Role of cations and confinement in asymmetric photochemistry: Enantio- and diastereo-selective photocyclization of tropolone derivatives within zeolites

Article abstract of DOI:10.1039/b504865f

Asymmetric induction in photochemical reactions has been explored using the photochemistry of tropolones as a model. Three approaches have been examined: chiral inductor, chiral auxiliary and [chiral inductor + chiral auxiliary]. All three methods gave excellent asymmetric induction in zeolite and very little or zero induction in solution. Results presented on tropolones clearly illustrate the remarkable influence that a confined space studded with cations can have on asymmetric induction. Tropolone derivatives, upon irradiation undergo 4π-electron electrocyclization to yield a bicyclic product and a rearranged product. Enantiomeric excess up to 68% has been achieved in the cyclized product. In systems where a chiral inductor has been covalently linked, diastereomeric excess as high as 88% has been achieved within a zeolite while the same system in solution gave 10%. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b504865f

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A R T I C L E
Role of cations and confinement in asymmetric photochemistry:
enantio- and diastereo-selective photocyclization of tropolone
derivatives within zeolites†
Abraham Joy, Lakshmi S. Kaanumalle and V. Ramamurthy*
Department of Chemistry, University of Miami, Coral Gables, FL 33124, USA.
E-mail: murthy1@miami.edu; Fax: 305 284 4571; Tel: 305 284 1534
Received 7th April 2005, Accepted 14th June 2005
First published as an Advance Article on the web 13th July 2005
Asymmetric induction in photochemical reactions has been explored using the photochemistry of tropolones as a
model. Three approaches have been examined: chiral inductor, chiral auxiliary and [chiral inductor + chiral
auxiliary]. All three methods gave excellent asymmetric induction in zeolite and very little or zero induction in
solution. Results presented on tropolones clearly illustrate the remarkable influence that a confined space studded
with cations can have on asymmetric induction. Tropolone derivatives, upon irradiation undergo 4p-electron
electrocyclization to yield a bicyclic product and a rearranged product. Enantiomeric excess up to 68% has been
achieved in the cyclized product. In systems where a chiral inductor has been covalently linked, diastereomeric excess
as high as 88% has been achieved within a zeolite while the same system in solution gave 10%.
studies in solid state more than a ‘black art’.9 In spite of the
Introduction
above studies we believe that there is still room for establishing
The past few decades have brought about an abundance
additional methodologies for chiral induction in photochemical
of methodologies to carry out ground state reactions
reactions. In this context we have explored the use of zeolites
stereoselectively.1,2 At the same time asymmetric photoreactions
as hosts to bring about stronger interaction between a chiral
having not been investigated with the same kind of rigor have
perturber and the reaction site.10 Zeolites offer a confined
witnessed a slower advance.3 Short lifetimes of excited states
medium, which is in between strict solution and solid phases
are insufficient to develop an effective interaction between
for conducting photoreactions of interest. In this medium, the
the substrate and the chiral perturber. Further, the presence
freedom of molecules is (a) reduced compared to solution-
of small or negligible activation barriers in photochemical
increasing selectivity, and (b) enhanced compared to the solid
reactions make them more difficult to manipulate and hence
state-increasing reactivity. Within zeolites even liquid samples
imaginative methods are needed to achieve asymmetric induc-
can be ‘caged’ close to a chiral perturber thus making this
tion in photochemical reactions. Despite all these mitigations,
approach more general than crystals as reaction media.
noteworthy progress has been made in asymmetric photoreac-
In order to establish the value of zeolites as media for
tions in solution during the last two decades with the use of
achieving enantio- and diastereo-selectivity, during a photore-
action we have investigated the photocyclization of 16 a-
tropolone derivatives. The photochemistry of a-tropolone ethers
imaginative methodologies.3 These include studies by Inoue’s
group wherein they have obtained 73% ee at −110 ◦C during
geometric isomerization of cis-cyclooctene by chiral sensitizers.4
has been investigated in solution and organized media and
Using chiral complexing agents, Bach’s group has obtained
the results of these experiments form the basis of the current
remarkable success (ca. 90% ee at −60 ◦C) with several systems.5
investigation.11–19 Upon exposure to UV light, a-tropolone ethers
These include the photoaddition of 2-quinolone to alkenes
undergo a 4p-electron disrotatory electrocyclic ring closure to
yield bicyclo[3.2.0]hepta-3,6-dien-2-ones. As a result of an equal
probability of ‘in’ and ‘out’ cyclizations a racemic product
(98% ee at −60 ◦C), cyclization of 2-pyridones (23% ee at
−20 ◦C), and intramolecular photoaddition of 4-alkenyloxy-2-
quinolones (>90% ee at −60 ◦C). The use of chiral auxiliaries to
mixture is obtained (Scheme 1). Although no chiral induction
achieve excellent diastereoselectivity (100% de intramolecular
has been reported during solution irradiation of tropolones,
cycloaddition) during the photocycloaddition of enones has
significant chiral induction has been reported during the ir-
been masterfully established by Pete and co-workers.6 In spite
radiation of tropolones in the solid state.13–19 Irradiation of a
of these achievements, chiral induction in photoreactions in
solid cyclodextrin complex of tropolone methyl ether gives the
solution is still pursued only by a few laboratories. As opposed
cyclized product in 28% ee.13,17 Remarkably, very high selectivity
to solution photochemistry, solid state chiral induction has been
investigated for over four decades. Starting from the initial
(ca. 90%) has been reported during the irradiation of tropolone
alkyl ethers complexed to organic chiral diol hosts.15 Using
success of Schmidt and co-workers (photodimerization, e.e
an ionic chiral auxiliary approach Scheffer and Wang have
70%),7 several groups have repeatedly shown that near quanti-
reported an ee of 60–80% during the cyclization of tropolone
tative chiral induction could be achieved during photoreactions
derivatives.14 In this report we show that zeolites are able to
in crystalline state. Recent achievements of Scheffer and co-
bias the cyclization towards one of these two modes. The
workers using ionic chiral auxiliaries8 and by Toda and co-
diastereomeric and enantiomeric excesses obtained in this study
workers using chiral hosts have made the chiral induction
† Electronic supplementary information (ESI) available: experimental
details including synthesis, characterization of reactants and char-
acterization of photoproducts; and computational details and co-
ordinates for the geometry optimized structures. See http://dx.doi.org/
10.1039/b504865f
Scheme 1
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 4 5 – 3 0 5 3
3 0 4 5
©

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with the tropolone derivatives within zeolites are far superior to
those obtained in solution. The results discussed below provide
an insight into how a zeolite is able to enforce a close interaction
between a reactant and a chiral perturber.
