Enantioselective reductive alkylation

Reductive alkylation using Ir ferrocenyl diphosphine catalysts. Because the synthesis, isolation, and purification of the MEA imine are cost factors, the most attractive method would be an enantioselective reductive alkylation, in analogy to the existing process for rac-metolachlor. At that time, enantioselective reduc-... 

SCHEME 2.65 Enantioselective reduction/alkylation of cinnamaldehyde derivatives 196. 

Blaser H-U, Buser H-P, Jalett H-P, Pugin B, Spindler F. Iridium ferrocenyl diphosphine catalyzed enantioselective reductive alkylation of a hindered aniline. Synlett 1999 (1 Suppl) 867-868. 

The enantioselective reduction of alkyl 3-oxobutanoates by carbonyl reductase (SI) from C. magnoliae was also performed in organic-aqueous two-phase reaction system (Figure 8.15) [llc,d]. 

An attractive alternative to these novel aminoalcohol type modifiers is the use of 1-(1-naphthyl)ethylamine (NEA, Fig. 5) and derivatives thereof as chiral modifiers [45-47]. Trace quantities of (R)- or (S)-l-(l-naphthyl)ethylamine induce up to 82% ee in the hydrogenation of ethyl pyruvate over Pt/alumina. Note that naphthylethylamine is only a precursor of the actual modifier, which is formed in situ by reductive alkylation of NEA with the reactant ethyl pyruvate. This transformation (Fig. 5), which proceeds via imine formation and subsequent reduction of the C=N bond, is highly diastereoselective (d.e. >95%). Reductive alkylation of NEA with different aldehydes or ketones provides easy access to a variety of related modifiers [47]. The enantioselection occurring with the modifiers derived from NEA could be rationalized with the same strategy of molecular modelling as demonstrated for the Pt-cinchona system. 

Scheme 13.17 depicts a synthesis based on enantioselective reduction of bicyclo[2.2.2]octane-2,6-dione by Baker s yeast.21 This is an example of desym-metrization (see Part A, Topic 2.2). The unreduced carbonyl group was converted to an alkene by the Shapiro reaction. The alcohol was then reoxidized to a ketone. The enantiomerically pure intermediate was converted to the lactone by Baeyer-Villiger oxidation and an allylic rearrangement. The methyl group was introduced stereoselec-tively from the exo face of the bicyclic lactone by an enolate alkylation in Step C-l. 

Enantioselective reduction of ketones.1 The ability of diborane in combination with the vic-amino alcohol (S)-2-amino-3-methyl-l,l-diphenyl-l-butanol (12, 31) to effect enantioselective reduction of alkyl aryl ketones involves formation of an intermediate chiral oxazaborolidine, which can be isolated and used as a catalyst for enantioselective borane reductions (equation I). 

Radical chemistry has seen tremendous progress in the past two decades and can now be considered as an eminent sub discipline in synthetic organic chemistry [1-6]. Diastereoselective radical chemistry is well established and many examples of enantioselective radical reactions have appeared in the recent literature. For reviews on diastereoselective radical chemistry see [7-11] for reviews on enantioselective radical chemistry see [12-16] and for reviews on conjugate additions, see [17,18]. This review will detail different ways to introduce asymmetry during a radical reaction. These transformations can be broadly classified into atom transfer reactions, reductive alkylations, fragmentations, addition and trapping experiments, and electron transfer reactions. 

The cationic iridium complex [Ir(cod)(PPh3)2]OTf, when activated by H2, catalyzes the aldol reaction of aldehydes 141 or acetal with silyl enol ethers 142 to afford 143 (Equation 10.37) [63]. The same Ir complex catalyzes the coupling of a, 5-enones with silyl enol ethers to give 1,5-dicarbonyl compounds [64]. Furthermore, the alkylation of propargylic esters 144 with silyl enol ethers 145 catalyzed by [Ir(cod)[P(OPh)3]2]OTf gives alkylated products 146 in high yields (Equation 10.38) [65]. An iridium-catalyzed enantioselective reductive aldol reaction has also been reported [66]. 

The enzyme-catalyzed regio- and enantioselective reduction of a- and/or y-alkyl-substituted p,5-diketo ester derivatives would enable the simultaneous introduction of up to four stereogenic centers into the molecule by two consecutive reduction steps through dynamic kinetic resolution with a theoretical maximum yield of 100%. Although the dynamic kinetic resolution of a-substituted P-keto esters by chemical [14] or biocatalytic [15] reduction has proven broad applicability in stereoselective synthesis, the corresponding dynamic kinetic resolution of 2-substituted 1,3-diketones is rarely found in the literature [16]. 

