Chiral photochemistry in a confined space: torquoselective photoelectrocyclization of pyridones within an achiral hydrophobic capsule

Article abstract of DOI:10.1016/j.tet.2009.01.110

Chiral induction during the photoelectrocyclization of pyridones included within octa acid (OA) capsule has been established. Chiral induction is brought about by a chiral auxiliary appended to the reactive pyridone moiety. Importantly, the same chiral au

Full text of DOI:10.1016/j.tet.2009.01.110

Tetrahedron 65 (2009) 7277–7288
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Chiral photochemistry in a confined space: torquoselective photoelectro-
cyclization of pyridones within an achiral hydrophobic capsule
,
Arun Kumar Sundaresan a, Corinne L.D. Gibb b, Bruce C. Gibb b, V. Ramamurthy a
*
a Department of Chemistry, University of Miami, Coral Gables, FL 33124, USA
b Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral induction during the photoelectrocyclization of pyridones included within octa acid (OA) capsule
has been established. Chiral induction is brought about by a chiral auxiliary appended to the reactive
pyridone moiety. Importantly, the same chiral auxiliary while ineffective in acetonitrile solution is found
to be effective within the confined space of OA capsule. The diastereomeric excess of 92% obtained here is
comparable only to that in solid state. OA capsule, we believe, provides restriction to the rotational
motions of the reactant pyridone and chiral auxiliary and thus places the chiral auxiliary in a selective
conformation with respect to the reactive pyridone part. A correlation between the position of the
methyl group on the pyridone ring and diastereoselectivity was noted. Structures of the host–guest
complexes were examined by 1H NMR and the data were used to obtain preliminary information con-
cerning the mechanism of chiral induction within the confined spaces of OA capsule.
Received 13 November 2008
Accepted 21 January 2009
Available online 21 March 2009
On the occasion of 70th birthday V.R. dedi-
cates this manuscript to his beloved mentor
and teacher Professor R. S. H. Liu
Keywords:
Host–guest
Chiral photochemistry
Electrocyclization
Pyridones
Ó 2009 Elsevier Ltd. All rights reserved.
Confined space
Supramolecular assemblies
1. Introduction
complexes of optically pure host and achiral guest molecules often
resulted in quantitative chiral induction.7 The elegant technique of
Chiral chemistry in confined spaces has attracted considerable
attention during the last two decades.1 Although a number of ele-
gant and efficient chiral induction strategies have evolved for
thermal reactions, the short lifetimes of excited states have ham-
pered the development of effective interaction between excited
reactant and a chiral perturber thus slowing down similar progress
with photoreactions. The chiral sources that have been employed to
achieve stereoselectivity in photochemical reactions in solution
include circularly polarized light, chiral-sensitizers, -solvents,
-substituents, and -hosts.2–6 During the last two decades supra-
molecular approaches toward chiral photochemistry have attracted
considerable attention. For example, use of chiral hosts such as
cyclodextrins, proteins, and DNA to complex achiral reactant mol-
ecules in aqueous solution has resulted in low to moderate chiral
induction in photoproducts, but significantly higher than in iso-
tropic solvents.4
transformation of chiral crystals of achiral molecules into chiral
photoproducts in 100% enantiomeric excess (ee) is noteworthy.8
Some achiral molecules that failed to crystallize in a chiral space
group were forced to crystallize in a chiral space group by using an
ionic or a co-valent chiral auxiliary and which upon subsequent
irradiation yielded products with 100% diastereomeric excess (de).9
We have recently demonstrated the use of confined cavities of
a zeolite and the resident charge compensating cations in inducing
enantio- and diastereoselectivities in products of photoreactions
such as geometric isomerization, hydrogen abstraction, and cycli-
zation.10 Based on the literature, we believe that solid-state chiral
photochemistry is more advanced than the solution counterpart
and we should apply the solid-state concepts to solution chiral
photochemistry. In this context the supramolecular approach in
solution holds promise.
We had explored the use of chiral cyclodextrins as hosts for
a number of unimolecular photoreactions toward developing
a solution-based chiral induction strategy.11–13 The best w20%
ee we could obtain in solution is largely due to cyclodextrin–
guest complexes’ poor solubility in water. The similarities in
shape and size of cyclodextrins and the recently synthesized
cavitand octa acid (OA) led us to explore OA’s effectiveness in
In comparison to solution, supramolecular approaches in the
solid state have provided promising leads. Solid host–guest
* Corresponding author.
E-mail address: murthy1@miami.edu (V. Ramamurthy).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.110

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A.K. Sundaresan et al. / Tetrahedron 65 (2009) 7277–7288
Figure 1. (i) Chemical structure of cavitand octa acid (OA). (ii) Simplified representation showing the 4 equiv subunits of OA. (iii) Cartoon representation of OA cavity. (iv)–(vi)
Cartoon representation of 2:1 host–guest complexes formed with OA and 4-methyl dibenzyl ketone, 4,40-dimethylstilbene and 2:2 host/guest complex with adamantane.
O
N
X
O
N
X
O
N
X
O
N
X
O
N
X
O
N
Y
1a
1b
1c
1d
1e
1f
H
H
N
X=
Y=
N
CH3
CH3
(R)
(R)
O
O
Scheme 1. Structures of pyridones examined in this study.
bringing about chiral induction in photoreactions. While the
guest is only partially surrounded by cyclodextrin (as 1:1
guest@host complex), two molecules of OA self-assemble and
encapsulate the guest (as either a 2:2 or a 1:2 guest@host
capsule) (Fig. 1).14,15 Thus the OA capsule provides a relatively
‘confined-solid-like’ reaction cavity resembling crystals and
zeolites. Our experience with the latter two solid media sug-
gested that the restriction provided by a closed tight enclosure
would enhance the influence of
a chiral auxiliary during
a photoreaction. In this study this prediction has been realized
with the guest pyridone systems 1a–e, appended with the chiral
auxiliary
a
-methylbenzyl amide (Scheme 1) in OA.16–18 The
position of the methyl group on the pyridyl ring was changed
with the hope that it would influence the orientation of the
guest, and thereby the free space, within the OA cavity. Prior
studies with molecules like 4,40-dimethylstilbene and dibenzyl
ketone (Fig. 2) that are comparable in dimension to 1a–e as-
sured us accommodation of these guests inside OA cavity.
Binding properties of compounds 1a–e with OA were examined
by NMR spectroscopy prior to initiating the photochemical
studies. Both NMR and photochemical results are presented in
this report.
Figure 2. Ball and stick representation (i) of 1c, (ii) 4,40-dimethyl-trans-stilbene, and
(iii) 4,40-dimethyl dibenzyl ketone showing the relative dimensions of each molecule
in an extended conformation.

