Asymmetric chelation control

Hallberg and coworkers [19] have reported an asymmetric chelation-controlled Mizoroki-Heck arylation of prolinol-derived vinyl ether 33 (Figure 7.13). In the presence of a catalytic amount of Pd(OAc)2, a regio- and stereo-selective a-arylation of 33 occurs with... 

Nilsson P, Larhed M, Hallberg A. A new highly asymmetric chelation-controlled Heck arylation. J. Am. Chem. Soc. 2003 125(12) 3430-3431. 

Addition to a-Hydroxy or a-Alkoxy Carbonyl Compounds Chelation-Controlled 1,2-Asymmetric Induction... 

On the other hand, a double asymmetric version where both radical fragments are chiral has been investigated (equation 12) . The stereochemistry of the rearrangement products 20a and 20b is not the result of chelation control, but is determined by the stereochemistry of the hthium-bearing terminus. The significant difference in the stereospecificity of 19a and 19b reveals that a substantial level of mutal recognition of the radical enantiomers takes place during the recombination process. 

The asymmetric addition of organomagnesium and organolithium reagents to a,P-unsaturated carbonyl compounds and especially imines can be achieved in situations where rigid chelation controls the geometry of the transition state. Stereospecific alkyl addition occurs in the case of a chiral leucine-derived imine to provide overall asymmetric alkyl addition to an a,P-unsaturated aldehyde (Scheme 107).380 381... 

The efficiency of this method is highlighted by highly diastereoselective Michael addition arising from specific chelation control by metals. Using the concept of these catalytic reactions, asymmetric carbon-carbon bond-formation can be performed. Reactions of isopropyl 2-cyanopropanoate with vinyl ketones were conducted highly enantioselectively in the presence of RhH(CO)(PPh3)3 with (S,S)-(R,R)-TRAP [14] (R = C6H4-p-OMe 99%, 89% ee) [15]. 

The design for a direct catalytic asymmetric aldol reaction of aldehydes and unmodified ketones with bifunctional catalysts is shown in Figure 36. A Brpnsted basic functionality (OM) in the heterobimetallic asymmetric catalyst (I) could deprotonate the a-proton of a ketone to generate the metal enolate (II), while at the same time a Lewis acidic functionality (LA) could activate an aldehyde to give (III), which would then react with the metal enolate (in a chelation-controlled fashion) in an asymmetric environment to afford a P-keto metal alkoxide (IV). 

The stereochemistry of addition of organomagnesium compounds to ketones is governed by similar factors to those influencing their addition to aldehydes (see Section 6.1.1). For addition of achiral organomagnesium compounds to a-chiral ketones, steric approach control is commonly observed, but chelation control may also operate [63, 64], It is noteworthy that a pioneering asymmetric synthesis — one of the first which could be regarded as virtually stereospecific, was of this type [65] ... 

The directed aldol reaction in the presence of TiC found many applications in natural product synthesis. Equation (7) shows an example of the aldol reaction utilized in the synthesis of tautomycin [46], in which many sensitive functional groups survived the reaction conditions. The production of the depicted single isomer after the titanium-mediated aldol reaction could be rationalized in terms of the chelation-controlled (anft-Felkin) reaction path [37]. A stereochemical model has been presented for merged 1,2- and 1,3-asymmetric induction in diastereoselective Mukaiyama aldol reaction and related processes [47]. 

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... 

Despite the great deal of attention devoted to nucleophilic additions to a-chiral carbonyls, the source of stereoselectivity in these reactions (predicted by Cram s rules of asymmetric induction ) remains largely unresolved. Neither direct structural studies nor correlation of reactant and product stereochemistries have yielded any conclusive support for a single comprehensive model. Similarly, the effect of Lewis acids on these systems is only understood at the level of chelation-controlled additions (vide infra). 

The high levels of 1,2-asymmetric induction observed with ketones did not extend to aldehydes. However, Asami and cowoikers achieved it by pretreating a-alkoxy aldehydes with ZnBr2. - TTie reaction is used in the synthesis of exo-(-t-)-brevicomin and L-rhodinose (Scheme 9). Chelation-controlled addition of a Lewis acidic reagent MeTiCb is reported, and a chelation intermediate is actually detected by low temperature NMR techniques (equation 25). A tied-up method, which involves the precom-plexation of a-alkoxy aldehydes with a Lewis acid and addition of soft C-nucleophiles, shows a high level of asymmetric induction. SnCU and TiCU, capable of forming six-coordinate octahedral complexes, are well suited. RjZn, TMS-CN, allylsilanes or silyl enol ethers are employed as the nucleophiles (equation 26). ... 

A high level of 1,3-asymmetric induction was achieved by the assistance of a Lewis acid. Complexa-tion of a 3-alkoxy aldehyde with TiCU followed by addition of Bu2Zn, allylsilane or silyl enol ethers at -78 C results in chelation-controlled products in >85% selectivities (Scheme 12). Even a considerable level of 1,4-asymmetric induction is observed with the Me2Zn-TiCl4 system (equation 33). ... 

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... 

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