Enolates asymmetric

Alkylation of Enolates Asymmetric syntheses involving enolate reactions such as alkylations, aldol additions and acylations in which the chiral auxiliary A -H is both readily obtained and easily recoverable after the desired bond construction had been achieved by Evans et al.175). 

A group of compounds that protect cartilage from enzymatic degradation Asymmetric alkylation of Evans s chiral enolates Asymmetric synthesis from an enantiomerically enriched hydroxy-acid Part V - Conformational Control and Resolution Kinetic or Not ... 

Fluorination of enolates. Asymmetric fluorination is observed in moderate yields and enantiomer excesses with reagent (1). 

Finally, a method to generate enantioenriched a-fluoro carboxylic acids using N-heterocyclic carbene catalysts was reported by Rovis (Scheme 13.12) [28]. Starting from achiral a-fluoroenals, initial attack of the carbene to the aldehyde and subsequent tautomerization generated a chiral enolate. Asymmetric protonation of this enolate followed by displacement of the azolium species by water produced enantiopure a-fluoro carboxylic acids. Thus, in contrast to the other methods... 

An alternative method for the formation of enantioenriched a-chloroesters, using A-heterocyclic carbene catalysts, was reported by Reynolds and Rovis (Scheme 13.14) [34]. In a similar mechanism to that presented in Scheme 13.12, initial attack of the carbene to the aldehyde and loss of HCl generated a chiral enolate. Asymmetric protonation of this enolate followed by displacement of the azolium species by a phenol produced enantiopure a-chloroesters. In contrast to the approach to chiral a-chloroesters presented in Scheme 13.13, a variety of aryl esters can be incorporated into the product by using different aryl alcohols (ArOH). Additionally, a carbon-chlorine bond is not formed in this reaction. Rather the introduction of a stereocenter in the chlorinated products is achieved via asymmetric protonation. This method was elaborated to use water as the proton/alcohol source to produce chiral a-chloro carboxylic acids (i.e., as in Scheme 13.12) [28]. Moreover, the use of D2O generated chiral a-chloro-a-deutero carboxylic acids. 

A useful catalyst for asymmetric aldol additions is prepared in situ from mono-0> 2,6-diisopropoxybenzoyl)tartaric acid and BH3 -THF complex in propionitrile solution at 0 C. Aldol reactions of ketone enol silyl ethers with aldehydes were promoted by 20 mol % of this catalyst solution. The relative stereochemistry of the major adducts was assigned as Fischer- /ir o, and predominant /i -face attack of enol ethers at the aldehyde carbonyl carbon atom was found with the (/ ,/ ) nantiomer of the tartaric acid catalyst (K. Furuta, 1991). 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

In all cases examined the ( )-isomers of the allylic alcohols reacted satisfactorily in the asymmetric epoxidation step, whereas the epoxidations of the (Z)-isomers were intolerably slow or nonstereoselective. The eryfhro-isomers obtained from the ( )-allylic alcohols may, however, be epimerized in 95% yield to the more stable tlireo-isomers by treatment of the acetonides with potassium carbonate (6a). The competitive -elimination is suppressed by the acetonide protecting group because it maintains orthogonality between the enolate 7i-system and the 8-alkoxy group (cf the Baldwin rules, p. 316). 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone appHes a tandem Claisen rearrangement and intramolecular ene-reaction (Eig. 23). StereochemicaHy pure (185) is synthesized from (2R)-l,2-0-isopropyhdene-3-butanone in an overall yield of 86% in four chemical steps. Heating a toluene solution of (185), enol ether (187), and 2,6-dimethylphenol to 180°C in a sealed tube for 60 h produces (190) in 76% yield after purification. Ozonolysis of (190) followed by base-catalyzed epimerization of the C8a-hydrogen to a C8P-hydrogen (again similar to conversion of (175) to (176)) produces (184) in 46% yield from (190). Aldehyde (184) was converted to 9,11-dehydroestrone methyl ether (177) as discussed above. The overall yield of 9,11-dehydroestrone methyl ether (177) was 17% in five steps from 6-methoxy-l-tetralone (186) and (185) (201). 

The Darzens condensation reaction has been used with a wide variety of enolate equivalents that have been covered elsewhere. A recent application of this important reaction was appljed toward the asymmetric synthesis of aziridine phosphonates by Davis and coworkers.In this application, a THF solution of sulfinimine 34 (0.37 mmol, >98% ee) and iodophosphonate 35 (0.74 mmol) was treated with LiHMDS (0.74 mmol) at -78 °C to give aziridine 36 in 75% yield. Treatment of 36 with MeMgBr removed the sulfinyl group to provide aziridine 37 in 72% yield. 

The first asymmetric Mn(salen)-catalyzed epoxidation of silyl enol ethers was carried out by Reddy and Thornton in 1992. Results from the epoxidation of various silyl enol ethers gave the corresponding keto-alcohols in up to 62% ee Subsequently, Adam and Katsuki " independently optimized the protocol for these substrates yielding products in excellent enantioselectivity. 

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

For example in the so-called Mukaiyama aldol reaction of an aldehyde R -CHO and a trimethylsilyl enol ether 8, which is catalyzed by Lewis acids, the required asymmetric environment in the carbon-carbon bond forming step can be created by employing an asymmetric Lewis acid L in catalytic amounts. 

Asymmetric Michael addition of chiral enolates to nltroalkenes provides a useful method for the preparation of biologically important compotmds. The Michael addition of doubly deprotonated, optically active fi-hydroxycarboxylates to nltroalkenes proceeds v/ith high dias-tereoselecdvity to give fityr/iro-hydroxynitroesters fEq, 4,58, ... 

Enandoselecdve synthesis of the anddepressant rohpram can be done by the asymmetric Michael addidon of the enolate of iV-acetyloxa2ohdone to nitrostyrene, Chiially branched pyrrohdones like rohpram are highly acdve anddepressants v/ith novel postsynapdc modes of acdon. The synthesis is shown in Scheme 4,13, ... 

A chiral sulfoxide can be used as a leaving group for the asymmetric inducdon via addidon-eliminadonprocess. 5-Lactam enolates are converted into the corresponding nitroalkenes subsdnited with lactams fEq. 4.101. ... 

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