Organic Chemistry Portal
Organic Chemistry Highlights

Monday, August 25, 2014
Douglass F. Taber
University of Delaware

Diels-Alder Cycloaddition: Pancratistatin (Cho), Reddy (Nootkatone), Zhang/Lee (Platensimycin), Nakada (Scabronine G), Isoglaziovianol (Trauner)

Samuel J. Danishefsky of Columbia University and the Memorial Sloan-Kettering Cancer Center made (Proc. Nat. Acad. Sci. 2013, 110, 10904. DOI: 10.1073/pnas.1309795110) the unexpected observation that methylation of the enolate derived from conjugate addition to the readily-prepared 1 followed by intramolecular alkene metathesis led to the trans fused ketone 2. This can be constrasted to the diastereo- and regioisomer 3, the product from Diels-Alder cycloaddition of 2-methylcyclohexenone to isoprene. The trans ring fusion of 2 is particularly significant because ozonolysis followed by aldol condensation would deliver the angularly-methylated trans-fused 6/5 C-D ring system of the steroids and related natural products.

Cheon-Gyu Cho of Hanyang University added (Org. Lett. 2013, 15, 5806. DOI: 10.1021/ol4028623) the activated dienophile 4 to the dienyl lactone to give, after oxidation, the dibromide 5. Debromination followed by oxidation led to the antineoplastic lactam Pancratistatin (6).

D. Srinivasa Reddy of CSIR-National Chemical Laboratory Pune devised (J. Org. Chem. 2013, 78, 8149. DOI: 10.1021/jo401033j) a cascade protocol of Diels-Alder cycloaddition of 8 to the diene 7 followed by intramolecular aldol condensation, to give the enone 9. Oxidative manipulation followed by methylenation completed the synthesis of the commercially important grapefruit flavor Nootkatone (10).

Xinhao Zhang and Chi-Sing Lee of the Peking University Shenzen Graduate School uncovered (J. Org. Chem. 2013, 78, 7912. DOI: 10.1021/jo401105q) another cascade transformation, intermolecular addition of 11 to 12 followed by intramolecular Conia ene cyclization, to give the tricyclic 13. Further manipulation led to an established intermediate for the total synthesis of Platensimycin (14).

Masahisa Nakada of Waseda University prepared (Angew. Chem. Int. Ed. 2013, 52, 7569. DOI: 10.1002/anie.201303224) the enantiomerically-pure allene 15. Oxidation of the phenol to the monoketal of the cyclohexadienone set the stage for intramolecular cycloaddition to give 16. Oxidative cleavage followed by intramolecular alkene metathesis led to (+)-Scabronine G (17).

Dirk Trauner of the University of Munich assembled (Org. Lett. 2013, 15, 4324. DOI: 10.1021/ol401787n) the enantiomerically-pure alcohol 18. Oxidation gave the quinone, leading to intramolecular Diels-Alder cycloaddition. The free alcohol then added to the exocyclic alkene of that product, to give, after further oxidation, the ether 19. Deprotection followed by reduction then completed the synthesis of (-)-isoglaziovianol (20).

D. F. Taber, Org. Chem. Highlights 2014, August 25.