4-Hydroxy cularines

Secocularine (228) and secocularidine (229) were synthesized by Hofmann degradation of the corresponding cularine and cularidine methiodides, respectively (181). Both secocularidine (229) and norsecocularine (230) were transformed to secocularine (228) by O- and N-methylation, respectively (181,182). Total synthesis of noyaine (231) was achieved by Ullmann condensation of 8-hydroxy-7-methoxy-2-methyltetrahydroisoquinoIine (232) with 6-bromoveratric acid methyl ester followed by oxidation of the intermediate 233 (183) (Scheme 35). 

There are several reports of tetrahydroisoquinolines with a fused furan ring that could be argued (for the sake of the classification used in this collection) as an oxidative attack by the a-hydrogen of the 1-benzyl onto the 8-HO substituent, in a manner similar to the formation of a seven-membered ether ring seen in the cularines. It can also be seen as a similar oxidative attack from an a-hydroxy group (a commonly encountered benzyl substituent) on the 8-hydrogen position. The first of these two mechanisms (illustrated above) is used in this collection. 

In addition a range of oxidised cularines matching that of the oxidised aporphines is also known. The bases limousamine (92) and 4-hydroxysarcocapnine (93) represent hydroxy substitution unknown in the benzylisoquinoline and.bisbenzylisoquinoline series (probably because of the ease with which such compounds can be converted into pavines and isopavines) but... 

A possible mode of biogenesis of alkaloids of the cularine type has been simulated by the oxidation of l-(4-hydroxy-3-methoxybenzyl)-8-hydroxy-6,7-dimethoxy-2-methyltetrahydroisoquinoline to the dienone (164), and rearrangement of this... 

C(14) or C(10)-to-nitrogen bonding arrangement. The position of the acetoxy-group in (316 R = Ac) and thus the hydroxy-group in cancentrine was determined by examination of their n.m.r. spectra and by n.o.e. measurements. Cancentrine is a unique dimeric alkaloid constructed from morphine and cularine subunits and represents a formidable challenge for biogenetic-type synthesis. 

Other differences among this class of alkaloids resides in the type of substituent (hydroxy, methoxy, or methylenedioxy) and in the presence or absence of a methyl group at the nitrogen. They show an absorption maximum at about 283 nm in the UV spectrum, in common with many isoquinoline alkaloids. For those cularines with a phenolic group, under basic conditions, this band shifts to 294 nm. 

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