Enhanced diastereoselectivity via confinement: Photoisomerization of 2,3-diphenylcyclopropane-1-carboxylic acid derivatives within zeolites

Article abstract of DOI:10.1021/jo049365i

From the perspective of asymmetric induction, the photochemistry of 24 chiral esters and amides of cis-2,3-diphenylcyclopropane-1-carboxylic acid from excited singlet and triplet states has been investigated within zeolites. The chiral auxiliaries placed

Full text of DOI:10.1021/jo049365i

En h a n ced Dia ster eoselectivity via Con fin em en t:
P h otoisom er iza tion of 2,3-Dip h en ylcyclop r op a n e-1-ca r boxylic Acid
Der iva tives w ith in Zeolites
J . Sivaguru,† Raghavan. B. Sunoj,‡ Takehiko Wada,§ Yumi Origane,| Yoshihisa Inoue,§,| and
Vaidhyanathan Ramamurthy*,†
Department of Chemistry, Tulane University, New Orleans, Louisiana 70118, Department of Chemistry,
Indian Institute of Technology, Bombay, Mumbai 400076, India, Department of Molecular Chemistry and
PRESTO (J ST), Osaka University, 2-1 Yamada-oka, Suita 565-0871, J apan, and
ICORP Entropy Control Project, J ST, 4-6-3 Kamishinden, Toyonaka 560-0085, J apan
murthy@tulane.edu
Received April 15, 2004
From the perspective of asymmetric induction, the photochemistry of 24 chiral esters and amides
of cis-2,3-diphenylcyclopropane-1-carboxylic acid from excited singlet and triplet states has been
investigated within zeolites. The chiral auxiliaries placed at a remote location from the isomerization
site functioned far better within a zeolite than in solution. Generally, chiral auxiliaries with an
aromatic or a carbonyl substituent performed better than the ones containing only alkyl substituents.
A model based on cation-binding-dependent flexibility of the chiral auxiliary accounts for the
observed variation in de between aryl (and carbonyl) and alkyl chiral auxiliaries within zeolites.
Cation-dependent diastereomer switch was also observed in select examples.
In tr od u ction
Asymmetric photochemistry in the crystalline state is
based on “chance” crystallization of achiral molecules in
a chiral space group.3a,b Because of its limited probability,
there are only very few examples of asymmetric induction
during photolysis of achiral molecules in the crystalline
state. A more general methodology known as the “ionic
chiral auxiliary approach” introduced by Scheffer facili-
tated achiral molecules to crystallize in a chiral space
group.3c This approach is limited to molecules with
carboxylic acid groups that form crystallizable salts with
chiral amines or vice versa. Recognizing the problem of
crystallizing achiral molecules in a chiral space group,
several researchers have explored chiral hosts as the
reaction medium.3d The success of this approach is
limited to guests that can form solid solutions with the
host without disturbing the host’s macrostructure. The
reactivity of molecules in the crystalline state and in solid
host-guest assemblies is controlled by the details of
molecular packing. Currently, molecular packing and
consequently the chemical reactivity in the crystalline
state cannot be reliably predicted. Therefore, even after
successfully crystallizing a molecule in a chiral space
group or complexing a molecule with a chiral host or a
chiral auxiliary, there is no guarantee that the guest will
react in the crystalline state. Hence, even though crystal-
line and host-guest assemblies have been very useful
in conducting enantioselective photoreactions, their gen-
eral applicability thus far has been limited.
Following the communication by Hammond and Cole
in 1965 on the photosensitized isomerization of cis-
diphenylcyclopropane,1 several groups have performed
enantio- and diastereoselective phototransformations
both in solution2 and in the solid state.3 In solution,
despite considerable efforts, the enantiomeric excess (ee)
obtained under ambient conditions continues to be less
than 50%. The best results in solution have been obtained
via the chiral auxiliary methodology4 yielding in select
examples diastereomeric excess (de) close to 100%.
Unfortunately, the generality of this approach is yet to
be established.
† Tulane University.
‡ Indian Institute of Technology.
§ Osaka University.
| ICORP Entropy Control Project.
(1) Hammond, G. S.; Cole, R. S. J . Am. Chem. Soc. 1965, 87, 3256.
(2) (a) Inoue, Y. Chem. Rev. 1992, 92, 741. (b) Rau, H. Chem. Rev.
1983, 83, 535-547. (c) Laarhoven, W. H.; Cuppen, T. J . H. M. J . Chem.
Soc., Chem. Commun. 1977, 47. (d) Laarhoven, W. H.; Cuppen, T. J .
H. M. J . Chem. Soc., Perkin Trans. 2 1978, 315-318. (e) Balavoine,
G.; Moradpour, A.; Kagan, H. B. J . Am. Chem. Soc. 1974, 96, 5152. (f)
Zandomeneghi, M.; Cavazza, M.; Pietra, F. J . Am. Chem. Soc. 1984,
106, 7261-7262. (g) Moradpour, A.; Kagan, H.; Baes, M.; Morren, G.;
Martin, R. H. Tetrahedron 1975, 31, 2139. (h) Tsuneishi, H.; Hakushi,
T.; Inoue, Y. J . Chem. Soc., Perkin Trans. 2 1996, 1601-1605. (i) Inoue,
Y.; Wada, T.; Asaoka, S.; Sato, H.; Pete, J .-P. J . Chem. Soc., Chem.
Commun. 2000, 251-259.
(3) (a) Vaida, M.; Popovitz-Biro, R.; Leserowitz, L.; Lahav., M. In
Photochemistry in Organized and Constrained Media; Ramamurthy,
V., Ed.; VCH: New York, 1991; pp 247-302. (b) Evans, S. V.; Garcia-
Garibay, M.; Omkaram, N.; Scheffer, J . R.; Trotter, J .; Wireko, F. J .
Am. Chem. Soc. 1986, 108, 5648-5650. (c) Leibovitch, M.; Olovsson,
G., Scheffer, J . R.; Trotter, J . Pure Appl. Chem. 1997, 67, 815-823.
(d) Toda, F. Acc. Chem. Res. 1995, 28, 480. (e) Tanaka, K.; Fujiwara,
T.; Urbanczyk-Lipkowska, Z. Org. Lett. 2002, 4, 3255-3257.
(4) (a) Nehrings, A.; Scharf, H. D.; Runsink, J . Angew. Chem. 1985,
97, 882-883. (b) Inoue, T.; Matsuyama, K.; Inoue, Y. J . Am. Chem.
Soc. 1999, 121, 9877.
We believe that zeolites offer a solution to the above
limitations. For example, guest molecules present within
zeolites possess greater freedom than in crystals/solid
host-guest assemblies and less freedom than in isotropic
solvents. This permits molecules within zeolites to react
more freely than in crystals/solid host-guest assemblies
10.1021/jo049365i CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/31/2004
J . Org. Chem. 2004, 69, 6533-6547
6533

Sivaguru et al.
SCHEME 1
and more selectively than in solutions. Zeolites, unlike
organic host systems, can include a large number of
molecules, with the only limitation being that the dimen-
sions of the guest be less than the pore dimensions of
the zeolite.5 A variety of molecules can therefore be
included within a zeolite and induced to react. A major
deficiency is that the zeolite is not chiral. To provide the
asymmetric environment lacking in zeolites during the
reaction, a chiral source had to be employed. For this
purpose, in the approach we refer to as the “chiral
inductor method”, where optically pure chiral inductors
such as ephedrine were used, the nonchiral surface of
the zeolite becomes “locally chiral” in the presence of a
chiral inductor.6 This approach gave close to 15% ee with
several achiral cis-2,3-diphenylcyclopropane-1-carboxylic
acid derivatives in the presence of chiral inductors such
(5) (a) Ramamurthy, V. In Photochemistry in Organized and Con-
strained media; Ramamurthy, V., Ed.; VCH: New York, 1991; p 429.
(b) Breck, D. W. Zeolite Molecular Sieves, Structure, Chemistry and
Use; J ohn Wiley & Sons: New York, 1974. (c) Dyer, A. An introduction
to zeolite molecular sieves; J ohn Wiley & Sons: New York, 1988. (d)
Meier, W. M.; Olson, D. H. Atlas of Zeolite Structure Types, 3rd ed.;
Butterworth-Heinemann: London, 1992.
6534 J . Org. Chem., Vol. 69, No. 20, 2004

