Studies on the enantioselective catalysis of photochemically promoted transformations: "Sensitizing receptors" as chiral catalysts

Article abstract of DOI:10.1021/jo020630e

A strategy for the enantioselective catalysis of photomediated reactions in solution is described, involving the use of chiral molecular receptors possessing appendant triplet-sensitizing moieties. Energy transfer is selectively directed to bound substrate as a consequence of the distance dependence of triplet-triplet energy transfer. This effect, which is equivalent to a binding-induced rate enhancement, enables substoichiometric chirality transfer from the receptor template to the substrate, as observed in the intramolecular enone-olefin photo [2 + 2]cycloaddition of a quinolone substrate.

Full text of DOI:10.1021/jo020630e

Stu d ies on th e En a n tioselective Ca ta lysis of P h otoch em ica lly
P r om oted Tr a n sfor m a tion s: “Sen sitizin g Recep tor s” a s Ch ir a l
Ca ta lysts
David F. Cauble, Vincent Lynch, and Michael J . Krische*
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712
mkrische@mail.utexas.edu
Received October 1, 2002
A strategy for the enantioselective catalysis of photomediated reactions in solution is described,
involving the use of chiral molecular receptors possessing appendant triplet-sensitizing moieties.
Energy transfer is selectively directed to bound substrate as a consequence of the distance
dependence of triplet-triplet energy transfer. This effect, which is equivalent to a binding-induced
rate enhancement, enables substoichiometric chirality transfer from the receptor template to the
substrate, as observed in the intramolecular enone-olefin photo[2 + 2]cycloaddition of a quinolone
substrate.
In tr od u ction
covalent chiral auxiliaries” for enantioselective photo[2
+ 2]cycloadditions.8
The use of asymmetric media (e.g., chiral solvents,9
chiral liquid crystalline phases,10 and chiral polymer
matrixes11) embodies another approach to stoichiometric
chirality transfer in photomediated transformations.12
However, in contrast to photochemical reactions that take
place in the well-defined chiral microenvironment of non-
centrosymmetric crystal lattices13 and synthetic host-
Many important classes of chemical transformations
exist for which catalytic enantioselective variants do not
exist or have not been optimally developed. Photocyclo-
additions represent a powerful means of stereogenic C-C
and C-O bond formation that have found extensive use
in synthesis,1 yet generally effective strategies for cata-
lytic asymmetric induction in photochemically mediated
transformations are largely undeveloped.2 Thus far,
methods affording useful enantiomeric excess have been
restricted to stoichiometric chirality transfer from pre-
existing stereocenters in the substrate3 and the use of
chiral auxiliaries4 (i.e., diastereoselection), solid-state
photochemical transformations5 including clathrates,6
and unimolecular photochemical reactions in chirally
modified zeolites.7 Most recently, chiral molecular recep-
tors have been shown to serve as highly effective “non-
(5) For selected examples of enantioselective solid-state photochem-
istry, see: (a) Takahashi, M.; Sekine, N.; Fujita, T.; Watanabe, S.;
Yamaguchi, K.; Sakamoto, M. J . Am. Chem. Soc. 1998, 120, 12770.
(b) Leibovitch, M.; Olovsson, G.; Scheffer, J . R.; Trotter, J . J . Am. Chem.
Soc. 1997, 119, 1462. (c) Leibovitch, M.; Olovsson, G.; Scheffer, J . R.;
Trotter, J . Pure Appl. Chem. 1997, 69, 815. (d) Gamlin, J . N.; J ones,
R.; Leibovitch, M.; Patrick, B.; Scheffer, J . R.; Trotter, J . Acc. Chem.
Res. 1996, 29, 203.
(6) For selected examples of enantioselective photochemistry in
clathrates, see: (a) Toda, F.; Miyamoto, H.; Tamashima, T.; Kondo,
M.; Ohashi, Y. J . Org. Chem. 1999, 64, 2690. (b) Toda, F. Acc. Chem.
Res. 1995, 28, 480.
(7) For selected examples of enantioselective photochemistry in
zeolites, see: (a) Sen, S. E.; Smith, S. M.; Sullivan, K. A. Tetrahedron
1999, 55, 12657. (b) J oy, A.; Scheffer, J . R.; Corbin, D. R.; Ramamurthy,
V. J . Chem. Soc., Chem. Commun. 1998, 1379. (c) J oy, A.; Robbins, R.
J .; Pitchumani, K.; Ramamurthy, V. Tetrahedron Lett. 1997, 38, 8825.
(d) Kaprinidis, N. A.; Landis, M. S.; Turro, N. J . Tetrahedron Lett. 1997,
38, 2609.
* To whom correspondence should be addressed. Tel: (512) 232-
5892. Fax: (512) 471-8696.
(1) For selected reviews on photochemistry in natural product
synthesis, see: (a) Bach, T. Synthesis 1998, 683. (b) Winkler, J . D.;
Bowen, C. M.; Liotta, F. Chem. Rev. 1995, 95, 2003. (c) Crimmins, M.
T. Chem. Rev. 1988, 88, 1453. (d) Demuth, M. Pure Appl. Chem. 1986,
58, 1233.
(2) For selected reviews on enantioselective photochemistry and
solution-state asymmetric photochemistry, see: (a) Inoue, Y. Chem. Rev.
1992, 92, 741. (b) Rao, H. Chem. Rev. 1983, 83, 535.
(3) For selected examples of diastereoselective photochemical trans-
formations, see: (a) Crimmins, M. T.; Wang, Z.; McKerlie, L. A. J . Am.
Chem. Soc. 1998, 120, 1747. (b) Alibes, R.; Bourdelande, J . L.; Font,
J .; Gregori, A.; Parella, T. Tetrahedron 1996, 52, 1267. (c) Alibes, R.;
Bourdelande, J . L.; Font, J .; Parella, T. Tetrahedron 1996, 52, 1279.
(d) Carreira, E. M.; Hastings, C. A.; Shepard, M. S.; Yerkey, L. A.;
Millward, D. B. J . Am. Chem. Soc. 1994, 116, 6622. (e) Organ, M. G.;
Froese, R. D.; Goddard, J . D.; Taylor, N. J .; Lange, G. L. J . Am. Chem.