A.K. Sundaresan et al. / Tetrahedron 65 (2009) 7277–7288
7279
O
product.19–21 Since the OA capsule is non-chiral, the photo-
cyclization had to be influenced either through co-inclusion of
a chiral inductor within the achiral capsule or through a chiral
auxiliary co-valently linked to the reactant molecule. Our un-
successful attempts at the former approach led us to explore the
chiral auxiliary strategy that we had previously exploited in zeolites
and crystals. This led us to investigate the photobehavior of pyr-
idones 1a–e within OA capsule. The results presented here high-
light the influence of chiral auxiliary on the photocyclization when
the reaction space is tightly controlled. Although the observed high
de is remarkable we still do not fully understand the mechanics of
the restricted space of the OA capsule in bringing about an in-
teraction between the chiral auxiliary and the reaction center. We
plan to continue to explore the origin and rules of chiral induction
in photochemical reactions within the restricted space of OA
capsule.
R
N
hν
hν
R
O
R
N
N
O
H
H
R
R
N
N
H
H
O
O
Scheme 2. Mechanism of the 4e disrotatory cyclization reaction of pyridone.
2. Results
The probe molecules 1a–e undergo concerted 4e disrotatory
photocyclization in the excited singlet state. The mechanism of the
photocyclization reaction is shown in Scheme 2. Planar achiral
pyridone undergoes disrotatory cyclization (via two modes: in and
out rotation) to yield the chiral 2-azabicyclo[2.2.0]hex-5-en-3-one.
The products distinguished by the stereochemistry at the ring
junction exist as enantiomers. Note that the planar reactant be-
comes bent (w110ꢀ) in the product. In a homogeneous environ-
ment, the cyclization occurs by both modes of rotation with equal
efficiency. In a supramolecular chiral assembly, the host could
provide torquoselectivity during the disrotatory cyclization process
thus possibly leading to chiral enrichment on the photocyclized
2.1. Preparation and characterization of 1a–e@OA2 complexes
Methyl-substituted pyridones 1b–e were synthesized and their
complexation behavior within OA was examined. The procedure for
synthesis of these compounds is presented in the experimental
section. Complexes of OA and pyridones 1a–e were prepared using
the following general procedure. A known volume of the guest from
a stock solution in CD3CN was transferred to a sample vial. The
solvent was evaporated in a stream of air. To the solid pyridone thus
deposited in the vial, solution of OA in buffered D2O (2 equiv OA,
5ꢁ10ꢂ3 M solution) was added and the mixture stirred for 30 min.
Figure 3. (bottom) 1H NMR spectra (500 MHz, 298 K, buffered D2O) of OA (10ꢂ3 M in 10ꢂ2 M Na2B4O7) and 1b@OA2 in 1:0.5 ratio (5 ꢁ 10ꢂ3 M solution of OA in Na2B4O7/D2O) (top).
The two methyl group signals of 1b are marked as shown in Figure 8. Host hydrogens are labeled as shown in Figure 1.

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Figure 4. Partial 1D selective TOCSY NMR spectra (500 MHz, 298 K, D2O, 0.12 s mixing
time) of 1b@OA2 complex (5ꢁ10ꢂ3 M OA and 5ꢁ10ꢂ2 M Na2B4O7) showing OA signals.
Signal that is being irradiated is marked with an arrow. Observed TOCSY correlations
(Hc–He, Hd–Ha, and Ha–Hd) are shown in the right.
Formation of host–guest complexes was monitored by 1H NMR
spectroscopy. To characterize the nature of complexes formed, Total
Correlation Spectroscopy (TOCSY), Nuclear Overhauser Effect
Spectroscopy (NOESY), and Diffusion Ordered Spectroscopy (DOSY)
experiments were carried out.22,23 In this section we present the
NMR spectra relating to 1b@OA2 complex only. 1H NMR spectra of
other four complexes are provided in Supplementary data. 1H NMR
spectra of free OA and 1b@OA2 complex are shown in Figure 3 and
1D TOCSY and NOESY spectra are shown in Figures 4 and 5, re-
spectively. NMR signals of aromatic and alkyl parts of OA complexes
of 1a–e are provided in Figures 6 and 7, respectively.
2.2. Stoichiometry of the complex
Host–guest ratio of the complex was established by two
methods. Firstly, when greater than 0.5 equiv of the guest was
Figure 6. Partial 1H NMR spectra (500 MHz, D2O) showing the aromatic signals of the
complex formed between OA and (i) 1a, (ii) 1b, (iii) 1c, (iv) 1d, and (v) 1e. Each host
signal is shown in different color as labeled in (v).
added to 1 equiv of OA solution, the solution became turbid in-
dicating presence of free undissolved guest. No signals due to the
uncomplexed guests were recorded in the 1H NMR. Integration of
the 1H NMR spectrum of the complex at this stage showed a 2:1
host to guest ratio. Secondly, DOSY experiments were performed to
identify the diffusion constants (D) of the complexes. The calcu-
lated diffusion coefficients in the units of 10ꢂ10 m2 sꢂ1 are 1.32
(1a@OA2), 1.27 (1b@OA2), 1.26 (1c@OA2), 1.29 (1d@OA2), and 1.35
(1e@OA2). The measured diffusion coefficients were lower than
that of free OA (1.88ꢁ10ꢂ10 m 2sꢂ1) and were comparable to the 2:1
host–guest complexes formed between OA and guests like dibenzyl
Figure 5. NOESY NMR spectrum (500 MHz, 298 K, D2O, 0.5 s mixing time) of 1b@OA2
complex (5 ꢁ 10ꢂ3 M OA and 5 ꢁ 10ꢂ2 M Na2B4O7).

