Isostrychnine

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... 

Strychnine A-oxide, 10 isostrychnine, 20 to 30 methylstrychnine, 100 strychnine methosulphate, 30 strychninic acid, 25 to 30 iso-strychninic acid, 30 to 35. Rats, mice, rabbits, cats, dogs and frogs were used, and the figures are comparative lethal doses for mammals. 

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...

Following the application of a Heck cyclization to a concise synthesis of the Strychnos alkaloid dehydrotubifoline [287, 288], and earlier model studies [289], Rawal employed a similar strategy to achieve a remarkably efficient synthesis of strychnine [290]. Thus, pentacycle 277 is smoothly cyclized and deprotected to isostrychnine (278) in 71% overall yield — an appropriate finale to this section ... 

Tabelle 1. Logaritkmen der DRjHR-VerhaUnisse der Methosalze von Strychnin (1), 19,20-Dihydrostrychnin (2), 19,20-Dihydro-isostrychnin-I (3) und Yohimbin (4)... 

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. 

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. 

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... 

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). 

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

Hydrogenolysis of isostrychnine methochloride (XCV R = H) and isopseudostrychnine methochloride (XCV R = OH) leads to the same product (XCVI) (95, 96). On the other hand, 0-methyl pseudostrychnine metho salt (XCVII R = H) gives mainly the corresponding quaternary dihydro derivative, and only a small yield of base XCVIII (R = H) (97). Allylic hydrogenolysis, however, again predominates in the case of... 

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. 

Finally, in Rawafs total synthesis of ( )-strychnine, Heck cyclization of vinyl iodide 68 was employed to access the hexacyclic Strychnos alkaloid skeleton and deliver ( -) isostrychnine (69) in 74% yield [25J. Rearrangement in this case would not have been expected since the intermediate formed upon 6-exo closure would contain a particularly unstable tertiary C—Pd bond. The success of the transformation of 68 to 69 in spite of this potential obstacle is noteworthy. 

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