8-azabicyclo octane system

The tropane alkaloids contain as a common structural element the azabicyclo [3.2.1] octane system, and the systematic name of tropane is 8-methyl-8-azabicyclo [3.2.1] octane (Fig. 1). Contradictory results concerning the C-6 and/or C-7 substitution of several C-3,C-6- and C-3,C-7-disubstituted and C-3,C-6,C-7-trisubstituted tropane alkaloids have been presented in the literature. In many cases both optical antipodes of these tropane alkaloids are known, either separately or as a racemic mixture. 

In connection with the enantioselective alkylation of Pro or 4-hydroxy-proline, the azabicyclo[3.3.0]octane system 81 was obtained after reaction with pivaldehyde (81HCA2704 85HCA155). In a more complex transformation A-protected L-Pro was transformed into the same bicyclic system (Scheme 49) (81JA1851 84JA4192). The product was prepared as a model substance in the total synthesis of pumiliotoxin. A related compound 82 was prepared from 5-(hydroxymethyl)-2-pyrrolidinone (prepared from L-pyroglutamic acid) by an acid-catalyzed condensation with benzaldehyde (86JOC3140). 

The alcohol portion in hyoscyamine is tropine in hyoscine it is the epoxide scopine. Tropine is an example of an azabicyclo[3,2,l]octane system with a nitrogen bridge, whereas scopine is a tricylic system with a three-membered epoxide ring fused onto tropine. Note that systematic nomenclature considers an all-carbon ring system with one carbon replaced by nitrogen hence, tropane is an azabicyclooctane (see Section 1.4). 

Wilken, J., Thorey, C., Groger, H., Haase, D., Saak, W., Pohl, S., Muzart, J., Martens, J. Utilization of industrial waste materials. Part 11. Synthesis of new, chiral P-sec-amino alcohols. Diastereodivergent addition of Grignard reagents to a-amino aldehydes based on the (all-R)-2-azabicyclo[3.3.0]octane system. Liebigs Ann. Chem. 1997, 2133-2146. 

The Quinoline Family. The amino acid tryptophan is the precursor of the quinoline alkaloids. Far less numerous than the isoquinoline alkaloids, the quinoline family is distinguished by having the famous dmg quinine as a member. Quinine has been used for ages in the treatment of malaria. It is isolated from the bark of the Cinchona tree. Quinine (3.20) has the rare stmctural feature of a bicyclic amine (a derivative of the l-azabicyclo[2.2.2]octane system) as a substituent. 

The initial medicinal chemistry route to the azabicyclo[3.3.0]octane-3-carboxylic acid produced the azabicyclo system in a diastereoselective but racemic manner, and required a classical resolution to achieve enantioenriched material (Teetz et al., 1984a, b 1988). Reaction of (R)-methyl 2-acetamido-3-chloropropanoate (43) and 1-cyclopentenylpyrrolidine (44) in DMF followed by an aqueous acidic work-up provided racemic keto ester 45 in 84% yield (Scheme 10.11). Cyclization of 45 in refluxing aqueous hydrochloric acid provided the bicyclic imine, which was immediately reduced under acidic hydrogenation conditions. The desired cis-endo product 46 was obtained upon recrystaUization. The acid was protected as the benzyl ester using thionyl chloride and benzyl alcohol, providing subunit 47 as the racemate. Resolution of 47 was accomplished by crystallization with benzyloxy-carbonyl-L-phenylalanine or L-dibenzoyl-tartaric acid. 

The cephalosporins, discovered in the 1950s, are produced by various species of the mold Cephalosporium. Cephalosporin C (9.46) is the prototype of these antibiotics, and its structure shows a close similarity to the penam stmcture. The 5-thia-l-azabicyclo[4.2.0] octane ring system is therefore called the cepham ring. The parent compound carries the aminoadipate side chain, which can be cleaved to supply the 7-amino-cephalosporanic acid. This amine can easily be acylated and thus forms the basis of many useful derivatives. The 3-acetoxymethyl substiment is also amenable to modifications. 

For the most part the parent unsubstituted bicyclic azetidines have not been reported. Those unsubstituted ring systems which have been reported are l-azabicyclo[2.2.0]hexane (4) (64HCA2145), l-azabicyclo[4.2.0]octane (5) (60JA2609) and the cis- and trans-6-azabicyclo[4.2.0]octanes (6) (66JOC1372). 

Quinuclidine (l-azabicyclo[2.2.2]octane) is a heterocyclic system which is part of the structure of a number of natural physiologically active compounds and synthetic drugs.1 Among the natural alkaloids, the following quinoline and indole derivatives contain the quinuclidine ring cinchonine, cinchonamine (alkaloids of Cinchona species),8-12... 

