Azabicyclo nonane synthesis

The mercuration-demercuration reaction of cw,cw-l,5-cyclooctadiene (3) has been widely studied in order to get some insight into the synthesis of 9-oxa and 9-azabicyclo-nonane derivatives. However, the results of the reaction have often been the subject of some controversy since the ratio of the two isomeric bicyclo[3.3.1]- [199 and 201] and [4.2.1]- [198 and 200] nonanes, after reduction (equation 166), strongly depended on the reaction conditions of the mercuration step168,169. 

Azabicyclo[4.2.l]nona-2,4-diene-9-carboxylic acid, 7-0X0-ethyl ester synthesis, 7, 524 Azabi cyclononadienones synthesis, 7, 524 1 -Azabi cyclo[5.2.0]nonane nomenclature, 7, 342... 

The pyrrolizidines and indolizidines are a group of alkaloids that are characterized by the presence of the basic azabicyclo[3.3.0]octane and azabicyclo[4.3.0]nonane frameworks, respectively. These alkaloids exhibit remarkably diverse types of biological activity and have been reported to act as antitumor, hypotensive, anti-inflammatory, carcinogenic, or hepatoxic agents. Various pyrrolizidines and indolizidines have been prepared by 1,3-dipolar cycloaddition.115 Synthesis of these is described in the section 8.2 discussing cycloaddition. 

Several examples of transition metal catalysis for the synthesis of piperidines appeared this year. Palladium catalyzed intramolecular urethane cyclization onto an unactivated allylic alcohol was described as the key step in the stereoselective synthesis of the azasugar 1-deoxymannojirimycin . A new synthetic entry into the 2-azabicyclo[3.3.1]nonane framework was accomplished through a palladium mediated intramolecular coupling of amine tethered vinyl halides and ketone enolates in moderate yields . A palladium catalyzed decarboxylative carbonylation of 5-vinyl... 

Recently, Sugimoto et al. presented a strategy toward the synthesis of tricyclic lactones containing a 2-azabicyclo[3.3.1]nonane skeleton via tandem intra-... 

The synthesis of a new class of compounds possessing the general structure 4,4,8,8-tetraalkyl-2,3 6,7-dibenzo-9-azabicyclo[3.3.1]nonane-l,5-diol (84) deserves mention since the basic skeleton is analogous to that of the pavines (Scheme 12) (124-129). Oxidation of a series of indeno[2,l-a]indenes 82 with chromic acid yielded dibenzocyclooctanediones 83. Treatment of these diketones with various amines resulted in a transannular reaction to afford species 84 in good yields. 

Vogel and Delavier (26) reported a synthesis of the 6-azabicyclo[3.2.2]nonane skeleton 130 using an intramolecular azide-alkene cycloaddition strategy (Scheme 9.26). When refluxed in xylene, the azide 126 underwent an intramolecular 1,3-dipolar cycloaddition with the internal alkene. Nitrogen extrusion and subsequent rearrangement led to a mixmre of compounds 128, 129, and 130. Reactions of azides with the double bond of dienes were also used in various total syntheses of alkaloids, and will be discussed later in Section 9.2.2. 

Another example is the synthesis of (5R)-1-azabicyclo[3.3.1]nonan-2-one which involves a resolution step followed by ring formation. The bicyclic structure in the product inhibits a planar arrangement of the substituents around the amide nitrogen. The configuration at nitrogen is determined by the configuration at C-5. Thus, only the absolute configuration at C-5 had to be established (see p 438)47-48. 

The Pd-catalyzed intramolecular aminocarbonyiation has also been applied to the formal total synthesis of Anatoxin-A 219, an acetylcholine mimic (Equation (16)). Thus, the reaction of 5-(methoxycarbonylamino)-cyclooctene 216a in the presence of a catalytic amount of PdCl2 and cupric chloride (CUCI2) (3 equiv.) in methanol under ambient pressure of CO gave the desired azabicyclo[4.2.1]nonane 217 as the predominant product. The regioselectivity of this reaction is highly dependent on the nature of the A -substituent. Thus, the... 

