Preparation of optically active secondary alcohols

Microbial reduction of ketones is a useful method for the preparation of optically active secondary alcohols. Recently, both enantiomers of secondary alcohols were prepared by reduction of the corresponding ketones with a single microbe.Thus, reduction of aromatic ketones with Geotrichum candidum IFO 5767 afforded the corresponding 5-alcohols in an excellent ee when Amberlite XAD-7, a hydro-phobic polymer, was added to the reaction system the same microbe afforded... 

During the past two decades the homogeneous and heterogeneous catalytic enan-hoselective addition of organozinc compounds to aldehydes has attracted much attention because of its potential in the preparation of optically active secondary alcohols [69]. Chiral amino alcohols (such as prolinol) and titanium complexes of chiral diols (such as TADDOL and BINOL) have proved to be very effective chiral catalysts for such reactions. The important early examples included Bolm s flexible chiral pyridyl alcohol-cored dendrimers [70], Seebach s chiral TADDOL-cored Frechet-type dendrimers [28], Yoshida s BINOL-cored Frechet-type dendrimers [71] and Pu s structurally rigid and optically active BlNOL-functionalized dendrimers [72]. All of these dendrimers were used successfully in the asymmetric addition of diethylzinc (or allyltributylstannane) to aldehydes. 

Two research groups have described similar approaches towards the preparation of optically active secondary alcohols via nucleophilic... 

In summary, this organocatalytic alkylation of aldehydes and ketones is a promising route for preparation of optically active secondary and tertiary alcohols and is of general interest. Certainly, improvement of the asymmetric induction as well as applications of other nucleophiles will be the next major challenge in this field to make this synthetic concept competitive with alternative routes. 

OH - —NTfCHj. Primary or secondary alcohols are converted to protected secondary amines by this triflamide under Mitsunobu conditions (triphenylphos-phine, diethyl azodicarboxylate) in 70-86% yield. The reaction proceeds with inversion, and is useful for preparation of optically active secondary amines. 

An optically active acetylenic alcohol is an useful starting material to prepare various chiral compounds, because it has two functional groups. However, the optical resolution of an acetylenic alcohol by the diastereomeric method for its phthalic acid half-ester is complicated and successful only in a few cases,1 Recently, the preparation of optically active secondary acetylenic alcohol by the enantioselective reduction of ethynyl ketone or by the enantioselective addition of lithium acetylide to aldehyde has been reported. However, these methods are not applicable to the preparation of optically active tertiary acetylenic alcohols. 

It is well known that bakers yeast is capable of reducing a wide range of ketones to optically active secondary alcohols. A recent example involves the preparation of the (R)-alcohol (7) (97 % ee) (a key intermediate to ( norephedrine) from the corresponding ketone in 79 % yield1281. Other less well-known organisms are capable of performing similar tasks for instance, reduction of 5-oxohexanoic acid with Yamadazyma farinosa furnishes (R)-5-hydroxyhexanoic acid in 98 % yield and 97 % ee[29]. 

Chiral carbamates were prepared from racemic or optically active secondary alcohols A H and used to determine the induced diastereoselectivity of the osmium-catalyzed hydroxyamination reaction93. 

The asymmetric catalytic reduction of ketones (R2C=0) and imines (R2C=NR) with certain organohydrosilanes and transition-metal catalysts is named hydrosilylation and has been recognized as a versatile method providing optically active secondary alcohols and primary or secondary amines (Scheme 1) [1]. In this decade, high enantioselectivity over 90% has been realized by several catalytic systems [2,3]. Therefore the hydrosilylation can achieve a sufficient level to be a preparative method for the asymmetric reduction of double bond substrates. In addition, the manipulative feasibility of the catalytic hydrosilylation has played a major role as a probe reaction of asymmetric catalysis, so that the potential of newly designed chiral ligands and catalysts can be continuously scrutinized. 

Asymmetric syntheses based on chiral diamines. Optically active secondary alcohols are obtained by reduction of prochiral ketones with the chiral hydride reagent 1 prepared from lithium aluminium hydride and ( )-2-(N-substituted aminomethyl)-... 

Asymmetric synthesis of 8-functionalized optically active secondary alcohols was realized hy TarB-N02-catalyzed enantios-elective reduction of a-halo ketones to an intermediate terminal epoxide and sequential ring opening with various nucleophiles. Optically active st)Tene oxide was prepared from a-bromoacetophenone with NaBH4 and TarB-N02 in high yield and with high enantioselectivity (98% 3ueld and 94% ee). fi-Functionalized secondary alcohols could be obtained from the epoxides by nucleophilic attack under appropriate conditions (eq41). 

Reduction of ketones with Grignard reagents prepared from certain optically active halides yields optically active secondary alcohols. Mosher and his associates (Burrows et al., 1960 Birtwistle et al., 1964 and references therein) have studied both the qualitative and quantitative aspects of such asymmetric reductions. 

