Octahydroisoquinoline

The Grewe synthesis of /V-methylmorphinan [3882-38-0] (40), which paved the way for the preparation of dextromethorphan and numerous analogues, follows standard reactions to 2-meth5l-l-benzyl-l,2,3,4,5,6,7,8-octahydroisoquinoline. Cyclization of this compound with phosphoric acid gave a mixture of isomers from which /V-methylmorphinan was separated. 

An intramolecular Heck cyclization of substrate 178 was the central feature in Overman s synthesis of pyridinomorphinans [139]. Octahydroisoquinoline 178, derived from an allylsilane-iminium ion cyclization as a single stereoisomer, was cyclized under forcing conditions to afford enantiomerically pure 179, an intermediate for a (-)-morphine (180) analog. 

N-Methylmorphinane. 2.7 g of the decahydro compound above in 25 ml of 85% phosphoric acid is refluxed for 70 hours and then poured onto ice. The aqueous phase is extracted with ether and the product is salted out with potassium carbonate. It is then taken up with ether, dried, and distilled at 130-132° at 0.7 mm of vacuo to give 1 g ofN-Methyl morphinane mixed with a small amount of octahydroisoquinoline, which can be removed by column chromatography. Use 0.5 g of product in 4 ml of low boiling petroleum ether and add onto the top of 30 g of aluminum oxide in a 50 ml buret or column. Elute with 20 ml portions of low boiling ether to which is added 0,0,0,1,3,5,5, and 5 ml of ethyl ether, respectively. The last three portions eluted over 0.3 g of purified product. 

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]. 

Dondio, G., Clarke, G.D., Giardina, G., et al. Potent and selective non-peptidic delta opioid ligands based on the novel heterocycle-condensed octahydroisoquinoline structure, Reg. Pept. 1994, 1, 43-44. 

Scheme 12.12 The stereochemistry of hydrogenation of octahydroisoquinolines over platinum.

A similar approach to S selective antagonists was undertaken by Dondio and Ronzoni [197]. They prepared pyrrolo-octahydroisoquinoline derivatives. Studies of the binding of the racemic form of compound (129) showed a <5 Ki value of 2.15 nM and pi/5 and k 18 selectivity ratios of 45 and 403 respectively. In the MVD, compound (129) exhibited a Ke value of 7 nM against DADLE. 

Several approaches to the synthesis of morphinans start with cyclohexanone intermediates leading to octahydroisoquinolines such as 3 by way of a route similar to that exploited by Grewe (Scheme 3.1). Amination of 2-hydroxymethylenecyclohexanone (6) followed by reaction with malonic ester afforded the hexahydroisoquinoline, 7, that was decarboxylated and converted on a commercial scale to 5,6,7,8-tetrahydroisoquinoline(9) via the 3-chloro intermediate. 

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 diazomethane-iminium insertion reaction was utilized during the formation of a methylene bridge in the synthesis of a morphinan-type compound from a corresponding octahydroisoquinoline (Scheme 17). The requisite octahydroisoquinoline (85) was prepared from the tetrahydropyri-... 

Where no assistance can be expected from intramolecularity, or from a reactive rearomatizing o-qui-nodimethane system as above, [4 + 2] cycloadditions with inverse electron demand are required. Thus, reaction of the 2-aza-1,3-butadiene (146) with the electron-rich enamine (147) at room temperature affords the octahydroisoquinoline (148) in high regio- and diastereo-selectivity (Scheme 68). ... 

Subsequently the method of obtaining angular-substituted phenan-threnes was extended to the synthesis of the morphine skeleton. 1 -Benzyl-2-methyl-1 2 3 4 5 6 7 8-octahydroisoquinoline [liv] was heated with syrupy phosphoric acid at 150° C. for three days, when N-mothylmorphinano [lv] was obtained in 50 per cent, yield [10, 22],... 

As even the optimized hydrogenation conditions gave rise to not more than 89% enantioselectivity it became very important to find an efficient purification procedure which would allow the enrichment of the desired (-(-enantiomer. A rapid screening of several weak and strong acids led to an acceptable solution. The acetates of both the racemate 11 as well as the (-)-enantiomer 12 are readily crystalline salts but the acetate of the desired (S)-enantiomer is less soluble in toluene at 0°C than that of the racemate by a factor of 10. Thus it could be crystallized in overall yield of 84%, content 99.1%, 98.9% ee. Finally it was noticed that traces of iridium (70-200 ppm) in the acetate salt hindered the following reaction in the synthetic sequence, by leading to decomposition of the formic acid (used as for-mylation reagent). A treatment of the octahydroisoquinoline solution with charcoal prior to precipitation of the acetate salt lowers the Ir content to 20-40 ppm. This new quality can then be formylated without problems under the standard conditions. 

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). 

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