Modern Methods for Asymmetric Hydrogenation of Ketones

Asymmetric methods for the hydrogenation of ketones constitute an emerging area in organic synthesis, of significant interest to industry (pharmaceutical, agrochemicals) as well as to academics. Chiral alcohols, and in particular chiral amino alcohols, play an important biological role and can be used as chiral auxiliaries.

I. Asymmetric Transfer Hydrogenation (ATH)

Due to the easy availability of hydrogen sources and simple experimental procedures, asymmetric transfer hydrogenation (ATH) has become more common as an alternative to asymmetric hydrogenation. The Lu and Wan research group from the Chinese Academy of Sciences (PRC) have recently reported on the ATH of ketones in water (Tetrahedron Lett. 2005, 46, 7341. DOI: 10.1016/j.tetlet.2005.08.129). The reduction of acetophenone (1) could be accomplished by utilizing [RuCl₂(p-cymene)₂] / ligand (a chiral amino alcohol) in water at room temperature (Scheme 1), with quantitative conversions and moderate to high enantioselectivity. Best results were obtained with ephedrine hydrochloride (5 gave optimal enantioselectivity 75% ee and 99.3% conversion).

Scheme 1 - Asymmetric transfer hydrogenation (ATH) of acetophenone (1) in water.

This group found that (-)-ephedrine hydrochloride, a stable, efficient and cost-effective ligand when combined with [RuCl₂(p-cymene)₂], is an efficient catalyst system for ATH with other ketones and gave excellent yields and good enantioselectivity (up to 83% ee).

This year, Wills and co-workers from the University of Coventry (UK) reported (Tetrahedron 2006, 62, 1864. DOI: 10.1016/j.tet.2005.11.036) on the AHT of cyclic and acyclic α,β-unsaturated ketones using η⁶-p-cymene/ruthenium (II) and η⁵-pentamethylcyclopentadienyl/rhodium (III) complexes as catalysts. Best results were obtained with the catalyst (R,R)-9 (up to 54% yield and up to 99% ee) (Scheme 2). While (1R,2S)-10 failed to catalyse the reduction of ketones 7 (R = OCH₂Ph, NHCO₂Me), both catalysts (R,R)-9 and (1R,2S)-10 failed when R = tBu, probably due to steric reasons. The catalyst (R,R)-11 showed less regioselectivity, and alcohol 8 (R = NHCO₂Me) was isolated in only 7% yield. Thus, the main products resulted from 1,4-reduction and the corresponding saturated carbamate derivatives.

Scheme 2 - Asymmetric transfer hydrogenation (ATH) of cyclic α,β-unsaturated ketones 7 catalysed by η⁶-p-cymene/ruthenium (II) and η5-pentamethylcyclopentadienyl/rodhium (III) complexes .

This group also investigated acyclic α,β-unsaturated ketones (Scheme 3). Ketones 12 (R = Me, Et) gave 13 in 75 and 90% conversion, while with a more bulky substituent (R=tBu) ketone 14 was the major product. These results showed that chemoselectivity decreased as the bulkiness of the alkyl group increased; however, the enantioselectivity of 13 increased.

Scheme 3 - Asymmetric transfer hydrogenation (ATH) of acyclic α,β-unsaturated ketones 12 with catalyst (R,R)-9.

II. Palladium-Catalysed Asymmetric Hydrogenation

Zhou and co-workers from the Chinese Academy of Sciences (PRC) (Org. Lett. 2005, 7, 3235. DOI: 10.1021/ol051007u) developed a novel and highly enantioselective (up to 92% ee), homogeneous palladium catalytic system using a Pd/phosphine complex in 2,2,2-trifluoroethanol (TFE). This group investigated a number of reaction conditions such as temperature, hydrogen pressure, solvent effect, Pd catalysts and several chiral ligands. The results showed that hydrogen pressure had no dramatic effect on ee, that the best solvent is TFE and that Pd(0) failed to give catalysis - indeed, the best catalyst is Pd(CF₃CO₂)₂.

