Diastereoselective reductions, sodium borohydride

Professor Fraga reported the study of diastereoselective reduction In cyclic 1,3-keto ester substrates in 2004 [1], using CaCU as additive to form complexation with 1,3-keto esters substrates to control the reduction. Sodium borohydride was added to the mixture and the selective reduction of ketone carbonyl group happened with 90 % diastereoselectivity. The transition state proposed is shown in Fig. 3.5. 

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. 

By heating 2-benzyloxycyclohexanone 208 and (R)-l-phenylethylamine in refluxing toluene for 4 days in a Dean-Stark apparatus, the imine 209 was formed, then a rearrangement occurred to give first the a-aminocyclohexanone derivative 210 and finally the Q, o -disubstituted imine 211 with moderate diastereoselectivity. Reduction of this imine with sodium borohydride gave a mixture of two trans diamines (S,S)-212 and (R,R)-212, which were separated by chromatography. The enantiomers of 1-benzyl-1,2-diaminocyclohexanes 213 were then obtained by hydrogenolysis [99] (Scheme 31). 

Enantiopure 3-phenyl-2-cyanoazetidines (S)-238 and (K)-238, which are epimeric at C2, are prepared in high yields from (K)-phenylglycinol. A one-pot sequence, including addition of organohthium or allyhnagne-sium bromide to the cyano group and in situ reduction of the resulting imine with sodium borohydride, allowed for the preparation of 2-(l-aminoalkyl)azetidines, which were then protected as N-Boc derivatives (R,S)-239 and (S,it)-239 [112] (Scheme 36). Complete anti diastereoselectivity (dr more than 95 5 by NMR) was observed in both cases. The same sequence... 

The stereoselective epoxidation of chalcones, followed by acid-catalysed ring closure and concomitant cleavage of the epoxide ring, provides a very efficient route to chiral flavon-3-ols and, subsequently, by borohydride reduction to produce flavan-3,4-diols [13, 14], It has been shown that diastereoselective reduction of the chiral flavon-3-ols by sodium borohydride in methanol yields the trans-2,3-dihydroxy compounds, whereas borohydride reduction in dioxan produces the cis-isomers [14] the synthetic procedure confirms the cis configuration of the 2,3-hydroxy groups of naturally occurring leucodelphinidins [14]. 

In related experiments, it was reported that reduction with sodium borohydride of acyl intermediate 43 forms the a,/f-unsaturated product 42 in excellent stereoselectivity and in 58-84% yield [59]. The diastereoselectivity of the reduction was predicted by the Felkin-Anh model (Fig. 7) (Scheme 15). 

A different approach to enantiotopic group differentiation in bicyclic anhydrides consists of their two-step conversion, first with (/ )-2-amino-2-phcnylethanol to chiral imides 3, then by diastereoselective reduction with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) to the corresponding chiral hydroxy lactames 4, which may be converted to the corresponding lactones 5 via reduction with sodium borohydride and cyclization of the hydroxyalkyl amides 101 The overall yield is good and the enantioselectivity ranges from moderate to good. Absolute configurations of the lactones are based on chemical correlation. 

Common achiral reducing agents such as borohydrides produce the anri-isomer 18 as the major product of the reduction of the carbamate protected y-amino-p-oxo esters 31 (Table 4, entries a-e)J36 38 41 50l The syn-isomer is accessible with high diastereoselectivity by reduction of the corresponding AA-dibenzyl p-oxo esters using sodium borohydride stereoselective reduction under nonchelation control (Table 4, entry f).t45 52l... 

Reduction of chiral /3-enamino ketones with sodium borohydride in acetic acid is convenient, stereoselective, and high yielding and allowed the preparation of enan- (g) tiopure y-amino alcohols with syn diastereoselectivity. A mechanistic hypothesis (Scheme 15) has been presented.321... 

A diphenylprolinol derivative, having hydrophobic perfluoroalkyl phase tags, has been synthesized and used as a pre-catalyst to generate in situ a fluorous oxaz-aborolidine catalyst for the reduction of prochiral ketones with borohydride. The system afforded high enantioselectivities and the pre-catalyst is easily separated and recycled.272 Reduction of enantiopure A-p-toluenesulfinyl ketimines derived from 2-pyridyl ketones with sodium borohydride affords A-p-toluenesulfinylamines with good yields and diastereoselectivities.273... 

