Azabicycle

Theoretically, valence isomerization of 3//-azepincs can give rise to 2-azabicyclo[3.2.0]hepta-2,6-dienes 20 and/or the isomeric fused azetines, 6-azabicycIo[3.2.0]hepta-2,6-dienes 21. Practically, however, 2-alkoxy- and 2-amino-3//-azepincs 19, on photolysis, yield the 2-azabicyclic systems 20 exclusively, since such structures are stabilized by imidate or amidine resonance.238... 

A novel approach to azabicyclic ring systems, based on an epoxide-initiated electrophilic cyclization of an alkyl azide, has been developed by Baskaran. A new stereo- and enantioselective synthesis of the 5-hydroxymethyl azabicyclic framework 91a, present in (+)- and (-)-indolizidines 167B and 209D, for example, was... 

Reactions of this type are mostly performed with internal nucleophiles attached to the carbon atom adjacent to the iminium nitrogen, thus leading to tropane-like azabicyclic systems. Both allyl- and propargylsilanes, activated and unactivated alkenes, and ketones have been successfully used as nucleophiles. The products 1 and 2 are also obtained via two consecutive C —C bond-forming reactions in a single operation. 

Enantiopure 1-azabicyclic compounds of dilferent ring size have also been prepared using the described method [245]. 

Under suitable conditions, oxidation of /V-alkyl-a-amino acids, accompanied by decarboxylation, has made it possible to carry out regioselective syntheses of nitrones which were utilized in the synthesis of 1-azabicyclic alkaloids (Scheme 2.6) (48, 49). 

In this section, whatever the saturation level of the aza-bicyclic compound considered, we will focus only on the bond-formation step which leads to the azabicyclic skeleton of pyrrolizines and their derivatives. The reported routes will be classified according to the number of atoms in the newly formed bond, as already done in CHEC-II(1996) <1996CHEC-II(8)12> and shown in Figure 1. Not all of these modes were equally employed the most popular are 1,8- 1,2- 2,3- 3,4- 1,8 2,3- 1,2 3,4- and 1,8 3,4-bond formations. Each of these modes will be described in this section all other bond-formation modes will be discussed in Section 11.01.9. 

In the synthesis of the azabicyclic core of the Stemona alkaloids, methyl (2/W,3.9/ ,3a/W)-2-(2-cthoxycarbonylethyl)-hexahydropyrrolo[l,2- ]isoxazole-3-carboxylate was hydrogenolyzed over 10% Pd-C in EtOAc and acetic acid at room temperature to give after cyclization the bicyclic lactam 153 <2005JOC3157> (Equation 22). This route was also used to produce pyrrozilidinone-based dipeptide isosteres <2005T8836>. 

The validity of the oxauracil strategy for a stereoselective construction of the azabicyclic core has been proven for the syntheses of biologically important polyguanidinium alkaloids, namely, batzelladine A and D [58]. Reaction (7.48) shows that treatment of 41 under the standard free-radical conditions furnished the desired azabicycle in a 77 % yield, in a high diastereoisomeric ratio. Here it can be seen the effect of H donation from the more accessible face of the molecule. 

An interesting neophyl-type radical rearrangement process has been established for the synthesis of azabicycles, which are not readily accessible by other means. Barton McCombie deoxygenation of xanthate 70 under slow addition of (TMS)3SiH and AIBN in refluxing toluene furnished the 2-azabenzonorbor-nane derivative in good yield (Reaction 7.72) [82]. 

Alkyl halides can also be used to generate the radical center, and N -substituted uracil and thymine derivatives have been used to prepare octahydropyrrolo[l,2-f]pyrimidinedione derivatives <2001TL6637, 2006CC844> as demonstrated by diasteroeoselective synthesis of the azabicycle 447 <2006CG844>. 

The chiral adduct 753, obtained from the unsaturated oxazolone 632 derived from (R)-glyceraldehyde and Danishefsky s diene, has been conveniently elaborated to the valuable azabicyclic intermediate 844 used for the synthesis of... 

Azabicyclic derivatives of isothiazolopyridines have been used for therapeutic use as a 7-nACh receptor activators <2007W0038367>. 

The same type of cascade cyclization has been applied to the one-step synthesis of fused azabicyclic compounds with medium to large-membered rings (Scheme 10). ... 

Conformational isomers were detected (68JCS(B)1241 85JOC2080) in other N-acyl azabicyclic derivatives. However, owing principally to their molecular complexity, they do not represent molecular systems of particular interest for understanding the factors influencing the conformational properties of acyl heterocycles. 

A number of azabicyclic derivatives have also been investigated (7 ICC 1104) as model compounds to study the effect of increasing the nitrogen inversion barrier upon the amide rotational barrier. From the experimental results and simplified MO pictures of the inversion and rotational mechanism, the authors (71CC1104) conclude that changes in the amide rotational barrier do not necessarily correspond to enhancement of the nitrogen inversion barrier. 

Reddy, P. G., Baskaran, S. (2004) Epoxide-initiated cationic cyclization of azides a novel method for the stereoselective construction of 5-hydroxymethyl azabicyclic compounds and application in the stereo- and enan-tioselective total synthesis of (+)- and ( —) -indolizidine 167B and 209D. J Org Chem 69, 3093-3101. 

Steve Martin of UT Austin has reported (J. Org. Chem. 68 8867,2003) a detailed study of the synthesis of bridged azabicyclic structures via ring-closing alkene metathesis. Some examples of his work include the conversion of 12 to 13, efficiently forming six, seven and eight membered rings. He also demonstrated five-membered ring formation with the conversion of 14 to IS, which has the cocaine skeleton. 

Tribromo acids of this type (41) can also be used for the synthesis of quinolizidine and other 1-azabicyclic alkanes with functional substituents. 

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