Alkyl zinc. enantioselective addition

Many other electrophiles are able to react with metalated ferrocenylalkyl amines, e.g., trimethyl borate (Fig. 4-27 a), which gives, after hydrolytic workup, compounds like (S,S)-l-(iV,iV-dimethyl-l-aminoethyl)ferrocene-2-boronic acid [106]. Important intermediates for further derivatization are the halogens. For the lithiation technique, I2 (Fig. 4-27b) [151] and BrCN [106] lead to the desired compounds, but when BrCN is used, partial substitution of the dimethylamino group by cyanide occurs (see Sect. 4.3.3.2 and Fig. 4-17). For palladated amines, Brj is applicable [152]. (i ,S)-l-Iodo-2-(iV,iV-dimethyl-l-aminoethyl)ferrocene is the starting material for catalytically active zinc compounds for the enantioselective addition of zinc alkyls to carbonyl compounds [151] (see Chapter 3 for this topic). 

The chiral catalysts 1 to 4 are highly enantioselective in the addition of di(prira-alkyl)zincs to aromatic aldehydes. (IS, 2i )-iV,iV-dibutylnorephedrine [1 (DBNE)] [5] possesses the advantage of its utility as a highly enantioselective catalyst even for the alkylation of aliphatic aldehydes to afford aliphatic sec-alcohols with up to 93% ee [5]. DBNE is also an appropriate chiral catalyst for the addition of diisopropylzinc [di(sec-alkyl)zinc] (98% ee) [15]. (S)-Diphenyl(l-meth-ylpyrrolidin-2-yl)methanol [2 (DPMPM) [6] catalyzes the enantioselective ethylation of aromatic aldehydes to afford almost enantiomerically pure sec-alcohols... 

Quinine [1, (8a,9/Q-6 -methoxy-9-cinchonanol] is the most familiar of the cinchona alkaloids. Quinine has been used as a catalyst in the enantioselective addition of zinc alkyls to aldehydes (together with its acetic ester) (Section D. 1.3.1.4.), for the addition of thiols and selenols to activated double-bond systems (Sections D.2.1., D.5. and D.6.), and as a chiral ligand for cobalt catalysts in the hydrogenation of 1,2-diketones to a-hydroxycarbonyl compounds (Section D.2.3.1.) and C-C double bonds (Section D.2.5.1.2.2.). Quinine and quinidine can also be incorporated into more complex systems (forming ethers and esters with its hydroxy function) where they may act as a chiral leaving group. This technique has been applied to the synthesis of chiral binaphthols (Section D.1.1.2.2.). 

The. V-alkylation of ephedrine is a convenient method for obtaining tertiary amines which are useful as catalysts, e.g., for enantioselective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.), and as molybdenum complexes for enantioselective epoxidation of allylic alcohols (Section D.4.5.2.2.). As the lithium salts, they are used as chiral bases, and in the free form for the enantioselective protonation of enolates (Section D.2.I.). As auxiliaries, such tertiary amines were used for electrophilic amination (Section D.7.I.), and carbanionic reactions, e.g., Michael additions (Sections D. 1.5.2.1. and D.1.5.2.4.). For the introduction of simple jV-substituents (CH3, F.t, I-Pr, Pretc.), reductive amination of the corresponding carbonyl compounds with Raney nickel is the method of choice13. For /V-substituents containing further functional groups, e.g., 6 and 7, direct alkylations of ephedrine and pseudoephedrine have both been applied14,15. 

Polymer-bound ephedrine has interesting possibilities for heterogeneous catalysis. It has been used as a catalyst for enantioselective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.) and for the enantioselective reduction of ketones to secondary alcohols16. 

The simple amino alcohols discussed have been used as catalysts for enantioselective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.). In most cases, the reactive amino function is used for the formation of derivatives (including hcterocycles. such as dihydrooxa-zoles. which are formed with acids) which are useful as sources of chiral carbanions (see Sections C., D.l.1.1.2., D.l.3.1.4., D.l.6.1.2.1.. D.1.6.1.3., D.1.6.1.5., D.2.1. and D.2.3.I.). 

An extremely selective catalyst for the enantioselective addition of zinc alkyls to carbonyl compounds is (-)-3-e.w-(dimethylamino)isoborneol [(-)-35, Section D.1.3.1.4.). It is obtained either by direct alkylation of the primary amine group with iodomethane37, or by reductive alkylation35 ... 

DAIB =((-)-3-exo-(Dimethylamino)isobomeol) was introduced as a chiral auxiliary (AX) for the enantioselective addition of dialkylzincs to aldehydes [112]. It has been applied for both intermolecular [113a] and intramolecular [113b] formation of ( -aIlyl alcohols from acetylenes and aldehydes via (l-alkenyl)(alkyl)zinc intermediates. 

Enantioselective additions of metal aryl species to ketones are more challenging transformations than the use of aldehydes as acceptors. This situation is related not only to the decreased reactivity of ketones as acceptors, but also to the greater difficulty for a Lewis acid to differentiate between the two lone pairs of a ketone carbonyl. An early example of an enantioselective phenyl transfer to aryl-alkyl ketones 23 was reported by Fu in 1998 (Scheme 8.7) [21]. The use of Noyori s dimethylaminoisobomeol (DAIB) Ugand 24 provided tertiary alcohols 25 in moderate to high yields and enantioselectivities. The addition of methanol was found to be necessary in order to form a mixed alkoxy phenyl zinc species which is less reactive than Ph2Zn. 

While the mechanism of the ammonium salt catalyzed alkylation is unclear, in polar solvents the enantioselectivity of the addition of dialkylzincs to aldehydes generally drops considerably, probably due to uncatalyzed product formation or complexation of the zinc reagent with the polar solvent rather than with the chiral auxiliary. 

Asymmetric conjugate addition of dialkyl or diaryl zincs for the formation of all carbon quaternary chiral centres was demonstrated by the combination of the chiral 123 and Cu(OTf)2-C H (2.5 mol% each component). Yields of 94-98% and ee of up to 93% were observed in some cases. Interestingly, the reactions with dialkyl zincs proceed in the opposite enantioselective sense to the ones with diaryl zincs, which has been rationalised by coordination of the opposite enantiofaces of the prochiral enone in the alkyl- and aryl-cuprate intermediates, which precedes the C-C bond formation, and determines the configuration of the product. The copper enolate intermediates can also be trapped by TMS triflate or triflic anhydride giving directly the versatile chiral enolsilanes or enoltriflates that can be used in further transformations (Scheme 2.30) [110],... 

The C2-symmetric bifunctional tridentate bis(thiazoline) 222 has been shown to promote the zinc(II)-catalyzed asymmetric Michael addition of nitroalkanes to nitroalkenes in high enantioselectivity <06JA7418>. The corresponding bis(oxazoline) ligand provides comparable enantioselectivity but higher product yield. The same bis(thiazoline) ligand has also been evaluated in the enantioselective Friedel-Crafts alkylation of indoles, but the enantioselectivity is moderate <06OL2115>. 

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