The intramolecular capture of benzocyclobutyl, benzocyclopentyl, and benzocyclohexyl carbocations 7 by azides produces spirocyclic aminodiazonium ions 8, which undergo 1,2-C-to-N rearrangement with loss of dinitrogen to produce benzo-fused iminium ions resulting from either aryl (9) or alkyl (10) migration to the electron-deficient nitrogen atom. Reduction of the iminium ions affords regioisomeric benzo-fused 1-azabicyclo[m.n.0]alkanes, e.g., benzopyrrolizidines, benzoindolizidines, benzoquinolizidines, or perhydrobenzo[f]pyrrolo[1,2-a]azepines in two regioisomeric versions, anilines (e.g., 11-14) and benzylic amines (e.g., 15-18), the result of aryl and alkyl migrations, respectively. Generally, aryl migration is preferred, despite modeling that shows that the lowest energy aminodiazonium ions are those where the departing dinitrogen is preferentially antiperiplanar to the migrating alkyl group rather than the aryl group. The utility of this methodology was illustrated by a formal synthesis of the alkaloid gephyrotoxin 4. A dependence on the efficiency and regioselectivity of the Schmidt reaction upon subtle changes in the structure of the cation precursor was observed, necessitating the exploration of a variety of substrates. Fortunately, these materials were easily made. Ultimately, the azido-alkene 81 bearing a 2-bromoethyl side-chain was useful for the Schmidt reaction, producing the known benzo-fused indolizidine 49, which had been transformed by Ito et al. into gephyrotoxin 4. The synthesis of 49 required nine steps (five purifications) from commercially available 4-methoxy-1-indanone 60 and proceeded in 22% overall yield.

A serious outbreak of hepatoenteritis in 1979 on Palm Island (Queensland, Australia) requiring the hospitalization of about 100 people was found to be due to drinking water in which the cyanobacterium (blue-green alga) Cylindrospermopsin raciborskii was growing. 1 It was discovered that this freshwater alga produces a toxic substance causing hepatotoxicity symptoms in mice identical to those that afflicted the human victims. In 1992, Moore and co-workers 2 described the isolation of the toxin, which was named cylindrospermopsin, and using extensive NMR evidence proposed the tetracyclic structure and stereochemistry shown in 1 for this metabolite. More recently, the same hepatotoxin was isolated from the alga Umezakia natans collected in Lake Mikata (Fukui, Japan) 3 and from Aphanizomenon oValisporum found in Lake Kinneret in Israel. 4 The latter cyanobacterium was also found to coproduce a minor metabolite 7-epicylindrospermopsin, formulated as 2, which was reported to be as toxic as 1. 5 A key premise in the assignment of stereochemistry at C-7 for 1 and 2 is that the molecules exist in the rigid conformations shown, enforced by a hydrogen bond between an enolic uracil D-ring tautomer and the guanidine C-ring. Such a conformation was used to rationalize the observed C-7,8 proton coupling constants in the two isomers. A third metabolite in the series, 7-deoxycylindrospermopsin (3), was also recently isolated from C. raciborskii. 6 Interestingly, this latter compound proved to be nontoxic. Cylindrospermopsin continues to be a serious public health problem, particularly in tropical areas, and has recently been traced to the deaths of livestock in Australia. 7 On the basis of work reported by Runnegar and co-workers it appears that cylindrospermopsin exerts its toxic effects by inhibiting biosynthesis of cell-reduced glutathione. 8 We 9 and others 10 have described studies on the synthesis of cylindrospermopsin, and the Snider group has recently reported a total synthesis of this structurally unique natural product. 10c In this paper we disclose a synthesis which completely controls the six stereogenic centers of the proposed cylindrospermopsin structure 1 and which now proves that the stereochemical assignments at C-7 in fact have been reversed in cylindrospermopsin and the 7-epi compound. Thus, cylindrospermopsin has the constitution shown in 2 and 7-epicylindrospermopsin is 1 (vide infra). Our approach utilizes a novel stereospecific intramolecular [4 + 2]-cycloaddition of an N-sulfinylurea heterodienophile 11 and application of our new efficient uracil synthesis 9c as key strategic steps.Construction of the requisite Diels-Alder precursor 12 with the attendant four stereogenic centers contained in the piperidine A-ring was effected as outlined in Scheme 1. Using the methodology of Comins, 12 an efficient high-yield sequence was developed for preparation of vinylogous urethane 4 involving N-acylation of 4-methoxypyridine with benzyl chloroformate, followed by addition of (allyldimethylsilyl)methylmagnesium bromid...

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Two methods for the generation of iminium ions of the type ArN+(X)=CHR (X = H or alkyl, R = H or alkyl) are reported: (1) the Bronsted‐acid‐promoted rearrangement of benzylic azides and (2) the intermolecular Schmidt reactions of azides XN3 (X = aliphatic) with benzylic carbocations derived from benzylic alcohols ArCH(R)OH. The iminium ions ArN+(X)=CHR behave as cationic 2‐azabutadienes in the presence of alkenes and alkynes, producing 1,2, 3,4‐tetrahydroquinolines and 1,2‐dihydroquinolines by a hetero Diels–Alder reaction.

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