norephedrine and pseudoephedrine within the cages of the
zeolites. Although a large number of chiral inductors were
tested the best results were obtained only with the above three
inductors and results from these are discussed. The experimental
procedure of including the tropolone derivatives and the chiral
inductor within a zeolite, irradiation procedure, extraction and
analysis conditions are provided in the Experimental section.
The loading level (represented as ꢀSꢁ and defined as the average
number of molecules per supercage)22 of the chiral inductor
was maintained at one molecule in every supercage, while the
loading level of the substrate was kept at one molecule in
every ten supercages. A higher ratio of the chiral inductor was
employed to maximize the chances of the substrate molecule
being adjacent to the chiral inductor within the supercage.
Sample handling was carried out under laboratory conditions
(T = 20 ◦C, humidity 50%). Results of the experiments carried
out with achiral tropolone derivatives are presented in Table 1.
In every one of the examples, irradiation of tropolone derivatives
in NaY adsorbed with the optical antipode of the chiral inductor
led to the opposite enantiomer of the product with nearly the
same ee [cf. (+) and (−) isomers of the same chiral inductor]
suggesting that the systems are well behaved. With all three
systems the ee obtained was dependent upon the nature of
the alkali ion; for example, in the case of 1b with ephedrine
as the chiral inductor, LiY: 22%; NaY: 69%; KY: 11%; RbY: 2%
(Table 2).
The effect of temperature on the reaction was examined by
carrying out the irradiation at various temperatures. In the case
of 1a a decrease in temperature increased the ee whereas in 1b
it had a negligible effect. Thus the effect of temperature upon
chiral induction within zeolites was not clear cut and was not
pursued in detail.23 The remarkable consequence of carrying
out the reaction under anhydrous conditions is seen in Table 1.
Irradiation of 1b in NaY modified with (−)-ephedrine under
dry conditions gave the product in 68% ee whereas irradiation
under wet conditions gave the product in only 17% ee. A similar
dramatic decrease in ee under wet conditions was also observed
with 1a and 1c.
Results
Three sets of experiments have been performed. In the first
one the photochemistry of achiral tropolones within achiral
zeolites in the presence of chiral inductors has been studied. In
the second the photochemistry of chiral tropolones (tropolones
linked with chiral auxiliaries) within achiral zeolites has been
investigated. In the last set, chiral tropolones within achiral
zeolites in the presence of chiral inductors have been subjected
to excited state investigation. The first one is called the ‘chiral
inductor approach’, the second the ‘chiral auxiliary approach’
and the last one the ‘[chiral auxiliary + chiral inductor]
approach’. Our interest is to show the effectiveness of zeolites
in inducing chiral induction during the photocyclization of
tropolone derivatives.20,21 In order to excite only the tropolone
moiety, all the tropolone derivatives were irradiated using a
300 nm filter – this choice of wavelength ensured that no
sensitization was involved during the reaction. The absolute
configuration of the cyclized product was not known. Products
were not crystalline and they could not be easily converted
to crystalline derivatives. Although knowledge of the absolute
configuration of the cyclized product could be very useful in
determining the mechanism of chiral induction, our inability to
obtain this information did not deter us from establishing the
value of the zeolite-based method for achieving chiral induction
in photoreactions. We wish to emphasize that the lack of
information of the absolute configuration of the photo product
does not decrease the value of the results presented below. In
the absence of this knowledge we note the two enantiomeric or
diastereomeric product peaks in GC or HPLC as A and B. The
isomer that eluted first was always assigned as A.
Chiral inductor approach
As a result of the absorption of light, product 2 rearranges
to the isomeric chiral product 3.11,12 To make sure that the
chiral induction in product 2 is not due to the preferential
transformation of one enantiomer of 2 to 3, irradiations of 1b
in NaY/(−)-ephedrine for varying lengths of time were carried
Structures of the three achiral tropolone derivatives examined
in the context of chiral inductor approach are provided in
Scheme 2. The zeolites employed were commercially available
Y samples that are not chiral. The zeolites were rendered
chiral by adsorbing chiral organic molecules such as ephedrine,
Table 2 Cation dependence. Enantiomeric excess (%) obtained in the
photoproducts 2a–c during the irradiation of tropolone derivatives 1a–c
included in various alkali ion exchanged Y zeolites
2a
2b
2c
Medium
(−)-Norephedrine
(+)-Ephedrine (−)-Norephedrine
LiY
NaY
KY
RbY
CsY
15 A
35 A
31 A
40 A
20 A
22 B
69 B
11 B
2 B
20 A
37 A
49 A
30 A
7 B
—
Scheme 2
Table 1 Enantiomeric excess (%) obtained in photoproducts 2a–c during irradiation of tropolone derivatives 1a–ca
Medium
Chiral inductor
2ab
2b (dry)
2b (wet)
2cb
NaY
NaY
NaY
NaY
NaY
NaY
NaY
NaY
(−)-Norephedrine at 22 ◦
(+)-Norephedrine
(−)-Ephedrine
C
35 A
34 B
17 A
—
1 A
50 A
—
38 A
—
68 A
69 B
20 A
—
23 B
—
17 B
—
8 B
—
22 A
37 B
37 A
41 B
—
31 B
28 A
37 A
—
(+)-Ephedrine
(−)-Pseudoephedrine
(−)-Norephedrine at −40 ◦
C
(+)-2-Amino-3-methoxy-1-phenyl-1-propanol
12 B
28 A
(+)-Diethyl tartarate
—
—
a (−)-Borneol and (−)-menthol gave 1–2% ee in 2a. b Dry conditions.
