IsoStrychnines isomerism

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. 

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. 

XXXVI, R = Br) (56). The position of the double bond in isostrychnine-I follows from the UV-spectrum, which shows it not to be in conjugation with the lactam carbonyl (57). Alcoholic potassium hydroxide causes a conversion back to strychnine in 20 % yield, presumably by isomerization of the double bond back into conjugation with the lactam carbonyl followed by /3-addition of the allyl alcohol oxygen. No product corresponding to a double-bond isomer of isostrychnine could be isolated, or even detected UV-spectroscopically in the noncrystalline part of the reaction mixture (57). 

Dilute HBr hydrolysis of the less soluble bromodeoxyisostrychnine (XXXV R = Br) yields isostrychnine-I (56, 58), whereas hydrolysis of the more soluble salt gives the isomeric isostrychnine-II (XXXVI R = OH), the position of the double bond being fixed by its ease of reduction by sodium amalgam. Isostrychnine-II has not been directly obtained from either strychnine or isostrychnine-I. 

Under mild conditions, that is, with piperidine as catalyst, isostrychnine condenses to give the yellow compound LVIII (57). Under more vigorous conditions, however, the colorless pyridone derivative (LIX) (70) is produced by double-bond migration (4). This easy isomerization was of structural value in demonstrating clearly the presence of a hydrogen atom on C-8. Isodihydrostrychnine and the isodihydro-brucines also give yellow and colorless benzylidene derivatives (71). 

Although strychnine is isomerized, to a limited extent (10%), to isostrychnine by hydrobromic acid-acetic acid mixture, the main product is bromodesoxyisostrychnine (65%), C2iH220N2Br (LXXVI, R = H) (174), while 15% of a more soluble salt is recoverable from the filtrate. A similar reaction occurs with brucine but a simultaneous demethylation leads to bisapomethylbromodesoxyisobrucine (LXXVI, R = OH) (176). Hydrolysis of bromodesoxyisostrychnine by 1 A hydrobromic acid (174) or Letter... 

An efficient synthesis of the alkaloid strychnine makes good use of an intramolecular Heck reaction. Oxidative addition of palladium(O) into the alkenyl iodide 212 and cyclization onto the cyclohexene gave, after p-hydride elimination and silyl deprotection, isostrychnine 213 (1.214). isomerization of the new alkene to give the enone and cyclization of the alcohol onto the enone gives strychnine. 

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