Strychnine synthesis

Woodward s strychnine synthesis commences with a Fischer indole synthesis using phenylhydrazine (24) and acetoveratrone (25) as starting materials (see Scheme 2). In the presence of polyphosphor-ic acid, intermediates 24 and 25 combine to afford 2-veratrylindole (23) through the reaction processes illustrated in Scheme 2. With its a position suitably masked, 2-veratrylindole (23) reacts smoothly at the ft position with the Schiff base derived from the action of dimethylamine on formaldehyde to give intermediate 22 in 92% yield. TV-Methylation of the dimethylamino substituent in 22 with methyl iodide, followed by exposure of the resultant quaternary ammonium iodide to sodium cyanide in DMF, provides nitrile 26 in an overall yield of 97%. Condensation of 2-veratryl-tryptamine (20), the product of a lithium aluminum hydride reduction of nitrile 26, with ethyl glyoxylate (21) furnishes Schiff base 19 in a yield of 92%. 

Scheme 4.20 [S-H elimination selectivity in relevant Heck cyclizations by the Rawal group and in the MacMillan strychnine synthesis...

Strecker synthesis 26,99 Strychnine synthesis 58 Sulfamate synthesis, cyclic, by Rh-mediated intramolecular nitrene C-H insertion 8, 153... 

The amines 43, 46, and 47 constituted dehydro analogs of two intermediates in Rawal s strychnine synthesis, 49 and 50 (Scheme 20).7h This suggested that a simple reduction of the C ring double-bond, while conserving a C14-C15 unsaturation, would access synthetic relay points only two (via a Heck cylization of 50) or three (via alkylation of 49 with side chain 45, then Heck reaction) steps from 1, and allow the claim of a formal synthesis. 

Scheme 57. Intramolecular Heck cyclization in Rawal s strychnine synthesis...

The sluggishness of the reaction of TIPSOTf with tertiary alcohols can be exploited to advantage as was the case in Magnus strychnine synthesis. The equilibrium favors the tertiary hemiketal, but silylation favors the primary alcohol. 

The crucial compound in this strychnine synthesis is azabicyclo[3.2.1]octane 31, which is the substrate for the aza-Cope-Man-nich sequence (Scheme 4). In the preparation of 31, meso-diester 20 is subjected to acetylcholine esterase catalyzed hydrolysis to yield 21 with high enantiomeric purity. Eighteen ensuing steps then provide 31 in 14 % yield. The allylic carbonate obtained from 21 is... 

Whether the four new total syntheses represent a fundamental improvement over Woodward s strychnine synthesis can certainly be debated, as well as the extent of this improvement. It cannot, however, be contested that Overman et al. accomplished the first and only enantioselective synthesis of the natural product, and that Kuehne and Rawal with their respective 17- and 15-step syntheses devised approaches with markedly fewer reaction steps than Woodward s 28-, Magnus 27-and Overman s 25-step syntheses. The considerable improvement in the overall yields relative to that of the first total synthesis is also noteworthy. Whereas Magnus improved the yield by a factor 1000, Overman, Kuehne and Rawal upped the overall yield by a factor of 100000 These impressive numbers cannot be attributed solely to improved synthetic methods and modem reagents, but emphasize the importance that sequential reactions [17] have achieved in the construction of complex natural products. 

Nearly 40 years after Woodward s pioneering work (19,20), Magnus et al. accomplished the second total synthesis of strychnine using a transannular oxidative cyclization (56,57), which simultaneously constructed the C and D rings, as the key reaction (Scheme 3). Magnus strychnine synthesis began with... 

Once again, this volume of "The Alkaloids Chemistry and Biology is comprised of four quite different chapters, from three different continents, on mechanisms of c)dotoxic action, the calystegines, strychnine synthesis, and substituted quinoline alkaloids. This diversity reflects the need to see alkaloids as a class of natural product having tremendous biological potential and of continued broad scientific interest. 

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