The pyrrolizidine nucleus is also affordable by intramolecular carbolithiation reaction starting from stannane 212. After transmetallation, cyclization and trapping with electrophiles the pyrrolizidines 213 were isolated as their picrate salts, as an inseparable (3 1) mixture of diastereoisomers. The preference for a chair-shaped transition state, with a ris-fused l-azabicyclo[3.3.0]octane ring system, suggests that the major diastereoisomer would be the first, though this was not completely ascertained (Scheme 57)96. 

Cyclic analogs of fentanyl in which the N-acyl group is joined to N-phenyl,(52) N-phenyl linked to C-3 of the piperidine ring,<53) and the N-phenethyl substituent incorporated in a ring system<54) were all of low potency or inactive. Analogs based on 2-azabicyclo[2.2.2]octanes also lacked measurable analgesic activity.(55)... 

The intramolecular insertion into the N — H bond of y-lactams can be appropriate for constructing l-azabicyclo[3.3.0]octane ring systems such as 65 [93AG(E)285]. 

The intramolecular carbenoid insertion into the N — H bond of j8-lactams is frequently used for constructing the l-azabicyclo[4.2.0]octane ring system. Thus, in the synthesis of (-)-homothienamycin, the crucial ring closure was effected by refluxing compound 160 in a benzene solution containing Rh2(OAc)4 (80TL1193). Such an approach was used to advantage in... 

E. Suarez and co-workers prepared chiral 7-oxa-2-azabicyclo[3.2.1]octane and 8-oxa-6-azabicyclo[3.2.1]octane ring systems derived from carbohydrates via an intramolecular hydrogen abstraction reaction promoted by A/-centered radicals. The A/-centered radicals were obtained under mild conditions (Suarez modification) from phenyl and benzyl amidophosphates and alkyl and benzyl carbamate derivatives of aminoalditols by treatment with PIDA/I2 or PhlO/l2. The initial A/-radical undergoes a 1,5-hydrogen abstraction to form an alkyl radical, which is oxidized to the corresponding stabilized carbocation (oxocarbenium ion) under the reaction conditions. The overall transformation may be considered as an intramolecular N-glycosidation reaction. 

Francisco, C. G., Herrera, A. J., Suarez, E. Intramolecular Hydrogen Abstraction Reaction Promoted by N-Radicals in Carbohydrates. Synthesis of Chiral 7-Oxa-2-azabicyclo[2.2.1]heptane and 8-Oxa-6-azabicyclo[3.2.1]octane Ring Systems. J. Org. Chem. 2003, 68, 1012-1017. 

Most examples of ring contraction of eight-membered nitrogen heterocycles involve 1,5-transannular C-N closure to give the l-azabicyclo[3.3.0]-octane (pyrrolizidine) system.115 For example, treatment of iV-cyclohexyl-l-azacyclooctane-5-ol (74), with acid gave iV-cyclohexyl-l-azabicydo[3.3.0]-octane iodide (75, R1 = C6H12, R2 = H).115... 

Synthetic access to quinidine positions other than C2 and C3 is more challenging. Treatment of quinine in superacid, for example, delivers a tricyclic derivative 96 via nucleophilic ring closure between the C9 OH oxygen and a carbocation at C5 (Scheme 12.27). However, cyclization occurs only subsequent to a rearrangement of the azabicyclo[2.2.2]octane unit into a thermodynamically more stable [3.2.1]-system [65]. 

As yet, the l-azabicyclo[3.2.2]nonane scaffold has been encountered in nature only rarely, for example, in tronoharine, vincathicine, and communesin B, in contrast to the l-azabicyclo[2.2.2]octane moiety of cinchona alkaloids. A short and simple access to this particular bicyclic system is thus ofhigh interest for exploring its biological and chemical properties. 

Luis, Martens and coworkers developed a closely related flow system [35] which was based on Frechet-type polymeric monoliths (refer also to Sect. 3.2) [36]. They immobilized azabicyclo[3.3.0]octane-3-carboxyhc acid 7 both by grafting and by polymerization (Fig. 4). The addition of diethyl zinc to ben-zaldehyde in a coliunn was studied. It was foimd that the monolithic catalyst prepared by polymerization turned out to be superior (up to 99% ee) compared to the catalyst prepared by grafting (compare with Schemes 7 and 8). Differences in appropriate chiral cavities inside the polymer maybe responsible for these results, the other factors being differences in reaction conditions and most probably the avoidance of diffusional problems in the monolithic catalyst at high flow rates. 

Two well-known alkaloids, cocaine (3.11) and atropine (3.12), are ester derivatives of the 8-azabicyclo[3.2.1]octane ring system. Cocaine, isolated from a variety of the poppy plant, has been used as a topical anesthetic, but it is highly addictive if it enters the bloodstream and is now a controlled substance. Atropine, however, is highly useful in medicine with anticholinergic properties. It is isolated from the Belladonna plant and has been used for many years to dilate the pupil of the eye. It is also an effective antidote to poisoning by anticholinesterase chemicals, when these are used as insecticides or in extremely toxic form as chemical warfare agents. 

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