Stereoselective reduction borohydride

Other Borohydrides. Potassium borohydride was formerly used in color reversal development of photographic film and was preferred over sodium borohydride because of its much lower hygroscopicity. Because other borohydrides are made from sodium borohydride, they are correspondingly more expensive. Generally their reducing properties are not sufficiently different to warrant the added cost. Zinc borohydride [17611-70-0] Zn(BH 2> however, has found many appHcations in stereoselective reductions. It is less basic than NaBH, but is not commercially available owing to poor thermal stabihty. It is usually prepared on site in an ether solvent. Zinc borohydride was initially appHed to stereoselective ketone reductions, especially in prostaglandin syntheses (36), and later to aldehydes, acid haHdes, and esters (37). 

A McMurry coupling of (176, X = O Y = /5H) provides ( )-9,ll-dehydroesterone methyl ether [1670-49-1] (177) in 56% yield. 9,11-Dehydroestrone methyl ether (177) can be converted to estrone methyl ether by stereoselective reduction of the C —double bond with triethyi silane in triduoroacetic acid. In turn, estrone methyl ether can be converted to estradiol methyl ether by sodium borohydride reduction of the C17 ketone (199,200). 

The properties of chlorine azide resemble those of bromine azide. Pon-sold has taken advantage of the stronger carbon-chlorine bond, i.e., the resistance to elimination, in the chloro azide adducts and thus synthesized several steroidal aziridines. 5a-Chloro-6 -azidocholestan-3 -ol (101) can be converted into 5, 6 -iminocholestan-3l -ol (102) in almost quantitative yield with lithium aluminum hydride. It is noteworthy that this aziridine cannot be synthesized by the more general mesyloxyazide route. Addition of chlorine azide to testosterone followed by acetylation gives both a cis- and a trans-2iddMct from which 4/S-chloro-17/S-hydroxy-5a-azidoandrostan-3-one acetate (104) is obtained by fractional crystallization. In this case, sodium borohydride is used for the stereoselective reduction of the 3-ketone... 

Halterman and McEvoy studied hydride reduction of a functionalized 2,2-diarylcyclopen-tanone 8 (Fig. 5) containing an unsubstimted phenyl group and a para-substituted phenyl group, both geminal substituents being assumed to be sterically equivalent [67]. The stereoselective reduction with sodium borohydride of a... 

Chemo- and stereoselective reduction of (56) to (55) is achieved In highest yield by sodium borohydride in ethanol. The isolated ketone is reduced more rapidly than the enone and (55) is the equatorial alcohol. Protection moves the double bond out of conjugation and even the distant OH group in (54) successfully controls the stereochemistry of the Simmons-Smith reaction. No cyclopropanation occurred unless the OH group was there. Synthesis ... 

TABLE 3-3. Asymmetric Acylation Using (2A,5A)-24 and Subsequent Stereoselective Reduction with Zinc Borohydride in THF at —78°C... 

The stereoselective total synthesis of both ( )-corynantheidine (61) (170,171) (alio stereoisomer) and ( )-dihydrocorynantheine (172) (normal stereoisomer) has been elaborated by Szdntay and co-workers. The key intermediate leading to both alkaloids was the alio cyanoacetic ester derivative 315, which was obtained from the previously prepared ketone 312 (173) by the Knoevenagel condensation accompanied by complete epimerization at C-20 and by subsequent stereoselective sodium borohydride reduction. ( )-Corynantheidine was prepared by modification of the cyanoacetate side chain esterification furnished diester 316, which underwent selective lithium aluminum hydride reduction. The resulting sodium enolate of the a-formyl ester was finally methylated to racemic corynantheidine (171). 

Kosicki, G. W., Westheimer, F. H. Oxaloacetate decarboxylase from cod. Mechanism of action and stereoselective reduction of pyruvate by borohydride. Biochemistry 7, 4303—4309 (1968). 

Phillips, T. M., Kosicki, G. W., Schmidt, D. E., Jr. Stereoselective reduction of pyruvate by sodium borohydride catalyzed by pyruvate kinase. Biochim. Biophys. Acta 293, 125-133 (1973). 

The applications of sodium acyloxyborohydrides, formed from sodium borohydrides in carboxylic acid media, are reviewed. ° Useful reviews of the stereoselective reduction of endocyclic C=N compounds and of the enantioselective reduction of ketones have appeared. ... 

Reductive defluorination reactions have also been described in ether, difluoroallylic alkoxides undergo stereoselective reduction (Eq. 138) to the E-mono-fluoro derivatives upon treatment with lithium tetrahydridoaluminate [354]. Sodium borohydride [355] and Red-Al [346] have also been used to achieve this transformation. 

Stereoselective reduction. 2,3-Epoxycyclohexanones can be reduced predominately to the trans-epoxy alcohol by sodium borohydride if catalytic amounts of CeClj are present.1... 

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... 