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7281
Figure 7. Selected regions of the 1H NMR spectra (500 MHz, D2O, 5ꢁ10ꢂ3 M OA, and 5ꢁ10ꢂ2 M sodium tetraborate) showing the aliphatic regions of OA complexes of 1a, 1b, 1c, 1d,
and 1e. Methyl groups of the chiral auxiliary and of the pyridone ring are labeled 1 and 2, respectively, as shown in Figure 8. Change in chemical shift upon binding to OA with
respect to the NMR spectrum recorded in CDCl3 (Dd) is also shown for each signal.
ketone. In the DOSY NMR spectra (Supplementary data), both the
host and the guest signals show similar diffusion coefficients,
confirming that the complexes formed were stable in the NMR time
scale.
(2.2 ppm) denoting its position in the central wider region of the
capsule.
2.4. Effect of guest binding on the NMR spectra of the host
Further analysis of the NMR spectra of the complexes is divided
into two sections, one concerning the guest and the other of the
host. With the host–guest ratio of 2:1 we visualize the complex has
a capsular structure and refer to the complex as a capsule in the
text. The capsule is made up of two host cavities. Since addition of
more than half an equivalent of the guest to 1 equiv of the host
resulted in turbidity, binding constant measurements could not be
carried out. Further, addition of more than half an equivalent of
guest did not result in any new peaks indicating that no free guest
remained in solution. Also, during the titration experiments no
peak shifts were observed suggesting that at 5 mM all the com-
plexes assembled and disassembled slowly (but close to, vide infra)
on the NMR time scale.
In the NMR spectrum of free OA (Fig. 3, bottom), six aromatic
signals (signals a–f) can be seen. Theoretically, in the ternary
complex formed between a guest (1a–e) and two OA, two kinds of
signal splitting are expected. First, the complex is chiral and so
protons that are enantiomeric in the free host (Ha and He) become
diastereotopic in the complex. Second, because each molecule of
OA accommodates different parts of the guest, the two OA ‘hemi-
spheres’ (top and bottom, Fig. 1) are non-equivalent. Hence, there
should be two signals for protons Hb, Hc, Hd, and Hf (the top/bottom
divide), whilst protons Ha and He should be split into four signals
(diastereotopicity and the top/bottom divide). The complex with
1b@OA2 does not show this degree of splitting; only two signals are
split into two. To help identify these signals, a 1D selective TOCSY
NMR of the complex with 1b was collected. Figure 4 shows the
partial spectrum. In OA, three sets of interacting aromatic hydro-
gens Ha and Hd, Hc and He, and Hb and Hf (Fig. 1) are present. TOCSY
correlations were observed for two of these: Ha and Hd, and Hc and
He. Thus, in the complex with 1b@OA2 only the signals from Ha and
He are seen to split (Fig. 3, top, Fig. 4) and there is no observable top/
bottom divide for Hb, Hc, Hd, and Hf. It is not possible to identify
with this experiment whether the splitting of Ha and He is due to
their inherent diastereotopicity, or because the top/bottom divide
leads to relatively large splitting for these particular protons and
the assembly and disassembly rate of the capsule is such that only
the splitting of these protons is observable (kc¼2.22Dn). 1D TOCSY
spectra of the complexes between OA with other guests (Supple-
mentary data) were used to identify aromatic signals of each host
and are collected in Figure 6.
2.3. Effect of host binding on the NMR spectra of the guest
As anticipated, magnetic shielding by the aromatic walls of the
host induced upfield shifts of the guest signals. Analysis of the high
field region was especially useful with this set of guests. Shown in
Figure 7 are the partial 1H NMR spectra (0 to ꢂ4 ppm) of the
complexes formed by guests 1a–e. Chemical shifts of the methyl
signals from the chiral auxiliary are in the same region in all five
spectra. This observation reveals that for all the different guests, the
methyl groups present in the chiral auxiliary are in a similar posi-
tion inside the capsule.
Chemical shifts of signals corresponding to the methyl group on
the pyridone ring were affected to different extents. Difference in
chemical shifts of the methyl signals in CDCl3 and when bound to
octa acid (Dd) is also shown in Figure 7. The maximum shift of
4.7 ppm was observed for 1c (Fig. 7). Such a large shift of the methyl
signal denotes strong shielding because it resides in the narrower
region of the capsule where aromatic walls of the host converge.
The shielding effect is lesser with the methyl groups of 1b and 1d
(4.2 ppm each). Pyridyl methyl of 1e was the least shielded
The position of the methyl substituent on the pyridone ring in
1a–e had a significant impact on the NMR spectra of the host.
Among the five complexes, host signals were split most with guests
1c and 1d (Fig. 6). While the diastereotopic Ha signals appeared as
doublets in every complex, multiplicity of other aromatic hydrogen

