Octahydroisoquinoline ring

Another 6-exo closure from our enantioselective total synthe.ses of (—)-morphine (40) and its enantiomer was published in 1993 (Scheme 6-7) [12]. The pivotal cyclization of 38 to 39 was accomplished in 60% yield. This is a demanding intramolecular Heck reaction, since the palladium-bond arylmethyl side chain of 38 must rotate over the octahydroisoquinoline ring to coordinate with the trisubstituted alkene. Reflecting this difficulty, Pd(OCOCF3)2(PPh3)7 [a precatalyst that generates the reactive Pd(0) catalyst Pd(PPh3)2] cyclization temperature of 120 °C were required. 

A radical cyclization has been used by Hart, at The Ohio State University, to prepare the manzamine tricyclic core (139). Utilizing tri-w-butyltin hydride to mediate the cyclization of selenide 171, the desired stereochemistry of the octahydroisoquinoline ring (172) was established (Scheme 13) electrophilic catalysis generated the tricyclic intermediate 174. An anionic cyclization leading to a tricyclic intermediate is being developed by Marko, at the University of Sheffield, toward which he has recently reported a model study (140). 

In the synthesis of morphine, bis-cyclization of the octahydroisoquinoline precursor 171 by the intramolecular Heck reaction proceeds using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the 7r-allylpalladium intermediate 172, which attacks the phenol intramolecularly to form the benzofuran ring (see Section 1.1.1.3). Based on this method, elegant total syntheses of (—)- and ( + )-dihydrocodei-none and (-)- and ( + )-morphine (173) have been achieved[141]. 

The reaction of 5-acetoxy-5,6,7,8-tetrahydroisoquinoline 109 with Mel followed by reduction afforded the octahydroisoquinoline 110, which upon treatment with ethyl chloroformate followed by hydrolysis gave 111. The condensation of 111 with 2-bromoisovanillin afforded 112, which was reduced to give the benzyl alcohol intermediate 113. Heck reaction of 113 led to the formation of 0-ring affording 115. The yield of the above intramolecular cyclization was increased significantly via prior protection of the alcohol in 113 as silyl ether 114. Conversion of 115 to benzyl chloride 116 was achieved via the treatment with NCS and triphenylphosphine. Further, Heck reaction of 116 afforded the tertiary amine 117 via an intramolecular A -benzylation. The amine 117 was converted into the corresponding iV-methylammonium iodide 118, which was then subjected to Stevens rearrangement with PhLi to afford ( )-desoxycodeine 119 in 83 % yield. ... 

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