Carbonyl compounds asymmetric reduction

The Darzens-type products from a-halo sulfoxides and carbonyl compounds undergo reductive desulfurization by the action of butyllithium. This is a useful synthetic route to various epoxides. Yamakawa and coworkers disclosed a novel asymmetric synthesis of epoxides (109) using optically active 1-chlo-roalkyl p-tolyl sulfoxide (107). This method is most effective when the starting ketones are symmetrical, because only one diastereomer is then formed in the Darzens-type condensation (equation 26). 

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 prime functional group for constructing C-C bonds may be the carbonyl group, functioning as either an electrophile (Eq. 1) or via its enolate derivative as a nucleophile (Eqs. 2 and 3). The objective of this chapter is to survey the issue of asymmetric inductions involving the reaction between enolates derived from carbonyl compounds and alkyl halide electrophiles. The addition of a nucleophile toward a carbonyl group, especially in the catalytic manner, is presented as well. Asymmetric aldol reactions and the related allylation reactions (Eq. 3) are the topics of Chapter 3. Reduction of carbonyl groups is discussed in Chapter 4. 

Asymmetric reduction of carbonyl compounds can usually be achieved either through direct catalytic hydrogenation or by metal hydride reduction. It should be mentioned here that reduction of carbonyl compounds by catalytic hydrogenation may not be chemoselective. Other co-existing functional groups such as the C=C bond may also undergo hydrogenation. 

Boranes have opened the door to asymmetric reduction of carbonyl compounds. The first attempt at modifying borane with a chiral ligand was reported by Fiaud and Kagan,75 who used amphetamine borane and desoxyephedrine borane to reduce acetophenone. The ee of the 1-phenyl ethanol obtained was quite low (<5%). A more successful borane-derived reagent, oxazaborolidine, was introduced by Hirao et al.76 in 1981 and was further improved by Itsuno and Corey.77 Today, this system can provide high stereoselectivity in the asymmetric reduction of carbonyl compounds, including alkyl ketones. 

In the fourth and final chapter, Howard Haubenstock discusses asymmetric reduction of organic molecules. Within this general topic of wide and continuing interest, Haubenstock s chapter deals with chiral derivatives of lithium aluminum hydride, their preparation from suitable amino or hydroxy compounds, and their use in reducing carbonyl groups. Related reactions of the Meerwein-Ponndorf-Verley type or involving tri-alkylaluminum reagents are also presented. 

The asymmetric reduction of prochiral ketones to their corresponding enantiomerically enriched alcohols is one of the most important molecular transformations in synthetic chemistry (20,21). The products are versatile intermediates for the synthesis of pharmaceuticals, biologically active compounds and fine chemicals (22,23). The racemic reversible reduction of carbonyls to carbinols with superstoichiometric amounts of aluminium alkoxides in alcohols was independently discovered by Meerwein, Ponndorf and Verley (MPV) in 1925 (21—26). Only in the early 1990s, first successful versions of catalytic... 

Native ADH catalyzes the asymmetric reduction of carbonyl compounds to the corresponding R-configured alcohols using NADPHh-H as cofactor (Scheme 3.2.2). 

The field of organoboron chemistry pioneered by Brown [40] also provides a wealth of excellent transformations. Consider the asymmetric reduction of carbonyl compounds by Alpine-Borane [41]. Alpine-Borane is prepared by the following sequence ... 

The oxazoline-mediated asymmetric addition of Grignard reagents to carbonyl compounds and the asymmetric reduction of ketones have been examined as well. Optical purities vary from 0.5 to 25% in the former process, and from 0.5 to 65% in the latter reaction (74TL1333,1337,1341). 

Many other uses of a-sulfinyl carbanions are found in the literature, and in the recent past the trend has been to take advantage of the chirality of the sulfoxide group in asymmetric synthesis. Various ways of preparation of enantiopure sulfoxides have been devised (see Section 2.6.2) the carbanions derived from these compounds were added to carbonyl compounds, nitriles, imines or Michael acceptors to yield, ultimately, with high e.e. values, optically active alcohols, amines, ethers, epoxides, lactones, after elimination at an appropriate stage of the sulfoxide group. Such an elimination could be achieved by pyrolysis, Raney nickel or nickel boride desulfurization, reduction, or displacement of the C-S bond, as in the lactone synthesis reported by Casey [388]. 

A variety of macrocycles with asymmetric centers have been reported, examples of which are shown in (57) to (66). Chiral discrimination has been observed in the study of thiolysis of activated ester bonds with tetracysteinyl[18]crown-6 (67), e.g. Gly-L-Phe reacts up to 80 times faster than Gly-D-Phe with this ligand.231 The chiral macrocyclic ligand (66) is also capable of enantiomeric discrimination, by assisting in the selective reduction of carbonyl compounds with high optical yields.232,233... 

Sodium borohydride (160) was found to serve as a hydrogen donor in the asymmetric reduction of the presence of an a,pi-unsaturated ester or amide 162 catalyzed by a cobalt-Semicorrin 161 complex, which gave the corresponding saturated carbonyl compound 163 with 94-97% ee [93]. The [i-hydrogen in the products was confirmed to come from sodium borohydride, indicating the formation of a metal enolate intermediate via conjugate addition of cobalt-hydride species (Scheme 2.17). 

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... 

Asymmetric reduction of a,/ -unsaturated carbonyl compounds using chiral complexes (Section 5.4.1, p. 521) could feasibly lead to optically active allylic alcohols. Other reducing agents which have some merit of regioselectivity, but not stereoselectivity, are sodium cyanoborohydride,244 and sodium boro-hydride in the presence of lanthanide salts.245... 

In conclusion, this new organocatalytic direct asymmetric Mannich reaction is an efficient means of obtaining optically active //-amino carbonyl compounds. It is worthy of note that besides the enantioselective process, enantio- and diastereose-lective Mannich reactions can also be performed, which makes synthesis of products bearing one or two stereogenic centers possible. Depending on the type of acceptor or donor, a broad range of products with a completely different substitution pattern can be obtained. The range of these Mannich products comprises classic / -amino ketones and esters as well as carbonyl-functionalized a-amino acids, and -after reduction-y-amino alcohols. 

Shimoda K, Kubota N et al (2004) Asymmetric reduction of a,P-unsaturated carbonyl compounds with reductases from Nicotiana tabacum. Tetrahedron Asymmetry 15 2443-2446... 

Chiral (l-hydroxy esters are versatile synthons in organic synthesis, specifically in the preparation of natural products [62-64], The asymmetric reduction of carbonyl compounds using Baker s yeast has been demonstrated and reviewed... 

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