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signals was not consistent. Figure 6 shows the aromatic region of
the NMR spectra of each complex. A brief description of each
complex is provided below.
moved toward coalescence. This is in agreement with the obser-
vation that from the perspective of the host aromatic protons as-
sembly and disassembly are close to the NMR time scale.
Unfortunately, due to experimental limitations spectra could not be
recorded at temperatures higher than 313 K.
In addition to the above assembly–disassembly, rotation of
a bound guest molecule is possible along the longitudinal (polar)
axis and along the equatorial axis of the complex (Fig. 12). 1H NMR
data reported here suggest dynamic behavior along both axes. For
ease of visualization, the two OA molecules are distinguished using
two colors (red and blue) in Figure 12. Guest rotation along the long
axis (axis II in Fig. 12) is generally rapid. The four subunits of OA are
not distinguished in the NMR spectra due to the rotation of the
guest along the long axis.
Rotation of the guest along the equatorial axis of the host (axis 1
in Fig. 12) is relatively challenged by the available space inside the
capsule, especially with guests like 1a–e. However, with guests like
4-methylanisole,24 acetophenone,25 and quioniline25 incarcerated
in smaller hemicarceplexes, rotation of the guest along the short
axis of the host has been reported. Such a guest rotation remained
a possibility in our guest–host complexes also.
In the NOESY NMR spectrum of 1d@OA2 complex (Fig. 13),
NOESY correlations between the methyl group 2 of 1d and both the
Hg signals of the host supported the exchange of guest between the
two OA molecules that form the capsule. In the absence of rotation
along axis-2, each ring of the guest must be confined to the cavity of
one host molecule, and hence, NOE correlation for the methyl
group must also be restricted to only one Hg signal. Rotation of the
guest is rapid enough that signals of equal intensity are observed in
the NOESY NMR spectrum. However, NOE relationship with both Hg
signals could also be due to the occurrence of assembly–disas-
sembly in the NMR time scale. Given that we have collected data at
long mixing time scale (0.5 s) this can’t be ruled out. We plan to
carry out NOE experiments at several mixing time to ascertain what
is responsible for the NOE correlation with Hg protons of the top
and bottom parts of the capsule. Absence of clearly split Hg signals
in the NMR spectrum of other complexes limits our analysis to this
example.
(i) In 1a@OA2 complex, two signals were observed for Ha. The
signal from Hd was also broadened significantly. Other host
signals were not split.
(ii) Relatively sharp, host signals were observed for 1b@OA2
complex. However, only diastereotopic Ha and He signals were
split into doublets.
(iii) The complexes 1c@OA2 showed a good deal of splitting, but
overall the peaks were poorly resolved.
(iv) The complexes 1d@OA2 showed the theoretical splitting for all
the signals, but overlap of the Ha and Hb signals, and overlap
among the four signals for He, was evident.
(v) With the 1e@OA2 complex, only Ha signal was split. Unlike the
complexes formed with 1c and 1d, one set of signals for Hc, Hd,
and Hf was observed.
These results demonstrate that from the perspective of the ar-
omatic signals of the host, assembly and disassembly are close to
the NMR time scale. It is only because of the large shifts experi-
enced by the methyl groups of the guest that assembly and disas-
sembly appear slow on the NMR time scale (kc¼2.22Dn) from their
perspective.
Although only the methyl signals of the guest were observable
(other guest signals were either obscured by those from the host or
too small to readily identify) some useful NOE interactions between
host and guest were observed. These provided insight into the
relative position of the guest inside the capsule. While the NOESY
spectrum of 1a@OA2 lacked any informative correlations, in the
NOESY NMR spectrum of the other guests (Fig. 5 and Supplemen-
tary data) NOEs between the inward pointing Hg signal of the host
and the pyridyl methyl of the guest were evident. In contrast, the
benzyl methyl of 1c, 1d, and 1e shows NOE correlations with
‘equatorially’ positioned Hd of the host. This result is significant in
assigning the two methyl signals of 1e@OA2 complex. In the
1e@OA2 complex, NOE interaction between Hg and only one guest
methyl is observed, and it is assigned as the pyridyl methyl. The
NOESY interactions in complexes of guests 1b–e are pictorially
represented in Figures 8 and 9. In the two figures two possible
conformations of each pyridone ring are presented. However, of the
two, the intramolecular hydrogen-bonded conformations shown in
Figure 9 are expected to be favored within the non-polar OA cap-
sule. All further discussions use this conformation to represent 1
within OA capsule.
Based on NMR analysis, we visualize the structures of the
complex formed between OA and guests 1a–e as in Figure 10. In
summary, NMR experiments demonstrated that OA formed stable
2:1 complexes with the guests 1a–e, in which the guest adopts
a general orientation shown in Figure 10. It should be apparent that
we represent all five molecules in intramolecular hydrogen-bonded
conformations within the OA capsule. The only difference between
these host–guest structures is the location of the methyl group in
each case within the OA capsule.
In summary, formation of stable 2:1 complexes of OA and guests
1a–e was established by NMR spectroscopy. The differential mag-
netic shielding effect of the host on the guest resonances was il-
lustrated with the chemical shifts of the two methyl group signals
of the guests. Dynamic behavior of the bound guest was also
identified using NOESY and TOCSY NMR analysis of the complexes.
Note that the NMR data provide information on the rotational
motion in a much longer time scale than excited state time scale
(w10ꢂ9 s). In the excited state time scale, most likely, the guest
molecule is stationary and the photobehavior could be understood
on the basis of the average structures presented in Figure 10.
2.6. Results of photochemical studies
1H NMR spectra of the complexes of guests 1a–e and OA sug-
gested a possibility of co-existence of 2:1 and 1:1 host–guest
complexes at 298 K, when less than 10ꢂ3 M solution of OA was
used. To increase the binding and the stability of the complex, the
photocyclization reactions were carried out using 5ꢁ10ꢂ3 M OA
solutions (2.5ꢁ10ꢂ3 M guest). As indicated in the earlier section at
this concentration only 2:1 complex was present in solution.
Products of irradiations were analyzed by HPLC using chiral sta-
tionary phase column. In the photolysis studies, compounds A and
B represent the photoproducts formed from the disrotatory/con-
rotatory cyclization of the pyridone. When analyzed by HPLC, the
first product signal was arbitrarily assigned as A and the second
signal as B. The structures of A and B are as shown in Scheme 2. No
attempt was made to ascertain the absolute configuration of the
2.5. Dynamic behavior of the guests inside the capsule
In the proposed structures of the complexes (Fig. 10), each OA
molecule of the capsule accommodates either the phenyl ring or
the pyridone ring of the guest. To investigate the dynamics of guest
movement, variable temperature NMR spectra were recorded.
Figure 11 shows the NMR spectra of 1d@OA2 complex recorded
between 278 K and 313 K. Below room temperature, signals were
observed to sharpen, while at higher temperatures, most signals

