Hydrazones enantioselective alkylation

Enders, D., Eichenauer, H. Asymmetric syntheses via metalated chiral hydrazones. Enantioselective alkylation of cyclic ketones and aldehydes. Chem. Ber. 1979, 112, 2933-2960. 

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). 

In an elegant asymmetric synthesis of natural serricornin (148) by Mori et al.164), an overall enantioselective alkylation of diethyl ketone via its SAMP-hydrazone (144) was again the key step. (148) is the sex pheromone of the female cigarette beetle,... 

Enders D, Bockstiegel B (1989) Enantioselective alkylation of 2,2-dimethyl-l,3-dioxan-5-one using the SAMP-/RAMP-hydrazone method. Synthesis... 

Hydrazones for enantioselective alkylation. The THF solvent can become the electrophile in the presence of an activator such as t-BuMe2SiOTf. 

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. ... 

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

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. 

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. 

Excellent enantioselectivities up to complete asymmetric induction are achieved in the preparation of a-alkylated aldehydes, acyclic and cyclic ketones via (-)-(S)- and (+ )-(7 )-1 -amino-2-methoxymethylpyrrolidine (SAMP/RAMP-hydrazones) (see Section 1.1.1.4.2.). Due to the unique mechanism of metalation and alkylation, the absolute configuration of the final products can be predicted. Since both antipodes of the auxiliary are available, either enantiomer of the desired alkylated carbonyl compound can be prepared... 

Cyclic ketones are alkylated via their corresponding SAMP/RAMP-hydrazones in good overall yield and excellent enantioselectivities (72-99%, see Table 2). The enantiomeric excesses can be optimized by the use of diethyl ether instead of tetrahydrofuran as solvent8-29. 

In the case of the asymmetric syntheses of conformationally much more flexible aldehydes and acyclic ketones applying the SAMP-method, the control of both metalation and alkylation selectivity is necessary to reach an excellent overall stereoselectivity. A variety of acyclic ketones can be prepared via the related SAMP-hydrazones in good chemical yields and routinely with overall enantioselectivities of 94-99.5% e.e. 

Recently, Nicolaou et al.167) reported an elegant asymmetric synthesis of the ionophore antibiotic X-14547 A (153) isolated at Hoffmann-La Roche from Strepto-myces antibioticus NRRL 8167. The key step in this synthesis was an enantioselective a-alkylation of n-butanal via its SAMP-hydrazone (151) to produce the intermediate (152). The asymmetric induction as determined by NMR-spectra of the product SAMP-hydrazone, was 95 % e.e. 

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),... 

In addition to the results described, enantioselective access to 2-phosphino alcohols could be accomplished, too [71]. Starting from a borane-protected a-phosphino aldehyde hydrazone 91 as the key intermediate and available by two different approaches, the enantioselective synthesis of the desired 2-phosphino alcohols 93 could be accomplished. Thus, the electrophilic phosphinylation of aldehyde hydrazones 90 (via route I with the chlorodiphenylphosphine-borane adduct or via route II with chlorophosphines and subsequent phosphorus-boron bond formation) and the alkylation of phosphino acetaldehyde-SAMP hydrazones 92 (route III) was carried out (Scheme 1.1.26). 

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. 

Enders, D., Schubert, H. Enantioselective synthesis of P-substituted primary amines, a-alkylation/reductive amination of aldehydes via SAMP hydrazones. Arrgew. Chem., Int. Ed. Engl. 1984, 23, 365-366. 

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