Angewandte
Chemie
Patel, J. R. Fuchs, M. Kvaratskhelia, A. Engelman, Proc. Natl.
tion of the BI-DIME ligands and the unprecedented bis(tri-
fluoromethane)sulfonamide-catalyzed tert-butylation ren-
dered the synthesis of this complex molecule robust, practical,
and economical. Furthermore, the overall synthesis was
conducted in an asymmetric and diastereoselective fashion
with respect to the imbedded atropisomer. The overall
synthesis was shortened to twelve steps, of which the longest
linear sequence entailed eight transformations. More impor-
tantly, the overall yield was increased to 27% as compared to
the unpractical 1.8% from the initial discovery approach.[7]
This complex synthesis was conducted on multi-kilogram
scale using newly developed innovative processes without any
complications.
[10] W. Li, P. De Cross, K. R. Fandrick, J. J. Gao, N. Haddad, Z.-H.
Lu, B. Qu, S. Rodriquez, C. H. Senanayake, Z. Zhang, W. Tang
(Gilead Sciences, Inc., USA), WO 2012/138670A1, 2012.
[11] a) N. G. Anderson, Practical Process Research & Development,
Academic Press, San Diego 2000, p. 354; b) Practical Process
Development: Current Chemical and Engineering Challenges
(Eds.: J. Blacker, M. T. Williams), RSC Publishing 2011, p. 374.
[13] S. R. LaPlante, L. D. Fader, K. R. Fandrick, D. R. Fandrick, O.
Keywords: acylation · asymmetric synthesis ·
phosphine ligands · Suzuki couplings · tert-butylation
[15] Thermodynamically less preferred.
[16] W. Li, D. P. Nelson, M. S. Jensen, R. S. Hoerrner, D. Cai, R. D.
[18] a) P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F.
b) J. J. Song, N. K. Yee, Z. Tan, J. Xu, S. R. Kapadia, C. H.
[1] K. M. Barton, B. D. Burch, N. Soriano-Sarabia, D. M. Margolis,
[19] B. Scheiper, M. Bonnekessel, H. Krause, A. Fꢂrstner, J. Org.
[20] X. j. Wang, X. Sun, L. Zhang, Y. Xu, D. Krishnamurthy, C. H.
[21] F. Babudri, V. Fiandanese, G. Marchese, A. Punzi, Tetrahedron
[24] S. Oikawa, I. Hirosawa, K. Hirakawa, S. Kawanishi, Carcino-
[4] A. Engelman, G. Englund, J. M. Orenstein, M. A. Martin, J.
Virol. 1995, 69, 2729 – 2736.
[5] a) T. H. Evering, M. Markowitz, Drugs Today 2007, 43, 865 – 877;
b) V. Summa, A. Petrocchi, F. Bonelli, B. Crescenzi, M. Donghi,
M. Ferrara, F. Fiore, C. Gardelli, O. G. Paz, D. J. Hazuda, P.
Jones, O. Kinzel, R. Laufer, E. Monteagudo, E. Muraglia, E.
Nizi, F. Orvieto, P. Pace, G. Pescatore, R. Scarpelli, K. Stillmock,
c) B. Grinsztejn, B.-Y. Nguyen, C. Katlama, J. M. Gatell, A.
Lazzarin, D. Vittecoq, C. J. Gonzalez, J. Chen, C. M. Harvey,
[6] a) J. L. Mbisa, S. A. Martin, P. A. Cane, Infect. Drug Resist. 2011,
4, 65 – 76; b) J.-F. Mouscadet, O. Delelis, A.-G. Marcelin, L.
Buzꢁn, J. Dalmau, M. C. Puertas, J. Puig, B. Clotet, J. Martinez-
[25] a) S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya, R. Noyori, J.
ˇ
[26] D. Sterk, M. S. Stephan, B. Mohar, Tetrahedron Lett. 2004, 45,
535 – 537.
[27] The associated ligand survey is provided in the Supporting
Information.
[28] W. Tang, N. D. Patel, G. Xu, X. Xu, J. Savoie, S. Ma, M.-H. Hao,
S. Keshipeddy, A. G. Capacci, X. Wei, Y. Zhang, J. J. Gao, W. Li,
S. Rodriguez, B. Z. Lu, N. K. Yee, C. H. Senanayake, Org. Lett.
[29] G. Xu, W. Fu, G. Liu, C. H. Senanayake, W. Tang, J. Am. Chem.
[30] The tert-butyl ether could be installed using a large excess of the
super acid trifluoromethanesulfonic acid (TfOH) at low temper-
atures. The temperature control is critical as the system would
readily reverse above 08C, and significant precaution is required
handling large amounts of the highly corrosive TfOH.
[31] A. Armstrong, I. Brackenridge, R. F. W. Jackson, J. M. Kirk,
[32] Direct elimination pathways could be operating whereby the
counterion could mediate the basicity of the metal or metal
imidate/amide complex, which in turn could competitively
eliminate the tert-butyl cation.
[7] L. D. Fader, E. Malenfant, M. Parisien, R. Carson, F. Bilodeau, S.
Landry, M. Pesant, C. Brochu, S. Morin, C. Chabot, T. Halmos,
Y. Bousquet, M. D. Bailey, S. H. Kawai, R. Coulombe, S.
LePlante, A. Jakalian, P. K. Bhardwaj, D. Wernic, P. Schroeder,
M. Amad, P. Edwards, M. Garneau, J. Duan, M. Cordingley, R.
Bethell, S. W. Mason, M. Bçs, P. Bonneau, M.-A. Poupart, A.-M.
Faucher, B. Simoneau, C. Fenwick, C. Yoakim, Y. Tsantrizos,
[8] F. Christ, A. Voet, A. Marchand, S. Nicolet, B. A. Desimmie, D.
Marchand, D. Bardiot, N. J. Van der Veken, B. Van Remoortel,
S. V. Strelkov, M. De Maeyer, P. Chaltin, Z. Debyser, Nat. Chem.
[9] a) F. Christ, S. Shaw, J. Demeulemeester, B. A. Desimmie, A.
Marchand, S. Butler, W. Smets, P. Chaltin, M. Westby, Z.
4365 – 4374; b) J. J. Kessl, N. Jena, Y. Koh, H. Taskent-Sezgin, A.
Slaughter, L. Feng, S. de Silva, L. Wu, S. F. J. Le Grice, A.
Feng, J. J. Kessl, Y. Koh, W. Wang, A. Ballandras-Colas, P. A.
Received: February 17, 2015
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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