Thioesters natural product synthesis

An illustration of the use of -methyl-substituted thioesters in the synthesis of natural products is present in the total synthesis of a /3-D-mannosyl phosphomycoketide from Mycobacterium tuberculosis (Figure 5). Addition of MeMgBr to ethyl 6-benzyloxy-2-hexene thioate catalyzed by Cu/Josiphos (92% yield, 93% ee) furnished one of the building blocks. The other four methyl groups were introduced using copper/phosphoramidite-catalyzed dimethylzinc addition. 

The Claisen rearrangement has been instrumental in the synthesis of a number of natural products.279-289 Many useful derivatives have been prepared using the Claisen-type rearrangement including enol ethers,290 amides,291-293 esters and orthoesters,294-296 acids,297-298 oxazolines,299 ketene acetals,300-301 and thioesters.302 Many of these variants use a cyclic primer to control relative and absolute stereochemistry. The Claisen and oxy Cope provide the best candidates for scale up as a result of the irreversible nature of these reactions. 

Keto derivatives (esters, thioesters, amides) are hydrogenated to the secondary alcohol with 93% to 99% e.e. Ketones having a heteroatom a to the carbonyl (—OH, —NRj, —halide) also undergo clean, stereochemically directed reduction. Coordination of the carbonyl oxygen and the heteroatom of the other functional group to the metal forms a chelate ring responsible for the enantiomeric differentiation. This clean process favorably competes with the use of bakers yeast, and is applied to the synthesis of natural products like carnitine and compactine" ... 

The reduction has successfully been applied in the synthesis of a number of natural products (Scheme 25), where the carboxylic acid intermediates are conveniantly converted to the thioesters. The compatibility of the reaction with a variety of functional groups and chiral centers makes it the method of choice for the selective reduction to aldehydes. Evans and co-workers prepared the aldehyde intermediate 44 in the synthesis of ratamycin Smith and co-workers utilized the aldehyde 45 in the total synthe-... 

Scheme 5 The ACA of MeMgBr to a,p-unsaturated thioesters in the synthesis of the deoxypropionate motif present in many natural products...

The preceding survey of the recent developments in the synthesis of CICs and their application in small molecules and bioactive natural products reflects an active current interest in this highly versatile class of useful reagents. From a practical point of view, CICs have revolutionized the application of IMCRs, in particular that of U-4CR, due to their mild removal conditions that are compatible with many commonly used functional handles and their odorless, fragrant-like smell. Post-Ugi modification using CICs provides a method of transforming Af-terminal secondary amides into carboxylic acids, esters, thioesters, ketones, aldehydes, and alcohols for further chemical diversification and thus helped remedy the lack of commercial isocyanide inputs. 

The hydroesteriflcation and hydrocarboxylation reactions catalyzed by transition metals and their complexes demonstrate the versatility of these processes. Palladium complexes are particularly useful catalysts for these reactions. Indeed, the hydrocarbonylation of a large variety of substrates has been selectively achieved by using palladium catalysts in homogeneous, heterogeneous, or biphasic systems. The results obtained for the thiocar-bonylation showed excellent regio- and stereoselectivity control for most substrates. It is anticipated that the prochiral nature of most of the reactants and products will open a new venue for the asymmetric synthesis of acids, esters, and thioesters of substantial development in the future. 

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