3 0 4 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 4 5 – 3 0 5 3

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out. When the sample was irradiated for 10 min the ee of the
reaction was 78% at which time the ratio of 2b to 3b was 24.1 : 1.
When the sample was irradiated for 45 min the ee did not change
significantly (72%), but the ratio of 2b to 3b changed to 7 : 1.
This demonstrates that the chiral induction in this reaction is a
result of the interaction of the chiral inductor with the substrate
and not due to preferential conversion of one enantiomer of 2
to 3.
The following control experiments established that the enan-
tioselectivities obtained with the achiral tropolone derivatives
1a–c within chirally modified zeolites were not due to experi-
mental artifacts: (a) irradiation of the tropolone derivatives in
Y zeolites that had not been chirally modified yielded a racemic
product mixture; (b) to ensure that one of the enantiomers did
not get preferentially adsorbed within the zeolite the racemic
product mixture was included within NaY modified with a chiral
inductor and then extracted, and no preferential adsorption
was noticed; (c) following irradiations, multiple extractions were
carried out to make sure that one of the enantiomers of the
product did not get preferentially adsorbed within the chirally
modified zeolite.
another approach that we have pursued – the chiral auxiliary
approach – wherein the chiral inductor is covalently attached
to the substrate. Here there is no ambiguity about the location
of the substrate and the chiral source. To examine the viability
of this approach the photochemical behavior of 13 tropolone
derivatives (Scheme 3) covalently linked with a chiral auxiliary
adsorbed within achiral LiY, NaY, KY, RbY and CsY zeolites
was examined. The details of the experiments are outlined in the
Experimental section and the diastereomeric excess (de) values
estimated by HPLC or GC are summarized in Tables 3 and 4. As
representatives of all 13 tropolone derivatives, results obtained
with 4 and 7e are highlighted below. When a chiral auxiliary is
present in an optically pure form two diasteromeric products
are expected. When the optical antipode of the chiral auxiliary
is introduced the enantiomers of the earlier two products should
be formed. Therefore, four signals are theoretically expected and
in fact were observed in the case of 7c and 7d. We are confident
that all four isomers are separated under our analysis conditions.
In spite of the tropolone ether 4 having a chiral auxiliary,
irradiation in methylene choride–hexane solution led to a 1 : 1
Table 3 Amines as chiral auxiliaries. Diastereomeric excess (%) ob-
tained in the photoproducts 8a–f during the irradiation of tropolone
derivatives 7a–f included in various alkali ion exchanged Y zeolites
Chiral auxiliary approach
In the above experiments a chiral environment within a zeolite
was created by the adsorption of a chiral organic molecule into
the supercages of an achiral zeolite. Ideally the substrate and the
chiral inductor should occupy the same supercage leading to the
transfer of chiral information during a photochemical reaction.
However, one is not certain of the location of the substrate
with respect to the chiral inductor within a zeolite. Efficient
chiral induction can only occur if the chiral inductor and the
substrate are near one another. We present below the results of
Medium
8a
3 A
8b
8c R(+)
8d S(−)
8e
8f
2 B
CH3CN
LiY
0
2 A
64 B
83 B
26 B
5 B
—
10 A
80 B
88 B
41 B
14 B
2 B
17 B
44 B
15 A
10 A
2 A
24 B
54 B
12 A
7 A
63 A
82 A
31 A
—
36 B
45 B
28 B
17 B
2 B
NaY
KY
RbY
CsY
10 A
5 A
—
Scheme 3
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 4 5 – 3 0 5 3
3 0 4 7

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Table 4 Amino acid methyl esters and amino alcohols as chiral
auxiliaries. Diastereomeric excess (%) obtained in the photoproducts
8g–m during the irradiation of tropolone derivatives 7g–m included in
various alkali ion exchanged Y zeolites
adsorbed on a silica surface gave both diastereomers in equal
amounts. When a 1 : 1 diastereomeric product mixture of 5
was included within NaY and extracted with diethyl ether, it
was seen that the ratio of the diastereomers remained unaltered
ruling out a selective adsorption of one of the diastereomers of
the product. In order to prevent the first photoproduct from
undergoing further rearrangement, the irradiation times were
kept short (15–20 min) such that less than 20% of the secondary
product was formed
Medium
8g
7 A
8h
2 A
8i
3 B
8j
8 B
8k
3 A
8l
8m
9 B
CH3CN
LiY
14 A
68 A
65 A
50 A
25 A
17 A
15 B
55 B
2 B
4 B
2 B
29 B
53 B
15 B
29 A
21 A
49 B
76 B
86 B
60 B
3 B
10 A
20 A
46 B
46 B
50 B
50 A
77 A
22 A
5 B
39 B
74 B
2 A
2 A
0
NaY
KY
RbY
CsY
4 B
[Chiral auxiliary + chiral inductor] approach
Prompted by the fact that chirally modified MY zeolites (zeolite
adsorbed with a chiral inductor) brought forth asymmetric
induction during the photorearrangement of achiral tropolone
derivatives, we were motivated to examine their influence on
chiral tropolone derivatives. For this purpose a chiral inductor
and (S)-tropolone-2-methylbutyl ether 4 were included in NaY
from hexane, the guest–NaY complex was dried under vacuum
and irradiated under anhydrous conditions. Irradiation of 4
(ꢀSꢁ = 0.28) in NaY adsorbed with (−)-ephedrine for 20 min
led to the formation of the product (A isomer) in 90% de. As
expected, irradiation in NaY/(+)-ephedrine led to the formation
of the B isomer of the product, but with a lower de (70%).