Three years after Narasaka and Pai s disclosure, Prasad et al. developed a modified procedure to improve syn -diastereoselecti vi ty in the reduction of certain (3-hydroxy ketones6 (Scheme 4.Id). When methoxydiethylborane, in lieu of tributylborane, reacts with p-hydroxy ketones at —70 C in anhydrous methanol, the complex 5BEt2 is formed. Subsequent treatment of the complex with sodium borohydride and quenching the reaction mixture with acetic acid affords yyn-diols in excellent levels of diastereoselectivity regardless of the structure of p-hydroxy ketones. Another practical advantage of Prasad et al. s modification may be an enhanced safety feature, as methoxydiethylborane is generally less hazardous to handle than triethylborane.6... 

An excellent application of the Narasaka reduction is a diastereoselective synthesis by Merck scientists of 7, a structurally novel analog of the natural product compactin (8)7, which is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase8 (Scheme 4.1e). The key step in the construction of the P-hydroxy-8-lactone moiety in 7 is the highly diastereoselective reduction of the P-hydroxy ketone 9 using a triethyl borane/sodium borohydride system. The yyn-diol 10 was obtained in high yield and with a remarkably high level of diastereoselectivity. 

In the stereoselective synthesis of epothilone A (11), Carreira used a syn -reduction methodology in the synthesis of the key intermediate (14)9 (Scheme 4.If). Reduction of the isoxazoline 12 with samarium iodide at 0 C in THF gave the ketone 13. Narasaka reduction of the P-hydroxy ketone 13 using triethylb-orane/sodium borohydride afforded the. syn-diol 14 in high yield and with high diastereoselectivity. 

P-Keto sulfoximines 300 undergo diastereoselective reductions at -78 °C with sodium borohydride or diborane to give mixtures of diastereomeric P-hydroxy sulfoximines. The product diastereoselection increases as the steric demand of the substituent R of 300 increases (Table 19). Reductive removal of the P-sulfoximine group of the diastereomeric mixture of P-hydroxy sulfoximines gives secondary alcohols with the (S)-configuration.125... 

The same diastereoselectivity was observed for reduction with sodium borohydride of enamine functions present in natural products, both in the presence and absence of acetic acid as catalyst126-129. 

Moreover, when 1,6-heptadiene was allowed to react with arylamines in the presence of mercury(II) acetate in tetrahydrofuran at 20 C, mercurated derivatives of piperidine were obtained. After treatment with potassium bromide, sodium borohydride reduction of aminomer-curials in aqueous basic media and tetrahydrofuran/aniline as cosolvents gave 2,6-disubstituted piperidines 4 in good yield. The reaction proceeds with high diastereoselection and the m-iso-... 

The reduction of iV-diphenylphosphinyl imines of substituted cycloalkanones with lithium tri-sw-butylborohydride (L-Selectride) provides highly diastereoselective conversions to protected axial primary amines in 83-96% yield17. The reduction of cyclohexylidene diphenylphos-phinyl imines with sodium borohydride is less diastereoselective17. 

An example of the diastereoselective reduction of a chiral iminium ion compound has recently been reported. The diastereomers were formed, in this case, in a 3 1 ratio20. Chiral iminium ions21,22 derived from chiral (lS)-l-arylethylamines (Ar = phenyl, 2-chlorophenyl, or 2,6-dichlorophenyl) have been reduced stereo selectively with sodium borohydride in 61 77% yield. Diastereoselection of the C=N reduction ranged from 88 12 to 100 0. 

We decided to investigate this reduction further and probe the effect of solvent, temperature, and reducing agent on the diastereoselectivity. Remarkably, changing the solvent to THF reversed the sense of selectivity. More bulky L-selectride showed improved selectivity over that observed with sodium borohydride. Lowering the temperature and moving to more nonpolar solvents increased the selectivity to 10 1 (Table 5.1). 

Nonchelate control. Diastereoselectivity for reduction is important in a synthetic context. Accessibility to defined stereoisomers by reduction of a-amino-P-hydroxy ketones is desirable. Different profiles from reduction with zinc borohydride and sodium borohydride (with slight modification of the substrates) are observed. The results are accountable in terms of chelate and nonchelate transition states."... 

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