C-H Functionalization: The Snyder Synthesis of (+)-Scholarisine A

Thomas R. Hoye of the University of Minnesota devised (Nature 2013, 501, 531. DOI: 10.1038/nature12492) the reagent 2, that cyclized to a benzyne that in turn dehydrogenated the alkane 1 to the alkene 3. Abigail G. Doyle of Princeton University developed (J. Am. Chem. Soc. 2013, 135, 12990. DOI: 10.1021/ja407223g) a reagent combination for the allylic fluorination of a terminal alkene 5 to the branched product 6.

Yan Zhang and Jianbo Wang of Peking University oxidized (Angew. Chem. Int. Ed. 2013, 52, 10573. DOI: 10.1002/anie.201305731) the methyl group of 7 to give the nitrile 8. Hanmin Huang of the Lanzhou Institute of Chemical Physics found (Org. Lett. 2013, 15, 3370. DOI: 10.1021/ol401419u) conditions for the aminocarbonylation of the benzylic site of 9, leading to the amide 11.

Yu Rao of Tsinghua University effected (Angew. Chem. Int. Ed. 2013, 52, 13606. DOI: 10.1002/anie.201307090) the direct methoxylation of 12, to give 13. Pd-mediated methoxylation had previously been described (Chem. Sci. 2013, 4, 4187. DOI: 10.1039/C3SC51993G) by Bing-Feng Shi of Zhejiang University. M. Christina White of the University of Illinois, Urbana found (J. Am. Chem. Soc. 2013, 135, 14052. DOI: 10.1021/ja407388y) that with variant ligands on the Fe catalyst, the oxidation of 14 could be directed selectively to either 15 or 16.

C-H bonds can also be converted to C-N bonds. Sukbok Chang of KAIST oxidized (J. Am. Chem. Soc. 2013, 135, 12861. DOI: 10.1021/ja406383h) the unsaturated ester 17 to the enamide 18. Gong Chen of Pennsylvania State University cyclized (Angew. Chem. Int. Ed. 2013, 52, 11124. DOI: 10.1002/anie.201305615) the amide 20 to the γ-lactam 21. Professor Shi reported (Angew. Chem. Int. Ed. 2013, 52, 13588. DOI: 10.1002/anie.201306625) a related approach to β-lactams.

Ethers are easily oxidized. Taking advantage of this, Yun Liang of Hunan Normal University coupled (Synthesis 2013, 45, 3137. DOI: 10.1055/s-0033-1338534) the bromoalkyne 23 with tetrahydrofuran 22 to give 24. Guangbin Dong of the University of Texas, Austin devised (J. Am. Chem. Soc. 2013, 135, 17747. DOI: 10.1021/ja410389a) a protocol for the β-arylation of ketones, including the diastereoselective conversion of 25 to 27. Huw M. L. Davies of Emory University cyclized (Org. Lett. 2013, 15, 6120. DOI: 10.1021/ol4028978) the diazo ester 28 to the β-lactone, that under the conditions of the reaction lost CO₂ to give the allyl silane 29 with high geometric control.

Richard S. Grainger of the University of Birmingham generated (Org. Biomol. Chem. 2013, 11, 6856. DOI: 10.1039/C3OB41390J) the alkylidene carbene from 30 using two different procedures. Addition of lithiated TMS diazomethane led to a reactive free alkylidene, that primarily inserted into the Si-O bond to give 32. Chloromethylenation followed by exposure to KHMDS gave a less reactive, more slowly reacting carbene, that gave a much larger proportion of the desired 31.

(+)-Scholarisine A (35) was isolated from Alstonia scholaris, used in traditional Chinese medicine for the treatment of respiratory disease. Scott A. Snyder, now at Scripps/Florida, devised (J. Am. Chem. Soc. 2013, 135, 12964. DOI: 10.1021/ja406546k) a concise synthesis of 35, a key step of which was the cyclization of 33 to 34.