Glucosepane is a structurally complex protein posttranslational modification that is believed to exist in all living organisms. Research in humans suggests that glucosepane plays a critical role in the pathophysiology of both diabetes and human aging, yet comprehensive biological investigations of this metabolite have been hindered by a scarcity of chemically homogeneous material available for study. Here we report the total synthesis of glucosepane, enabled by the development of a one-pot method for preparation of the nonaromatic 4H-imidazole tautomer in the core. Our synthesis is concise (eight steps starting from commercial materials), convergent, high-yielding (12% overall), and enantioselective. We expect that these results will prove useful in the art and practice of heterocyclic chemistry and beneficial for the study of glucosepane and its role in human health and disease.

Cyclic gamma-silyloxy-beta-hydroxy-alpha-diazoesters undergo efficient rupture of the Cbeta-Cgamma bond when treated with tin tetrachloride to provide tethered aldehyde ynoate products in high yield.

A synthesis of the steroidal alkaloid demissidine from epiandrosterone is reported. A ring fragmentation reaction that efficiently ruptured the D-ring of a diazo ester derivative of epiandrosterone to provide an aldehyde tethered ynoate product was key to this sequence. Incorporation of the indolizidine framework was achieved by an azomethine ylide 1,3-dipolar cycloaddition.

The evolution of the synthetic strategy resulting in a total synthesis of vinigrol is presented. Oxidative dearomatization/intramolecular Diels-Alder cycloaddition has served as the successful cornerstone for all of the approaches. Extensive radical cyclization efforts to form the tetracyclic core resulted in interesting and surprising reaction outcomes, none of which could be advanced to vinigrol. These cyclization obstacles were successfully overcome by using Heck instead of radical cyclizations. The total synthesis features a trifluoroethyl ether protecting group being used for the first time in organic synthesis. The logic of its selection and the group’s importance beyond protecting the C8a hydroxyl group is presented along with a discussion of strategies for its removal. Because of the compact tetracyclic cage the route is built around many unusual reaction observations and solutions have emerged. For example, a first of its kind Grob fragmentation reaction featuring a trifluoroethyl leaving group has been uncovered, interesting interrupted selenium dioxide allylic oxidations have been observed as well as intriguing catalyst and counterion dependent directed hydrogenations.

Detailed in this account are our efforts towards the total synthesis of vinigrol. A highly expedient and convergent synthetic approach made possible by the use of a strategic oxidative dearomatization reaction coupled with a series of ensuing substrate controlled transformations is discussed.In 1987 researchers at Fujisawa Pharmaceutical company reported the isolation of a novel diterpenoid, they had named vinigrol (Figure 1, 1), with an unprecedented 1,5-butane tethered cis-decalin core. 1 Vinigrol has since been shown to be potent as an antihypertensive and platelet-inhibiting agent, as well as having an inhibitory effect on Ca 2+ movement. 2 Subsequently vinigrol was shown to be a tumour necrosis factor (TNF) antagonist 3 with the ability to inhibit the progression of AIDS-related complex to AIDS. 4 Giving this promising biological profile and structure, it is not surprising that a number of synthetic research groups took notice. 5 Twenty years since its isolation, vinigrol has yet to succumb to total synthesis. Interestingly, the first published route by Hanna remains one of the most advanced progresses towards vinigrol.In our quest towards completing an expedient total synthesis of vinigrol we have focused our efforts on synthetic strategies utilizing an oxidative dearomatization coupled with an intramolecular Diels-Alder reaction as the key steps. Towards that end we have disclosed our efforts employing the Wessely and Adler-Becker oxidative dearomatization reactions. 6 Although these disconnections were shown to be conceptually sound they both suffered from weakeness in either one of the key transformations. This communication details our current route, which overcomes the limitations encountered in the previous routes in addition to being more efficient and easily processable.Retrosynthetic analysis for our proposed total synthesis of vinigrol (1) is detailed in Scheme 1. Late stage substrate controlled hydrogenation of both olefins followed by formation of an enol triflate, cross coupling of the triflate to form the allylic alcohol and deprotection will advance intermediate 2 to vinigrol. The natural product core will be revealed using a retroMichael fragmentation of caged structure 3, which in turn can be rapidly accessed via 4 following substrate controlled hydrogenation of the exo olefin and samarium mediated deoxygenation of the mixed ketal moiety. Tandem 6-exo radical cyclizations will deliver the jn96@cornell.edu. Supporting Information Available: Experimental Details and spectral data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. pre-fragmentation polycyclic core (4) from cycloadduct 5. This intermediate will be assembled from the oxidative dearomatization/Diels-Alder union of pyrogallol derivative 6 and acrylic acid 7. In the ideal synthetic scenario a one pot samarium cascade can be envisioned starting from 5 directly to ring expanded 3 via consecutive 6-exo ketyl mediated radical cyclizations followed by double α-keto deo...