And enantioselectivity alkylation

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.

In route 1 a racemate, rac-42, is used as the starting material. Deprotonation and enantioselective alkylation of the resulting enolate give the desired products of type 43. The alternative, second route is based on use of the glycinate 44 as starting material. Alkylation steps with different alkyl halides furnish the desired product 43. 

Ferraris D, Young B, Cox C, Drury HI WJ, Dudding T, Lectka T (1998b) Diastereo- and enantioselective alkylation of alpha-imino esters with enol silanes catalyzed by (R)-Tol-BINAP-CuC10(4).(MeCN)(2). J Org Chem 63 6090-6091... 

TABLE 5. Regio- and enantioselective alkylation of 2-methylcyclopentanone (31a) and 2-methylcyclohexanone (31b) with an optically active Lewis acid... 

Unlike alkyllithium and Grignard reagents, dialkylzinc does not add to ketones even in the presence of (1). Thus the chemo- and enantioselective alkylation of a keto aldehyde (4-benzoylbenzaldehyde) with Et2Zn using (5)-(l) affords the corresponding optically active hydroxy ketone with 93% ee in 99% yield. ... 

A reversal of regioselectivity in favor of the branched product can also be achieved by using Mo, W, or Ir instead of Pd catalysts. Pfaltz has shown that a tungsten complex containing a chiral phosphinooxazoline leads to regio- and enantioselective alkylation. Fig.4 [41,78]. 

Woodward el al. have reported a series of stereo- and enantioselective alkylations of non-symmetrical allylic electrophiles derived from MBH products. The allyl halides or allyl mesylate 225 derived from a MBH adduct are chemo- and regiospecifically transformed into 3, (3-disubstituted a-methylene-propionates 226 on treatment with either diorganozincs or organozinc halides in the presence of catalytic amounts of copper(i) salts (3-20mol.%) in high... 

A catalytic and enantioselective alkylation of Af,0-acetals, protected by the SES group, is an interesting method to prepare various chiral a-amino esters from a common precursor, the SES hydroxyglycine (21), which is easier to form and more resistant to hydrolysis than the corresponding imine (eq 21). A first equivalent of enol silyl ether reacts with iV,0-acetal (21) to form the imine intermediate in situ. Eventually, a second equivalent of enol silyl ether is necessary to perform the alkylation of the Cu(I) SES imine complex. 

A P,N ligand containing a chiral oxazolidine moiety was shown to be efficient for the regio- and enantioselective alkylation of arylsubstituted allylic acetate (eq 61). ... 

In cases where Noyori s reagent (see p. 102f.) and other enantioselective reducing agents are not successful, (+)- or (—)-chlorodiisopinocampheylborane (Ipc BCl) may help. This reagent reduces prochiral aryl and tert-alkyl ketones with exceptionally high enantiomeric excesses (J. Chandrasekharan, 1985 H.C. Brown, 1986). The initially formed boron moiety is usually removed hy precipitation with diethanolamine. Ipc2BCl has, for example, been applied to synthesize polymer-supported chiral epoxides with 90% e.e. from Merrifield resins (T. Antonsson, 1989). 

On the basis of this successful application of 23d, this catalyst was applied in a series of reactions (Scheme 6.22). For all eight reactions of nitrones 1 and alkenes 19 in which 23d was applied as the catalyst, diastereoselectivities >90% de were observed, and most remarkably >90% ee is obtained for all reactions involving a nitrone with an aromatic substituent whereas reactions with N-benzyl and N-alkyl nitrones led to lower enantioselectivities [65]. 

A novel approach to azabicyclic ring systems, based on an epoxide-initiated electrophilic cyclization of an alkyl azide, has been developed by Baskaran. A new stereo- and enantioselective synthesis of the 5-hydroxymethyl azabicyclic framework 91a, present in (+)- and (-)-indolizidines 167B and 209D, for example, was... 

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. 

The synthesis of 4-alkyl-y-butyrolactones 13 and 5-alkyl-<5-valerolactones 14 can be achieved in high enantiomeric excess by alkylation of ethyl 4-oxobutanoate and ethyl 5-oxopentanoate (11, n = 2, 3). The addition of diethylzinc, as well as dimethylzinc, leads to hydroxy esters 12 in high optical purity. When methyl esters instead of ethyl esters are used as substrates, the enantioselectivity of the addition reaction is somewhat lower. Alkaline hydrolysis of the hydroxy esters 12, followed by spontaneous cyclization upon acidification, leads to the corresponding y-butyro- and -valerolactones32. 

Metalated SAMP- or RAMP-hydrazones derived from alkyl- or arylethyl ketones 3 add to arylaldehydes both diastereo- and enantioselectively. Substituted / -hydroxy ketones with relative syn configuration of the major diastereomer are obtained with de 51-80% and 70-80% ee. However, recrystallization of the aldol adducts, followed by ozonolysis, furnishes diastereo- and enantiomerically pure (lS, S )-. yn-a-mcthyl-/3-hydroxy ketones 5 in 36-51% overall yield. The absolute configuration of the aldol adducts was established by X-ray crystallographic analysis. Starting from the SAMP- or RAMP-hydrazone either enantiomer, (S,S) or (R,R), is available using this methodology16. 

Chapters 1 and 2 focus on enolates and other carbon nucleophiles in synthesis. Chapter 1 discusses enolate formation and alkylation. Chapter 2 broadens the discussion to other carbon nucleophiles in the context of the generalized aldol reaction, which includes the Wittig, Peterson, and Julia olefination reactions. The chapter and considers the stereochemistry of the aldol reaction in some detail, including the use of chiral auxiliaries and enantioselective catalysts. 

Phosphine ligands based on the ferrocene backbone are very efficient in many palladium-catalyzed reactions, e.g., cross-coupling reactions,248 Heck reaction,249 amination reaction,250 and enantioselective synthesis.251 A particularly interesting example of an unusual coordination mode of the l,l -bis(diphenylphosphino)ferrocene (dppf) ligand has been reported. Dicationic palladium(II) complexes, such as [(dppf)Pd(PPh3)]2+[BF4 ]2, were shown to contain a palladium-iron bond.252,253 Palladium-iron bonds occur also in monocationic methyl and acylpalladium(II) complexes.254 A palladium-iron interaction is favored by bulky alkyl substituents on phosphorus and a lower electron density at palladium. 

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphi-noxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereo- and enantioselective allylation of substituted nitroalkanes has also been reported.9513... 

---