Soc. 1994, 116, 3312.
(4) For representative examples of chiral auxiliaries in photochemi-
cal transformations, see: (a) Dussault, P. H.; Han, Q.; Sloss, D. G.;
Symonsbergen, D. J . Tetrahedron 1999, 55, 11437. (b) Bertrand, S.;
Hoffman, N.; Pete, J .-P. Tetrahedron 1998, 54, 4873. (c) Yamaguchi,
T.; Uchida, K.; Irie, M. J . Am. Chem. Soc. 1997, 119, 6066. (d) Faure,
S.; Piva-Le Blanc, S.; Piva, O.; Pete, J .-P. Tetrahedron Lett. 1997, 38,
1045.
(8) Bach, T.; Bergmann, H.; Grosch, B.; Harms, K. J . Am. Chem.
Soc. 2002, 124, 7982 and references therein.
(9) For selected examples of photochemical reactions in chiral
solvents, see: (a) Boyd, D. R.; Campbell, R. M.; Coulter, P. B.;
Grimshaw, J .; Neill, D. C.; J ennings, W. B. J . Chem. Soc., Perkin Trans.
1 1985, 849. (b) Seebach, D.; Oei, H.-A.; Daum, H. Chem. Ber. 1977,
110, 2316. (c) Brittain, H. G.; Richardson, F. S. J . Phys. Chem. 1976,
80, 2590. (d) Seebach, D.; Oei, H. A. Angew. Chem., Int. Ed. Engl. 1975,
14, 629-636. (e) Seebach, D.; Daum, H. J . Am. Chem. Soc. 1971, 93,
2795.
(10) For selected examples of photochemical reactions in chiral liquid
crystals, see: (a) Finzi, L.; Maccagnani, G.; Masiero, S.; Samori, B.;
Zani, P. Liq. Cryst. 1989, 6, 199. (b) Hilbert, M.; Solladie, G. J . Org.
Chem. 1980, 45, 5393. (c) Eskanazi, C.; Nicoud, J . F.; Kagan, H. B. J .
Org. Chem. 1979, 44, 995-999. (d) Nakazaki, M.; Yamamoto, K.;
Fujiwara, K.; Maeda, M. J . Chem. Soc., Chem. Commun. 1979, 1086.
(e) Nakazaki, M.; Yamamoto, K.; Fujiwara, K.; Chem. Lett. 1978, 863.
(11) For selected examples of photochemical reactions in chiral
polymer matrixes, see: Tazuke, S.; Miyamoto, Y.; Ikeda, T.; Tachibana,
K. Chem. Lett. 1986, 953.
10.1021/jo020630e CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/20/2002
J . Org. Chem. 2003, 68, 15-21
15

Cauble et al.
SCHEME 1. (Left) Syn th esis of Ch ir a l P h otoca ta lyst 6; (Righ t) X-r a y Cr ysta l Str u ctu r e of
(R,S)-Ma n d ela m id e 2
SCHEME 2. P r op osed Ca ta lytic Cycle
guest complexes,8 the “loose” asymmetric environment
of chiral solvents and liquid crystals confers low levels
of enantioselection.
Methods for substoichiometric chirality transfer have
met with limited success. The use of circularly polarized
lasers, i.e., so-called absolute asymmetric synthesis, gives
disappointing enantiomeric enrichments.14 Chiral pho-
tosensitizers provide modest enantiomeric enrichments
for a limited range of substrates.15 The asymmetric
protonation of dienols generated via photodeconjugation
of γ,γ-disubstituted enones or enoates in the presence of
substoichiometric amounts of chiral amino alcohols pro-
ceeds with synthetically useful enantioinduction.16 For
this process, enantiodiscrimination does not occur in the
excited state but in the tautomerization of the photo-
chemically produced ground-state dienol.
Discu ssion
tive approach to the enantioselective catalysis of pho-
tomediated transformations in solution will require that
(1) the substrate be placed in a well-defined chiral
microenvironment upon binding to the template and (2)
substrate-template binding confers a kinetic advantage
to the transformation of interest. In principle, chiral
molecular receptors that incorporate triplet-sensitizing
residues meet these requirements.
With regard to the former requirement, the high levels
of asymmetric induction observed for solution state
photo[2 + 2]cycloadditions in synthetic host-guest sys-
tems strongly suggest that cycloaddition proceeds in a
well-defined chiral microenvironment.8 Here, hydrogen-
bond formation dictates the orientation of the substrate
with respect to the chiral receptor template in a distinct
and predictable fashion. In general, the use of H-bond
interactions as stereochemical control elements in pho-
tochemical cycloadditions is well precedented.17
Design a n d Syn th esis of P h otoca ta lyst 6. As for
any catalytic enantioselective process, a generally effec-
(12) For selected reviews on photochemistry in organized media,
see: (a) Weiss, R. G. Photochemistry in Organized and Constrained
Media; Ramamurthy, V., Ed.; VCH Publishers: New York, 1991;
Chapter 14. (b) Ganapathy, S.; Weiss, R. G. Organic Phototransfor-
mations in Nonhomogeneous Media; Fox, M. A., Ed., American Chemi-
cal Society: Washington, DC, 1985; Chapter 10.
(13) Obata, T.; Tetsuro, S.; Yasutake, M.; Shinmyozu, T.; Kawami-
nami, M.; Yoshida, R.; Somekawa, K. Tetrahedron 2001, 57, 1531 and
references therein.
(14) For selected examples of enantioselective photochemistry via
circularly polarized lasers, see: (a) Feringa, B. L.; van Delden, R. A.
Angew. Chem., Int. Ed. 1999, 38, 3418. (b) Salam, A.; Meath, W. J . J .
Chem. Phys. 1997, 106, 7865. (c) Salam, A.; Meath, W. J . Chem. Phys.
Lett. 1997, 277, 199. (d) Shimizu, Y. J . Chem. Soc., Perkin Trans. 1
1997, 1275. (e) Moradpour, A.; Kagan, H.; Baes, M.; Morren, G.;
Martin, R. H. Tetrahedron 1975, 31, 2139.
