Enantioselectivity, conjugate addition

For Type II reactions also a variety of useful compounds can be synthesized by changing the combination of the starting materials. In the Michael reaction with cyclic enones, availability of the La-linked-BINOL complex broadened the scope of the Michael acceptor (Scheme 14). It should be noted that less reactive medium-ring-size cyclic enones (7-9membered ring size) underwent conjugate addition highly enantioselectively (up to > 99 % ee) [17]. 

Alder reactions, 1,3-dipolar cycloadditions (Jen et al. 2000), and conjugate additions of electron rich aromatic and heteroaromatic compounds can be catalyzed using chiral amino acid derived imidazolidinones as catalysts (Scheme 17 Eqs. 35-38 Paras and MacMillan 2001, 2002 Austin and MacMillan 2002 Brown et al. 2003b). In addition, highly enantioselective epoxidations (Marigo et al. 2005b) and cyclopropana-tions (Kunz and MacMillan 2005) have recently been developed. 

Enol Amination. The Cu[(S,5)-t-Bu-box] (OTf)2 complex was found to be optimal for promoting the enantioselective conjugated addition of enolsilanes to azodicarboxylate derivatives (eq 13). This methodology provides an enantioselective catalytic route to differentially protected ot-hydrazino carbonyl compounds. Isomerically pure enolsilanes of aryl ketones, acylpyrroles, and thioesters add to the azo-imide in greater than 95% ee. The use of an alcohol additive was critical to achieve catalyst turnover. Amination of cyclic enolsilanes was also possible. For example, the enolsilane of 2-methylindanone provides the adduct containing a tetrasubstituted stereogenic center in 96% ee and high yield. Acyclic (Z)-enolsilanes react in the presence of a protic additive with enantioselection up to 99%. ... 

Conjugate Addition. Catalytic enantioselective conjugate addition of cyanotrimethylsilane to a,/3-unsaturated imides has been reported to afford 1,4-addition products in excellent yield and enantiomeric excess (eq 35). Under the catalysis of a chiral gadolinium complex, cyanotrimethylsilane can undergo facile conjugate addition to enones (eq 36) and a, 6-unsaturated... 

In addition to enantioselective alcoholysis of meso anhydrides [84, 85], a series of sulfonamide derivatives of quinidine was prepared and shown to elFec-tively catalyze the conjugate addition of bicyclic a-substituted [l-ketoesters to P-nitroalkenes (Scheme 6.38) [86]. 

Quite a number of asymmetric thiol conjugate addition reactions are known [84], but previous examples of enantioselective thiol conjugate additions were based on the activation of thiol nucleophiles by use of chiral base catalysts such as amino alcohols [85], the lithium thiolate complex of amino bisether [86], and a lanthanide tris(binaphthoxide) [87]. No examples have been reported for the enantioselective thiol conjugate additions through the activation of acceptors by the aid of chiral Lewis acid catalysts. We therefore focussed on the potential of J ,J -DBFOX/ Ph aqua complex catalysts as highly tolerant chiral Lewis acid catalyst in thiol conjugate addition reactions. 

Enantioselectivities were found to change sharply depending upon the reaction conditions including catalyst structure, reaction temperature, solvent, and additives. Some representative examples of such selectivity dependence are listed in Scheme 7.42. The thiol adduct was formed with 79% ee (81% yield) when the reaction was catalyzed by the J ,J -DBFOX/Ph aqua nickel(II) complex at room temperature in dichloromethane. Reactions using either the anhydrous complex or the aqua complex with MS 4 A gave a racemic adduct, however, indicating that the aqua complex should be more favored than the anhydrous complex in thiol conjugate additions. Slow addition of thiophenol to the dichloromethane solution of 3-crotonoyl-2-oxazolidinone was ineffective for enantioselectivity. Enantioselectivity was dramatically lowered and reversed to -17% ee in the reaction at -78 °C. A similar tendency was observed in the reactions in diethyl ether and THF. For example, a satisfactory enantioselectivity (80% ee) was observed in the reaction in THF at room temperature, while the selectivity almost disappeared (7% ee) at 0°C. 

Copper-catalyzed Enantioselective Conjugate Addition Reactions of Organozinc Reagents... 

A number of conjugate additions delivering excelent enantioselectivities tlirougli tlie use of organocuprates in tlie presence of stoichiomenic amounts of cliital fnon-transferable) ligands ate known today [7-9],... 

The reaction of butyllithium with 1-naphthaldehyde cyclohexylimine in the presence of (/C )-l,2-diphenylethane-1,2-diol dimethyl ether in toluene at —78 °C, followed by treatment with acetate buffer, gave 2-butyl-1,2-dihydronaphthalene-l-carbaldehyde, which was then reduced with sodium borohydride in methanol to afford (1 R,2.S)-2-butyl-1 -hydroxymcthyl-1,2-dihydronaphthalene in 80% overall yield with 91 % ee83. Similarly, the enantioselective conjugate addition of organolithium reagents to several a,/J-unsaturated aldimines took place in the presence of C2-symmetric chiral diethers, such as (/, / )-1,2-butanediol dimethyl ether and (/, / )- ,2-diphenylethane-1,2-diol dimethyl ether. 

Combination of nickel bromide (or nickel acetylacetonate) and A. A -dibutylnorephcdrinc catalyzed the enantioselective conjugate addition of dialkylzincs to a./Tunsaturated ketones to afford optically active //-substituted ketones in up to ca. 50% ee53. Use of the nickel(II) bipyridyl-chiral ligand complex in acetonitrile/toluenc as an in situ prepared catalyst system afforded the //-substituted ketones 2, from aryl-substituted enones 1, in up to 90% ee54. 

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