Enhanced Diastereoselectivity via Confinement
SCHEME 2
as optically pure 1-cyclohexylethylamine, pseudoephe-
drine, and norephedrine.7 Therefore, we have explored a
different strategy termed the “chiral auxiliary method”
in which the chiral perturber is connected to the reactant
via a covalent bond. We envisioned that a confined space
offered by a zeolite would augment the influence of a
chiral auxiliary.6,8 It is gratifying to observe that this has
been the case during the photoisomerization from S1 and
T1 of a number of cis-2,3-diphenylcyclopropane-1-car-
boxylic acid derivatives within alkali ion exchanged Y
zeolites.8a,9 The systems investigated and the products
of photoreactions are listed in Scheme 1. Chiral perturb-
ers were internally built into the reactants such that it
is present at a slightly remote location from the reaction
site. As discussed in this paper, these remotely located
chiral perturbers function much more effectively within
a zeolite than in an organic solvent medium. In this
process, alkali ions present within a zeolite play a crucial
role.
Resu lts
To explore the role of constrained environment (zeolite)
on the asymmetric induction during the geometric isomer-
ization of cis- to trans-diphenylcyclopropane, a detailed
photochemical study of cis-2,3-diphenylcyclopropane-1-
carboxylic acid derivatives affixed with chiral auxiliaries
(24 compounds in total) was undertaken. The results of
these studies are presented in this section.
(6) (a) Sivaguru, J .; Natarajan, A.; Kaanumalle, L. S.; Shailaja, J .;
Uppili, S.; J oy, A.; Ramamurthy, V. Acc. Chem. Res. 2003, 36, 509-
521. (b) Sivaguru, J .; Shailaja, J .; Uppili, S.; Ponchot, K.; J oy, A.;
Arunkumar, N.; Ramamurthy, V. In Organic Solid State Reactions;
Toda, F., Ed.; Kluwer Academic Press: Dordrecht, The Netherlands,
2002; pp 159-188. (c) J oy, A.; Ramamurthy, V. Chem. Eur. J . 2000,
6, 1287-1293.
(7) (a) Cheung, E.; Chong, K. C. W.; J ayaraman, S.; Ramamurthy,
V.; Scheffer, J . R.; Trotter, J . Org. Lett. 2000, 2, 2801-2804. (b)
Kaanumalle, L. S.; Sivaguru, J .; Sunoj, R. B.; Lakshminarasimhan,
P.; Chandrasekhar, J .; Ramamurthy, V. J . Org. Chem. 2002, 67, 8711-
8720.
(8) (a) Sivaguru, J .; Scheffer, J . R.; Chandarasekhar, J .; Ramamur-
thy, V. J . Chem. Soc., Chem. Commun. 2002, 830-831. (b) Kaanumalle,
L. S.; Sivaguru, J .; Arunkumar, N.; Karthikeyan, S.; Ramamurthy, V.
J . Chem. Soc., Chem. Commun. 2003, 116-117. (c) Uppili, S.; Rama-
murthy, V. Org. Lett. 2002, 4, 87-90.
(9) Sivaguru, J .; Shichi, T.; Ramamurthy, V. Org. Lett. 2002, 4,
4221-4224.
The stereoisomers (RR- and SS-isomers) of trans-8
were obtained in pure form by preparative HPLC (Chiral-
cel OD column). The absolute configuration of the isolated
isomers was assigned by matching their chiral GC/HPLC
retention times with those of pure isomers synthesized
as outlined in the Supporting Information. (2R,3R)-1-
Acetyl-2,3-diphenylcyclopropane 25 synthesized by a
procedure reported by Aggarwal and co-workers10,11
(Scheme 2) was used as the precursor for trans-26-RR.
J . Org. Chem, Vol. 69, No. 20, 2004 6535

Sivaguru et al.
TABLE 1. Ster eoselective P h otoisom er iza tion of cis-Dip h en ylcyclop r op a n e Der iva tives: Ester s a s Ch ir a l Au xilia r ies
% diastereomeric excess (de)a
medium
trans-1
trans-2
trans-3
trans-4
trans-5
trans-6
trans-7
solutionb
LiY
NaY
KY
RbY
CsY
TlY
4 (B)
50 (B)
55 (B)
30 (B)
22 (B)
5 (B)
3 (B)
25 (A)
40 (A)
6 (A)
5 (A)
3 (A)
5 (B)
12 (A)
32 (B)
7 (A)
5 (A)
2 (A)
0
4 (B)
7 (B)
16 (A)
7 (A)
5 (A)
2 (A)
5 (A)
2 (A)
6 (B)
7 (B)
13 (B)
13 (B)
4 (A)
78 (B)
19 (A)
11 (A)
1 (A)
14 (A)
19 (B)
13 (B)
5 (B)
2 (B)
38 (B)
51 (B)
SiO2
2 (B)
3 (A)
0
0
a
The first peak that elutes out of the GC/HPLC column is assigned as A and the second as B. Conversion was kept <25% (90 min
b
irradiation). A mixture of 0.5 mL of dichloromethane and 15 mL of hexane was used as solvent. 8 mL of acetonitrile as solvent gave
similar results.
TABLE 2. Ster eoselective P h otoisom er iza tion of cis-Dip h en ylcyclop r op a n e Der iva tives: Am id e a s Ch ir a l Au xilia r ies
% diastereomeric excess (de)a
medium
trans-8c
trans-9
trans-10
trans-11
trans-12c,d
solutionb
LiY
NaY
KY
RbY
CsY
TlY
2 (SS-isomer)
80 (SS-isomer)
28 (RR-isomer)
14 (RR-isomer)
5 (RR-isomer)
5 (RR-isomer)
37 (RR-isomer)
8 (RR-isomer)
3 (A)
17 (A)
30 (A)
20 (A)
6 (A)
6 (A)
10 (A)
7 (A)
2 (B)
29 (B)
24 (A)
26 (A)
29 (A)
37 (A)
2 (B)
7 (A)
7 (A)
3 (A)
12 (B)
23 (B)
4 (SS-isomer)
69 (SS-isomer)
7 (RR-isomer)
33 (RR-isomer)
0
8 (SS-isomer)
3 (SS isomer)
11 (SS isomer)
SiO2
a
The first peak that elutes out of the GC/HPLC column is assigned as A and the second as B. Conversion was kept <25% (90 min
irradiation). The absolute configurations of the isomers (except in the cases of 8 and 12) are not known, and they are not essential to
b
understand the mechanism of the chiral induction. A mixture of 0.5 mL of dichloromethane and 15 mL of hexane was used as solvent.
8 mL of acetonitrile as solvent gave similar results. c The absolute configuration identified by absolute asymmetric synthesis. The
d
irradiation was done both with Pyrex and quartz cutoff. The de did not change with the mode of excitation.
TABLE 3. Ster eoselective P h otoisom er iza tion of
(2R,3R)-1-Acetyl-2,3-diphenylcyclopropane was oxidized
cis-Dip h en ylcyclop r op a n e Der iva tives: Am in o Alcoh ols
a s Ch ir a l Au xilia r ies
to (2R,3R)-diphenylcyclopropane-1-carboxylic acid (trans-
26-RR) by the iodoform reaction (Scheme 2).12 trans-26-
RR was converted to trans-8-RR, trans-12-RR, and
trans-18-RR by ETC/DMAP coupling13 with (S)-(-)-1-
phenylethylamine, (S)-(-)-1-naphthylethylamine, and L-
valine methyl ester, respectively. The knowledge of the
absolute configurations of 8, 12, and 18 is vital in
understanding the role of confined medium and cations
on asymmetric induction during photoisomerization.
Dia ster eoselective P h otoisom er iza tion of cis-2,3-
Dip h en ylcyclop r op a n e-1-ca r boxylic Acid Der iva -
tives: Dir ect Excitation . Irradiation of cis-2,3-diphenyl-
cyclopropane-1-carboxylic acid derivatives in dichloro-
methane/hexane (0.5 mL/15 mL) or acetonitrile (8 mL)
solution gave the trans isomers with low diastereomeric
excess (de) (Tables 1-4). For zeolite irradiations, follow-
ing the protocol described in the Experimental Section,
% diastereomeric excess (de)a
medium
trans-14c,d
trans-15c
trans-17e
solutionb
LiY
NaY
KY
RbY
CsY
30 (A)
25 (B)
60 (A)
13 (A)
2 (A)
0
22 (A)
58 (A)
89 (A)
15 (A)
9 (A)
8 (A)
11 (A)
9 (A)
15 (B)
23 (B)
0
5 (A)
TlY
3-B
a
The first peak that elutes out of the GC/HPLC column is
assigned as A and the second as B. Conversion was kept <25%
(90 min irradiation). The absolute configurations of the isomers
are not known, and they are not essential to understand the
b
mechanism of the chiral induction. A mixture of 0.5 mL of
dichloromethane and 15 mL of hexane was used as solvent. 8 mL
of acetonitrile as solvent gave similar results. c The diastereomers
were separated in two different columns (Chiralpak-AD-RH and
Chiralpak-AD: Chiral stationary phases) on the HPLC to verify
d
the selectivity. The amide of ephedrine derivative 16 did not
(10) Aggarwal, V. K.; Smith, H. W.; Hynd, G.; J ones, R. V. H.;
Fieldhouse, R.; Spey, S. E. J . Chem. Soc., Perkin Trans. 1 2000, 3267-
3276.
(11) Aggarwal, V. K.; Thompson, A.; J ones R. V. H.; Standen, M. C.
H. J . Org. Chem. 1996, 61, 8368-8369.
separate on the HPLC and did not show up in the GC; hence, the
value is not reported. The ephedrine derivative 16 was attempted
to observe the effect of N-methylation directly with respect to the
norephedrine derivative 14. e The diastereomeric peaks on the
HPLC were very broad, and hence, the error limit might be (5.
(12) (a) Fuson, R. C.; Bull, B. A. Chem. Rev. 1934, 15, 275. (b) Seelye,
R. N.; Turney, T. A. J . Chem. Educ. 1959, 36, 572. (c) House, H. O.
Modern Synthetic Reactions, 2nd ed.; W. A. Benjamin: Reading, MA,
1972; pp 464-465. (d) Lieben, A. Ann. (Suppl.) 1870, 7, 218. (e) March,
J . Advanced Organic Chemistry, 4th ed.; Wiley-Interscience: New
York, 1992; p 632. (f) Vogel’s Textbook of Practical Organic Chemistry;
Revised byFurniss, B. S., Hannaford, A. J ., Rogers, V., Smith, P. W.
G., Tatchell, A. R.; Longman Scientific & Technical, J ohn Wiley & Sons,
New York, 1978.
(13) Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 46, 4475-
4478. (b) Kress, J .; Rosner, A.; Hirsch, A. Chem Eur J . 2000, 6 (2),
247-257. (c) Taha, T. S. M.; Miller, S. F. Biochemistry 1992, 31, 9090-
9097.
cis-2,3-diphenylcyclopropane-1-carboxylic acid derivatives
were included within alkali cation (Li+, Na+, K+, Rb+,
and Cs+) exchanged Y zeolites and irradiated, and prod-
ucts were extracted. Mass balance was estimated by GC
by using docosane as the internal standard (mass balance
∼75% for ∼30% conversion). Diastereomeric excess was
calculated by either GC or HPLC analysis (<25% conver-
sion, Tables 1-4). Lower mass balance at prolonged
6536 J . Org. Chem., Vol. 69, No. 20, 2004