(15) For selected examples of enantioselective photochemistry via
chiral photosensitizers, see: (a) Asaoka, S.; Kitazawa, T.; Wada, T.;
Inoue, Y. J . Am. Chem. Soc. 1999, 121, 8486. (b) Inoue, Y.; Matsushima,
E.; Takehiko, W. J . Am. Chem. Soc. 1998, 120, 10687. (c) Inoue, Y.;
Tsuneishi, H.; Hakushi, T.; Tai, A. J . Am. Chem. Soc. 1997, 119, 472.
(d) Inoue, Y.; Yamasaki, N.; Yokoyama, T.; Tai, A. J . Org. Chem. 1993,
58, 1011. (e) Inoue, Y.; Yamasaki, N.; Yokoyama, T.; Tai, A. J . Org.
Chem. 1992, 57, 1332. (f) Inoue, Y.; Yokoyama, T.; Yamasaki, N.; Tai,
A. J . Am. Chem. Soc. 1989, 111, 6480.
The latter requirement is met through the incorpora-
tion of a triplet-sensitizing moiety. Here, the triplet
lifetime of the sensitizer, in relation to the rates of
diffusion and sensitization, defines a highly localized
sphere of sensitization whereby energy transfer occurs
via intermediacy of a triplet exciplex.18 The stringent
(16) For asymmetric photodeconjugation, see: (a) Piva, O.; Morteza-
ei, R.; Henin, F.; Muzart, J .: Pete, J .-P. J . Am. Chem. Soc. 1990, 112,
9263. (b) Piva, O.; Pete, J .-P. Tetrahedron Lett. 1990, 31, 5157. (c) Pete,
J .-P.; Heinin, F.; Mortezaei, R.; Muzart, J .; Piva, O. Pure Appl. Chem.
1986, 58, 1257.
(17) Crimmens, M. T.; Choy, A. L. J . Am. Chem. Soc. 1997, 119,
10237 and references therein.
16 J . Org. Chem., Vol. 68, No. 1, 2003

“Sensitizing Receptors” as Chiral Catalysts
SCHEME 3. Ir r a d ia tion of Qu in olon e 7 in th e P r esen ce a n d Absen ce of Selected Exogen ou s
Ch r om op h or esa
a
Conditions: [7] ) 0.075 M, [additive] ) 0.15 M. Irradiations were performed in CDCl3 for 15 min using a medium-pressure Hg vapor
lamp.
distance dependence of energy transfer is equivalent to
a binding-induced rate enhancement, i.e., excitation of
bound substrate should be favored over excitation of
exogenous, untemplated substrate. If the lifetime of the
exciplex is comparable to the rate of cyclization, exciplex
formation can be enantiodiscriminating.
in the form of the 6:8 complex. Finally, dissociation of
cycloadduct 8 regenerates the uncomplexed receptor 6
to complete the cycle. Efficient templating of the cyclo-
addition will require the sensitized reaction to be fast
relative to the unsensitized process. To suppress the
background reaction of untemplated substrate, the sub-
strate-product exchange equilibrium (6:8 + 7 / 6:7 + 8)
should be fast, yet the cycloaddition of the templated
substrate should be faster than the substrate off-rate
(Scheme 2).
To establish the capability of receptor 6 to mediate
energy transfer and to assess the sensitivity of the
cycloaddition with respect to the presence of exogenous
donor/acceptor chromophores, parallel experiments were
conducted in which quinolone 7 was irradiated in the
presence and absence of selected additives. Irradiation
of 7 in the absence of an exogenous chromophore for 15
min results in 6% conversion. When 7 is irradiated in
the presence of sensitizing (benzophenone, triplet energy
) 69 kcal/mol) or quenching (naphthalene, triplet energy
) 61 kcal/mol) chromophores, 58% conversion and trace
conversion is observed, respectively.21 Finally, when 7 is
irradiated in the presence of sensitizing receptor 6 and
quenching receptor 9, which incorporate benzophenone
and naphthalene residues, respectively, 33% and 0%
conversions are observed. The expectation that sensitiza-
tion and quenching efficiencies should be augmented in
virtue of bringing the donor/acceptor chromophores to-
gether in the form of the 6:7 and 9:7 complexes is borne
out for the irradiation performed in the presence of 9.
However, irradiation of quinolone 7 in the presence of
sensitizing receptor 6 resulted in conversions lower than
those observed in the irradiation of 7 in the presence of
benzophenone (Scheme 3).
Predicated on this simple analysis, “sensitizing recep-
tor” 6 is proposed. The binding motif embodied by 6
derives from structurally related carboxylic acid recep-
tors.19 The proposed substrate, 4-butenyloxy-2-quinolone
7, embodies an identical array of H-bond donor-acceptor
sites with respect to carboxylic acid guests and under-
goes quantitative photo[2 + 2]cycloaddition, making it a
suitable test substrate. A binding-induced rate enhance-
ment is engineered by equipping receptor 6 with a triplet-
sensitizing moiety in the form of a benzophenone residue.
Although modeling of the host-guest complex indicates
this first generation receptor 6 does not optimally obscure
an enantiotopic π-face of the bound quinolone, exception-
ally high levels enantiofacial bias are not necessary to
illustrate proof of concept (vide supra).
The synthesis of receptor 6 is straightforward and
involves the modular introduction of sensitizing and
binding residues via amide bond formation. The sensitiz-
ing moiety, optically pure 4-(1-aminoethyl)-benzophenone
3, is prepared from 4-ethyl-benzophenone 1 as outlined
in Scheme 1. Resolution of racemic 3 is achieved through
conversion to the (R)-mandelic acid amide, followed by
chromatographic separation of the diastereomers and
subsequent amide hydrolysis. Coupling of the resolved
sensitizing amine fragment to the indicated monoamide
monoacid 5 provides the sensitizing receptor 6 (Scheme
1).
