Thioesters amide synthesis

The synthetic utility of azolides is exemplified by many examples of their use in the synthesis of carboxylic acids, esters, and thioesters, amides and thioamides, aldehydes and ketones, and phosphorylated imidazoles and benzimidazoles. 

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" ... 

As previously described (see section 2) the solvent dependence of ESIPT in flavonols has been found to play a key role in the reactivity of the photogenerated intermediates. Porco and co-workers reported that protic solvents such as 2,2,2-trifluoroethanol (TFE) are able to promote ESIPT pathway, leading to an increase of the population of the excited phototautomers (It) 119 7hus, the irradiation of 3-hydroxyflavone derivatives in chloroform/ TFE (TFE) 70 30 mixture and in the presence of methylcynnamate resulted in an improved cycloaddition yield (up to 55%) and diasteroselectivity (up to 5 1 d.r.). Furthermore, the use of protic TFE increased the photo-tautomerization yield, allowing the use of less reactive dipolarophiles including cinnamyl thioesters, amides or nitriles.The enanthioselective synthesis of potent cytotoxic (-)-Silvestrol (37) via TADDOL derivatives-mediated [3-1-2] cycloaddition has been reported. (Scheme 10). ... 

Hydrazides (RCONHNH2) are highly useful starting materials and intermediates in the synthesis of heterocyclic molecules.2 They can be synthesized by hydrazinolysis of amides, esters and thioesters.3 The reaction of hydrazine with acyl chlorides or anhydrides is also well known,4 but it is complicated by the formation of 1,2-diacylhydrazines, and often requires the use of anhydrous hydrazine which presents a high thermal hazard. Diacylation products predominate when hydrazine reacts with low molecular weight aliphatic acyl chlorides, which makes the reaction impractical for preparatory purposes.5... 

Reduction is used for carbonyl functionalities [71, 230] such as thioesters [231], amides [232], and carbamates [233], as well as for sulfur [234] and selenium [122] compounds. Recently, the synthesis of a potential carbohydrate vaccine is described via an reduction-oxidation sequence [235]. An efficient solid-phase synthesis of pyrimidine derivatives that involved reduction of the corresponding nitro derivatives was developed by Makara et al. in 2001 (Scheme 3.9) [236]. 

The hydration of heteroatom-substituted alkynes proceeds well under general acid catalysis. This reaction provides a convenient synthesis of amides,308 esters309 and thioesters.308 Equation (203) illustrates the utility of this reaction for the regiospecific synthesis of 3-alkenamides. 

Absolute asymmetric synthesis was observed in the solid-state photoreaction of benzoylbenzamide 59 to phthalide 60 however, the reaction mechanism was completely different from that of thioester 57. [35] Recrystallization of these amides 59a-c from the chloroform-hexane solution afforded colorless prisms in all cases. X-ray crystallographic analysis revealed that all prochiral amides 59a-c adopted orthorhombic chiral space group P2 2 2 and were frozen in chiral and helical conformation in the crystal lattice. 

With regard to the use of protease in the synthetic mode, the reaction can be carried out using a kinetic or thermodynamic approach. The kinetic approach requires a serine or cysteine protease that forms an acyl-enzyme intermediate, such as trypsin (E.C. 3.4.21.4), a-chymotrypsin (E.C. 3.4.21.1), subtilisin (E.C. 3.4.21.62), or papain (E.C. 3.4.22.2), and the amino donor substrate must be activated as the ester (Scheme 19.27) or amide (not shown). Here the nucleophile R3-NH2 competes with water to form the peptide bond. Besides amines, other nucleophiles such as alcohols or thiols can be used to compete with water to form new esters or thioesters. Reaction conditions such as pH, temperature, and organic solvent modifiers are manipulated to maximize synthesis. Examples of this approach using carboxypeptidase Y (E.C. 3.4.16.5) from baker s yeast have been described.219... 

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. 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

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. 

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