Total Synthesis of 9-Isocyanoneopupukeanane.

Abstract

Sponges elaborate the largest number of bioactive marine natural products, which often possess fascinating structures of great varieties. Our involvement in this area of chemistry has resulted in the synthesis of curcuphenol and curcudiol,1 (-)-furodysin,2 (-)-furodysinin,3 the enantiomer of herbasolide,4 and tavacpallescensin.5 More recently, efforts in attaining the isocyanopupukeananes also bore fruit;6 we now describe our approach to 9-isocyanoneopupukeanane (1), which is a constituent of a Ciocalypta sp.7 Besides the syntheses of 2-isocyanopupukeanane (2a, Chart 1)8 and 9-isocyanopupukeanane (2b),9,10 formal syntheses of the latter that terminated at 9-pupukeanone11-13 have also been reported. On the other hand, we are not aware of 1, which possesses a rearranged skeleton, having been yielded to synthesis. This work stemmed from our general interest in synthesis design related to molecular symmetry.14 In a retrosynthetic analysis of isocyanoneopupukeanane, the disconnection of the isopropyl group and functional group interchange at the isocyano-substituted center led to the symmetrical ketone 10. Further tracking indicated the tricyclic olefin 8, and the cyclohexadiene 7 to be useful synthetic precursors. To secure these compounds, we started from 3, which is readily available15 from a reaction sequence consisting of Birch reduction of p-cresyl methyl ether, Diels-Alder reaction with methyl acrylate (after in situ conjugation), and Grignard reaction with MeMgCl. Treatment of 3 with HClO4 led to enone 4 (63%), which was epoxidized at the side chain with hydrogen peroxide-urea in acetic anhydride to give 5 in 70% yield (75% by using m-CPBA). Reduction of the epoxy enone with lithium aluminum hydride afforded the diol 6a (62%, inseparable diastereomers), which was acetylated (Ac2O, py, DMAP) to provide diacetate 6b (92%, inseparable diastereomers). Pyrolysis of 6b in a sealed tube at 450 °C for 1 h furnished directly the desired tricyclic olefin 8 (54%), indicating the generation of 7 as an intermediate. With the acquisition of 8 the functionalization of its double bond was in order. We expected that hydroboration-oxidation would give rise to 9 predominantly because the formation of the regioisomeric alcohol 9a is less favorable due to steric hindrance from the bridgehead methyl substituents. Indeed, a separable mixture was produced in 52% and 10% yield, respectively. By PCC oxidation of the major alcohol 9 to afford ketone 10 (85%) the work entered its last stage. Thus, after exposure of 10 to i-PrMgBr/CeCl3 (91%) and then Me3SiCN/H2SO4, the formamide 12 was obtained in 42.5% yield. Completion of our synthesis was attained by subjecting 12 to TsCl-py at room temperature. 9-Isocyanoneopupukeanane was isolated in 83% yield. The final product showed spectral data in good agreement with the reported values. In conclusion, this report delineates the first total synthesis of isocyanoneopupukeanane. It is interesting that we did not isolate the dimethyltwistene isomer from the pyrolysate of 6b.