Zinc borohydride ketone reduction

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). 

In the early work on the synthesis of prostaglandins, zinc borohydride was used for the reduction of the 15-ketone function and a 1 1 mixture of epimeric 15(S)- and 15(/ )-alcohols was generally obtained. Subsequent studies led to reaction conditions for highly selective reduction to the desired 15(S)-alcohol. Some of the results are summarized in the following table. The most practical method is E which utilizes borane as the stoichiometric reductant and a chiral, enzyme-like catalyst which is shown. 

Zinc borohydride has been found to effect very efficient reductive amination in the presence of silica. The amine and carbonyl compound are mixed with silica and the powder is then treated with a solution of Zn(BH4)2. Excellent yields are also obtained for unsaturated aldehydes and ketones.96... 

Selective reductions.2 Zinc borohydride in DME can reduce saturated ketones and a,p-enals at —15° without effect on a,P-enones or saturated aldehydes. 

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. 

Zinc borohydride has some interesting properties it is less basic than NaBH4 and thus it is especially suitable for the reduction of base-sensitive compounds. Also, the zinc cation has a better coordinating ability than either Na or Li , making Zn(BH4)2 often the reagent of choice for chelation-controlled, stereoselective reductions of acyclic ketones (see Section 4.12). 

Zinc borohydride is a mild reducing agent permitting the reduction of aldehydes in the presence of ketones. Moreover, it selectively reduces a nonconjugated keto group in the presence of a conjugated keto group. 

Because Zn+2 is a good chelating cation, highly diasteroselectivity reductions of a or p-hydroxy ketones and esters can be achieved with zinc borohydride. Reviews (a) Narasimhan, S. Balakumar, R. Aldrichimica Acta 1998, 31. 19-26. 

A modestly enantioselective pyrrole carbinol formation has been investigated <05SL2420>. Treatment of lithium pyrrolate with a ketoaldehyde in the presence of a chiral ligand preferentially led to the formation of pyrrole carbinol 49 (50% ee). A hydroxy-directed reduction of the ketone in the side chain by the addition of zinc borohydride provided 50 (88% de). Pyrrole carbinols serve as convenient precursors to aldehydes. A subsequent deprotective Horner-Wadsworth-Emmons reaction involving 50 and phosphonate ester 51 gave unsaturated ester 52. 

Helm, R. F., and Ralph, J. (1993) Stereospecificity for zinc borohydride reduction of a-aryloxy-b-hydroxy ketones. J. Wood Chem. Technol. 13(4), 593-601. 

A significant improvement was the introduction of zinc borohydride, which has become the reagent of choice for a variety of chelation-controlled reductions. With a-hydroxy ketones as substrates (Table 3)15,16 the zinc-based reagent is reliably superior to lithium aluminum hydride, presumably because of the increased tendency of zinc(II) ions, compared with lithium ions, to form chelated complexes. The results arc not uniformly excellent, but in many cases the selectivity is highly satisfactory. The method can give useful results with relatively complex substrates, e.g., the reduction of. sv w-3-hydroxy-4-mcthyl-5-triphenylmethoxy-2-pentanone. 

Table 3. anti-, 2-Diols by Selective Reduction of a-Hydroxy Ketones with Zinc Borohydride (Method A)15 16 or Lithium Aluminum Hydride (Method B)13 14... 

In contrast, a,/ -epoxy ketones are good substrates for chelation-controlled reductions. Zinc borohydride is generally effective25, and even sodium borohydride gives the ami-isomer quite selectively provided that the a-carbon bears a hydrogen2h. 

Methoxy-a-(phenylthio) ketones, e.g., 3-methoxy-l-phenyl-2-phenylthiopropanone and 5-methoxy-l-phenyl-4-phenylthio-l-penten-3-onc (Table 6), can also be reduced with syn selectivity by zinc borohydride. calcium borohydride and lithium triethylborohydride82. For zinc and calcium borohydride, at least, it is reasonable to suppose that the transition state 4 (where R3 = MOM) is reinforced by /1-chclation. These reagents are actually more successful than L-Selectride in the reduction of 3-methoxy-1-phenyl-2-phenylthiopropanone, where the L-Se-lectridc result is anomalously poor. A /5-hydroxy substrate, 3-hydroxy-2-mcthylthio-l-phenyI-propanone, could be reduced to 2-methylthio-l-phenyl-l,2-propanediol with good syn selectivity using zinc borohydride (yield 65% d.r. 93 7)81. 

The wH/f-selective reduction of a-alkylthio ketones is less straightforward. Zinc borohydride has been used successfully in some cases, implying that chelation control involving an alkyl(or aryl)thio group is possible. However, the method is not general, as illustrated by the results in the zinc borohydride reductions of 3-methyl-2-methylthio-l-phenylbutanone and 4-methyl-3-phenyl thio-2-pentanone 81. 

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."... 

By Reduction of Carbonyl Compounds. Use of high (10 kbar) pressures has been shown to effect trialkylstannane reductions of ketones in the absence of radical initiators or Lewis acids.10 Zinc borohydride has been demonstrated to be a mild reducing agent for the conversion of benzenethiol esters into alcohols in good yield. Use of mixed solvents containing methanol has been found to confer some chemoselectivity upon reductions with lithium borohydride and permits enhanced rates of reduction of esters, lactones, and... 

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