Enolates prochiral

Reaction of lithium enolate 2 with prochiral 3-buten-2-one (4) proceeds with minimal selectivity to produce nearly equal amounts of the two diastereomers of structure 540,41. 

Either diastereomer 2 or 3 may be preferentially produced with high selectivity depending on the nature of the enolate counterion present2642-44. Mechanistic details of the diastercofacial differentiation process are not clear in many cases the diastereomeric ratio of the products exhibits a complex dependence on stoichiometry, enolate counterion and reaction conditions26. The dependence of the d.r. on the nature of the enolate counterion is roughly outlined (vide supra) while examples of conditions employed for the reaction of the enolates 1 with prochiral aldehydes arc listed (Table 4). 

Reaction of the lithium enolate 2 with prochiral aldehydes at low temperature proceeds with little selectivity, producing all four possible diastereomers 3, 4, 5, and 6 in similar amounts50. Transmetalation of the lithium enolate by treatment with three equivalents of diethylaluminum chloride or with one equivalent of copper cyanide generates the corresponding cthylaluminum and copper enolates which react at — 100°C with prochiral aldehydes to produce selectively diastereomers 1 and 2, respectively50. The reactivity of tin enolates of iron- propanoyl complexes has not been described. 

Enantioselective deprotonation of prochiral 4-alkylcyclohexanones using certain lithium amide bases derived from chiral amines such as (1) has been shown (73) to generate chiral lithium enolates, which can be trapped and used further as the corresponding trimethylsilyl enol ethers trapping was achieved using Corey s internal quench described above. 

The asymmetric synthesis of 2,3-diamino acids can be accomplished by the addition of chiral enolates to prochiral imines. For example, reaction of morpholine-2-one 103, derived from (S)-phenylglycinol, with N-benzyl ben-zaldimine in the presence of pyridine and para-toluenesulfonic acid at high... 

Asymmetric conjugate addition of dialkyl or diaryl zincs for the formation of all carbon quaternary chiral centres was demonstrated by the combination of the chiral 123 and Cu(OTf)2-C H (2.5 mol% each component). Yields of 94-98% and ee of up to 93% were observed in some cases. Interestingly, the reactions with dialkyl zincs proceed in the opposite enantioselective sense to the ones with diaryl zincs, which has been rationalised by coordination of the opposite enantiofaces of the prochiral enone in the alkyl- and aryl-cuprate intermediates, which precedes the C-C bond formation, and determines the configuration of the product. The copper enolate intermediates can also be trapped by TMS triflate or triflic anhydride giving directly the versatile chiral enolsilanes or enoltriflates that can be used in further transformations (Scheme 2.30) [110],... 

In the presence of a chiral promoter, the asymmetric aldol reaction of pro-chiral silyl enol ethers 71 with prochiral aldehydes will also be possible (Table 3-6). In this section, a chiral promoter, a combination of chiral diamine-coordinated tin(II) triflate and tributyl fluoride, is introduced. In fact, this is the first successful example of the asymmetric reactions between prochiral silyl enol ethers and prochiral aldehyde using a chiral ligand as promoter. 

In contrast to the oxidation of prochiral esters and amides, which induces only moderate ee, sodium enolates of ketones give high stereoselectivity with (+)-147 or (—)-147 as the oxidant (Scheme 4-56 and Table 4-21). The highest stereoselectivity has been observed in the oxidation of the sodium enolate of deoxybenzoin 150, in which benzoin 149 can be obtained in over 95% optical purity. 

TABLE 4-21. Asymmetric Oxidation of Prochiral Ketone Enolates to a-Hydroxyl Ketones Using 147... 

Following their success with chiral ketone-mediated asymmetric epoxidation of unfunctionalized olefins, Zhu et al.113 further extended this chemistry to prochiral enol silyl ethers or prochiral enol esters. As the resultant compounds can easily be converted to the corresponding a-hydroxyl ketones, this method may also be regarded as a kind of a-hydroxylation method for carbonyl substrates. Thus, as shown in Scheme 4-58, the asymmetric epoxidation of enol silyl... 

Asymmetric Hydrogenation of Enol Esters. Prochiral ketones represent an important class of substrates. A broadly effective and highly enantioselective method for the asymmetric hydrogenation of ketones can produce many useful chiral alcohols. Alternatively, the asymmetric hydrogenation of enol esters to yield a-hydroxyl compounds provides another route to these important compounds. 

Chiral //-hydroxylester 61 cannot be satisfactorily obtained through the reaction between a prochiral ketone and the enolate. It can, however, be synthesized via the chiral ligand-induced asymmetric Reformatsky reaction of ketones (Scheme 8-21). 

Camell and co-workers have recently applied lipase-catalysed resolution to formally desymmetrize prochiral ketones that would not normally be considered as candidates for enzyme resolution, through enantioselective hydrolysis of the chemically prepared racemic enol acetate. " For example, an NK-2 antagonist was formally desymmetrized by this approach using Pseudomonas fluorescens hpase (PFL) (Scheme 1.40). By recychng the prochiral ketone product, up to 82 % yields of the desired (5)-enol acetate (99 % ee) could be realized. This method offers a mild alternative to methodologies such as base-catalysed asymmetric deprotonation, which requires low temperature, and biocatalytic Baeyer-Villiger oxidation, which is difficult to scale up. 

