Azabicyclic alkaloids synthesis

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). 

The pyrrolidine synthon (48) is useful for the chiral synthesis of pyrrolizidine, pyrrolidine, indolizidine and azabicyclic alkaloids (see Scheme 23). 

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>. 

Similarly, chiral bases have found use in the preparation of building blocks for synthesis of alkaloids. A range of A-protected azabicyclic ketones was deprotonated to yield corresponding silylenol ethers (Scheme 30)68-70. The highest ee (93%) was obtained using 42 under internal quench conditions. These chiral ethers found use as key intermediates in the preparation of naturally occurring alkaloids. 

These compounds can then be readily converted into 7-azabicyclo[2.2.1]heptan-2-ones of type 1090 (Scheme 212), which have been shown to be useful precursors for the synthesis of the novel alkaloid epibatidine <1996JOC7189>. Epibatidine has been found to be 200-400 times more potent than morphine as an analgesic, and more importantly should prove to be useful for the preparation of its analogs with reduced toxicity. The approach with phenyl 1,2-propadienyl sulfone 1091 (R = S02Ph, R = H) proved to be more efficient and high yielding than the ester sequence and provided azabicycle 1090 in 19% overall yield (four steps). 

In 1998, Kawahara and Nagumo reported the first total synthesis of a member of the TAN1251 series [63] and five years later both authors revisited the TAN1251A alkaloid by means of a new enantioselective synthesis (see Section 5.6). The retro synthetic analysis of TAN 1251A is outlined in Scheme 37. The target compound could be obtained by aldol reaction of tricyclic lactam 119, whose disconnection at the amide bond led to the bicyclic amino acid 120, which could be prepared from azaspirocyclic compound 121 by means of alkylation of the secondary amine and Mitsunobu-type chemistry. Azabicycle 121 may be prepared by an intramolecular alkylation of 122, which in turn could be available from allyl derivative 123. The latter can be prepared from carboxylic acid 124 by alkylation and subsequent Curtius rearrangement. 

A further extension of the Pd-catalyzed intramolecular 1,4-oxidation was the use of amide, whose amino functionality had the ability of making a twofold nucleophilic attack. The use of nitrogen as nucleophile led to pyrrolizidine and indolizidine derivatives. This strategy was applied for the synthesis of another alkaloid, ( )-heliotridanef (Scheme 36). Pd-catalyzed reaction of dieneamide, obtained from the known ester 167, in THF employing CUCI2/O2 as the oxidant afforded the azabicyclic product 168 in 85% yield. The mechanism of this tandem cyclization involved a TT-allylpalladium... 

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