Ikarugamycin synthesis

Harding and Clement s synthesis of trichodiene uses the predictable stereochemical course of the 4tt-electrocycliza-tion to control relative stereochemistry at two adjacent allcarbon atom quaternary centers. Harding and Clement s strategy is conceptually related to Whitesell and Minton s ikarugamycin synthesis that was discussed in the context of Scheme 19.1. 

Complexes of unsymmetrically substituted conjugated dienes are chiral. Racemic planar chiral complexes are separated into their enantiomers 84 and 85 by chiral HPLC on commercially available /f-cyclodextrin columns and used for enantioseletive synthesis [25]. Kinetic resolution was observed during the reaction of the meso-type complex 86 with the optically pure allylboronate 87 [26], The (2R) isomer reacted much faster with 87 to give the diastereomer 88 with 98% ee. The complex 88 was converted to 89 by the reaction of meldrum acid. Stereoselective Michael addition of vinylmagnesium bromide to 89 from the opposite side of the coordinated Fe afforded 90, which was converted to 91 by acetylation of the 8-OH group and displacement with EtjAl. Finally, asymmetric synthesis of the partial structure 92 of ikarugamycin was achieved [27],... 

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 1972 Ito and Flirata reported on the isolation and structure elucidation of (-i-)-ikarugamycin as the first representative of a new class of macrolactam antibiotics [5]. Besides its remarkable biological activity, ikarugamycin is of interest because of its unusual architeeture and it represents an attractive target strueture for organic synthesis [6, 7, 8]. 

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). ... 

Clathrin-mediated endocytosis can be blocked by several pharmacologic inhibitors, including the antipsychotic drug chlorpromazine (Thorazine), the natural product ikarugamycin, and the antiviral drug amantadine. The metabolic poisons phenylarsine oxide and sodium azide also block CMF but additionally inhibit protein synthesis. Culture of cells under conditions that deplete potassium or calcium, treatment of cells with hypertonic sucrose, or acidification of the cytoplasm by addition of... 

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. 

An application of [( n -diene)Fe(CO)3] complexes in acyclic stereocontrol during the asymmetric synthesis of the aj-indacene unit of ikarugamycin has been described OO. The use of the Ti -diene complex [(Ti -Me02CCH=CHCHs=CHCHO)Fe CO)3] in the stereoselective synthesis of the C15-C24 fragment of the bioactive macrolide macrolactin A has been reported ... 

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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