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Monday, January 28, 2013
Douglass F. Taber
University of Delaware

C-H Functionalization: The Hatakeyama Synthesis of (-)-Kaitocephalin

John F. Hartwig of the University of California, Berkeley showed (Nature 2012, 483, 70. DOI: 10.1038/nature10785) that intramolecular C-H silylation of 1 selectively gave, after oxidation and acetylation, the bis acetate 2. Gong Chen of Pennsylvania State University coupled (J. Am. Chem. Soc. 2012, 134, 7313. DOI: 10.1021/ja3023972) 3 with 4 to give the ether 5. M. Christina White of the University of Illinois effected (J. Am. Chem. Soc. 2012, 134, 9721. DOI: 10.1021/ja301685r) selective oxidation of the taxane derivative 6 to the lactone 7.

Most of the work on C-H functionalization has focused on the formation of C-C, C-O and C-N bonds. Donald A. Watson of the University of Delaware developed (Angew. Chem. Int. Ed. 2012, 51, 3663. DOI: 10.1002/anie.201200060) conditions for the complementary conversion of an alkene 8 to the allyl silane 9, a powerful and versatile nucleophile.

Kilian Muņiz of ICIQ Tarragona oxidized (J. Am. Chem. Soc. 2012, 134, 7242. DOI: 10.1021/ja3013193) the enyne 10 selectively to the amine 11. Phil S. Baran of Scripps/La Jolla devised (J. Am. Chem. Soc. 2012, 134, 2547. DOI: 10.1021/ja212020b) a protocol for the OH-directed amination of 12 to 13. Professor White developed (J. Am. Chem. Soc. 2012, 134, 2036. DOI: 10.1021/ja211600g) a related OH-directed amination of 14 to 15, that proceeded with retention of absolute configuration. Tom G. Driver of the University of Illinois, Chicago showed (J. Am. Chem. Soc. 2012, 134, 7262. DOI: 10.1021/ja301519q) that the aryl azide 16 could be cyclized directly to the amine, that was protected to give 17.

As illustrated by the conversion of 18 to 20 devised (Adv. Synth. Catal. 2012, 354, 701. DOI: 10.1002/adsc.201100563) by Martin Klussmann of the Max-Planck-Institut, Mülheim, C-H functionalization can be accomplished by hydride abstraction followed by coupling of the resulting carbocation with a nucleophile. Olafs Daugulis of the University of Houston used (Angew. Chem. Int. Ed. 2012, 51, 5188. DOI: 10.1002/anie.201200731) a Pd catalyst to couple 21 with 22 to give 23 with high diastereocontrol. Yoshiji Takemoto of Kyoto University cyclized (Angew. Chem. Int. Ed. 2012, 51, 2763. DOI: 10.1002/anie.201108889) the chloroformate 24 directly to the oxindole 25. Carlos Saá of the Universidad de Santiago de Compostela used (Angew. Chem. Int. Ed. 2012, 51, 723. DOI: 10.1002/anie.201107344) a Ru catalyst to add 27 to the alkyne 26, generating a metallocarbene that cyclized to the cyclopentane 28.

To be used early in a multi-step preparation, a synthesis protocol must be robust and easily scalable. It is a tribute to the power of the C-H amination method developed by Justin Du Bois, exemplified by the cyclization of 29 to 30, that Susumi Hatakeyama of Nagasaki University was able to use it (Org. Lett. 2012, 14, 1644. DOI: 10.1021/ol300431n) as a key step in a synthesis of (-)-Kaitocephalin (31). This same C-H amination protocol was used again a little later in that synthesis.

D. F. Taber, Org. Chem. Highlights 2013, January 28.