Thiolester enolates

The method outlined here competes well with the method developed earlier by Danheiser, et al.618 Its superiority is based on the fact that phenyl ester enolates give almost the same results as the S-phenyl thiolester enolates. However, handling the malodorous benzenethiol for the preparation of the active acid derivative and during workup of the p-lactone can be avoided. In addition, phenol is much cheaper than benzenethiol. The method is well suited for the preparation of p-lactones from symmetrical and unsymmetrical ketones. In addition to 3,3-dimethyM-oxaspiro[3.5]nonan-2-one, ( )-3-ethyl-1-oxaspiro[3.5]nonan-2-one and (3R, 4R )- and (3R, 4S )-4-isopropyl-4-methyl-3-octyl-2-oxetanone were prepared by this procedure in high yields (Notes 11 and 12). In the case of unsymmetrical ketones the less sterically crowded diasteroisomer is formed preferentially. With aldehydes as the carbonyl component the yields are unsatisfactory, because of the competitive formation of 1,3-dioxan-4-ones.6... 

The thiolester group was used for deracemization of terpenic esters [254]. Racemic 5-phenyl thiocyclogeranate was deprotonated by n-BuLi, and the resulting enolate was protonated by a chiral aminoalcohol, ( )-N-isopropylephedrine. The thiolester was obtained with the highest enantioselectivity (99% e.e.) reported for such a process (carried out on a 40 g scale). With a sulfur group a selective (Z)-enolate was formed and protonation was slower than for esters. 

A much more general synthesis of these silyl enol ethers, however, is based on the reductive cleavage of the carbon-sulphur bond of the silyl enol ether of a thiolester using sodium metal and chlorotrimethylsilane, once again in a silyl acyloin reaction (Scheme 22)97,98. 

Enolates prepared by deprotonation of carboxylic acid derivatives can also undergo elimination to yield ketenes. This is rarely seen with amides, but esters, thiolesters, imides, or N-acylsulfonamides can readily decompose to ketenes if left to warm to room temperature (Scheme 5.58). At -78 °C, however, even aryl esters can be converted into enolates stoichiometrically without ketene formation [462, 463],... 

Michael reactions. This system promotes a Michael addition of silyl enol ethers to a,(3-unsaturated thiolesters, which are excellent Michael acceptors. Trityl salts are less effective, as are Lewis acids in combination with SnCl2. 

Hydroxy derivatives. 2-Hydroxy derivatives usually exist as the oxo tautomers, unless the hydroxy tautomer is appreciably stabilized by electron-withdrawing or chelating substituents. The tendency for enolic hydroxy compounds to revert to the oxo form can be understood by reference to simple aliphatic ketones where the keto-enol equilibrium constants are of the order of 108. In the five-membered heterocycles under consideration, this tendency will be in opposition to the loss of aromatic resonance energy that increases in the order furan << thiophene < pyrrole. For the 2-hydroxy compounds 217 some extra stabilization of the oxo tautomers 218 and 219 is derived from the resonance energy of the X-C=0 group, which by analogy with open-chain compounds should increase in the sequence thiolester, ester << amide. 

The hydrolysis of the thiolester occurs by simple substitution at the carbonyl group (Chapter 12). Since a thiol is a good leaving group (pJfa RSH about 7) no strong acid or base is needed. The two bromine atoms will also accelerate nucleophilic attack both because they are electron-withdrawing and because they prevent enolization. 

Alkenes. Titanocene bis(triethyl phosphite), which is prepared in situ from titanocene dichloride, triethylphosphite, and Mg, promotes carbonyl olefmation with gem-dichlorides and dithioacetals [e.g., l,l-bis(phenylthio)cyclobutane ] including those derived from enals (to give 1,3-dienes). Enol ethers-and alkenyl sulfides are obtained in the analogous reaction with dithioorthoformates and trithioorthoformates. Cross-coupling of dithioacetal and thiolesters furnishes predominantly (Z)-alkenyl sulfides. ... 

The reactions of aldehydes with enoxysilanes of ketones usually exhibit poor stereoselectivity. Enoxysilanes derived from esters and thiolesters, on the other hand, give good results. Chirality has been introduced either on the Lews acid or by using an ester of an enantiopure alcohol. As in the case of enolate reactions, one or two new stereocenters may be created. All these reactions take place at low temperatures, and they are sometimes limited by the instability of certain ketene silylacetals. 

The epimeric mixture of 16-ethoxycarbonylmethyl-17-oxo-compounds (45) was prepared from the jS-keto-thiolesters (44) by successive alkylation with bromoacetic ester and treatment with Raney nickel. The epimeric 16-phenyl-selenylandrostenones (46) were prepared via LDA-PhSeCl reaction of the 17-oxo-compound appropriately protected at C-3. Similar reaction of a 20-oxopregnane gave the 21-phenylselenyl derivative (47), and the preparation of the 17a-phenylselenyl analogue involved the reaction of the A -enol acetate... 

Another reaction that goes better with thiol esters than with ordinary esters is enolization. This is an equilibrium reaction and the enol has lost the conjugation present in the ester. Again, a thiol ester has less to lose so is more enolized, and it is the enolization of thiolesters of coenzyme A that we are now going to discuss. 

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