Asymmetric fluorination of α-branched cyclohexanones enabled by a combination of chiral anion phase-transfer catalysis and enamine catalysis using protected amino acids

Article abstract of DOI:10.1021/ja500882x

We report a study involving the successful merger of two separate chiral catalytic cycles: a chiral anion phase-transfer catalysis cycle to activate Selectfluor and an enamine activation cycle, using a protected amino acid as organocatalyst. We have demonstrated the viability of this approach with the direct asymmetric fluorination of α-substituted cyclohexanones to generate quaternary fluorine-containing stereocenters. With these two chiral catalytic cycles operating together in a matched sense, high enantioselectivites can be achieved, and we envisage that this dual catalysis method has the potential to be more broadly applicable, given the breadth of enamine catalysis. It also represents a rare example of chiral enamine catalysis operating successfully on α-branched ketones, substrates commonly inert to this activation mode.

Full text of DOI:10.1021/ja500882x

Communication
pubs.acs.org/JACS
Asymmetric Fluorination of α‑Branched Cyclohexanones Enabled by
a Combination of Chiral Anion Phase-Transfer Catalysis and Enamine
Catalysis using Protected Amino Acids
Xiaoyu Yang,† Robert J. Phipps,† and F. Dean Toste*
Department of Chemistry, University of California, Berkeley, California 94720, United States.
S
* Supporting Information
simple phenols can be employed as substrates in enantioselective
fluorinative dearomatization11 and or as directing groups in
ABSTRACT: We report a study involving the successful
enantioselective fluorination of alkenes.12 On the basis of these
merger of two separate chiral catalytic cycles: a chiral anion
phase-transfer catalysis cycle to activate Selectfluor and an
enamine activation cycle, using a protected amino acid as
organocatalyst. We have demonstrated the viability of this
approach with the direct asymmetric fluorination of α-
substituted cyclohexanones to generate quaternary fluo-
rine-containing stereocenters. With these two chiral
catalytic cycles operating together in a matched sense,
high enantioselectivites can be achieved, and we envisage
that this dual catalysis method has the potential to be more
broadly applicable, given the breadth of enamine catalysis.
It also represents a rare example of chiral enamine catalysis
operating successfully on α-branched ketones, substrates
commonly inert to this activation mode.
results and with the ultimate goal of expanding our methodology
to encompass the most elementary of substrates, we targeted the
enantioselective fluorination of simple ketones. We were aware
that this is a challenging undertaking as evidenced by the fact that
only one highly enantioselective ketone fluorination procedure
has been reported to date.4b,5 This elegant example, using a
cinchona-alkaloid-derived primary amine catalyst in combination
with NFSI, was however limited to the fluorination of non-α-
branched ketones.5,13
Specifically, we supposed that inclusion of a catalytic amount
of a primary amine would form a transient enamine that should
be reactive to electrophilic fluorination and act as a hydrogen-
bond donor for binding to the chiral phosphate catalyst (Figure
1, cycle 1).14 This would also present the opportunity to
introduce a chiral controlling element onto the enamine partner
(e.g., an amino acid derivative, as depicted). Independently, the
lipophilic chiral phosphate would undergo anion exchange with
the achiral tetrafluoroborate counteranions of insoluble Select-
fluor to catalytically generate a soluble chiral electrophilic
fluorinating reagent (cycle 2). If compatible, the union of these
two independent catalytic cycles should be capable of achieving
direct asymmetric ketone α-fluorination (Figure 1, leading
scheme), a general approach which has been referred to variously
as ‘dual’, ‘synergistic’, or ‘cooperative’ catalysis.15 Such processes
which involve two catalysts simultaneously activating two
different reactants have the potential to be extremely powerful
