Chelation control zinc borohydride reduction

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. 

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... 

Acylation, Alkylation, and Aldolization (Acyl Species-+ a-, P-, or a/fi-Functionalized Acyl Product) Alkylation reactions of sodium enolates of various lV-acyl-a-methyltoluene-2,a-sultams with selected (both activated and nonactivated ) alkyl iodides and bromides proceed with good C(a)-re stereocontrol (90-99% de). Analogous acylations with various acid chlorides can also be performed, giving p-keto products (97-99% de). Selective reduction of these latter products with Zinc Borohydride (chelate controlled, 82.6-98.2% de) or N-Selectride (nonchelate controlled, 95.8-99.6% de) can provide syn- and anft-aldol derivatives, respectively. ... 

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). 

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. 

Acylation of an oxygen would also be expected to lower its ability to coordinate to a metal ion, and thus to form chelates. Results from the reduction of (5)-4,5-dihydro-5-(l -oxopropyl)furan-2(3//)-one, available in optically active form from glutamic acid, support this notion24. Thus, zinc borohydride gives the chelation-controlled other hand, excellent syn selectivity in the Felkin-Anh sense can be achieved with L-Selectride. The latter method was extended to several other substrates and was uniformly successful24. 

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. 

Zinc borohydride can also be used to achieve chelation-controlled reduction of enantiomerically pure 3-(3-oxoacyl)-2-oxazolidinones. Diastereomeric ratios (syn anti) of > 99 < 1 and yields of >95% were recorded34. 

The. yj/t-sclcctivc reduction with DIBAL-H and zinc(II) chloride is exemplified in Table 12. These reactions presumably occur under chelation control via hydride delivery to the less hindered face of an intermediate such as 5. However, the fact that the combination of sodium borohydride and zinc(II) chloride reacts unselectively has prompted the suggestion that a specific interaction between intermediate 5 and DJBAL-H may also be involved137. Zinc(ll) chloride is not required in stoichiometric amounts (Table 12), although the selectivity may be unsatisfactory if loo little is employed137. 

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."... 

The synthesis of Cbz-protected D-valine methyl ester (296) (Scheme 40) begins with addition of an organometallic reagent to the ester function of 282. The resulting phosphonate 290 undergoes a Wittig reaction with isobutyraldehyde to afford 291. Chelation-controlled reduction of the ketone with zinc borohydride furnishes the a /-alcohol 292 (98% de). A [3,3] rearrangement of trifluoroacetimidate 293 produces allylic amine 294. Elaboration of the olefin to an ester furnishes the D-valine derivative 296 with 85% ee [101]. 

Chelation-controlled addition of 2-propenylmagnesium bromide to 589 affords a 4 1 mixture of allylic alcohols 601 and 285. Since the stereochemistry of the major syn isomer 601 does not possess the correct configuration for the C-5 carbon of the fragment, it is converted to the desired anti isomer 285 by oxidation to an intermediate enone followed by reduction of the carbonyl with zinc borohydride (20 1 ds). 

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