Stereoselective reductions based on complexed borohydrides have also proved of value in many instances in particular they have been of use in the synthesis of epimeric cyclic alcohols. For example, the reduction of 4-t-butylcyclo-hexanone to the cis-alcohol [99.5%, arising from equatorial hydride ion attack (i)] is effected by L-Selectride (lithium tri-s-butylborohydride, cf. Section 4.2.49, p. 448), or LS-Selectride53 (lithium trisiamylborohydride, cf. Section 4.2.49, p. 448) but to the trans-alcohol [98%, arising from axial hydride ion attack (ii)] with lithium butylborohydride.54 The experimental details of these reductions are given in Expt 5.34. 

Stereoselective reduction of 3-ketogibberellin adds.1 The 3-ketogibberellin acid 1 is reduced by this borohydride almost entirely to the 3/(-alcohol. Reduction with lithium tri-.wr-hutylhorohydride proceeds with the opposite stereoselectivity. The dilfcrence is considered lo be the result of differences in size between potassium and lithium borate complexes with the carboxylic acid group. 

Stereoselective reduction to the appropriate tetrahydro derivatives is observed in the case of the reaction of heteroannelated dihydroazines (R5and R6 are Het, X is N, for example, compounds 346, 348 and 350) with sodium borohydride [174, 295, 296, 297] or with hydrogen in the presence of Pd on A1203 under 3,000 Torr [298] (Scheme 3.93). Reduction of the enamines 346 and... 

In the reactions discussed and exemplified above, reactants, transient species and products are related by linear sequences of elementary reactions. The transient species can be regarded as a kinetic product and, if isolable, subject to the usual tests for stability to the reaction conditions. Multiple products, however, may also occur by a mechanism involving branching. Indeed, the case shown earlier in Fig. 9.5b, where the transient is a cul de sac species, is the one in which the branching to the thermodynamic product P and kinetic product T occurs directly from the reactant. In the absence of reversibility, the scheme becomes as that shown in Scheme 9.8a, where the stable products P and Q are formed as, for example, in the stereoselective reduction of a ketone to give diastereoisomeric alcohols. The reduction of 2-norbornanone to a mixture of exo- and cndo-2-norbornanols by sodium borohydride is a classic case. The product ratio is constant over the course of the reaction and reflects directly the ratio of rate constants for the competing reactions. The pseudo-first-order rate constant for disappearance of R is the sum of the component rate constants. 

In preparation for the eventual removal of the undesired oxygen function at C-10 of 313 via a Birch reduction, the phenol 313 was phosphorylated with diethyl phosphorochloridate in the presence of triethylamine to give 314, which underwent stereoselective reduction with sodium borohydride with concomitant N-deacylation to deliver the amino alcohol 315. N-Methylation of 315 by the Eschweiler-Clarke protocol using formaldehyde and formic acid followed by ammonolysis of the ester group and acetylation of the C-2 hydroxyl function afforded 316. Dehydration of the amide moiety in 316 with phosphorus oxychloride and subsequent reaction of the resulting amino nitrile 317 with LiAlH4 furnished 318, which underwent reduction with sodium in liquid ammonia to provide unnatural (+)-galanthamine. 

The allyl glycoside of a-D-Abe-(l ->3)-a-D-Man 115 was prepared by a different approach.200 The ethyl 1-thio-D-abequopyranoside donor 113 was obtained from methyl (3-D-galactopyranoside derivative 110 according to Scheme 33. The cyclic sulfate intermediate 111 was the precursor for the stereoselective reduction with tetrabutylammonium borohydride to 112 which was further derivatized to the thioglycosyl donor 113. Donor 113 was reacted with acceptor 114 to give 115 after deprotection. 

Stereoselective reduction. A new synthesis of (3S,4S)-statine (4) from N,N-dibenzyl-D-valine (1) depends on reduction of a (3-keto ester (2) with sodium borohydride with nonchelation control owing to the adjacent N,N-dibenzylamino group. 

Zinc borohydride has found many synthetic applications in the context of a chelation-controlled reduction.17 In the synthesis of the antibiotic tirandamycin 30, DeShong et al. prepared a key intermediate (32) via stereoselective reduction of a P-silyloxy ketone18 (Scheme 4.11). Reduction of 31 with Zn(BH4)2 gave the mono-TBS-protected 1,2-syn -2,3-anti -diol 32 stereoselectively. Oxidation of... 

Stereoselective reduction of cyclohexylimines. Imines of alkyl-substituted cyclohexyl ketones are reduced by this borohydride stereoselectively (>90%) to axial secondary amines. Axial primary cyclohexylamines are prepared conveniently by reduction of the imine derived from/ ,/) -dimethoxybenzhydrylamine and sub.scquent cleavage with formic acid (equation 1). 

Stereoselective reduction of ketones. This borohydride (1) is comparable to lithium tri-.ver-butylborohydride (4. 312-313) for stereoselective reduction of cyclic ketones to the less stable alcohols, but less stereoselective than lithium trisiamylborohydride (7, 216-217). The by-product formed in reductions with I can be removed as an insoluble ate complex formed by addition of water, simplifying isolation of the reduction product. 