if the two catalytic cycles are able to operate in synchrony.15a
They also offer the exciting opportunity to exert chiral influence
from both catalysts to accomplish particularly challenging
transformations, although few examples of such a scenario have
been reported to date; most rely on one chiral and one achiral
catalyst.16,17
he selective introduction of fluorine into small organic
T
molecules has rapidly become a field of great interest, due
to the beneficial pharmarcokinetic properties that judiciously
placed fluorine atoms can confer.1 Great progress has been made
employing chiral metal complexes for electrophilic fluorination
of activated ketones1a,2 and using nucleophilic fluorine sources
for enantioselective allylic fluorination.3 Chiral enamine catalysis
has furnished a number of protocols for highly enantioselective
α-fluorination of aldehydes4 and a single protocol for ketones.5
Cinchona alkaloids have been effective for fluorination of carbon
nucleophiles6 and in a dual catalysis mechanism to enable the
fluorination of acid chlorides.7
Within the burgeoning field of asymmetric catalysis controlled
by chiral counterions,8 we have recently introduced chiral anion
phase-transfer catalysis, employing chiral lipophilic BINOL-
derived phosphates in combination with dicationic electrophilic
reagents applied to enantioselective halogenation reactions.9 In
our approach, the catalytic activation of the electrophilic reagent
consists of its transport from the solid phase into the organic
phase where its chiral anions enable enantioselective trans-
formations. We envisage that this new approach to asymmetric
fluorination could prove to be broadly applicable across a range
of substrate classes given the proven versatility of chiral
phosphoric acids and the powerful fluorinating ability of
Selectfluor. However, in earlier reports, an amide group in the
substrate was crucial for high enantioselectivity.9a,10
We selected 2-phenylcyclohexanone as an evaluation sub-
strate, having previously observed that the benzoyl enamide
derived from this ketone10b as well as geometrically similar 2-
phenylphenol11 underwent highly enantioselective fluorination.
Under our standard conditions (5 mol % chiral phosphoric acid,
2 equiv ketone, 1 equiv Selectfluor, 2 equiv Na2CO3, toluene, rt)
in the absence of a primary amine cocatalyst, only trace amounts
of the desired product were obtained (Table 1, entry 1).
We hypothesized that this was due the need for a substrate
amide to form a hydrogen bond with the BINOL-phosphoric
acid catalyst in the transition state. We have since discovered that
Received: January 26, 2014
Published: March 31, 2014
© 2014 American Chemical Society
5225
dx.doi.org/10.1021/ja500882x | J. Am. Chem. Soc. 2014, 136, 5225−5228

Journal of the American Chemical Society
Communication
Table 1. Investigation of the Fluorination of 2-
Phenylcyclohexanone
phosphoric
yield based on: 1
a
b
entry
acid
amine
(Selectfluor)
ee
c
1
(R)-C8-TRIP
(R)-C8-TRIP
(R)-C8-TRIP
(R)-C8-TRIP
(R)-C8-TRIP
(R)-C8-TRIP
(R)-C8-TRIP
(R)-C8-TRIP
none
none
BnNH2
nBuNH2
A1
2 (5)
14 (29)
12 (24)
25 (50)
31−36 (63−73)
25 (50)
37 (74)
35 (70)
5 (10)
−2
−3
−2
c
2
c
3
c
4
+10
+63−78
+32
+88
−40
+10
+20
−24
+82
+67
+87
+21
+45
+35
+86
+87
+81
+61
+87
+83
+88
+94
c
5
D-A2
D-A2
D-A2
L-A2
Figure 1. Proposed dual catalytic cycle for the enantioselective
fluorination of ketones using (1) an enamine catalysis cycle and (2) a
chiral anion phase-transfer catalysis cycle.
d
6
e
7
e
8
e
9
D-A2
D-A2
D-A3
D-A2
D-A2
D-A2
D-A2
D-A4
D-A5
D-A6
D-A7
D-A8
D-A9
D-A10
D-A11
D-A12
D-A13
e
10
AP
28 (57)
4 (8)
Encouragingly, inclusion of 20 mol % of benzylamine increased
the yield of the fluorinated product to 29% and n-butylamine
gave 24% yield based on Selectfluor, although both gave
disappointingly low enantioselectivities (<5% ee, entries 2 and
3). Addition of catalytic glycine methyl ester gave the highest
yield (entry 4), and although the enantioselectivity was low
(10%), the effectiveness of this combination with regards to
reactivity was encouraging.
