Zimmerman-Traxler type transition states

A proposed simplified mechanism for the conjugate addition/aldol cyclization, as depicted in Scheme 2.25, is based on detailed mechanistic studies performed on related Rh-catalyzed enone conjugate additions [45]. A model accounting for the observed relative stereochemistry invokes the intermediacy of a (Z)-enolate and a Zimmerman-Traxler-type transition state as shown in 2-110 to give 2-111. 

The stereochemical outcome was rationalized by a Zimmerman-Traxler type transition state 45.64 Assuming the titanium enolate of 42 has a Z-geometry and forms a 7-membered metallacycle with a chairlike conformation, a model can be proposed where a second titanium metal coordinates to the indanol and aldehyde oxygens in a 6-membered chairlike conformation. The involvement of two titanium centers was supported by the fact that aldehydes that were not precomplexed with titanium tetrachloride did not react (Scheme 24.7).63 Ghosh and co-workers further hypothesized that a chelating substituent on the aldehyde would alter the transition state 46 and consequently the stereochemical outcome of the condensation, leading to. vyn-aldol products 47.64 Indeed, reaction of the titanium enolate of 42 with bidentate oxyaldehydes proceeded with excellent. s v -diastereo-selectivity (Scheme 24.8).65... 

The simultaneous use of urea, or thiourea [76] and DABCO catalyst was introduced by the Connon group for the addition of methyl acrylate and benzaldehyde [39]. The study revealed that, although both ureas and thioureas accelerated the reaction relative to the uncatalyzed process, urea was superior to thiourea in terms of stability and efficiency. Chiral thiourea derivatives may offer, however, superior enantioselectivity. It was postulated, that the catalysts operate mainly via a Zimmerman-Traxler-type transition state 69 for addition of the resulting enolate anion to the aldehyde (Scheme 5.15). 

Computational studies suggest that the mechanism of the proline catalyzed aldol cyclization is best described by the nucleophilic addition of the neutral enamine to the carbonyl group together with hydrogen transfer from the proline carboxylic acid moiety to the developing alkoxide. A metal-free partial Zimmerman-Traxler-type transition state involving a chair-like arrangement of enamine and carbonyl atoms and the participation of only one proline molecule has been established [118,119]. On the basis of density functional theory (DFT) calculations Cordova and co-workers [120,121] have studied the primary amino acid intermolecular aldol reaction mechanism. They demonstrated that only one amino acid molecule is involved in the... 

The authors proposed a Zimmerman-Traxler type transition state 56 bearing a Z-enolate, which was based on the fact that mainly T) -haptomeric rhodium enolates exist after conjugate additions. Additionally, this concept could be extended to parallel kinetic resolution reactions with racemic unsymmetrically substituted diones. 

Krische disclosed an intramolecular tandem 1,4-addition/aldol process in the presence of water (Scheme 8.40) [118]. Here, the rate of the aldol cyclization was faster than the competing hydrolysis of the rhodium enolate, so that 150 was isolated in 88% yield and 88% enantioselectivity. The configuration observed for the aldol reaction could be accounted for by the Zimmerman-Traxler-type transition state of the (Zj-enolate. 

Aldehydes react smoothly with these crotylboranes via a six-membered Zimmerman-Traxler type transition state (39), giving homoalkylic alcohols (40) with high enantioselectivity and essentially complete diastereoselectivity. 

Scheme 5.62 Enantioselective Mukaiyama aldol additions mediated by titanium-BINOL complexes 196 according to Mikami and Keck. Proposed Zimmerman-Traxler-type transition state model.

Synthesis of Lopinavir and Ritonavir Core In 2007, Menche and co-workers published an asymmetric reductive amination methodology for p-hydroxy ketones 132 for synthesizing a range of l,3-sy -ammo alcohols 135.The reaction was optimized using Ti(Oi-Pr)4 for the coordination of the intermediate imino alcohol 133 and polymethylhydrosiloxane (PMHS) as the hydride source. The reaction was believed to proceed via the initial formation of an imino alcohol that would coordinate to the Lewis acid to undergo reduction through a Zimmerman-Traxler-type transition state 134 to furnish the corresponding iy -l,3-amino alcohol (Scheme 39.40). 

In 1986, Nagao demonstrated the effectiveness of the acetyl thiazolidi-nethione 80 in combination with Sn(OTf)2 and N-ethylpiperidine for highly stereoselective acetate aldol additions (Scheme 4.9) [57]. It was proposed that the stereochemical outcome was the result of the intermediacy of a closed Zimmerman-Traxler-type transition state 81. This method was utilized in Romo s synthesis of the immunosuppressive agent (-)-pateamine A (84) [58]. The Nagao acetate aldol reaction was implemented twice in the route, giving excellent yields and superb diastereoselectivity. 

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