Organic Letters
Letter
(2) (a) Flannery, E. L.; Chatterjee, A. K.; Winzeler, E. A. Nat. Rev.
Microbiol. 2013, 11, 849−862. (b) Teixeira, C.; Vale, N.; Perez, B.;
́
Gomes, A.; Gomes, J. R. B.; Gomes, P. Chem. Rev. 2014, 114, 11164−
11220. (c) Nixon, G. L.; Moss, D. M.; Shone1, A. E.; Lalloo, D. G.;
Fisher, N.; O’Neill, P. M.; Ward, S. A.; Biagini, G. A. J. Antimicrob.
Chemother. 2013, 68, 977−985.
(3) World Health Organization. The 17 Neglected Diseases, http://
2015).
(4) (a) World Health Organization. World Malaria Report, http://
2015). (b) Burrows, J. Nature 2015, 520, 628−630.
(5) Ashley, E. A.; Dhorda, M.; Fairhurst, R. M.; Amaratunga, C.; Lim,
P.; Suon, S.; Sreng, S.; Anderson, J. M.; Mao, S.; Sam, B.; Sopha, C.;
Chuor, C. M.; Nguon, C.; Sovannaroth, S.; Pukrittayakamee, S.;
Jittamala, P.; Chotivanich, K.; Chutasmit, K.; Suchatsoonthorn, R.;
Runcharoen, T. T.; Hien, N. T.; Thuy-Nhien, N.; Thanh, C. V.; Phu,
N. H.; Htut, Y.; Han, K.-T.; Aye, K. H.; Mokuolu, O. A.; Olaosebikan,
R. R.; Folaranmi, O. O.; Mayxay, M.; Khanthavong, M.;
Hongvanthong, B.; Newton, P. N.; Onyamboko, M. A.; Fanello, C.
I.; Tshefu, A. K.; Mishra, N.; Valecha, N.; Phyo, A. P.; Nosten, F.; Yi,
P.; Tripura, R.; Borrmann, S.; Bashraheil, M.; Peshu, J.; Faiz, M. A.;
Ghose, A.; Hossain, M. A.; Samad, R.; Rahman, M. R.; Hasan, M. M.;
Islam, A.; Miotto, O.; Amato, R.; MacInnis, B.; Stalker, J.;
Kwiatkowski, D. P.; Bozdech, Z.; Jeeyapant, A.; Cheah, P. Y.;
Sakulthaew, T.; Chalk, J.; Intharabut, B.; Silamut, K.; Lee, S. J.;
Vihokhern, B.; Kunasol, C.; Imwong, M.; Tarning, J.; Taylor, W. J.;
Yeung, S.; Woodrow, C. J.; Flegg, J. A.; Das, D.; Smith, J.; Venkatesan,
M.; Plowe, C. V.; Stepniewska, K.; Guerin, P. J.; Dondorp, A. M.; Day,
N. P.; White, N. J. N. Engl. J. Med. 2014, 371, 411−423.
(d) Brzozowski, M.; Forni, J. A.; Savage, G. P.; Polyzos, A. Chem.
Commun. 2015, 51, 334−337. (e) Tsubogo, T.; Oyamada, H.;
Kobayashi, S. Nature 2015, 520, 329−332. Prof. P.H. Seeberger
reported a flow-enabled route toward the synthesis of artemisinin and
its derivatives: (f) Lev
2012, 51, 1706−1709. (g) Kopetzki, D.; Lev
Chem.Eur. J. 2013, 19, 5450−5456. (h) Gilmore, K.; Kopetzki, D.;
Lee, J. W.; Horvath, Z.; McQuade, D. T.; Seidel-Morgensternb, A.;
́
esque, F.; Seeberger, P. H. Angew. Chem., Int. Ed.
́
esque, F.; Seeberger, P. H.
́
Seeberger, P. H. Chem. Commun. 2014, 50, 12652−12655.
(14) More information regarding the HEL FlowCat platform can be
(15) Ouchi, T.; Battilocchio, C.; Hawkins, J. M.; Ley, S. V. Org.
Process Res. Dev. 2014, 18, 1560−1566.
(16) For further details on the optimization process, see Supporting
Information.
(17) Kiya, N.; Kawasaki, S.; Ewaka, K.; Sugiyama, K.; Kitaura T.
Process for producing alicyclic monoketones and process for
producing alicyclic diketones. U.S. Patent 6,313,351 B1, Nov 6, 2001.
(18) To the best of our knowledge, this protocol represents the first
Griesbaum reaction performed under continuous flow conditions. For
selected batch protocols, see: (a) Dong, Y.; Chollet, J.; Matile, H.;
Charman, S. A.; Chiu, F. C. K.; Charman, W. N.; Scorneaux, B.;
Urwyler, H.; Santo Tomas, J.; Scheurer, C.; Snyder, C.; Dorn, A.;
Wang, X.; Karle, J. M.; Tang, Y.; Wittlin, S.; Brun, R.; Vennerstrom, J.