e
11
(R)-C8-TRIP
(R)-TRIP
e
12
34 (69)
32 (65)
26 (52)
24 (48)
39 (78)
23 (47)
26 (53)
32 (64)
35 (70)
28 (56)
13 (27)
36 (72)
14 (29)
e
13
(R)-TCYP
e
14
(R)-P1
e
15
(R)-P2
e
16
(R)-C8-TRIP
(R)-C8-TRIP
(R)-C8-TRIP
(R)-C8-TRIP
(R)-C8-TRIP
(R)-C8-TRIP
(R)-C8-TRIP
(R)-C8-TRIP
(R)-C8-TRIP
(R)-C8-TRIP
e
17
e
18
We next examined D-phenylalanine methyl ester as enamine
catalyst and were excited to see that the enantioselectivity
increased to 78% ee with good conversion and clean reaction
(entry 5).18 The employment of Selectfluor as limiting reagent
with excess ketone is due to the formation of trace amounts of
difluorinated byproducts observed if Selectfluor was used in
excess, which were very difficult to separate from the desired
product. For clarity we have therefore displayed yields based on
both components, with the yield based on the limiting reagent
Selectfluor in parentheses. The high enantioselectivity initially
obtained in this reaction was found to be unrepeatable, and after
careful examination, we found that inconsistent levels of
moisture in the Na2CO3 employed (dried under vacuum at 80
°C for 2h) led to this capriciousness. Using Na2CO3 dried at 200
°C for 4 h gave only 32% ee (entry 6), suggesting that a small
amount of water is essential for the high enantioselectivity.
Finally, we found using commercially available Na2CO3·H2O
improved the ee to 88%, with excellent repeatability (entry 7).
Recovery and analysis of the unreacted starting material showed
the ee of the starting material to be <5% demonstrating that this
is not a kinetic resolution. Evaluation of L-phenylalanine methyl
ester under these optimized conditions showed that in this case
the catalysts are mismatched, giving 40% ee of the opposite
enantiomer in good yield based on Selectfluor (entry 8).
Removing the chiral phosphoric acid resulted in low conversion
and little enantioselectivity (entry 9), demonstrating that both
e
19
e
20
e
21
e
22
e
23
e
24
e
f
25
31 (62)
a
Yield determined by 19F-NMR spectroscopy by comparison with an
b
internal standard. Determined by chiral HPLC analysis of the crude
reaction mixture after a short plug of silica gel. Na2CO3 ground and
dried under vacuum at 80 °C for 2 h. Na2CO3 ground and dried at
200 °C for 4 h. Commercially available Na2CO3.H2O used as
received. Isolated in 61% yield based on Selectfluor.
c
d
e
f
catalysts are crucial; in the absence of either, both yield and
enantiomeric excess are poor (<10% in each case).