Enhanced Diastereoselectivity via Confinement
TABLE 4. Ster eoselective P h otoisom er iza tion of cis-Dip h en ylcyclop r op a n e Der iva tives: Am in o Acid Der iva tives a s
Ch ir a l Au xilia r ies
% diastereomeric excess (de)a
medium
trans-18c
trans-19
trans-20
trans-21
trans-22
trans-23
trans-24
solutionb
LiY
NaY
KY
RbY
CsY
2 (RR-isomer)
83 (SS-isomer)
21 (RR-isomer)
80 (RR-isomer)
47 (RR-isomer)
5 (RR-isomer)
20 (A)
39 (B)
31 (A)
61 (A)
34 (A)
0
3 (A)
26 (B)
22 (A)
46 (A)
22 (A)
9 (A)
5 (B)
34 (B)
22 (A)
31 (A)
44 (B)
5 (B)
2 (A)
10 (A)
32 (A)
53 (A)
32 (A)
6 (A)
1 (A)
21 (A)
40 (A)
44 (A)
7 (B)
4 (B)
3 (B)
2 (B)
14 (B)
4 (B)
5 (B)
5 (B)
a
The first peak that elutes out of the GC/HPLC column is assigned as A and the second as B. Conversion was kept <25% (90 min
b
irradiation). A mixture of 0.5 mL of dichloromethane and 15 mL of hexane was used as solvent. 8 mL of acetonitrile as solvent gave
similar results. c The absolute configuration was identified by absolute asymmetric synthesis.
F IGUR E 1. Diastereoselectivity in trans-8 during photo-
isomerization of cis-8 in various media. GC traces correspond-
ing to trans-8 are shown. Results emphasize the differences
between solution and zeolites and the cation dependence.
F IGUR E 2. Diastereoselectivity in trans-8 during photo-
isomerization of cis-8 in various media. GC traces correspond-
ing to trans-8 are shown. Results emphasize the importance
of cations during diastereoselective photoisomerization.
irradiation time (>6 h) was due to the formation of side
products such as indans and alkenes whose formation
has previously been recorded in the literature.14
Perusal of Tables 1-4 reveals that the diastereoselec-
tivities within zeolites are consistently higher than in
isotropic solution. The ester derived from menthol cis-1
gave 55% diastereomeric excess in NaY compared to 4%
in solution. Other isomeric menthyl esters (cis-2 and cis-
3) gave moderate diastereoselectivity (Table 1). Based on
the assumption that bulkiness of the chiral auxiliary
might play a role in the chiral induction process, more
bulky fenchyl ester cis-5 and isopinocampheol ester cis-6
and less bulky S-(-)-2-methyl butyl ester cis-4 were
examined. The diastereoselectivities observed in all of
these systems within zeolites were low, even though the
observed selectivity was higher than in solution. The best
de was obtained with 1-phenylethyl ester cis-7 (78% in
LiY).
In the context of asymmetric induction a variety of
amide-linked chiral auxiliaries (amides derived from
amines, amino alcohols, and amino acids) were also
explored. Remarkable success was observed with these
systems (Tables 2-4). The very first amide examined,
S-(-)-1-phenylethyl amide cis-8, gave 80% diastereomeric
excess compared to 2% in solution. The highest chiral
induction was observed with the amide derived from
pseudoephedrine (cis-15; 89% in NaY). Due to additional
products (formation of indans and alkenes) at longer
irradiation times, the diastereoselectivity at the photo-
stationary state could not be measured. However, the de
remained the same for 90 min, 3 h, 6 h, and 12 h
irradiations of cis-1 and cis-8.
F IGUR E 3. Diastereoselectivity in trans-18 during photo-
isomerization of cis-18 in various media. GC traces corre-
sponding to trans-18 are shown. Results emphasize the dif-
ferences between solution and zeolites and the cation de-
pendence.
A number of observations suggested that alkali metal
ions present in zeolites play an important role in the
asymmetric induction process. (a) The de was dependent
on the nature of the alkali metal ion (e.g., % de in the
case of cis-8 in LiY, NaY, KY, RbY, and CsY were 80,
28, 14, 5, and 5, respectively; Table 2, Figure 1). (b) The
de varied with water content of NaY used (cis-8: dry,
80%, and wet, 10%; Figure 2). (c) The de upon irradiation
of cis-8 adsorbed on silica gel, a surface that does not
contain cations, was only 8% (Figure 2). (d) Diastereo-
meric excess in the case of cis-8 decreased from 80% to
10% when the Si/Al ratio of LiY zeolite was changed from
2.4 to 40 (Figure 2). The number of cations per unit cell
decreases from 56 to 5 upon changing the Si/Al ratio from
2.4 to 40 (refer to the Experimental Section for calcula-
tion of the number of supercages and number of cations).
A closer examination of Tables 1-4 reveals that the
cation not only controls the extent of diastereoselectivity
but also the isomer being enhanced. The most remarkable
(14) (a) Valyocsik, E. W.; Sigal, P. J . Org. Chem. 1971, 36, 66-72.
(b) Griffin, G. W.; Covell, J .; Petterson, R. C.; Dodson, R. M.; Klose, G.
J . Am. Chem. Soc. 1965, 87, 1410-1411.
J . Org. Chem, Vol. 69, No. 20, 2004 6537

