Organic Letters
Letter
apparently similar. However, as is obvious from the optimized
structures, catalyst 5a has a closed structure between the ethynyl
group and the quinoline ring (Figure 1b). A closed space
limitation was also observed for catalyst 5k having an arylethynyl
group (Figure 1c). In contrast, the space over the quinoline ring
of catalyst 4b was more open (Figure 1a). The other spaces
around both catalysts 4 and 5 were almost fully occupied by the
sterically demanding 3,5-bis-CF3-aryl groups and n-butyl ether of
5a,k.
JSPS KAKENHI Grant Number JP 16H01142 in Middle
Molecular Strategy, and the Advanced Catalytic Transformation
(ACT-C) from the JST Agency.
REFERENCES
■
(1) (a) Wilkins, E.; Fisher, M.; Brogan, J.; Talbird, S. E.; La, E. M. HIV
Med. 2016, 17, 505. (b) Mandala, D.; Thompson, W.; Watts, P.
Tetrahedron 2016, 72, 3389. (c) Roshni, P. R.; Thampi, A.; Ashok, B. A.;
Joy, J.; Thomas, T.; Kumar, K. P. G. Int. J. Pharm. Sci. Rev. Res. 2016, 36,
8. (d) Larru, B.; Eby, J.; Lowenthal, E. D. Pediatr. Health, Med. Ther.
2014, 5, 29.
Thus, the transition-state arrangements shown in Figure 2 are
plausible (Figure 2). The alkenyl ketones 3a,b can be stabilized
(2) Young, D. S.; Britcher, F. S.; Payne, S. L.; Tran, O. L.; William, L.
C., Jr. Benzoxazinones as Inhibitors of HIV Reverse Transcriptase.
World Patent 9520389, Aug 3, 1995.
(3) (a) Nakakeeto, O. N.; Elliott, B. V. Globalization and Health 2013,
(4) (a) Li, S.; Ma, J. A. Chem. Soc. Rev. 2015, 44, 7439. (b) Wu, G.;
Huang, M. Chem. Rev. 2006, 106, 2596. (c) Huang, Y.; Yang, X.; Chen,
Z.; Verpoort, F.; Shibata, N. Chem. - Eur. J. 2015, 21, 8664. (d) Wang, J.;
Sanchez-Rosello, M.; Acena, J. L.; del Pozo, C.; Sorochinsky, A. E.;
́
́
̃
Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432.
(5) (a) Parsons, R. L., Jr.; Fortunak, J. M.; Dorow, R. L.; Harris, G. D.
G.; Kauffman, S.; Nugent, W. A.; Winemiller, M. D.; Briggs, T. F.; Xiang,
B.; Collum, D. B. J. Am. Chem. Soc. 2001, 123, 9135. (b) Tan, L.; Chen,
C.; Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J. Angew. Chem., Int. Ed.
1999, 38, 711.
Figure 2. (a) Plausible transition state structures for the formation of 2a
by 5a from 3a; (b) formation of 2b by 5k from 3b.
by a π−π interaction with the quinoline ring. The methoxy group
(OMe) of quinoline assists the positioning of ketones 3 by a
steric interaction, while a corresponding cinchonidine variant
without an OMe group tends to lower the enantioselectivity.7b
The CF3 anion approaches from the Si-face of ketones 3a,b.
We disclosed the highly organocatalyzed enantioselective
trifluoromethylation of alkenyl aryl ketones with the Ruppert−
Prakash reagent to provide trifluoromethyl alcohols in high yields
with high enantioselectivities. These are the key intermediates of
the anti-HIV drug, Efavirenz. Previously unknown ethynyl and
arylethynyl cinchona alkaloid ammonium salts were found to be
very effective for this transformation. Over 90% ee has been
achieved for the first time under a nonmetal system. Both Merck
and Lonsa key intermediates for Efavirenz were accessed with
91−93% ee, both of which were nicely converted into Efavirenz
in one or two steps without a major loss of enantiopurity of the
trifluoromethylated alcohols. Application of this method for the
asymmetric flow synthesis of Efavirenz is now being investigated.
