Strychnine vinyl iodide synthesis

An elegant and efficient stereocontrolled total synthesis of strychnine has been achieved by applying intramolecular Diels Alder and Heck reations as key reactions [47]. An unusual exo-Diels-Alder reaction of 102 afforded 103, which was converted to the vinyl iodide 104. The Heck reaction of 104 using Pd(OAc)2 gave the hexacyclic strychnan system 105 smoothly in 74% yield. Hydrolysis of 105 afforded isostrychnine, which was isomerized to strychnine (106) under basic conditions. 

Finally, in Rawafs total synthesis of ( )-strychnine, Heck cyclization of vinyl iodide 68 was employed to access the hexacyclic Strychnos alkaloid skeleton and deliver ( -) isostrychnine (69) in 74% yield [25J. Rearrangement in this case would not have been expected since the intermediate formed upon 6-exo closure would contain a particularly unstable tertiary C—Pd bond. The success of the transformation of 68 to 69 in spite of this potential obstacle is noteworthy. 

Now the Heck reaction can be induced to close the ring 162. In this case the vinyl iodide forms the palladium derivative and the regioselectivity of the attack is at the 5-position of the dienone mainly because of the tether. The closure of the last ring was already known and the synthesis of strychnine 164 complete. This synthesis uses three Heck reactions and two other palladium-catalysed reactions. 

A key step (Eq. 14.2) in a new synthesis of strychnine involves a C-C coupling in 14.6 to give the pentacyclic 14.9. Oxidative addition of vinyl iodide 14.6, together with deprotonation a to the ketone, gives... 

The cycloaddition/rearrangement IMDAF cascade of 2-amidofurans such as 319 was remarkably efficient given that two heteroaromatic systems are compromised in the reaction. Closure of 321 to the remaining D-ring of the Strychnos skeleton (i.e., 322) was carried out from the aza-tetracyclic intermediate 321 by an intramolecular palladium-catalyzed enolate-driven cross-coupling between the A-tethered vinyl iodide and the keto functionality. The cycloaddition/rearrangement approach was successfully applied to a synthesis of the heptacyclic fi-amework of ( )-strychnine 323 (Scheme 13.72) [114], which required only 13 steps from furanyl indole 319 and proceeded in an overall yield of 4.4%. 

The Strychnos alkaloids possess diverse chemical structures that have attracted considerable attention in organic synthesis during the last decades. Recent studies on the synthesis of akuammicine, strychnine and leuconicine A and by Andrade et al. proved that the intramolecular Heck reaction is extremely valuable for the construction of complex polycyclic molecules. Based on Rawal s method for the construction of the D ring of Strychnos alkaloids, vinyl iodides 37, 39, and 42 undergo a regioselective and stereoselective palladium-catalyzed cychzation in the presence of Pd(OAc)2, PPha in Et3N to furnish ( )-akuammi-cine 38, and the advanced intermediates 40 and 43 in excellent chemical yields (Scheme 13.11). 

Deshpande [74], has carried out carbon-carbon bond formation on a solid support using a polymer-supported aryl iodide and vinyl (or aryl) tins. In the area of natural-product synthesis. Overman and co-workers have carried out total syntheses of (—) and (+)-strychnine which include an aryltin/CO/alkenyltin coupling step [75] (a technique introduced earlier by Stille [1]). Very recently, Heathcock and co-workers have reported total syntheses of (—)-papuamine and (—)-haliclonadiamine which include a key step in which a 1,3-diene unit is constructed by coupling two alkenyltin moieties thus reaction (Scheme 4-27) only proceeds in the presence of copper (I) iodide [76]. 

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