Natural Product Synthesis by C–H Functionalization: (±)-Allokainic Acid (Wee), (–)-Cameroonan-7α-ol (Taber), (+)-Lithospermic Acid (Yu), (–)-Manabacanine (Kroutil), Streptorubin B, and Metacycloprodigiosin (Challis)

Abstract

Andrew G.H. Wee of the University of Regina showed (Org. Lett. 2010, 12, 5386) that with the bulky BTMSM group on N and the electron-withdrawing pivaloyloxy group deactivating the alternative C–H insertion site, the diazo ketone 1 cleanly cyclized to 2, with 21:1 diastereocontrol. Oxidative cleavage of the arene followed by amide reduction and methylenation of the ketone converted 2 into (±)-allokainic acid 3. Intermolecular C–H insertion was the key step in a complementary route to (±)-kainic acid reported (Org. Lett. 2011, 13, 2674) by Takehiko Yoshimitsu of Osaka University. Rh-mediated intramolecular C–H insertion was also the first step in our (J. Org. Chem. 2011, 76, 1874) synthesis of (–)-cameroonan-7α-ol 6. In the course of that synthesis, seven of the C–H bonds of 4 were converted to C–C bonds. Jin-Quan Yu of Scripps/La Jolla oxidatively activated (J. Am. Chem. Soc. 2011, 133, 5767) the ortho H of 8 with catalytic Pd, then engaged that intermediate with 7 in a Heck coupling, to give 9, and thus (+)-lithospermic acid 10. The starting acid 8 was prepared by enantioselective Rh-mediated intramolecular C–H insertion. Wolfgang Kroutil of the University of Graz found (Angew. Chem. Int. Ed. 2011, 50, 1068) that berberine bridging enzyme (BBE) from the California poppy could be used preparatively to cyclize a variety of tetrahydroisoquinolines, including 11 to give (–)-manibacanine 13. Although this is clearly a Mannich-type cyclization, a simple Mannich reaction gave a 40:60 mixture of regioisomers, each of them racemic. The enzyme effected cyclization to a 96:4 ratio of regioisomers, and only one enantiomer of 11 participated. Gregory L. Challis of the University of Warwick harnessed (Nature Chem. 2011, 3, 388) the [2Fe-2S] Rieske cluster enzyme RedG of Streptomyces coelicolor to effect oxidative cyclization of 14 to streptorubin B 15. An ortholog of the enzyme cyclized 14 to metacycloprodigiosin 16. It is interesting to speculate as to whether the cyclizations are initiated by the activation of an H on the alkyl sidechain or by oxidation of the pyrrole.