Organic Chemistry Portal
Organic Chemistry Highlights

Monday, January 20, 2014
Tristan H. Lambert
Columbia University

C-O Ring-Containing Natural Products: Cyanolide A (Krische), Bisabosqual A (Parker), Iso-Eriobrucinol A (Hsung), Trichodermolide A (Hiroya), Batrachotoxin Core (Du Bois)

Michael J. Krische at the University of Texas at Austin developed (Angew. Chem. Int. Ed. 2013, 52, 4470. DOI: 10.1002/anie.201300843) a total synthesis of cyanolide A (7) in only seven steps, a sequence so short it is shown below in its entirety. Diol 1 was subjected to enantioselective catalytic bisallylation under iridium catalysis to furnish 2 with very high levels of stereocontrol. Cross metathesis using ruthenium catalyst 3 first with ethyl vinyl ketone and then with ethylene resulted in the production of tetrahydropyran 4. Glycosylation of 4 with phenylthioglycoside 5, stereoselective reduction of the ketone function, and oxidative cleavage of the olefin then furnished the carboxylic acid 6. Finally, dimerization of 6 with 2-methyl-6-nitrobenzoic anhydride (MBNA) yielded cyanolide A.

Kathlyn A. Parker at Stony Brook University reported (J. Am. Chem. Soc. 2013, 135, 582. DOI: 10.1021/ja3108577) a tandem radical cyclization strategy for the total synthesis of bisabosqual A (11). The key substrate 9 was prepared in three steps from the diester 8. Treatment of 9 with tri-s-butylborane and TTMS in the presence of air induced the tandem 5-exo, 6-exo radical cyclization to produce the complete core 10 of the natural product as a mixture of diastereomers, which could be equilibrated. Some further redox maneuvers then led to bisabosqual A.

Yu Tang of the School of Pharmaceutical Science and Technology in Tianjin and Richard P. Hsung at the University of Wisconsin at Madison disclosed (Org. Lett. 2013, 15, 3130. DOI: 10.1021/ol401335u) a very brief synthesis of iso-eriobrucinol A and related isomers using a unique cascade sequence. First, phloroglucinol (12) and citral (13) were condensed using piperidine and acetic anhydride. The product of this operation was the tetracyclic cyclobutane 14, the result of an oxa-[3+3] annulation followed by a step-wise, cationic [2+2] cycloaddition. Treatment of 14 with methyl propiolate in the presence of catalytic indium(III) chloride under microwave irradiation furnished iso-eriobrucinol A, as well as the isomeric natural product iso-eriobrucinol B.

A concise approach to trichodermatide A (19) was developed (Angew. Chem. Int. Ed. 2013, 52, 3646. DOI: 10.1002/anie.201210099) by Kou Hiroya at Musashino University. Aldehyde 16, which was synthesized from L-tartaric acid, was condensed with 1,3-cyclohexanedione in the presence of piperdine, resulting in diketone 17. Compound 17 was treated under carefully selected acidic conditions to furnish the pentacyclic pyran ketal 18. The selective installation of three additional hydroxyl groups then completed the synthesis of trichodermatide A.

Justin Du Bois at Stanford reported (Chem. Sci. 2013, 4, 1059. DOI: 10.1039/C2SC21723F) an efficient synthesis of the core structure of batrachotoxin or "BTX" (26), a selective and extremely potent sodium channel agonist. Addition of the anion of 3-bromofuran to tricarbonyl 20 followed by MOM protection produced 21 as a 2:1 mixture of isomers. Lithium-halogen exchange then converted the endo isomer to the tetracycle 22. Following some manipulation to 23, the ketone function was stereoselectively reduced under chelation control using DIBAL-H to furnish alcohol 24. Some final transformations, particularly to forge the homomorpholine ring, then yielded 25, the core of batrachotoxin (26) and several related structures.

T. H. Lambert, Org. Chem. Highlights 2014, January 20.