Organic Letters
Letter
Table 2. Reaction Yield and Enantiomeric Excess for Various
Silyl Enol Ethers
working hypothesis is that hydrogen bonding between 2b and
phenol in the ground state is responsible for the loss of ee. That
is, upon excitation, ESPT from 2b to phenol can generate
PhOH2+ which is still sufficiently acidic to protonate substrate,
a
23
but all chiral induction is lost. Attempts to limit hydrogen
bonding by using thiol proton sources (ethanethiol, thiophenol,
etc.) or the sterically hindered 2,6-di-tert-butyl-methylphenol
yielded no product and no enantioselective product,
respectively. In the former case, insoluble brown precipitation
was quickly generated, likely due to the formation of sulfide
b
c
entry
R1
yield (%)
ee (%)
1
2
3
4
5
−CH (3a)
64 (4)
64 (4)
78 (4)
68 (4)
35
20
25
49
13
3
24
−C H (3b)
adduct by photoinitiated radical reaction of thiols. Presum-
ably with an achiral sacrificial proton donor that lacks hydrogen
2
5
−CH(CH ) (3c)
3
2
−C H (3d)
bonding and has the appropriate pK to regenerate the ESPT
6
5
a
d
(trimethylsiloxy)indene (3e)
80 (5 )
dye but not protonate substrate, enantioselective ESPT catalysis
could be realized.
a
All of the reactions were carried out with 1 mM of the substrates and
mM of 2b for 2 h. Yield of the product was calculated by H NMR
using triphenylmethane as the internal reference. Determined by
HPLC (OD chiral column, Flow rate 1 mL/min, hexane/isopropanol
b
1
1
In summary we have introduced a new strategy to
enantioselectively protonate prochiral substrates using excited
state proton transfer from a chiral dye. The reaction is effective
with a range of silyl enol ethers and can also be achieved with
visible light upon the addition of triplet sensitizer. The low ee
of the protonated product is due to the racemization of the
ESPT dye in the excited state as indicated by circular dichroism.
The development of new enantiopure ESPT dyes that cannot
photoisomerize will likely improve the ee and increase the
utility of enantioselective ESPT in organic synthesis.
c
d
=
99:1). 2-Methyl-1-indanone.
yield. However, we observe a >30% decrease in ee as the steric
bulk is increased from methyl to ethyl and isopropyl groups.
The highest ee we report here, 49%, was achieved with a
triphenylsilyl group. Interestingly, with 2-methyl-3-(trimethyl-
siloxy)indene we observe the highest reaction yield (80%; 74%
isolated yield) but the lowest ee (13%).
In accord with our previous work, enantioselective ESPT can
also be achieved under visible light by using the appropriate
triplet sensitizer molecule and the unsubstituted ESPT dye by
triplet energy transfer (TET) (Figure 3). Irradiating a mixture
ASSOCIATED CONTENT
Supporting Information
■
*
S
UV spectra of all ESPT dyes, CD spectra (PDF)
AUTHOR INFORMATION
■
*
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Authors are grateful to the American Chemical Society
Petroleum Research Fund (54435-DNI4) for financial support.
■
Figure 3. Sensitized enantioselective proton transfer under visible light
(445 nm). SENS = Bis(4,6-difluorophenylpyridine) (picolinate)-
iridium(III).
REFERENCES
■
of substrate (1 mM), VANOL (2a, 1 mM), and bis(4,6-
difluorophenyl-pyridine)(picolinate)iridium(III) (SENS, 0.05
mM) in 0.5 mL of toluene with 445 nm light gave (R)-2-
phenylcyclohexanone in 68% yield and 25% ee. The same
reaction with (S)-VANOL yielded (S)-2-phenylcyclohexanone
in similar yield and ee. It is worth emphasizing that the
sensitized reactions are achieved using the nonbrominated
ESPT dye since the triplet state is generated on the sensitizer
and then transferred to the dye.
(
5
1) Halpern, J.; Trost, B. M. Proc. Natl. Acad. Sci. U. S. A. 2004, 101,
347.
2) Schultz, D. M.; Yoon, T. P. Science 2014, 343, 1239176.
3) Brimioulle, R.; Lenhart, D.; Maturi, M. M.; Bach, T. Angew.
Chem., Int. Ed. 2015, 54, 3872−3890.
(4) (a) Neumann, M.; Fuldner, S.; Konig, B.; Zeitler, K. Angew.
(
(
̈
̈
Chem., Int. Ed. 2011, 50, 951−954. (b) Zou, Y.-Q.; Chen, J.-R.; Liu, X.-
P.; Lu, L.-Q.; Davis, R. L.; Jørgensen, K. A.; Xiao, W.-J. Angew. Chem.,
Int. Ed. 2012, 51, 784−788. (c) Tucker, J. W.; Zhang, Y.; Jamison, T.
F.; Stephenson, C. R. J. Angew. Chem., Int. Ed. 2012, 51, 4144−4147.
Initial attempts to realize enantioselective ESPT catalysis
have been unsuccessful. In our previous report ESPT catalysis
was demonstrated with phenol as the sacrificial proton source
to regenerate 7-bromo-2-naphthol (1 mol % relative to
(
d) Du, J.; Skubi, K. L.; Schultz, D. M.; Yoon, T. P. Science 2014, 344,
3
5
2
92−396. (e) Cismesia, M. A.; Yoon, T. P. Chem. Sci. 2015, 6, 5426−
434. (f) Hurtley, A. E.; Lu, Z.; Yoon, T. P. Angew. Chem., Int. Ed.
014, 53, 8991−8994. (g) Zhang, P.; Le, C. C.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2016, 138, 8084−8087. (h) Shaw, M. H.; Shurtleff, V.
W.; Terrett, J. A.; Cuthbertson, J. D.; MacMillan, D. W. C. Science
2016, 352, 1304.
8
substrate) after the proton transfer event. Similar catalytic
protonation of substrate by 2b in the presence of phenol was
observed, but the reaction was not enantioselective. Our
C
Org. Lett. XXXX, XXX, XXX−XXX