Keck method

The 15-hydroxy acids 10a and 10b (Scheme 2) were cyclized with the reliable Yamaguchi (2,4,6-trichlorobenzoylchloride, TEA, DMAP, toluene) [10, 11, 13, 16] and Keck methods (DCC, DMAP, DMAPxHCl, CHCI3) [23, 28]. Both delivered the macrolactones in good to excellent yields, the first (90 % 9b and 78 % 9c) being superior to the latter. 

Keck, J. C. (1978). Rate-controlled constrained equilibrium method for treating reactions in complex systems. In Maximum Entropy Formalism" (R. D. Levine and M. Tribus, eds). M.I.T. Press, Cambridge, MA. 

A further advance occurred when Chesnavich et al. (1980) applied variational transition state theory (Chesnavich and Bowers 1982 Garrett and Truhlar 1979a,b,c,d Horiuti 1938 Keck 1967 Wigner 1937) to calculate the thermal rate coefficient for capture in a noncentral field. Under the assumptions that a classical mechanical treatment is valid and that the reactants are in equilibrium, this treatment provides an upper bound to the true rate coefficient. The upper bound was then compared to calculations by the classical trajectory method (Bunker 1971 Porter and Raff 1976 Raff and Thompson 1985 Truhlar and Muckerman 1979) of the true thermal rate coefficient for capture on the ion-dipole potential energy surface and to experimental data (Bohme 1979) on thermal ion-polar molecule rate coefficients. The results showed that the variational bound, the trajectory results, and the experimental upper bound were all in excellent agreement. Some time later, Su and Chesnavich (Su 1985 Su and Chesnavich 1982) parameterized the collision rate coefficient by using trajectory calculations. 

Keck reported that the reduction of (3-hydroxy ketones with Sml2 is an excellent method for the preparation of 1,3-arth-diols.13 For example, reduction of 9 with Sml2 in THF with MeOFi gave 1,3-anfz-diol 10 in 95% yield and 98% de. The reaction proceeds by initial coordination of Sm(II) to the free hydroxyl, followed by intramolecular electron transfer to the ketone carbonyl to form ketyl radical anion 11. A second electron transfer gives alkylsamarium... 

Variational transition state theory was suggested by Keck [36] and developed by Truhlar and others [37,38]. Although this method was originally applied to canonical transition state theory, for which there is a unique optimal transition state, it can be applied in a much more detailed way to RRKM theory, in which the transition state can be separately optimized for each energy and angular momentum [37,39,40]. This form of variational microcanonical transition state theory is discussed at length in Chapter 2, where there is also a discussion of the variational optimization of the reaction coordinate. 

This reaction has been utilized in the context of natural product synthesis. A recent example is the synthesis of colletodiol by Keck, shown in equation (45). In this example, no problems were encountoed with epimerization or ester cleavage. The desireid ( )-ester (182) was synttesized in 80% yield. Two examples are outlined (in equations 46 and 47) in which epimerization was a substantial problem with sodium or potassium salts, while the LiCl/amine method effectively suppressed this side reaction. When the phosphonate was allowed to react with the cyclohexanal derivative (183), the sodium salt gave epi-merized material. Use of LiCl and diisopropylethylamine gave an 88% yield of alkene (184), free of epimer (equation 46). In the synthesis of norsecurinine, Heathcock found that the phosphonate anion... 

A. Furstner and co-workers devised an efficient synthesis of (-)-gloeosporone, a fungal germination inhibitor. They utilized the Keck asymmetric allylation method to create the 7(R>homoallylic alcohol subunit. The reaction of the substrate aldehyde in the presence of the in situ generated catalyst provided the product with high yield and as the only diastereomer. It is important to note that it was essential to use freshly distilled Ti(/-OPr)4 for the preparation of the catalyst in order to get high enantioselectivity and reproducible results. 

A convergent, stereocontrolled total synthesis of the microtubule-stabilizing macrolides, epothilones A and B was achieved in the iaboratory of S.J. Danishefsky. During their investigations, they examined several approaches to construct these natural products. One possible strategy to introduce the Cl 5-hydroxyl group in an enantioselective fashion was to use Keck s asymmetric allylation method. Under standard conditions, the reaction provided the desired homoallylic alcohol in good yield and excellent enantioselectivity. 

Rhizoxin is a macrocyclic natural product possessing antibiotic and antifungal properties, and it also exhibits antitumor activity. G.E. Keck and co-workers described a synthetic approach for the construction of this natural product, where they utilized the catalytic asymmetric allylation method as a key strategic element to establish the C13 stereochemistry. ... 

S.J. Danishefsky and co-workers reported the total synthesis of pentacyclic sesquiterpene dilactone, merrilactone A. ° In their approach, they utilized Keck s radical allylation method to achieve the required chain extension. This sidechain was later used to construct one of the cyclopentane rings of the natural product. 

The total synthesis of Stemona alkaloid (-)-tuberostemonine was accomplished by P. Wipf. Late in the synthesis, the introduction of an ethyl sidechain was required. This could be achieved in a novel four-step sequence. First, the allyl sidechain was introduced by the Keck radical allylation. To this end, the secondary alkyl phenylselenide substrate was treated with allyltriphenyltin in the presence of catalytic amounts of AIBN. This was followed by the introduction of a methyl group onto the lactone moiety. The allyl group then was transformed into the desired ethyl group as follows the terminal double bond was isomerized to the internal double bond by the method of R. Roy. This was followed by ethylene cross metathesis and catalytic hydrogenation to provide the desired ethyl sidechain. 

Boden, E. P., Keck, G. E. Proton-transfer steps in Steglich esterification a very practical new method for macrolactonization. J. Org. Chem. 1985, 50, 2394-2395. 

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