Chiral alcohols from ketones

Another possibility for asymmetric reduction is the use of chiral complex hydrides derived from LiAlH. and chiral alcohols, e.g. N-methylephedrine (I. Jacquet, 1974), or 1,4-bis(dimethylamino)butanediol (D. Seebach, 1974). But stereoselectivities are mostly below 50%. At the present time attempts to form chiral alcohols from ketones are less successful than the asymmetric reduction of C = C double bonds via hydroboration or hydrogenation with Wilkinson type catalysts (G. Zweifel, 1963 H.B. Kagan, 1978 see p. 102f.). 

Enantioselective organic synthesis using modified skeletal catalysts has wide application in areas such as pharmaceutical production for example, synthesis of chiral alcohols from ketones [90], which is described in detail elsewhere in this book. 

Asymmetric catalytic reduction reactions represent one of the most efficient and convenient methods to prepare a wide range of enantiomerically pure compounds (i.e. a-amino acids can be prepared from a-enamides, alcohols from ketones and amines from oximes or imines). The chirality transfer can be accomplished by different types of chiral catalysts metallic catalysts are very efficient for the hydrogenation of olefins, some ketones and oximes, while nonmetallic catalysts provide a complementary method for ketone and oxime hydrogenation. 

The formation of chiral alcohols from carbonyl compounds has been fairly widely studied by reactions of aldehydes or ketones with organometallic reagents in the presence of chiral ligands. Mukaiyama et al. 1081 obtained excellent results (up to 94% e.e.) in at least stoichiometric addition of the chiral auxiliary to the carbonyl substrate and the organometallic reagent. 

Yeast reductions have provided the synthetic organic chemist with highly versatile methods to prepare chiral alcohols from prochiral ketones of which Saccharomyces cerevisiae (baker s yeast) is the most commonly used biocatalyst. In addition to prochiral ketone reductions, hundreds of... 

Several methods promoted by a stoichiometric amount of chiral Lewis acid 38 [51] or chiral Lewis bases 39 [52, 53] and 40 [53] have been developed for enantioselective indium-mediated allylation of aldehydes and ketones by the Loh group. A combination of a chiral trimethylsilyl ether derived from norpseu-doephedrine and allyltrimethylsilane is also convenient for synthesis of enan-tiopure homoallylic alcohols from ketones [54,55]. Asymmetric carbonyl addition by chirally modified allylic metal reagents, to which chiral auxiliaries are covalently bonded, is also an efficient method to obtain enantiomerically enriched homoallylic alcohols and various excellent chiral allylating agents have been developed for example, (lS,2S)-pseudoephedrine- and (lF,2F)-cyclohex-ane-1,2-diamine-derived allylsilanes [56], polymer-supported chiral allylboron reagents [57], and a bisoxazoline-modified chiral allylzinc reagent [58]. An al-lyl transfer reaction from a chiral crotyl donor opened a way to highly enantioselective and a-selective crotylation of aldehydes [59-62]. Enzymatic routes to enantioselective allylation of carbonyl compounds have still not appeared. 

Chapter 64 Enzymatic Reduction A Chiral Alcohol from a Ketone... 

Other selected examples are summarized in Table 1-10. In addition to aldehydes, both cyclic and acyclic ketones can be reduced equally well. jf c-Phenethyl alcohol (59, R=Ph) as hydride source works more effectively than i-PrOH. Based on this finding, the asymmetric MPV reduction of unsymmetrical ketones [63] with chiral alcohol in the presence of catalyst 58 was examined. Treatment of 2-chloroacetophenone (60) with optically pure (f )-(-t-)-sec-phenethyl alcohol (1 equiv) under the influence of catalytic 58 afforded (5)-(-t)-2-chloro-1 -phenyletha-nol (61) with moderate asymmetric induction (82%, 54% ee). Switching chiral alcohols from (/ )-(-f)-sec-phenethyl alcohol to (/ )-(-i-)-a-methyl-2-naphthalene-methanol and (f )-(-H)- fcc-o-bromophenethyl alcohol further enhanced the optical yields of 61 in 70 and 82% ee, respectively [62]. 

Yeast reductions have shown great versatility by the synthetic organic chemist to prepare chiral alcohols from prochiral ketones, most of which have used Sac-charomyces cerevisiae (Baker s yeast). In addition to prochiral ketone reductions, hundreds of other examples of yeast reductions have been cited in the literature using a variety of substrates such as P-keto esters, [l-dikctones, and analogs such as sulfur and nitrogen-containing compounds [49-52]. Examples of yeast reductions used to prepare some important chiral intermediates as reported by several pharmaceutical companies are given in this section. 

A route to chiral alcohols from enones relies on stereoselective hydride transfer (Meerwein-Ponndorf-Verley reduction) from the isobomeol moiety after the substrates are attached to the monoterpene skeleton through Michael reaction with a 10-thiol group. Aromatic ketones are reduced by the system of t-BuOK- -PrOH and 91. ... 

