Kinetic diastereoselectivity

Steric influences of enolate substituents (Ri R2) play a dominent role in kinetic diastereoselection. 

An analogous set of four transition states for the (Z)-imine geometry could also be constructed. The transition state descriptors, such as B(Z,E) and C(Z,E), may be employed to denote boat (B) or chair (C) transition states respectively, possessing (Z)-enolate and ( )-imine geometries. The interrelationships between the stereochemical features of reactants, transition states, and products are summarized in Table 28. Unfortunately, the kinetic diastereoselection in such condensations as a function of either enolate or imine geometry has not been systematically studied. In all the early work in this field... 

The indium-mediated aqueous Barbier-type reaction of crotyl bromide with benzaldehyde shows no diastereo-selectivity. However, the use of preformed crotylindium sesquibromide in DMF affords. sy/z-l-phenyl-2-methyl-3-buten-l-ol (ca. 40% de) after aqueous acidic workup. At 22 °G in DMF prior to workup, a greater relative proportion of //-intermediate is decomposed as compared to its yy/z-diastereomer. The resultant kinetic diastereoselection upgrades the syn anti ratio to 99 1 with a concomitant drop in overall yield (Scheme 14).127... 

Remaricable diastereocontrol was also reported by Trost during alkylation of allylic sulfones with epoxide. A very high kinetic diastereoselectivity was observed in the case of terminal epoxide and branching on the vinyl carbon proximal to sulfone (Scheme 83). 

Syn selective reductions Anti selective reductions The Evans-Tishchenko reduction Kinetic diastereoselection of 1,3-diols Aldol revisited... 

While we are on the subject of anti and yy -l,3-diols, there is a very useful reaction that allows their separation by means of reaction rather than, say, chromatography. The reaction is a kinetic diastereoselection. With a kinetic resolution, one enantiomer of substrate reacts faster than the... 

FDP aldolase exhibits kinetic diastereoselectivity with unnatural chiral aldehyde acceptor substrates. However, even though there is significant discrimination ( 20 1) between the d- and t-enantiomers of the natural substrate Gly 3-P12S1, this is usually not the case with unnatural aldehydes. In fact, resolutions of racemic aldehydes are normally only successful if carried out under thermodynamic control. Often the aldol products can cyclize via formation of a hemiketal, leading to... 

An analogous approach is the stabilization of phosphonium ions by addition of phos-phanes (PMcs, PEts, PPhMca, and PPhaMe) to methyl ketones (acetone, methyl ethyl ketone, 1,1,1-trifluoroacetone, and fluoroacetone) in an aqueous solution of Ga4L (Scheme 10.4). These cations decompose in water but they are persistent for weeks in the nanovessel. However, this stability is pH-dependant. The pH should be low because the guest should be protonated and is regularly exposed to the bulk of water as a consequence of the dynamic behavior of the assembly, but the pH should not be too low because in that case the host would disassemble. Therefore, the optimal value is 5.2. The exact mechanism is still unknown it has been ascertained that the protonated phosphane can be encapsulated but it is not possible to determine where the addition to the ketone occurs, inside or outside the cavity. Due to the chirality of the Ga4L tetrahedron, a kinetic diastereoselectivity is also obtained with chiral ions leading to diastereomeric excesses of 30-50%. 

B. Development of kinetic diastereoselective aldol addition variants through the discovery of optimal metal architectures [B(III), Ti(IV), Sn(II)]. 

Li+, Mg 2+. AP+= enolates give comparable levels of diastereoselection for kinetic aldol reactions. 

Excellent chemical yields, high regio- and, in several cases, high diastereoselectivities are observed. A correlation between enolate geometry and product stereochemistry is found, with (Z)-eno-lates producing ////// -adducts and (L )-cnolates yielding. vvw-adducts preferentially, if these reactions are performed with kinetic control (see Table 1, entries 1 -10)21 -23. 

Optically active y-alkoxycyclopentenones have become popular in the diastereoselective synthesis of hms-3,4-disubstituted cyclopentanones. The Michael addition to these cyclic enones catalyzed by sodium ethoxide in ethanol277 or by potassium tm-butoxide278 279 proceeds under kinetic control trans with respect to the y-substituent. 

A diastereoselective route to d.v-2,3-disubstituted cyclohexanones is based on the kinetically controlled protonation of the enolate obtained via the addition of an arylacetonitrile to 2-sub-stituted 2-cycloalkenones in THF or in THF/HMPA mixtures at — 70-0 °C 299,30°, see also refs 301, 302 and 403. 

When the cyclic enone is unsubstituted, but the resulting enolate is quenched with an electrophile under conditions of kinetic control the irons adduct is formed exclusively303. Particularly successful is the sequential Michael addition/enolate alkylation in diastereoselective routes to frans-a,/j-difunctionalized cycloalkanones and lactones304-308. The key steps in the synthesis of methyl ( + )-jasmonate (3)309-310 (syn/anti diastereoselection) and (-)-khushimone (4) (syn/anti and induced diastereoselection) illustrate this sequence311 (see also Section D. 1.1.1.3.). 

Intermolecular befera-Diels-Alder reactions of enamino ketones with highly substituted vinyl ethers. Effect of high pressure on the kinetics and diastereoselectivity [77]... 

Lubineau and coworkers [18] have shown that glyoxal 8 (Ri = R2 = H), glyoxylic acid 8 (Ri = H, R2 = OH), pyruvic acid 8 (Ri = Me, R2 = OH) and pyruvaldehyde 8 (Ri = H, R2 = Me) give Diels-Alder reactions in water with poor reactive dienes, although these dienophiles are, for the most part, in the hydrated form. Scheme 6.6 illustrates the reactions with (E)-1,3-dimethyl-butadiene. The reaction yields are generally good and the ratio of adducts 9 and 10 reflects the thermodynamic control of the reaction. In organic solvent, the reaction is kinetically controlled and the diastereoselectivity is reversed. 

Owing to the fully reversible equilibrium nature of the aldol addition process, enzymes with low diastereoselectivity will typically lead to a thermodynamically controlled mixture of erythro/threo-isomers that are difficult to separate. The thermodynamic origin of poor threo/erythro selectivity has most recently been turned to an asset by the design of a diastereoselective dynamic kinetic resolution process by coupling of L-ThrA and a diastereoselective L-tyrosine decarboxylase (Figure 10.47)... 

---