Organic Chemistry Portal
Organic Chemistry Highlights

Search Org. Chem. Highlights:

Match: or and

Total Synthesis

Monday, January 6, 2020
Douglass F. Taber
University of Delaware

The Sarpong and Rawal Syntheses of Ambiguine P

The pentacyclic indole alkaloid ambiguine P (3), isolated from the cultured cyanobacterium Fischerella ambigua, includes a cyclic quaternary center in addition to the challenging cycloheptatriene. Richmond Sarpong of the University of California, Berkeley assembled 3 via the stepwise Lewis acid-mediated cyclization of 1 to 2 (J. Am. Chem. Soc. 2019, 141, 2233. ).

The preparation of 1 began with the known coupling of carvone 4 with indole 5 to give 6. Addition of 7 followed by oxidative rearrangement led to 8. Complexation of the alkyne of 8 with Co2(CO)8 activated the tertiary alcohol for ionization (Nicholas reaction), and also bent the geometry to favor bond formation. The cyclization to 2 was then carried out in two steps, the first to ionize the tertiary alcohol, then the second to activate the disubstituted alkene.


The construction of the requisite cyclic quaternary center began with conjugate addition of cyanide, to give 9. Rh-mediated nitrile hydration followed by formylation/cyclization and subsequent reduction in the presence of methanol led to 10. Amide dehydration followed by alcohol activation and radical deoxygenation gave 11, that was coupled with 12 to complete the preparation of 13.

To reach the triene 15, the amide 13 was inverted to the isonitrile 14, that was eliminated by exposure to tBuOK in DMSO. Oxidation of the nearly prochiral 15 proceeded with low diastereocontrol to give ambiguine P (3).

Almost simultaneously, Viresh H. Rawal of the University of Chicago reported an alternative route to 3, starting from 19, with the cyclic quaternary center already in place. Beginning with limonene (16), hydroboration followed by ketene cyclization led to 17. Following Baran, Favorskii rearrangement followed by reduction led to 18, that was opened and dehydrated to 19 (J. Am. Chem. Soc. 2019, 141, 4820. )

D. F. Taber, Org. Chem. Highlights 2020, January 6.
URL: https://www.organic-chemistry.org/Highlights/2020/06January.shtm