Camell, A.J., Barkely, J. and Singh, A., Desymmetrisation of prochiral ketones by catal3ftic enantioselective hydrolysis of their enol esters using enzymes. Tetrahedron Lett., 1997, 38, 7781-7784 Allan, G.R., Carnell, A.J. and Kroutil, W., One-pot deracemisation of an enol acetate derived from a prochiral cyclohexanone. Tetrahedron Lett., 2001, 42, 5959-5962. 

An attractive feature of this type of resolution is that the prochiral ketone can be recycled. The homochiral (5)-enol ester 8 was obtained in 82 % yield by recycling the ketone without prior separation from the enantioenriched enol ester. For a cyclic enzyme... 

Camell, A.J., Swain, S.A. and Bickley, J.E., Chiral enol acetates derived from prochiral oxabi-cyclic ketones using enz3mies. Tetrahedron Lett., 1999, 40, 8633. 

Camell, A.J., Barkley, J. and Singh, A., Desymmetrisation of prochiral ketones by catalytic enantioselective hydrolysis of their enol esters using enzymes. Tetrahedron Lett., 1997,38,7781. 

Allan, G., Camell, A.J. and Kroutil, W., One-pot deracemisation of an enol acetate derived from a prochiral cyclohexanone. Tetrahedron Lett., 2001, 42, 5959. 

If stoichiometric quantities of the chiral auxiliary are used (i.e., if the chiral auxiliary is covalently bonded to the molecule bearing the prochiral centres) there are in principle three possible ways of achieving stereoselection in an aldol adduct i) condensation of a chiral aldehyde with an achiral enolate ii) condensation of an achiral aldehyde with a chiral enolate, and iii) condensation of two chiral components. Whereas Evans [14] adopted the second solution, Masamune studied the "double asymmetric induction" approach [22aj. In this context, the relevant work of Heathcock on "relative stereoselective induction" and the "Cram s rule problem" must be also considered [23]. The use of catalytic amounts of an external chiral auxiliary in order to create a local chiral environment, will not be considered here. 

The reactivity of lithium enolates has been explored in a theoretical study of the isomers of C2H30Li, such as the lithium enolate, the acyl lithium, and the a-lithio enol. Imides containing a chiral 2-oxazolidine have been employed for enantioselective protonation of prochiral enolates.A degree of kinetic control of the product E/Z-enolate ratio has been reported for the lithiation of 3,3-diphenylpropiomesitylene, using lithium amides/alkyls. " °... 

A new chiral proton source (111), based on an asymmetric 2-oxazoline ring, has been found to be capable of effecting asymmetric protonation of simple prochiral metal enolates (112) to give corresponding ketones (113) which need not bear polar groups. 

Catalytic asymmetric protonation of a prochiral amide enolate by a chiral diamine (10mol%) has been achieved through careful optimization of the proton-shuttle conditions which must apply. ... 

Larry Overman also used (J. Am. Chem. Soc. 2004,126, 14043) a chiral pool starting material, but in a different way. The prochiral enolate 12 showed substantial diastereoselectivity in its reaction with the bis-triflate 13, almost 10 1. Through the power of algebra, it followed that the three diastereomers of 14 were formed in a ratio of 90 9 1. The crystalline 14 was easily isolated in diastereomerically-pure form, and carried on to phenserine 15. This is a new method for the stereocontrolled construction of chiral quaternary centers. 

B. Giese, W. Damm, T. Witzel, and H. G. Zeitz, The influence of substituents at prochiral centers on the stereoselectivity of enolate radicals. Tetrahedron Lett. 34 7053 (1993). 

Enantioselective condensation of aldehydes and enol silyl ethers is promoted by addition of chiral Lewis acids. Through coordination of aldehyde oxygen to the Lewis acids containing an Al, Eu, or Rh atom (286), the prochiral substrates are endowed with high electrophilicity and chiral environments. Although the optical yields in the early works remained poor to moderate, the use of a chiral (acyloxy)borane complex as catalyst allowed the erythro-selective condensation with high enan-tioselectivity (Scheme 119) (287). This aldol-type reaction may proceed via an extended acyclic transition state rather than a six-membered pericyclic structure (288). Not only ketone enolates but ester enolates... 

Diastereoselective Michael additions of enolates, prepared from the chiral amides (127) and (128), to prochiral a.p-unsaturated esters were utilized in the synthesis of (+)-dehydroiridodiol (129) and its isomer (130 Scheme 49).143... 

Significant progress has been made on the asymmetric Pd-catalyzed aliylic alkylation of prochiral enolates, with a number of ligands now available that provide products with high ee. Trost was the first to demonstrate that high enantiomeric excesses were capable with ketoester substrates [29] now asymmetric aliylic alkylation of ketoesters and simple ketone substrates has been achieved in several more cases. Table 4 summarizes the ligands, substrates, and ee for recent examples. 

Recently it has been reported that the catalytic isomerization of allylic alcohols is promoted by [Rh(diphosphine)(solvent)2]+ at 25°C yields synthetically useful quantities of the corresponding simple enols and that the transformation of allylic alcohols to enols and thereby to ketonic products proceeds catalytically via hydrido-7t-allylic and hydrido-7t-oxy-allylic intermediates, respectively [20]. Consistently observed, enantioselection has been in the process of conversion of a prochiral enol to a chiral aldehyde. Thus, the prochiral substrate 32 is transformed to the optically active aldehyde 34 with 18% ee by using [Rh(BINAP)]+ catalyst (eq 3.13). Accordingly, this isomerization proceeds via a different mechanism from that of the isomerization of allylamine. For the reaction mechanism of the... 

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