In contrast to the synthesis of bicyclic azetidinones containing a carboxyl group on the atom adjacent to the lactam nitrogen (see Section 5.12.3.4), few examples are reported in which bicyclic azetidinones without this carboxyl group are prepared from azetidinone precursors. One unique approach, however, utilized a free radical ring closure to obtain 6-oxa-l-azabicyclo[5.2.0]nonan-9-one (116) in modest yield (81TL2689). 

One of the few examples of a synthetically useful 6-exo-trig cyclization from 3-aza-6-heptenyl radicals is found in the total synthesis of ( )-melinonine-E (159, Scheme 31) by Bonjoch et al. [66]. The cyclization precursor, a,P-unsaturated nitrile 157 was prepared from 1,4-cyclohexanedione monoethylene acetal (156) and tryptamine in 5 steps with 41% overall yield. Initially, when 157 was treated with 1.1 equiv. of n-BujSnH and 0.1 equiv. of AIBN in toluene for 16 h, the expected cyclization to the 2-azabicyclo[3.3.1]nonane ring took place to give 158 only as a minor product, along with its C(14) chloro- and dichloro-substituted derivatives as major products. An additional treatment of the crude mixture with 2.2 equiv. of BujSnH brought about the reduction of the C-Cl bonds to provide nitrile 158 in 38% yield over... 

The synthesis continued with the formation of the 2-azabicyclo[3.3.1]nonane ring (D, E-rings), and epimerization of the cyano group at C-20 to an axial position. Closure of the C ring using a Bischler-Napieralski cyclization gave the quaternary indole alkaloid, ( )-melinonine-E (159). A closely related analog, ( )-strychnoxanthine, was also synthesized by a similar method [67]. 

New total syntheses9 of azabicyclo[4.2.1]nonanone (10) have now been elaborated. The first synthesis started with 5-azidocyclo-oct-l-ene (7). Reduction and iV-methylation (via the urethane), followed by treatment of the secondary amine with hypobromous acid and with base, gave a mixture of 9-methyl-9-azabicyclo[4.2.1]nonan-2a-ol (8) and its 2/3-isomer (9), contaminated with some azabicyclo[3.3.1]nonane analogue cf. (18). The second synthesis starts with the monoepoxide from cyclo-octa-1,5-diene (11). Treatment with methylamine and... 

One of the most popular methods for creating the anatoxin-a skeleton is by transannular cyclization of a suitably substituted cyclooctene. This approach was used in the first synthesis of racemic anatoxin-a (Campbell et al. 1979). They carried out two different methodologies in order to reach the 9-azabicyclo[4.2.1]nonane structure (Scheme 7.3). The 1,5-cyclooctadiene (10) starting compound was transformed into the methyl amine 11 which was treated with hypobromous acid to produce the desired bicycle 12 as a mixture of diastereoisomers in 29% overall yield, with some amount of the azabicyclo[3.2.1] analogue (Bastable etal. 1972). 

Wiseman and Lee (1986) also reached the ketone 14 by a route involving the cyclization of 1,5-cyclooctanediol (16 Scheme 7.4). This transformation involved the Jones oxidation of 16 to give the hemiketal 17, which was transformed into the 9-methyl-9-azabicycle[3.3.1]nonan-l-ol 18 by treatment with methylamine, followed by addition of sulphuric acid (Quinn et al. 1973). This skeleton was reconverted into the 9-azabicyclo[4.2.1]nonane by bromination-reorganisation with pyri-dinium bromide perbromide in hot acetic acid in one direct step (Stjernlof et al. 1989). This constitutes the key step of this synthesis, affording the ketone 14 in 56% yield. 

Brough, RA., Gallagher, T., Thomas, P., Wonnacott, S., Baker, R., Abdul Malik, K.M., and Hursthouse, M.B. 1992. Synthesis and X-Ray crystal structure of 2-acetyl-9-azabicyclo[4.2.1]nonan-3-one. A conformationally locked s-cis analogue of anatoxin-a. J Chem Soc Chem Commun 1087-1089. 

ShonOjT, Matsumura, Y., Uchida, K., andXagami, K. 1987. Anew method offormationof9-azabicyclo-[4.2.1]nonane skeleton and its application to synthesis of( )-anatoxin-a. Chem Lett 919-922. 

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