Synthesis -meloscine

Selig, P. and Bach, T. (2008) Enantioselective total synthesis of the melodinus alkaloid (+ )-meloscine. Angewandte Chemie, International Edition, 47, 5082-5084. 

The stereocontrolled total synthesis of the structurally unusual pentacyclic Melodinus alkaloid ( )-meloscine (29a) and ( )-epimeloscine (29b) was achieved starting from the aza-Cope precursor 231139. 

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. 

As in the case of all variations of the Clasien rearrangement, the [3,3]-sigmatropic process is routinely applied for the construction of stereogenicity at quaternary carbon centers. During studies toward the total synthesis of meloscine, orthoester Johnson-Claisen rearrangement was utilized as the key bond formation event when many other attempts to construct the C5 quaternary stereocenter in this sterically-demanding environment failed. Treatment of 351 with trimethyl orthoacetate at elevated temperature readily afforded the ester 352 with moderate diastereoselection." ... 

Mukai and coworkers reported the concise total synthesis of Melodinus alkaloid ( )-meloscine (40) [Route (a), Fig. 13], in which the final key transformation involved an alkene RCM of the triene precursor (42) in the presence of Hoveyda-Grubbs II catalyst [55], The RCM between the A(-allyl group and the top-oriented vinyl moiety exclusively occurred to generate the desired diastereomer (40) in almost quantitative yield. The extremely high diastereoselectivity could be rationalized on the basis of ring strain to favor one conformer. Shortly after this work, Curran et al. disclosed another approach to the total syntheses of ( )-epimeloscine (41) and ( )-meloscine (40) applying the same RCM protocol for the final ring formation [Route (b), Fig. 13] [56],... 

Feldman et al. " and Oshima et al. have independently reported reactions of vinylcyclopropanes in the presence of olefins to obtain vinylcyclopentanes. Zhang and Curran used a divinylcyclopropane in a cascade radical annulation process, diastereoselectively generating three stereogenic centers (123 124) for the synthesis of Melodinus alkaloids epimeloscine and meloscine. This constitutes a new example of the synthetic value of radical chemistry in promoting a quick elaboration of complex polycyclic structures through cascade processes (Scheme 25.59). 

Zhang H, Curran DP. A short total synthesis of ( )-epimeloscine and ( )-meloscine enabled by a cascade radical annulation of a divinylcyclopropane. J. Am. Chem. Soc. 2011 133(27) 10376-10378. 

Total Synthesis of Meloscine Meloscine 189, a member of the Melodinus alkaloids group, is noted for containing a six-membered quinolone ring within a mono-terpenoid Aspidosperma carbon skeleton. 

Although the Melodinus alkaloids do not possess useful biological activity for humans, synthetic organic chemists are attracted to their unique structural features. Bach and co-workers reported on a total synthesis of meloscine by employing a three-step reductive amination domino sequence among the total 15 steps to synthesize the racemic target molecule in 9% overall yield (Scheme 39.54). 

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