Ikarugamycin, total synthesis

A. Total Synthesis of Natural Products Total Synthesis of Ikarugamycin... 

In order to utilize such a chiral substructure as a source of absolute stereoehemical information in a synthesis, it is necessary to employ the complexes A and ent-A in non-racemie form. While the enan-tioselective preparation of such chiral complexes was achieved in the past more or less exclusively via resolution of raeemic mixtures, the diastereo-selective complexation of chirally modified ligands was shown more recently to be a practical alternative [2]. Another possibility, the enantiose-lective conversion of prochiral metal complexes by means of chiral reagents, has been achieved by W. R. Roush 3]. In a remarkable (formal) total synthesis of the antibiotic (-i-)-ikarugamycin (1), Roush et al. apply their method and demonstrate in a highly convincing fashion the synthetic usefulness of acyclic butadiene-FefCOfj complexes [4]. 

In comparison to the other syntheses of ikarugamycin [6, 8] or tricyclic precursors [9], the (formal) total synthesis according to Roush [4] and Boeckmann [6a] is particularly convincing because of its relatively small number of steps, its extremely high selectivity and its significant overall yield (> 1 % over 28 steps). 

As a Chiral Starting Material in Total Synthesis. Two examples illustrate the reagent s use in total synthesis efforts. A Wit-tig oleflnation followed by an enolate Claisen rearrangement was employed to relay the reagent s chirality into key carbon-carbon bond stereochemistry in the total synthesis of (+)-ikarugamycin (eq 8). ... 

A final example of the use of tartrate-derived crotylboronates in natural product synthesis is illustrated in the formal total synthesis of ikarugamicin (Scheme II-11) [179]. Here, Roush and Wada used the asymmetric crotylboration of meso-(t/" -2,4-hexadien-1,6-dial)iron tricarbonyl 266 with (S,S)-(E)-219 to set three stereocenters in their synthesis of the a,s-indacene unit of ikarugamycin. This key reaction provided 267 in 90% yield and >98% ee. Homoallylic alcohol 267 was converted to the allylic acetate 268, which underwent stereoselective ethylation with EtsAl with retention of stereochemistry. The resulting adduct 269 was subsequently elaborated to as -indacene unit 271 through a 15-step synthetic sequence, including the intramolecular Diels-Alder reaction of 270. 

A number of applications in the synthesis of complex structures have been documented. The versatility of the Roush allylboron reagents is demonstrated in the diverse range of substrates that have been successfully employed. In a formal total synthesis of ikarugamycin, the diene in 31 was protected as the iron complex, and the aldehyde in 31 underwent crotylation to afford 33 in 98% ee (Equation 5) [63]. 

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