Metalation enantiomeric purity

The remarkable stereospecificity of TBHP-transition metal epoxidations of allylic alcohols has been exploited by Sharpless group for the synthesis of chiral oxiranes from prochiral allylic alcohols (Scheme 76) (81JA464) and for diastereoselective oxirane synthesis from chiral allylic alcohols (Scheme 77) (81JA6237). It has been suggested that this latter reaction may enable the preparation of chiral compounds of complete enantiomeric purity cf. Scheme 78) ... 

Enantiometrically pure alcohols are important and valuable intermediates in the synthesis of pharmaceuticals and other fine chemicals. A variety of synthetic methods have been developed to obtain optically pure alcohols. Among these methods, a straightforward approach is the reduction of prochiral ketones to chiral alcohols. In this context, varieties of chiral metal complexes have been developed as catalysts in asymmetric ketone reductions [ 1-3]. However, in many cases, difficulties remain in the process operation, and in obtaining sufficient enantiomeric purity and productivity [2,3]. In addition, residual metal in the products originating from the metal catalyst presents another challenge because of the ever more stringent regulatory restrictions on the level of metals allowed in pharmaceutical products [4]. An alternative to the chemical asymmetric reduction processes is biocatalytic transformation, which offers... 

It is now clear that pure pheromones can be synthesized in quantity. The problem is how to prepare them simply and efficiently. New synthetic methodologies are always welcome to improve the existing syntheses. Organoborane reactions and organotransition metal chemistry contributed much to improve the efficiency of carbon-carbon bond formation, while asymmetric epoxidations and dihydroxylations as well as enzymatic reactions greatly improved the enantiomeric purity of synthetic pheromones. 

The enantioselective synthesis of an allenic ester using chiral proton sources was performed by dynamic kinetic protonation of racemic allenylsamarium(III) species 237 and 238, which were derived from propargylic phosphate 236 by the metalation (Scheme 4.61) [97]. Protonation with (R,R)-(+)-hydrobcnzoin and R-(-)-pantolactone provided an allenic ester 239 with high enantiomeric purity. The selective protonation with (R,R)-(+)-hydrobenzoin giving R-(-)-allcnic ester 239 is in agreement with the... 

A tremendous number of transformations of allenes have been reported owing to their high jt-coordination ability towards transition metals. Among them, intramolecular cycloaddition reactions of allenes, in particular, appear to be a practical means of carbon-carbon bond formation in a complicated system. The allenic moiety, however, should be precisely designed for the synthetic purpose of more complex frameworks. A formidable challenge is the synthesis of diversely functionalized allenes of high chemical and/or enantiomerical purity. 

One of the most versatile methodologies of EPC synthesis of allenes is the chirality transfer reaction which involves highly stereoselective, mechanism-controlled, metal-mediated propyn-yl-allenyl transpositions. Of these, the organocopper(l)-mediated reactions are especially useful and provide a relatively straightforward route to a broad variety of allenes of high enantiomeric purity. 

Due to the unique SE2 -front alkylation of metalated SAMP-hydrazones, the absolute configuration of the alkylation products is determined by the geometry of the azaenolate C—C double bond. Thus a uniform C—C geometry is essential in order to achieve high enantiomeric purities. 

Enantioselective alkylation of ketones. Chiral imines prepared from cyclic ketones and 1 on metalation and alkylation are converted to chiral 2-alkyleyclo-alkanones in 87-100% enantiomeric purity.1 The high cnantioselectivity is dependent on chelation of the lithium ion in the anion by the methoxyl group, which results in a rigid structure. 

In ordinary reagent- or catalyst-based enantioselective reactions of prochiral substrates (equations 4 and 5, respectively), 100% enantiomeric purity of the chiral source is assumed, and the major concern is the efficiency of the chirality transfer from the chiral source to the substrate, namely, optical yield. In some special cases, however, a chiral metal complex can even amplify chirality (equation 6). A catalyst that is itself only partially resolved may form a chiral product with very high enantiomeric purity (24) (Chapter 5). 

When 1 is added to a solution of a mixture of enantiomers, A and A, it associates differently with each of the two components to produce the diastereo-meric complexes A+ 1 and A 1. The nmr spectrum of the mixture then shows shift differences that are large compared to the uncomplexed enantiomers (because of the paramagnetic effect of the europium) and normally the resonances of the A+ 1 complex will be distinct from those of the A 1 complex. An example of the behavior to be expected is shown in the proton nmr spectrum (Figure 19-4) of the enantiomers of 1-phenylethanamine in the presence of 1. Although not all of the resonances are separated equally, the resolution is good for the resonances of nuclei closest to the metal atom and permits an estimate of the ratio of enantiomers as about 2 1 and the enantiomeric purity as 33%. 

The chiral bicyclic phosphines 5 (and in particular 5a [7b]) are currently the most active phosphorus-based acylation catalysts, enabling use of low reaction temperatures. Under these conditions (i.e. —40 °C) selectivity factors as high as 370-390 were achieved (Scheme 12.2). This is the best selectivity factor ever reported for metal-free, non-enzymatic kinetic resolution. As a consequence, very good enantiomeric purity of both the isobutyric esters 7 and the remaining alcohols 6 was obtained, even at substrate conversions approaching 50% (Scheme 12.2) [7, 8],... 

While the newly developed Brpnsted acid catalyzed Nazarov reaction primarily generates the cfv-cyc I ope n tcnones, the asymmetric metal catalyzed variations described so far often provide the /ran.v-producl (Liang et al. 2003 Aggarwal and Belfield 2003 Liang and Trauner 2004). To demonstrate that a route to these isomers is also possible we effectively isomerized the cyclopentenone cis-32a to the corresponding cyclopentenone trans-32a without loss of enantiomeric purity (Scheme 8). 

There are many examples of the asymmetric and diastereoselective hydroxylation of metal enolates using the enantiomerically pure camphor-derived A -sulfonyloxaziridines (- -)-146 and (+)-202, commercially available in both enantiomerically pure forms <20030R1>. The enantiomeric purity of the a-hydroxy products is good to excellent and can be obtained in both enantiomeric forms, as the absolute configuration of the oxaziridine controls the stereoinduction. Examples are given in Table 21. 

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