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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Azides bearing a suitably disposed alkene, when treated with either mercuric perchlorate or mercuric trifluoromethanesulfonate, produce bicyclic iminium ions. This new version of the Schmidt reaction proceeds by capture of the mercuronium ion intermediate by the azide to produce an aminodiazonium ion, which suffers a 1,2-shift to give an iminium ion (e.g., 10 --> 16 --> 17 --> 18). Reduction of the iminium ion may then be carried out to produce an amine. Compared to earlier work on the protic acid-promoted intramolecular Schmidt reaction of azido-alkenes, the mercury-promoted Schmidt reaction has several advantages. First, the acid-promoted Schmidt reaction of azido-alkenes requires that the intermediate carbocations be tertiary, allylic, benzylic, or propargylic. The mercury-promoted method has no such limitation; thus even 1,2-disubstituted alkenes may be used. Second, the mercury-promoted method is milder, allowing the presence of acid-sensitive functionality. The protic version, typically employing trifluoromethanesulfonic acid, is limited in its functional group tolerance. Third, whereas carbocation rearrangement is often observed prior to cyclization/rearrangement in the acid-promoted Schmidt reaction, the mercury-promoted method avoids this problem. Fourth, the presence of the mercurio group during the rearrangment may alter the regioselectivity of the 1,2-migration. Finally, the mercury-bearing iminium ions that are the result of the Schmidt reaction were found to be sensitive to protodemercuration, precluding their use in other transformations.

Mammalian flavin-containing monooxygenase (FMO) is active towards many drugs with a heteroatom having the properties of a soft nucleophile. Thiocarbamides and thiones are S-oxygenated to the sulfenic acid which can either react with glutathione and initiate a redox-cycle or be oxygenated a second time to the unstable sulfinic acid. In this study, we utilized LC-MS/MS to demonstrate that the oxygenation by hFMO of the thioureas under test terminated at the sulfenic acid. With thiones, hFMO catalyzed the second reaction and the sulfinic acid rapidly lost sulfite to form the corresponding imidazole. Thioureas are often pulmonary toxicants in mammals and, as previously reported by our laboratory, are excellent substrates for hFMO2. This isoform is expressed at high levels in the lung of most mammals, including non-human primates. Genotyping to date indicates that individuals of African (up to 49%) or Hispanic (2–7%) ancestry have at least one allele for functional hFMO2 in lung, but not Caucasians nor Asians. In this study the major metabolite formed by hFMO2 with thioureas from Allergan, Inc. was the sulfenic acid that reacted with glutathione. The majority of thiones were poor substrates for hFMO3, the major form in adult human liver. However, hFMO1, the major isoform expressed in infant and neonatal liver and adult kidney and intestine, readily S-oxygenated thiones under test, with Kms ranging from 7–160 μM and turnover numbers of 30–40 min−1. The product formed was identified by LC-MS/MS as the imidazole. The activities of the mouse and human FMO1 and FMO3 orthologs were in good agreement with the exception of some thiones for which activity was much greater with hFMO1 than mFMO1.

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