Sivaguru et al.
TABLE 5. Tr ip let-Sen sitized Ster eoselective P h otoisom er iza tion of cis- Dip h en ylcyclop r op a n e Der iva tives
% diastereomeric excess (de)e
mediuma
trans-7
trans-8d
trans-9
trans-14
trans-18d
trans-24
solutionb
LiY
NaY
KY
16 (A)
75 (B)
46 (B)
18 (B)
44 (B)
72 (B)
51 (B)
15 (RR-isomer)
33 (SS-isomer)
40 (RR-isomer)
61 (RR-isomer)
15 (RR-isomer)
2 (RR-isomer)
37 (RR-isomer)
17 (A)
52 (A)
61 (A)
8 (A)
2 (A)
7 (A)
7 (A)
23 (B)
59 (B)
43 (B)
17 (B)
1 (B)
0
7 (B)
3 (B)
8 (B)
17 (B)
4 (B)
0
52 (SS-isomer)
18 (RR-isomer)
81 (RR-isomer)
45 (RR-isomer)
13 (RR-isomer)
RbY
CsY
TlYc
10 (A)
3 (B)
a
p-Methoxyacetophenone used as the sensitizer for all zeolite irradiation. Loading level of the sensitizer kept at one molecule per
b
supercage; substrate: one molecule per 12 supercages for all zeolite irradiation (24 h irradiation). Acetone was used as the sensitizer
and solvent (90 min irradiation). Sensitization with p-methoxyacetophenone as sensitizer in solution (CH2Cl2/hexane) gave similar results.
d
c Direct irradiation (90 min irradiation). No sensitizer was employed. The absolute configuration of isomers was determined by absolute
asymmetric synthesis. e The first of the two diastereomeric peaks was assigned as A and the second peak as B.
TABLE 6. Asym m etr ic P h otoisom er iza tion of cis-8 w ith
example is provided by the amide derived from L-valine
Va r iou s Loa d in g Levels of th e Sen sitizer In sid e KY
Zeolite
methyl ester cis-18. Within LiY the trans-18-SS was
favored to 83% in excess, whereas in KY trans-18-RR was
favored to 80% in excess (Scheme 1, Figure 3, Table 4).
A similar alkali ion dependent diastereomer switch was
observed in the case of cis-8; LiY favored trans-8-SS to
80% excess, and NaY favored trans-8-RR to 28% excess.
Enhancement of one isomer in LiY and the other dia-
stereomer in NaY-CsY was true with many diphenyl-
cyclopropane systems (Tables 1-4).6a To confirm that the
cation-dependent diastereomer switch was not due to an
overlapping impurity, the diastereoselectivities in se-
lected cases were monitored both by GC and HPLC.15
Both analyses gave the same results.
loading level of
cis-8 : trans-8
after irradiation
the sensitizera
% de (trans-8)b
9.9
78:22
75:25
65:35
57:43
45:55
49:51
54 (RR-isomer)
48 (RR-isomer)
55 (RR-isomer)
54 (RR-isomer)
63 (RR-isomer)
56 (RR-isomer)
3.96
1.98
1.32
1.00
0.79
a
p-Methoxyacetophenone (4MAP) was used as the sensitizer
for all zeolite irradiation. The reaction was performed inside dry
KY zeolite, 24 h irradiation with positive N2 pressure. Loading
level is defined as the number of supercages per molecule of the
sensitizer. For calculation of the number of supercages refer to
b
the Experimental Section. The absolute configuration of the
While investigating a series of amides derived from
chiral amino alcohols (Table 3), we noticed that the
cation-dependent diastereomer switch was absent in the
case of the amide derived from (-)-pseudoephedrine cis-
15 while it was observed in the case of the amide derived
from (-)-norephedrine cis-14. The only difference be-
tween the chiral auxiliary employed in the above two
cases is that N-H in (-)-norephedrine is replaced with
N-CH3 in (-)-pseudoephedrine. If indeed N-methylation
prevents the cation-dependent diastereomer switch as
observed in the case of (-)-pseudoephedrine, then it
should be effective in other chiral auxiliaries with an
N-H group. The two N-H amides that showed the
cation-dependent diastereomer switch with high stereo-
selectivity cis-8 and cis-18 were N-methylated to the
corresponding N-methyl derivatives cis-9 and cis-24,
respectively. The photoisomerization of N-methyl-1-
phenylethyl amide derivative cis-9 and N-methyl-L-valine
methyl ester derivative cis-24 was studied within alkali
metal ion (Li+, Na+, K+, Rb+, and Cs+) exchanged
Y-zeolite. In both cases, cation-dependent diastereomer
switch was not observed (Tables 2 and 4).
Dia ster eoselective P h otoisom er iza tion of cis-2,3-
Dip h en ylcyclop r op a n e-1-ca r boxylic Acid Der iva -
tives: Tr ip let Sen sitiza tion . Acetone and p-methoxy-
acetophenone sensitization of cis-diphenylcyclopropane
derivatives 7, 8, 9, 14, 18, and 24 in solution gave the
corresponding trans-isomers with de varying between 0
and 17% (Table 5). Although direct excitation resulted
in side products (alkene and indan), triplet sensitization
both in solution as well as within zeolites gave mainly
the products of geometric isomerization, and the photo-
isomer was determined by absolute asymmetric synthesis.
TABLE 7. Tr ip let-Sen sitized P h otoisom er iza tion of
cis-8 a n d cis-18 w ith Va r iou s Sen sitizer s
% diastereoselectivitya-c
sensitizer
acetophenone
p-methoxyacetophenone
p-cyanoacetophenoned
p-methylacetophenone
p-fluoroacetophenone
p-chloroacetophenone
xanthone
trans-8
trans-18
75 (RR-isomer)
61 (RR-isomer)
57 (RR-isomer)
50 (RR-isomer)
45 (RR-isomer)
40 (RR-isomer)
30 (RR-isomer)
85 (RR-isomer)
81 (RR-isomer)
43 (RR-isomer)
78 (RR-isomer)
36 (RR-isomer)
71 (RR-isomer)
40 (RR-isomer)
stationary state was achieved within 24 h in zeolites.
Photoisomerization was efficient when the triplet energy
of the sensitizer (ET) was higher than 69 kcal/mol (e.g.,
acetone and acetophenone) and inefficient with sensitiz-
ers having triplet energy lower than 69 kcal/mol, viz.
fluorenone (ET ) 50.9 kcal/mol), benzil (ET ) 53 kcal/
mol), acetonaphthone (ET ) 59.9 kcal/mol), and benzo-
phenone (ET ) 67 kcal/mol).16
Photoisomerization by triplet sensitization was per-
formed by including the sensitizer (acetophenone deriva-
tives) and cis-2,3-diphenylcyclopropane-1-carboxylic acid
derivatives (Scheme 1) within alkali ion (Li+, Na+, K+,
Rb+, Cs+, and Tl+) exchanged Y zeolites. The experimen-
tal procedures adopted for inclusion of reactants within
zeolites, irradiation, and extraction and analysis of
products are described in the Experimental Section.
(16) (a) Hixson, S. S.; Boyer, J .; Gallucci, C. J . Chem. Soc., Chem.
Commun. 1974, 540-542. (b) Sivaguru, J .; J ockusch, S.; Turro, N. J .;
Ramamurthy, V. Photochem. Photobiol. Sci. 2003, 2(11), 1101-1106.
(15) Refer to the Supporting Information for details.
6538 J . Org. Chem., Vol. 69, No. 20, 2004