P r op osed Ca ta lytic Mech a n ism : Recep tor -Di-
r ected En er gy Tr a n sfer . The proposed catalytic cycle
is depicted in Scheme 2. Receptor 6 binds quinolone 7 to
give the complex 6:7. Energy transfer should be directed
to the bound quinolone 7 owing to the distance depen-
dence of energy transfer.20 Thus, cycloaddition should
occur in the chiral microenvironment of the 6:7 host-
guest complex to yield optically enriched cycloadduct 8
The fact that irradiation in the presence benzophenone
induced higher levels of conversion than irradiation in
the presence of sensitizing receptor 6 suggests the
receptor scaffold contains a weakly quenching chro-
mophore. Indeed, control experiments involving irradia-
tion of quinolone 7 in the presence of structural subunits
of receptor 6 reveal that the iso-phthaloyl moiety inhibits
the cycloaddition (Scheme 4). The presence of a weakly
quenching chromophore in the receptor 6 scaffold proves
to be advantageous as it provides an innocuous means of
dissipating excitation energy when the receptor 6 binding
site is unoccupied or nonproductively occupied by product
(18) Corey, E. J .; Bass, J . D.; LeMahieu, R.; Mitra, R. B. J . Am.
Chem. Soc. 1964, 86, 5570.
(19) Bilz, A.; Stork, T.; Helmchen, G.; Tetrahedron: Asymmetry
1997, 24, 3999.
(20) See: Turro, N. Comparison of the Theoretical Distance De-
pendencies of Energy-Transfer Rates and Efficiencies. In Modern
Molecular Photochemistry; University Science Books: Sausalito, 1991;
pp 319-321.
(21) See: Birks, J . Photophysics of Aromatic Molecules; J ohn
Wiley: New York, 1970.
J . Org. Chem, Vol. 68, No. 1, 2003 17

Cauble et al.
SCHEME 4. Id en tifica tion of Qu en ch in g Ch r om op h or e in th e Recep tor 6 Sca ffold a
a
Conditions: [7] ) 0.075 M, [additive] ) 0.15 M. Irradiations were performed in CDCl3 for 15 min using a medium-pressure Hg vapor
lamp.
TABLE 1. P h otocycloa d d ition in th e P r esen ce of
Va r ia ble Qu a n tities of P h otoca ta lyst 6a
entry 10 (mol %) temp (°C) time (h) conversion (%)b ee (%)c
1
2
3
4
5
6
200
200
200
100
50
30
-20
-70
-70
-70
-70
8
12
24
30
40
70
100
100
100
100
100
100
0
8
21
22
20
19
F IGURE 1. Stoichiometry determination.
25
a
Conditions: [7] ) 0.075 M, [additive] ) 0.15 M. Irradiations
were performed in CDCl3 for 15 min using a medium-pressure Hg
b
1
vapor lamp. Reactions were periodically monitored by H NMR,
which enabled a determination of the percent conversion. The
formation of byproducts was not observed by 1H NMR. c Enantio-
meric excess was determined by chiral stationary phase HPLC
analysis using a Chiracel OD column.
the following concentration and stoichiometry: [6] ) 0.15
M, [7] ) 0.075 M. Within this concentration range, the
dimeric association of quinolone 7 was undetectable via
1H NMR titration in room-temperature CDCl3.
En a n tioselective Ca ta lytic P h otocycloa d d ition .
The stage was now set for proof-of-principle experiments.
Irradiation of quinolone 7 in the presence of 2 equiv of
sensitizing receptor 6 at ambient temperature gave
quantitative conversion to 8 but without any detectable
asymmetric induction (Table 1, entry 1). However, for
reactions conducted at successively reduced tempera-
tures, enantiodifferentiation became increasing apparent.
Specifically, at -20 and -70 °C, quantitative conversion
to 8 occurred in 8% and 21% enantiomeric excess,
respectively. Notably, the time required for complete
conversion of 8 increases as the rate of intermolecular
exchange decreases in response to temperature. For a
catalytic asymmetric process, the degree of asymmetric
induction observed at -70 °C should persist upon suc-
cessively reduced loadings of sensitizing receptor 6.
Indeed, reactions performed at -70 °C involving the use
of equimolar quantities of sensitizing receptor 6 and
quinolone 7 gave quantitative conversion to 8 with 21%
enantiomeric excess. Similarly, for substoichiometric
loadings of sensitizing receptor 6, 0.5 equiv and 0.25
equiv, quantitative conversion to 8 occurred in 20% and
19% enantiomeric excess, respectively.
F IGURE 2. 1H NMR titration plot.
8, i.e., energy is transferred to the iso-phthaloyl residue
rather than to exogenous untemplated substrate, which
would enhance the rate of the background reaction.
Ch a r a cter iza tion of Host-Gu est Bin d in g In ter -
a ction s. Confirmation of the anticipated 1:1 binding
stoichiometry was obtained by applying J ob’s method of
continuous variation to NMR results for species in rapid
exchange (Figure 1).22 An association constant for the
1
formation of the 6:7 complex was determined via H NMR
titration experiments (log Ka ) 2.5 ( 0.2 at 23 °C in
CDCl3) (Figure 2).23 On the basis of the calculated Ka
value, complex formation should be quantitative under
(22) Blanda, M. T.; Horner, J . H.; Newcomb, M. J . Org. Chem. 1989,
54, 4626.
(23) CHEM-EQUILI is a computer program for the calculation of
equilibrium constant and related values from many types of experi-
mental data (IR, NMR, UV-vis, and fluorescence spectrophotometry,
potentiometry, calorimetry, conductometry, etc.). It is possible to use
any combination of such kinds of methods simultaneously for reliable
calculations of equilibrium constants. For a detailed description, see:
(a) Solov’ev, V. P.; Vnuk, E. A.; Strakhova, N. N.; Raevsky, O. A.
Thermodynamic of Complexation of the Macrocyclic Polyethers with
Salts of Alkali and Alkaline-Earth Metals; VINTI: Moscow, 1991. (b)
Solov’ev, V. P.; Baulin, V. W.; Strakhova, N. N.; Kazachenko, V. P.;
Belsky, V. K.; Varnek, A. A.; Volkova, T. A.; Wipff, G. J . Chem. Soc.,
Perkin Trans. 2 1998, 1489.
