A number of 2-(1,2,3,4-tetrahydro-1-isoquinolyl)-ethanol derivatives 7a-e have been synthesized in diastereomerically and enantiomerically pure form and have been evaluated for their binding affinity at mu and kappa opioid receptors. The amido ketones 5a-c and ent-5a-c, which were accessible by employing 3b and ent-3b for Asymmetric Electrophilic Amidoalkylation reactions, served as starting compounds. Upon reduction of 5a-c and ent-5a-c the amido alcohols l-6a-c, u-6a-c, ent-l-6a-c and ent-u-6a-c were obtained. Hydrolysis of these compounds yielded the secondary amino alcohols l-7a-c, u-7a-c, ent-l-7a-c and ent-u-7a-c and upon reductive methylation of l-7b-c, u-7b-c, ent-l-7b-c and ent-u-7b-c with CH2O and NaCNBH3 the tertiary amino alcohols l-7d-e, u-7d-e, ent-l-7d-e and ent-u-7d-e were obtained. The binding affinities of the final compounds l-7a-e, u-7a-e, ent-l-7a-e and ent-u-7a-e at both the mu and the kappa receptor were strongly dependent on their stereochemistry. In each case isomers exhibited higher affinity at the mu than at the kappa receptor. For the secondary amino alcohols 7a-c the affinity at the mu receptor followed the stereochemical order l-7 > ent-l-7 > ent-u-7 > u-7 whereas for the tertiary amino alcohols the order l-7 > u-7 > ent-l-7 > ent-u-7 was found. The stereoisomers l-7d and l-7e of the tertiary amino alcohols were found to be the most active compounds the latter exhibiting a Ki value of 7.17 which is close to that of Morphine (Ki = 1.64). In an in vivo model, the Writhing Test, both compounds l-7d and l-7e displayed high analgetic activity.
The camphanic acid amide 4 has efficiently been oxidized with triphenylcarbenium tetratluoroborate (3) to yield the c h i d N-acyliminium ion 1. Trapping reactions of 1 with the silyl nucleophiles 7a-c and 1Oa-f proceeded with stereoselective bond formation, affording the diastereomers (R)-8/(S)-9a-c and (R)-ll/(S)-lta-f, respectively, with diastereoselectivities of up to 93.9/6.1.The amid0 ketones (R)-8/(S)-9a-c were employed in the synthesis of the secondary amines (R)-16a-c, (S)-16a and for the preparation of (-)-homolauda-By X-ray crystallography the conformation of 1 in the crystal lattice was established and the preferred conformation of 1 in solution was elucidated by NOE experiments. Finally, the addition reaction of 7a to the iminium ion 21 derived from menthy1 carbarnate 20 was investigated, which reaction, however, proceeded only with insignificant asymmetric induction. About 50 years ago some patents of the German Tropon-Werke*) directed to the preparation of certain I-arylalkyl substituted tetrahydroisoqui-CH3 nolines, such as, e.g. Ia and Ib, were published. This class of compounds attracted attention mainly since members thereof had been found to be analgetically active.Two decades later a research group at Hoffmann-La Roche, stimulated by that results, developed a series of most interesting synthetic isoquinoline analgetics3). A typical representative is methopholine (10. From animal experiments with methopholine and related compounds it could be concluded that only the respective R-enantiomer is analgetically active. Furthermore, the Swiss group synthesized several analgetics which were far more active than methopholine, for example the aminoalcohols 111 that turned out, however, to be very addictive. It was shown that the analgetic activity strongly depends on the relative configuration of the two chiral centers in I11 (by a factor of 10 or more), although their relative configuration was not determined. Studies concerning the optically active isomers of 111 were not included eithe?), the question as to the stereochemical requirements for the analgetic activity of compounds I11 so remaining unsettled.Therefore, we launched a project which we expected to provide a general access to enantiomerically pure tetrahydroisoquinolines with a chiral center in position 1. In addition to the analgetically active compounds mentioned above some structurally closely related, naturally occuring substances, the phenethylisoquinoline alkaloids4) caused our interest in this project. Recently isolated homola~danosine~)
Hydride abstraction from the heterocyclic carboxamide (I), followed by coupling with the trimethylsilyl enol ethers (IV), yields a mixture of the diastereomers (V) and (VI).
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