Chiral alcohols hydrogenation

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.). 

N O Y O R I Chiral homogeneous hydrogenation Homogeneous chiral hydrogenation ol unsaluraled alcohols, or cartMxyNc acids, enamides, ketones in the presence ol BINAP Ru or Rh complex 8 as catalyst. 

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. 

In another context, chiral thioimidazolidine ligands have been successfully applied to the ruthenium-catalysed asymmetric hydrogen transfer of several aryl ketones by Kim et al., furnishing the corresponding chiral alcohols with high yields and enantioselectivities of up to 77% ee (Scheme 9.12). ... 

As another successful application of Noyori s TsDPEN ligand, Yan et al. reported the synthesis of antidepressant duloxetine, in 2008. Thus, the key step of this synthesis was the asymmetric transfer hydrogenation of 3-(dime-thylamino)-l-(thiophen-2-yl)propan-l-one performed in the presence of (5,5)-TsDPEN Ru(II) complex and a HCO2H TEA mixture as the hydrogen donor. The reaction afforded the corresponding chiral alcohol in both high yield and enantioselectivity, which was further converted in two steps into expected (5)-duloxetine, as shown in Scheme 9.17. 

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. 

On the other hand a direct hydrogen transfer through a Meerwein-Ponndorf mechanism, involving coordination of both the donor alcohol and the ketone to the copper site may also be considered. In this case, by using alcohols other than 2-propanol, we could expect some difference in stereochemistry. This would also imply the possibility of carrying out the enantioselective reduction of a prochiral ketone with a chiral alcohol as donor. 

Edegger, K., Gruber, C.C., Poessl, T.M. et al. (2006) Biocatalytic deuterium- and hydrogen-transfer using overexpressed ADH- A enhanced stereoselectivity and 2/7-labeled chiral alcohols. Chemical Communications, (22), 2402-2404. 

Inoue, K., Makino, Y. and Itoh, N. (2005) Production of (A l-chiral alcohols by a hydrogen-transfer bioreduction with NADH-dependent Leifsonia alcohol dehydrogenase (LSADH). Tetrahedron Asymmetry, 16 (15), 2539-2549. 

Among the most active catalysts for the asymmetric transfer hydrogenation of prochiral ketones and imines to chiral alcohols and amines are arene-ruthenium(II) amino-alcohol (or primary/ secondary 1,2-diamine)-based systems, with an inorganic base as co-catalyst, developed by Noyori139-141 and further explored by others (Scheme 27).142-145... 

A chiral BDPP-Rh complex is an efficient catalyst for the hydrogenation of 3-(2, 4 -dimethoxyphenyl)-3-phenyl-2-propenol. The chiral alcohol product, with enantiomeric excess up to 95%, has been used for the synthesis of chiral 4-methoxydalbergione (Scheme 6).251,251a... 

The development of Ir-chiral N,P ligand system opens another promising way for the hydrogenation of allylic alcohol and its derivatives. For example, a cationic Phox-Ir complex catalyzes the hydrogenation of ( )-2-methyl-3-phenyl-9-propen-l-ol in a highly enantioselective fashion.178 With 1 mol.% (5)-92-Ir catalyst, the hydrogenation proceeds completely to provide the chiral alcohol product in 96% ee. Under the same conditions, a para- Bu-substituted chiral alcohol derivative is obtained with 94% ee for the synthesis of lilial (Equation (59)). Heterocyclic N, P-ligand, HetPHOX 113, is also efficient for this reaction.191... 

BINAP system with excellent ee s. For example, 0// 0-bromoacetophenone can be converted into the corresponding chiral alcohol with 96% ee (Equation (72)). However, this type of substrate can be hydrogenated more effectively with the Ru/chiral phosphine/diamine system.279 Asymmetric hydrogenation of phenylthioketones has been realized with Ru catalysts. BINAP, MeO-BIPHEP,280 BDPP281 and Me-CnrPHOS,62c are efficient for this transformation (Table 17). 

One method of accessing chiral alcohols is through the enantioselective hydrogenation of the corresponding enol acetates. Despite this substrate class having similar structures to enamides, far fewer successful examples of this reaction... 

Besides the phosphite ligands based on BINOL, phosphite ligands based on bisphenol are also used in rhodium-catalyzed hydrogenation. These ligands are shown in Scheme 28.7 and consist of a bisphenol with different substituents on the 3,3, 5,5, and 6,6 -positions. The ligands without substituents on the 6,6 -positions are only fluxionally chiral. The use of readily available chiral alcohols (21 aa-21 aj) such as menthol in combination with bisphenol was thought to induce one of the bisphenol conformations in preponderant amounts [49]. The... 

Immobilized catalysts on solid supports inherently have benefits because of their easy separation from the products and the possibility of recycling. They are also expected to be useful for combinatorial chemistry and high-throughput experimentation. The polystyrene-bound BINAP/DPEN-Ru complex (beads) in the presence of (CH3)3COK catalyzes the hydrogenation of l -acetonaphthone with an SCR of 12 300 in a 2-propanol-DMF mixture (1 1, v/v) to afford the chiral alcohol in 97% ee (Fig. 32.35) [113]. This supported complex is separable... 

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