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The total synthesis of (+/-)-strychnopivotine, (+/-)-tubifolidine, (+/-)-strychnine, and (+/-)-valparicine is reported. The central step in the synthesis consists of an intramolecular [4 + 2]-cycloaddition/rearrangement cascade of an indolyl-substituted amidofuran that delivers an aza-tetracyclic substructure containing the ABCE-rings of the Strychnos alkaloid family. A large substituent group on the amide nitrogen atom causes the reactive s- trans conformation of the amidofuran to be more highly populated, thereby facilitating the Diels-Alder cycloaddition. The reaction also requires the presence of an electron-withdrawing substituent on the indole nitrogen for the cycloaddition to proceed. The cycloaddition/rearrangement cascade was remarkably efficient given that two heteroaromatic systems are compromised in the reaction. Closure to the remaining D-ring of the Strychnos skeleton was carried out from the aza-tetracyclic intermediate by an intramolecular palladium-catalyzed enolate-driven cross-coupling between the N-tethered vinyl iodide and the keto functionality. The cycloaddition/rearrangement approach was successfully applied to (+/-)-strychnopivotine (2), the only Strychnos alkaloid bearing a 2-acylindoline moiety in its pentacyclic framework. A variation of this tactic was then utilized for a synthesis of the heptacyclic framework of (+/-)-strychnine. The total synthesis of (+/-)-strychnine required only 13 steps from furanyl indole 18 and proceeded in an overall yield of 4.4%.

A new strategy for the synthesis of the Strychnos alkaloid (±)-strychnine has been developed and is based on an intramolecular [4+2]-cycloaddition/rearrangement cascade of an indolyl substituted amidofuran. The critical D-ring was assembled by an intramolecular palladium catalyzed enolatedriven cross-coupling of an N-tethered vinyl iodide.Strychnos alkaloids belonging to the curane type constitute an important group of architecturally complex and widely distributed monoterpenoid indole alkaloids. 1,2 The curane family is characterized by the presence of a pentacyclic 3,5-ethanopyrrolo [2,3-d]carbazole framework (i.e., 1) bearing a two-carbon appendage at C-20 and an oxidized one-carbon substituent (C-17) at the C-16 position (Figure 1). 3 The synthesis of various members of the Strychnos family has been an area of interest ever since the structural elucidation of strychnine (4), the most famous of this group of alkaloids, by Robinson in 1946. 4 Strychnine was first isolated in 1818 from the Indian poison nut 5 (Strychnos nux vomica) and possesses highly toxic properties as a result of its interaction with the glycine receptor site thereby blocking the flux of chloride ions and disruption of nerve-cell signaling. 6 Its complex heptacyclic structure, containing 24 skeletal atoms and six contiguous stereogenic centers, has fascinated organic chemists for the past sixty years. Nearly 40 years after Woodward's pioneering achievement of strychnine 7 , a number of other research groups have reported on its synthesis. 8 Efficient approaches toward the Strychnos pentacyclic framework would allow not only the synthesis of other members of this family of natural products (i.e., strychnopivotine (2) and akuammicine (3)), but also related non-natural products possessing biological activity. Along these lines, we have recently become involved in the development and optimization of a new approach for the construction of the pentacyclic framework of the Strychnos system. In this communication, we report a concise stereocontrolled total synthesis of (±)-strychnine (4) wherein an efficient [4+2]-cycloaddition/rearrangement method previously developed in our laboratories plays a crucial role. 9In Rawal and Iwasa's elegant synthesis of (±)-strychnine, 8e an ingenious palladium-catalyzed intramolecular Heck reaction was used as the key step for the creation of the D-ring. As in Woodward's original approach, 7 isostrychnine (5) was the final critical intermediate used in this synthesis. Its Prelog-Taylor cyclization to strychnine 10 (Scheme 1), however, suffers from an unfavorable 3:1-equilibration ratio of these two compounds. From this perspective, the alternative biomimetic route to strychnine involving condensation of the Wieland-Gumlich aldehyde (6) with an acetate equivalent for the formation of the G ring seemed to us to be the more attractive approach, 11 as it avoids the unfavorable equilibration ratio. As illustrated in Scheme 2, our retrosynthetic analysis of strychnine (4) Some years ago, we commenced a program o...

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The rhodium(II)-catalyzed cyclization/cycloaddition cascade of a o-carbomethoxyaryl diazo dione is described as a potential route to the oxatricyclo[6.3.1.0(0,0)]dodecane substructure of the icetexane diterpene komaroviquinone. The initially formed carbonyl ylide dipole prefers to cyclize to an epoxide at 25 degrees C but can be induced to undergo cycloaddition across the tethered pi-bond at higher temperatures. [reaction: see text]

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Using a rhodium(II)-catalyzed cyclization/cycloaddition sequence as the key reaction step, the icetexane core of komaroviquinone was constructed by an intramolecular dipolar-cycloaddition of a carbonyl ylide dipole across a tethered π-bond. The ylide was arrived at by cyclization of a rhodium carbenoid intermediate onto a proximal ester group. Efforts towards the preparation of the required precursor for elaboration to the natural product are discussed.