L. J. Med. Chem. 2005, 48, 4953−4961. (b) Zhao, Q.; Vargas, M.;
Dong, Y.; Zhou, L.; Wang, X.; Sriraghavan, K.; Keiser, J.; Vennerstrom,
J. L. J. Med. Chem. 2010, 53, 4223−4233. (c) Fontaine, S. D.;
DiPasquale, A. G.; Renslo, A. R. Org. Lett. 2014, 16, 5776−5779.
(19) Griesbaum, K.; Liu, X.; Kassiaris, A.; Scherer, M. Liebigs Ann.
Recueil 1997, 1381−1390.
(20) Tang, Y.; Dong, Y.; Karle, J. M.; DiTusa, C. A.; Vennerstrom, J.
L. J. Org. Chem. 2004, 69, 6470−6473.
(21) (a) Battilocchio, C.; Baxendale, I. R.; Biava, M.; Kitching, M. O.;
Ley, S. V. Org. Process Res. Dev. 2012, 16, 798−810. (b) O’Brien, M.;
Baxendale, I. R.; Ley, S. V. Org. Lett. 2010, 12, 1596−1598.
(22) Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem.
Soc. 2010, 132, 1770−1771.
(6) Caminadea, C.; Kovats, S.; Rocklov, J.; Tompkins, A. M.; Morse,
A. P.; Colon-Gonzalez, F. J.; Stenlund, H.; Martens, P.; Lloyd, S. J.
́ ́
Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 3286−3291.
(7) Barnett, D. S.; Guy, R. K. Chem. Rev. 2014, 114, 11221−11241.
(8) Vennerstrom, J. L.; Dong, Y.; Chollet J.; Matile, H. Spiro and
dispiro 1,2,4-trioxolane antimalarials. U.S. Patent 6486199 B1, Nov 26,
2002.
(9) (a) Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman, S. A.;
Chiu, F. C. K.; Chollet, J.; Dong, Y.; Dorn, A.; Hunziker, D.; Matile,
H.; McIntosh, K.; Padmanilayam, M.; Santo-Tomas, J.; Scheurer, C.;
Scorneaux, B.; Tang, Y.; Urwyler, H.; Wittlin, S.; Charman, W. N.
Nature 2004, 430, 900−904. (b) Charman, S. A.; Arbe-Barnes, S.;
Bathurst, I. C.; Brun, R.; Campbell, M.; Charman, W. N.; Chiu, F. C.;
Chollet, J.; Craft, J. C.; Creek, D. J.; Dong, Y.; Matile, H.; Maurer, M.;
Morizzi, J.; Nguyen, T.; Papastogiannidis, P.; Scheurer, C.;
Shackleford, D. M.; Sriraghavan, K.; Stingelin, L.; Tang, Y.; Urwyler,
H.; Wang, X.; White, K. L.; Wittlin, S.; Zhou, L.; Vennerstrom, J. L.
Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 4400−4405.
(10) Moehrle, J. J.; Duparc, S.; Siethoff, C.; van Giersbergen, P. L.;
Craft, J. C.; Arbe-Barnes, S.; Charman, S. A.; Gutierrez, M.; Wittlin, S.;
Vennerstrom, J. L. Br. J. Clin. Pharmacol. 2013, 75, 524−537.
(11) Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.;
Johnson, T. A.; Kleine, H. P.; Knight, C.; Nagy, M. A.; Perry, D. A.;
Stefaniak, M. Green Chem. 2008, 10, 31−36.
(12) Selected recent reviews on continuous flow synthesis: (a) Valera,
F. E.; Quaranta, M.; Moran, A.; Blacker, J.; Armstrong, A.; Cabral, J.
T.; Blackmond, D. G. Angew. Chem., Int. Ed. 2010, 49, 2478−2485.
(b) Wegner, J.; Ceylan, S.; Kirschning, A. Chem. Commun. 2011, 47,
4583−4592. (c) Hessel, V.; Gursel, I. V.; Wang, Q.; Noel, T.; Lang, J.
Chem. Eng. Technol. 2012, 35, 1184−1204. (d) Pastre, J. C.; Browne,
D. L.; Ley, S. V. Chem. Soc. Rev. 2013, 42, 8849−8869. (e) McQuade,
D. T.; Seeberger, P. H. J. Org. Chem. 2013, 78, 6384−6389.
(f) Baxendale, I. R. J. Chem. Technol. Biotechnol. 2013, 88, 519−552.
(g) Ley, S. V.; Fitzpatrick, D. E.; Ingham, R. J.; Myers, R. M. Angew.
Chem., Int. Ed. 2015, 54, 3449−3464.
(13) For selected recent contributions to this field, see: (a) Ingham,
R. J.; Battilocchio, C.; Fitzpatrick, D. E.; Sliwinski, E.; Hawkins, J. M.;
Ley, S. V. Angew. Chem., Int. Ed. 2015, 54, 144−148. (c) Souto, J. A.;
Stockman, R. A.; Ley, S. V. Org. Biomol. Chem. 2015, 13, 3871−3877.
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