Chelation ketone reduction

With an oxygen-bearing stereocenter in proximity to the C-16 ketone carbonyl in 155, the prospects for achieving a diastereose-lective ketone reduction seemed favorable. From the work of Mori and Suzuki, it was known that similarly constituted ketones are amenable to /i-chelation-controlled reductions with lithium alumi-... 

A survey of several of alkylborohydrides found that LiBu3BH in ether-pentane gave the best ratio of chelation-controlled reduction products from a- and (3-alkoxy ketones.134 In this case, the Li+ cation acts as the Lewis acid. The alkylborohydrides provide an added increment of steric discrimination. 

Reduction of jl-hydroxyketones through chelated transitions states fovors syn-1,3-diols. Boron chelates have been exploited to achieve this stereoselectivity.86 One procedure involves in situ generation of diethylmethoxyboron, which then forms a chelate with the /1-hydroxy ketone. Reduction with NaBH4 leads to the syn diol.87... 

Step 2 Chelation-controlled reduction of the ketone produces the anti-alcohol diastereoselectively. 

Dichloroindium hydride (Cl2InH), generated by the reaction of InCl3 with tributyltin hydride, is also successfully used for the reduction of carbonyl compounds and for the debromination of alkyl bromides.366 This reductant has features such as the chemoselective reduction of functionalized benzaldehydes, chelation-controlled reduction of benzoin methyl ether, and 1,4-reduction of chalcone. The stable carbene and tertiary phosphine adducts of indium trihydride, InH3 CN(Mes)CH=CHN(Mes) and InH3 P(c-G6H11)3, reduce ketones to alcohols (Equation (90)).367... 

Transition states for reduction according to our usual model of chelation-controlled 2-acyl 1,3-dithiane 1-oxide reactivity, together with steric approach control were proposed to rationalize the high levels of observed stereoselectivity. Previous work by Solladie suggests that ketone reduction by the DIBAL/ZnCl2 system does indeed involve such chelated transition states.15... 

A boat form can also be invoked 83). It should be noted that the direction of attack is opposite to that proposed for chelation controlled reduction of p-hydroxy ketones 104W. 

The stereocontrolled reduction of optically pure P-keto sulfoxides (60) with DIBAL-H anti selective, >93 7) or DlBAL-H in the presence of zinc chloride (syn selective, >95 5) provided an entry to enantio-merically pure alcohols after desulfurization (Scheme 9). The stereoselectivity may be rationalized by consideration of transition states analogous to those described for P-hydroxy ketone reduction (31 and 32), cyclic chelation by zinc chloride and external hydride delivery giving the syn isomer, and coordination of the DIBAL-H to the sulfoxide and internal hydride delivery giving the anti product. 

E. Ghigi and G. Scaramelli. Boll, sci. facolth chim. ind. univ. Bologna 4, 83-5 (1943). Chelation and reduction potential pyrrole ketones. 

The first noncarbohydrate-based asymmetric synthesis of kedarosamine uses the A,0-protected D-threonine 166. It is first converted into the corresponding Weinreb amide via the acyl chloride. Subsequent coupling with the allyl Grignard reagent provides 167. The nonchelation controlled reduction of ketone 167 with NaBH4 is syn selective, whereas 1,2-chelation controlled reduction... 

Moreover, (C6F5)3B-promoted reduction of simple a-substituted ketone 33a with Bu3SnH gave a mixture of diastereomeric alcohols 34, whereas chelation controlled reduction of a-methoxy-a-methyl ketone 33b with (CgFsfrB/Bu SnH afforded single diastereomer 35 exclusively (Scheme 1-11) [46], ... 

Diisobutylaluminum hydride (DIBAH) is undoubtedly one of the most common reducing agents in organic synthesis and recent interest in the synthetic utility of DIBAH has been directed toward diastereoselective reduction of carbonyl substrates. High, i-syn diastereoselectivity has been achieved in the chelation-controlled reduction of P-hydroxy ketones with DIBAH in THF [49], The choice of solvents strongly affects the selectivity. Use of CH2CI2 or toluene in place of THF did not show any diastereoselectivity. 

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. 

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. 

With the exception of the chelation-controlled reduction of the 1,2-dioxy-substituted radical (Scheme 5) and the radical reactions of ketones with Sml2, most of the radicals illustrated so far were generated from the homolytic cleavage of a carbon-halide or carbon-selenide bond. Radicals can also be generated by other chemical means, such as by the addition of radicals to an a,j8-unsaturated ester as Sato and Nagano have shown (Scheme 8). 