This trend was repeated in the case of norephedrine. When
the irradiation was carried out in NaY/(−)-norephedrine and
NaY/(+)-norephedrine the product was obtained in 92% (A)
and 70% (B) respectively. When the irradiation of (S)-tropolone-
2-methylbutyl ether 4 is carried out in NaY modified with (+)-
ephedrine, there are two opposing influences in operation. The
zeolite directs the reaction towards the diastereomer A while the
chiral inductor directs the reaction towards the diastereomer
B. To monitor the influence of these two opposing reaction
forces complexes with different loading levels of the chiral
inductor with a fixed amount of 4 were irradiated. Irradiations
were carried out in NaY complexed with (+)-ephedrine varying
between 5 and 30 mg. When the amount of (+)-ephedrine was
5 mg, the de of the reaction was 38% (A). On increasing this
amount the competitive selectivity for the B diastereomer is seen.
At a loading of 7 mg, which corresponds to ꢀSꢁ = 4.48, the two
opposing influences cancel each other and a 1 : 1 diastereomeric
mixture is obtained. From this point onwards, the effect of the
external chiral inductor overrides the influence of the zeolite
and leads to a de of 75% (B) when the loading level is 30 mg
of (+)-ephedrine (ꢀSꢁ = 1.03) (Fig. 1). A similar pattern of
opposing influences was observed for (+)-norephedrine. The
dramatic increase in chiral induction observed within the chirally
modified zeolite was not general. Irradiation in presence of (−)-
pseudoephedrine, N-benzyl-L-prolinol, L-methylbenzyl amine
and L-valinol gave the product with diastereoselectivites similar
to that obtained in NaY without any chiral inductor. Chirally
modified NaY had no special effect during the transformations
of 7c and 7d. We believe that the role of the chiral inductor during
phototransformation of molecules containing chiral auxiliary
needs further attention.
diastereomeric mixture of product 5. On the other hand,
irradiation of 4 (ꢀSꢁ = 0.28) in NaY led to the formation of
5 in 53% de. When the loading level of 4 in NaY was increased,
irradiation of the NaY–4 complex led to a decrease in the
selectivity. As the loading level was increased to 0.56 and 0.83,
the de decreased to 41 and 28% respectively. Irradiation of 4 in
NaY, KY, RbY and CsY brought out the effect of the nature of
the cation on the chiral induction. Irradiation in NaY gave the
product in 53% de, whereas irradiation in KY and RbY gave the
product in 21 and 12% de respectively. Irradiation in NaY, KY
and RbY gave the A diastereomer as the major diastereomer,
but irradiation of 4 in CsY resulted in the preferential formation
of the B diastereomer (17% de).
The highest diastereoselectivity was obtained with the
tropolone derivative appended with S(−)-naphthyl ethylamide
as the chiral auxiliary (7e: NaY, 88%; Table 3). The same
molecule in solution gave only 10%. The following observations
with this system suggest that alkali metal ions present in zeolites
play an important role during the asymmetric induction process.
(a) The de was dependent upon the nature of the alkali metal
ion (e.g. % de in the case of 7e in LiY, NaY, KY, RbY and CsY
were 80, 88, 41, 14 and 2 respectively; Table 3). (b) The de varied
with water content of NaY used (dry: 88%; wet:10%). (c) Upon
irradiation of 7e adsorbed on silica gel, a surface that does not
contain cations, the de was 0%. (d) The diastereomeric excess in
the case of 7e decreased from 88 to 40% when the Si/Al ratio of
NaY zeolite was changed from 2.4 to 40. The number of cations
per unit cell decreases from 56 to 5 upon changing the Si/Al
ratio from 2.4 to 40.10
Results of the following control experiments support our con-
clusion that the zeolite cavity is essential to achieve significant
asymmetric induction during the photochemical rearrangement
of tropolone derivatives appended with a chiral auxiliary.
Irradiation of (S)-tropolone-2-methylbutyl ether 4 in methylene
chloride–hexane (1 : 4) did not yield any diastereoselectivity
in the product. Irradiation of 4 (4 mg) in methylene chloride–
hexane (1 : 4) containing (−)-ephedrine (25 mg) yielded a 1 :
1 racemic mixture of the product. Similarly, irradiation of 4
(4 mg) in methylene chloride–hexane (1 : 4) containing (−)-
norephedrine (25 mg) yielded a 1 : 1 racemic mixture of the
product. Irradiation of 4 (4 mg) and (−)-ephedrine (25 mg)
Fig. 1 GC traces (GC chiral column Supelco b-dex 325) illustrating the variation of the de as a function of the loading level of (+)-ephedrine.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 4 5 – 3 0 5 3
3 0 4 8

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in this study (Tables 1 and 2). For example, irradiation of
1c in NaY/(−)-ephedrine gave 17% ee when the zeolite was
hydrated and 68% ee when it was dry. Among the various chiral
inductors examined, the ones with two functional groups such
as ephedrine, pseudoephedrine, norephedrine, etc., functioned
better and the ones with only hydroxyl or amino groups (e.g.
borneol, menthol, bornylamine and methylbenzyl amine) gave
poor ee values (<10% in the case of 1a and 1b). Based on
the above observation we postulate that there are multiple
interactions between the achiral tropolone derivative, the chiral
inductor and the alkali ion present in the zeolite interior. The
recognition points are likely to be the hydroxyl, the amino
and the phenyl groups of ephedrine (or norephedrine), and
the phenyl ring, the ether oxygen and the carbonyl oxygen of
the tropolone derivative. The chiral inductor and the tropolone
derivative are held on the surface through their interaction with
the alkali metal ion.
