Indolizomycin

The fragility of this natural product notwithstanding, S.J. Danishefsky and his group at Yale disclosed, in 1-990, the first chemical synthesis of racemic indolizomycin (1).2 The construction of such a vulnerable substance in the laboratory is a most admirable achievement. The remainder of this chapter is devoted to Danishefsky s elegant total synthesis of ( )-indolizomycin [( )-1],... 

L-idose 293, 311 ff. imine formation 57 imine-enamine tautomerization 467 iminium-RhH jt complex 351 f. imipenem 348 indoline ligands 681, 684 indolizomycin 47 Iff. -.retrosynthetic analysis 472ff. 

Further studies on the mechanism of resistance of aminoglycoside antibiotics focused on resistance genes existing in antibiotic-producer strains (mainly by Drs. Y. Okami and Kunimoto Hotta), and gradually clarified the relationship between the antibiotic-producing and -regulating mechanism. During this search, indolizomycin (1984) was discovered by cell fusion of two kinds of strains. 

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. 

Ring closure to an episulfide is a feasible reaction for thiocarbonyl ylides. In most cases, the sulfur is further extruded under the reaction conditions to afford an olefin as the final product. This cascade transformation has been utilized by Danishefsky and co-workers in their total synthesis of ( )-indolizomycin (Scheme 16)." In the Danishefsky s approach, diazo ketone 137 is treated with a catalytic amount of Rh2(OAc)4 to generate thiocarbonyl ylide 138, which cyclizes to give episulfide 139. This episulfide isomerizes to mercaptan 140, which is then desulfurized by partially deactivated W-2 Raney nickel. 

S Gomi, D Ikeda, H Nakamura, H Naganawa, F Yamashita, K Hotta, S Kondo, Y Okami, H Umezawa. Isolation and structure of a new antibiotic indolizomycin produced by a strain SK2-52 obtained by interspecies fusion treatment. J Antibiot 37 1491-1494, 1984. 

The first total synthesis of racemic indolizomycin was accomplished by S.J. Danishefsky et a. The natural product s trienyl side chain was elaborated using the classical J-L olefination. The macrocyclic a, 3-unsaturated aldehyde was treated with an ( )-allylic lithiated sulfone to give epimeric acetoxy sulfones upon acetylation. The mixture of epimers was exposed to excess sodium amalgam in methanol to afford the desired ( , , ) triene stereospecifically. 

The isolation, structural elucidation, and biological activity of the extraordinary metabolite indolizomycin (63) were described in the earlier review on simple indolizidine and quinolizidine alkaloids in Volume 28 of this series (7). The compound was obtained from a mutant Streptomyces strain bioengineered by protoplast fusion of two strains that do not normally produce antibiotics 54). It was reported to be exceedingly unstable, undergoing decomposition within a few hours under neutral conditions at room temperature. 

Groaning and Meyers have recently synthesized the (5)-( + )-enantiomer of Danishefsky s early intermediate 65 by a short alternative route (Scheme 9) (57). In one of the key steps, cyclopropanation of the chiral unsaturated bicyclic oxazolidinone 77 took place preferentially on the convex face (>20 1). Subsequent treatment of the product 78, a masked acyliminium ion, with aliyltrimethylsilane and titanium tetrachloride introduced the allyl group at the angular position, again with good stereocontrol (20 1). The preparation of (+ )-65 in effect represents a formal synthesis of (- )-indolizomycin (63). 

An advanced example of this simple approach was used by Danishefsky in the synthesis of the antibiotic indolizomycin.30 This example illustrates the compatibility of the Julia olefination with many sensitive functional groups. The enal 154 was combined with the lithium derivative of an allylic sulfone and the adduct acylated to give a mixture of isomers of the adduct 155. Elimination with sodium amalgam gave a good yield of the , , -triene 156. [The R s are protecting groups.]... 

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