The persistence of the observed 20% enantiomeric
excess across a range of receptor stoichiometries strongly
suggests that the observed level of asymmetric induction
results from the intrinsic enantiofacial bias conferred by
18 J . Org. Chem., Vol. 68, No. 1, 2003

“Sensitizing Receptors” as Chiral Catalysts
SCHEME 5. Con tr ol Exp er im en t In volvin g Ir r a d ia tion of Qu in olon e 7 in th e P r esen ce of Recep tor 6a ,b
a
Conditions: [7] ) 0.075 M, [additive] ) 0.15 M. Irradiations were performed in CDCl3 for 15 min using a medium-pressure Hg vapor
lamp. bEnantiomeric excess was determined by chiral stationary phase HPLC analysis using a Chiracel OD column.
visualized under UV light. Flash chromatography was per-
formed on silica gel 60 (200-400 mesh). 1H NMR spectra were
obtained at either 300 or 400 MHz, as indicated. 13C NMR
spectra were obtained at 75 MHz. Melting points were
obtained in open capillaries and are uncorrected. Enantiomeric
purity of sensitizing amines (R)-3 and (S)-3 was determined
via chiral stationary phase HPLC.
the association of quinolone 7 to the sensitizing receptor
6. To support this contention, a control experiment was
performed. Irradiation of quinolone 7 was carried out
under conditions identical to those described in Table 1
but in the presence of sensitizer 12 for which the binding
site has been deleted. Quantitative conversion to cycload-
duct 8 was observed, but without any detectable asym-
metric induction. Collectively, these and the aforemen-
tioned results establish substoichiometric chirality transfer
from a receptor template to the prochiral substrate
(Scheme 5).
4-(1-Br om oeth yl)-ben zop h en on e. 4-Ethylbenzophenone
1 (15.0 g, 71.36 mmol, 100 mol %) and N-bromosuccinimide
(16.52 g, 92.81 mmol, 130 mol %) were combined in CCl4 (350
mL). To this solution was added benzoyl peroxide (180 mg,
0.72 mmol, 1 mol %), and the reaction mixture was heated at
reflux for 12 h. After reflux, the solution was cooled to 0 °C,
and the solid precipitate was filtered. The filtrate was washed
with 1 M aqueous Na2CO3, saturated aqueous NaS2O3, and
brine. The organic layer was dried (Na2SO4), filtered, and
evaporated, and the residue was purified via column chroma-
tography (SiO2, 0 f 2.5% ethyl acetate-hexane) to provide
4-(1-bromoethyl)-benzophenone as a red oil (15.4 g, 53.3 mmol)
Con clu sion a n d Ou tlook
While the use of transition metal templates in conjunc-
tion with chiral ligands has proven successful for myriad
reaction types,24 application of this approach to photo-
chemical reactions is complicated by two factors: (1) most
metals possess intense charge transfer bands in the
spectral region of interest for organic photochemistry, and
(2) photochemically promoted ligand loss is often a
consequence of such absorptions, which disrupts the
chiral microenvironment of the metal template at the
crucial moment of bond formation. As supported by the
collective results reported herein, a potentially general
strategy for the enantioselective catalysis of photomedi-
ated transformations involves the use of molecular recep-
tors equipped with appendant chiral sensitizing moieties.
Future studies will focus on the development and opti-
mization of receptor-sensitizer templates that confer
heightened levels of enantiodiscrimination.
1
in 74% yield. H NMR (400 MHz, CDCl3): δ 2.06 (d, J ) 7.2
Hz, 3H), 5.21 (q, J ) 6.8 Hz, 1H), 7.43-7.58 (m, 5H), 7.74-
7.78 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 26.80, 48.19, 76.68,
70.00, 77.31, 126.28, 127.81, 129.45, 129.94, 132.00, 136.74,
136.76, 146.77. HRMS: calcd [M + 1] for C15H13OBr, 289.0228;
found, 289.0233. FTIR (film): 3019, 2400, 1659, 1608, 1278,
1216, 762, 702, 669, 420 cm-1
.
4-(1-Azid oeth yl)-ben zop h en on e. To a solution of 4-(1-
bromoethyl)-benzophenone (14.24 g, 49.24 mmol, 100 mol %)
in DMF (100 mL) was added NaN3 (9.6 g, 147.7 mmol, 300
mol %). The reaction mixture was stirred at ambient temper-
ature for 11 h and then partitioned between H2O and Et2O.
The aqueous layer was washed with Et2O, and the combined
organic fractions were washed with brine, dried (Na2SO4),
filtered, and concentrated in vacuo to yield the title compound
as a yellow oil (11.9 g, 47.4 mmol) in 96% yield. The title
compound was used without further purification. 1H NMR (400
MHz, CDCl3): δ 1.54 (d, J ) 6.8 Hz, 3H), 4.67 (q, J ) 6.8 Hz,
1H), 7.39-7.45 (m, 4H), 7.51-7.55 (m, 1H), 7.74-7.79 (m, 4H).
13C NMR (75 MHz, CDCl3): δ 21.80, 60.49, 76.67, 77.00, 77.32,
125.66, 127.72, 129.36, 129.93, 131.88, 136.55, 136.73, 144.71.
Exp er im en ta l Section
Gen er al. Tetrahydrofuran (THF) was distilled from sodium-
benzophenone ketyl prior to use. Dichloromethane was dis-
tilled from P2O5 when used as reaction media. All reactions
were performed under Ar atmosphere unless otherwise noted.
Literature procedures were used for the preparations of
quinolone substrate 7,25 4-ethylbenzophenone,26 and 2-ami-
nopyridine derivative 10.27 Photocycloaddition product 8 was
HRMS: calcd [M + 1] for
252.1130. FTIR (film): 3059, 2979, 2113, 1662, 1609, 1447,
1412, 1279, 1061, 939, 703, 436 cm-1
C15H13N3O, 252.1137; found,
.