Discussion
Chiral inductor approach
Results of the chiral inductor, the chiral auxiliary and the [chiral
inductor + chiral auxiliary] methods as applied to tropolone
derivatives are discussed independently below. This section deals
with the chiral inductor approach. The results presented on three
systems 1a–c (Scheme 2) reveal that chiral induction during
the photoreactions of achiral tropolone derivatives is significant
within zeolites compared to that in solution (0% ee). The highest
ee obtained was with tropolone ethyl phenyl ether 1b. Irradiation
of 1b in NaY in the presence of (−)-ephedrine gave the product
with 68% ee at 22 ◦ C.
We believe that the photoreaction occurs within and not
on the external surface of a zeolite. Since the external surface
constitutes less than 1% of the total surface area of NaY zeolite
one would expect the molecules to be adsorbed on the internal
rather than on the external surface. Following inclusion, washing
the zeolite with hexane (in which the tropolone derivative is
soluble) did not remove any molecules. If the substrate had
been on the external surface it would have been dislodged easily
by hexane. The effect of residual water observed in this study
highlights the importance of using ‘dry’ conditions to obtain
the maximum influence of a zeolite. We hypothesize that water
molecules ‘turn off’ the interactions between the alkali metal
ion, the tropolone derivative and the chiral inductor that are
required for asymmetric induction within the zeolites (Fig. 2).
To gain an insight into the role of reactant–cation–chiral
inductor interactions within zeolites we have carried out DFT
calculations on the tropolone ethyl phenyl ether (1b)–ephedrine–
NaY system using the B3LYP method and 6-31G(d) basis set
(Gaussian 98 package).24 We realize that the computational
results that pertain to the gas phase are less relevant to the much
more complex zeolite environment. However, in the absence of
any other spectroscopic and structural data, we believe that the
above gas phase computational results serve as a good starting
point. Our goal was to examine whether the Na+ ion would
bring the reactant tropolone ethyl phenyl ether and the chiral
inductor ephedrine close to one another. Also we were interested
in obtaining a minimum energy structure of the supramolecular
complex of Na+, ephedrine and tropolone ethyl phenyl ether.
One should keep in mind that within a zeolite the cations are
bound to oxygens on the framework. As a result, the metal ions
are likely to interact less strongly than when they are free.
Geometry optimization of tropolone ethyl phenyl ether re-
sulted in two conformers with similar energies (Fig. 3). These
conformers were allowed to interact with Na+. Interaction of
Na+ with the conformer I resulted in one structure whereas
that with the conformer II gave rise to two structures. As
illustrated in Fig. 3 although the two conformers have nearly
the same energies, the three structures resulting from interaction
of these with Na+ have distinctly different energies. Of these
Fig. 2 Cartoon representation of tropolone methyl ether (1a) and
ephedrine included within a supercage under wet and dry conditions.
The model helps to rationalize the difference in ee obtained under the
two sets of conditions. Dark circles represent the cations. Interaction
between the cation, the chiral inductor and 1a are disturbed by water
molecules.
three, structure 1 in which the Na+ interacts with the C O
=
and the phenyl group has the highest binding affinity. During
the calculation, the metal ion was free to move to find the
most stable position. Calculations did not include any structural
moiety from the zeolite. At this stage our interest was to monitor
computationally whether the Na+-bound tropolone ethyl phenyl
ether would interact with the chiral inductor ephedrine in any
specific fashion. For this purpose (−)-ephedrine was placed
closer to the Na+-bound tropolone ethyl phenyl ether structure
1 and optimized at the RB3LYP/6-31G(d) level. This resulted in
three supramolecular structures with different energies (Fig. 4).
The point we wish to make is that in the most stable structure the
Na+ acts as a ‘glue’ between the chiral inductor and the reactant.
In this structure there are interactions between the cation
and the carbonyl and the phenyl ring of 1b, and the amino
nitrogen and the alcohol oxygen of ephedrine.25–34 We believe
that the role of the alkali metal ion is to ‘hold’ the chiral
inductor near the reactant molecule in a specific geometry such
that the reaction environment becomes locally chiral. The chiral
induction observed within the zeolites, we hypothesize, results
from such a phenomenon. In solution, the absence of such a
supramolecular assembly probably leads to racemic products.
The presence of water not only influenced the extent of chiral
induction, it also affected the enantiomer being enhanced. For
example, in the presence of (−)-ephedrine under ‘wet’ condi-
tions the second enantiomer (B) of the product was obtained
in excess whereas under dry conditions the first enantiomer
(A) of the product was obtained in excess (Table 1). This
increase in enantioselectivity with a switch in the isomer being
enhanced was also observed with chiral inductors such as (−)-
pseudoephedrine, (−)-norephedrine, (+)-2-amino-3-methoxy-
1-phenyl-1-propanol and (+)-diethyl tartrate (Table 1). Exam-
ination of Table 1 reveals that the extent of chiral induction is
reactant-, chiral inductor- and alkali metal ion-specific. We have
been unable to identify a universal alkali metal ion and chiral
inductor that would function well for all tropolone derivatives.