Optically active secondary alcohols have been prepared by the highly stereoselective reduction of ketone complexes or by the addition of Grignard reagents to substituted benzaldehyde complexes (Meyer and Dabard, 1972). The complexed benzaldehydes (LXXIV) and aromatic ketones (LXXV) are obtained from the corresponding acids (Meyer, 1973). Reduction of the ketones (LXXV) with KBH4 or reaction of the benzaldehyde complex (LXXIV) with the appropriate Grignard reagent leads to the same diastereo-... 

O-Methylmandelic acid has also been used to prepare esters with the aim of assigning the configuration of optically active alcohols by X-ray analysisl89. However, O-methylmandelates are mainly used for the establishment of absolute configurations of secondary alcohols by NMR. Problems associated with the ester formation are, therefore, covered in Section 4.3.4.1.1.3. 

Later, Brown and co-workers developed the method described above for the preparation of enantiomerically pure Ipc2BH (>99% ee) and applied the reagent in the asymmetric hydroboration of prochiral alkenes. Oxidation of the trialkylboranes provided optically active alcohols. In the case of cis-alkenes, secondary alcohols were obtained in excellent enantiomeric purity (Figure 1). The reaction is general for most types of cw-alkene, e.g. C(S-2-butene forms (R)-2-butanol in 98.4% ee, and c(s-3-hexene is converted to (R)-3-hexanol in 93% ee. However, the reagent is somewhat limited in reactions with unsymmetrical alkenes e.g. c/s-4-methyl-2-pentene yields 4-methyl-2-pentanol with 96% regioselectivity but only 76% ee (Figure 1). ... 

Asymmetric allyation of carbonyl compounds to prepare optically active secondary homoallyhc alcohols is a useful synthetic method since the products are easily transformed into optically active 3-hydroxy carbonyl compounds and various other chiral compounds (Scheme 1). Numerous successful means of the reaction using a stoichiometric amount of chiral Lewis acids or chiral allylmetal reagents have been developed and applied to organic synthesis however, there are few methods available for a catalytic process. Several reviews of asymmetric allylation have been pubHshed [ 1,2,3,4,5] and the most recent [5] describes the work up to 1995. This chapter is focussed on enantioselective allylation of carbonyl compounds with allylmetals under the influence of a catalytic amount of chiral Lewis acids or chiral Lewis bases. Compounds 1 to 19 [6,7,8,9,10,11,12,... 

Ishizaki and Hoshino prepared optically active secondary alkynyl alcohols (up to 95% e.e.) by the catalytic asymmetric addition of alkyl zinc reagents to both aromatic and aliphatic aldehydes. The chiral ligands studied were based on the pyridine scaffold. Of the three aryl substitutions studied, the a-napthyl derivative was found to be superior (Scheme 21.10). Mechanistically, it was proposed that (S)-l would react with dialkynyl zinc alkoxide A and ethyl zinc alkoxide B. Coordination of additional di-alkynyl zinc and alkynylethyl zinc with these alkoxides (A, B) would give C and D, respectively (Scheme 21.11). More bulky alkoxide (C) would have severe steric interactions with the alkynyl group and pyridine moiety, which might cause undesired conformational changes of the l-zinc complexes. Consequently, the enatioselectivity would be decreased. 

Preparation of cyclic ethers by intramolecular reactions of the primary (29 and 33) and the secondary alcohols (31 and 35) proceeds more easily using CS2CO3 or K3PO4, and binaphthyl-based monophosphine ligands VI-1, VI-9 [9], The five-, six-, and seven-membered cyclic ethers 30, 32, and 34 were prepared from the aryl chloride 31 and bromides 29 and 33. The benzoxazapine 36 was obtained without racemization of chiral alcohol by the cyclization of the optically active bromo alcohol 35. 

The method used for the optical resolution of acetylenic alcohols by complexation with brucine was found to be applicable to cyanohydrins ( ) 7 and some secondary alcohols ( ). Surprisingly, it was also found that racemic cyanohydrins are converted into one optically active isomer in yields of more than 50% in the presence of brucine. For example. When a solution of racemic (1.0 g) and an equimolar amount of brucine (2.1 g) in MeOH (2 ml) was kept in an uncapped flask at room temperature for 24 h, a brucine complex of (+) J crystallized out. Decomposition of the complex gave 100% ee (+)- in almost quantitative yield. This is not a simple optical resolution method but a novel preparation method of optically active cyanohydrins. This eantiomerization method can be applied to... 

Nokami reported a study that documents the asymmetric rearrangement of chiral oxonium ions (Scheme 16.19) [97]. These reactive intermediates are generated upon condensation of optically active alcohols and aldehydes. The requisite alcohol 158 was prepared by diastereoselective addition of cro-tylmagnesium chloride 156 to menthone 157. Subsequent treatment of the alcohol with an aldehyde such as PhSCH2CH2CHO under acidic conditions induced formation of 159. The ensuing [3,3]-rearrangement gave 160, and in situ hydrolysis of the chiral auxiliary afforded the secondary homoallylic alcohol with excellent optical purity (99% ee). 

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