6-Azabicyclo octane ring system

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. 

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. 

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. 

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. 

Nuclear analogues of jS-lactam antibiotics have featured strongly during 1979 either as potential drugs or as intermediates. A typical example is the synthesis of the 3-oxa-l-azabicyclo[4.2.0]octane ring system as an intermediate in the synthesis of thienamycin. The interesting reaction, shown in Scheme 137, is the... 

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). 

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). 

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)... 

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... 

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... 

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]. 

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