Asymmetric borohydride reduction

In water, the third-generation (16) and fourth-generation dendrimers (17) induced chirality toward the (S)-enantiomer (50% ee for 16 and 98% ee for 17). In THF high enantiomeric excess was achieved only with the third-generation dendrimer (99% (S) ee for 16 and 3% (S) ee for 17). Dendrimer 16 was recovered from the heterogeneous reaction mixture by nanofiltration on a Millipore microporous membrane system. After regeneration of the catalytic activity by treatment with 

HCl/methanol, it could be reused, yielding the same results (for as many as 10 times). 

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Consequently, Dehmlow and coworkers modified the cinchona alkaloid structure to elucidate the role of each ofthe structural motifs of cinchona alkaloid-derived chiral phase-transfer catalysts in asymmetric reactions. Thus, the quinoline nucleus of cinchona alkaloid was replaced with various simple or sterically bulky substituents, and the resulting catalysts were screened in asymmetric reactions (Scheme 7.2). The initial results using catalysts 8-11 in the asymmetric borohydride reduction of pivalophenone, the hydroxylation of 2-ethyl-l-tetralone and the alkylation of SchifF s base each exhibited lower enantiomeric excesses than the corresponding cinchona alkaloid-derived chiral phase-transfer catalysts [14]. 

Efficient asymmetric borohydride reduction of ketones catalyzed by a chiral aldiminatocobalt(II) complex has recently been developed by Mukaiyama s... 

Asymmetric borohydride reduction. Colonna and Fornasier have examined the reduction of ketones with sodium borohydride under phase-transfer conditions in the presence of optically active ammonium salts containing at least one hydroxyl group. Of the seven catalysts tested (-)-benzylquininium chloride (1) (7, 311) was the most effective for asymmetric reduction of r-butyl phenyl ketone (pivalo-phenone) to the corresponding carbinol with optical yields as high as 32%. Two factors would appear to be important for this asymmetric reduction the catalyst must be conformationally rigid and the hydroxyl group must be in the 8-position to the onium function. ... 

Addition of alkenylzinc 322 to the aldehyde 321 resulted in a diastere-omer mixture (1 1) of allylic alcohol, which was oxidized to afford ketone 303. Although Terashima s asymmetric aluminum reagent did not give the desired alcohol, the asymmetric borohydride reduction catalyzed by the Corey-Bakshi-Shibata reagent gave a 5 1 mixture of separable diastereomers, in favor of the (17J )-alcohol 323. Finally, protective group manipulation and oxidations led to a seco-acid, which was subjected to Yonemitsu-modified Ya-maguchi macrolactonization to yield the macrocycle (201) (Scheme 68). 

It is quickly deacylated in vivo and may qualify as a prodrug. The published synthesis is rather long and bears conceptual similarities to the synthesis of cannabinoids. It has some five asymmetric centers. Dane salt formation between 3,5-di-methoxyani1ine and ethyl acetoacetate followed by borohydride reduction gives synthon The amino group is protected by... 

An interesting example of asymmetric induction has been used for the synthesis of (—)-l from L-tryptophan. Pictet-Spengler cyclization of the corresponding amide (127) with 5-chloropentanal afforded (—)-128 as the sole product. Removal of the unwanted carboxamide function was achieved in good yield by sodium borohydride reduction of die corresponding a-amino nitrile (—)-129, resulting in (—)-l (98). 

Brimble and coworkers176 studied the asymmetric Diels-Alder reactions of cyclopentadiene with chiral naphthoquinones 272 bearing different chiral auxiliaries. The highest endo and facial selectivities were obtained using zinc dichloride as the Lewis acid catalyst and (—)-pantolactone as the chiral auxiliary. Thus, the reaction between cyclopentadiene and 272 afforded a 98 2 mixture of 273 and 274 (equation 76). The chiral auxiliary was removed easily by lithium borohydride reduction. 

Isosorbide (3) and isomannide (4) act as chiral auxiliaries for the sodium borohydride reduction of some prochiral ketones optical yields of up to 20% were achieved. It seems that the isohexides form chiral complexes with sodium borohydride, whereby the chiral information is transferred to the substrate.219 Optical active alcohols were obtained by reduction of appropriate ketones with sodium or lithium borohydride in the presence of isosor-bide.219 Asymmetric reduction of propiophenone using sodium borohydride, modified with (+)-camphoric acid and isosorbide, resulted in C -phenylethylcarbinol in 35% enantiomeric excess.2,9b... 

Organocatalytic asymmetric carbonyl reductions have been achieved with boranes in the presence of oxazaborolidine and phosphorus-based catalysts (Section 11.1), with borohydride reagents in the presence of phase-transfer catalysts (Section 11.2), and with hydrosilanes in the presence of chiral nucleophilic activators (Section 11.3). 

In this approach (17), the prochiral fragment was attached to the auxiliary at only one point making the acid-catalysed release after transformation a simple procedure. Chirality was induced by the borohydride reduction of a carbonyl group on the pro-chiral fragment in the asymmetric environment created by complexation of calcium ions between the Cl and C2 oxygens of the hexose. The diastereomeric purity was good (-70%) but separation of the diastereomers was more problematic. 

