Stereoselective Reductive Amination with Chiral Ketones

Stereoselective Reductive Amination with Chiral Ketones 

Optimal conditions required the a chiral ketone (steroid) to be stirred with Ti(OiPr)4 (1.3 equiv) and the amine (3.0 equiv) in a dilute solution of MeOH (0.08 M) over 12h. The reaction was then cooled to 78°C, NaBH4 (1.0 equiv) added, and stirred for 2h [29]. Yields were generally poor (6 45%), except when methylamine (77% yield) and 1,2 diethylamine (61% yield) were used. For all 13 examples, the diastereoselectivity is reported to be excellent ( 95%). No mention was made of the lability of the a chiral stereogenic center adjacent to the ketone, presumably it is resilient to epimerization due to the conformational rigidity afforded by the extended steroid skeleton. 

Although the above examples represent a limited breadth of demonstrated 

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Stereoselective Reductive Amination with Chiral Ketones... 

C2-symmetrical secondary amines by applying the stereoselective reductive amination protocol using chiral amines as the source of chirality. In 2005, Nugent et al. published a novel method for the asymmetric reductive amination of prochiral aliphatic ketones116 where the (/ )- or (5)-a-methylbenzylamine (MBA) were employed as the cheap chiral ammonia equivalent. Ti(0 Pr)4/Raney Ni/H2 were employed as the catalyst system for the one-pot conversion of the prochiral ketones 116a-e to the corresponding chiral amines 117a-e with excellent dia-stereoselectivity (Scheme 39.33). 

Over the years, stereoselective synthesis with the help of chiral auxiliaries has emerged as an important synthetic tool for synthesizing chiral molecules. This methodology allows for enantioselective synthesis of a target molecule via a diastereoselective reaction with a chiral auxiliary. The two major counterparts in reductive amination protocol are the carbonyl compound and the amine. So, enantioselective synthesis can be made possible by either taking a chiral ketone or a chiral amine as the chiral auxiliary. Both methodologies have been reported in the literature, and they are of immense synthetic importance. 

Product stereoselectivity occurs when ste-reoisomeric metabolites are generated (l)dif-ferently (in quantitative and/or qualitative terms) and (2) from a single substrate with a suitable prochiral center or face. Examples of metabolic pathways producing new centers of chirality in substrate molecules include ketone reduction, reduction of carbon-carbon double bonds, hydroxylation of prochiral methylenes, oxygenationof tertiary amines to N-oxides, and oxygenation of sulfides to sulfoxides. Product stereoselectivity may be a re-... 

In contrast to the considerable amount of successful attention devoted to the asymmetric reduction of prostereogenic ketones to chiral alcohols with metal hydride reagents (see Section D.2.3 and ref 1), corresponding studies and identification of useful stereoselective conversions of stereo-genic imine derivatives to amines have been sparse, and only limited success has been obtained. 

Literature on the hydrosilylation of ketones and imines is extensive. This chemistry provides a method for the reduction of these unsaturated substrates with reagents that are inexpensive and either liquids or solids, rather than gases (H ). As noted in the introduction, much of this literature focuses on the enantioselective hydrosilylation of ketones and imines to form non-racemic chiral alcohols and amines. In addition to the conveniaice of using a liquid reagent, the ability to vary the substituents on a silane allows for tuning of the stereoselectivity of the reductions. 

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