Azabicyclic alkaloids

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). 

Of particular use is the reaction of [hydroxy(tosyloxy)iodo]benzene (HUB, also known as Koser s reagent) with ketones leading to a-tosyloxyketones [185-187], This is a highly chemoselective reaction different functional groups, aromatic rings and carbon-carbon double bonds are well tolerated under the reaction conditions [188], Scheme 3.59 shows a representative example of synthetic application of HUB for the functionalization of the azabicyclic alkaloid anatoxin-a, which is one of the most potent nicotinic antagonists. Specifically, the reaction of A-Boc anatoxin-a 140 with HTIB is the method of choice for the preparation of the synthetically versatile a-tosyloxy ketone 141 (Scheme 3.59) [189],... 

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. 

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). 

Shibanuma, Y., Okamoto, T. Synthetic approach to diterpene alkaloids construction of the bridged azabicyclic ring system of kobusine. Chem. Pharm. Bull. 1985, 33, 3187-3194. 

The [2.2.2]azabicyclic cage of the alkaloids is not immutable. The first and second cage expansions have been discovered only during the past decade. A general cinchona alkaloid solvolysis and rearrangement scheme and a unified theory have been presented. Classical solvolysis chemistry with conventional hydrocarbon substrates is complemented. The resulting azabicyclo[3.2.2]nonanes have hardly been studied. 

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. 

Yolacan,., Bagdatli, E., Ocal, N. and Kaufmann, D.E. (2006) Epibatidine alkaloid chemistry 5. Domino-Heck reactions of azabicyclic and tricychc systems. Molecules, 11, 603-14. 

We investigated the incorporation of [ 1,2- C2lacetate into the tropane alkaloids independently and chose to work with Datura stramonium which produces 6)3-hydroxytropine (15). In this alkaloid the symmetry of the parent azabicyclic system is broken and all carbon atoms are represented by well separated signals in the C NMR spectrum. In the C NMR spectrum of (15) isolated from this experiment a coupling pattern was observed which indicated that in this sample as well two labeled species were present which were bond-labeled between C-2/C-3 and C-3/C-4, respectively. 

The epoxide-initiated Schmidt reaction proceeds in a similar fashion to the mercury-promoted version. Treatment of epoxyazide 40 with a Lewis acid brings about cyclization to give the aminodiazonium intermediate 42, regioslective ring expansion results in the bicyclic iminium ion 43, and in situ reduction of 43 affords 5-hydroxymethyl azabicyclic compound 44. This alcohol has been converted to indolizidine alkaloids 167B and 209D. 

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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