Cylindrospermopsin (CY), a sulfate ester of a tricyclic guanidine substituted with a hydroxymethyluracil, is a cyanobacterial toxin of increasing environmental import as it frequently occurs in drinking water reservoirs. As a toxin, CY mainly targets the liver but also involves other organs. In hepatocytes CY inhibits the synthesis of protein and of glutathione, leading to cell death. The total chemical synthesis of CY has recently been reported (Xie et al., 2000, J. Am. Chem. Soc. 22, 5017-5024). The synthesis has provided analogues of CY to study aspects of the relationship between chemical structure and activity that contribute to toxicity. Protein synthesis inhibition was measured in vitro using a rabbit reticulocyte system. Primary cultures of rat hepatocytes were used to determine the biological activity of CY and analogues in intact cells. Protein synthesis and cell glutathione levels were measured. We could distinguish between CY transport and biological activity by comparing the results in vitro to those in intact cells. The role of the sulfate group in CY toxicity was examined by comparing biological effects of CY with that of CY-DIOL (synthetic CY lacking the sulfate group). The sulfate group was found not to play a role in CY activity or in its uptake into cells, since there was no significant difference in biological activity in vitro or in cells between natural CY and CY-DIOL. The orientation of the hydroxyl group at C7 also had no impact on biological activity or transport of CY, since the C7 epimer of CY (EPI-CY) and the corresponding diol (EPI-DIOL) had activity similar to RAC-CY in vitro and in intact cells. AB-MODEL, the analogue lacking an intact C ring, and the methyl and hydroxyl groups of ring A could inhibit protein synthesis (but at concentrations 500-1000-fold higher than natural CY). Other structurally simpler synthetic analogues lacked biological activity.

The first total synthesis of the novel hepatotoxin (()-cylindrospermopson (1) has been accomplished in 20 steps from 4-methoxy-3-methylpyridine (12) in 3.5% overall yield. The substituted piperidine A ring 19 was generated stereospecifically by a four-step sequence using the addition of trimethylsilylethynylmagnesium bromide to 12 to give 16 and stereospecific addition of vinylcuprate to 16 to form 17. The reaction of diamine 26 with cyanogen bromide produced the cyclic guanidine C ring of 27. The key step in the synthesis was bromination of ketone 31, followed by hydrogenation to liberate the free guanidine, which underwent an intramolecular S N 2 reaction to form the tetrahydropyrimidine ring B of 32. Further hydrogenation reduced the ketone to yield 42% of 32 containing the fully functionalized tricyclic system and protected hydroxymethyluracil side chain of cylindrospermopsin. Hydrolysis of the pyrimidine in concentrated hydrochloric acid and selective monosulfation completed the synthesis of cylindrospermopsin.

In connection with the de elopment of a practical synthesis of the right half, and its analog E7389, of halichondrin B, an efficient and scalable synthesis of the two major building blocks is reported. In addition, a new synthesis of the C20–C26 segment via a regiospecific and stereoselecti e SN2' process is presented. A sulfonamide class of ligands is shown to be effective for asymmetric Ni/Cr-mediated reactions under both stoichiometric and catalytic conditions, and the X-ray structure reveals this class of ligands to be tridentate. On the basis of three X-ray structures, a possible mechanism is suggested for this process. Stable and crystalline Cr(III)/sulfonamide complexes are shown to be effective for catalytic Cr-mediated coupling reactions of allyl, alkenyl, and alkyl halides with aldehydes, and some examples for application of the stoichiometric and catalytic asymmetric processes are presented.

Oxidative cycloaddition of a 2-cyclohexenone or R-tetralone and an alkene with dried Mn(OAc) 3 in benzene at 80-140 °C provides a general route to dihydrobenzofurans 15 and dihydronaphthofurans 17. Although the yields are modest, this one-pot reaction provides simple access to these compounds, which have previously been prepared by multistep routes. Oxidative cycloaddition of 2-cyclohexenones with β-methylstyrenes provides a new route to benzofuranoid neolignans, which was applied to the synthesis of conocarpan ( 22). The formation of 2-acetoxyhexanedioic acids 27 and 47 from acetoxylation of 2-cyclohexenones in HOAc, but not in benzene, opens up a new class of Mn(OAc) 3 reactions and explains Watt and Demir's discovery that much higher yields of R′-acetoxy enones are obtained in benzene than in HOAc.In 1976, Williams and Hunter reported that Mn-(OAc) 3 ‚2H 2 O oxidation of enones in HOAc at reflux affords 6-35% of R′-acetoxy enones. 1,2 In a series of papers initiated in 1984, Watt, Demir, and co-workers reported that using Mn(OAc) 3 dried over P 2 O 5 in benzene at reflux for 1 h to 2 d improves the yields of R′acetoxylation to 50-90%. 3 These reactions proceed by kinetic enolization of 2-cyclohexenone (1a) to give Mn(III) enolate 2a, which loses Mn(II) to give R′-keto radical 3a, which is oxidized by a second equivalent of Mn(OAc) 3 to give R′-acetoxy enone 4a. No explanation was provided for the vastly improved yields obtained in benzene.We found that intramolecular trapping of the R′-keto radicals obtained from cyclohexenones by suitably situated double bonds is much faster than acetoxylation, affording good yields of bicyclic dienones in favorable cases. 4 For instance, oxidative cyclization of 5 with 5 equiv of Mn(OAc) 3 and 1 equiv of Cu(OAc) 2 in benzene at reflux for 40 h affords 61% of 6 as a 3.4:1 E/Z mixture. We therefore decided to examine the intermolecular reactions of cyclohexenones and alkenes. Results and DiscussionOxidative Cycloadditions in Benzene. To our surprise, we found that oxidative addition of 2-cyclohexenones 1a-e with methylenecyclohexane (7a) in benzene at 80 °C for 3 d using Mn(OAc) 3 dried over P 2 O 5 in vacuum as described by Watt affords 25-42% of dihydrobenzofurans 15aa-ea and 0-18% of 6-(1-cyclohexenylmethyl)-2-cyclohexenones 12aa-ea (the first letter corresponds to the 2-cyclohexenone (1a-g) and the second to the alkene 7a-c or 19ab). Grisan (15aa), so named because it contains the griseofulvin skeleton, has been prepared twice by multistep routes 5 and is now available in a single step. No monomeric products are formed from 1a and 1-octene under these reaction conditions.The following mechanistic scheme is consistent with these results. Oxidation of cyclohexenone 1 will form R′keto radical 3. Addition of radical 3 to methylenecyclohexane (7a) will give radical 8, which is tertiary and is therefore readily oxidized by Mn(OAc) 3 to cation 11. 2 Loss of a proton from cation 11 will give 2-alkenyl-2-cyclohexenone 12. Cyclization of 11 will give bicyclic cation 10. Loss of ...