In order to confirm that the chiral phosphate catalyst is playing
an important role in enantioinduction, we used D-phenylalanine
methyl ester in combination with the lipophilic achiral
phosphoric acid AP. In this case the yield of fluorination was
good, as expected, but the enantioselectivity was poor (20% ee,
entry 10). This result, taken with those using achiral amines with
a chiral phosphate (entries 2−4), demonstrates the requirement
for chiral controlling elements on both catalysts in order to
achieve high enantioselectivity. Use of the N-methylated D-
5226
dx.doi.org/10.1021/ja500882x | J. Am. Chem. Soc. 2014, 136, 5225−5228

Journal of the American Chemical Society
Communication
phenylalanine methyl ester gave negligible conversion, as
expected given that condensation of this secondary amine with
the hindered ketone is likely disfavored (entry 11 vs entry 7),
providing strong evidence for the proposed enamine mechanism,
rather than an alternative mechanistic scenario where the amine
may act as a base. A survey of a handful of chiral phosphoric acids
showed C8-TRIP to be optimal (entries 12−15).19 Having
established the indispensability of both the chiral phosphoric acid
and chiral amino acid ester catalysts, we surveyed a range of
amino acid esters.20 Use of the tert-butyl ester of phenylalanine
(45% ee, entry 16) or the less bulky alanine methyl ester (35% ee,
entry 17) was detrimental to the enantioselectivity. Leucine
methyl ester performed almost as well as phenylalanine methyl
ester (86% ee, entry 18), as did two O-substituted tyrosine
derivatives (entries 19 and 20). Moving the side-chain aromatic
ring closer to the amine in phenyl glycine proved to be
detrimental (61% ee, entry 21), while replacing the phenyl-
alanine aromatic ring with cyclohexyl resulted in no loss of
enantioselectivity but low conversion (87% ee, entry 22). With
the aim of increasing the steric bulk of the phenylalanine
aromatic ring, we investigated naphthyl and anthryl variants
(entries 23−25). This resulted in the identification of catalyst
A13, delivering the fluorinated product with an excellent 94% ee
in 61% isolated yield, based on the limiting Selectfluor (entry 25).
Under our employed conditions using excess ketone, a
substantial amount of unreacted ketone can be recovered. For
example 81% of the excess ketone employed in synthesis of 2a
(Table 1, entry 25) could be reisolated (see SI for details).
We next explored the scope and limitations of the trans-
formation (Table 2). A two-fold excess of ketone is used, and the
resulting yields calculated based on the limiting reagent
Selectfluor are quoted in parentheses, after that based on the
excess ketone. A range of substituted aryl groups are tolerated in
the α-position of the cyclohexanone (2a−2j). This encompasses
para and meta substituted arenes as well as a furan (2i) that is
untouched by the Selectfluor and highlights the mild electro-
philic fluorinating conditions. Similarly untouched in the α-
fluorination is an aryl iodide (2j), despite the precedent for aryl
iodides being readily oxidized to I(III) by Selectfluor under
homogeneous conditions.21 Substitution (2k) and the presence
of heteroatoms (2l and 2m) are well tolerated at the 4-position of
the cyclohexanone. In three cases, phenylalanine catalyst A2 gave
marginally (<5%) higher enantioselectivity than naphthyl variant
A13. In the case of furyl substrate 2i, bulky 9-anthryl catalyst A12
gave an advantage of 10% ee over A13.
Table 2. Substrate Scope of the Asymmetric Fluorination of 2-
Aryl Cyclohexanones
a b c
, ,
a
Reactions were carried out with ketone (0.2 mmol), Selectfluor (0.1
mmol) amine catalyst (0.02 mmol), phosphoric acid catalyst (0.005
mmol), and Na2CO3·H2O (0.2 mmol) in toluene (1.0 mL) for 40 h at
b
rt. Yields are isolated yields after chromatography. Primary yields
calculated based on the excess ketone employed. Yields in parentheses
calculated based on Selectfluor, the limiting reagent in all cases.
c
Absolute configurations assigned by analogy to 2j, determined by X-
d
ray crystallography. Characterized as the N-tosyl derivative.
Table 3. Asymmetric Fluorination of 2-Alkenyl and 2-Alkynyl
a
Cyclohexanones
We demonstrate that several 2-alkenyl and 2-alkynyl cyclo-
hexanones are also viable substrates in our fluorination,
delivering high enantioselectivies (Table 3). In these cases,
complete regioselectivity is observed for fluorination at the α-
position of the ketone, with no undesired fluorination of the
alkene or alkyne. In the alkynyl substrates the enantioselectivities
were somewhat reduced, and a catalyst survey revealed 9-anthryl
catalyst A12 to be optimal (2o−2q). Disappointingly, no
fluorination is observed for 2-alkylcyclohexanones under the
present conditions, and we do not observe fluorination of closely
related acyclic ketones under these conditions, demonstrating
the present limitations of the methodology.22 Finally, selective
transformation of the products into other chiral fluorinated
derivatives was investigated (Scheme 1).