Precursor of Useful Chiral Ligands. OPEN is widely used for the preparation of chiral ligands. Organometallic compounds with these ligands act as useful reagents or catalysts in asymmetric induction reactions such as dihydroxylation of olefins, transfer hydrogenation of ketones and imines, Diels-Alder and aldol reactions, desymmetrization of meso-diols to produce chiral oxazolidinones, epoxidation of simple olefins, benzylic hydroxylation, and borohydride reduction of ketones, imines, and a,p-unsaturated carboxylates. ... 

When borohydride reductions are carried out in the presence of either a chiral phase transfer catalyst or a chiral crown ether, asymmetric reduction of ketones occurs but optical yields are low. In the reduction of acetophenone with NaBH4 aided with a phase transfer catalyst (57), 10% ee was obtained. Similarly, reduction of acetophenone with NaBH4 in the presence of the chiral crown ether (58) was ineffective (6% ee)J Sodium borohydride reduction of aryl alkyl ketones in the presence of a protein, bovine semm albumin, in 0.01 M borax buffer at pH 9.2 affords (R)-carbinols in maximum 78% cc. ... 

Although the catalytic asymmetric borane reductions mentioned above are a powerful tool to obtain highly enantio-enriched alcohols, these require the use of a rather expensive and potentially dangerous borane complex. Sodium borohydride and its solution are safe to handle and inexpensive compared to borane complexes. Thus sodium borohydride is one of the most common industrial reducing agents. However its use in catalytic enantioselective reductions has been limited. One of the most simple asymmetric catalysts is an enantiopure quaternary armnonium salt that acts as phase-transfer catalyst. For instance, in the presence of the chiral salt 81 (Fig. 9), sodium borohydride reduction of acetophenone gave the secondary alcohol in 39% ee [124]. The polymer-supported chiral phase-transfer catalyst 82 (Fig. 10) was developed for the same reduction to give the alcohol in 56% ee [125]. 

Optically active P-hydroxysulfoximines which catalyze the asymmetric borane reduction of ketones [110], also catalyze the same reaction with sodium borohydride/trimethylsilyl chloride system as reducing agent [126]. Reduction of a protected a-hydroxyacetophenone afforded the alcohol with 90% ee. 

Both (R)-(-t-)- and (S)-(-)-tertiarybutylphenylphosphine sulphides (6) have been synthesised in high optical purity from (S)-(-)- and (R)-(+)-tertiarybutylphosphinothioic acids, respectively, by formation of the mixed anhydride (5) followed by borohydride reduction (Scheme 2). Reactions of the product (6) have been used to provide routes to optically active phosphinothioic iodides, phosphinodithioates and thioselenophosphinic acids of known configurations. A new method for the asymmetric synthesis of tertiary phosphine oxides has been reported.5 An Arbusov reaction of the optically active 1,3,2-... 

Borohydride reduction of C=0 to CHOH. This salt (1) is a particularly effective catalyst for the reduction of carbonyl groups by potassium or sodium borohydride in a two-phase system (benzene—H O). Indeed, the rate of reduction is faster than in a homogeneous system. Studies with related salts indicate that the hydroxyl group j3 to the N atom is a contributing factor. (Cf. N,N-Dimethylephedrinium bromide, this volume.) Even though (1) is optically active, no asymmetric induction was found in these reductions. 

Borohydride reduction of ketones. The reduction of ketones to alcohols by sodium borohydride in benzene-water has been reported to be catalyzed by this salt (6, 249). However, no asymmetric induction was noted in the case of 2-octanone, 1-phenyl-1-propanone, or acetophenone. More recently, asymmetric induction has been observed with more hindered ketones. The maximum was observed with r-butyl phenyl ketone when an enantiomeric excess of 14% of the (R)-alcohol could be obtained. The enantiomeric excess is only 3.6% in the reduction of isopropyl phenyl ketone. No asymmetric induction was observed when ( —)(R)-N,N-dimethyl-N-dodecylamphetaminium bromide was used as catalyst. The structure of the chiral catalyst is evidently important. ... 

Micelles formed from dodecyl glycosides allowed asymmetric sodium borohydride reduction of alkyl phenyl ketones. The a-D-glucopyranoside gave 98% enantiomeric excess with phenyl ethyl... 

Asymmetric aldolysation of glycolaldehyde has been achieved using the asymmetric acetal derivative (1) with triethylamine or calcium hydroxide the mixture of tetritol stereoisomers (2) obtained after borohydride reduction showed small stereoselectivities for... 

S. Colonna and R. Fornasier. Asymmetric induction in the borohydride reduction of carbonyl compounds by means of chiral phase-transfer catalysts. Part 2. J.C.S. Perkin 1,1978, 371. 

Very low asymmetric inductions have also been observed in the phase transfer borohydride reduction of ketones catalysed by quaternary ammonium derivatives (21) of ephedrine. 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

J -Dehydroquinolizidine reacts with the enantiomeric (—)- and (-l-)-menthyl chloroformates forming (—)- and (-l-)-menthoxycarbonyl- -dehydroquinolizidines. These can be reduced as such or in the form of their immonium salts with sodium borohydride to (—)- and (+)-l-menthoxy-carbonylquinolizidines, which give (+)- and (-)-lupinin, respectively, on reduction with lithium aluminum hydride (243). The optical yield of the asymmetric reduction is about 10%. 

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