Alternatively, we surmised that the lactone 14 could be converted to Weinreb amide 40, which provided additional options for generation of the homoallylic alcohol 42. For example, through the influence of an a-alkoxy group, homoallylic alcohol 42 could be obtained by either a chelation-controlled reduction of p,y-unsaturated ketone 41 or a non-chelation-controlled allylation of 13 (Scheme 14). Thus, elaboration of lactone 35 into amide 40 began by treatment of 35 with N,0-hydroxylamine hydrochloride in the presence of trimethylaluminum to give the amide 39 in 93% yield. Further, protection of the revealed... 

Ketone reduction. The diastereoselective reduction by this borohydride can take advantage of oxygen substituents at a -position. Addition of TiCU to form chelates before reduction occurs leads to the syn isomers as major products. 

Addition of Grignard reagent to 80 provided ketone 81, thus allowing the introduction of the PI functionality (Scheme 19). Chelation-controlled reduction of 81 with Zn(B 114)2 afforded 82 with diastereoselectivities ranging from 90 10 to 80 20 depending on the PI side chain. The high diastereo-... 

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]. 

The major rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl Coenzyme A reductase (HMG-CoA reductase), has been a therapeutic target for many research groups. A synthesis of the functionalized thiophene 172, prepared for its biological activity, illustrates the utility of 162 for the introduction of one of the hydroxy chiral centers present in the molecule. This chiral center is then exploited for the introduction of the second chiral hydroxy center. Treatment of aldehyde 169 with the double anion of 162 at —95 °C in THF affords as the major product 170 (98.8 1.2). Treatment of the adduct with excess tert-butylacetate enolate at — 78 °C followed by acidic work-up furnishes the jS-hydroxyketone 171 in 86% isolated yield. Chelation-controlled reduction of the ketone, accomplished by initial complexation of the ketone and the hydroxy group with triethylborane followed by sodium borohydride addition, provides the desired dihydroxyester 172 (Scheme 39) [47]. 

Stereoselective Reductions. The reduction of 4-f-butylcyclo-hexanone and (1) by LiAlHa occurs from the axial direction to the extent of 92% and 85%, respectively. When a polymethylene chain is affixed diaxially as in (2), the equatorial trajectory becomes kineticaUy dominant (93%). Thus, although electronic factors may be an important determinant of r-facial selectivity, steric demands within the ketone carmot he ignored. The stereochemical characteristics of many ketone reductions have heen examined. For acychc systems, the FeUdn-Ahn model has heen widely touted as an important predictive tool. Cram s chelation transition state proposal is a useful interpretative guide for ketones substituted at C with a polar group. Cieplak s explanation for the stereochemical course of nucleophilic additions to cychc ketones has received considerable scmtiny. ... 

Interactive model for chelation-controlled ketone reduction... 

Many of the chiral bidentate phosphines synthesized in the last years have also been tested for enantioselective ketone reduction. Some of the results achieved are compiled in Table 2. The influence of phosphine structure on optical selectivity and catalytic activity is considerable, but a reliable correlation could not yet be found. It seems that chiral bidentate 6w(diphenyl)phosphines, like prophos forming 5-membered chelate rings with the rhodium atom and used with great success for the hydrogenation of dehydroaminoacids, are not suitable for ketone reduction because of very low reaction rates. 

Suyama and Gerwick reported a shorter, more practical route to both enantiomers of epiquinamide from the commercially available L-omithine derivative 2127 or its enantiomer.The route to (+)-epiquinamide (2104) is illustrated (Scheme 268). After conversion of 2127 into the Wein-reb amide (—)-2128, reaction with aUylmagnesium bromide produced the ketone (+)-2129, which required no purification apart from washing and extraction. Highly diastereoselective chelation-controUed reduction with lithium tri(teft-butoxy) aluminum hydride followed by mesylation gave the crystalline mesylate (—)-2130, which also did not require chromatographic... 

The ester and catalj st are usually employed in equimoleciilar amounts. With R =CjHs (phenyl propionate), the products are o- and p-propiophenol with R = CH3 (phenyl acetate), o- and p-hydroxyacetophenone are formed. The nature of the product is influenced by the structure of the ester, by the temperature, the solvent and the amount of aluminium chloride used generally, low reaction temperatures favour the formation of p-hydroxy ketones. It is usually possible to separate the two hydroxy ketones by fractional distillation under diminished pressure through an efficient fractionating column or by steam distillation the ortho compounds, being chelated, are more volatile in steam It may be mentioned that Clemmensen reduction (compare Section IV,6) of the hj droxy ketones affords an excellent route to the substituted phenols. 

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