A.K. Sundaresan et al. / Tetrahedron 65 (2009) 7277–7288
7283
Figure 8. Pictorial representation of NOE correlations observed between OA and guest molecules. Also see Figure 9.
photoproducts. However, since the products were not distin-
guished from one another, we did not assign the structures spe-
cifically in Scheme 2. Similarly, HPLC analysis showed that
product A (i.e., the first product signal) was formed in excess in all
substrates.
The first methyl-substituted pyridone analyzed as OA complex
was 1c, where the methyl substituent is para to the nitrogen and
hence, para to the chiral auxiliary. The observed diastereoselectivity
increased from 17% observed for 1a to 41% for 1c. Further en-
hancement of de was achieved by changing the reaction tempera-
ture to 278 K. The selectivity increased to 64% from 41% at 298 K.
Encouraged by the observations, other methyl-substituted de-
rivatives were examined. Results of photochemical investigation
with guests 1a–e in acetonitrile and as OA complex are summarized
in Table 1. All guests were solids and not soluble in water or borate
buffer. Hence irradiation of these guests (in the absence of OA) was
not performed in buffer solutions and comparison was made to the
results in acetonitrile.
Our initial studies with 1a appended with either (S) or (R) a-
methylbenzyl amine chiral auxiliary were encouraging. These gave
16% and 17% excess of one diastereomer as monitored by HPLC.
Although the de obtained was small, difference between acetoni-
trile solution without OA (1% de) and water with OA (17% de)
suggested that OA is capable of forcing an interaction between the
chiral auxiliary and reaction center. Prompted by this result we
investigated the photochemistry of methylated systems 1b–e.
Choice of methylation was dictated by our previous observation
with methylstilbenes and methylcyclohexene bound to OA, which
suggested that the guest’s methyl substituent could help better
anchor the guest in the OA cavity.
Introduction of methyl substituent had considerable impact on
the photochemistry of the bound guest. As with 1c, not only did the
photochemistry of the guests show
a remarkable diaster-
eoselectivity after methyl substitution, the observed selectivity also

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Figure 9. Pictorial representation of NOE correlations observed between OA and each guest. The guests are represented by intramolecular hydrogen-bonded structures.
varied with the position of the substituent. In general, the dia-
stereoselectivity was greater when the reaction was carried out at
278 K (5 ꢀC). While the highest selectivity was observed with
3-methyl derivative (1b), the 73% preference for one diastereomer
at 298 K increased to 92% at 278 K in the case of 1b@OA2. The
diastereoselectivity obtained from room temperature irradiation of
1d@OA2 was 60% and it improved to 70% at 278 K. Finally, with
methyl substituent at the ortho-position (1e) 50% and 56% selec-
tivity were observed at 298 K and 278 K, respectively.
We believe that the observed diastereoselectivity is not con-
trolled entirely by anyone participant (chiral auxiliary, the host,
and/or the methyl substituent), but by a combination of all three.
Control experiments carried out in the absence of anyone of the
three ‘participants’ confirmed this hypothesis. When the reaction is
Figure 10. Proposed structures of 2:1 complexes formed between OA and guests 1a–e.

