Eschenmoser contraction

Macrocyclic lactones. Ireland and Brown1 have adapted the Eschenmoser contraction of sulfides to a synthesis of five- and six-membered lactones. An example is formulated in equation (1). A hydroxy thioamide is esterified to give a chloro ester, which is then treated in sequence with Nal and phosphine I. The inelhod can also be used for preparation of macrocyclic lactones under high-dilution... 

Homologation of the lactam carbonyl was also efficiently accomplished through standard methods (Scheme 18).58 Hydrogenation of 240 stereoselectively generated 241, which had a cis relationship of the substituents on the heterocyclic system.57-59 Conversion of 241 to the corresponding thiolactam 242, followed by Eschenmoser contraction/sulfide extrusion gave lien ami no ester 243.58 Stereoselective reduction of the a,(S-unsaturated ester moiety could be achieved with NaBHyCN (predominantly 244) or H2 with Pd/C (predominantly 245). 

In the oxidative Eschenmoser sulfide contraction (Scheme 11), thioamide 59 is oxidized by benzoyl peroxide to give either a symmetrical disulfide or the O-benzoate of the thiolactam-S-oxide. In any event, the once-nucleophilic thioamide sulfur atom is now forced to adopt the role of electrophile a reactivity umpolung has, in effect, been achieved.13 The nucleophilic enamide 65 attacks the sulfur atom leading to the formation of sulfur-bridged intermediate 66. The action of a phosphine or a phosphite thiophile on the putative episulfide then gives vinylogous amidine 67. 

Eschenmoser reagent 784 Eschenmoser coupling -.oxidative 102 Eschenmoser sulfide contraction 102, 117ff 122, 474, 478 -.alkylative 119 -.oxidative 119 Eschenmoser-Claisen rearrangement 605 ff., 617 f.. estrone 153 ff. 

This procedure illustrates a broadly applicable method which is essentially that of Roth, Dubs, Gotschi, and Eschenmoser,2 for the synthesis of enolizable /1-dicarbonyl compounds. Although there are various methods for the preparation of /3-dicarbonyl systems,3 the scheme of sulfide contraction widens the spectrum of available methods. The procedure can also be utilized in the synthesis of aza and diaza analogs of /3-dicarbonyl systems. Eschenmoser2 has utilized the method to produce vinylogous amides and amidines in connection with the total synthesis of corrins and vitamin B12.4... 

The synthesis of thiiranes with subsequent elimination of sulfur is an important procedure for the creation of C=C bonds, especially for sterically crowded systems (47,48), in analogy to the Eschenmoser-sulfide-contraction reaction (116). The spontaneous elimination of sulfur was observed in the rhodium-catalyzed reaction of diazo compound 62, which gave rise to the formation of cyclopentenone derivative 63 (117) (Scheme 5.24). A synthesis of indolizomycin was published by Danishefsky and co-workers (118) and involved a similar annulation step. In this case, however, the desulfurization reaction was achieved by treatment with Raney Ni. 

Initial cyclizadons were effected by the addition of an enamine to an imidate ester, both groups being suitably located by ligand coordination.263 An analogous process can be carried out on a thioimidate but a sulfide is formed and removal of sulfur with consequent ring contraction yields the corrin (100).264 These two complementary routes can be effected with different metal ions, nickel(II), palladium(II) and cobalt(III) in the first route, zinc(II) in the second. Removal of zinc ions easily provides the free corrin macrocycle. These two routes are summarized in Scheme 64. The sulfide contraction route was used in the Eschenmoser-Woodward total synthesis of vitamin Bn-265... 

The Eschenmoser reaction is extremely useful for the conversion of amides into enaminoesters via the thioamide reaction with a-haloesters, and triphenylphosphine mediated sulfide contraction, and we are fortunate that Shiosaki has published a thorough review on this topic [180]. The accompanying scheme shows a typical example for which an organometallic route with a lithium or a zinc enolate was not successful [181]. 

Few novel examples of the mono-heteronines have been reported recently. Azonane analogue 321 of antimalarial alkaloid ( )-deoxyfebrifugine is the product of an Eschenmoser sulfide contraction of intermediate thioimidate 320 (Equation 46, <2006SL383>). 

Sakurai, O., Ogiku, T, Takahashi, M., Horikawa, H., and Iwasaki, T. 1994. A new synthetic method of Ib-methylcarbapenems utilizing the eschenmoser sulfide contraction. Tetrahedron Lett 25, 2187-2190. 

The Eschenmoser sulfide contraction has been used for the introduction of C-substituents into nucleosides and A-heterocycles in general, "" e.g. formation of 18. ... 

Piperidine-based aminoketones similar to 456 also featured in syntheses of (+ )-427 by Munchhof and Meyers (Scheme 57) 412), and by Solladie and Chu (Scheme 58) 413). In the former, the enantiomerically pure bicyclic oxazolidine-thione 457 underwent Eschenmoser sulfide contraction under forcing conditions to produce the vinylogous urethane 458, which was simultaneously hydrogenated and hydrogenolyzed over Pearlman s catalyst to give the 2,6-c/s-disubstituted piperidine... 

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