Synthesis of - -Strychnine

The total synthesis of (-)-strychnine 3 reported (J. Am. Chem. Soc. 125 9801, 2003) by Miwako Mori of Hokkaido University is a tour deforce of selective organopalladium couplings. 

The sidechain of 7 was extended by one carbon, to give the nitrile 8. A second organopalladium step then was used to cyclize 8 to 2. Using Ag CO, as the base suppressed unwanted alkene migration. The reaction ran more slowly in DMSO than in DMF, but byproduct formation was suppressed. 

For strychnine 3, the ketone 11 was converted to the alkene 12 by reduction of the enol triflate derived from the more stable enolate. Deprotection and acylation gave 13, which was cyclized with Pd to give, after equilibration, the diene 14. Alkylation, to give 15, followed by Pd-mediated cyclization then gave 16, which was reduced and cyclized to (-)-strychnine 3. 

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

The latter, which is not normally isolated, may, under favorable conditions, be trapped in the presence of a strong nucleophile, as in the conversion of 340 into 338. It was surmised that the biogenetically modelled synthesis of strychnine-type systems was a demonstration of such a reaction. 

Scheme 9. Pyridone ring reduction (a) and synthesis of (-)-strychnine (1) (b).

The structural homology between intermediate 4 and isostrych-nine I (3) is obvious intermediates 3 and 4 are simply allylic isomers and the synthetic problem is now reduced to isomerizing the latter substance into the former. Treatment of 4 with hydrogen bromide in acetic acid at 120°C results in the formation of a mixture of isomeric allylic bromides which is subsequently transformed into isostrychnine I (3) with boiling aqueous sulfuric acid. Following precedent established in 194810 and through the processes outlined in Scheme 8a, isostrychnine I (3) is converted smoothly to strychnine (1) upon treatment with potassium hydroxide in ethanol. Woodward s landmark total synthesis of strychnine (1) is now complete. 

The prerequisite for an evaluation of the utility of the aza-Cope/ Mannich strategy for a synthesis of strychnine has now been satisfied. Using unsaturated azabicyclo[3.2. ljoctanols closely related to 14, the Overman group had previously demonstrated the impressive facility with which the aza-Cope/Mannich reaction can construct the complex molecular frameworks of ( )-dehydrotubifoline and... 

Kaburagi, Y, Tokuyama, H., Fukuyama, T. (2004) Total Synthesis of (—)-Strychnine. Journal of the American Chemical Society, 126, 10246-10247. 

Bonjoch and coworkers have developed a general synthetic entry to strychnos alkaloids of the curan type via a common 3a-(2-nitrophenyl)hexahydroindole-4-one intermediate. Total synthesis of (-)-strychnine is presented in Scheme 9.5.20 The first step is based on the SNAr reaction of o-iodonitrobenzene with 1,3-cyclohexanone. 

Scheme 4.1 Oxidative cleavage of an electron-rich aromatic ring was a key component of Woodward s proposal for a biogenesis of the Strychnos alkaloids and a key step in his subsequent synthesis of strychnine...

Scheme 4.4 Diels-Alder disconnections used in the synthesis of strychnine...

Another challenge associated with the synthesis of strychnine, as well as other Strychnos alkaloids, is the stereoselective construction of the F-hydroxyethylidene side chain (Scheme 4.5). Strategies that rely on a late-stage olefination reaction of a C20 ketone often suffered from low diasterocontrol for the newly formed alkene, with the best exception provided by Kuehne (15 > 16) [10a, b, d, f]. Overman,... 

A synthesis of strychnine by the Stork group was apparently disclosed in lecture form, and some of the details are provided in the review by Bonjoch and Sole from 2000 [15a]. While we prefer not... 

Scheme 4.30 Completion of a six-step linear synthesis of strychnine using a Brook rearrange-ment/conjugate addition to generate the Wieland-Gumlich aldehyde...

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