Alkaloids azide 1,3-dipolar cycloadditions

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. 

Ciufolini et al. (61) reported a facile assembly of the benzazocenone 307 as a part of the total synthesis of the antitumor alkaloids mitomycin C (309) and FR 900482 (310) based on intramolecular 1,3-dipolar cycloadditions of aryl azides with electron-rich alkenes (Scheme 9.61). Azide 305 was heated in refluxing toluene with a catalytic amount of K2CO3 to give the triazoline 306 in 55% yield. Irradiation of a solution of the triazoline 306 in wet THF with a sun lamp gave an 84% yield of the required benzazocene 308, which was converted to the target molecules 309 and 310. 

Hudlicky et al. (65) reported a formal stereoselective total synthesis of the oxygenated pyrrolizidine alkaloids platynecine (336), dihydroxyheliotridane (337), hastanecine (341), and tumeforcidine (342), involving an intramolecular azide-diene cycloadditions (Scheme 9.65). Intramolecular 1,3-dipolar cycloaddition of... 

Pearson et al. (68) reported a versatile approach to pyrrolizidine and indolizidine alkaloids such as 355, 247, and 362 using intramolecular cycloadditions of azides with electron-rich dienes (Scheme 9.68). Azido dienes 353, 357, and 360 that possess a electron-donating group on the diene were prepared from the respective compounds 352, 356, and 359. On heating at 100 °C, the azido diene 353 underwent smooth intramolecular 1,3-dipolar cycloaddition in a stereoselective... 

The dipolar cycloaddition of an alkyl azide with an alkene to form an aziridine has been exploited in the total synthesis of the alkaloid ( )-aspidospermidine <20050BC213>. Enone 353 was prepared in 11 steps from 3-ethoxycyclohexenone and coupled to 2-iodo nitrobenzene under Ullman cross-coupling conditions. The acetate group of 354 was hydrolyzed and the resulting alcohol converted to an azide using standard conditions in 75% overall yield. The cycloaddition of the azide with the enone was conducted in refluxing benzene for 3 days. The fused-ring aziridine 355 was the only product isolated. None of the initial dipolar cycloadduct triazoline was observed. The... 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

Using rw-chloroalkenes (e.g., 42) in 1,3-dipolar cycloaddition reactions, Pearson et al. described the synthesis of several alkaloids [20-22]. The reaction proceeds by an intramolecular cycloaddition of an azide onto an alkene, producing an intermediate triazohne. Fragmentation of the triazoUne and rearrangement to a monocyclic imine occurs, which is internally N-alkylated by the alkyl chloride, resulting in iminium ion 43. Reduction with sodium borohydride leads to the racemic lycorane (44). 

Many classes of alkaloids reveal a pyrrolizidine skeleton as a key structural element. Hudlicky et al. and Pearson et al. demonstrated the applicability of 1,3-dipolar cycloaddition of an azide with an alkene moiety in a conjugated diene to generate pyrrolizidines [38-42]. The triazoline 73 was formed by an... 

Azides are very versatile and valuable synthetic intermediates, known for their wide variety of applications, and have been employed for the synthesis of a number of important heterocyclic compounds. Azides also represent a prominent class of 1,3-dipoles, and their cycloaddition to multiple tt-bonds is an old and widely used reaction (1988CR297). The dipolar cycloaddition of an azide to an alkene furnishes a triazoline derivative (2003MI623). Azide-alkene cycloadducts can extrude nitrogen at elevated temperatures to form aziridines or imines, depending upon the substrate and reaction conditions. The cycloaddition of azides with alkynes affords triazolidine derivatives which have been a focus in the area of chemical biology and have received much recent attention (2008AGE2596, 2008CR2952). In this section of our review, we recount some developments of the 1,3-dipolar cycloaddition reaction of azides that have been used for the synthesis of various alkaloids. 

Further utihzation of this general method for the preparation of other alkaloids was subsequendy demonstrated by Pearson and Schkeryantz in the total synthesis of ( )-lycorane (118) (1992JOC6783). The intramolecular 1,3-dipolar cycloaddition of azide 115 in benzene at 140 °C followed by extrusion of nitrogen gave the unstable iminium salt 117. This intermediate was then reduced with sodium borohydride to afford ( )-y-lycorane 118 in 63% yield from azide 115 (Scheme 27). 

Mann and coworkers recently demonstrated the synthesis of the pyrro-hzidine alkaloid amphorogynine C 122 using an azido-olefin dipolar cycloaddition as the key step (2012EJO4347). Heating a sample of azide 119 in toluene at 140 °C for 24 h produced triazohne 120 which subsequendy lost nitrogen to give imine 121 along with lesser quantities of an aziridine by-product. Imine 121 was eventually converted into the natural product 122 in several additional steps (Scheme 28). 

Recently, a high yielding synthesis of a,p-unsaturated alkyhmines was developed using azides tethered to an allyhc alcohol (i.e., 123) (2012OL5728). Thus, treatment of 123 with p-toluenesulfbnic acid gave rise to unsaturated imines of type 125. A very reasonable pathway to explain this result would involve an initial 1,3-dipolar cycloaddition to give triazoline 124 as a transient intermediate which is easily dehydrated to produce the observed product (Scheme 29). The efficiency of the method was nicely demonstrated by the total synthesis of the Costa Rica ant venom alkaloid 127 from the MOM-masked cycHzation precursor 126. 

Our group has been interested in the synthesis of alkaloids [67] and related compounds [68,69]. In connection with our research on peptide-scaffold hybrids (see Section 14.3), we have synthesized a variety of partially reduced aromatic heterocyles [70-73]. As a step further, we have recently developed a methodology based in the sequential transformations of azide-alkene containing an electrophilic center, which is initiated by a 1,3-dipolar cycloaddition, followed by nitrogen extrusion, and latter transformation to an enamine that, in turn, reacts as nucleophile with the electrophile present in the molecule (Figure 14.6). 

The pentacyclic alkaloid ( )-meloscine (134) was prepared by Feldman and Antohne using a clever allenyl azide cycloaddition/cyclization cascade to deliver the core azabicyclo[3.3.0]octadiene substructure (2012OL934). Strain-driven release of nitrogen from the dipolar cycloadduct 129 derived from 128 promotes formation of the azatrimethyl-enemethane diradical 130 en route to the bicyclic product 131 (Scheme 30). For the synthesis ofmelo-scine 134, the thermolysis of a dilute solution of allene 132 in toluene gave the desired bicycle 133 whose structure was estabfrshed by single crystal X-ray analysis. Subsequent manipulation of the peripheral functionality in 133 then delivered ( )-meloscine 134. 

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