Stereoselective reduction double bond hydrogenation

U. Kazmaier, J. M. Brown, A. Pfaltz, P. K. Matzinger, H. G. W. Leuenberger, Formation of C-H Bonds by Reduction of Olefinic Double Bonds Hydrogenation, in Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952-, Stereoselective Synthesis (G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann, Eds.), Vol. E21d, 4239, Georg Thieme Verlag, Stuttgart, 1995. 

The Birch reductions of C C double bonds with alkali metals in liquid ammonia or amines obey other rules than do the catalytic hydrogenations (D. Caine, 1976). In these reactions regio- and stereoselectivities are mainly determined by the stabilities of the intermediate carbanions. If one reduces, for example, the a, -unsaturated decalone below with lithium, a dianion is formed, whereof three different conformations (A), (B), and (C) are conceivable. Conformation (A) is the most stable, because repulsion disfavors the cis-decalin system (B) and in (C) the conjugation of the dianion is interrupted. Thus, protonation yields the trans-decalone system (G. Stork, 1964B). 

Another possibility for asymmetric reduction is the use of chiral complex hydrides derived from LiAlH. and chiral alcohols, e.g. N-methylephedrine (I. Jacquet, 1974), or 1,4-bis(dimethylamino)butanediol (D. Seebach, 1974). But stereoselectivities are mostly below 50%. At the present time attempts to form chiral alcohols from ketones are less successful than the asymmetric reduction of C = C double bonds via hydroboration or hydrogenation with Wilkinson type catalysts (G. Zweifel, 1963 H.B. Kagan, 1978 see p. 102f.). 

The hydrogenolyaia of cyclopropane rings (C—C bond cleavage) has been described on p, 105. In syntheses of complex molecules reductive cleavage of alcohols, epoxides, and enol ethers of 5-keto esters are the most important examples, and some selectivity rules will be given. Primary alcohols are converted into tosylates much faster than secondary alcohols. The tosylate group is substituted by hydrogen upon treatment with LiAlH (W. Zorbach, 1961). Epoxides are also easily opened by LiAlH. The hydride ion attacks the less hindered carbon atom of the epoxide (H.B. Henhest, 1956). The reduction of sterically hindered enol ethers of 9-keto esters with lithium in ammonia leads to the a,/S-unsaturated ester and subsequently to the saturated ester in reasonable yields (R.M. Coates, 1970). Tributyltin hydride reduces halides to hydrocarbons stereoselectively in a free-radical chain reaction (L.W. Menapace, 1964) and reacts only slowly with C 0 and C—C double bonds (W.T. Brady, 1970 H.G. Kuivila, 1968). 

New selected possibilities created by reduction of new types of oxazines (603) in the synthesis of polyfunctional products (473, 554) are presented in Scheme 3.285. Coupling the reduction of the C=N bond with NaBH CN followed by hydrogenation of the N-0 bond or a one-step catalytic hydrogenation, and the double-bond transfer from the C(3) to the C(4) position, enables the synthesis and detection of 14 types of reduction products. In some cases, reduction is stereoselective. 

Substituting deuterium for hydrogen gas in the reduction of BT to DHBT with the catalyst precursor [Rh(NCMe)3(Cp )](BF4)2 has shown that the stereoselective ds-deuteration of the double bond is kinetically controlled by the tj2-C,C coordination of BT. The incorporation of deuterium in the 2- and 3-positions of unreacted substrate and in the 7-position of DHBT has been interpreted in terms of reversible double-bond reduction and arene-ring activation, respectively (Scheme 16.14) [55]. 

Several catalysts are used in the field of microbial reductions. The common features of these catalysts are the high selectivity and their use only on a laboratorial scale. They are applied, for example, in the stereoselective synthesis of pharmaceutical intermediates. The reductions are exclusively selective either in the hydrogenation of the C=C double bond or in that of other reducible groups. One of the most widely used catalysts is baker s yeast. In the following hydrogenations, which are catalyzed by Saccharomyces cerevisiae, high enantioselectivities were achieved (equations 35-38)105-108. 

The stereoselectivity of different catalysts in catalytic hydrogenations is discussed in the chapter on catalysts (pp. 4, 50). In addition to catalytic hydrogenation, a few other methods of reduction can be used for saturation of carbon-carbon double bonds. However, their practical applications are no match for catalytic hydrogenation. 

Stereoselective hydrogenations. The stereochemistry of the hydrogenation of a double bond catalyzed by this Ir(I) complex is markedly controlled by the presence of a carboxamide group. The effect is attributed to coordination between the CONH group and iridium. Reductions of the same substrates with Pd/C show no stereoselection.2... 

Reductive desulfonylation.1 A stereocont rolled method for addition of the steroid side chain to a 17-keto steroid is outlined in scheme (I). The various steps proceed selectively to the sulfone 5. Reductive desulfonylation of 5 with Na/Hg, Na2HP04 in CH3OH gives the desired 6 (57% yield) and the undesired alkene in a 2 1 ratio. The desired stereoselectivity was obtained with lithium in ethylamine. The final step was hydrogenation of the 17(20)-double bond to give a protected cholesterol (7). 

Although the hydrogen atoms are transferred one at a time, this reaction is fast enough that both of these atoms usually end up on the same side of the C=C double bond. This can t be seen in most alkanes produced by this reaction because of the free rotation around C—C bonds. Reduction of a cycloalkene, however, gives a stereoselective product. 

However, in this section, the total synthesis of yingzhaosu A, the lead compound of a particular class of antimalarial 1,2-dioxocins, is reported. The synthesis involves eight steps and a 7.3% overall yield starting from (A)-limonene (Scheme 64). Besides the TOCO procedure that allowed the formation of five bonds in one step, the most intriguing steps involved the selective hydrogenation of a C-C double bond in the presence of a peroxide and an aldehyde functionalities (step vi) and the stereoselective reduction of the side-chain carbonyl with (R)-CBS catalyst (step viii). Last but not least, the old classical fractional recrystallization allowed the separation of yingzhaosu A from its C-14 epimer and saved two synthetic steps <2005JOC3618>. 

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