Organic Chemistry Portal
Organic Chemistry Highlights

Search Org. Chem. Highlights:

Match: or and


Monday, January 14, 2008
Douglass F. Taber
University of Delaware

Alkaloid Synthesis: Paliurine F, Lepadiformine, and 7-Deoxypancratistatin

The sedative alkaloid paliurine F (7) is a pentapeptide bridged by an arene. Gwilherm Evano of the Université de Versailles took advantage of this in his synthesis (Angew. Chem. Int. Ed. 2007, 46, 572. ) of 7, although it was necessary to prepare, from serine, one of the amino acid derivatives, the protected 3-hydroxyprolinol 2. The key step in the synthesis was the Cu-catalyzed intramolecular coupling of 5 to give the macrolactam 6. Deprotection and acylation then gave paliurine F (7).

Lepadiformine (14), isolated from the tunicate Clavelina lepadiformis, shows moderate cytotoxicity, and is also a K+ channel blocker. The synthesis of 14 (Angew. Chem. Int. Ed. 2007, 46, 2631. ) by Donald Craig of Imperial College started with the aziridine 8, prepared from the corresponding epoxide. Opening of the protected aziridine with the anion of methyl phenyl sulfone set the stage for condensation of the dianion derived from 9 with the aldehyde 10, to give, with high diastereocontrol, the amine 11. Deprotection followed by cyclization then led to the activated ether 12. While the opening of 12 with an alkyl Grignard reagent proceeded with undesired inversion at the reacting center, opening with the alkynyl Grignard delivered mainly the desired 13. Reduction followed by oxidation, epimerization and reduction then gave lepadiformine (14).

The Amaryllidaceae alkaloid 7-deoxypancratistatin (21) has potent antiviral activity. A challenge in the assembly of 21 is that the ring fusion is trans, less stable than the corresponding cis diastereomer. The synthesis of 21 (J. Org. Chem. 2007, 72, 2570. ) by Albert Padwa of Emory University started with 17, the preparation of which by the combination 15 and 16 he had previously reported in the course of his synthesis of lycoricidine (Advances in the Diels-Alder Reaction: Synthesis of (±)-Lycoridine and of Dolabellatrienone 2005, December 11). Ester 17 had the desired trans ring fusion, but with an angular ester substituent that had to be removed.

While it would be expected from the mechanism that Rh-mediated decarbonylation of an aldehyde would proceed with retention of absolute configuration, and this had been confirmed experimentally, this reaction had not been applied to such a challenging substrate. In the event, the transformation proceeded smoothly, to give the desired trans 19. Dehydration and dihydroxylation of 19 led to the cyclic sulfate 20, selective SN2 opening of which delivered 7-deoxypancratistatin (21).

The decarbonylation of 18 was reported on a 2.1 mmol scale, using 3.2 mmol of Wilkinson’s catalyst, (Ph3P)3RhCl. For larger scale reactions, it will be important to make this transformation truly catalytic. It has been reported (J. Am. Chem. Soc. 1978, 100, 7083; J. Org. Chem. 1984, 49, 3195) that inclusion of a bridging ligand such as 1,3-bis-diphenylphosphinopropane (dppp) in the decarbonylation can lead to turnover numbers in excess of 100,000.

D. F. Taber, Org. Chem. Highlights 2008, January 14.