Chelate-controlled 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. 

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

Further alkylation of the lithium (Z)-enolate of 25 with methyl iodide gave 26, introducing the C16 stereocentre (3 1 dr) and completing the carbon backbone. Oxidation at Cl and carbamate formation gave 27 which underwent a chelation-controlled reduction at C17 (30 1 dr). Finally, global deprotection completed the synthesis of discodermolide (1), with an overall yield of 4.3% achieved over 24 steps in the longest linear sequence. 

Fig. 11.11. Wittig-Horner synthesis of stereouniform alkenes via ketophosphine oxide B. The reaction proceeds via its Felkin-Anh-selective or chelate-controlled reduction to form the syn-configured hydroxyphosphine oxides D and the anti-configured hydroxyphosphine oxides E. D and E continue to react—after deprotonation with KO-tert-Bu—via a syn-elimination to give the trans- and cis-alkene, respectively. R1 in the formula A-C corresponds to a primary (prim-alkyl) or a secondary alkyl residue (sec-altyl).

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... 

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... 

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 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... 

Chelation-controlled reduction is an important method for stereochemical control in open-chain compounds. 

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. 

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. 

Figure 4.14. Applications of oxathianes linalool [53], dimethyl acetylcitramalate [54], mevalolactone [56], malyngolide [55], and the mosquito oviposition attractant [39]. For the latter, the C-5 stereocenter was formed by a chelate-controlled reduction while the C-6 position could be produced as either epimer by a chelate or acyclic mechanism, depending on the reducing agent.

Scheme 5. Chelation-controlled reduction of 1,2-dioxy-substituted radicals...

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... 

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]. 

The reduction of a diastereomeric mixture of enantiomerically pure /3-keto sulfoxides (7) furnished one of the four possible isomers with good overall stereoselectivity (90%), when carried out under conditions which favor epimerization of the a chiral center (eq 16). This outcome derives from a chelation-controlled reduction (involving the sulfoxide oxygen) coupled with a kinetic resolution of the two diastereoisomers of (7). ... 

Guindon Y, Lavallee J-F, Llinas-Brunet M, Homer G, Rancourt J (1991) Stereoselective chelation-controlled reduction of a-iodo-p-alkoxy esters under radical conditions. J Am Chem Soc 113 9701-9702... 

Scheme 69 Chelate-controlled reduction to the B ring fragment of leucascandrolide A [23]...

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