Hydrazones chiral, enantioselective alkylation

Chiral hydrazones have also been developed for enantioselective alkylation of ketones. The hydrazones can be converted to the lithium salt, alkylated, and then hydrolyzed to give alkylated ketone in good chemical yield and with high enantioselec-tivity83 (see entry 4 in Table 1.3). 

Enders, D., Eichenauer, H. Enantioselective alkylation of aldehydes via metalated chiral hydrazones. Tetrahedron Lett. 1977, 191-194. 

Enders, D., Eichenauer, H., Baus, U., Schubert, H., Kremer, K. A. M. Asymmetric syntheses via metalated chiral hydrazones. Overall enantioselective a-alkylation of acyclic ketones. Tetrahedron 1984,40, 1345-1359. 

The stereoselective formation and reaction of hydrazone anions has been reported enantioselective alkylations of aldehydes and ketones (both cyclic and acyclic ) via their chiral hydrazones (97) are achieved in good yield and high optical purity (Scheme 71). 

Conversion of a ketone into the corresponding chiral hydrazone derivative (19) enables alkylation to beachieved with high (<87%)enantioselectivity (Scheme 24). Even more impressive, enantioselective alkylations are observed when the chiral enamine (18) is metalated and treated with alkyl halide. ... 

Chapter 2 provided a general introduction to the a-alkylation of carbonyl compounds, as well as the enantioselective nucleophilic addition on carbonyl compounds. Chiral auxiliary aided a-alkylation of a carbonyl group can provide high enantioselectivity for most substrates, and the hydrazone method can provide routes to a large variety of a-substituted carbonyl compounds. While a-alkylation of carbonyl compounds involves the reaction of an enolate, the well known aldol reaction also involves enolates. 

Regiospecific and enantioselective aldol reactions 168) were also performed with SAMP (137). Lithiated hydrazones obtained from ketones (154) as described above were alkylated with carbonyl compounds and the adducts then treated with chloro-trimethylsilane. The resulting trimethylsilylethers (155) were finally oxidatively hydrolyzed to yield the chiral (3-hydroxyketones (156) (e.e. = 31-62%)168),... 

Hantzsch dihydropyridine synthesis. The original Hantzsch synthesis2 involves condensation of two equivalents of a keto ester with an aldehyde in the presence of ammonia. In an enantioselective version.5 the chirality is introduced by use of a chiral hydrazone (2) of an alkyl acetoacetate prepared from 1. The anion of 2 is then treated with Michael acceptors to form adducts (3), which cyclize to 4-aryl-l,4-dihydropyridines (4), in 64-72% overall yield and in 84-98% ee. 

Application of the Enders SAMP/RAMP hydrazone alkylation method on 1,3-dioxan-5-one derivatives leads to versatile C3 building blocks. To demonstrate the usefulness of the above method, the research group of D. Enders applied it during the first asymmetric total synthesis of both enantiomers of streptenol A. " To obtain the natural isomer, the RAMP hydrazone of 2,2-dimethyl-1,3-dioxan-5-one was used as starting material. This compound was deprotonated with f-butyllithium and alkylated with 2-bromo-1-fert-butyldimethylsilyloxyethane. The chiral auxiliary could be hydrolyzed under mildly acidic conditions to provide the ketone in excellent yield and enantioselectivity. 

The alkylation products of SAMP-hydrazones with A-tosylaziridine can be convertied to chiral y-amino nitriles and ketones.4,5,5-Trisubstituted oxazolidinones such as 12 have been studied in the context of their capacity for inducing enantioselectivity during alkylation of their A(-acyF and (V-methylthiomethyl derivatives. ... 

Acylhydrazones, R CH=N-NHCOR , undergo stereoselective Mannich reactions with silyl ketene acetals to give j8-hydrazido esters, using activation by a chiral silicon Lewis acid. Alternatively, the use of silyl ketene imine gives a /3-hydrazido nitrile. Enantioselective (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) hydrazone alkylation of aldehydes and ketones is the subject of a computational study, providing a useful screening method for possible new candidates. " ... 

Enders, MUller and Demir showed that metallated chiral alkyl acetoacetate hydrazones could be used to generate select 1,4-dihydropyridine derivatives in modest yields with high enantioselectivities." For example, treatment of SADP-hydrazone 246, prepared from the condensation of alkyl acetoacetates and 5-(-)-1 -amino-2-(dimethylmethoxymethyl)pyrrolidine... 

Enantioselective free-radical additions to N-acyl hydrazones mediated by chiral Cu(II) Lewis acids have been demonstrated by Friestad and coworkers [16]. Addition of a variety of alkyl radicals to valerolactam-derived N-acyl hydrazone (54) catalyzed by one equivalent of dehydrated [Cu((S,S)-tBu-box)(H20)2(OTf)](OTf) (55) proceeds with moderate to good yield and high enantioselectivity (Scheme 17.11). Catalytic loadings could be decreased without loss of reactivity, but significant erosion of enantioselectivity was observed. Nevertheless, this methodology represents a viable alternative to classical Strecker and Mannich reactions for asymmetric amine synthesis. 

Chronologically, the successful and efficient asymmetric alkylation of enolates was preceded by the development of chiral azaenolates indeed, the meanwhile classic reagents hke Meyers oxazolines [4], Enders hydrazones RAMP and SAMP [5], and Schollkopf s bislactim ethers [6] were the first auxiharies to enable carbon-carbon bond formation with high (overall) enantioselectivity. 

The deprotonation of chiral hydrazone 13 is obtained using tert-butylUthium as the base at -78°C in THE. The reaction mixture is then cooled to -100°C before the electrophile is added, and the reaction is allowed to warm to room temperature overnight. The corresponding alkylated product 14 is obtained in moderate to good yields with excellent dia-stereoselectivities ranging from 88% to >95%. Ozonolysis finally releases the ketone without any noticeable erosion of the enantioselectivity (Scheme 2.32). 

Extending the application of his strained silacycle reagents, Leighton et al. published a procedure for the enantioselective Friedel-Crafts alkylation with benzoyl hydrazones, catalyzed by a simple chiral silane Lewis acid. The enantiopure silanes were prepared in bulk in a single step from (S,S)- or (k,k)-pseudoephedrine and PhSiCls. After use in the catalytic reaction the pseudoephedrine was recovered in nearly quantitative yield during the workup. Scheme 16.16 shows the best example, in which by employing enantiopure silane 23 a 92% yield and 90% ee of the product was obtained in 48 h [62]. 

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