Ketones, enantioselective stereoselective additions

As an extension of this highly enantioselective Michael addition of silyl nitronates with a, p-unsaturated aldehydes, the reactions with cyclic a,p-unsaturated ketones as a Michael acceptor were also tested (Scheme 9.15). Cyclohexenone and cyclohepte-none were employed as a useful Michael acceptor with various silyl nitronates in the presence of catalyst (R,R)-6c, and gave the corresponding enol silyl ethers 28 with excellent stereoselectivities [30]. 

Alkenylboronic acids and esters underwent conjugated addition to ct,/ -unsaturated ketones in the presence of trifluoroborane etherate589 or cyanuric fluoride (Equation (129)).590,591 Alkadienyl trifluoromethyl ketones were stereoselectively prepared from (2-alkoxyvinyl) trifluoromethyl ketones (Equation (130)).592 Alkynyl boronates can transfer the alkynyl groups regioselectively and enantioselectively to enones (Equation (131 )).593... 

Evans has recently reported the use of structurally well-defined Sn(II) Lewis acids 119 and 120 (Fig. 9)for the enantioselective aldol addition reactions of a-heterosubstituted substrates [83]. These complexes are easily assembled from Sn(OTf)2 and C2-symmetric bisoxazoline Hgands 124 and 126 (Fig. 10). The facile synthesis of these ligands commences with optically active 1,2-amino alcohols 122, which are themselves readily available from the corresponding a-amino acids 121 [84, 85]. The Sn(II) bis(oxazoHne) complexes were shown to function optimally as catalysts for enantioselective aldol addition reactions with aldehydes and ketone substrates that are suited to putatively chelate the Lewis acid. For example, using 10 mol % of 119, thioacetate and thiopropionate derived silyl ketene acetals add at -78 °C in CH2CI2 to glyoxaldehyde to give hydroxy diesters 130 in superb yields and enantioselectivities as well as diastereo-selectivities (Eq. 12). The process represents an unusual example wherein 2,3-anti-aldol adducts are obtained in a stereoselective manner. 

The Barbas group further identified catalyst Id for asymmetric Michael additions using brine as the reaction medium 10 mol% diamine Id/TFA at ambient temperature afforded q n-Michael adducts in high yields and good to excellent stereoselectivities for cyclic ketones. The stereoselectivities decreased when aliphatic aldehydes were used as donors (Scheme 9.13). Moreover, the same authors demonstrated the first example of sym-metrical/unsymmetrical a,a-diallgrlaldehydes as donors in asymmetric Michael reactions to produce adducts featuring an all-carbon quaternary stereocentre. The use of 30 mol% (S )-l-(2-pyrrolidinylmethyl)pyrrolidine la in combination with an equal amount of TFA yielded products with moderate to high levels of diastereo- and enantioselectivity (Scheme 9.14). ... 

In 2006, Xu and Xia et al. revealed the catalytic activity of commercially available D-camphorsulfonic acid (CS A) in the enantioselective Michael-type Friedel-Crafts addition of indoles 29 to chalcones 180 attaining moderate enantiomeric excess (75-96%, 0-37% ee) for the corresponding p-indolyl ketones 181 (Scheme 76) [95], This constitutes the first report on the stereoselectivity of o-CSA-mediated transformations. In the course of their studies, the authors discovered a synergistic effect between the ionic liquid BmimBr (l-butyl-3-methyl-l/f-imidazohum bromide) and d-CSA. For a range of indoles 29 and chalcone derivatives 180, the preformed BmimBr-CSA complex (24 mol%) gave improved asymmetric induction compared to d-CSA (5 mol%) alone, along with similar or slightly better yields of P-indolyl ketones 181 (74-96%, 13-58% ee). The authors attribute the beneficial effect of the BmimBr-D-CSA combination to the catalytic Lewis acid activation of Brpnsted acids (LBA). Notably, the direct addition of BmimBr to the reaction mixture of indole, chalcone, d-CSA in acetonitrile did not influence the catalytic efficiency. 

Figure I.IAJ shows that after addition of NADP, reductions were more efficient. Gonversion of acetophenone was complete after a reaction time of 20 min. ADH activity in E. coli BL21(DE3)/pAW-3 is threefold higher than in E. coli BL21(DE3)/ pAW-4 cells. Enantioselective reductions of various ketones are more efficient using E. coli BL21(DE3)/pAW-3 than with pAW-4. All ketones were reduced completely in a stereoselective manner alcohols were formed with >99% ee and de.

The (diastereoselective) conjugate addition of silylcuprate reagents to a variety of chiral derivatives of a,(3-unsaturated carboxylic acids can be used to prepare optically active p-silyl esters.258 259 Best results are obtained with substrates of type (25). The (related) p-silyl ketones, which also constitute valuable building blocks for (acyclic) stereoselective synthesis, are now accessible in high ee via palladium-catalyzed enantioselective 1,4-disiiylation of a,p-unsaturated ketones (Scheme 76).260... 

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). 

Aluminum salen complexes have been identified as effective catalysts for asymmetric conjugate addition reactions of indoles [113-115]. The chiral Al(salen)Cl complex 128, which is commercially available, in the presence of additives such as aniline, pyridine and 2,6-lutidine, effectively catalyzed the enantioselective Michael-type addition of indoles to ( )-arylcrolyl ketones [115]. Interestingly, this catalyst system was used for the stereoselective Michael addition of indoles to aromatic nitroolefins in moderate enantiose-lectivity (Scheme 36). The Michael addition product 130 was easily reduced to the optically active tryptamine 131 with lithium aluminum hydride and without racemization during the process. This process provides a valuable protocol for the production of potential biologically active, enantiomerically enriched tryptamine precursors [116]. 

Although the enantioselective construction of aldol products has long been a workhorse for acyclic stereoselection, there are still new things being done. The use of proline and proline amides 3.20 as a catalyst was reported for the enantioselective addition of ketones to aldehydes. 

The mode of addition and the reaction temperature both affect the enantioselectivity of the reaction. The best results are obtained when the ketone is added slowly to a solution of the oxazaborolidine (or oxazaborolidine-borane complex) and the borane source, at as low a temperature that provides a reasonable reaction rate. This is in contrast to a previous report that indicated that oxazaborolidine-catalyzed reductions lose stereoselectivity at lower temperatures . With unsubstituted (R = H) oxazaboro-... 

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