Enhanced Diastereoselectivity via Confinement
F IGURE 4. Binding affinities and structural details of Li+-bound cis-8 and cis-10 optimized at the RHF/3-21G level.
Results of product studies are summarized in Table 5.
The extent of diastereoselectivity as shown in Table 6
was independent of the loading level of the triplet
sensitizer (e.g., cis-8). This observation supports the view
that the photoisomerization occurs only from the triplet
state and is triggered by the sensitizers. Had there been
photoisomerization that is not triggered by the sensitizer,
the selectivity would have been different with different
loading levels of the sensitizer (Table 6).
The importance of cations in the diastereoselective
process is evident from the following observations: The
diastereoselectivity during photoisomerization of cis-8
within wet KY zeolite (intentionally exposed to water)
was only 14%, whereas within dry KY it was 61%.
Sensitized photoisomerization of cis-8 adsorbed on silica
surface, a medium that lacks cation, gave low de (12%).
Direct irradiation of TlY zeolite gave product distribution
similar to triplet-sensitized irradiation, which is most
likely due to the heavy cation effect (Tl+)-induced inter-
system crossing from the singlet to triplet state.5a
As mentioned above, efficient photoisomerization was
observed when the triplet energy of the sensitizer (ET)
was higher than 69 kcal/mol. However, for substituted
acetophenone sensitizers with similar triplet energies the
substituent on the aryl ring determined the extent of
diastereoselectivity. While all sensitizers listed in Table
7 efficiently isomerized cis-8 and cis-18, the observed
diastereoselectivities in the products within KY were not
the same. We believe that the site of cation binding to
the sensitizer plays a role in this process. It is quite likely
that the substituent on the aryl ring alters the manner
in which the cation is bound to the sensitizer and the
reactant. Further studies are needed to understand this
phenomenon.
The following observations concerning diastereo-
selective photoisomerization in the triplet state are
noteworthy: (a) The diastereomeric excesses obtained
under sensitized conditions are different from the ones
obtained upon direct excitation. (b) The diastereoselec-
tivity was dependent on the nature of the cation within
the zeolite; high selectivity was usually observed within
NaY or KY. (c) Although the phenomenon of cation-
dependent diastereomer switch is observed also during
triplet sensitization, the results are not identical to the
ones obtained during direct excitation. For example, in
the case of cis-7 and cis-14 the switch is observed under
direct excitation but not under triplet sensitization. In
the case of cis-8 and cis-18, although the switch is
J . Org. Chem, Vol. 69, No. 20, 2004 6539

Sivaguru et al.
F IGURE 5. Binding affinities and structural details of Li+-bound cis-11 and cis-18 optimized at the RHF/3-21G level.
observed, the extent of de in various zeolites under both
conditions is not the same. (d) The observed diastereo-
selectivity was independent of the duration of irradiation
(e.g., % de in trans-8: 12 h, 57%; 24 h, 60%; 48 h, 61%
and 72 h, 61%).
Recognizing the importance of cations in asymmetric
induction process, the photoisomerization of cis-8 and cis-
18 were carried out in the presence of 1 M LiClO4 and
NaClO4 in acetone that served both as a solvent and
sensitizer. The diastereoselectivity remained the same
in the presence and absence of alkali ion salts. Probably,
the factors that make the perchlorate salt soluble in
acetone, solvation of the cation by the solvent, makes the
cation inaccessible to the reactant molecule. In the case
of a zeolite, which provides a medium of “naked cations”
ensures an interaction between the reactant molecule
and the cation.
excitation results in isomerization from S1 (with no triplet
contribution) and triplet sensitization leads to reaction
from T1.16-18
Although with the results on hand we cannot 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 zeo-
lites. Examination of Tables 1-4 (24 chiral auxiliaries
employed) reveals that aryl chiral auxiliaries (e.g., 7, 8,
12, 14, and 15) are more effective than alkyl chiral
auxiliaries (e.g., 10) within zeolites.6a,8a,b For example, cis-
2,3-diphenylcyclopropane-1-carboxamides with phenyl
chiral auxiliary cis-8, the naphthyl chiral auxiliary cis-
12, and systems based on amino alcohol chiral auxiliaries
cis-14 and cis-15 gave 80% (LiY), 69% (LiY), 60% (NaY),
and 89% (NaY) de. However, the cis-2,3-diphenylcyclo-
propane-1-carboxamide appended with alkyl chiral aux-
iliary (cyclohexyl as in cis-10 instead of phenyl as in cis-
8) gave only 29% de. Several chiral esters containing
Discu ssion
Results presented in Tables 1-5 establish that a chiral
auxiliary functions better within a zeolite than in an
organic solvent both during direct excitation and triplet
sensitization. Further, the cations present within a
zeolite appear to play an important role in the chiral
induction process. It has been established that direct
(17) Griffin, G. W.; Covell, J .; Petterson, R. C.; Dodson, R. M.; Klose,
G. J . Am. Chem. Soc. 1965, 87, 1410-1411.
(18) (a) Hixson, S. S. In Organic Photochemistry; Padwa, A., Ed.;
Marcell Dekker: New York, 1979; Vol. 4, pp 191-260 and selected
references therein. (b) Hixson, S. S.; Garrett, D. W. J . Am. Chem. Soc.
1974, 96, 4872-4879. (c) Hixson, S. S. J . Am. Chem. Soc. 1974, 96,
4866-4871.
6540 J . Org. Chem., Vol. 69, No. 20, 2004

Enhanced Diastereoselectivity via Confinement
F IGURE 6. Binding affinities and structural details of Li+ bound to various conformers of cis-8 optimized at RB3LYP/6-31G*.
alkyl substituents (e.g., cis-2, -3, -4, -5, and -6: <25% in
LiY) gave lower de than the phenyl ester cis-7 (de, 78%
in LiY). Although we did not examine the triplet-
sensitized photochemistry of several systems we are
confident that the above trend will be maintained during
triplet-sensitized isomerization as well. In our laboratory,
we have observed similar trend with several other
photoreactions as well.6a
An insight into how cations play a role in the above
chiral discrimination process is revealed by the results
of ab initio computations of several 2,3-diphenylcyclo-
propane-1-carboxamides. While one may question the
value of gas-phase computational data in understanding
the chemical behavior of molecules within a zeolite, a
much more complex environment, we find them useful
as a guide in building a preliminary model. The binding
affinities and geometries (Figure 4) of Li+ bound cis-8
(representing aryl chiral auxiliary) and cis-10 (represent-
ing alkyl chiral auxiliary) computed at the restricted
Hartree-Fock level (RHF/3-21G) level19 provided insight
into the role of aryl group in enhancing the power of a
chiral auxiliary within zeolites. Both molecules interacted
strongly with Li+ with binding affinities >80 kcal/mol.
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 case of cis-8 (with
aryl chiral auxiliary), the cation interacts simultaneously
with phenyl group by cation-π interaction20 as well as
with the amide carbonyl oxygen by dipolar interaction21,22
(Figure 4, left side). Such interactions are expected to
reduce the rotational freedom of the chiral auxiliary and
thus make it “rigid”. On the other hand, in the case of
cis-10 (with alkyl chiral auxiliary) the cation interacts
only with the amide carbonyl oxygen via dipolar-type
interaction (Figure 4, right side). Such an interaction
would have no effect on the rotational mobility of the
chiral auxiliary. A model based on cation-binding-
dependent flexibility of the chiral auxiliary accounts for
the observed variation in de between aryl and alkyl chiral
auxiliaries within zeolites.
(20) Ma, J . C.; Dougherty, D. A. Chem. Rev. 1997, 97, 1303-1324.
(21) Raber, D. J .; Raber, N. K.; Chandrasekhar, J .; Schleyer, P. v.
R. Inorg. Chem. 1984, 23, 4076.
(22) (a) Dunbar, R. C. J . Phys. Chem. A 2000, 104, 8067-8074. (b)
Siu, F. M.; Ma, N. L.; Tsang, C. W. J . Am. Chem. Soc. 2001, 123, 3397-
3398. (c) J ockusch, R. A.; Lemoff, A. S.; Williams, E. R. J . Am. Chem.
Soc. 2001, 123, 12255-12265. (d) Wyttenbach, T.; Witt, M.; Bowers,
M. T. J . Am. Chem. Soc. 2000, 122, 3458-3464. (e) J ockusch, R. A.;
Price, W. D.; Williams, E. R. J . Phys. Chem. A 1999, 103, 9266-9274.
(f) Hoyau, S.; Ohanessian, G. Chem. Eur. J . 1998, 4, 1561-1569.
(19) Gaussian 98, Revision A.9; Gaussian, Inc.: Pittsburgh, PA,
1998.
J . Org. Chem, Vol. 69, No. 20, 2004 6541