In spite of this deficiency the observations made are unique
and novel and offers a new approach to chiral induction in
photochemical reactions.
The hydrogen bonding interactions between tropolone deriva-
tives and the chiral inductor alone are insufficient to bring about
enantioselectivity. Despite the fact that such interactions are
likely to be present even on a silica surface, no ee was observed
in this medium with 1a–c. A feature that distinguishes the zeolite
surface from that of silica is the presence of alkali metal ions.
Importance of alkali metal ions in the asymmetric induction
process has been revealed clearly in all examples investigated
Chiral auxiliary approach
Results noted above have allowed us to recognize the need to
place each reactant molecule next to a chiral inductor within a
zeolite and this led us to explore the chiral auxiliary approach
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 4 5 – 3 0 5 3
3 0 4 9

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Fig. 3 Geometry optimized B3LYP/6-31G(d) structures and energies of tropolone ethyl phenyl ether (left) and geometry optimized structures and
binding affinities of their Na+-bound forms (right).
tropolone-2-methylbutyl ether (4). Irradiation of 4 in isotropic
solvents like hexane, methylene chloride and acetonitrile gave
a 1 : 1 diastereomeric mixture of the primary photoproduct
(Scheme 3). Clearly the chiral center in the tropolone derivative
is unable to provide chiral discrimination during the 4p-
electrocyclization reaction. However, when 4 included in anhy-
drous MY zeolite was irradiated diastereomer A of the product
was obtained in 53% excess. Simple confinement of the substrate
within the reaction cavity of the zeolite has enabled the transfer
of chiral information from the substituent to the reaction center.
One possible mechanism for the observed diastereoselectivity in
this reaction could be that one molecule in the ground state is
acting as a chiral inductor for another molecule in the excited
state. If this is true, one would expect the diastereoselectivity to
increase with the loading level of the substrate within the zeolite.
But the observation was the opposite: the diastereoselectivity for
the A diastereomer decreased with the increased loading. This
prompted us to conclude that the chiral center in the side chain
was capable of functioning both as an external chiral inductor
and as an internal chiral auxiliary and these two acts led to
opposite isomers. At low loading levels a higher chiral induction
could be achieved where the chiral center acts only as an internal
chiral perturber (auxiliary).
It is clear that the confined medium and the cation can
enforce stronger interaction between the chiral auxiliary and
Fig. 4 Geometry optimized B3LYP/6-31G(d) structures and energies
of Na+-bound forms tropolone ethyl phenyl ether and (−)-ephedrine.
the reacting parts of the same molecule. To test the generality
of the chiral auxiliary approach the photochemistry of 13
independent tropolone derivatives (7a–m; Scheme 3) included
within achiral MY zeolites was examined. The chiral auxiliaries
derived from optically pure arylamines, alkylamines, amino acid
methyl esters and amino alcohols were linked to the reactive
tropolone skeleton via an amide bond. Results presented in
Note that the tropolone ethyl phenyl ether and the chiral inductor
(−)-ephedrine are brought closer by the alkali ion Na+.
in which the chiral perturber is connected to the reactant via a
covalent bond. In this approach, most supercages of the zeolite
are expected to contain both the reactant as well as the chiral
perturber. The first system we examined in this context was (S)-
3 0 5 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 4 5 – 3 0 5 3

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Tables 3 and 4 establish that a chiral auxiliary functions better
within a zeolite than in an organic solvent. Variation in de with
respect to the water content and the nature of the alkali metal
ion establish that the cations present within a zeolite play an
important role in the chiral induction process. Although with the
results on hand we can’t provide a detailed understanding of the
process, we believe that we are in a position to point out some of
the important factors that control the diastereoselectivity within
zeolites. The chiral auxiliaries employed could be divided into
two sets: one with aryl substitution and the other with alkyl
substitution. Examination of Tables 3 and 4 reveals that chiral
auxiliaries with aryl substitution (e.g. 7c, d, e, i, k and l) are
more effective than the ones without aryl substitution (e.g. 7a,
b, f, g, h and j) with an exception of 7m. The ones with aryl
chiral auxiliaries gave the product with a de in the range 68–
88% (the best numbers are quoted) whereas the ones with alkyl
chiral auxiliaries gave the product with a de in the range 46–
54% (the best numbers are quoted). An insight into how cations
play a role in the above chiral discrimination process is revealed
by the results of ab initio computations of two systems, 7d and
7f. The binding affinities (BA values) and geometries (Figs. 5
and 6) of Na+-bound 7d (representing aryl chiral auxiliary)
and 7f (representing alkyl chiral auxiliary) computed at the
Restricted B3LYP/6-31G(d) level provided insight into the role
of the aryl group in enhancing the power of a chiral auxiliary
within zeolites.35 Both molecules interacted strongly with Na+
with binding affinities >45 kcal mol−1. Since alkali metal ions
are bound to the surface of a zeolite, the binding affinities
between the cation and the guest molecules within a zeolite are
expected to be smaller than the values computed above, but the
trend is likely to remain the same. In the most stable structure
of 7d–Na+ the cation interacts simultaneously with the phenyl
group through a cation–p interaction25,36 as well as with the
amide carbonyl and the tropolone carbonyl oxygens via dipolar
interactions26,33 (Fig. 5). Such interactions are expected to reduce
the rotational freedom of the chiral auxiliary and thus make it
‘rigid’. On the other hand, in the most stable structure of 7f–Na+
the cation interacts mainly with the carbonyl and ether oxygens
of the tropolone (Fig. 6). Very weak interactions between the
Na+ and C–H bonds are also observable in the model. The
above type of binding we believe would have very little effect on
the rotational mobility of the chiral auxiliary. A model based on
the alkali metal ion binding-dependent flexibility of the chiral
auxiliary accounts for the observed variation in de between the
aryl and alkyl chiral auxiliaries within the zeolites.
