Isostrychnine structure

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. 

Scheme 4.2 Strychnine is readily accessed via isostrychnine or the Wieland-Gumlich aldehyde using chemistry discovered during structural elucidation/degradation studies...

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). 

New extractions of the root bark of Sri Lankan Strychnos nux vomica have disclosed the presence, besides strychnine, brucine, and isostrychnine, of 12-hydroxystrychnine, 12-hydroxy-11-methoxystrychnine, and a minor base, named protostrychnine (168), because of the obvious possibility that it may be an immediate biosynthetic precursor of strychnine. The overall structure (168), but not necessarily the configuration at C-17, was confirmed by allowing the 18-0-tigloyl ester to react with phosphorus oxychloride in pyridine saponification of the product, followed by treatment with dilute hydrochloric acid, then gave strychnine. 

The carbon patterns of the products (Chart 3.1) of the drastic degradation of strychnine can all be discerned in the parent molecule but cannot by themselves be used to deduce a unique formula. That the A and B rings were six and five membered respectively was reconfirmed over the years often at the cost of considerable labour. One such case concerned dinitrostrychol-carboxylic acid, one of the nitric acid oxidation products of strychnine. It was first obtained about the turn of the century and after considerable work in the late twenties was found in the early thirties to be 5,7-dinitroindole-2-carboxylic acid. Actually the structure of strychnine would probably have been realized much earlier than it was if any one of a number of degradations had been persevered with in a systematic way. The constitution arrived at by the chemical methods rests on the properties of the functionalities in their special environments and their interlocking reactions. The advent of commercial recording infrared and ultraviolet machines played an important part in the latter phase of this work. A synthesis of the alcohol, isostrychnine I (strychnine with its cyclic ether opened at dotted line and A double bond) has confirmed these conclusions as has the determination of the structure and absolute stereochemistry by the X-ray crystallographic method. 

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