Enantioselective Hydrogenation of Alkenes

The pivotal role of natural a-amino acids among a myriad of biologically active molecules is widely appreciated, and is of particular importance in the pharmaceutical industry. Unnatural a-amino acids also have a prominent position in the development of new pharmaceutical products. It has been shown that substitution of natural a-amino acids for unnatural amino acids can often impart significant improvements in physical, chemical and biological properties such as resistance to proteolytic breakdown, stability, bioavailability, and efficacy. One of the many synthetic methods available for the production of enantiomerically enriched a-amino acids is the metal-catalyzed enantioselective reduction of a-de-hydroamino acid derivatives [90]. 

The parent DuPhos and BPE ligands exhibit excellent enantioselectivities routinely in excess of 95% with the majority of model a-dehydroamino acid substrates (Table 24.1) [4a, 8, 12, 13, 20, 90]. High molar SCRs (in the order of 1000 1), as well as TOFs in excess of 1000 h 1, are indicative of the high catalyst activity and productivity typically found with DuPhos and BPE systems with these simple substrates. Burk reported that in the enantiomeric hydrogenation 

UlluPHOS [43, 44], catASium M [48, 95], Kephos [45, 96] and Butiphane [97] - four ligand systems which possess larger P-Rh-P bite angles than DuPhos [44, 46, 97] - all achieved enantioselectivities 95% when used in the hydrogenation of some model substrates. Much importance has been attached to P-Rh-P bite angles larger than the parent DuPhos system. It is believed that the pos- 

Substrate Ligand SCR Reaction conditions a) TON TOF [h-1] % ee (config.) Refer- ence(s) 

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Table 6.18 Enantioselective hydrogenation of alkenes catalyzed by Group III and lanthanide complexes.

This chapter describes, from an historic perspective, the development of ligands and catalysts for enantioselective hydrogenations of alkenes. There is no in-depth discussion of the many ligands available as the following chapters describe many of these, as well as their specific applications. The purpose here is to provide an overall summary and perspective of the area. By necessity, a large number of catalyst systems have not been mentioned. The discussion is also limited to the reductions of carbon-carbon unsaturation. In almost all cases, rhodium is the transition metal to catalyze this type of reduction. In order to help the reader, the year of the first publication in a journal has been included in parentheses under each structure. 

Enantioselective Hydrogenation of Alkenes with Ferrocene-Based Ligands... 

Enantioselective Hydrogenation of Alkenes in Two-Phase Aqueous Systems... 

Table 38.2 Enantioselective hydrogenation of alkenes in aqueous-organic two-phase systems. 

Table 1 Enantioselective hydrogenation of alkenes 2-4 with complexla ...

Table 2 Enantioselective hydrogenation of alkenes 11-16 with complexes5 -10...

Enantioselective Hydrogenation of Alkenes. (R,S,R,S)-Mc-PennPhos has been employed as catalyst in combination with Rh(I) for enantioselective hydrogenation of alkene carbon-carbon double bonds in a variety of substrates. A representative sampling of these asymmetric hydrogenations is shown in Table 1 Chang-... 

Finally, (R)-. -[ R)-1-phenylethyl]-2-quinuclidinecarboxamide (11) is mentioned, which can be considered as a synthetic analog of the cinchona alkaloids. The compound (as well as its diastereomer) is obtained from 2-quinuclidinecarboxylic acid (resolved with dibenzoyltartaric acid9) by reaction of the acid chloride with (/ )- -phenylethylamine1 °. It has been used as a chiral ligand for cobalt(II) in enantioselective hydrogenations of alkenes (Section D.2.5.1.2.1.3.). 

Simple phosphinite 178 afforded high enantiomeric excess in Pd-catalysed alkylation of allylic acetates <01TL5553>, and enantioselective hydrogenation of alkenes <01AG(E)4445>. 

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