Phenol oxidation. Part III. Synthesis of the benzylisoquinoline alkaloid cularine

Abstract

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...

O-Annulation Leading to Five-, Six-, and Seven-Membered Cyclic Diaryl Ethers Involving C–H Cleavage

“…In 1974, Jackson et al reported an oxidative intramolecular coupling of tetrahydrobenzylisoquinoline derivatives 93a in the presence of K 3 [Fe(CN) 6 ] to produce cularine 94a and isocularine 95a in 2.5%, and 5% yield, respectively. 70 The Instead, the synthesis of didehydronorcularine 97 was achieved by Rodrigues and Abramovitch using C 6 F 5 I(OCOCF 3 ) 2 , yielding the desired cyclic diaryl ether in 87%, together with traces of ortho-cyclised derivative 98 (Scheme 23). 72 The same team also reported the synthesis of cularines through the use of nitrenium ions (Scheme 24), generated in situ by acid-catalysed decomposition of the azide precursor 99.…”

“…method was improved by using an N-borane complex of 93b, treating it with VOF 3 to yield 94b in 56% yield (Scheme 22). 71 Scheme 22 Synthesis of cularines and isocularines with K 3 [Fe(CN) 6 ] 70 and VOF 3…”

Cularine, Cancentrine, and Quettamine Alkaloids

“…Aristoyagonine (40) (+ )-Norcularicine (10) ( + )-Celtine (6) Norsecocularine (43) (+)-Celtisine (3) Noyaine (45) ( + )-Claviculine (22) Oxocompostelline (21) (+)-Culacorine (1) Oxocularine (20) ( + )-Cularicine (9) Oxosarcocapnidine (29) ( + )-Cularidine (5) Oxosarcocapnine (30) ( + )-Cularimine (8) Oxosarcophylline (28) ( + )-Cularine (7) (+ )-Sarcocapnidine (23) (±)-Dihydrolinaresine (37) (+)-Sarcocapnine ( 25) Gouregine (31) Secocularidine (41) (+ )-4-Hydroxysarcocapnine (27) Secocularine (42) (+ )-Limousamine (14) Yagonine (39) (±)-Linaresine (36) Alphabetical List of the Cancentrine Alkaloids and the Quettamines…”

“…Mass spectral mass numbers are followed in parentheses by relative abundance of ions, when these have been reported in the original literature. Synthetic (3,4) 3-(+)-CELTISINE IR: (CHC13) 3560 (7) PMR: (CDC13) (7) See also (5) MS: 327 (M+, 100) (7) See also (5,8) Sources: Synthetic (5-10) 157°( Et2Q-MeOH) (4,12,16) (HC104) 297°(MeOH) (11) [a22D: +292°(c = 0.99, CHC13) (11, 18a) UV: 284 Fumariaceae: Corydalis claviculata (L.) DC. (11, 13) Dicentra cucullaria (L.) Bernh.…”

Totalsynthese der Mansouramycine A-E aus Streptomyces sp. und Rhodium-katalysierte 1,2-Additionen an cyclische Enone

“…[7] O ). [8] Ausgehend vom 6-Methyl-7-isochinolinol (21), welches nach Jackson [9] in einer 5stufigen Synthese in 80% Ausbeute ausgehend von m-Methoxytolualdehyd hergestellt wurde, konnte nach einer Methode von Tsizin [10] 22 in 50% Ausbeute gewonnen werden. Isochinolindion 31.…”