The Total Synthesis of Strychnine

The total synthesis was achieved in 1954 by Woodward and his collaborators (156). Before this, various unsuccessful attempts had been made to make a start toward a synthesis of strychnine (179, 180, 181, 182,) but these are now of little interest, with the exception of Robinson s idea (182) to emulate the postulated biosynthesis by attempting to synthesize the dialdehyde CCXVI, which then might be induced to cyclize by a combination of Mannich and aldol type condensations to the Wieland-Gumlich aldehyde (LV) the synthesis of CCXVI unfortunately was not realized. Much more recently, however, this idea has been used by van Tamelen et al. (184), who successfully synthesized the dialdehyde CCXVII and converted it in aqueous acetic acid-sodium 

A reaction between IV-tosyloxindolylethylamine and 3,4-dimethoxy-phenylacetaldehyde, designed to simulate a possible biosynthetic step, led, under very mild conditions, to the linking up of the indoline /2-carbon, C-16, and Nb a subsequent POCI3 ring closure gave CCXVIII-A (185). 

Another recent observation bearing on possible simplified strychnine syntheses is the rearrangement of CCXIX in boiling concentrated hydrochloric acid to CCXX (186). 

Woodward s synthesis of strychnine stands out as a major synthetic achievement (156). The plan of this synthesis was also strongly influenced by biogenetic considerations, but no short cuts were taken, and the synthesis proceeds step by step, at all stages fully under control. 

The next step, the ozonolysis of the veratrole ring to give CCXXVII is extraordinary and is probably the most original in the whole synthesis. It was perhaps conceived in parallel with the then extremely fruitful, if now no longer widely accepted, biogenetic notion of the Woodward fission. The fission in the synthesis of course plays a completely different structural role. The yield in this step is 29%. 

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Scheme 7.20. Zn-mediated domino reduction/biscyclization process in the total synthesis of (-)-strychnine (7-76).

The final stage was reached when Woodward and his collaborators announced the total synthesis of strychnine, a truly great achievement (see Section IV) (39). 

In the laboratory of S.F. Martin, a biomimetic approach toward the total synthesis of ( )-strychnine was developed by using tandem vinylogous Mannich addition and HDA reaction to construct the pentacyclic heteroyohimboid core of the natural product.The commercially available 4,9-dihydro-3/-/-P-carboline was first converted to the corresponding A/-acylium ion and then reacted with 1-trimethylsilyloxybutadiene in a vinyiogous Mannich reaction. The resulting cycloaddition precursor readily underwent the expected HDA reaction in 85% yield. 

The next steps in the synthesis include the multistep conversion of E)-15 into 16, subsequent cleavage of the silyl ether protecting group, and cyclization of 17, which cannot be isolated, to provide hexacyclic 18. With the reductive removal of the sulfonamide Magnus et al. arrived at their first goal, the total synthesis of the Wieland-Gumlich aldehyde (2). The conclusion of the total synthesis of strychnine is also within reach the authors succeed in converting 2 into the natural prod-... 

In the total synthesis of strychnine, Overman prepared the alkenyl aryl ketone 67 in 80 % yield by the carbonylation of the aryl iodide 65 with the alkenylstannane 66 using AsPhs as a ligand [31]. 

H elimination occurs by the treatment of jr-allylpalladium enolates in boiling MeCN to give a.jS-unsaturated ketones and aldehydes. Shibasaki and co-workers used the enone formation in the total synthesis of strychnine [204], The silyl enol ether 555 was treated with diallyl carbonate 556 in MeCN and the cyclohexanone 557 was obtained in high yield. 

The total synthesis of (-)-strychnine 120 was accomplished using a tandem aza-Cope-Mannich reaction sequence. Amine 115 was exposed to paraformaldehyde to generate 116. This intermediate initiated the aza-Cope reaction to produce 117 and directly underwent the Mannich reaction to ultimately afford 118. Redrawing 118 gives 119 and advanced compound on the way to 120. 

Examples from total synthesis studies provide some of the most challenging cross-coupling processes mediated by catalytic Pd(0). In what would be an otherwise difficult one-pot preparation, Pd(0)-catalyzed carbonylative coupling of stannane 41 with the triazone-protected 2-iodoaniline 42 proceeds smoothly to afford enone 43, a key intermediate in the total synthesis of strychnine. A similar process was used in the total synthesis of akuammicine (eq 25). ... 

The structural complexity of strychnine, coupled with its biological activity, has served as the impetus for numerous synthetic investigations. The first total synthesis, one of the most significant achievements in the history of organic synthesis, was reported by Woodward et al. in 1954 (19,20). Nearly 53 years after Woodward s pioneering work, 13 groups have achieved the synthesis of strychnine using novel procedures. The present paper provides a survey of the relevant literature to the end of 2006. The excellent review by Bonjoch and Sole (2) extensively covered the total synthesis of strychnine from 1954 to 1999 Woodward... 

In 2002, we achieved the total synthesis of (—)-strychnine using a catalytic asymmetric Michael reaction and a novel domino cyclization that simultaneously... 

One classic application of the Tsuji-Trost reaction in natural products synthesis is found in the synthesis of strychnine by Overman and co-workers in 1993. Reaction of acetoacetate derivative 138 with enantiopure allylic carbonate 137 in the presence of Pd2(dba)3, PPh3, and NaH in THF yielded the cw-adduct 139 in 91%. It is worth noting that the selective displacement of carbonate group occurs with retention of the configuration and proceeds via the reactive 7i-allyl intermediate (see. Scheme 13.38). Derivative 139 could then be elaborated in a number of steps, to complete the total synthesis of strychnine. 

SCHEME 13.38. The application of the Tsuji-Trost reaction in the total synthesis of strychnine. 

SCHEME 21.36. [4-1-2]-Cycloaddition/rearrangement cascade for the total synthesis of strychnine. 

Woodward RB, Cava MP, Ollis WD, Hunger A, Daeniker HU, Schenker K. The total synthesis of strychnine. Tetrahedron 1963 19(2) 247-288. 

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