Scheme 4 - Palladium catalysed asymmetric hydrogenation of phthalimide-protected amino ketones 17.

Several functionalized ketones 17 bearing both electron-rich and electron-deficient groups were hydrogenated to the corresponding amino alcohols with high enantiocontrol under optimized reaction conditions (Scheme 4). The ligand (R,R)-16 proved to be the most effective ligand.

III. Asymmetric Hydrogenation Using BINAP-type Ligands

Lin and Hu from University of North California have recently reported (Org. Lett. 2005, 7, 455. DOI: 10.1021/ol0474812) on the modification of the binaphthyl skeleton of BINAP and its application on the Ru-catalyzed asymmetric hydrogenation of phthalimide-protected amino ketones and 1,3-diaryl diketones with high enantioselectivity.

Figure 1 - Proposed structures for the precatalyst 19.

All precatalysts 19 (Figure 1) were able to perform the asymmetric hydrogenation of ketones 21 to amino alcohols 22 with high enantioselectivity (Scheme 5), under the conditions reported by Zang and co-workers (J. Am. Chem. Soc. 2004, 126, 1626. DOI: 10.1021/ja039153n). Higher enantioselectivity was obtained with 19 X = H and TMS, while X = P(O)(OEt)₂, Br, Ph and 1-hydroxycyclopentyl gave lower ees. The best result was achieved for the hydrogenation of 21 (R = Ph) with 19 X = TMS (99% ee). However, for X = Ph and Br the observed ees were lower than for BINAP (for the α-phthalimido ketone). The authors have successfully explored the use of the same precatalysts 19 (X = H and TMS) for the hydrogenation of 1,3-diaryl symmetrical and unsymmetrical ketones with up to 99% ee.

Scheme 5 - Ru-catalysed asymmetric hydrogenation of phthalimide-protected amino ketones 21 with 4,4’-substituted BINAP ligands.

The same authors reported on the use of 4,4´-disubstituted BINAPs for the Ru-catalyzed asymmetric hydrogenation of β-aryl β-ketoesters and aromatic ketones (Angew. Chem. Int. Ed. 2004, 43, 2501. DOI: 10.1002/anie.200353415). According to the authors, a plausible explanation for the observed higher enantioselectivity over the non-substituted BINAP is that the bulky substituents on the 4,4´-positions of BINAP generate repulsive interactions with the aryl group of the substrate in the disfavoured transition state.

Noyori and Ohkuma from Nagoya University reported on the asymmetric hydrogenation of tert-alkyl ketones using a BINAP/PICA (α-picolylamine) - Ru complex (J. Am. Chem. Soc. 2005, 127, 8288. DOI: 10.1021/ja052071+), a significant achievement considering the difficulties reported in the literature related to steric factors. A variety of reaction conditions were tested such as addition of base (KOtBu), pressure, time, substrate/catalyst ratio; ethanol turned to be the best solvent.

Ketones 23 (Scheme 6) were hydrogenated to the corresponding alcohols 24 with high enantioselectivity. Alcohol (S)-24 (R = Me) was obtained with 97% ee when catalyst (R)-25a was used, while with (S)-25a the alcohol (S)-24 (R = Me) was formed with 98% ee; both hydrogenations proceeded in 100% yield.

Scheme 6 - Asymmetric hydrogenation of tert-butyl ketones 23 using BINAP/PICA - Ru complex as catalyst.

In addition, this procedure is very carbonyl-selective, since high ees were obtained with no attack on the rings for R = 2-furyl and 2-thienyl; furthermore, no hydrogenation of the double bound occurred with R = (E)-CH=CHPh. Aromatic, heteroaromatic, aliphatic and olefinic tert-butyl ketones were hydrogenated with very high ee values, and exhibited similar enantiofacial selectivity. However, the authors underline the need for a careful choice of the reaction conditions to achieve a successful result.

The PICA ligand was shown to be essential for the observed enantioselectivity as compared to the results in the absence of PICA, due to its structural characteristics.