GENERAL ¨ ARTICLE The Total Synthesis of Strychnine

Edited by Setty Mallikarjuna Babu and Subramania Ranganathan

The enormous reach of R B H N Woodward in the design and H synthesis of carbon constel- N lationsisfurtherexempli- H H fied with the total synthesis O O H ofstrychnine(p.641),which even when viewed from the Either we make Strychnine or take Strychnine. vantage of ensuing signifi- – R B Woodward cant developments in or- ganic synthesis is an amaz- ing feat! This is followed by Strychnine! No other molecule has captured the popular imagina- the total synthesis of chlo- tion as strychnine, perhaps because thousands of writers of fiction rophyll (p.645), where RB have used it to dispatch the recipient and then several have made pledged the entire efforts on thrillers using ingenious deduction to catch the perpetrator! Known an untested porphyrin to since the 16th century from the forests including the Coramandal purpurin change, an essen- Coast of India, it was isolated in a pure form in 1818 and the tialtransformation toachieve structure established in 1947! Unlike the 181 atoms scattered in the total synthesis. The third space as in B , strychnine, having six asymmetric centres additional example is the to- 12 tal synthesis of cepha- and 7 rings is packed with a mere 24 skeleton atoms! losporin C (p.649), The 2-Veratryl (1) readily prepared by Fischer indole synthesis Nobel Lecture delivered by from acetoveratrone was transformed to tryptamine 3,whose RB, above all, reflects the fact that in all these cre- Schiff’s with CHOCOOEt underwent smooth cyclization ations, he identified an an- with TsCl/Py to generate the spiro ring-V, 4 which was trans- chor from which he never formed to 5. followed by treatment with MeOH/HCl wavered – in this case the generated the critical pyridone 6 (ring-III) (Scheme 1). Initial simple molecule cysteine. efforts to effect a Dieckman condensation of the two groups were thwarted by the highly electrophilic Ts group present, forming in preference, the Sciff’s base. The Ts group was removed(HI,redP)andreplacedbyAc(Ac2O, Py), esterified

(CH2N2). The resulting 7 underwent smooth Dieckman condensa- tion to give 8, generating ring-IV. Keywords Strychnine.


+ - CH2NMe3 I I NH2 CHO OMe 1. CH O, Me NH 1. NaCN, DMF N 2 2 OMe N OMe CO2Et H N H 2. MeI H 2. LAH OMe OMe OMe 1 2 3 Ts-Cl N V CO2Et V N Ts N Ts N OMe TsCl, Py CO2Et NaBH4 Ac2O, Py OMe CO2Et N N OMe H H B: OMe OMe OMe 4

N Ts N Ts N Ts CO Et CO2Et HI, red P CO2Et O , AcOH 2 MeOH, HCl CH CO Me OMe 3 N N 2 2 N CO2Me III Ac Ac CO2Me O OMe 6 5

Scheme 1. The ester group in 8 was transformed to acrylate 9 and then subjected to reduction. This process creates another chiral centre where the major product turned out to be unwanted E-ester which was readily epimerised to the more stable D-acid, 10.The structure of compound 10 was conformed from a sample secured from natural strychnine. For this purpose 10 was readily resolved using quinidine and esterified to the methyl ester corresponding to 10 which was identical to that obtained from the natural sources. This enabled further transformations with the more readily ob- tained material from the natural sources. The linking of the D- carboxyl group in 10 to the that would generate ring-VI necessitated the inversion of this centre; this was achieved in an

unusual manner by treatment of 10 with Ac2O and pyridineto form the enol acetate 11 (Scheme 2).

The formation of 11 could be rationalized by the initially formed anhydride, that undergoes nucleophilic acyl transfer, decarboxyla- tion and of the thus generated enolate! Vigorous acid hydrolysis of 11 afforded 12 (Scheme 3). The protanation of the enolate takes place from the E-side. Thus 12 is not disposed for linking with the trans-NH. Woodward did not consider this as an impediment because of the ready epimerisation of this centre.

642 ¨July 2014 GENERAL ¨ ARTICLE

H N H N Ac N Ac CO H IV 2 1. AC2O,Py CO2Me OH TsCl, Py N CH2CO2H CH2CO2Me NaOMe, MeOH N N CO2Me 2. CH2N2 O O O 7 8

H H H N Ac N Ac N Ac De activated OTs PhCH SNa SCH Ph H ,Pd-C N 2 N 2 Ra ney Ni N 2 CO2Me CO2Me CO2Me O O O 9

H H H N Ac N Ac N Ac [OH- ] N N N AC2O,Py Me aq HCl, AcOH CO2Me CO2H OAc O O O 10 11

H H N H N N Ac VI O O 8 Se O ,EtOH N O N 1.HC CNa, THF N 2 13 Me O O H 2. H2 , Lindlar catalyst O O 12 O

12 13

H N H O O N N HO LAH AlZ O H N + R N H N 1.HBr, AcOH, 120 O HC CH2 XO HC HO 2. aq H2SO4 CH2 O

14 15

H H N N H H N KOH, EtOH N H H H O O H O 16 17 OH Isostrychnine I Strychnine

Scheme 2 (top). Scheme 3 (bottom).


Indeed this turned out to be true! Treatment of 12 with SeO2-EtOH gave 13 with the generation of ring-VI. The 3D representation of 13 clearly shows that the epimerization has indeed taken place!

The pathway to strychnine now involves addition of two carbon atoms and creation of chiral centres at 8, 13 and 12 positions (12) (Scheme 3). At this stage compound 13 is highly concave and the carbon at 8 rests at the bottom of it. To deliver an H to this carbon is the kind of challenge that Nature often posed and Woodward overcame this using an Al-courier! Compound 13 was treated with acetylide in THF and the acetylinic moiety was reduced to provide 14. Compound 14 when reacted with LAH in refluxing effected the reduction of the present in ring-VI and delivered the hydrogen to the most inaccessible carbon-8 to form 15. Compound 15 is related to isostrychnine 16 where the allyl is isomerised to provide a hydroxy methyl . This transformation proved exceptionally difficult. Eventually, treat- ment of 15 with HBr/AcOH at 120oC, and the resulting mixture of

halo compounds on hydrolysis in boiling aq. H2SO4 generated the desired 16, isostrychnine! The action of ethanolic KOH led to the closure of the 7-memberd oxide ring-VII, which also generated the chiral centre at 12 and 13 in a correct order.

Even in the light of significant developments in during the intervening six decades, Woodward’s synthesis of strychnine defies the imagination of chemists! Here again Wood- ward had to overcome the problems raised by Nature in placing one of the Hs inside the bowl with 4 outside!

Suggested Reading

[1] R B Woodward, M P Cava, W D Ollis, A Hunger, H U Daeniker and K Schenker, Tetrahedron, Vol.19, p.247, 1963.

644 RESONANCE ¨July 2014