3- Azabicyclo 3.3,1 nonene

A rare example of a higher-order [5 + 3]-cycloaddition was reported by Liesbeskind and Arrayas. Homochiral 7]3-pyranyl- and // -pyridinyl-molybdcnum 7r-complexes react with an oxyallyl cation that is generated in situ from the precursor 88. After decomplexation of the molybdenum, oxa- and azabicyclo[3.3.1]nonenes are obtained in moderate yields and in excellent ee s (Scheme 27).89 Related work using 3-pyranyl- and 3-pyridinyl-molybdenum 7r-complexes as five-carbon components in [5 + 2]-cycloadditions is discussed in Section 10.13.2.1.2. 

Bolton, G. L. Solid Phase Synthesis of Azabicyclo[4.3.0]nonen-8-one Amino Acid Derivatives via Intramolecular Pauson-Khand Cyclisation, Tetrahedron Lett. 1996, 37, 3433—3436. 

Several routes to cycloalkanes have been developed (Fig. 4). Bolton [29] described the synthesis of azabicyclo[4.3, 0]nonen-8-ones using an intramolecular Pauson-Khand cycliza-tion. The relative stereochemistry was controlled in this cyclization step which proceeded in good yield regardless of whether the nitrogen atom bore an allyl (shown) or propargyl (not shown) substituent. The ene reaction was employed in a route to trans-substituted cyclopentane and cyclohexanes [30], Reductive cleavage from the resin with LiBFL, provided the diol or, alternatively, cleavage with Ti(OEt)4 produced the diester. 

The nature of the dienophilic part of the molecule did not have any influence on the stereochemistry of the IMDA reaction. 27 was reacted with methoxyamine, and the terminal hydroxyl of the obtained oxime was oxidized to give an aldehyde function (Figure 10.). Chain extension of the latter with allylidenetriphenylphosphorane led to the formation of a mixture of four diastereomers of 34, i.e. E-syn, E-anti, Z-syn, Z-anti, respectively. A similar mixture has been obtained from 31 with methoxyamine. When the diastereomeric mixture of 34 was heated in toluene for 8 h the azabicyclo 4.3.0 nonene 35 diastereomer was formed exclusively. The conformation of this ring system is similar to that of 33 (30,31) (Figure 11.) as evidenced by 5 (6.5 Hz). 

Tomita T, Kita Y, Kitamura T, Sato Y, Mori M (2006) Further studies on enantioselective synthesis of (-l-)-anatoxin-a using en5oie metathesis unexpected inversion of chirality via a skeletal rearrangement of 9-azabicyclo[4.2.1]nonene derivative. Tetrahedron 62 10518-10527. doi 10.1016/j.tet.2006.05.088... 

The influence of the stereochemistry of branched aUylsilanes on addition to carbonyl compounds is displayed in the next example, which contains an enan-tioselective construction of 9-azabicyclo[3.3.1]nonene via iminium ion initiated cychzation of aUylsilanes (Scheme 3.41) [66]. 

Scheme 3.41 Preparation of enantiomerically pure 9-azabicyclo [3.3.1]nonene derivatives from vinyl silanes.

Azabicyclo[3.3.1]nonenes are common structure types present in a variety of different alkaloids [67]. An elegant and fast approach to these structure types starts from oxazolidines 203 harboring a vinylsilane in the side chain. From this vinylsilane the branched aUylsilane is stereospecifically generated in a [3,3]-sigmatropic aza-Cope rearrangement Acid-catalyzed iminium cychzation leads to the formation of the desired 9-azabicyclo[3.3.1]nonene 204. 

Submitting both geometrical isomers to the cyclization conditions resulted in exclusive cyclization of the (Z)-isomer 203 to give 9-azabicyclo[3.3.1]nonene 204. The (Tj-isomer did notcyclize at all (see Scheme 3.43). This very surprising result was rationalized as depicted in Scheme 3.44. 

The total synthesis of (-l-)-anatoxin-a was achieved by Martin et al. 12a, b and Mori et al. [12c, d] by using the same strategy. The key step is the constraction of an azabicyclo[4.2.1]nonene ring system. For that purpose, the 2,5-ds-disubstituted pyrrolidine derivative 34 was synthesized from (-l-)-pyroglutamic acid. Ene-yne metathesis appHed to 34 was carried out using second-generation catalyst [Ruj-II to form the azabicychc compound 35 [12a, b], which was chemoselectively dihy-droxylated to provide 36. From the latter compormd, anatoxin-a was synthesized (Scheme 6.9). 

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