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7285
Figure 11. Partial 1H NMR spectra (500 MHz, D2O) of 1d@OA2 complex (5ꢁ10ꢂ3 M OA and 5ꢁ10ꢂ2 M Na2B4O7) recorded at temperatures between 278 K and 313 K. The temperature
at which each spectrum was recorded is shown on the left side of the spectrum. Host signals are labeled a–f as shown in Figure 1. Guest methyl signals are labeled 1 and 2 as shown
in Figure 8. Intensity (Y-axis) of the methyl signals is greater than the intensity of the aromatic region.
performed in acetonitrile (i.e., in the absence of the host, but in the
presence of the auxiliary and the methyl group), the product was
racemic. Similarly, selectivity was low from 1a bound to OA, illus-
trating the importance of the methyl substituent. To ensure that the
reaction is not affected by OA alone (in the absence of the chiral
auxiliary), photolysis of OA complexes of N-propyl-2-pyridone and
N-pentyl-2-pyridone was carried out. A racemic mixture of photo-
products was isolated. Based on these control experiments, we
conclude that the three groups viz., OA, chiral auxiliary, and the
methyl substituent have a synergetic effect on the photocyclization
process.
on the pyridone ring control the extent of de? (c) How does the
chiral communication occur between the chiral auxiliary and the
reaction center within the OA capsule?
We have previously established that high chiral induction on
a variety of photoreactions could be achieved within a zeolite,
a medium where cation/p interaction restricts the conformational
flexibility of the chiral auxiliary.26–30 We believe that similar re-
striction of the chiral auxiliary occurs within the OA capsule. How-
ever, within the OA capsule no weak interaction is expected as in
zeolite and therefore the conformational restriction must result from
tight inclusion. Thusthefreespacewithin thecapsuleis animportant
parameter to be considered during the chiral induction process
withintheOAcapsule. Togainanunderstandingofthis parameterwe
need to have knowledge of theguest structurewithin the OA capsule.
The NMR data have provided an insight into the structure of the
guest (in the NMR time scale) within the OA capsule. Although we
have inferred from the NMR data that the guest within OA capsule
3. Discussion
The results of photochemical reactions pose the following
questions: (a) Why there is a difference in de between isotropic
solution and OA capsule? (b) How does the position of the methyl
Figure 12. Representation of the two possible rotations of a guest bound to the host capsule.

7286
A.K. Sundaresan et al. / Tetrahedron 65 (2009) 7277–7288
In Figure 14 rotations that are more likely and less likely within
the capsule are also indicated. Rotations (rotations 1, 2, and 3 in
Fig. 14) that involve large positional change of the phenyl or pyr-
idone rings that are anchored at the two hemispheres of the cap-
sule are unlikely. As long as the CH2–CO–NH–CHR0 adopts a folded
structure in the mid-region of the capsule, rotation-4 is likely to flip
the molecule between the hydrogen-bonded and non-hydrogen-
bonded structures (Figs.
8 and 9). Considering that the
intramolecular hydrogen-bonded structure is more stable such
a rotation is unlikely within the capsule. Thus while in solution
phase rotations of various single bonds would be expected to freely
occur, within the OA capsule many such rotations would be re-
stricted. Thus while in an isotropic solution the chiral auxiliary is
expected to have conformational freedom and the chiral center is
unlikely to be rigid with respect to the reaction site, within OA
capsule the opposite holds. Thus, the role of OA is not only to retain
the substrate (pyridone ring) and the chiral auxiliary in close
proximity in its cavity for an extended period of time, but also to
hold the chiral group in a single conformation with respect to the
reaction site. We believe that this important difference is likely to
be the origin of chiral induction within the OA capsule.
Figure 13. Partial NOESY NMR spectrum (500 MHz, 298 K, buffered D2O, 0.5 s mixing
time) of 1d@OA2 complex (5 ꢁ 10ꢂ3 M OA and 5 ꢁ 10ꢂ2 M Na2B4O7) showing the in-
teractions between the two methyl groups of the guest and the host.
is mobile in the NMR time scale the guest is expected to be rigid and
not to undergo rotational motions within the capsule in the excited
state (S1, <10ꢂ9 s) time scale. We believe that the host–guest
structure shown in Figure 10 is a good starting point for un-
derstanding the chiral induction within the OA capsule.
The 1H NMR chemical shift of the methyl-1 (on the chiral aux-
iliary) is nearly identical (d approx. –0.15 ppm, Fig. 7) in all five
Compared to unsubstituted pyridone system 1a, methylated
pyridone systems 1b–e gave higher chiral induction in the photo-
products (21% vs 56–92%). Clearly the methyl group, independent
of its location in the pyridyl ring, has a significant impact on the
chiral induction (Table 1). We speculate that this most likely results
from the snug fit of the methyl substitued pyridone (with respect to
the unmethylated 1a) within the capsule. The presence of greater
free space within the 1a@OA2 capsule does not seem to signifi-
cantly differentiate the inward and outward motions during the
disrotatory cyclization of the pyridone ring (Scheme 2). Results
with pyridone 1f (Table 1) provided further support to the above
rationale. The chiral auxiliary part in 1f is much smaller than that in
1b–e. Therefore this molecule would be expected to fit loosely
leaving considerable free space within the OA capsule. As expected
based on free space model this molecule would be expected to yield
low de. In fact 1f yields 0% de both in acetonitrile solution and in OA
capsule at room temperature.
Our answer to ‘Why the de depends on the position of the
methyl group on the pyridone ring’ admittedly, is speculative. As
stated above the pyridone part occupies one half of the capsule
such that N–R (R¼chiral auxiliary) bond is parallel to the long
axis of the capsule. With the dimensions of the differently
methyl-substituted pyridones provided in Figure 15 it is easy to
visualize how the width of the pyridone part would determine
how deep it would penetrate the capsule. For example, the nar-
rower 1c would go deeper than 1e, which is wider at the top.
Such a positioning would leave considerable unoccupied space
below the pyridone ring in 1e. Pyridone 1e gives the lowest de
(56%) amongst the four methylated pyridones. This possibly
suggests that larger free space in the capsule allows for ring
closure by either mode shown in Scheme 2 leading to moderate
de. The second lowest de (64%) with 1c expected to fit snugly
within the capsule makes us wonder if a tight fit, like too loose
one, is not conducive to distinguish the two modes of rotations.
The best de is obtained with 1b and 1d (92% and 70%) that have
similar width (Fig. 15). These two molecules as indicated in Fig-
ures 8 and 9 would be expected to have their pyridone rings
midway between the widest and narrowest regions of the cap-
sule with a free space intermediary between those of 1c and 1e.
This delicate balance between free space and tight fit may be
responsible for the observed higher de in these two cases, es-
pecially in 1b. Overall we believe that free space plays a critical
role in the chiral induction process within the capsule. At this
stage we are unable to estimate the exact amount of free space
and link it mechanistically to the extent of de.
guests suggesting that its position remains almost the same within
OA capsule in all five structures, most likely in the broader region
slightly below the middle portion of the capsule. Thus the chiral
auxiliary part (a-methylbenzyl amide) is envisioned to be at one
half of the capsule with the
a
-methyl in the mid-region and the
benzyl stretching to the bottom. The 1H NMR chemical shifts of the
methyl-2 (on the pyridone ring) vary between 0.2 and ꢂ2.5 ppm
(Fig. 7). The maximal and minimal shifts for 1c and 1e, respectively,
suggest that in the former it is at the deepest part and in the latter it
is in the mid-region of the capsule. Nearly identical shifts in 1d and
1b suggest that the methyl-2 in these two cases is slightly below
the mid-region of the cavity. Based on the 1H NMR chemical shift of
the methyl-2 we believe that the pyridone ring resides in one half
of the capsule such that pyridone N–R (R¼chiral auxiliary) bond is
parallel to the long axis of the capsule. Similarly, based on the near
identical chemical shift of methyl-1 in pyridones 1b–e we believe
that the benzyl part of the chiral auxiliary is anchored into the other
half of the capsule and the Ph–C(CH3)H bond is parallel to the long
axis of the capsule. The mid-part of the molecule (CH2–CO–NH–
CHR0) connecting the pyridone and the chiral auxiliary (
a-methyl
benzyl group) probably adopting a folded structure remain in the
mid-region of the capsule.
Table 1
Diastereomeric excessa,b observed in the cyclization reaction of guests 1a–e in
acetonitrile and as OA complexes at different temperatures
Guest
Medium
% deb at two temperatures
298 K
278 K
1a
1b
1c
1d
1e
CH3CN
OA complex
1 (A)
17 (A)
d
21 (A)
CH3CN
OA complex
4 (A)
73 (A)
d
92 (A)
CH3CN
OA complex
2 (B)
41(A)
d
64 (A)
CH3CN
OA complex
0
d
60 (A)
70 (A)
CH3CN
2 (A)
d
OA complex
50 (A)
56 (A)
1f
CH3CN
OA complex
2
2
a
The results are based on HPLC analysis using chiral column and are average of at
least three independent runs.
b
The first photoproduct signal is assigned A and the second signal is assigned as B.
% de is calculated using the ratio [area of Aꢂarea of B]ꢁ100/[area of Aþarea of B].

