Chelation with zinc borohydride

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. ... 

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. 

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. 

Similar results were obtained with rather more elaborate substrates 4. Treatment with zinc borohydride (Method A) yielded ihe a-chelation" products with d.r. s ranging from 93 7 to >99 <1. while L-Selectride (Method B) gave preferentially the. v vn-products"2. 

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."... 

Another way to stabilize an eclipsed or gauche conformation is to coordinate heteroatom substituents with a metal ion via chelation. Oishi and co-workers reduction of 153 with zinc borohydride proceeds via a chelated species, 154. 2 Chelation of zinc to the hydroxyl and carbonyl groups effectively locks the conformation into that shown in the transition state required for reaction. The methyl and hydrogen are held in place, and the hydride is delivered from the less hindered face (over the hydrogen in 154) to complete the reaction (see secs. 4.4.B and 4.7.B). Since transition metal salts usually behave as Lewis acids, the presence of a heteroatom with... 

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). 

Addition of -butylmagnesium bromide to 624 followed by Swem oxidation affords the ketone 642. Zinc borohydride addition occurs with almost exclusive anri-selectivity (>99 1), leading to 646 in accordance with an a-coordinated transition-state model in which the r -face of the carbonyl is exposed to the reagent. Presumably the MOM-ethers display a crown ether effect to facilitate a-chelation. In marked contrast, L-Selectride shows excellent 5y -selectivity to provide 645 (92 8), consistent with a j5-chelation and/or Felkin— Anh model. The a ri-adduct 646 is converted in five steps to ketone 647, which undergoes a similar highly selective hydride reduction with zinc borohydride to yield the anti,syn,syn-alcohol 648 (96 4). This product is converted in six steps to the r n5-(2i ,57 )-pyrroline 649, which undergoes a Wacker oxidation followed by catalytic reduction to (— )-indolizidine 195B (650) and its C-5 epimer (86 14) (Scheme 142). 

NaBlLt does not seem to be the best reagent for the stereoselective reduction of chiral unfunctionalized acyclic ketones. Bulky complex hydrides such as Li(s-Bu)3BH usually afford better results. When a heteroatom is present in the a- or fi-position, the stereochemical course of the reduction depends also on the possible intervention of a cychc chelated transition state. Also, in this case other complex hydrides are often better suited for favoring chelation (see Zinc Borohydride). Nevertheless, cases are known where excellent degrees of stereoselection have been achieved with the simpler and less expensive NaBUj. Some... 

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... 

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). ... 

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. 

For 2-alkyl-3-oxo esters, zinc borohydride is again the method of choice for chelation-controlled reduction16 2,5. The levels of selectivity are consistently higher than for (i-alkoxy and /(-hydroxy ketones, but follow a similar pattern in that good results are only obtained with unsaturated R1 groups. 

The Cram chelation model (sec. 4.7.B) is an example where the chelation effects of the heteroatom influence the rotamer population and, thereby, the selectivity of the reduction. Zinc borohydride [Zn(BH4)2], effectively chelates the carbonyl oxygen and alcohol oxygen atoms in the reduction of 42 and leads to intermediate 43. Transfer of hydride to the carbonyl gave primarily the anti diastereomer, 45 (4 96, 44/45). When the chelating hydroxyl group was blocked as a tert-butyldiphenylsilyl ether (in 46 - sec. 7.3.A.i), reduction with Red-Al (sec. 4.3) led to a reversal in selectivity (96 4, 47/48).The ability to chelate a heteroatom varies with the reagent used. Lithium aluminum hydride shows less selectivity, due in part to poorer coordination with the heteroatom and reduction of 42 gave a 27 73 mixture of 44 and 45,... 

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. 

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