Ketones enantioselective addition

In addition, the most efficient mem-ligand depicted above was successfully applied, in 2006, to the alkynylation of ketones. Thus, Liu et al. showed that this ligand was able to catalyse the enantioselective addition of phenylacetylene to various ketones, using Cu(OTf)2 as the starting base in toluene. The results were excellent and homogeneous not only for substituted aryl alkyl ketones, but also for aliphatic methyl ketones (Scheme 4.6). 

It was independently found by two groups that the exo-diol derived from bis(camphorsulfonyl)-substituted tra .s-cyclohexane-1,2-diamine ligand (HOCSAC) was an excellent promoter for the enantioselective addition of dialkyIzinc reagents to any type of ketones, even dialkyl ketones, in the presence of Ti(Oi-Pr)4. As shown in Scheme 4.11, excellent enantioselectivities of up to 99% ee were obtained in these conditions in combination with high yields and with a low catalyst loading of 2-10 mol%. 

The use of cyclic a,p-unsaturated ketones as starting materials in the enantioselective addition of dimethyl- and diethylzinc reagents catalysed by the HOCSAC ligand was introduced by Walsh and Jeon, in 2003. As shown in Scheme 4.16, the corresponding cyclic tertiary alcohols were formed in high enantioselectivities of up to 99% ee. 

In addition, the enantioselective addition of akynylzinc reagents to aromatic ketones has been developed by Wang et al. using novel C2-symmetric... 

Reactions of organometallic derivatives with ketones, which are less electrophilic than aldehydes, usually require an equimolar amount of a chiral ligand. The first catalytic enantioselective addition of an organometallic reagent, namely ZnPh2, to dialkyl and aryl alkyl ketones was reported in 1998 by Dosa and Fu (Scheme 110).288 The procedure... 

CATALYTIC ASYMMETRIC ADDITIONS OF DIALKYLZINC TO KETONES ENANTIOSELECTIVE FORMATION OF TERTIARY ALCOHOLS... 

Fu and Dosa139 report the enantioselective addition of diphenylzinc to a range of aryl-alkyl and dialkyl ketones with good to excellent stereocontrol. Addition of 1.5 eq. of MeOH in the presence of a catalytic amount of (+)-DAIB 135 results in enhanced enantioselectivity and improved yield (Scheme 2-53). Table 2-16 gives the results of this reaction. 

Similarly, Ramon and Yus140 reported the enantioselective addition of diethylzinc and dimethylzinc to prochiral ketones catalyzed by camphorsulfona-mide-titanium alkoxide derivatives as shown in Scheme 2-54. 

Nakamura et al.141 reported a closely related reaction, that is, the enantioselective addition of allylzinc reagent to alkynyl ketones catalyzed by a bisox-azoline catalyst 137. High ee values were obtained in most cases (Scheme 2-55). 

Cyanohydrination (addition of a cyano group to an aldehyde or ketone) is another classic reaction in organic synthesis. Enantioselective addition of TMSCN to aldehyde, catalyzed by chiral metal complexes, has also been an active area of research for more than a decade. The first successful synthesis using an (5,)-binaphthol based complex came from Reetz s group142 in 1986. Their best result, involving Ti complex, gave 82% ee. Better results were reported shortly thereafter by Narasaka and co-workers.143 They showed that by... 

Moreover, Soai et al.53c found that the enantioselective addition of Reformatsky reagents to prochiral ketones proceeds well when N,N-dialkylnorephedine 59 is used as the chiral ligand. When (15, 2R)-59a is used, the //-hydroxyl ester is obtained in 74% ee and 65% yield with ( -configuration predominant. When (lR,25,)-59a is used, the product is obtained in 74% ee and at 47% yield with (R)-configuration prevailing. 

