Cristian Draghici

Total Synthesis of Vinigrol

Diterpenoids are an important and structurally diverse class of natural products. In 1987, Hashimoto and co-workers reported a new diterpenoid with a unique bridged bicyclic core densely decorated with eight stereocenters.1 The authors named this new natural product vinigrol. As evident from the three structural perspectives shown in Figure 1, vinigrols architecture is quite striking. Most notable is the bis-axial four carbon tether that bridges the two six-membered rings of the decalin in such a way that a very rigid and compact framework results. Vinigrol has been evaluated in numerous biological assays and shown to impact platelet aggregation2 and act as a tumor necrosis factor (TNF) antagonist,3 as well as displaying other interesting properties. 4 Vinigrols unprecedented structure and intriguing biological profile have prompted numerous attempts at its synthesis.5 In 2009, Baran6 and co-workers reported the first total synthesis of vinigrol and a few years later Barriault7 published a formal synthesis of vinigrol.

Rapid Assembly of Vinigrol’s Unique Carbocyclic Skeleton

Detailed in this account are our efforts toward 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.

Lewis Acid Promoted Carbon−Carbon Bond Cleavage of γ-Silyloxy-β-hydroxy-α-diazoesters

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.

Preparation of Tethered Aldehyde Ynoates and Ynones by Ring Fragmentation of Cyclic γ-Oxy-β-hydroxy-α-diazo Carbonyls

Cyclic gamma-oxy-beta-hydroxy-alpha-diazo carbonyls undergo Lewis acid induced ring fragmentation to provide either ynoates or ynones tethered to an aldehyde, ketone, or ester. The fragmentation precursors are convenient to prepare by adding lithiated alpha-diazo carbonyls to alpha-oxy ketones. The fragmentation appears general and provides a variety of functional group-rich products in good to excellent yield.

Evolution of an oxidative dearomatization enabled total synthesis of vinigrol

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 groups 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.

An Efficient Synthetic Approach to Polycyclic 2,5-Dihydropyrroles from α-Silyloxy Ketones

A three-step sequence to prepare polycyclic 2,5-dihydropyrroles from alpha-silyloxy ketones is presented. A Lewis acid-mediated ring fragmentation of cyclic gamma-silyloxy-beta-hydroxy-alpha-diazo esters provided tethered aldehyde ynoate intermediates which, when treated with amino acid silyl esters, underwent intramolecular azomethine ylide 1,3-dipolar cycloadditions. The 2,5-dihydropyrrole products were formed in good to excellent yield as single diastereomers.

Synthesis of Demissidine by a Ring Fragmentation 1,3-Dipolar Cycloaddition Approach

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 Realization of an Oxidative Dearomatization–Intramolecular Diels–Alder Route to Vinigrol

Abstract Detailed in this chapter is the Njardarson group vinigrol total synthesis saga. Even though the Njardarson group synthetic strategy had undergone multiple modifications over time, it remained faithful to several key reaction design elements, namely: (a) oxidative dearomatization/Diels–Alder cascade, (b) radical or palladium cascade, (c) creation of a tetracyclic cage for substrate control purposes, and (d) a late-stage C C bond fragmentation reaction to unravel the vinigrol core. The saga begins with the earliest oxidative dearomatization explorations followed by detailed descriptions of the modifications that were made in response to the obstacles encountered en route to the completed total synthesis of vinigrol.