Rapid Assembly of Vinigrol’s Unique Carbocyclic Skeleton

Abstract

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...

Synthetic approaches and total syntheses of vinigrol, a unique diterpenoid

“…25 Horner-Wadsworth-Emmons condensation between phosphonate 214 and aldehyde 215 afforded enoate 216 . The terminal alkyne group was then converted into a vinyl iodide and the ester group reduced with diisobutylaluminum hydride to allylic alcohol 217 .…”

Fragmentation Enables Complexity in the First Total Synthesis of Vinigrol

“…A number of approaches have been established towards the total synthesis of vinigrol since its isolation. [1,[3][4][5][6][7][8][9] These key achievements are summarized in Scheme 1. The Corey group attempted to reach the tricyclic core by a late stage intramolecular Diels-Alder (DA) reaction (2!1).…”

“…[9] These pioneering studies have focused primarily on the construction of the cis tricyclic core. The cis oriented C8 methyl and C8a hydroxy groups, and the late installation of the C3 hydroxymethyl group still remained problematic.…”

Totalsynthese von Vinigrol: Komplexität durch Fragmentierung

“…Einige Ansätze zur Totalsynthese von Vinigrol wurden seit seiner Isolierung bereits vorgestellt [1,[3][4][5][6][7][8][9] und sind in Schema 1 zusammengefasst. So versuchte man in der CoreyGruppe, den tricyclischen Kern durch eine späte intramolekulare Diels-Alder(DA)-Reaktion (2!1) aufzubauen, [3] aber selbst unter einer Vielzahl an Bedingungen und mit einer Reihe von Dienmodifikationen führte dieser Ansatz nicht zum Erfolg.…”

“…[9] Diese Pionierarbeiten konzentrierten sich zuvorderst auf den Aufbau des cis-tricyclischen Kerns. Nach wie vor problematisch blieben die cis-orientierten C8-Methyl-und C8a-Hydroxygruppen sowie die späte Einführung der C3-Hydroxymethylgruppe.…”