Enantioselective alkylations

Selectivity, Steering of reaction directions by the type of catalyst cation, eg, O- vs C-alkylation (7), substitution vs dibalocarbene addition (8), as weU as enantioselective alkylations by optical active catalysts (9) have been achieved in some systems. Extensive development is necessary, however, to generate satisfactorily large effects. 

The oxazaborolidines are easily prepared by heating ephedrine with borane dimethyl sulfide or the appropriate boronate ester. The aluminum reagent C is obtained by mixing ephedrine and trimethylaluminum. Borolidinc A is superior to its methyl derivative B and to the aluminum analog C. The diastereomeric borolidine obtained from borane and (S,S)-pseu-doephedrine failed to show any cnantioselectivity25. A variety of aromatic aldehydes can be enantioselectively alkylated in the presence of A, however, with heptanal the enantioselectivity is poor25. 

Efficient enantioselective alkylations are known.In another method, enantio-selective alkylation can be achieved by using a chiral base to form the enolate. 

The zinc alkoxide of 2-methyl-l-(3-quinolyl)propan-l-ol was used in a catalytic amount to give ee up to 94% in the enantioselective alkylation of quinoline-3-carbaldehyde by diisopropyl-... 

In the following example, although the synthesis of the azoniaspirocycle does not involve an acyclic compound, the reaction itself is very similar to those described in this section, hence its inclusion here (Equation 34). Maruoka and co-workers have designed a C2-symmetric chiral quarternary ammonium salt, which is then employed as a phase-transfer catalyst in an enantioselective alkylation <1999JA6519, 2001JFC(112)95, 2004TA1243>. 

To carry out enantioselective alkylation of 2-thiazolyl nitrone (319) (Scheme 2.136), chiral additives presented in Fig. 2.22 and Lewis acids (MgBr2, Et2AlCl,... 

Woodward and co-workers recently achieved catalytic enantioselective alkylation of aldehydes with (R3Al)2 DABCO complexes or R3A1 (R = Me or Et) in the presence of Ni(acac)2/Feringa s ligand 196 (Equation (81 )).439... 

Catalytic RCM and Zr-Catalyzed Enantioselective Alkylation of Unsaturated Heterocycles... 

Scheme 2. Ru-catalyzed RCM efficiently provides substrates required for the Zr-catalyzed enantioselective alkylation...

TABLE 2-3. Enantioselective Alkylations and Conversions of 16 to Carboxylic Acids23... 

Figure 2-5. Enantioselective alkylation catalyzed by protonic auxiliary HX. M = Metallic species X = chiral heteroatom ligand.

Both the aldehyde and diethylzinc are activated by the zinc amide, and the ethyl group transformation from diethylzinc to aldehyde furnishes the highly enantioselective alkylation of aromatic aldehydes. 

Scheme 6.3. Zr-catalyzed enantioselective ethylmagnesation and metal-catalyzed alkene metathesis make effective partners. In the two cases shown here, the alkene substrate is synthesized and enantioselectively alkylated in the same vessel.

Subsequent to these studies by the author s group, Whitby and co-workers reported that enantioselective alkylations of the type illustrated in Scheme 6.6 can also be carried out with the non-bridged chiral zirconocene 31 [19]. Enantioselectivities are, however, notably lower when alkylations are carried out in the presence of 31. For example, this new chiral metallocene affords 29 and 30 (Scheme 6.5) with 82% and 78% ee, respectively. 

Scheme 6.13. Zr-catalyzed enantioselective alkylation with neat Et3AI can lead to an alternative reactivity pattern (formation of 39 rather than 40).

Zr-Catalyzed Enantioselective Alkylation of Alkenes with Alkylaluminum Reagents 194... 

The efficient enantioselective alkylation of the P/y-unsaturated ester 39 was achieved1351 by use of the N-anthracenylmethyl catalyst 12 (R=benzyl, X=Br) together with CsOH-H20 under phase transfer conditions analogous to those in the alkylation of the O Donnell imine 23, as shown in Scheme 13. The enantioselectivity of the alkylation correlates with Hammett o constants, and the N,N-dimethylamino substituents in 39 showed the most effective enantioselectivity. The tight ion pair in which the enolate... 

Catalyst Species for Enantioselective Alkylation by Phase-Transfer Catalysis , Tetrahedron 1994, 50... 

R Lygo, J. Crosby, J. A Peterson, Enantioselective Alkylation of Alanine-Derived Imines Using Quaternary Ammonium Catalysts , Tetrahedron Lett. 1999, 40, 8671-8674. 

Based on these reactions, Imada et al. reported the first enantioselective alkylation of 2,3-alkadienyl phosphates 96 by employing malonate derivatives 97 in the presence of palladium complex catalysts bearing MeOBIPHEP or BINAP as ligand (Scheme 14.21) [49]. The highest enantioselectivity (90% ee) was obtained by the catalyst combination Pd2(dba)3-CHC13 and (R)-MeOBIPHEP. 

Among other enantioselective alkylations, a series of 3-aminopyrrolidine lithium amides (67 derived from 4-hydroxy-L-proline) have been used to induce high ee% in the addition of alkyllithiums to various aldehydes. Structure-activity relationships are identified, and the role of a second chiral centre (in the R group) in determining the stereochemistry of the product is discussed. 

In connection with the enantioselective alkylation of Pro or 4-hydroxy-proline, the azabicyclo[3.3.0]octane system 81 was obtained after reaction with pivaldehyde (81HCA2704 85HCA155). In a more complex transformation A-protected L-Pro was transformed into the same bicyclic system (Scheme 49) (81JA1851 84JA4192). The product was prepared as a model substance in the total synthesis of pumiliotoxin. A related compound 82 was prepared from 5-(hydroxymethyl)-2-pyrrolidinone (prepared from L-pyroglutamic acid) by an acid-catalyzed condensation with benzaldehyde (86JOC3140). 

Enantioselective alkylative ring opening of these oxabicyclic alkenes has also been studied. Lautens and coworkers discovered that palladium complexes efficiently catalyze the addition of organozinc reagents to these activated alkenes with concomitant ring opening. In the presence of (Tol-BINAP)PdCl2, diethylzinc adds to oxabenzonor-... 

The powerful enantioselective alkylation methodology developed by MacMillan for the addition heteroaromatics and anilines to a,P-unsaturated... 

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