The enantioselective addition of a nucleophile to a carbonyl group is one of the most versatile methods for C C bond formation, and this reaction is discussed in Chapter 2. Trifluoromethylation of aldehyde or achiral ketone via addition of fluorinated reagents is another means of access to fluorinated compounds. Trifluoromethyl trimethylsilane [(CF SiCFs] has been used by Pra-kash et al.87 as an efficient reagent for the trifluoromethylation of carbonyl compounds. Reaction of aldehydes or ketones with trifluoromethyltrime-thylsilane can be facilitated by tetrabutyl ammonium fluoride (TBAF). In 1994, Iseki et al.88 found that chiral quaternary ammonium fluoride 117a or 117b facilitated the above reaction in an asymmetric manner (Scheme 8-42). 

The quaternary ammonium salt 48 derived from (+)-ephedrine was utilized for the enantioselective addition of diethyl zinc to aldehydes.1421 The chiral ammonium fluorides 7 (R=4-CF3 or 2,4-(CF3)2, X=F) were also useful for the enantioselective trifluoro-methylation of aldehydes and ketones with moderate enantioselectivity,1431 shown in Scheme 17... 

Additions of organometallics to the C=N bond of imines, oximes, hydrazones, and nitrones have been reviewed, with emphasis on the issues of reactivity and selectivity. Recent advances in enantioselective addition to imines of ketones are highlighted. 

Enantioselective addition of diethylzinc to benzaldehyde has been promoted by indole-containing chiral oxazolidines (which are able to use both O and N atoms to effect metal coordination in the transition state), and by chiral o-hydroxyphenyl diaza-phospholidine oxide,and by chiral aziridino alcohols.Enantioselective addition of dialkylzinc to prostereogenic ketones has been promoted using chiral camphorsul-fonamide derivatives. 

A similar Cu(I)-catalyzed reaction has been reported, and one example represents a modestly enantioselective addition to a ketone (Eq. 112). ... 

The enantioselective addition of organomagnesium compounds to ketones can be most conveniently performed by using a chiral auxiliary in the substrate molecule. Primary aUsyhnagnesium reagents react with aryl and heteroaryl ketones in the presence of magnesium TADDOLate at — 100°C, yielding products with up to 98% ee (equation 143). Chiral a-ketoacetals 214, prepared in two steps from a-substituted cinnamic aldehydes, add organomagnesium species with up to 98% diastereoselectivity (equation 144). 

Interestingly, the chhal diamine 508 catalyzes the enantioselective addition of boronic acids to aromatic ketone.s like acetophenone. The reaction produces interesting tertiary diarylcarbinols such as 509 in up to 93% ee. Bolm and coworkers have shown that this approach can also be used for a simple preparation of chiral diarylcarbinols (such as 510) in the presence of the chiral ferrocenyl ligand 511 (Scheme 122) . The addition of... 

Nowadays, this chemistry includes a wide range of applications. The organozinc compounds employed in the enantioselective addition include dialkylzincs, dialkenylzincs, dialkynylzincs, diarylzincs and the related unsymmetrical diorganozincs. Electrophiles have been expanded to aldehydes, ketones and imines. Asymmetric amplification has been observed in the enantioselective addition of organozincs. Recently, asymmetric autocatalysis, i.e. automultiplication of chiral compounds, has been created in organozinc addition to aldehydes. 

On the other hand, in the presence of Lewis acid, addition of dialkylzinc to ketones occurs (equation 14)45. A stoichiometric amount of Ti(OPr-i)4 and a catalytic amount of camphorsulfonamide 33 enable an enantioselective addition of dialkylzincs to ketones46. Later, bis(sulfonamide) ligand 34 was found to be a more enantioselective catalyst in this... 

Enantioselective addition of alkynyl groups to aldehydes and ketones afford enantioen-riched alkynyl alcohols62. Early approaches to the catalytic enantioselective addition of dialkynylzincs and alkynylalkylzincs to aldehydes employed catalytic amounts of chiral amino alcohol63 and amino pyridine64. Stoichiometric enantioselective addition of alkynylzinc halide is reported using the lithium alkoxide of IV-methylephedrine65. 

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