Organic Chemistry Portal
Organic Chemistry Highlights

Monday, January 30, 2012
Douglass F. Taber
University of Delaware

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

Andrew G. H. Wee of the University of Regina showed (Org. Lett. 2010, 12, 5386. DOI: 10.1021/ol1021564) 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. DOI: 10.1021/ol200772f) 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. DOI: 10.1021/jo200075v) 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. DOI: 10.1021/ja2010225) 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 7 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. DOI: 10.1002/anie.201006268) 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. DOI: 10.1038/nchem.1024) the [2Fe-2S] Rieske cluster enzyme RedG of Streptomyces coelicolor to effect oxidative cyclization of 14 to Streptorubin B (15). An orthologue of the enzyme cyclized 14 to Metacycloprodigiosin (16). It is interesting to speculate as to whether the cyclizations are intiated by the activation of an H on the alkyl sidechain, or by oxidation of the pyrrole.

D. F. Taber, Org. Chem. Highlights 2012, January 30.