Diaryl methanols

The asymmetric formation of industrially useful diaryl methanols can be realized through either the addition of aryl nucleophiles to aromatic aldehydes or the reduction of diaryl ketones. The latter route is frequently the more desirable, as the starting materials are often inexpensive and readily available and nonselective background reactions are not as common. For good enantioselectivity, chemical catalysts of diaryl ketone reductions require large steric or electronic differentiation between the two aryl components of the substrate and, as a result, have substantially limited applicability. In contrast, recent work has shown commercially available ketoreductase enzymes to have excellent results with a much broader range of substrates in reactions that are very easy to operate (Figure 9.6). ... 

A large number of diaryl ketone substrates, including those listed in Table 9.3, have been reduced with high enantioselectivity with the protocol described here. Unlike analogous chemical catalysts, the commercially available biocatalysts displayed no dependence on ortho substitutions or electronic dissymmetry, and produced diaryl methanols with good to excellent ee values in nearly all cases. 

The synthesis of optically active diaryl methanols 27 is of particular synthetic value, since their core structure represents a molecular scaffold which is relevant to numerous biologically active compounds and pharmaceuticals possessing an-tihistaminic, anticholinergic, local-anesthetic, and laxative properties. Examples include neobenodine 28, orphenadrine 29, and carbinoxamine 30 [31]. 

Furthermore, it was recently shown, that enantiopure diaryl methanols can undergo stereospecific SN2-type substitution reactions with enolates at the (di)benzylic carbon affording 1,1-diarylalkyl derivatives (31 — 32 —> 33 Scheme 2.1.2.4). This discovery widened the preparative applicability of diaryl methanols significantly, and was used by Merck in the synthesis of selective PDE-IV inhibitors 34 and 35 [32]. 

Two strategies for the synthesis of enantiomerically enriched diaryl methanols 27 are apparent first, asymmetric reductions of the corresponding diaryl ketones 36 [33], and, second, enantioselective aryl transfer reactions to the respective benzaldehyde derivatives 37 (Scheme 2.1.2.5) [34, 35]. 

Our first results in this field were published in 1999 [13], when we reported that ferrocene 9 was capable of catalyzing the enantioselective addition of diphe-nylzinc to aromatic aldehydes, affording diaryl methanols with good to high enantioselectivities. For example, from the reaction between p-chlorobenzaldehyde 37a and diphenylzinc 7 in the presence of 5 mol% ferrocene 9 (at 0 °C), product 27a was obtained with 82% ee (Scheme 2.1.2.6). 

Moreover, when the reaction was performed with a multifunctional substrate, such as 4-acetyl-benzophenone (85), the yield in diaryl methanol was 1.3 times higher than that derived from the reduction of the acetyl group. On the other hand, when the non-imprinted polymer was used, the regioselectivity was reversed, with the yield of reduced acetyl being 1.7 times higher than the diarylmethanol. 

Catalytic asymmetric synthesis of enantiopure diaryl-methanols and -methylamines (important pharmaceutical intermediates) has been reviewed (76 references), focusing on (i) aryl transfers on to aryl-aldehydes and -imines and (ii) asymmetric reductions of diaryl-ketones and -ketoimines.284... 

Enantioface selection of prochiral diaryl ketones is generally difficult because electronically and sterically similar two aryl groups are attached to the carbonyl group. Overreduction of diaryl methanols to diaryl methanes is also another problem, but these problems are overcome by use of the Ru ternary catalyst system (Scheme 2.4b). Thus, by using (S,S)-20/KOC(CH3)3, 2-substituted benzophenones are quantitatively reduced to the diaryl methanols without any detectable diaryl methanes [102], With 3- or 4-substituted benzophenones, enantioselectivities are moderate. Benzoylferrocene is hydrogenated in the presence of trans-RuCl2 (S)-tol-binap (S)-daipen and a base to afford the S alcohol in 95% e.e. 

Enantiopure diaryl methanols (1) are important intermediates for the synthesis of biologically active compounds.[1] Here, a synthetic approach which employs aromatic aldehydes and readily accessible and commercially available aryl boronic acids is reported.[2,3] The catalysis with planar chiral ferrocene (2)[4] yields a broad range of optically active diaryl methanols with excellent enantioselectivities. Upon addition of DiMPEG (dimethoxy polyethyleneglycol) to the reaction mixture the enantioselectivity is increased. 

The reported procedure allows the transfer of aryl moieties to aromatic aldehydes affording diaryl methanols with excellent enantiomeric excesses in high yields (Table 8.2). It relys on the use of a readily available ferrocene catalyst and... 

SCHEME 8.26. Reaction of diaryl methanol derivatives with aldehydes published by Cozzi. 

Wu and coworkers have demonstrated the feasibility of decarboxylative 1,2-addition of carboxylic acids to aldehydes or imines for the efficient preparation of diaryl methanols and diaryl iV-tosyl amines, respectively (Scheme 22.10) [19]. Aliphatic aldehydes and ketones did not react under the conditions optimized for the aryl reagents. 

In synthetic contexts, thiyl radicals are known to engage in a number of useful reactions [191-198], including C-H bond abstraction [197, 199-203]. Recently, MacMillan has demonstrated the capacity of catalytically generated thiyl radicals to cleave the C-H bond of benzylic ethers for radical coupling reactions (Fig. 27) to form diaryl methanols (a) [204] or p-amino ethers (b) [205]. The light source is either a Blue LED or a Compact fluorescent lamp (CFL), as designated above. In both reactions, a wide variety of arene components and ether substitutions are tolerated to furnish a diverse set of products and only a catalytic amount of methyl thioglycolate is necessary to affect the desired C-H HAT event. In the formation of diaryl ethers (Fig. 27a), phosphate serves as the base, whereas the P-amino ether... 

Asymmetric reduction of prochiral diaryl ketones (33 34, Scheme 12) is an important chemical transformation due to the practical significance of the resulting diaryl methanol derivatives 34 for biochemical and pharmaceutical applications [24]. It is also a challenging problem due to the lack of sufficient stereochemical bias between the two aromatic groups and coupled with a lower reactivity of diaryl ketones compared to the related aryl alkyl analogues. Chan reported catalytic... 

Arylboronic acids can be added to electron-deficient aryl aldehydes in the presence of iron(III) chloride and 2-(di-/ert-butylphosphano)biphenyl as ligand (Scheme 4-321). The resulting diaryl methanols are obtained in moderate to excellent yield. ... 

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