4- Aryl-2-azabicyclo octanes

Ifenprodil (= l-Methyl-2-hydroxy-2-(4-hydroxyphenyl) ethyl-1 -(4-benzyl-piperidine)] -(aryl piperidine) [at(/o-3-(Indol-2-yl)-8-methyl-8-azabicyclo-[3.2.1] octane] (indolotropane) [Kynurenic acid (= 4-Hydroxy-2-quinolinecarboxylic acid)] (quinoline carboxylic acid) [Memantine (= 1-Amino-3,5 dimethyladamantane)] (amino adamantane, amino cyclic aliphatic) [Methadone (= 6-Dimethylamino-4,4-diphenyl-3-heptanone)] (aryl tertiary amine) [em/o-3-(l -Methylindol-2-yl)-8-methyl-8-azabicyclo-[3.2.1] octane(indolotropane) exo- 3-( 1 -Methylindol-2-yl)-8-methyl-8-... 

Isomeric l-aryl-6-azabicyclo[3.2.1]octanes (24) that possess a five-membered heterocyclic ring and that may be thought of as bridged analogs of profadol<16) have been described and evaluated for analgesic responses.(17 20) Synthesis was from a previously reported arylcyclohexanone ketal (25) according to Scheme 5.6. 

An X-ray study(20) of (+)-24 (R = OH R1 = Me or H) (1.R) suggested a configurational relationship between it and (+)-5b (5.R) (p. 218). Thus, the dominant biological activity resides in compounds that are stereochemically related. This relationship was confirmed by the chemical conversion, with retention of configuration, of the quaternary l-aryl-6-azabicyclo[3.2.1]octane (26) to (+)-5b, Scheme 5.7. 

Aryl-2-azabicyclo[2.2.2]octanes (28) show a similar pattern of activities.(19) Although these compounds are not analgesic in the MW test, some of them (28, R and R1 = H andR = H. andR1 = Me) have pentazocinelike antagonist properties. 

This method of diastereoselective cyclopropanation can also be used with reasonable success for the enantioselective entry to tropanes by a tandem cyclopropanation Cope rearrangement of the 2-diazobut-3-enoate with the (i )-pan-tolactone auxiliary group in the presence of N-( err-butoxycarbonyl)pyrrole (8.185). The product 8.186 was obtained by Davies and Huby (1992) with 69% ee. It can be transferred in three steps into 8-azabicyclo[3.2.1]octane-2-carboxylates (8.187), which are the parent compounds for the corresponding 3-aryl derivatives. The latter are valuable probes for studying the neurochemistry of cocain abuse (Carroll et al., 1992 Lewin et al., 1992 Abraham et al., 1992). 

---