4-(1-Am in oeth yl)-ben zop h en on e. To a solution of 4-(1-
azidoethyl)-benzophenone (11.9 g, 47.36 mmol, 100 mol %) in
THF (400 mL) and H2O (2.5 mL, 142.06 mmol, 300 mol %)
was added triphenylphosphine (18.63 g, 71.03 mmol, 150 mol
%). The reaction mixture was heated at reflux for 20 h and
then concentrated to 20% volume. The reaction mixture was
partitioned between H2O and Et2O, and the organic phase
extracted with three portions of 1 M aqueous HCl. The
combined aqueous washes were neutralized with 2 M aqueous
NaOH and extracted three times with Et2O. The combined
organic layers were washed with brine, dried (Na2SO4), and
then evaporated onto silica gel. Column chromatography (SiO2,
0 f 10% methanol-dichloromethane) afforded 4-(1-amino-
1
characterized by H and 13C NMR, and results were found to
be consistent with those reported in the literature.23 Analytical
TLC was performed on 0.25 mm silica gel 60-F plates and
(24) For an authoritative account, see: Comprehensive Asymmetric
Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Heidelberg, 1999.
(25) Kaneko, C.; Suzuki, T.; Sato, M.; Naito, T. Chem. Pharm. Bull.
1987, 35, 112.
(26) Bachmann, W. E.; Carlson, E., J r.; Moran, J . C. J . Org. Chem.
1948, 13, 916.
(27) Turner, J . A. J . Org. Chem. 1983, 48, 3401.
J . Org. Chem, Vol. 68, No. 1, 2003 19

Cauble et al.
ethyl)-benzophenone as a yellow oil (7.92 g, 35.2 mmol) in
74.2% yield. 1H NMR (400 MHz, CDCl3): δ 1.53 (d, J ) 6.6
Hz, 3H), 1.94 (s, 2H), 4.31 (q, J ) 6.6 Hz, 1H), 7.55-7.61 (m,
4H), 7.66-7.72 (m, 1H), 7.88-7.93 (m, 4H). 13C NMR (75 MHz,
CDCl3): δ 25.31, 50.81, 76.57, 77.00, 77.42, 125.38, 127.92,
129.61, 130.11, 131.97, 135.77, 137.43, 152.24, 195.97.
HRMS: calcd [M + 1] for C15H15NO, 226.1227; found, 226.1232.
FTIR (film): 3370, 3299, 3058, 2965, 2249, 1658, 1607, 1447,
25.55, 28.96, 31.43, 52.25, 68.49, 119.68, 122.61, 131.56,
159.13, 166.08. HRMS: calcd [M + 1] for C16H22O5, 295.1546;
found, 295.1542. FTIR (film): 3054, 2986, 2685, 2305, 1716,
1673, 1628, 1421, 1363, 1265, 1161, 978, 896, 738, 704 cm-1
.
Mp: 52-53 °C.
Meth yl 5-Hexyloxy-N-p yr id in -2-yl-isop h th a la m a te. To
a solution of 2-aminopyridine (1.98 g, 21.02 mmol, 100 mol %)
in THF (125 mL, 0.17 M) at -78 °C was slowly added a
solution of n-butyllithium in hexanes (13.14 mL, 1.6 M, 100
mol %). The solution was allowed to stir for 0.5 h and then
transferred dropwise via cannula into a -78 °C THF solution
(50 mL, 0.85 M) of dimethyl-5-hexyloxyisophthalate (12.37 g,
42.03 mmol, 200 mol %). The reactions mixture was allowed
to stir for 3 h, at which point 150 mL of 1 M aqueous NaHCO3
was carefully added. The reaction mixture was partitioned
between Et2O and H2O, and the aqueous layer was extracted
with Et2O. The combined ethereal layers were washed with
brine, dried (Na2SO4), filtered, and evaporated. The residue
was purified via column chromatography (SiO2, 0 f 40% ethyl
acetate-hexane) to yield the title compound (5.9 g, 16.6 mmol)
1280, 939, 852, 734, 443 cm-1
.
Der iva tiza tion of 4-(1-Am in oeth yl)-ben zop h en on e a s
(R)-Ma n d elic Acid Am id e Dia st er eom er s (R,R)-2 a n d
(R,S)-2. To a 0 °C solution of 4-(1-aminoethyl)-benzophenone
(11.88 g, 52.7 mmol, 100 mol %) and (R)-mandelic acid (8.83
g, 58 mmol, 110 mol %) in DCM (250 mL) was added DCC
(11.97 g, 58 mmol, 110 mol %) and HOBT (710 mg, 5.3 mmol,
10 mol %). The reaction was allowed to stir for 14 h, during
which time it was allowed to reach ambient temperature. The
reaction mixture was filtered, and the filtrate was washed with
first 1 M aqueous Na2CO3, 1 M aqueous H2SO4, and brine.
The organic layer was dried (Na2SO4), filtered, and concen-
trated in vacuo. The residue was purified via column chroma-
tography (SiO2, 20% f 40% ethyl acetate-hexane) to yield the
upper Rf (R,R) diastereomer (7.4 g, 20.6 mmol) in 78% yield
and the lower Rf (R,S) diastereomer (8.2 g, 22.8 mmol) in 87%
1
in 79% yield as a white solid. H NMR (400 MHz, CDCl3): δ
0.89-0.93 (t, J ) 7.1 Hz, 3H), 1.32-1.51 (m, 6H), 1.77-1.84
(quintet, J ) 7.4 Hz, 2H), 4.04-4.08 (t, 6.8 Hz, 2H), 7.13-
7.18 (t, J ) 6.2 Hz, 1H), 7.76 (s, 1H), 7.84-7.89 (m, 2H), 8.21-
8.23 (d, J ) 5.4 Hz, 1H), 8.69-8.72 (d, J ) 7.6 Hz, 1H), 9.05
(s, 1H), 11.54 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.04,
22.61, 25.67, 29.12, 31.56, 68.54, 116.24, 119.02, 119.68,
120.07, 121.51, 132.26, 134.76, 140.27, 144.96, 152.16, 159.43,
165.29, 170.93. HRMS: calcd [M + 1] for C20H24N2O4, 357.1814;
found, 357.1812; FTIR (film) 3054, 2986, 2955, 2873, 2306,
1724, 1683, 1595, 1578, 1518, 1434, 1302, 1265, 1046, 896, 747
cm-1. Mp: 112-114 °C.
