Methylenation thioesters

CPv. / Ti Al Tebbe reagent methylenation of aldehydes, ketones, esters, thioesters, amides, carbonates can also induce olefin metathesis in situ preparation [711-713]... 

Cp2TiMe2, THF or PhMe, 60-75 °C methylenation of aldehydes, ketones, esters, amides, imides, thioesters, acylsilanes, anhydrides, carbonates [708,709,720]... 

Recently, treatment of the esters or amides of l-methylpyridinium-3,5-dicarboxylic acid salts with an alkanethiol and TEA in methylene chloride was found to give a mixture of dihydropyridines (Scheme 77) (80CC1147). These yellow adducts are particularly useful as thiolate transfer agents. Excellent yields of thioesters, for example (133), are formed by the reaction of the adducts with activated acid derivatives. 

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... 

Another characteristic and helpful reaction takes place between DAST and sulfoxides, resulting in fluorination of the ot methyl or methylene group166. The reaction found many applications, especially in making fluoronucleosides167 and fluoroolefins168. Another sulfur-containing family, the thioesters, was found to react with DAST as well, resulting in the difficult to obtain difluoromethyl ethers (equations 92 and 93)169. 

Reagents other than R—SH derivatives arc also employed. Thioethers 275 arc successfully obtained by using thioesters in the presence of a phenolic catalyst, and dithiocarbamic esters 276 (Fig. 106) arc prepared by inserting CS2 (or COS) between the methylene and the amino group of various Mannich bases. The CS2 insertion has been achieved on 2,6-dialkylphcnols, in the course of Mannich synthesis, presumably as a consequence of electrophilic CS2 attack on the N atom with formation of the adduct 278, followed by intramolecular rearrangement ... 

C-Acylation. C-Acylation of active methylene compounds is usually conducted under basic conditions. Masamune et al. have developed a new method for conducting this reaction under neutral conditions that is patterned on the enzymic synthesis of fatty acids. The acylating reagent is the imidazolide of a carboxylic acid (1) prepared in situ. The substrate is the neutral magnesium salt of a mono ester or thioester of a malonic acid (2), prepared with magnesium ethoxide. The reaction of 2 with 1 is conducted in THF at 25-35° for 18-24 hours the yield of products (3) is generally >85%. ... 

Polyketide and fatty acid biosyntheses begin with condensation of the coenzyme A thioester of a short-chain carboxylic acid starter unit such as acetate or propionate with the coenzyme A thioester of a dicarboxylic acid extender unit such as malonate or methyl malonate. The driving force for the condensation is provided by the decarboxylation of the extender unit. In the case of fetty acid synthesis, the resulting -carbonyl is completely reduced to a methylene however, during the synthesis of complex poly-ketides, the -carbonyl may be left untouched or variably reduced to alcohol, olefinic, or methylene functionalities depending on the position that the extender unit will occupy in the final product. This cycle is repeated, and the number of elongation cycles is a characteristic of the enzyme catalyst. In polyketide biosynthesis, the full-length polyketide chain cyclizes in a specific manner, and is tailored by the action of additional enzymes in the pathway. 

In addition to phenylacetonitrile and fluorene, various active methylene compounds such as indene, propiophenone, phenyl propionate, benzyl phenylacetate afforded the corresponding carboxylated products by the carboxylation reaction with La(0 Pr)3-Ph-N=C=0-C02 system. Of fundamental and practical importance is that S-benzyl thiopropionate was effectively carboxylated into a thioester of 2-methylmalonate in a good yield, since this reaction is related to the biological carboxylation of propionyl coenzyme A with a biotin enzyme. Other thioesters were also carboxylated similarly, where successful examples were thioesters of phenylacetic, acetic, and isovaleric acids carrying active methylene and methyne groups, respectively. 

The principles used in the design of antimetabolites have been applied to synthesize atropine-like compounds. The ester group in atropine-like compounds has been replaced by a thioester, an amide, an ether group, or a chain of methylene carbons (Table 3.3). 

To probe the substrate specificity further, the incorporation of the NAC thioester of 6-fluorohexanoate was examined. The 470 MHz F NMR spectrum of the metabolite (derivatised as its tetramethyl ether) showed a very strong triplet of triplets at 6 -218.2 ppm, similar to that observed in the thioester. The mass spectrum showed a large amount of a new metabolite of MW 444 (Fig. 12b). In the 500 MHz H NMR spectrum (Fig. 12a), the 6 -methylene signal of the 6 -fluoroanalogue (81) appeared as a doublet of triplets, whereas the... 

A more satisfying proposal is that methyl transferase activities are present within the polyketide synthase, which catalyses the formation of carbon-carbon bonds at activated methylene groups of the )8-keto thioester intermediates. This idea has been postulated by O Hagan and co-workers, who have predicted a domain and module sequence of the putative PKS responsible for cubensic acid 76 biosynthesis (see Fig. 8) [115,116]. 

DEPC in combination with NEtj has proved to be a new efficient reagent for the direct C-formylation of active methylene compounds with carboxylic acids and also for the iV-acylation (peptide bond formation), 5-acylation (thioester formation) and O-acylation (esterification).4,5 Reaction of DEPC with carboxylic acids 11 in the presence of triethylamine produces transient acyl cyanides, which in the presence of alcohols or thiols results in the formation of the corresponding esters (12) or thioesters (13). 

Hydroxy-thioesters are prepared by the reaction of an aldehyde or ketone with the lithium salt of phenyl ethanethioate. These thioesters form -lactones readily since -lactones can be converted into alkenes, in quantitative yield, this sequence represents an alternative process for methylenation of a ketone (Scheme 44). 

Although, a thioester-substituted p-diketone ligand was eventually chosen for the sensor, many vinyl-substituted p-diketones were found to be unsuitable for making stable europium complexes. For example, methylene substituted... 

---