Amaryllidaceae alkaloids Amidation

One of these products (49) was used as a key intermediate for the synthesis of the Amaryllidaceae alkaloids a- and /-lycorane (Scheme 12)53. A copper-catalyzed Grignard reaction with 49 afforded 50 via a selective y-anti displacement of the chloride. Hydrogenation followed by Bischler-Napieralski cyclization gave 51. Interestingly, reversal of the latter two steps gave the isomer 52 where an epimerization at the benzylic carbon had occurred in the cyclization step (>99% selectivity). Subsequent reduction of the amide in each case afforded the target molecules a- and y-lycorane, respectively. The purity of the final product was very high with respect to the opposite stereoisomer. Thus <0.2% of /-lycorane was present in a-lycorane and vice versa. 

Studies directed toward the synthesis of amaryllidaceae alkaloids provide instructive examples of the combined use of spirocylization and Michael addition pathways in phenolic oxidations (03MI1). For example, treatment of the norbelladine derivative 164 with BTIB leads, by way of C,C-bond formation, to the spiroannulated azepine 165 (Scheme 47) (96JOC5857, 98JOC6625). Hydrolysis of the amide moiety in 165 results in Michael addition of the nitrogen center to the dienone ring and affords ( )-oxomaritidine (166). BTIB-oxidation of the appropriate... 

A similar strategy has been used to prepare 682, a compound closely related to Amaryllidaceae alkaloids. In this case, the aryne presumably adds to a 1-azadiene, formed from the amide and base. With 2 equivalents of LDA the yield of682 was only 25%, but a large excess (16 equiv) raised the yield to 74%. The reaction may involve a nonsynchronous cycloaddition or a nucleophilic attack on the aryne a loss of hydride is necessary to complete the reaction. 

Phenanthridone-type alkaloids have the highest oxygenated C ring in all Amaryllidaceae alkaloids, and they always show an amide group in ring B. On the contrary, alkaloids of the phenanthridine type often show completely aromatic ring system, occasionally with a methylation quaternary nitrogen atom, such as alkaloid bicolorine 214 (Table 17.12). 

The same year, Canesi s group reported an asymmetric s5mthesis of the levoro-tatory enantiomer of the Amaryllidaceae alkaloid fortucine [105]. The L-tyrosine-derived phenol 163 was treated with DIB in HFIP to induce an oxo-spirocyclization into the para-quinolic lactone 164, which was treated with methanolic KOH to mediate both the opening of the lactone unit and an aza-Michael addition of the amide onto the cyclohexa-2,5-dienone moiety in high yield and stereoselectivity. The resulting aza-bicyclic intermediate 165 was then converted in 11 steps into (-)-fortucine (Fig. 41). This first asymmetric synthesis of fortucine led to the correction of the absolute configuration of the natural (+)-fortucine [105]. 

Another domino application of an oxidative carbo-spirocyclization and an aza-Michael addition was developed by She and co-workers to construct the core skeleton of the Amaryllidaceae alkaloids tazettine and 6a-epipretazettine. In 2013, they disclosed their approach that requires the phenolic amide 185 as key precursor of the intended carbo-spirocyclization [112]. Both DIB and BTI were first used to mediate this oxidative para-para phenolic coupling reaction, but the more electrophilic Kita s p-oxoBTI reagent (see Fig. 4) in TFE gave higher yields. The addition of potassium hydroxide in the reaction mixture then promoted the aza-Michael addition to furnish the known tazettinone intermediate 187 in 72% yield as a single diastereomer (Fig. 46) [112]. 

Magnus developed also a combination of iodosyl benzene and trimethylsilyl azide to azidate the j8-carbon of silyl enol ethers (Scheme 8.22). ° ° The total synthesis of lycorane amaryllidaceae alkaloids takes advantage of this process. A tentative ionic mechanism is proposed for this process. However, involvement of radicals cannot be totally excluded. Under the same reaction conditions, anilines and amides lead to the isolation of C-H substituted products at carbon atoms adjacent to nitrogen (Scheme 8.23). These azidoamines/azidoamides are precursor of iminium/acycliminium ions that are useful intermediates for C-C bond formation. 

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