IsoStrychninic acid

Isostrychninic acid, like strychninic acid, is an amino acid which gives a crystalline A -nitroso derivative and couples with various diazonium salts with the formation of colored azo compounds (177). Regeneration of isostrychnine results from dehydration of the acid with acetic anhydride or benzoyl chloride (241). 

Strychnine JV-oxide, 10 wostrychnine, 20 to 30 methylstrychnine, 100 strychnine methosulphate, 80 strychninic acid, 25 to 80 isostrychninic acid, 80 to 85. Rats, mice, rabbits, cats, dogs and frogs were used, and the figiues are comparative lethal doses for mammals. 

When strychnine is treated with hydrogen bromide and red phosphorus in boiling acetic acid, it is converted into a complex bromodeoxyiso-strychnine hydrobromide, (C2iH2iON2Br)a , which is hydrolysed by boiling N-sulphuric acid to isostrychnine (see above), now distinguished as I, and fsostrychnine-II, m.p. 218-9°, — 258° (EtOH), which with acetic... 

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. 

As in Rawal s synthesis (Scheme 20), deprotection of the silyl ether 51 under acidic conditions provided isostrychnine (2) in almost quantitative yield (Scheme 29). The synthetic material was identical with the natural compound in its and I3C NMR spectra and by TLC. 

More vigorous conditions, such as aqueous barium hydroxide at 140° (47) or sodium hydroxide in boiling amyl alcohol give isostrychnic acid (XXXIII) (48), in which the configurations of C-12 and C-13 have been inverted (49). This reaction probably proceeds by way of XXXIV, and the subsequent closure of the ether ring, since isostrychnine-I (XXXV R = OH) also gives isostrychnic acid (44). It would seem that the... 

This ring opening is simply an acid- or base-catalyzed elimination of the ether oxygen made possible by the Na lactam carbonyl, to which the ether oxygen is in a jS relationship the key step is removal of a proton from C-l 1. This reaction is undergone by strychnine, dihydrostrychnine, and dihydrobrucine strangely, it has not been reported for brucine. Strychnine is converted into isostrychnine-I (XXXV R = OH), which... 

The conversions of isostrychnine into strychnine and isostrychnic acid (see Sections II, B, 2 and IV) also involve nucleophilic addition at C-12. 

Sodium amalgam has also been used in many instances to reduce carbonyl groups, as in the important conversion of strychninonic (XXXVIII) into strychninolic acid (XXXIX) (59). Conjugated double bonds have also been reduced, as in the conversion of Hanssen C19 acid (CXXVII) into its dihydro derivative by reduction of the maleic acid moeity (103), the conversion of 11-benzalstrychnine (LVII) into 11-benzylstrychnine (104), and the reduction of isostrychnine-II (XXXVI R = OH) to its 11,12-dihydro derivative (58). 

CH2, and the N lactam carbonyl intact. Unbelievable Vigorous acid treatment finally caused an allyl rearrangement and gave isostrychnine (CCXXXV). Since this had already been converted into strychnine (see Section II, B, 2), the total synthesis was complete. 

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... 

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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