Stereoselective reduction of -hydroxy ketones." Boron chelates of p-hydroxy ketones are reduced by sodium borohydride stcrcoseicctivciy to, vvn-l,3-diols (equation I). Even higher, sy -selectivity obtains on similar reduction of. wn-a-substituted-p-hydroxy... 

Stereoselective reduction of chiral 2-alkyl-3-keto amides. The chiral propionamide (1) derived from tran.t-2,5-bis(methoxymethoxymethyl)pyrrolidine undergoes stereoselective acylation of the enolate in the presence of ZnCh to give 2-alkyl-3-oxo amides (2). These products undergo reduction with zinc borohydride to give syn-2-alkyl-3-hydroxy amides (3). 

To demonstrate the versatility of his S3mthesis strategy Yamada used ketoester 151 as relais substance to S3mthesize two further picrotoxane alkaloids isolated from Dendrobium species, nobilonine (90) and 2-hydroxydendrobine (87) (Scheme 14) (84). Monobromination of 151 with bromine in dioxane and subsequent treatment with water resulted in hydroxy-y-lactam 152, whereas attempts to hydroxylate 151 by Barton oxidation led to rearrangements. Chemo- and stereoselective reduction with zinc borohydride converted 152 into the en fo-alcohol. To counterbalance the unfavorable conformational equilibrium this alcohol had to be converted into the alcoholate to achieve lactonization. Chemoselective reduction of the hydroxylac-tam moiety of lactone 153 again followed Borch s protocol, which led in this case to boron complexed amino compounds necessitating successive acid treatment to obtain racemic 2-hydroxydendrobine (87) in low yield accompanied by dendrobine (82). 2-Hydroxydendrobine (87) was converted into nobilonine (90) by Eschweiler-Clark methylation. 

Zinc borohydride was effective for the reduction of a,P-epoxy ketones (49) to the corresponding anti-a,3-epoxy alcohols (50) in ether at 0 °C irrespective of the substituents on the epoxide (equation 14). The selectivity was rationalized by intramolecular hydride delivery from a five-membered zinc chelate avoiding the epoxide ring. In a limited study of the stereoselective reduction of y,8-epoxy ketones (51), LAH and di-2-(o-toluidinomethyl)pyrrolidine in ether at -78 C gave the desired c/j-epoxy alcohols (52) required for ionophore synthesis with good selectivity (>10 1) (equation 15). ... 

Stereoselective reduction of a-alkyl-3-keto acid derivatives represents an attractive alternative to stereoselective aldol condensation. Complementary methods for pr uction of either diastereoisomer of a-alkyl-3-hydroxy amides from the corresponding a-alkyl-3-keto amides (53) have been developed. Zinc borohydride in ether at -78 C gave the syn isomer (54) with excellent selectivity ( 7 3) in high yield via a chelated transition state. A Felkin transition state with the amide in the perpendicular position accounted for reduction with potassium triethylborohydride in ether at 0 C to give the stereochemi-cally pure anti diastereoisomer (55). The combination of these methods with asymmetric acylation provided an effective solution to the asymmetric aldol problem (Scheme 6). In contrast, the reduction of a-methyl-3-keto esters with zinc borohydride was highly syn selective when the ketone was aromatic or a,3-unsaturated, but less reliable in aliphatic cases. Hydrosilylation also provided complete dia-stereocontrol (Scheme 7). The fluoride-mediated reaction was anti selective ( 8 2) while reduction in trifluoroacetic acid favored production of the syn isomer (>98 2). No loss of optical purity was observed under these mild conditions. 

Metal-alcohol reductions have also been used in the stereoselective reduction of 3a-hydroxy-7-keto-cholanic acid (26) to the commercially important equatorial 7 3-ol (27). These reductions have been carried out with several alkali metals in secondary and tertiary alcohols, where reduction with K in tertiary alcohols is more stereoselective than Na-isopropyl alcohol. These reductions afford the equatorial alcohol as the major product in good yield, in contrast to sodium borohydride reduction, which provides the axial alcohol (28) almost exclusively. 

Stereoselective reduction of an enone lactone was a key step in the construction of the 20-hydroxyec-dysone side chain. Totally different mixtures of products were obtained when the reduction was carried out with sodium borohydride or by catalytic hydrogenation (Scheme 30). In all cases, the 1,4-reduction mode is preferred. With borohydride, however, this process is followed by a subsequent reduction of the saturated ketone and base-catalyzed rearrangement of the 5-lactone into a y-lactone. 

Yoshikawa, M, Cha, B C, Nakae, T, Kitagawa, I, S3mtheses of pseudo-alpha-D-glucopyranose and pseudo-beta-L-idopyranose, two optically-active pseudo-hexopyranoses, from D-glucose by using stereoselective reductive deacetoxylation with sodium-borohydride and cyclitol formation from nitrofuranose as key reactions, Chem. Pharm. Bull, 36, 3714-3717, 1988. 

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