Pancratistatin, asymmetric synthesis

Figure 10.36 Enzyme-catalyzed asymmetric synthesis of a pancratistatin analog using a naphthalene dioxygenase and RhuA-catalyzed aldolization for the creation of four contiguous stereocenters.

The synthesis of nitrogen-containing natural products is also possible via diols such as these. Hudlicky and co-workers prepared the bicyclic alkaloid (+)-kifunensine, for example, from 284. 0 More complex molecules can also be prepared, as illustrated by the conversion of 285 into (+)-pancratistatin (291), via synthetic intermediate 290. Banwell et al. reported an asymmetric synthesis of (-)-patchoulenone from 287... 

Cleavage of aziridines has been employed in the asymmetric total synthesis of pancratistatin 57 [47], a compound that is the object of considerable attention thanks to its broad spectrum of antineoplastic activities [48]. The chemistry of vinylaziridines has for the most part been confined to their use in rearrangement sequences resulting in functionalized pyrrolines. Hence, because of the lack of data concerning the ring-opening of vinylaziridines with carbon nucleophiles,... 

Hudlicky, T., Tian, X., Konigsberger, K., Mauiya, R., Rouden, J. and Fan, B. (1996c) Toluene-dioxygenase-mediated as-dihydroxylation of aromatics in enantioselective synthesis. Asymmetric total syntheses of pancratistatin and 7-deoxypancratistatin, promising antitumor agents. J. Am. Chem. Soc., 118, 10752-10765. 

Pancralistatin, [29], The first asymmetric total synthesis of (+)-pancratistatin (94) was reported by Hudlicky 130,26], Thus the bromo olefin 114 (Scheme 15), obtained by a-addition of copper nitrenoid generated from (N-tosyiimino) phenyliodinane to 45, was debrominated to the olefinic aziridine 117. The latter underwent Irons 1,2-ring opening with diarylcyancuprate... 

The elegant asymmetrization methodology of a meso compound, achieved in high enantioexcess under chiral environment, was the highlight of the total synthesis of (+)-pancratistatin (94) reported by Trost and Pulley (31]. The synthesis commenced with ( )-conduritol-A (130), obtained from p-benzoquinone, (Scheme 18) which was converted into the acetonide 131 and thence, via the dialkoxide to the cis-bis carbonate 132 (Scheme 19). The chiral n-ailyl palladium complex A formed on treatment erf 132 with the catalyst generated from chiral bis-amide 133 and n-allyl palladium chloride underwent azide substitution from the less hindered face of the molecule to provide the monocarbonate 134 in excellent yield and with high optical induction. 

Azide is a reactive nucleophile and is used as an ammonia surrogate. Desym-metrization of the dicarbonate 229 occurred by the reaction with TMS azide to afford azide 230 in 82 % yield with higher than 95 % ee. The reaction is a key step in the asymmetric total synthesis of (+)-pancratistatin [83]. 

Recently, palladium-catalyzed asymmetric allylic substitution of an activated cyclohexenol derivative has allowed two enantioselective syntheses of (—)-galantha-mine (75) (234,235). Both approaches rely on the enantioselective preparation of the same tricyclic intermediate, which is subsequently converted to the alkaloid via stereocontrolled transformations the most efficient of which comprised stereoselective allylic oxidation of the cyclohexene moiety (Scheme 5). The same methodology allowed the synthesis of (—)-codeine and (—)-morphine (236). The same group had earlier reported the synthesis of (-l-)-pancratistatin following a related strategy (237). Use of a tosylamide as the nucleophile in the displacement of an activated aryl-cyclohexenol derivative enabled the preparation of a chiral intermediate which... 

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