Fig. 6 B3LYP/6-31G(d) optimized structures of Na+-bound 7f.
The alkali metal ion binding alone is unlikely to be responsible
for the observed asymmetric induction for 7a–m within achiral
zeolites. Systems with alkyl chiral auxiliaries and 4 whose chiral
auxiliary is made up of only alkyl groups gave respectable de
values within zeolites (40–60%; much higher than in solution).
Also, irradiation of 7e included in NaY with only five cations
per unit cell gave the product with 40% de. Although the
number decreased from 88% (Si/Al ratio 2.4; number of cations
per unit cell 56) to 40% it did not reach <5%, suggesting that
the chiral auxiliary is more effective within zeolites than in
solution even when there are no cations. Thus we conclude
that the performance of a chiral auxiliary improves dramatically
(with respect to solution) when its mobility is restricted through
cation binding and confinement. Confinement alone improves
asymmetric induction but not to the same degree as when cations
are also present.
[Chiral inductor + chiral auxiliary] approach
Tropolone derivatives 4 and 7a–m, in spite of having a chiral
auxiliary, did not yield the product with 100% de. We believed
that we could improve the asymmetric induction by including
chiral tropolones within chirally modified zeolites. For this
purpose we employed ephedrine and norephedrine as chiral
inductors and NaY as the medium. Dramatic improvement in
chiral induction was observed in the case of 4. An insight into
the process of asymmetric induction within the NaY zeolite
is obtained by analyzing the results obtained in the presence
and absence of ephedrine. Upon loading the zeolite with (−)-
ephedrine, the inductor is expected to distribute itself within
the supercages in three different ways: there could be singly
occupied cages (one chiral inductor), doubly occupied cages
(two chiral inductors) and empty cages (no chiral inductor).
When the substrate 4 is loaded it can arrange itself among these
three types of cages, and owing to space restrictions it is not
expected to enter a cage that already has two chiral inductor
molecules. Therefore it would be forced to enter either the single
chiral inductor-occupied or empty cages. If it occupies an empty
cage, upon irradiation it will give the product in ca. 50% de. The
diastereomeric excess of 90% obtained with (−)-ephedrine could
be accounted for by a distribution in which 80% of the cages are
occupied by both chiral inductor and the reactant and 20% of the
cages by the substrate alone. In this simple calculation we assume
that cages containing the reactant and (−)-ephedrine will give
Fig. 5 B3LYP/6-31G(d) optimized structures of Na+-bound 7d.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 4 5 – 3 0 5 3
3 0 5 1

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the product in 100% de. This distribution is consistent with the
results obtained with the optical antipode (+)-ephedrine (70%
de). Had all photoreactions occurred in a single type of cage
a complete switch would be expected with the antipode. This
implies that we have not yet reached a condition in which every
reactant site is adjacent to a chiral center.
NaY (300 mg), dried at 500 ◦C, was added to the above. This cor-
responded to a loading level of ꢀSꢁ = 0.28. The slurry was stirred
for 12 h, filtered and washed with hexane (3 × 5 ml). The zeolite
complexed with the tropolone ether was dried under vacuum
(3 × 10−3 Torr) at 65 ◦C for 6 h and irradiated (450 W medium
pressure Hg lamp) in dry hexane (5 ml) for 20 min. The products
were extracted from the zeolite by stirring with diethyl ether.
Conclusion
Loading and irradiation of (S)-tropolone-2-methylbutyl ether 4
In this report we have shown that the confined space offered
by the zeolite supercage forces an achiral reactant and a
chiral inductor to interact intimately to yield enantiomerically
enriched products. Lack of chiral induction in solution suggests
that such intimate interactions do not take place in this
medium. Examples presented above illustrate convincingly that
the influence of a chiral center present as a chiral auxiliary can
be enhanced significantly when the photoreaction is carried out
within a zeolite. Examination of the zeolite interior, in which the
reactant molecule is held, suggests that the most likely factor
responsible for the change in de. between solution and zeolite
is the difference in conformational preference for the reactant
molecule in these two media. In solution, the influence of cations
is wiped out by solvation of the cations by the solvent molecules.
Cations present in zeolites being only partially co-ordinated
to the surface oxygen are free to interact with included guest
molecules. Generality of the combination of chiral inductor and
chiral auxiliary method that works remarkably well in the case
of (S)-tropolone-2-methylbutyl ether is yet to be established.
in the presence of a chiral inductor in NaY
(−)-Ephedrine (30 mg, 182 mmol, ꢀSꢁ = 1.0) was dissolved
in a mixture of dry m◦ethylene chloride–hexane (1 : 4). NaY
(300 mg), dried at 500 C, was added to the above. The slurry
was stirred for 8 h, filtered and washed with hexane (3 × 5 ml).
The zeolite modified with the chiral inductor was dried under
vacuum (3 × 10−3 Torr) and added to a solution of (S)-tropolone-
2-methylbutyl ether (4 mg, 0.021 mmol, ꢀSꢁ = 0.28) in dry
methylene chloride–hexane (1 : 4). The slurry was stirred for
12 h, filtered and washed with hexane (3 × 5 ml). The zeolite
complexed with the chiral inductor and the tropolone ether was
dried under vacuum (3 × 10−3 Torr) at 65 ◦C for 6 h and
irradiated (450 W medium pressure Hg lamp) in dry hexane
(5 ml) for 20 min. The products were extracted from the zeolite
with diethyl ether. The chiral inductor was removed from the
reaction mixture by eluting from a silical gel column (20%
methlyene chloride–hexane).
