Hydrogenation of 3-quinuclidinone and bicyclo[2.2.2]octan-2-one with a combined catalyst system of RuCl(2)[(S)-binap][(R)-iphan] and t-C(4)H(9)OK in 2-propanol afforded the chiral alcohols in 97-98% ee. 2-Diphenylmethyl-3-quinuclidinone was hydrogenated with the same catalyst to the cis alcohol with perfect diastereo- and enantioselectivity. The reaction of unsymmetrical ketones with a bicyclo[2.2.1] or -[2.2.2] skeleton gave the corresponding alcohols with high stereoselectivity.

a-Substituted chiral ketones that have small steric and electronic differences around the reaction sites are difficult substrates to reduce with high diastereoselectivity. Metal hydride reduction of 2-(4-benzoylmorpholinyl) phenyl ketone and 3-(1-tert-butoxycarbonylpiperidinyl) phenyl ketone using sodium borohydride, zinc borohydride, and potassium tri-sec-butylborohydride as reducing agents affords the syn-and anti-alcohols in a lower than 80:20 ratio. Hydrogenation of these ketones with a catalyst system of RuCl 2 A C H T U N G T R E N N U N G (BIPHEP)A C H T U N G T R E N N U N G (DMEN) and potassium tert-butoxide in 2-propanol results in the syn-alcohols with ! 99:1 selectivity [BIPHEP = 2,2'-bis(diphenylphosphino)biphenyl, DMEN = N,N-dimethylethylenediamine]. The marked difference in the diastereoselectivity suggests that the stereoselection in this hydrogenation is primarily regulated by the structure of the catalysts reaction field ("catalyst-controlled diastereoselection") but not the internal stereocontrol of the substrates. This chemistry is applied to the asymmetric hydrogenation through dynamic kinetic resolution with aA series of aryl heterocycloalkyl ketones has been converted to the alcohols in excellent diastereo-and enantioselectivities. The modes of catalyst-controlled diastereoselection and enantioselection are interpreted by using transitionstate molecular models. (S,S)-Reboxetine, a selective norepinephrine uptake inhibitor, was synthesized from one of product alcohols.Keywords: diastereoselectivity; enantioselectivity; hydrogenation; ketones; reboxetine; ruthenium Diastereoselective reduction of a-substituted chiral ketones to the 1,2-syn-or 1,2-anti-alcohols is a fundamental and indispensable reaction in modern organic synthesis.[1] Metal hydride reducing agents have made notable contributions to advance this important class of chemistry. The stereoselective outcome has been explained by using transition-state molecular models, such as the Felkin-Anh model and the chelation-controlled model (Figure 1). [1][2][3] In both cases the metal hydride reagent is recognized as just a hydride, and it reacts within the region of the substrate molecules. Therefore, the intramolecular stereoinduction principally depends on the substrate structure (substrate control), but not the shape of the metal hydrides (reagent control).[4] High diastereoselectivity in this reaction is achieved only when the substrates have a-substituents (L, M, S, and X) with marked differences in size and/or electronic properties. Thus, we thought that a new conceptual approach is required to develop a general method for the diastereoselective reduction of a-substituted ketones.We selected heterocycloalkyl ketones 1a and 1c as substrates to examine the diastereoselective ability of reducing agents [Eq. (1)]. The small electronic and Figure 1. Typical transition-state models in the diastereoselective hydride reduction of a-substituted chiral ketones. L, M, and S = large-, medium-, and small-sized substituents, respectivel...

Nitrogen fixation using transition metals is a fascinating process. We have already reported on the incorporation of molecular nitrogen into organic compounds using a titanium–nitrogen complex reported by Yamamoto. We developed a novel titanium-catalyzed nitrogenation procedure using TiCl4 in the presence of an excess amount of Li and TMSCl. In this reaction, a 1 atm pressure of nitrogen gas can be used and the reaction proceeds at room temperature. The procedure is very simple. A THF solution of TiCl4 or Ti(OiPr)4 (1 equiv.), Li (10 equiv.), and TMSCl (10 equiv.) was stirred under an atmosphere of nitrogen at room temperature overnight to give titanium–nitrogen complexes. Although the structures of the titanium–nitrogen complexes have not yet been determined, they would consist of N(TMS)3, X2TiN(TMS)2, and XTi=NTMS. Using this procedure, various heterocycles, such as indole, quinoline, pyrrole, pyrrolizine, and indolizine derivatives, could be synthesized from molecular nitrogen in good-to-moderate yields as a stoichiometric reaction based on a titanium complex by a one-pot reaction. Furthermore, monomorine I and pumiliotoxin C were synthesized from molecular nitrogen as a nitrogen source. This procedure was further extended for the syntheses of heterocycles using a catalytic amount of titanium complex; also, indole and pyrrole derivatives were obtained in high yields.

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