Ketones, 3-asymmetric amino stereoselectivity

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

High stereoselectivities (94-100 %) are attained in the reduction of aromatic ketones by use of a new chiral borane complex with (S)-2-amino-3-methyl-l,l-diphenylbutan-l-ol,(S-68) readily prepared in two steps from (S)-valine, in an experimentally convenient procedure961. (S)-Valine methyl ester hydrochloride was converted with excess of phenylmagnesium bromide into (S-68). The same treatment of (R)-valine gave (R-68). In a typical asymmetric reduction the reagent, prepared from (S-68) and borane, and the ketone (69) in tetrahydrofuran were kept at 30 °C for some hours. The corresponding alcohols were obtained in high optical purity. (S-68) could be recovered to more than 80% without racemization 96). 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

The asymmetric hydrogen transfer of aryl ketones can be accomplished with ruthenium catalysts that contain amino alcohols 165 in modest to high enantioselectivities.211 With amino alcohol ligands, the optimal rate and stereoselectivities are produced from catalysts prepared in situ with [RuCl2(r)6-C6Me6)]2. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones and esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds. In recent years, various enantioselective Mannich reactions have been developed. Among them, catalytic enantioselective additions of silicon enolates to imines have been elaborated into one of the most powerful and efhcient asymmetric Mannich-type reactions, primarily because sihcon enolates can be prepared regio- and stereoselectively from various carbonyl compounds. ... 

Enders et al. also reported direct asymmetric Mannich reactions starting from the protected ketone 14 [10]. Several protected carbohydrates and amino sugars were assembled in a three-component reaction. Alongside L-proline (1) they employed the L-hydroxyproline-based catalyst 17 (Scheme 5.10). This catalyst proved to be beneficial in terms of reaction rate due to superior solubility properties. Remarkably, the addition of water had a positive effect on the stereoselectivity in case catalyst 17 was employed. 

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