Chiral alcohols from aldehydes

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. 

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]. 

Diorganozinc compds.jtitanium tetraisopropoxidej chiral 1,2-di (sulfonylamino ) cyclohexanes Sec. alcohols from aldehydes ... 

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

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. 

In contrast to phenolic hydroxyl, benzylic hydroxyl is replaced by hydrogen very easily. In catalytic hydrogenation of aromatic aldehydes, ketones, acids and esters it is sometimes difficult to prevent the easy hydrogenolysis of the benzylic alcohols which result from the reduction of the above functions. A catalyst suitable for preventing hydrogenolysis of benzylic hydroxyl is platinized charcoal [28], Other catalysts, especially palladium on charcoal [619], palladium hydride [619], nickel [43], Raney nickel [619] and copper chromite [620], promote hydrogenolysis. In the case of chiral alcohols such as 2-phenyl-2-butanol hydrogenolysis took place with inversion over platinum and palladium, and with retention over Raney nickel (optical purities 59-66%) [619]. 

Some enantiomerically pure substituted 2-oxazolidinones are excellent as chiral auxiliaries. From the pioneering studies 2 conducted in the early 1980 s of the uses of such auxiliaries has emerged what is perhaps the most widely used method today for the preparation of enantiomerically highly enriched a-alkylalkanoic acids, alcohols and aldehydes, that is, the alkylation of enolates from chiral 3-acylated 2-oxazolidinones followed by auxiliary removal2 59. The early work has been reviewed60-62. These enantiomerically pure cyclic imide auxiliaries have been used not only for alkylations but also in a plethora of a-functionalization reactions, such as diastereoselective aldol, a-hydroxylation, a-amination and Diels-Alder reactions and these are discussed elsewhere in this volume. 

The high synthetic utility of alcohols 38 stems from the fact that terminal alkynes are among the most versatile functional groups for the further elaboration of a carbon skeleton. Asymmetric synthesis of alcohols 38 from aldehydes with the concurrent formation of the two stereogenic C atoms has been accomplished mainly by two methods. The first features synthesis of chiral nonracemic allenylmetal compounds from the corresponding chiral nonracemic propargyl alcohols and addition of the former to aldehydes [26] and the second method in-... 

Synthesis of the enantiomerically pure (5)-chroman-2-carbaldehyde (257) follows a similar route to the above, but the chirality is introduced through the ketone (256) (82CC205). A particularly interesting feature of this synthesis is the derivation of the diol (255) from 2-methyl-3-(2-furyl)propenal using fermenting baker s yeast. Furthermore, the fermentation also produces the chiral alcohol (258), a source of the C15 unit which is the second component along with the aldehyde (257) in an a-tocopherol synthesis. 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Two principal approaches to the synthesis of an optically pure chiral secondary or tertiary alcohol from the reaction of an organometallic reagent with an aldehyde or ketone respectively are of current interest. In the first approach an alkyllithium or dialkylmagnesium is initially complexed with a chiral reagent which then reacts with the carbonyl compound. In this way two diastereo-isomeric transition states are generated, the more stable of which leads to an enantiometic excess of the optically active alcohol. This approach is similar in principle to the asymmetric reductions discussed in Section 5.4.1 (see also p. 15). Two chiral catalysts may be noted as successful examples, (10) derived... 

Atorvastin (Lipitor, 13.40) is a cholesterol-lowering drug that has been synthesized as a single enantiomer through use of a chiral auxiliary (Scheme 13.6).16 Ester 13.36 contains the auxiliary, a chiral alcohol. Deprotonation of the ester forms an enolate (13.37). The enolate then attacks an aldehyde. The asymmetry of the stereocenter on the auxiliary causes the reaction to favor stereoisomer 13.38 over 13.39. Several recrystallizations are required to obtain 13.38 in high enantiomeric excess. Cleavage of the auxiliary from 13.38 and further manipulations of the side-chain afford atorvastin. 

Dehydrogenases responsible for hydrogen transfer between substrates possess NAD+ (nicotinamide) as the coenzyme, owing to which chiral alcohols are formed from ketones and aldehydes. 

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. 

Oxocarbenium ions bearing a chiral auxiliary are useful for asymmetric allylation with 10. For example, oxocarbenium ions generated from aldehydes and homochiral Me3Si ether 15 are allylated with high diastereoselectivity (Scheme 104,104a,104b rp e resultant homoallyl ethers can easily be converted into homoallyl alcohols without epimerization. This two-step procedure is applicable to enantioselective allylation of ketones.105,1053... 

Aldehydes, ketones, and acetals react with allyltrimethylsilane in the presence of a catalytic amount of BiX3 (X = C1, Br, OTf) to give homoallyl alcohols or homoallyl alkyl ethers (Equation (52)).91-93 The BiX3-catalyzed allylation of aldehydes and sequential intramolecular etherification of the resulting homoallylic silyl ethers are involved in the stereoselective synthesis of polysubstituted tetrahydropyrans (Equation (53)).94,95 Similarly, these Lewis acids catalyze the cyanation of aldehydes and ketones with cyanotrimethylsilane. When a chiral bismuth(m) catalyst is used in the cyanation, cyanohydrines are obtained in up to 72% ee (Equation (54)). a-Aminonitriles are prepared directly from aldehydes, amines, and cyanotrimethysilane by the BiCl3-catalyzed Strecker-type reaction. 

With the exception of the diol 9, that was obtained from the corresponding aldehyde in up to 35% yield, most of the chiral diols mentioned above were isolated in yields of only 20-25%. The formation of the acyloin-type condensation products is in competition with the much more efficient reduction of the carbonyl carbon and saturation of the double bond of the unsaturated aldehydes that were used as substrates. We became interested in the mode of reduction of particular aldehydes such as 54-56 (Scheme 8) in a study of the total synthesis of natural a-tocopherol (vitamin E) (23). We expected to obtain chiral alcohols that would be useful for conversion into natural isoprenoids from the reduction of the a-double bond of the above aldehydes. Indeed, 54-56 afforded up to 75% yield of the saturated carbinols 57-59 by treatment with yeast. Whereas the ee of 57 and 58 was ca 85%-90%, that of 59 is 99%, as shown by NMR experiments on the (-)-MTPA derivative (24). The synthetic significance of carbinol 59 was based on the structural unit present in natural isoprenoids (see brackets in structural formulas). This protected synthon can be unmasked by ozonolysis, as indicated by the high yield conversion of 59 into (S)-(-) -3-methyl-y-butyrolactone 60 (Scheme 9). Product 59 is a bifunctional chiral intermediate which does not need protective manipulation in that... 

Chiral a-methyl aldehydes. Reaction of optically active 2,3-epoxy alcohols with AI(CH,)i results in a mixture of two diols that arc not separable by conventional chromatography. However, the 1,2-diol is oxidized by NaI04 to a chiral a-methyl aldehyde, which is easily separated from the 1,3-diol. 

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