Sivaguru et al.
F IGURE 7. Binding affinities and structural details of Li+ bound to various conformers of cis-9 optimized at RB3LYP/6-31G*.
The above model works well also in the case of amino
acid derived chiral auxiliaries. The structures cis-11 and
cis-18 differ only with respect to the substituent on the
chiral auxiliary; the methyl group in cis-11 is replaced
by a carbomethoxy group in cis-18. This change in
structure has a significant impact on the observed de
within LiY (cis-18, 83%; cis-11, 7%). Both cis-11 and cis-
18 interacted strongly with Li+ (Figure 5) with binding
affinities >80 kcal/mol. In the case of cis-18 (with
carbomethoxy chiral auxiliary), Li+ interacts simulta-
neously with both the carbonyl of the carbomethoxy
group and the amide carbonyl oxygen. Such an interac-
tion is expected to reduce the rotational freedom of the
chiral auxiliary and thus make it “rigid” as in the case
of the aryl chiral auxiliary. On the other hand, in the
case of cis-11 the cation interacts only with the amide
carbonyl oxygen via a dipolar-type interaction (as in the
case of cis-10). Such a type of interaction would have no
effect on the rotational mobility of the chiral auxiliary.
In general, amino acid derived chiral auxiliaries gave
higher diastereoselectivities within zeolites compared to
that in solution (Table 4).
ibility of the amino acids as: Gly > Ser > Asp, Asn, Ala
> Thr, Leu > Phe, Glu, Gln > His, Arg > Lys > Val >
Ile > Pro. It is encouraging to note that the observed
diastereoselectivites within the KY zeolite upon direct
irradiation of diphenylcyclopropane derivatives with
amino acid derivatives as chiral auxiliaries also follow
the same trend: Ala ) 31%; Leu ) 46%; Phe ) 53%; Val
) 80% (Table 4). We believe that rigidity of the chiral
auxiliary is very crucial in determining the extent of
diastereoselectivity. The lower the flexibility (more rigid
the chiral auxiliary), the higher the selectivity. The above
model applies for both direct and triplet-sensitized
isomerizations.
Examination of Tables 1-4 clearly indicates that the
cation not only controls the extent of diastereoselectivity
but also the isomer being enhanced. For the sake of
brevity, we restrict the discussion to amide derivatives.
The diastereomer switch occurs both during direct exci-
tation and triplet sensitization of cis-8 and cis-18,
although in the case of cis-14 this occurs only during
direct excitation. The most remarkable example is pro-
Recently, Nau et al.,23 based on intramolecular energy
transfer measurements, provided a measure of the flex-
(23) Huang, F.; Nau, W. M. Angew Chem., Int. Ed. 2003, 42, 2269-
2272.
6542 J . Org. Chem., Vol. 69, No. 20, 2004

Enhanced Diastereoselectivity via Confinement
SCHEME 3
vided by the amide derived from L-valine methyl ester
cis-18 (Figure 3). Within LiY, the trans-18-SS-isomer was
favored to 83% in excess, whereas in KY, the trans-18-
RR-isomer was favored to 80% in excess. In the case of
cis-8 (Figure 1), LiY favored trans-8-SS (80% excess) and
NaY favored trans-8-RR (28% excess). Similar striking
results were also observed during triplet sensitization of
cis-8 and cis-18 (Table 5). Triplet sensitization of cis-18
within LiY trans-18-SS was favored (de 52%), whereas
in KY trans-18-RR was favored (de 81%). In the case of
cis-8, LiY favored formation of trans-8-SS (de 33%) and
KY favored trans-8-RR (de 61%). One possibility is that
different cations bind to different sites on the reactant
molecule leading to cation-dependent diastereomer switch.
This suggestion, although in our case has no experimen-
tal support, has literature precedence.24c-f On the basis
of density functional calculations and low energy colli-
sionally activated and thermal radiative dissociation
experiments, a difference in binding pattern between Li+
and K+ ions with valine22c and glycine22d,f has been
proposed. For example, Li+ binds to these molecules
through N, O coordination (oxygen on the carboxyl group
and nitrogen on the amino group), whereas K+ binds
through O, O coordination (oxygens on the carboxyl
moiety). A similar switch in the binding site has also been
reported during the interaction of Li+ and Cs+ to
arginine.22e Such a phenomenon could be involved within
a zeolite and responsible for the observed cation-
controlled diastereomer switch within a zeolite.
nitrogen is substituted with a hydrogen atom or methyl
group. While NH derivatives showed diastereomer switch,
the corresponding N-CH3 derivatives did not (compare
cis-14 with cis-15; cis-8 with cis-9, and cis-18 with cis-
24; Tables 2-4). As illustrated in Scheme 3, the amides
being investigated, based on the rotation around cyclo-
propyl-carbonyl and carbonyl-N of the amide linkage,
could adopt four conformations. For simplicity we have
used the nomenclatures used in Scheme 3 to identify the
four conformers.
Restricted rotation around the carbonyl-N bond in
amides is well documented in the literature.24 For
example, in the case of N-methylformamide the energy
for rotation (Erot) was calculated to be around 0.4 kcal/
mol and in the case of N,N-dimethylformamide the
energy for rotation (Erot) was estimated to be around
∼3.82 kcal/mol.24 Based on this, one would expect the
rotational barrier for interconversion between syn and
anti conformations (with respect to the carbonyl-N bond)
in cis-8 to be much smaller than in cis-9.
1
1H NMR and H-1H COSY spectra suggest that cis-9
exists as two distinct conformers while cis-8 exists as a
single averaged conformer in solution. Two doublets for
R-methyl benzyl protons and two quartets for the benzylic
hydrogen of the chiral auxiliary corresponding to two
1
conformers are seen in the H NMR spectra of cis-9. This
suggests that the two conformers of cis-9 are thermody-
namically stable and do not interconvert at room tem-
1
perature in solution. Also, H NMR spectra reveal that
An examination of Tables 1-4 reveals that the above
diastereomer switch during both direct excitation and
triplet sensitization depends on whether the amide
the two conformers are not present in equal amounts in
solution at room temperature. On the other hand, in the
case of cis-8 only one doublet for R-methyl and a single
quintet for benzylic hydrogens are recorded in the 1H
NMR, suggesting that the two conformers are in fast
equilibrium in solution. The NMR results suggest, as
expected, a higher barrier for rotation around the amide
bond (OC-NCH3) in cis-9 than (OC-NH) in cis-8. We
believe that rotation around the cyclopropyl-carbonyl
(24) (a) Wiberg, K. B.; Rush, D. J . J . Org. Chem. 2002, 67, 826-
830. (b) Wiberg, K. B.; Rush, D. J . J . Am. Chem. Soc. 2001, 123, 2038-
2046. (c) Wiberg, K. B.; Rablen, P. R.; Rush, D. J .; Keith, T. A. J . Am.
Chem. Soc. 1995, 117, 4261-4270. (d) LeMaster, C. B.; True, N. S. J .
Phys. Chem. 1989, 93, 1307-1311. (e) Ross, B. D.; True, N. S. J . Am.
Chem. Soc. 1984, 106, 2451-2452. (f) Alema´n, C. J . Phys. Chem. A
2002, 106, 1441-1449.
J . Org. Chem, Vol. 69, No. 20, 2004 6543

