Preparation of optically-active 3-pyrrolidinol and its derivatives from 1-benzoylpyrrolidinol by hydroxylation with Aspergillus sp. and stereo-selective esterification by a commercial lipase.

An effective preparation scheme for optically-active 3-pyrrolidinol and its derivatives based on biological transformation is proposed. Aspergillus sp. NBRC 109513 hydroxylated 1-benzoylpyrrolidine, yielding (S)-1-benzoyl-3-pyrrolidinol with 66 % ee. Kinetic resolution of 1-benzoyl-3-pyrrolidinol by Amano PS-IM lipase formed optically-active 1-benzoyl-3-pyrrolidinol with >99 % ee. (S)-1-Benzoyl-3-pyrrolidinol was successfully converted to 3-pyrrolidinol and its derivatives with by chemical reactions (>99 % ee).

Amide-transforming activity of Streptomyces: possible application to the formation of hydroxy amides and aminoalcohols.

To develop an efficient bioconversion process for amides, we screened our collection of Streptomyces strains, mostly obtained from soil, for effective transformers. Five strains, including the SY007 (NBRC 109343) and SY435 (NBRC 109344) of Streptomyces sp., exhibited marked conversion activities from the approximately 700 strains analyzed. These strains transformed diverse amide compounds such as N-acetyltetrahydroquinoline, N-benzoylpyrrolidine, and N-benzoylpiperidine into alcohols or N,O-acetals with high activity and regioselectivity. N,O-acetal was transformed into alcohol by serial tautomerization and reduction reactions. As such, Streptomyces spp. can potentially be used for the efficient preparation of hydroxy amides and aminoalcohols.

Chiral ruthenabicyclic complexes: precatalysts for rapid, enantioselective, and wide-scope hydrogenation of ketones.

A novel ruthenabicyclic complex with base shows excellent catalytic activity in the asymmetric hydrogenation of ketones. The turnover frequency of the hydrogenation of acetophenone reaches about 35,000 min(-1) in the best case, affording 1-phenylethanol in >99% ee. Several aliphatic and base-labile ketones are smoothly converted to the corresponding alcohols in high enantioselectivity. The catalytic cycle for this hydrogenation, in which the ruthenabicyclic structure of the catalyst is maintained, is proposed on the basis of the deuteration experiment and spectroscopic analysis data.

Oxo-tethered ruthenium(II) complex as a bifunctional catalyst for asymmetric transfer hydrogenation and H2 hydrogenation.

Newly developed oxo-tethered Ru amido complexes (R,R)-1 and their HCl adducts (R,R)-2 exhibited excellent catalytic performance for both asymmetric transfer hydrogenation and the hydrogenation of ketonic substrates under neutral conditions without any cocatalysts to give chiral secondary alcohols with high levels of enantioselectivity.

Direct asymmetric reductive amination.

Asymmetric reductive amination of beta-keto amides catalyzed by the chiral catalyst Ru(OAc)(2)((R)-dm-segphos) produces unprotected beta-amino amides with high yields and high enantioselectivities (94.7-99.5% ee). This "one-pot" methodology is general in substrate scope and has been successfully employed to produce sitagliptin with 99.5% ee and 91% assay yield. The excellent reaction efficiency is attributed to the remarkable tolerance to high concentrations of ammonium ion, the high chemoselectivity, and the high enantioselectivity (99.5% ee) of the Ru catalyst system.

Asymmetric hydrogenation of aryl ketones mediated by a copper catalyst.

[reaction: see text] A novel asymmetric hydrogenation protocol using a copper catalyst is reported. A Cu(I) complex in the presence of nonracemic BDPP hydrogenates aryl ketones with moderate to high enantioselectivity.

Highly Enantio- and s-trans C=C bond selective catalytic hydrogenation of cyclic enones: alternative synthesis of (-)-menthol.

A highly enantioselective catalytic hydrogenation of cyclic enones was achieved by using the combination of a cationic Rh(I) complex, (S)-5,5'-bis{di(3,5-di-tert-butyl-4-methoxyphenylphosphino)}-4,4'-bi-1,3-benzodioxole (DTBM-SEGPHOS), and (CH2CH2PPh3Br)2. The presence of an s-cis C=C bond isopropylidene moiety on the cyclic enone influenced the enantioselectivity of the hydrogenation. Thus, the hydrogenation of 3-alkyl-6-isopropylidene-2-cyclohexen-1-one, which contains both s-cis and s-trans enones, proceeded in excellent enantioselectivity (up to 98 % ee). To obtain high enantio- and s-trans selectivities, the addition of a halogen source to the cationic Rh complex was the essential step. With the key step of the s-trans selective asymmetric hydrogenation of piperitenone, we demonstrated a new synthetic method for optically pure (-)-menthol via three atom-economical hydrogenations. Moreover, we found that the complete s-trans and s-cis C=C bond selective reactions were also realized by the proper choice of both the chiral ligands and halides.

Developments in asymmetric hydrogenation from an industrial perspective.

Examples of developments in asymmetric hydrogenation from various perspectives, in an effort to improve efficiency, are reported. Discussed in this Account are (1) the improved synthesis of BINAP ligands, (2) the design of SEGPHOS ligands for higher enantioselectivity, (3) a new protocol with fewer reaction steps to synthesize beta-aminoesters, and (4) a novel asymmetric hydrogenation mediated by a copper catalyst.