Loading and irradiation of amide derivatives of 2-[(1E,3Z,5Z)-
7-oxocyclohepta-1,3,5-trienyloxy]acetic acid (7a–m) in NaY
Experimental
About 2 mg of tropolone amide derivative was taken in a
test tube. To this 10 ml of methylene chloride–hexane solvent
mixture (3 : 7) was added. 300 mg of activated MY zeolite was
added and the contents were allowed to stir for 6–8 h. The
supernatant hexane layer was tested for complete loading by
removing hexane under positive pressure of nitrogen. Fresh, dry
hexane (5 ml) was added and irradiated as a hexane slurry for
5 min with a 380 nm cut-off filter. The irradiation layer was
removed and analysed. Products were extracted by stirring with
acetonitrile.
Loading and photolysis of tropolone alkyl ethers
All photolysis experiments were performed by using a 450 W
medium pressure mercury lamp placed in a water-cooled Pyrex
immersion well (transmits k > 290 nm). For solution phase
photolysis, the sample was taken in a Pyrex test tube and
dissolved in methylene chloride–hexane (1 : 4) solution. A
minimum of three samples was irradiated.
Loading and photolysis of achiral tropolone alkyl ethers (1a–c)
in presence of a chiral inductors in MY zeolites
In order to activate the zeolite, commercially available NaY
(300 mg) is kept in a furnace mantained at 500 ◦C for 12 h prior
to use. The resulting activated NaY was added to the solution
of the substrate, being careful not to add it too quickly which
would char the sample, and not too slowly which would hydrate
the zeolite from the moisture in the atmosphere. Tropolone alkyl
ether (ca. 4 mg) and the chiral inductor (25 mg) were stirred
with activated NaY (300 mg) in methylene chloride–hexane (1 :
4) for 12 h at room temperature. The loading level of the chiral
inductor was maintained at one molecule in every supercage,
while the loading level of the substrate was kept at one molecule
in every ten supercages. A higher ratio of the chiral inductor
is employed to maximize the chances of the substrate molecule
being adjacent to the chiral inductor within a supercage. The
zeolite containing both the reactant and the chiral inductor
was collected by filtration, washed with an excess of hexane
and irradiated (450 W medium pressure Hg lamp, Pyrex filter)
as a hexane slurry for 2 h. Sample handling was carried out
Analysis of the photoproducts of tropolone derivatives 1a–c
The photoproducts of the irradiation were analysed by gas
chromatography. A Hewlett Packard HP 5890 (FID detector)
with a SE-30 column (length 30 m, id 0.32 mm, film thickness
0.25 mm) was used for product analysis. The conditions of a
typica◦l run were: initial temperature, ◦100 ◦C; intial time, 1 min;
rate, 5 min−1; final temperature, 250 C; final time, 10 min.
Analysis of the enantiomeric excess of the photoproducts of
tropolone derivatives 1a–c
The enantiomeric excess (ee) of a reaction is given as (A − B/A +
B) × 100, where A refers to the area under the first peak of the
product and B refers to the area under the second peak.
1a. GC column Supelco b-dex 120 [phase, non-bonded;
20% permethylated b-cyclodextrin in SPB-35 poly(35%
diphenyl/65% dimethyl siloxane)]. Initial temperature, 120 ◦◦C;
initial time, 10 min; rate, 10◦ min−1; final temperature, 130 C;
final time, 5 min; rate A: 10 ◦C min−1; final temperature, 140 ◦C;
final time, 15 min.
◦
under laboratory conditions (T = 20 C, humidity 55%). The
product was extracted with methylene chloride and analysed
by chiral GC (Supelco b-dex column). The products 2a–c were
characterized by comparing their 1H NMR spectra to those in
the literature.
1b. HPLC chiral column OD (Chiralcel). The enantiomers
of the product were resolved with hexane–i-PrOH (95 : 5), with
a flow rate of 0.7 ml min−1; detection at 254 nm.
Loading and irradiation of (S)-tropolone-2-methylbutyl ether 4
in NaY
1c. GC chiral column Supelco bdex 350. Initial temperature,
◦
◦
(S)-Tropolone-2-methylbutyl ether (4 mg, 0.021 mmol), was
90 C; 1 min, rate, 0.4◦ min−1, final tempearture, 120 C; final
dissolved in a mixture of dry methylene chloride–hexane (1 : 4).
time, 20 min.
3 0 5 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 4 5 – 3 0 5 3

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Analysis of the diastereomeric excess of the photoproducts of
tropolone derivatives 4 and 7a–m
Acknowledgements
V. R. thanks the NSF for financial support (CHE-0212042).
4. GC chiral column Supelco b-dex 325 [phase, non-bonded;
25% 2,3-di-O-methyl-6-O-TBDMS-c-cyclodextrin in SPB-20
poly◦(20% phenyl/80% dimethyl siloxane)]. Initial temperature,
120 ◦ C; initial time, 20 min; rate, 10◦ min−1; final temperature,
130 C; final time, 5 min; rate A: 10 ◦C min−1; final temperature,
140 ◦C; final time, 30 min.
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7a. HPLC column-chiralpak AD-RH; mobile phase, 95 : 5
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7f. Chiral GC column Supe◦lco b dex 350. Temperature
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◦
◦
10 C min−1, final temperature 2, 200 C; final time 2, 20 min;
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7g. Chiral GC column Supel◦co b dex 350. Temperature
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◦
◦
10 C min−1, final temperature 2, 200 C; final time 2, 20 min;
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◦
◦
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 4 5 – 3 0 5 3
3 0 5 3