of the resulting enolates by the dithioester a-pro-tons298 in these cases where the prostereogenic centers reside exclusively in the enone part (see also Section D.2.I.). 

Several reviews of P-lactam chemistry have appeared including a general survey with 407 references <99MI335>. Other reviews include discussions of thioester enolate-imine reactions , enantio- and diastereo-selective routes to azetidinones <99MI221>, the use of diazoketones in diastereoselective synthesis <99MI43>, and solid-phase and combinatorial syntheses of p-lactams <99MI955>. 

The polyketides (23) form the only major class of natural products that has monomer couplings that do not involve the loss of phosphate like the nonribosomal peptides, the monomer couplings use a thioester intermediate. These molecules, which have biosynthetic pathways much like those of fatty acids, are assembled from the alpha-carboxylated two- and three-carbon metabolites malonyl-CoA and methylmalonyl-CoA (22). In these monomers, the alpha-carboxyl group is a caged form of carbon dioxide, and decarboxylation yields a thioester enolate... 

Figure 3 Biosynthetic pathways. (A) In the terpenoid coupling reaction, isomers of isopentenyl pyrophosphate are joined with the loss of pyrophosphate, leading to a linear intermediate that is cyclized to a terpenoid skeleton, as shown for the diterpene taxol. (B) In the polysaccharide coupling reaction, hexose and pentose monomers are joined with the loss of a nucleoside diphosphate, as shown for the epivancosaminyl-glucose disaccharide of vancomycin. (C) In the first step of the nonribosomal peptide coupling reaction, an aminoacyl adenylate is transferred to a carrier protein or thiolation domain (denoted T ) with loss of adenosine monophosphate. In the second step, this carrier protein-tethered aminoacyl group is coupled to the amine of an aminoacyl cosubstrate, forming a peptide bond, as shown for two residues in backbone of vancomycin. (D) In the polyketide coupling reaction, the loss of carbon dioxide from a two or three-carbon monomer yields a thioester enolate that attacks a carrier protein-tethered intermediate, forming a carbon-carbon bond as shown for the polyketone precursor of enterocin.

An example of a magnesium thioester enolate is shown in Eq. (20) [27]. These enolates were generated by reaction of thioesters with several bases, including /-PrMgCl, Et2NMgBr, and EtSMgCl. The thioester enolates were used in subsequent Claisen condensations. 

Braun, M., Sacha, H. Recent advances in stereoselective aldol reactions of ester and thioester enolates. J. Prakt. Chem. 1993, 335, 653-668. 

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]. 

Enoyl-CoA hydratase (ECH commonly known as crotonase), that catalyzes the cofactor-independent hydration of conjugated enoyl-CoA esters in yS-oxidation, has been the subject of considerable debate regarding the timing of bond-making reactions and, therefore, the importance of a thioester enolate anion on the reaction coordinate. The active site contains Glu 144 and Glu 164 as the only possible acid-base catalysts. In the nonphysiological dehydration direction, the value of the pKa... 

No information is available concerning the concentration of the thioester enolate anion intermediate, by either experiment or computation, so the partitioning of the rate acceleration between reductions in AG° and AG int is not possible. 

Further persuasive evidence in support of the expectation that the mechanism of the ECH-catalyzed reaction involves an Elcb mechanism with a stabilized thioester enolate anion intermediate is obtained from the membership of ECH in the mechanistically diverse enoyl-CoA hydratase superfamily [70]. Such superfamilies are derived from a common ancestor by divergent evolution the members of these share a partial reaction, usually formation of a common intermediate, e.g., an enolate anion. The reactions catalyzed by members of the enoyl-CoA hydratase superfamily (almost) always utilize acyl esters of CoA as substrates the reactions invariably can be rationalized with mechanisms that involve the formation of a thioester enolate anion intermediate, e.g., 1,3-proton transfer, 1,5-proton transfer, Dieckman and reverse Dieckman condensations, and yS-decarboxylation. Although mechanisms with thioester enolate anion intermediates are plausible for each of these reactions, as in the ECH-catalyzed reaction, evidence for their existence on the reaction coordinate is circumstantial because the intermediates do not accumulate, thereby avoiding spectroscopic detection. 

However, 4-chlorobenzoyl-CoA dehalogenase is also a member of the enoyl-CoA hydratase superfamily. The mechanism of its reaction involves nucleophilic aromatic substitution in which an active site Asp adds to the 4-position of the benzoyl ring to necessarily form a Meisenheimer complex this Meisenheimer complex is an analog of a thioester enolate anion. Although the Meisenheimer complex cannot be observed for displacement of chloride from 4-chlorobenzoyl-CoA due to the rate constants for formation and decomposition of the intermediate, the Meisen-... 

The reaction of ketenes with tin(ll) thiolates gives tin(II) thioester enolates with (Z)-configuration (Scheme 38). 

In the Woodward erythromycin synthesis, the lithium enolate of t-butyl thiopropionate was added to aldehyde (151) aldol (152) was obtained in 85% yield (equation 99). The remarkable diastereofacial selectivity observed in this reaction may be a general property of thioester enolates. (v/de infra). 

The S-thioester enolate/imine condensation as a shortest way to /1-lactams 00EJO563. 

A stereoselective synthesis of 6-amino acid derivatives by an aldol-type condensation of tin(II) carboxylic thioester enolates with imines has been reported (Scheme 90) the method was used to synthesize an intermediate of the carbapenem antibiotic... 

This reaction was first reported by Gilman and Speeter in 1943. It is an efficient preparation of 3-alkyl-substituted or unsubstituted j8-lactams by the condensation of a Reformatsky reagent and an imine. Therefore, this reaction is generally known as the Gilman-Speeter reaction or Gilman-Speeter condensation. In addition, the extended reactions between lithium ester enolate or lithium thioester enolate and imine are also considered as the Gilman-Speeter reaction. 

The modifications of the Gilman-Speeter reaction include the activation of zinc by tri-methylsilyl chloride (TMSCl) and the application of lithium ester enolate" or lithium thioester enolate as the substitute for the traditional Reformatsky reagent. In these modifications, it was found that TMSCl-activated zinc is much more effective in promoting the reaction between ethyl bromoacetate and Schiff bases. In addition, in the presence of a chiral ether ligand, the reaction between lithium ester enolate and imines affords 0-lactams of high enantiomeric excess, probably due to the formation of a ternary complex reagent. " The enantioselectivity and reactivity of the ternary complex depend on the size and nature of the lithium amide used. For example, the lithium amide from 2,2,6,6-tetramethylpiperidine (LTMP) is unfavorable for this reaction." ... 

P-Lactones can be prepared in good yield from thioester enolates. Suggest a mechanism for the reaction shown. 

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