Chelate control strategy

The scope of the strategy was then extended in spectacular fashion (Scheme 6). The mixture of 19 and 20 was transformed into the corresponding aldehydes 26 through reduction/oxidation of the ester groups. Treatment with the dianion derived from ethyl acetoacetate then led to hydroxyketones 27. Chelation-controlled, syn-selective reduction [9] of this mixture followed by menthonide formation gave 28 as four diaste-... 

The stereochemical outcome of the addition of carbanions to ketones yielding tertiary alcohols (or secondary alcohols in the case of aldehydes) is variable and depends on the substrate, the counterion and the solvent. Numerous applications of this strategy to natural product synthesis from carbohydrates can be found in the literature and this approach was fruitful in pioneering syntheses of polyketide-type products. Here again, the template effect of the sugar plays a tremendous role in the stereochemical outcome of the reaction. Chelation controlled nucleophilic addition can also be used to form chiral centers in a highly predictable way. 

C(3)-substituted allylsilanes (crotylsilanes) participate in chelation-controlled addition reactions with aldehydes to give syn addition products as the major stereoisomers. Generally, the ( )-crotylsilanes are highly selective in the syn sense (>9S 5). In contrast, the (Z)-crotylsilanes are much less selective (60-70 40-30 syn anti Scheme 42). Hayashi and Kumada have report a successful approach to optically active homoallyl alcohols using this strategy. They have reported that useful levels of asymmetric... 

Strategies that have been developed for butenolide constraction include the use of 2-trimethylsilyloxyfuran, which reacts with electrophiles at furan C-5," and, complimentarily, furans carrying a 2-oxy-tin (or 2-oxy-boron) substituent, which, via chelation control, react with electrophiles at C-3." 2,5-Dimethoxy-2,5-dihydrofuran can generate 2-trimethylsilyloxyfuran in situ ... 

A similar strategy utilizing 8-keto esters provided very high diastereoselectivities in the ketyl-alkene coupling process. In these examples, chelation control about the developing hydroxyl and carboxylate stereocenters was the source of the high diastere-oselectivity achieved (eq 23) ... 

Intramolecular cross coupling of aldehydes and ketones proceeds with excellent diastereoselectivity and high yield in suitably functionalized systems wherein chelation control by the resulting Smin species directs formation of the newly formed stereocenters (eq 27) A similar strategy has been utilized with a 8-keto amide substrate to provide a chiral, nonracemic oxazolidinone species. This strategy permits entry to highly functionalized, enan-tiomerically pure dihydroxycyclopentanecarboxylate derivatives (eq 28). 

A strategy for the synthesis of conduritols and related cyclitols by way of a stereodivergent vinylsilane-aldehyde cyclization has been reported (Scheme 13). The stereochemistry of the cyclization was rationalized in terms of boron trifluoroetherate coordination control and tin (TV) chloride chelation control. 

As a result of a chelation-controlled aldol reaction exclusive formation of compound 43 tvith the desired 6(R),7(S),8(R)-triad tvas observed. The structure has been confirmed by X-ray analysis after transformation to a crystalline six-membered lactone. In their macro-lactonizsation strategy to synthesize epothiione B Nicolaou et al. used the same ketone 41 in an aldol reaction vith aldehyde 19. The diastereoselectivity in the aldol addition vas only moderate, giving a ratio of 3 1 in favor of the natural epothiione configuration [33]. 

The Zr-Zn transmetalation, aldehyde addition strategy has also been used in the total syntheses of (-)-ratjadone [85] and fostriecin. In the latter example, the substrate was a chiral epoxyketone, which was converted to a tertiary alcohol in excellent diastereoselectivity by chelation control [86]. More recently, the reaction scope has been extended to the addition to C=N electrophiles to form allylic amides [87] as well as allyl hydroxylamines [88], and to the preparation of frans-1,2-disubstituted cyclopropanes [87, 89]. Powell and Rych-novsky found that the BF3-mediated addition to in situ formed oxacarbenium ions led to a mixture of alkyl and alkenyl ligand transfers [90] (Scheme 18). 

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