(6) (a) Chinkov, N.; Warm, A.; Carreira, E. M. Angew. Chem., Int. Ed.
2011, 50, 2957. (b) Dai, D.; Long, X.; Luo, B.; Kulesza, A.; Reichwagen,
J.; Guo, Y. Process for Preparation of Efavirenz by Cyclization. World
Patent 2012097510, Jul 26, 2012.
(7) (a) Kawai, H.; Kitayama, T.; Tokunaga, E.; Shibata, N. Eur. J. Org.
Chem. 2011, 2011, 5959. (b) Okusu, S.; Kawai, H.; Yasuda, Y.; Sugita, Y.;
Kitayama, T.; Tokunaga, E.; Shibata, N. Asian J. Org. Chem. 2014, 3, 449.
(8) For asymmetric synthesis of Efavirenz analogues, see: (a) Jiang, B.;
Dong, J. J.; Si, Y. G.; Zhao, X. L.; Huang, Z. G.; Xu, M. Adv. Synth. Catal.
2008, 350, 1360. (b) Xie, H.; Zhang, Y.; Zhang, S.; Chen, X.; Wang, W.
Angew. Chem., Int. Ed. 2011, 50, 11773. (c) Yuan, H.-N.; Wang, S.; Nie,
J.; Meng, W.; Yao, Q.; Ma, J.-A. Angew. Chem., Int. Ed. 2013, 52, 3869.
(d) Wang, J.; Liu, X.; Feng, X. Chem. Rev. 2011, 111, 6947. (e) Zhang, F.-
G.; Zhu, X.-Y.; Li, S.; Nie, J.; Ma, J.-A. Chem. Commun. 2012, 48, 11552.
(f) Zhang, F.-G.; Ma, H.; Zheng, Y.; Ma, J.-A. Tetrahedron 2012, 68,
7663. (g) Zhang, F.-G.; Ma, H.; Nie, J.; Zheng, Y.; Gao, Q.; Ma, J.-A. Adv.
Synth. Catal. 2012, 354, 1422. (h) Cai, H.; Nie, J.; Zheng, Y.; Ma, J.-A. J.
Org. Chem. 2014, 79, 5484.
(9) One compound is registered in the ScFinder database: Baptiste, T.;
Plaquevent, P. D.; Christophe, J.; Dominique, C. In A panoply of
polymer-anchored cinchona alkaloids for asymmetric phase-transfer
catalysis, International Sixth International Electronic Conference on
Synthetic Organic Chemistry (ECSOC-6), Basel, Switzerland, Sept 1−
30, 2002.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
■
S
(10) (a) Braje, W. M.; Frackenpohl, J.; Schrake, O.; Wartchow, R.; Beil,
W.; Hoffmann, H. M. R. Helv. Chim. Acta 2000, 83, 777. (b) Kacprzak,
K. M.; Lindner, W.; Maier, N. M. Chirality 2008, 20, 441.
(11) (a) Matoba, K.; Kawai, H.; Furukawa, T.; Kusuda, A.; Tokunaga,
E.; Nakamura, S.; Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2010, 49,
5762. (b) Kawai, H.; Yuan, Z.; Kitayama, T.; Tokunaga, E.; Shibata, N.
Angew. Chem., Int. Ed. 2013, 52, 5575. (c) Kawai, H.; Kusuda, A.;
Nakamura, S.; Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2009, 48,
6324.
Experimental procedures, NMR spectra, and HPLC charts
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research is partially supported by the Aichi Science &
Technology Foundation, the Platform Project for Supporting in
Drug Discovery and Life Science Research (Platform for Drug
Discovery, Informatics, and Structural Life Science) from the
Japan Agency for Medical Research and Development (AMED),
D
Org. Lett. XXXX, XXX, XXX−XXX