Organocatalysis of Carbocyclic Construction: The MacMillan Synthesis of (+)-Frondosin B

One of the more powerful applications of organocatalysis has been the enantioselective transformation of preformed prochiral rings. In the five-membered ring series, Nobuyuki Mase of Shizuoka University effected (Synlett 2010, 2340. DOI: 10.1055/s-0030-1258533) enantioselective addition of malonate to cyclopentenone 1, and Eric N. Jacobsen of Harvard University devised (Angew. Chem. Int. Ed. 2010, 49, 9753. DOI: 10.1002/anie.201005183) a guanidinium catalyst for the Claisen rearrangement of 4 to 5.

Jacek Mlynarski of Jagiellonian University accomplished (Tetrahedron Lett. 2010, 51, 4088. DOI: 10.1016/j.tetlet.2010.05.134) the enantioselective hydroxymethylation of 6. This worked equally well for cyclopentanone and cycloheptanone. The dynamic kinetic resolution/reductive amination of 8 described (Angew. Chem. Int. Ed. 2010, 49, 4612. DOI: 10.1002/anie.201001715) by Benjamin List of the Max-Planck-Institut, Mülheim worked best with cyclohexanones such as 8.

Organocatalysts can also be effective for the construction of carbocyclic rings. Teck-Peng Loh of Nanyang Technological University found (Chem. Sci. 2010, 1, 739. DOI: 10.1039/C0SC00123F,) a commercial phosphine catalyst that efficiently mediated the condensation of 10 with 11. David W. C. MacMillan of Princeton University used (J. Am. Chem. Soc. 2010, 132, 10015. DOI: 10.1021/ja104313x) a SOMO catalyst to combine 13 with 14 to make 15. Dawei Ma of the Shanghai Institute of Organic Chemistry employed (Org. Lett. 2010, 12, 3634. DOI: 10.1021/ol101414b) the Hayashi catalyst in the double Michael condensation of 16 with 17. Daniel Romo of Texas A&M University showed (Org. Lett. 2010, 12, 3764. DOI: 10.1021/ol101388h) that the appropriate organocatalyst could direct 19 to either diastereomer of the β-lactone 20. Professor Romo also reported (Angew. Chem. Int. Ed. 2010, 49, 9479. DOI: 10.1002/anie.201004671) the desymmetrization of 2-alkyl cyclohexane-1,3-diones using a similar approach.

In the six-membered ring series, José Alemán and José Luis García Ruano of the Universidad Autónoma de Madrid carried out (Eur. J. Org. Chem. 2010, 4482. DOI: 10.1002/ejoc.201000502) Robinson annulation of 17 with 21. Ying-Chun Chen of Sichuan University, again using the Hayashi catalyst, reported (Angew. Chem. Int. Ed. 2010, 49, 6418. DOI: 10.1002/anie.201002912) the addition of 17 to 23 to give 24.

In another elegant application of visible light-mediated organocatalysis, Professor MacMillan described (Chem. Sci. 2010, 1, 37. DOI: 10.1039/C0SC00204F) the addition of the commercial boronic acid 25 to 17. The addition of the anion 27 to the adduct 26 gave the allylic alcohol 28. Exposure of 28 to BBr₃ effected cyclization and demethylation, to complete a very short synthesis of (+)-Frondosin B (29).