P-keto thioester

Tan and co-workers reported the Michael reactions of di-thiomalonates and P-keto-thioesters to a range of acceptors, including maleimides, cyclic enones, furanones and acyclic dioxobutenes [129]. Unlike dimethyl malonate, additions with acidic thioesters proceeded in higher yields, and overall better enantioselectivities (Scheme 74). 

Metal thiolates or benzenethiols in the presence of triethylamine also react very smoothly with di-ketene to yield S-alkyl (35) or S-aryl acetothioacetates (36). The p-keto thioesters (35) can be used in exceptionally mild preparations of P-keto amides (37), whereas (36) can be cyclized by Lewis acids to form thiocumarins (38). The S-f-butyl thiol ester (35) is also a suitable substrate for C-alkylation in the P-position or, after double deprotonation, in the 8-position (Scheme 3). ... 

Ye, W., Jiang, Z., Zhao, Y. et a/. (2007) Chiral bicyclic guanidine as a versatile Brdnsted base catalyst for the enantioselective Michael reactions of dithiomalonates and P-keto thioesters. Advanced Synthesis and Catalysis, 349, 2454-2458. 

Acetate simultaneously labeled in the methyl group with three deuterium atoms and a was incorporated into terrein. From the spectrum of the metabolite, it was clear that three deuterium atoms were present in the starter methyl group. This result demonstrated that acetate served as a starter acid in terrein biosynthesis (Figure 2.2) [1]. The A-acetylcysteamine thioester (SNAC) and the diketide intermediate of erythromycin A were labeled simultaneously with H and labels. The intact incorporation of the labeled SNAC and diketide intermediate into erythromycin B demonstrated that SNAC was not oxidized to the p-keto thioester before incorporation (Section 7.6) (Figure 2.3) [2]. 

Transfer of an acyl group between the first and second domains is reversible, which allows butanoyl ACP to return to the first domain of mFAS where it reacts with a second malonyl-ACP. The resulting six-carbon P-keto thioester then proceeds through another reduction— dehydration—reduction sequence to give hexanoyl-ACP. 

Intermediates 123 tmdergo a two-step rearrangement to a p-keto thiol ester enolate 125, via elimination of thiolate to yield a ketene 124, followed by the nucleophilic attack of the thiolate on 124. Finally, the homologated p-keto thioester 126 is obtained on acidification of the reaction mixture. This is a two-carbon homologation via insertion of ynolate into the C-S bond of thiol esters. 

Esters are far less reactive as electrophiles when compared to aldehydes and ketones. Successful tandem vicinal dialkylations are possible using alkyl formates,67 but most esters lack the needed reactivity. More reactive thioesters can serve as electrophiles in these sequences.208 Presence of a potentially electrophilic ester group as a substituent in the conjugate enolate permits very efficient Dieckmann cycliza-tion to take place as the second step of a MIRC sequence (e.g. equations 5118 and 52).24 Ortho esters are far more reactive, giving p-keto esters as adducts when used in sequences that employ enones as substrates.230... 

Like the related fatty acid synthases (FASs), polyketide synthases (PKSs) are multifunctional enzymes that catalyze the decarboxylative (Claisen) condensation of simple carboxylic acids, activated as their coenzyme A (CoA) thioesters. While FASs typically use acetyl-CoA as the starter unit and malonyl-CoA as the extender unit, PKSs often employ acetyl- or propionyl-CoA to initiate biosynthesis, and malonyl-, methylmalonyl-, and occasionally ethylmalonyl-CoA or pro-pylmalonyl-CoA as a source of chain-extension units. After each condensation, FASs catalyze the full reduction of the P-ketothioester to a methylene by way of ketoreduction, dehydration, and enoyl reduction (Fig. 3). In contrast, PKSs shortcut the FAS pathway in one of two ways (Fig. 4). The aromatic PKSs (Fig. 4a) leave the P-keto groups substantially intact to produce aromatic products, while the modular PKSs (Fig. 4b) catalyze a variable extent of reduction to yield the so-called complex polyketides. In the latter case, reduction may not occur, or there may be formation of a P-hydroxy, double-bond, or fully saturated methylene additionally, the outcome may vary between different cycles of chain extension (Fig. 4b). This inherent variability in keto reduction, the greater variety of... 

Certain CoA thioester using enzymes catalyze reactions at the fS-carbon or other carbons of the acyl group more distant from the thioester functionality. The fatty acid fi-oxidation cycle provides some examples (Fig. 3). Fatty acids 7 enter the cycle by initial conversion to the CoA ester 8, which is then oxidized to the a,P-unsaturated thioester 9 by a flavin-dependent enzyme. Addition of water to the double bond to form the fi-hydroxy thioester 10 is catalyzed by the enzyme crotonase, which is the centerpiece of the crotonase superfamily of enzymes that catalyze related reactions (37), which is followed by oxidation of the alcohol to form the fi-keto thioester 11. A retro-Claisen reaction catalyzed by thiolase forms acetyl-CoA 12 along with a new acyl-CoA 13 having a carbon chain two carbons shorter than in the initial or previous cycle. 

Bouillon, J.P. Tinant, B. Nuzillard, J.M. Portella, C. Synthesis of new 3-(l-ethylsulfanyl-2-perfluoroalkyl)-5-hydroxy-5-methyl 5-phenyl)-l,5-dihydro-pyrrol-2-ones starting from y-keto thioesters and imines. Synthesis 2004, 711-721. 

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. 

Scheme 1.27 Michael additions of P-keto esters to acrylic esters, thioesters and N-acryloyl pyrrole catalysed by cinchona alkaloid.

The microorganisms first hydrolyze the triglycerides enzymatically (cf. 3.7.1) and then they degrade the free acids by a P-oxidation pathway (Fig. 3.41). The fatty acids methyl ketones, the C-skeletons of which have one C-atom less than those of the fatty acids. Apparently, the thiohydrolase activity of these fungi is higher than the p-ketothiolase activity. Hence, ester hydrolysis occurs instead of thio-clastic cleavage of the thioester of a P-keto acid (see a textbook of biochemistry). The P-keto acid released is rapidly decarboxylated enzymatically a portion of the methyl ketones is reduced to the corresponding secondary alcohols. 

Claisen condensations in cells result from the condensation of thioesters. The sulfur atom of the thioester is part of a relatively large molecule called coenzyme A. The pA of an a-hydrogen atom of a thioester is about 8.5. It is a hundred times more acidic that the a-hydrogen of P-keto ester. The increased acidity of thioesters results from the ineffective resonance stabihzation of the positive charge of the carbonyl carbon atom by sulfur compared to oxygen. 

Hydrolysis of the thioester gives 3-ketobutanoic acid (acetoacetic acid). We recall that P-keto acids readily undergo decarboxylation. In this case, the decarboxylation product is acetone. And that is the source of the acetone breath of people suffering from severe episodes of diabetes. 

Capitta F, Frongia A, Piras PP, Pitzanti P, Seed F. Enantioselective organocatal)Tic rearrangement of a-acyloxy-P-keto sulfides to a-acyloxy thioesters. Adv. Synth. Catal. 2010 352 2955-2960. 

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