1
yield as white solids. Da ta for (R,R)-2. H NMR (400 MHz,
CDCl3): δ 1.39 (d, J ) 6.8 Hz, 3H), 4.55 (d, J ) 4.1 Hz, 1H),
4.87 (d, J ) 4.5 Hz, 1H), 5.00 (qt, J ) 7.2 Hz, 1H), 7.07 (d, J
) 8.2 Hz, 1H), 7.20-7.31 (m, 6H), 7.39-7.43 (m, 2H), 7.51-
7.56 (m, 1H), 7.61-7.70 (m, 4H). 13C NMR (75 MHz, CDCl3):
δ 22.20, 48.66, 73.84, 76.69, 77.00, 77.31, 125.39, 126.15,
127.81, 127.89, 128.11, 129.50, 129.94, 132.04, 135.83, 136.80,
138.95, 147.26, 171.02, 195.60. HRMS: calcd [M + 1] for
C
23H21NO3: 360.1600; found 360.1598. FTIR (film): 3400,
5-Hexyloxy-N-p yr id in -2-yl-isop h th a la m ic Acid 5. To a
solution of methyl 5-hexyloxy-N-pyridin-2-yl-isophthalamate
(510 mg, 1.43 mmol, 100 mol %) in 3:1:1 THF/CH3OH/H2O (7
mL, 0.2 M) was added LiOH monohydrate (90 mg, 2.15 mmol,
150 mol %). The reaction mixture was allowed to stir at room
temperature for 14 h, at which point NH4Cl (115 mg, 2.15
mmol, 150 mol %) was added. The solution was concentrated
to dryness and subjected to silica gel chromatography (SiO2,
0 f 7% CH3OH-CH2Cl2) to yield the title compound (440 mg,
1.28 mmol) in 90% yield as an amorphous white solid. 1H NMR
(400 MHz, DMSO-d6): δ 0.85 (t, J ) 6.8, Hz, 3H), 1.26-1.37
(m, 4H), 1.39-1.40 (m, 2H), 1.68-1.75 (quintet, J ) 7.5 Hz,
2H), 4.05-4.08 (t, 6.2 Hz, 2H), 7.11-7.14 (t, J ) 5.5 Hz, 1H),
7.56 (s, 1H), 7.78-7.82 (m, 2H), 8.12 (s, 1H), 8.17 (d, J ) 8.2
Hz, 1H), 8.35 (d, J ) 3.8 Hz, 1H), 10.95 (s, 1H). 13C NMR (75
MHz, DMSO-d6): δ 13.87, 22.07, 25.13, 28.53, 30.97, 38.67,
38.95, 39.23, 39.50, 39.78, 40.06, 40.34, 68.11, 114.85, 117.76,
118.33, 119.90, 121.28, 132.39, 135.81, 138.09, 147.92, 152.09,
158.63, 165.05, 166.62. HRMS: calcd [M + 1] for C19H22N2O4,
343.1658; found, 343.1661. FTIR (film) 3683, 3614, 3261, 3019,
2958, 2934, 2400, 1672, 1594, 1580, 1470, 1340, 1217, 1045,
929, 750, 669, 419 cm-1. Mp: 204-206 °C.
Sen sitizin g Molecu la r Recep tor 6. To a solution of acid
5 (1.0 g, 2.92 mmol, 100 mol %) and 4-[(1S)-aminoethyl)]-
benzophenone (660 mg, 2.92 mmol, 100 mol %) in CH2Cl2 (15
mL) were added EDC (620 mg, 3.21 mmol, 110 mol %) and
DMAP (36 mg, 0.292 mmol, 10 mol %). The reaction mixture
was stirred at ambient temperature for 14 h, evaporated onto
silica gel, and subjected to column chromatography (SiO2, 15%
f 40% ethyl acetate-hexane) to yield the title compound (1.06
g, 1.9 mmol) in 66% yield as a white solid. 1H NMR (400 MHz,
CDCl3): δ 0.85 (t, J ) 6.5 Hz, 3H), 1.26-1.37 (m, 6H), 1.47 (d,
J ) 6.8 Hz, 3H), 1.68 (qt, J ) 6.8 Hz, 2H), 3.86 (t, J ) 6.5 Hz,
1H), 5.28 (qt, J ) 7.2 Hz, 1H), 6.89-6.92 (m, 1H), 7.24-7.39
(m, 4H), 7.47-7.67 (m, 9H), 7.98-7.07 (m, 2H), 8.21 (d, J )
8.2 Hz, 1H), 9.34 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.42,
21.92, 22.89, 25.90, 29.29, 31.74, 49.61, 68.49, 76.68, 77.00,
77.31, 114.14, 116.22, 116.60, 117.07, 119.60, 125.15, 125.80,
126.87, 128.04, 128.14, 135.09, 135.85, 137.89, 142.44, 147.10,
150.81, 158.94, 164.52, 164.93. HRMS: calcd [M + 1] for
3018, 2401, 1655, 1518, 1279, 1216, 771, 443 cm-1. Mp: 123-
124 °C. [R]22D ) -3.9° (c 1, CHCl3). Da ta for (R,S)-2. 1H NMR
(400 MHz, CDCl3): δ 1.42 (d, J ) 6.8 Hz, 3H), 4.43 (d, J ) 3.8
Hz, 1H), 4.96 (d, J ) 3.4 Hz, 1H), 5.05 (qt, J ) 7.2 Hz, 1H),
7.08 (d, J ) 7.9 Hz, 1H), 7.22-7.30 (m, 6H), 7.40-7.43 (m,
2H), 7.52-7.56 (m, 1H), 7.62-7.70 (m, 4H). 13C NMR (75 MHz,
CDCl3): δ 22.07, 49.54, 74.08, 76.68, 77.00, 77.31, 125.38,
126.18, 127.81, 127.93, 128.14, 129.50, 130.00, 132.02, 135.86,
136.83, 138.95, 147.10, 170.96, 195.56. HRMS: calcd [M + 1]
for C23H21NO3, 360.1600; found, 360.1596; FTIR (film): 3400,
3018, 2401, 1655, 1518, 1279, 1216, 771, 443 cm-1. Mp: 121-
123 °C. [R]22 ) -115.6° (c 1, CHCl3).