a
Conditions as in Table 2. Primary yields are isolated yields after
chromatography, calculated based on excess ketone employed. Yield in
parenthesis calculated based on the limiting reagent, Selectfluor.
enamine activation of the ketone and chiral anion phase-transfer
activation of the Selectfluor. The two activated components are
subsequently united most likely by direct interaction of the two
chiral components via a hydrogen-bonded transition state which
imparts high levels of stereoselectivity in the matched case.
Successful combination of two catalytic cycles that both involve
chiral catalysts is rare, and we believe that this study is among the
first to combine two chiral organocatalytic cycles. While the
current synthetic scope is limited to substituted cyclohexanones
and requires careful matching of the two chiral catalysts, this also
In summary, we have developed an asymmetric fluorination of
substituted cyclohexanones which generates quaternary fluorine-
containing stereocenters. We propose that this is achieved
through the combination of two separate catalytic cycles:
5227
dx.doi.org/10.1021/ja500882x | J. Am. Chem. Soc. 2014, 136, 5225−5228

Journal of the American Chemical Society
Communication
O.; Blessley, G.; Martinez del Campo, T.; Thompson, A. L.; Giuffredi, G.
T.; Bettati, M.; Walker, M.; Borman, R.; Gouverneur, V. Angew. Chem.,
Int. Ed. 2011, 50, 8105. (c) Shibata, N.; Suzuki, E.; Takeuchi, Y. J. Am.
Chem. Soc. 2000, 122, 10728.
Scheme 1. Further Transformations of Fluorinated Ketone
Products
(7) (a) Erb, J.; Paull, D. H.; Dudding, T.; Belding, L.; Lectka, T. J. Am.
Chem. Soc. 2011, 133, 7536. (b) Paull, D. H.; Scerba, M. T.; Alden-
Danforth, E.; Widger, L. R.; Lectka, T. J. Am. Chem. Soc. 2008, 130,
17260.
(8) (a) Lacour, J.; Moraleda, D. Chem. Commun. 2009, 7073.
(b) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nat. Chem. 2012, 4,
603. (c) Brak, K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2013, 52, 534.
(d) Mahlau, M.; List, B. Angew. Chem., Int. Ed. 2013, 52, 518.
(9) (a) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D.
Science 2011, 334, 1681. (b) Hamilton, G. L.; Kanai, T.; Toste, F. D. J.
Am. Chem. Soc. 2008, 130, 14984.
(10) (a) Honjo, T.; Phipps, R. J.; Rauniyar, V.; Toste, F. D. Angew.
Chem., Int. Ed. 2012, 51, 9684. (b) Phipps, R. J.; Hiramatsu, K.; Toste, F.
D. J. Am. Chem. Soc. 2012, 134, 8376. (c) Shunatona, H. P.; Fruh, N.;
̈
Wang, Y.-M.; Rauniyar, V.; Toste, F. D. Angew. Chem., Int. Ed. 2013, 52,
7724. (d) Wang, Y.-M.; Wu, J.; Hoong, C.; Rauniyar, V.; Toste, F. D. J.
Am. Chem. Soc. 2012, 134, 12928.
represents a rare example of chiral enamine catalysis operating
successfully on α-branched ketones, substrates which are
commonly inert to this activation mode.23
(11) Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2013, 135, 1268.
(12) Wu, J.; Wang, Y.-M.; Drljevic, A.; Rauniyar, V.; Phipps, R. J.;
Toste, F. D. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 13729.
(13) For the synthesis of enantioenriched α-fluoroketones via
decarboxylation, see: Nakamura, M.; Hajra, A.; Endo, K.; Nakamura,
E. Angew. Chem., Int. Ed. 2005, 44, 7248. and Mohr, J. T.; Nishimata, T.;
Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348.