The use of the chiral aminoborane (24) for the asymmetric synthesis of alcohols from ketones shows promise optical yields are in the range 14—23% for the three ketones tested. Stereoselective reduction of acetophenone and isobutyl methyl ketone has been observed on addition of the chiral phase-transfer catalyst (25) (derived from L-ephedrine) to sodium borohydride and the ketone in aqueous dichloromethane. ... 

Table 6.7 Production of chiral alcohols from various ketones by coli biocatalysts [10].

Alcohol dehydrogenase-catalyzed reduction of ketones is a convenient method for the production of chiral alcohols. HLAD, the most thoroughly studied enzyme, has a broad substrate specificity and accommodates a variety of substrates (Table 11). It efficiendy reduces all simple four- to nine-membered cycHc ketones and also symmetrical and racemic cis- and trans-decalindiones (167). Asymmetric reduction of aUphatic acycHc ketones (C-4—C-10) (103,104) can be efficiendy achieved by alcohol dehydrogenase isolated from Thermoanaerohium hrockii (TBADH) (168). The enzyme is remarkably stable at temperatures up to 85°C and exhibits high tolerance toward organic solvents. Alcohol dehydrogenases from horse Hver and T. hrockii... 

Closely related to the concept of chirality, and particularly important in biological chemistry, is the notion of prochirality. A molecule is said to be prochiral if can be converted from achiral to chiral in a single chemical step. For instance, an unsymmetrical ketone like 2-butanone is prochiral because it can be converted to the chiral alcohol 2-butanol by addition of hydrogen, as we ll see in Section 17.4. 

The reduction of ketones, aldehydes, and olefins has been extensively explored using chemical and biological methods. As the latter method, reduction by heterotrophic microbes has been widely used for the synthesis of chiral alcohols. On the contrary, the use of autotrophic photosynthetic organisms such as plant cell and algae is relatively rare and has not been explored because the method for cultivation is different from that of heterotrophic microbes. Therefore, the investigation using photosynthetic organisms may lead to novel biotransformations. 

OS 70] [R 25] [P 51] The temperature of a lithiation step was raised from -78 °C (batch) to -15 °C (micro reactor) without losing selectivity [83]. The temperatare of the subsequent alkylation of a ketone to a chiral alcohol could also be increased from -60 °C (batch) to 0 °C (micro reactor). 

Manufacture of ruthenium precatalysts for asymmetric hydrogenation. The technology in-licensed from the JST for the asymmetric reduction of ketones originally employed BINAP as the diphosphine and an expensive diamine, DAIPEN." Owing to the presence of several patents surrounding ruthenium complexes of BINAP and Xylyl-BINAP, [HexaPHEMP-RuCl2-diamine] and [PhanePHOS-RuCl2-diamine] were introduced as alternative catalyst systems in which a cheaper diamine is used. Compared to the BINAP-based systems both of these can offer superior performance in terms of activity and selectivity and have been used in commercial manufacture of chiral alcohols on multi-100 Kg scales. 

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... 

Two interesting yeast carbonyl reductases, one from Candida magnoliae (CMCR) [33,54] and the other from Sporobolomyces salmonicolor (SSCR) [55], were found to catalyze the reduction of ethyl 4-chloro-3-oxobutanoate to give ethyl (5)-4-chloro-3-hydroxybutanoate, a useful chiral building block. In an effort to search for carbonyl reductases with anti-Prelog enantioselectivity, the activity and enantioselectivity of CMCR and SSCR have been evaluated toward the reduction of various ketones, including a- and /3-ketoesters, and their application potential in the synthesis of pharmaceutically important chiral alcohol intermediates have been explored [56-58]. 

The usefulness of the carbonyl reductase from Candida magnoliae as an enzyme catalyst in the synthesis of chiral alcohol intermediates has been demonstrated by carrying out the reduction of several ketones on a preparative scale [56]. The isolated yields and enantiomeric excess of the product alcohols are summarized in Table 7.1, from which it can be seen that these chiral alcohols were obtained in essentially optically pure forms in excellent yields. These chiral alcohols are important intermediates in the synthesis of pharmaceuticals and agrichemicals. For example, optically active 2-hydroxy-3-methylbutyrate is an important chiral synthon... 

In an effort to develop easy-to-use ketoreductase toolbox , we have surveyed the activity and enantioselectivity of a collection of ketoreductases (KRED) from various sources toward the reduction of a variety of ketones [90,91]. These studies served as a useful guideline for developing enzymatic processes for the production of optically pure chiral alcohols. For example, several chiral chlorohydrins of pharmaceutical importance were synthesized in both enantiomeric forms using the enzymes in this ketoreductase collection (Table 7.2) [92]. Further applications of this collection and other commercially available ketoreductases can be found in a recent review [9]. 

Asymmetric hydrogenation of ketones is one of the most efficient methods for making chiral alcohols. Ru-BINAP catalysts are highly effective in the asymmetric hydrogenation of functionalized ketones,54,55 and this may be used in the industrial production of synthetic intermediates for some important antibiotics. The preparation of statine 65 (from 63b R = i-Bu) and its analog is one example (Scheme 6-28).56 Table 6-6 shows the results when asymmetric hydrogenation of 63 catalyzed by RuBr2[(R)-BINAP] yields threo-64 as the major product. 

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