D
4-[(1R)-Am in oeth yl]-ben zop h en on e (R)-3: Mandelamide
(R,R)-2 (1.0 g, 2.8 mmol, 100 mol %) was heated at reflux in
20 mL concentrated aqueous HCl for 14 h. The cooled solution
was extracted with Et2O, basified with 3 M aqueous NaOH
and extracted again with Et2O. The combined Et2O layers were
washed with brine, dried (Na2SO4), and concentrated. The
residue was purified via silica gel chromatography (2% f 7%
MeOH-DCM) to yield (R)-3 as a clear oil (0.4 g, 1.78 mmol)
in 64% yield and 99+% ee. [R]22 ) 25.9° (c 1, CHCl3).
D
4-[(1S)-Am in oeth yl]-ben zop h en on e (S)-3. Prepared as
described for (R)-3. [R]22 ) -24.9° (c 1, CHCl3).
D
Dim et h yl-5-h exyloxyisop h t h a la t e. To a DMF solution
(150 mL, 0.42 M) of compound 4 (13.07 g, 62.18 mmol, 100
mol %) was added 1-bromo-hexane (9.82 g, 59.22 mmol, 105
mol %) and K2CO3 (9.82 g, 71.06 mmol, 114 mol %), and the
mixture was heated at 65 °C for 14 h. The reaction mixture
was partitioned between H2O and Et2O. The aqueous layer
was separated and washed with Et2O. Combined organic
layers were washed with 1 M aqueous NaOH and brine, dried
(Na2SO4), filtered, and concentrated in vacuo. The residue
purified via column chromatography (SiO2, 10% ethyl acetate-
hexane) to yield the title compound (16.84 g, 57.2 mmol) in
92% yield as a yellow oil, which crystallized upon standing.
1H NMR (300 MHz, CDCl3): δ 0.88 (t, J ) 6.9 Hz, 3H), 1.29-
1.34 (m, 6H), 1.42-1.47 (quintet, 2H), 1.73-1.80 (quintet, J
) 7.2 Hz, 2H), 3.91 (s, 6H), 4.01 (t, J ) 6.7 Hz, 2H), 7.71 (s,
2H), 8.23 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 13.92, 22.50,
20 J . Org. Chem., Vol. 68, No. 1, 2003

“Sensitizing Receptors” as Chiral Catalysts
C34H36N3O4, 550.2706; found, 550.2726. FTIR (film) 3370, 3299,
3058, 2965, 2249, 2200, 1658, 1607, 1447, 1412, 1308, 1280,
924, 852, 734, 620, 443 cm-1. Mp: 146-147 °C. [R]22D ) +65.0°
(c 1, CHCl3).
496.2607; FTIR (film) 3370, 3299, 3058, 2965, 2249, 2200,
1658, 1607, 1447, 1412, 1308, 1280, 924, 852, 734, 620, 443
cm-1. Mp: 146-147 °C. [R]22 ) -31.1° (c 0.67, CHCl3).
D
Na p h th yl Recep tor 9. To a solution of acid 5 (1.0 g, 2.92
mmol, 100 mol %) and R-(+)-1-(2-naphthyl)ethylamine (850
mg, 3.21 mmol, 110 mol %) in CH2Cl2 (15 mL, 0.2 M) were
added EDC (620 mg, 3.21 mmol, 110 mol %) and DMAP (360
mg, 0.292 mmol, 10 mol %). The reaction mixture was allowed
to stir at ambient temperature for 14 h, at which point the
reaction mixture was evaporated onto silica gel and subjected
to column chromatography (SiO2, 10% f 40% ethyl acetate-
hexane to yield the title compound (0.99 g, 2.0 mmol) in 68%
yield as a waxy white solid. 1H NMR (400 MHz, CDCl3): δ
0.91 (t, J ) 6.8 Hz, 3H), 1.26-1.45 (m, 6H), 1.65 (d, J ) 7.2
Hz, 3H), 1.77 (qt, J ) 7.2 Hz, 2H), 1.94 (s, 1H), 3.98 (t, J ) 6.5
Hz, 1H), 5.45 (qt, J ) 7.2 Hz, 1H), 6.74 (d, J ) 7.9 Hz, 1H),
7.01-7.04 (m, 1H), 7.40-7.53 (m, 5H), 7.68-7.83 (m, 6H), 8.20
(d, J ) 4.1 Hz, 1H), 8.29 (d, J ) 8.6 Hz, 1H), 8.81 (s, 1H). 13C
NMR (75 MHz, CDCl3): δ 14.42, 21.92, 22.89, 25.90, 29.29,
31.74, 49.61, 68.49, 76.68, 77.00, 77.31, 114.14, 116.22, 116.60,
117.07, 119.60, 125.15, 125.80, 126.87, 128.04, 128.14, 135.09,
135.85, 137.89, 142.44, 147.10, 150.81, 158.94, 164.52, 164.93.
Ack n ow led gm en t is made to the Robert A. Welch
Foundation (F-1466), the NSF-CAREER program, the
Herman Frasch Foundation (535-HF02), the NIH (RO1
GM65149-01), donors of the Petroleum Research Fund
administered by the American Chemical Society (34974-
G1), the Eli Lilly Faculty Grantee program, and Re-
search Corporation Cottrell Scholar Award (CS0927) for
partial support of this research.
Note Ad d ed a fter ASAP P ostin g. A revised Table
of Contents graphics was posted on November 22, 2002.
Su p p or tin g In for m a tion Ava ila ble: Spectral data for all
new compounds (1H NMR, 13C NMR, IR, HRMS) and crystal-
lographic data for (R,S)-5. This material is available free of
charge via the Internet at http://pubs.acs.org.
HRMS: calcd [M + 1] for
C
31H33N3O3, 496.2600; found,
J O020630E
J . Org. Chem, Vol. 68, No. 1, 2003 21