A.K. Sundaresan et al. / Tetrahedron 65 (2009) 7277–7288
7287
N
N
N
N
N
O
H
O
H
O
H
O
H
O
H
O
O
O
O
O
N
N
N
N
N
H3C
H3C
H3C
H3C
H3C
Rotation-1
Rotation-2
Rotation-3
Rotation-4
Rotation-5
Unlikely rotations within the capsule
Likely rotations within the capsule
Figure 14. Probable and improbable rotational motions of 1a within OA capsule. This model is applicable to other systems as well.
4. Summary
We have achieved significant chiral induction (92%) during the
5.2. General procedure for synthesis of 1a–e
5.2.1. (R)-2-Bromo-N-(1-phenylethyl)ethanamide
photocyclization of pyridones within a hydrophobic capsule. Such
high chiral induction in a hydrophobic capsule, to our knowledge,
is unprecedented. Controlling free space and freedom of rotation
are major factors in deciding the efficiency of chirality transfer
between the chiral auxiliary and the reaction site. For instance,
reactions in solid state yield better selectivity than in solution
state due to the denser packing of molecules curbing the sub-
strate’s motion in the former. Similarly, one can expect the sub-
strate bound to OA to experience greater influence of the host
when the packing is efficient. At this stage ‘How the chiral com-
munication occurs between the chiral auxiliary and the reaction
center within the OA capsule’ remains a question. Given that this
is our inaugural publication on chiral induction within a hydro-
phobic capsule we are optimistic that with time we will be able to
better understand this phenomenon. We are optimistic that with
time this initial result of ours on chiral induction within a hydro-
phobic capsule would provide a better understanding of this
phenomenon.
Br
H2C
H
N
H2N
CH3
CH3
EDC.HCl, DMAP
CHCl3
+
HOOC
CH2Br
O
To a solution of bromoacetic acid (2.52 mmol, 1.1 equiv) in
CHCl3, N-ethyl-N0-(3-dimethylaminopropyl)carbodiimide hydrochlo-
ride (2.5 mmol,1.1 equiv), and 4-(dimethylamino)pyridine (0.5 mmol)
were added. The solution was stirred for 30 min at ambient tempera-
ture. (R)-a-Methylbenzyl amine (2.3 mmol, 1 equiv) was added in one
portion and the reaction mixture was stirred at room temperature for
further 16 h. The reaction was quenched by adding 10 mL of water. The
organic layer was separated and washed with three portions of water,
dried over anhydrous sodium sulfate, and concentrated. Excess bro-
moacetic acid and the coupling reagents were removed by flash
chromatography (silica gel, chloroform, methanol) to isolate the
product as white solid.
5. Experimental
5.2.2. (R)-2-(3-Methyl-2-oxopyridin-1(2H)-yl)-N-(1-
phenylethyl)ethanamide 1b
5.1. General methods
Host octa acid was synthesized and characterized using
literature procedures. Synthesis of compounds 1a–e using
reported procedures is explained below. 1H NMR spectra were
recorded using Bruker Avance 300, 400 or 500 MHz spec-
trometers at 298 K unless mentioned otherwise. Photoproducts
of 1a–e were separated by HPLC analysis using Rainin HPLC
instrument fitted with Chiralcel AD column and hexane and 2-
propanol as eluants.
H3C
Br
H
O
N
H3C
HO
H2C
N
CH3
H
N
K2CO3, NaY
CH3CN
CH3
+
O
N
O
Reagents used for this coupling required activation prior to
synthesis. NaY zeolite was dried in an oven for at least 5 h at 500 ꢀC.
Potassium carbonate was dried at 150 ꢀC for 3 h. 3-Methyl-2-
hydroxypyridone (1 equiv) in acetonitrile was refluxed with acti-
vated zeolite and potassium carbonate (2 equiv) for 1 h, following
which ((R)-2-bromo-N-(1-phenylethyl)ethanamide) was added.
After overnight stirring at reflux, the solution was filtered while
warm to remove the inorganic solids. Acetonitrile was distilled and
the crude mass was purified by passing through a silica column
with chloroform and methanol as eluants. The product was char-
acterized by 1H NMR and 13C NMR spectroscopy. Similar procedure
Figure 15. Width of the pyridone rings of the four methyl-substituted guests.