Enantioselective Birch reduction-alkylation The chiral benzoic acid derivative 1, prepared by condensation of o-hydroxybenzoic acid with L-prolinol followed by cyclization (Mitsunobu reaction), undergoes Birch reduction (K, NH3, THF, t-butyl alcohol) followed by alkylation with C2H5I to give essentially only 2. Acid hydrolysis returns the chiral auxiliary and provides the 2-alkylated cyclo-hexenone 3. 

Asymmetric reduction of ketones. Ipc BCl is somewhat superior to B-3-pin-anyl-9-borabicyclo[3.3.1]nonane (12, 397) for enantioselective reduction of alkyl aryl ketones at normal pressures to (S)-alcohols. In general, optical yields are 78-98%. It is also useful for asymmetric reduction of ketones in which one alkyl group is tertiary. Thus 3,3-dimethyl-2-butanone is reduced in 95% ee at 25°.1... 

Ethylpyridinium tetrafluoroborate, a readily accessible ionic liquid, is an effective solvent for BINOL-promoted enantioselective reduction of aryl alkyl ketones by LAH.324 A chiral diol modifies LAH reagents to give up to 98% ee.325... 

The intramolecular diene-carbene cycloaddition equivalence and an enantioselective Birch reduction-alkylation by the chiral auxiliary approach. Total synthesis of ( )- and (—)-longi-folene. Journal of Organic Chemistry,... 

Finally, this catalyst system was applied to the chemoselective, diastereose-lective, and enantioselective reduction of racemic 2-alkyl-l,3-diketones [57]. Scheme 11 shows examples of this transformation catalyzed by (R,R)-15. To minimize the effects of uncatalyzed reduction, four portions of 0.1 equivalents of modified borohydride with THFA and ethanol (i.e., total 0.4 equiv) were successively added to the substrate solution at -20°C. The selectivity of the carbonyl group at the benzylic position over the simple aliphatic carbonyl function (in... 

The binaphthol-modified lithium aluminum hydride reagents (BINAL-Hs) are also effective in enantioselective reduction of a variety of alkynyl and alkenyl ketones2 (Scheme 4.3b). When the reaction is carried out with 3 equivalents of (S)-BINAL-H at —100 to —78 C, the corresponding propargylic alcohol 3 and allylic alcohol 4 are obtained in high chemical yields with good to excellent levels of enantioselectivity. As is the case with aryl alkyl ketones, the alcohols with (.V)-con figuration are obtained when (S)-BINAL-H is employed. 

The oxazaborolidine-catalyzed enantioselective reduction of aryl alkyl ketones was used in the asymmetric synthesis of the naturally occurring molecule (15 )-(—)-salsolidine 4119 (Scheme 4.3o). The ketone 42 underwent oxazaboroli-dine-mediated reduction to furnish the alcohol 43 in excellent yield and greater than 95% ee. The alcohol 43 was then coupled with the reagent 44 under Mit-sunobu conditions to produce the aminoacetal 45. 

In 1979, Johnson reported the enantioselective reduction of ketones with stoichiometric amounts of optically active (1-hydroxy sulfoximine-borane complexes.131 Prochiral alkyl phenyl ketones (RCOPh) undergo enantioselective reduction with enantiomerically pure p-hydroxy sulfoximine borane complexes (301 and 302). These complexes are prepared by reaction of the corresponding P-hydroxy sulfoximine with borane at -78 °C. The structures 301 and 302 have been suggested for these complexes. In the case of the borane complex 301, the enantioselectivity increased as the steric bulk of the R substituent of the ketone (RCOPh) was decreased from IV to Me. The analogous reductions of methyl alkyl ketones (MeCOR) with these borane complexes were less enantioselective (3-27% ee).131... 

Chiral Ligand of L1A1H4 for the Enantioselective Reduction of Alkyl Phenyl Ketones. Optically active alcohols are important synthetic intermediates. There are two major chemical methods for synthesizing optically active alcohols from carbonyl compounds. One is asymmetric (enantioselective) reduction of ketones. The other is asymmetric (enantioselective) alkylation of aldehydes. Extensive attempts have been reported to modify Lithium Aluminum Hydride with chiral ligands in order to achieve enantioselective reduction of ketones. However, most of the chiral ligands used for the modification of LiAlHq are unidentate or bidentate, such as alcohol, phenol, amino alcohol, or amine derivatives. 

Table 1 Enantioselective Reduction of Alkyl Phenyl Ketones...

The ee s of the obtained alcohols increase according to the increase in steric bulkiness of the alkyl substituents of prochiral ketones. Thus the reduction of t-butyl phenyl ketone occurs with 86% ee whereas reduction of acetophenone gives 51% ee. The enantioselective reduction of f-butyl phenyl ketone and a-tetralone (86 and 88% ee, respectively) are among the most selective of those reported. ... 

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