Journal of the American Chemical Society
COMMUNICATION
’ AUTHOR INFORMATION
Corresponding Author
’ ACKNOWLEDGMENT
Financial support was provided by NIHGMS (R01
GM078201-01-01) and kind gifts from Merck. P.K. thanks the
Foundation for Polish Science and J.C.C. thanks NSERC for
postdoctoral fellowships.
’ REFERENCES
Figure 2. Chemo- and regioselective R-fluorination of polycycles.
(1) For reviews on fluorination in medicinal chemistry, see: (a) Kirk,
K. L. Org. Process Res. Dev. 2008, 12, 305. (b) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (c)
Hagmann, W. K. J. Med. Chem. 2008, 51, 887. (d) Ojima, I. ChemBio-
Chem 2004, 5, 628. Crop protection: (e) Jeschke, P. ChemBioChem
2004, 5, 570.
(2) (a) M€uller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(b) B€ohm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; M€uller,
K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637.
(3) Pioneering work: (a) Hintermann, L.; Togni, A. Angew. Chem.,
Int. Ed. 2000, 39, 4359. (b) Hamashima, Y.; Yagi, K.; Takano, H.; Tamꢀas,
L.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 14530. (c) Suzuki, T.;
Hamashima, Y.; Sodeoka, M. Angew. Chem., Int. Ed. 2007, 46, 5435.
(d) Paull, D. H.; Scerba, M. T.; Alden-Danforth, E.; Widger, L. R.;
Lectka, T. J. Am. Chem. Soc. 2008, 130, 17260. Reviews: (e) Lectard, S.;
Hamashima, Y.; Sodeoka, M. Adv. Syn. Catal. 2010, 352, 2708.
(f) Brunet, V. A.; O’Hagan, D. Angew. Chem., Int. Ed. 2008, 47, 1179.
(g) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1. (h) Prakash,
G. K. S.; Beirer, P. Angew. Chem., Int. Ed. 2006, 45, 2172. (i) Pihko, P. M.
Angew. Chem., Int. Ed. 2006, 45, 544. (j) Brunet, V. A.; O’Hagan, D.
Angew. Chem., Int. Ed. 2007, 46, 2. Recent examples: (k) Kalow, J. A.;
Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 3268. (l) Katcher, M. H.;
Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 17402.
(4) (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471.(b) Pihko, P. M.; Majander, I.; Erkkil€a, A. In Asymmetric
Organocatalysis; List, B., Ed.; Topics in Current Chemistry, Vol. 291;
Springer-Verlag: Berlin, 2009; p 29.
(5) (a) Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005,
127, 8826. (b) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjærsgaard, A.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703. (c) Steiner, D.;
Mase, N.; Barbas, C. F., III Angew. Chem., Int. Ed. 2005, 44, 3706.
(6) For cascade reactions employing aldehyde R-fluorination, see:
(a) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 15051. (b) Fadeyi, O. O.; Lindsley, C. W. Org. Lett.
2009, 11, 943. (c) Appayee, C.; Brenner-Moyer, S. E. Org. Lett. 2010, 12,
3356.
Despite competing difluorination, 2-fluoro-cycloheptanone was
obtained with excellent enantioselectivity and reasonable yield
(entry 13: 45%, 98% ee), while fluorination of cyclopentanone
proved to be more efficient (entry 14: 52%, 88% ee). It should be
noted that this enantioselective fluorination has yet to be
successfully implemented with acyclic ketones (diminished
yields and enantioselectivities are observed for this subclass).
Last, we turned our attention to the diastereoselective fluo-
rination of cyclic ketones that incorporate pre-existing stereo-
genicity. Using simple six-membered carbocycles such as (R)-3-
methyl cyclohexanone, nearly complete diastereocontrol (trans)
was observed (entry 10: 69%, 99:1 dr, 99% ee). Moreover, using
the pseudoenantiomeric cinchonidine catalyst (epi-34), the cis
fluorination product was readily obtained with similar levels of
reaction efficiency (entry 11: 62%, 99:1 dr, 99% ee). In a similar
fashion, R-fluorination of the meso substrate 4- phenyl-cyclohex-
anone (entry 12) proceeded with high enantioselectivity in the
desymmetrization step (97% ee).
Having successfully examined a series of prototypical cyclo-
hexanone systems, we next directed our standard fluorination
conditions to more complex substrates (Figure 2). With the
hydrogenated Hajos-Parrish ketone, issues of both carbonyl
chemoselectivity (cyclopentyl versus cyclohexyl) as well as R-
carbonyl positional selectivity (C(3) versus C(5)) were encoun-
tered. Remarkably, this new enamine activation reaction enabled
chemo-, regio- and diastereoselective fluorination of the C(5)
cyclohexyl ring (74%, 98:2 dr, >99:1 regiocontrol, >99:1 carbo-
nyl selectivity, 99% ee). The generality of such an approach was
again demonstrated with allo-pregnanedione wherein two ketones
and three R-methylene sites are effectively partitioned with high
levels of catalyst controlled selectivities (91% yield, 95:5 dr,
>99:1 regiocontrol, >99:1 carbonyl selectivity, 99% ee). Finally,
in the case of the steroid cholestanone, fluorination occurs with
complete regiocontrol and again with excellent efficiency (85%
yield, 97:3 dr, 99% ee, >99:1 regiocontrol).12
(7) Enders, D.; H€uttl, M. R. M. Synlett 2005, 991.
(8) Alkaloids have been used as stochiometric fluorinating agents
and it is possible that fluorination proceeds in this case via dual activation
of the ketone and fluorine source: Shibata, N.; Ishimaru, T.; Suzuki, E.;
Kirk, K. J. Org. Chem. 2003, 68, 2494.
In conclusion, a highly enantioselective ketone R-fluorination
reaction utilizing an electrophilic fluorine reagent (NFSI) and a
primary amine organocatalyst has been accomplished. The pri-
mary amine catalyst enables high levels of regio-, chemo-, enantio-
and diastereoselectivity for a variety of ketone substrates. The
resultant methodology serves as a direct entry into very useful
stereogenic carbon-fluorine synthons for chemical synthesis.
(9) Review of primary amine catalysts used for organocatalysis: (a)
Peng, F.; Shao, Z. J. Mol. Catal. A.: Chem 2008, 285, 1. Alkaloid-derived
catalysts used for enamine activation: (b) McCooey, S. H.; Connon, S. J.
Org. Lett. 2007, 9, 599. (c) Bencivenni, G.; Galzerano, P.; Mazzanti, A.;
Bartoli, G.; Melchiorre, P. Proc. Natl. Acad. Sci. U.S.A. 2010, 20642.
(d) Bergonzini, G.; Vera, S.; Melchiorre, P. Angew. Chem., Int. Ed. 2010,
49, 9685. Alkaloid-derived catalysts used for iminium activation:
(e) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.;
Melchiorre, P. Org. Lett. 2007, 9, 1403. (f) Carlone, A.; Bartoli, G.;
Bosco, M.; Pesciaioli, F.; Ricci, P.; Sambri, L.; Melchiorre, P. Eur. J. Org.
Chem. 2007, 5492. (g) Xie, J.-W.; Chen, W.; Li, R.; Zeng, M.; Du, W.;
Yue, L.; Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G. Angew. Chem., Int. Ed.
2007, 46, 389. (h) Xie, J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng,
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectral data. This material is available free of charge via the
1740
dx.doi.org/10.1021/ja111163u |J. Am. Chem. Soc. 2011, 133, 1738–1741