Asymmetric induction ketone hydrogenation

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

The results clearly show that these novel ligands are able to form a suitable asymmetric enviromnent around the metal resulting in high asymmetric induction. Their catalytic potential has been demonstrated in the highly enantioselective Rh-catalyzed hydrogenation of itaconates and a-enamides and Ru-catalyzed hydrogenation of p-functionalized ketone. 

Asymmetric hydrogenation of prochiral ketones,s Ketones substituted in the a- or (3-position by diverse polar groups, particularly OH,OR,NR2,COOR, can undergo highly enantioselective hydrogenation catalyzed by BINAP-Ru complexes. A key factor of asymmetric induction is undoubtedly chelation of the carbonyl group and the hetero atom to the Ru atom. 

Subsequently, List reported that although the method described above was not applicable to the reduction of a,P-unsaturated ketones, use of a chiral amine in conjunction with a chiral anion provided an efficient and effective procedure for the reduction of these challenging substrates [210]. Transfer hydrogenation of a series of cyclic and acyclic a,P-unsaturated ketones with Hantzsch ester 119 could be achieved in the presence of 5 mol% of valine tert-butyl ester phosphonate salt 155 with outstanding levels of enantiomeric control (Scheme 64). A simple mechanistic model explains the sense of asymmetric induction within these transformations aUowing for reliable prediction of the reaction outcome. It should also be noted that matched chirality in the anion and amine is necessary to achieve high levels of asymmetric induction. 

An early report of a promising level of asymmetric induction in the reduction of ketones by chiral PTC [62a] was disputed [26b,60c]. Several reviews concerning hydrogenation by enantioselective catalysis have appeared [5j-l]. 

Further reports on asymmetric synthesis in the presence of Cinchona alkaloids have been made.142 " For example, hydrogenation of methyl pyruvate with a platinum-alumina catalyst containing quinine gives (+)-(/ )-methyl lactate in 87% optical yield.1426 Asymmetric induction with optical yields up to 36 and 26% has been observed in the Michael addition of thiols and nitro-alkanes to ct/ -unsaturated ketones in the presence of quaternary salts derived from the Cinchona alkaloids.142"... 

The mode of asymmetric induction can be rationalized from the mechanism of the photopinacolization in the presence of aliphatic amines. The electron transfer from the amine to the excited triplet ketone furnishes charge transfer complex 5, from which a radical pair is formed by protoirtransfer. The weakly coordinated chiral amine seems to favor the dimerization of radical 6 from the si face leading to the (/ , ft)-enantiomer 3. The much lower selectivities observed with methanol as the cosolvent (3% ee at 27°C) indicate dipolar or hydrogen bonding interactions between the chiral diamine and the prochiral radical (Scheme 4). 

A similar selective oxidation can be carried out with tetrakis(triphenylphosphine)ihoditun(I) hydride and an a, >unsaturated ketone as hydrogen acceptor, in this case the use of an optically active phosphine provided an enantioselective synthesis, although the levels of asymmetric induction were rather low (Scheme 10). ... 

Precursor of Useful Chiral Ligands. OPEN is widely used for the preparation of chiral ligands. Organometallic compounds with these ligands act as useful reagents or catalysts in asymmetric induction reactions such as dihydroxylation of olefins, transfer hydrogenation of ketones and imines, Diels-Alder and aldol reactions, desymmetrization of meso-diols to produce chiral oxazolidinones, epoxidation of simple olefins, benzylic hydroxylation, and borohydride reduction of ketones, imines, and a,p-unsaturated carboxylates. ... 

Among the carbon electrophiles, carbonyl compounds [113,114] were first applied in the reaction with lithiated ferrocenylalkyl amines (Sect. 4.S.3.3 and Fig. 4-18). Analogously, carboxylic acids are obtained from CO2 [153]. The reactivity pattern of palladated ferrocenylalkyl amines with carbon electrophiles is somewhat different. Carbon monoxide in alcohols leads to the formation of esters of substituted ferrocenecarboxylic acids [124]. With prochiral alcohols, a moderate asymmetric induction is observed [154]. a, -Unsaturated ketones react with palladated ferrocenylalkyl amines not with addition to the carbonyl group, but with substitution of a hydrogen at the carbon—carbon double bond, allowing the introduction of longer side chains at the ferrocene ring (Fig. 4-27c) [124, 152]. 

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