Sivaguru et al.
F IGUR E 8. Photoisomeriztion of Li+-bound cis-8 anit,anti-conformer through rotation of C2-phenyl and C3-phenyl. Binding
affinities and structural details optimized at RB3LYP/6-31G*. As per this model, isomerization via C3-phenyl rotation would be
preferred.
bond most likely has a small barrier and syn and anti
conformations around this bond equilibrate fairly rapidly
in both N-H and N-CH3 systems in solution. We
visualized that within a zeolite depending on the cation
one of the four conformers of cis-8 would be preferred
leading to cation dependent diastereomer switch. In other
words, one thought was that the cation-dependent dia-
stereomer switch has its origin on the cation-dependent
conformer preference within a zeolite.
To gain a better insight on the role of cation binding
to different conformers of cis-8 and cis-9 and its effect
on the observed cation-dependent diastereomer switch,
density functional theory and ab initio calculations were
performed at the RB3LYP/6-31G* level.19 Binding affini-
ties for Li+-bound structures for cis-8 and cis-9 (RB3LYP/
6-31G* level) are given in Figures 6 and 7. In the case of
Li+-bound cis-8, of the four conformers examined (anti,
anti-, syn,anti-, anti,syn-, and syn,syn; Figure 6), the first
two were more stable than the latter two; the Li+-bound
anti,anti- and syn,anti-conformers have almost the same
energy (Figure 6). On the other hand, in the case of cis-9
cation binding leads to only one most stable conformer,
i.e., anti,anti- (Figure 7). During geometry optimization,
to our surprise, the Li+-bound syn,anti-conformer of cis-9
transformed itself to the Li+-bound anti,anti-conformer
(Figure 7). This is most likely due to steric interaction
between the N-CH3 and cyclopropyl C-H hydrogens in
the cation-bound syn,anti- conformation. If this trend is
maintained within a zeolite, cation-bound cis-9, irrespec-
tive of the cation, will adopt only the anti,anti-conforma-
tion. This could translate into the cation-independent
diastereomer enhancement. In the case of cis-8, according
to NMR, all four conformers (anti,anti-, syn,anti-, anti,
syn-, and syn,syn-) having nearly the same energies
equilibrate in solution. According to calculated data, upon
Li+ binding anti,anti- and syn,anti-conformers are dis-
tinctly more stable than anti,syn- and syn,syn-conform-
ers. Thus, within a zeolite only these two conformers are
expected to be present. It is quite possible that within a
zeolite depending on the alkali ion one of the two
conformers is preferred, leading to cation-dependent
diastereomer switch. Interestingly, computational results
discussed below suggest that Li+-bound anti,anti- and
syn,anti-conformers of cis-8 would give different amounts
of trans-8-RR and trans-8-SS. This provides a hope that
the model based on cation controlled conformational
preference may have some validity. Unfortunately, at this
stage we are unable to provide any experimental support
for this suggestion.
As shown in Figures 8 and 9, the trans-8-SS is
expected to be formed from cis-8 via phenyl rotation at
the C3 carbon and trans-8-RR via phenyl rotation at the
C2 carbon. The question is whether both anti,anti- and
syn,anti-conformers of cis-8 would give the same amounts
6544 J . Org. Chem., Vol. 69, No. 20, 2004

Enhanced Diastereoselectivity via Confinement
F IGURE 9. Photoisomeriztion of Li+-bound cis-8 syn,anti-conformer through rotation of C2-phenyl and C3-phenyl. Binding affinities
and structural details optimized at RB3LYP/6-31G*. As per this model, isomerization via both C3-phenyl and C2-phenyl rotation
would be equally preferred.
of trans-8-RR and trans-8-SS. In the absence of cations,
both rotations are equally possible, and therefore, dia-
stereoselectivity is expected to be small. However, Li+
binding to the two conformers makes a difference. As seen
in Figure 8, trans-8-SS is more easily formed from the
Li+-bound anti,anti-conformer of cis-8. Rotation around
the C3 carbon is helped by the developing cation-π
interaction20 with the C3-phenyl. Rotation around the C2-
carbon does not result in any such stabilization. Based
on this, one would predict that the trans-8-SS isomer
would be formed in excess upon excitation of Li+ bound
anti,anti-conformer of cis-8. On the other hand, as seen
in Figure 9, computational results suggest that trans-8-
SS and trans-8-RR isomers would be formed in near
equal amounts from syn,anti-conformer of cis-8. As
illustrated in Figure 9 rotation of C2-phenyl or C3-phenyl
does not result in any significant extra stabilization by
Li+ ion. Thus it is clear that Li+-bound anti,anti- and
syn,anti-conformers of cis-8 would not give trans-8 with
the same de. How much de is obtained and which isomer
is obtained in excess will depend on which one of the two
conformers is preferred within a zeolite. One wonders
whether selective formation of trans-8-SS within LiY is
an indication of anti,anti-conformer being preferred when
cis-8 is included within the zeolite. We do not have an
experimental verification of this prediction. Undoubtedly,
there are problems in the above approach. Computations
refer to ground-state structures while reactions originate
from excited singlet and triplet states. Computations deal
with closed shell molecules while the reaction involve
diradical and zwitterionic intermediates. Despite these
deficiencies, we are pleased to note that the ab initio
computational data of the ground-state structures of Li+-
cis-8 complexes provided an insight into the cause of
diastereoselectivty within alkali ion exchanged Y zeolites.
The fact that different amounts of diastereoselectivities
were obtained for the same systems during direct excita-
tion and triplet sensitization suggests that nature of
excited state and the intermediates involved should be
taken into consideration while predicting asymmetric
induction within zeolites. We are attempting to make
progress in this direction.
Con clu sion
The zeolite interior is clearly able to enhance the power
of a chiral auxiliary during reaction from excited singlet
and triplet states. In doing so, both the confined space
as well as the cations present in a zeolite are used
effectively by the zeolite. The cations and confined space
J . Org. Chem, Vol. 69, No. 20, 2004 6545

