Asymmetric Catalytic Reductions

The synthesis of the trisubstituted cyclohexane sector 160 commences with the preparation of optically active (/ )-2-cyclohexen-l-ol (199) (see Scheme 49). To accomplish this objective, the decision was made to utilize the powerful catalytic asymmetric reduction process developed by Corey and his colleagues at Harvard.83 Treatment of 2-bromocyclohexenone (196) with BH3 SMe2 in the presence of 5 mol % of oxazaborolidine 197 provides enantiomeri-cally enriched allylic alcohol 198 (99% yield, 96% ee). Reductive cleavage of the C-Br bond in 198 with lithium metal in terf-butyl alcohol and THF then provides optically active (/ )-2-cyclo-hexen-l-ol (199). When the latter substance is treated with wCPBA, a hydroxyl-directed Henbest epoxidation84 takes place to give an epoxy alcohol which can subsequently be protected in the form of a benzyl ether (see 175) under standard conditions. 

In 2000, Morken et al. reported the first examples of catalytic asymmetric reductive aldol reactions [21]. Using Rh(BINAP) (5mol%) as catalyst and Et2MeSiH as reductant, the syn-selective (1.7 1) coupling of benzalde-hyde and methyl acrylate produced the diastereomers 35-syn and 35-anti in 91% ee and 88% ee, respectively. Using phenyl acrylate as the nucleophilic partner, a favorable yield of 72% was obtained for the aldol product 36 (Scheme 12). Several aldehydes were examined, which exhibit higher levels of syn-selectivity. Expanding the scope of substrates and acrylates under... 

Catalytic asymmetric reduction of unsaturated compounds is one of the most reliable methods used to synthsize the corresponding chiral saturated products. Chiral transition metal complexes repeatedly activate an organic or inorganic hydride source, and transfer the hydride to olefins, ketones, or imines from one... 

Scheme 44 Catalytic asymmetric reductive Michael cyclisation...

The List group came up with a novel concept for a catalytic asymmetric reductive amination, which involves enolizable aldehydes (Scheme 18) [33]. 

The method Corey developed for catalytic asymmetric reduction of Solution... 

A dynamic kinetic resolution has been employed to achieve a catalytic asymmetric reductive amination of aldehydes.332 Reductive amination of ketones and aldehydes by sodium triacetoxyborohydride has been reviewed, highlighting its advantage over other reagents.333... 

C. Catalytic, asymmetric reduction of ketones with a chiral lanthanoid complex... 

C. Catalytic, Asymmetric Reduction of Ketones with a Chiral Lanthanoid... 

Scheme 15. Catalytic asymmetric reductive amination of aldehydes...

Hoffmann S, Nicoletti M, List B (2006) Catalytic asymmetric reductive ami-nation of aldehydes via dynamic kinetic resolution. J Am Chem Soc 128 13074-13075... 

Yang JW, Hechavarria Fonseca MT, List B (2005) Catalytic asymmetric reductive Michael cyclization. J Am Chem Soc 127 15036-15037 Yoshikawa N, Chiba N, Mikawa T, Ueno S, Harimaya K, Iwata M (1994) Mitsubishi Chemical Industries patent. Jpn Kokai Tokkyo Koho JP 0630600 Zeitler K (2005) Extending mechanistic routes in heterazolium catalysis— promising concepts for versatile synthetic methods. Angew Chem Int Ed Engl 44 7506-7510... 

Hermitage S, Howard JAK, Jay D, Pritchard RG, Probert MR, Whiting A (2004) Mechanistic studies on the formal aza-Diels-Alder reactions of N-aryl imines evidence for the non-concertedness under Lewis-acid catalysed conditions. Org Biomol Chem 2 2451-2460 Hoffmann S, Nicoletti M, List B (2006) Catalytic asymmetric reductive ami-nation of aldehydes via dynamic kinetic resolution. J Am Chem Soc 128 13074-13075... 

Scheme 19 Catalytic asymmetric reductive Mannich reaction of ketimines.

We have also examined the use of chiral bi-2-naphthol to resolve some other racemic amino alcohols. The S-diphenylpyrrolidinemethanol S-10, synthesised from S-proline is useful in the preparation of the CBS oxazaborolidine catalyst,16 widely used in catalytic asymmetric reductions. Accordingly, the corresponding R-10 enantiomer is also a valuable chiral compound. 

Not all organic chemists can be Involved in such exciting projects as the launching of a new anti-AIDS drug. But the chemistry used in this project was invented by chemists in other institutions who had no idea that it would eventually be used to make Crixlvan. The Sharpless asymmetric epoxlda-tion, the catalytic asymmetric reduction, the stereoselective enolate alkylation, and the various methods tried out for the enantiomerically pure amino indanol (resolution, enzymatic kinetic resolution) were developed by organic chemists in research laboratories. Some of these famous chemists like Sharpless invented new methods, some made new compounds, some studied new types of molecules, but all built on the work of other chemists. 

The asymmetric total synthesis of prostaglandin Ei utilizing a two-component coupling process was achieved in the laboratory of B.W. Spur. The hydroxylated side-chain of the target was prepared via the catalytic asymmetric reduction of a y-iodo vinyl ketone with catecholborane in the presence of Corey s CBS catalyst. The reduction proceeded in 95% yield and >96% ee. The best results were obtained at low temperature and with the use of the B-n-butyl catalyst. The 6-methyl catalyst afforded lower enantiomeric excess and at higher temperatures the ee dropped due to competing non-catalyzed reduction. 

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