(14) (a) Xu, L.-W.; Luo, J.; Lu, Y. Chem. Commun. 2009, 1807.
(b) Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 9748.
(15) (a) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633.
(b) Du, Z.; Shao, Z. Chem. Soc. Rev. 2013, 42, 1337. (c) Schindler, C. S.;
Jacobsen, E. N. Science 2013, 340, 1052.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
fdtoste@berkeley.edu
■
(16) (a) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M.
Science 2013, 340, 1065. (b) Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J.
Am. Chem. Soc. 2004, 126, 9928.
Author Contributions
†These authors contributed equally.
(17) For elegant studies combining chiral phosphoric acids and chiral
primary amines, see: (a) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006,
128, 13368. (b) Wang, X.; Reisinger, C. M.; List, B. J. Am. Chem. Soc.
2008, 130, 6070.
(18) For the addition of stoichiometric chiral cyclohexyl enamines to
Michael acceptors, see: (a) Pfau, M.; Revial, G.; Guingant, A.; d’Angelo,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge NIHGMS (RO1 GM104534), SIOC,
Zhejiang Medicine and Pharmaron (Fellowship to X.Y.) and the
European Commission (Marie Curie International Outgoing
Fellowship to R.J.P.) for financial support. We gratefully
acknowledge Ms. Z. Zhang for experimental assistance and Dr.
A. DiPasquale for obtaining X-ray crystallographic data for 2j.
J. J. Am. Chem. Soc. 1985, 107, 273. (b) d’Angelo, J.; Desmaele, D.;
̈
Dumas, F.; Guingant, A. Tetrahedron Asym. 1992, 3, 459.
(19) We propose that the C8H17 alkyl chains of C8-TRIP aid in the
phase-transfer process, promoting the asymmetric fluorination over any
background reaction.
(20) The quinidine-derived primary amine catalyst optimal in ref 5 was
found to give low yield and poor enantioselectivity in our ketone
fluorination. See SI for details of this catalyst and for a survey of solvents.
(21) Ye, C.; Twamley, B.; Shreeve, J. M. Org. Lett. 2005, 7, 3961.
(22) For example, neither 1,2-diphenylpropan-1-one nor propiophe-
none undergo fluorination under our presently employed conditions.
(23) Kang, J. Y.; Carter, R. G. Org. Lett. 2012, 14, 3178.
REFERENCES
■
(1) (a) Lectard, S.; Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal.
2010, 352, 2708. (b) Muller, K.; Faeh, C.; Diederich, F. Science 2007,
̈
317, 1881. (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320.
(2) (a) Hamashima, Y.; Yagi, K.; Takano, H.; Tamas, L.; Sodeoka, M. J.
́
Am. Chem. Soc. 2002, 124, 14530. (b) Hintermann, L.; Togni, A. Angew.
Chem., Int. Ed. 2000, 39, 4359.
(3) (a) Katcher, M. H.; Sha, A.; Doyle, A. G. J. Am. Chem. Soc. 2011,
133, 15902. (b) Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2010, 132,
3268.
(4) (a) Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
8826. (b) Enders, D.; Huttl, M. R. M. Synlett 2005, 991. (c) Marigo, M.;
̈
Fielenbach, D.; Braunton, A.; Kjærsgaard, A.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2005, 44, 3703. (d) Steiner, D. D.; Mase, N.; Barbas, C. F.
Angew. Chem., Int. Ed. 2005, 44, 3706. (e) Pihko, P. M. Angew. Chem., Int.
Ed. 2006, 45, 544.
(5) Kwiatkowski, P.; Beeson, T. D.; Conrad, J. C.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2011, 133, 1738.
(6) (a) Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura,
S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2008, 47, 4157. (b) Lozano,
5228
dx.doi.org/10.1021/ja500882x | J. Am. Chem. Soc. 2014, 136, 5225−5228