Cularine has been synthesised via phenolic coupling of 1.2.3.4-tetrahydro-I -(3-hydroxy-4-rnethoxbenzyl)-7methoxy-2-rnethyIisoquinolin-8-ol; the latter was prepared by a new variant of the Pomeranz-Fritsch synthesis which leads directly to isoquinolines in good yield, with introduction of the 1 -benzyl substituent by the Reissert method. Syntheses of open-chain phenolic bis-(2-phenylethy1)amine derivatives related to cularine are also described ; however, none of these could be oxidatively coupled to give cularine derivatives. Other routes to 7.8-dioxygenated isoquinolines were also investigated, but, although moderately successful, additions of 3.4-dial koxybenzylmagnesiurn halides to 3.4-dihydroisoquinolines could not be effected owing to formation of dihydrostilbenes from the benzyl halides. The synthesis of a 7.8-dialkoxy-3.4-dihydroquinolone from a bromoindanone is also described. pool, LiverpoolTHE alkaloid cularine (1) is the parent of a small group of benzylisoquinoline alkaloids which are distinguished by the possession of an intramolecular ether linkage between the carbocycle of the isoquinoline nucleus and the 1benzyl group.2 The presence of this ether bridge is associated with a relatively unusual 7,&oxygenation pattern in the isoquinoline system; petaline (2) is another recently discovered simple 1-benzylisoquinoline alkaloid with this oxygenation pattern.3 Cularine, its N-demethyl derivative, and two O-demethyl derivatives are found in certain plants of the Dicentra and Corydalis families. The structure of cularine was first elucidated by Manske over twenty years ago.2At the outset of this work two syntheses of cularine had been described, but both involved completion of the nitrogen-containing ring as one of the final ~t a g e s .~ In contrast, our interests lay in the possibility of synthesising cularine along ' biogenetic ' routes, with the eventual aim of studying the biosynthetic pathway in, vivo by radiotracer techniques using suitable precursors, In the light of earlier speculations,5 and related biosynthetic studies of other benzylisoquinoline alkaloids,6 it seemed likely that cularine might be formed in nature by one of two routes, either by oxidative phenolic coupling of a preformed 1-benzylisoquinoline such as (3a), or by phenolic coupling of a bis-(2-phenylethyl)amine (4a) followed by oxidative closure of the nitrogen-containing ring.'-@ Variants such as oxidative cyclisation of the isomeric phenolic amines (3b) and (4b) may also be envisaged and these could lead via dienone-type intermediates to cularine.1° The oxidative cyclisation of open-chain intermediates such as (4a) and (4b) also seemed attractive possibilities, as initial formation of the Part 11, A. ether bridge would direct the subsequent formation of the nitrogen-containing ring and account for the unusual 7,8-oxygenation pattern of cularine and its congeners.The corresponding amides (5a) and (5b) were therefore prepared by coupling of the appropriate phenylethylamine and phenylacetyl chlorides. Attempts to reduce these amid...

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An unusual fragmentation of 92 mass units from the parent ion of an 8-benzyloxytetrahydroisoquinoline is due to loss of the elements of toluene by concerted cleavage of the benzyl group and a hydrogen atom from the 1 -position ; this is confirmed both by the appearance of a metastable ion for the overall process, by deuterium labelling of the 1 -position, and by the absence of a corresponding peak in the spectrum of a 7-benzyloxytetrahydroisoquinoline.Deuterium labelling also confirms that the M -1 peak commonly observed in the mass spectra of tetrahydroisoquinolines is due to cleavage of a hydrogen atom from the 1 -position ; high-resolution measurements have confirmed the nature of the other major primary fragmentation processes.THE main features of the mass spectra of tetrahydroisoquinolines (I) were first described several years ag0.l The molecular ion is usually of low intensity, and the major fragmentation is often due to the loss of a substituent from the l-position, or to loss of a hydrogen atom. If, however, a benzylic ether substituent is present in the benzene ring then cleavage of the benzyl group may well be the predominant fragmentation process. Loss of the nitrogen atom and the 3-carbon atom together with substituents at these positions also appears to be a common feature of tetrahydroisoquinoline mass spectra, and this has been attributed to a reverse Diels-Alder type reaction as shown below. (A similar process is also observed in the mass spectra of tetrahydro-@-carbolines 2).

A synthetic procedure for 2‐14C‐N‐nitrosohexamethyl‐eneimine 1‐aza‐l‐nitroso‐(2‐14C)‐cycloheptane is presented. The starting material was 1‐14 C‐cyclohexanone which underwent ring expansion, reduction, and finally nitrosation. The synthesis resulted in a product in good yield (68% overall), which is chemically and radiochemically pure.

Ausgehend von dem Tosylat (Ib) des Amins (Ia) wird eine Synthese für Cularin (VIIIb) über die Stufen (II)‐(VIIIa) entwickelt; (VIIIb) wird schließlich durch Methylierung von (VIIIa) gewonnen.