7288
A.K. Sundaresan et al. / Tetrahedron 65 (2009) 7277–7288
was used for synthesis of compounds 1a and 1c–e using the ap-
propriate 2-hydroxypyridone.
stebpgp1s sequence. 1H NMR spectra of OA complexes of 1a, 1c, 1d,
and 1e (27 figures in total) are provided in Supplementary data.
5.2.3. NMR characterization
Acknowledgements
Compound 1a: 1H NMR (500 MHz, CDCl3)
d 7.69 (s, 1H), 7.39
(s, 2H), 7.26 (m, 4H), 6.59 (d, J¼8.5 Hz, 1H), 6.25 (d, J¼8.5 Hz,
V.R. greatly appreciates the continuous encouragement, pene-
trating discussions, and critical comments by Professor R. S. H. Liu
to whom this paper is dedicated. V.R. thanks the National Science
Foundation, USA for financial support (CHE-0213042 and CHE-
0531802). C.L.D.G. and B.C.G. thank the National Institute of Health
(RO1 GM074031) for financial support.
1H), 5.03 (t, J¼6 Hz, 1H), 4.68 (d, J¼14 Hz, 1H), 4.48 (d, J¼14 Hz,
1H), 1.43 (d, J¼5.5 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 166.5,
163.2, 143.5, 140.9, 139, 128.9, 127.5, 126.4, 120.8, 107.2, 53.7,
49.5, 22.5.
Compound 1b: 1H NMR (500 MHz, CDCl3)
d
7.45 (s, 1H), 7.3 (m,
6H), 6.2 (t, 1H), 5.1 (t, 1H) 4.6 (s, 2H), 2.2 (s, 3H), 1.4 (d, 3H). 13C NMR
(100 MHz, CDCl3) 166.8, 143.4, 138.1, 135.8, 130.3, 128.9, 127.5,
d
Supplementary data
126.2, 107, 54.8, 49.5, 22.6, 17.5.
Compound 1c: 1H NMR (500 MHz, CDCl3)
d 7.84 (s, 1H), 7.27–
General experimental procedures and extensive NMR data of
host–guest complexes are provided as electronic supplementary
file (28 pages). Supplementary data associated with this article can
be found in the online version, at doi:10.1016/j.tet.2009.01.110.
7.21 (m, 5H), 6.36 (s, 1H), 6.10 (d, J¼6.5 Hz, 1H), 5.023 (t, J¼7 Hz,
1H), 4.66 (d, J¼14.5 Hz, 1H), 4.45 (d, J¼14.5 Hz, 1H), 2.2 (s, 3H),
1.42 (d, J¼6.5 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 166.8, 152.8,
143.5, 137.7, 128.9, 127.5, 126.4, 119.2, 109.7, 53.4, 49.5, 22.5,
21.7.
References and notes
Compound 1d: 1H NMR (500 MHz, CDCl3)
d 7.8 (d, 1H), 7.25 (m,
6H), 6.53 (t, J¼9 Hz, 1H), 5.03 (q, J¼7 Hz, 1H), 4.62 (t, J¼14.5 Hz, 1H),
1. Inoue, Y.; Ramamurthy, V. Chiral Photochemistry; Marcel Dekker: New York, NY,
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127.5, 126.3, 120.4, 116.3, 54.1, 49.5, 22.6, 17.3.
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5 mM solutions of octa acid containing 50 mM sodium tetra-
borate in D2O. A stock solution of the guest dissolved in CD3CN,
typically in 1 mg/mL concentration was prepared. An aliquot of
the stock solution corresponding to 0.5 equiv of octa acid was
taken in a vial and the solvent was evaporated in a stream of
air. Octa acid (0.6 mL, 5 mM solution) was added and the so-
lution was stirred for 30 min. Complete solubilization of the
guest was achieved at this time based on NMR analysis of the
solution. The vial was sealed with a septum and nitrogen was
bubbled through the solution for 30 min prior to irradiation.
Irradiation was carried out to obtain 20–30% conversion (3–4 h).
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by HPLC analysis and were compared with the photoproducts
obtained when compounds 1a–e were irradiated in CH3CN.
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5.4. Parameters for 1H NMR, 1D selective TOCSY NMR, 2D
NOESY NMR, and DOSY NMR analysis
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presaturation technique with Bruker’s pulse program zgcppr. 1D
selective TOCSY NMR experiments were performed with Bruker’s
pulse sequence selnogp.3. The mixing time used for TOCSY experi-
ments was 0.120 s. 2D NOESY experiments were performed with
0.5 s mixing time. DOSY NMR experiments were recorded using
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