Sivaguru et al.
) 1.39 × 10-4 mol. Loading of 3 mg of cis-8 in 300 mg of NaY
(wet) ) 1.39 × 10-4 mol/8.8 × 10-6 mol )15.7. Thus, the
loading level of 3 mg of cis-8 corresponds to a loading of 1
molecule in 15.7 supercages.
Ca lcu la tion of Nu m ber of Ca tion s. Molecular formula
of one unit cell of NaY (wet): Na56[(AlO2)56(SiO2)136]‚250H2O.
Number of cations (alkali metal ions) ) number of aluminum
atoms ) 56.
P h otoisom er iza tion in Solu tion . cis-2,3-Diphenylcyclo-
propane-1-carboxylic acid derivative (2-3 mg) was dissolved
in 0.5 mL of dichloromethane in a quartz test tube followed
by the addition of 15 mL of hexane. The test tube was
stoppered with a rubber septum and wound with Parafilm.
The solution was irradiated (unfiltered output from a 450 W
medium-pressure mercury lamp) for 90 min, concentrated, and
analyzed by GC/HPLC.
P h otoisom er iza tion In sid e a Zeolite. cis-2,3-Diphenyl-
cyclopropane-1-carboxylic acid derivative (2-3 mg) was dis-
solved in 0.5 mL of dichloromethane in a test tube. Hexane
(15 mL) was added to the test tube and stirred. To the solution
was added zeolite MY (M ) Li+, Na+, K+, Rb+ and Cs+; ∼300
mg) activated at 500 °C. The test tube was stoppered with a
rubber septum, wound with Parafilm, and stirred for 8 h. The
slurry was filtered and washed with hexane. Analysis of the
filtrate (hexane solution) indicated that the diphenylcyclopro-
pane derivative was completely incorporated inside the zeolite.
The zeolite/substrate complex was dried in a vacuum (2 × 10-3
Torr) with heating at 60 °C for 8-10 h. The dried zeolite
complex was transferred into a quartz test tube inside the
drybox, and 10 mL of fresh dry hexane was added to the quartz
tube. The test tube was stoppered with a rubber septum and
wound with Parafilm. The slurry was irradiated (unfiltered
output from a medium pressure of Hg lamp) for 90 min and
filtered. Analysis of the hexane supernatant after irradiation
did not show the presence of reactant/photoproducts. The
reactant and the photoproducts were extracted from the zeolite
by stirring with acetonitrile for 8-10 h. The acetonitrile extract
was concentrated and analyzed by GC/HPLC.
coerce the molecule to adopt a conformation resulting in
a stronger interaction between the chiral center and the
site of reaction present within a single molecule. The very
low diastereomeric excess in most cases in solution
suggests that the conformation of the reactant molecule
is likely to be such that the chiral auxiliary and the
reactive site of the molecule are far apart. Within the
confined space of a zeolite, the cations force the molecule
to adopt a folded conformation there by bringing chiral
environment closer to the reactant part. Interactions
between chiral auxiliary, cation and the reaction site play
an important role in the overall asymmetric induction
process within a zeolite. The cations not only control the
extent of selectivity but also the stereoisomer being
enhanced in the photoreaction. Potential of the phenom-
enon presented in this report in photochemical and
thermal reactions is limitless. One wonders whether the
zeolite scaffold does play any role other than presenting
a “naked” cation to the reactants to interact with. We
are exploring the effect of cations in solution to bring
about the selectivity observed inside zeolite.
Exp er im en ta l Section
NaY zeolite was obtained from Zeolyst International, The
Netherlands. Monovalent cation-exchanged zeolites (LiY, KY,
RbY, and CsY) were prepared by refluxing 10 g of NaY with
100 mL of a 10% solution of the corresponding metal nitrate
in water for 24 h. The exchanged zeolite was filtered and
washed thoroughly with distilled water. This procedure was
repeated three times. Subsequently, the cation-exchanged
zeolite was dried at 120 °C for about 3 h and stored.
All solvents were used as purchased. THF was dried over
sodium/benzophenone under nitrogen prior to use. Deionized
water was used when needed. All chiral auxiliaries used as
alcohols or amines during synthesis were commercial samples.
cis-2,3-Diphenylcyclopropane-1-carboxylic acid trans-2,3-di-
phenylcyclopropane-1-carboxylic acid were prepared by a
literature procedure.25
Thermal reaction under the same reaction conditions (no
irradiation) showed no isomerization, and the compounds were
recovered with >95% mass balance.
Synthetic procedures and spectra data of all compounds (1-
24) used in this study are provided as Supporting Information.
The Supporting Information also contains HPLC/GC analysis
conditions of the photoproducts.
Tr ip let-Sen sitized P h otoisom er iza tion in Solu tion .
(a ) Aceton e Sen sitiza tion . cis-2,3-Diphenylcyclopropane-
1-carboxylic acid derivative (2-3 mg) was dissolved in 12 mL
of acetone in a test tube, stoppered, and wound with Parafilm.
The solution was degassed with N2 for 30 min and irradiated
(unfiltered output from a 450 W medium-pressure mercury
lamp) for 90 min. The solution was concentrated and analyzed
by GC/HPLC.
(b) p-Meth oxya cetop h en on e Sen sitiza tion . cis-2,3-Di-
phenylcyclopropane-1-carboxylic acid derivative (2-3 mg) and
p-methoxyacetophenone (∼5 mg) were dissolved in 0.5 mL of
dichloromethane in a test tube. Hexane (12 mL) was added,
and the test tube was stoppered and wound with Parafilm.
The solution was degassed with N2 for 30 min and irradiated
(unfiltered output from a 450 W medium-pressure mercury
lamp) until the photostationary state was reached (∼48 h). The
solution was concentrated and analyzed by GC/HPLC.
Sen sitized P h otoisom er iza tion w ith in Zeolites. 2,3-
Diphenylcyclopropane-1-carboxylic acid derivative (2-3 mg)
and the triplet sensitizer (20-25 mg) were dissolved in 0.5
mL of dichloromethane and 15 mL of hexane in a test tube
and stirred. MY (M ) Li+, Na+, K+, Rb+ and Cs+) zeolite (∼300
mg) activated at 500 °C was added with stirring. The test tube
was stoppered with a rubber septum and wound with Parafilm.
The slurry was stirred for 12 h in a water bath kept at 55 °C,
filtered, and washed thoroughly with fresh hexane (super-
natant was analyzed for the presence of reactant/sensitizer).
The zeolite was dried under high vacuum (2 × 10-3 Torr) at
60 °C for 12 h. The dried zeolite sample was transferred into
a test tube inside a drybox, and fresh dry hexane was added.
The test tube was stoppered with a rubber septum and wound
with Parafilm. The slurry was degassed with N2 for 30 min
and then irradiated (unfiltered output from a 450W medium-
pressure mercury lamp) as a hexane slurry under positive
Ca lcu la tion of th e Nu m ber of Su p er ca ges. Molecular
formula of one unit cell of NaY (wet): Na56[(AlO2)56(SiO2)136]‚
250H2O; weight of 1 unit cell of NaY (wet) ) [(56 × 22.99) +
(56 × 59 + (136 × 60) + 250 × 18)] ) 17 246 g mol-1; weight
of 1 unit cell of NaY (dry) ) 12 746 g mol-1. This implies 300
mg of NaY (wet) will have 222 mg of NaY (dry). The number
of supercages5 in 1 unit cell of NaY ) 8. Molecular weight of
1 supercage for wet NaY ) [12 746 g mol-1/8] ) 2155.75 g
mol-1. Molecular weight of 1 supercage for dry Na ) [12 746
g mol-1/8] ) 1593.25 g mol-1, Hence, the number of supercages
in 300 mg of NaY (wet) ) [0.3 g/2155.75 g mol-1] ) 1.39 ×
10-4 mol; (or) number of supercages in 222 mg of NaY (dry) )
[0.222 g/1593.25 g mol-1] ) 1.39 × 10-4 mol.
Ca lcu la tin g th e Loa d in g Level. For example, loading 3
mg of cis-8 in 300 mg of NaY (wet) corresponds to 1 molecule
in 15.7 supercages. As 3 mg of cis-8 (molecular weight: 341 g
mol-1) ) [3 mg/341 g mol-1] ) 8.8 × 10-6 mol. The number of
supercages in 300 mg of NaY (wet) ) [0.3 g/2155.75 g mol-1
]
(25) (a) Blatchford, J . K.; Orchin, M. J . Org. Chem. 1964, 29, 839.
(b) D’Yakanov, I. A.; Komendantev, M. I.; Gui, F.-S.; Korichev, G. L.
J . Gen. Chem. USSR 1962, 32, 928. (c) Applequist, D. E.; Gdanski, R.
D. J . Org. Chem. 1981, 46, 2502. (d) Inoue, Y.; Yamasaki, N.;
Shimoyama, H.; Tai, A. J . Org. Chem. 1993, 58, 1785-1793.
6546 J . Org. Chem., Vol. 69, No. 20, 2004

Enhanced Diastereoselectivity via Confinement
nitrogen pressure until the photostationary state (24-36 h),
filtered, and washed again with fresh hexane. The supernatant
was analyzed for the presence of reactant and photoproducts
(reactant/photoproducts were not observed). The reactant and
the photoproducts were extracted from the zeolite by stirring
with acetonitrile. The extract was concentrated and analyzed
by GC/HPLC.
The choice of starting geometries was primarily guided by the
restricted rotation around the amide bond (as in cis-8, cis-9,
etc.). Full-geometry optimization on cation-bound structures
was performed on four basic conformers of cis-8 and cis-9
(Scheme 4), first at the HF/3-21G and subsequently at the
B3LYP/6-31G* levels of theories. The binding affinities were
evaluated using the “super system” approach and does not
include basis set superposition error (BSSE) corrections.
Binding affinities in each of the unique binding modes were
determined on the basis of the optimized geometries of metal-
ion-bound and metal-ion-free geometries for that conformation.
Com p u ta tion a l Meth od s
Bin d in g En er gies a n d Str u ctu r es of Li+-Bou n d cis-
a n d tr a n s-8, cis- a n d tr a n s-9, cis-10, cis-11, a n d cis-18.
Ab initio molecular orbital calculations using the Hartree-
Fock as well as the hybrid Hartree-Fock density functional
theory methods with B3LYP functional were carried out using
the Gaussian98 suite of quantum chemical programs. The
3-21G and 6-31G* basis set, respectively, were used for HF
and B3LYP calculations. Stationary points were characterized
as true minima on the corresponding potential energy surfaces
by performing frequency calculations with the “no Raman”
option. For metal-bound structures, frequency calculations
were done on representative Li+-bound systems. These calcu-
lations does not include any explicit structural features of the
zeolite framework. For structures cis-10, cis-11, and cis-18,
calculations were done only at the HF/3-21G level.
Ack n ow led gm en t. V.R. thanks the National Sci-
ence Foundation for support of the research (CHE-
9904187 and CHE-0212042) and Professor J . R. Scheffer
and Dr. K. C. W. Chong for insightful discussions.
Su p p or tin g In for m a tion Ava ila ble: Synthetic proce-
dures and spectral data for compounds 1-19 and 22-24,
HPLC and GC analyses conditions for photoproducts from
1-24, methods adopted to determine the absolute configura-
tion of trans-2, and compilation of Cartesian coordinates and
total energies for computed structures related to Figures 4-9.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Bin d in g En er gies a n d Str u ctu r es of Li+-Bou n d cis-8
a n d Its Tr a n sfor m a tion to tr a n s-8-RR a n d tr a n s-8-SS.
J O049365I
J . Org. Chem, Vol. 69, No. 20, 2004 6547