Asymmetric induction during photocyclization of chiral and achiral α-oxoamides within achiral zeolites

Article abstract of DOI:10.1039/b611387g

The photochemistry of 31 α-oxoamides capable of undergoing γ-hydrogen transfer has been examined within zeolites. These molecules, upon excitation, yield two products - a β-lactam and oxazolidinone - in solution, both resulting from γ-hydrogen transfer. W

Full text of DOI:10.1039/b611387g

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Asymmetric induction during photocyclization of chiral and achiral
a-oxoamides within achiral zeolites†
Arunkumar Natarajan and V. Ramamurthy*
Received 7th August 2006, Accepted 20th October 2006
First published as an Advance Article on the web 14th November 2006
DOI: 10.1039/b611387g
The photochemistry of 31 a-oxoamides capable of undergoing c-hydrogen transfer has been examined
within zeolites. These molecules, upon excitation, yield two products—a b-lactam and oxazolidinone—
in solution, both resulting from c-hydrogen transfer. While in benzene the major product is
oxazolidinone, within an MY zeolite, the main product is a b-lactam. In this investigation, we have
focused our attention on asymmetric induction in the formation of the b-lactam product. Two
approaches—using a chiral inductor and chiral auxiliary—have been employed. While in solution, in
the presence of chiral inductors, achiral a-oxoamides yield b-lactams with zero enantioselectivity;
within zeolites, an ee of up to 44% has been achieved. a-Oxoamides appended with a chiral auxiliary
gave b-lactams with less than 5% diastereoselectivity in solution while within zeolites, the same
a-oxoamides gave the products with de’s of up to 83%. Such a remarkable influence of zeolites is
attributed to an alkali ion interaction with the reactant a-oxoamides and to the confined environment
of the zeolite interior. At this stage, we have not been able to provide a model with predictive power and
further work is needed to understand this valuable asymmetric induction strategy.
During the last two decades supramolecular approaches to-
Introduction
wards chiral photochemistry have attracted considerable atten-
tion. Lahav, Leiserowitz and their co-workers24 and Toda and
co-workers9,10 employed optically pure hosts to form solid host–
guest complexes with achiral guest molecules. The use of chiral
hosts such as cyclodextrins, proteins and DNA to complex
achiral reactant molecules in aqueous solution has resulted in low
chiral induction in photoproducts.4,25–31 In this context, a novel
method being developed by Bach and co-workers is particularly
noteworthy.1,2 In this approach, upon complexation an optically
pure template distinguishes the two pro-chiral faces of an achiral
molecule allowing chiral selectivity in the photoproducts. How-
ever, to obtain significant chiral induction, the irradiations had
to be conducted at low temperatures as the association constants
for host to guest with toluene as solvent were low. Thus chiral
photochemistry, clearly still in its infancy, needs development of
more general methods.
Towards this need our contribution to chiral photochemistry
has been the introduction of zeolite as a medium for photoreac-
tions. We proposed that the confining cavities of zeolites studded
with alkali ions would force a stronger interaction between the
reactant and a chiral inductor which would result in chiral
induction higher than that encountered in solution. During the
last decade, we have provided several examples in which enantio-
and diastereoselectivities were obtained in zeolites but not in
solution.32–39 Recognizing the lack of availability of chiral zeolites,
we have modified the interior of an achiral zeolite by adsorbing
optically pure chiral inductors. In another approach, we employed
covalently linked chiral auxiliaries to bring about chiral induction
in photoreactions. By this technique, we were able to achieve
chiral induction (de) over 85% with a few examples that gave less
than 5% de in solution. These examples revealed the importance
of a cation–p interaction in the chiral induction process within
zeolites.40 Beyond discovering more and newer examples, a clear
A number of elegant and efficient chiral induction strategies have
evolved for thermal reactions in the past few decades. The short
lifetimes of excited states have hampered the development of an
effective interaction between an excited reactant and a chiral
perturber thus slowing down similar progress with photoreactions.
Despite the stumbling blocks, due to the persistent efforts of vari-
ous groups notably of Bach,1,2 Inoue,3,4 Pete,5 Scharf,6 Scheffer,7,8
Toda,9,10 Turro11 and ours,12–14 advances have been made during the
last decade. In 1965, Hammond and Cole established that chiral
induction could be obtained in solution through sensitization of
an achiral molecule with a chiral sensitizer.15 A few years later,
the groups of Kagan16,17 and Calvin18 obtained chiral induction in
solution by irradiation of helicenes with circularly polarized light.
Schmidt and Penzien19 established in 1969 that global chirality
due to crystallization of achiral molecules into a chiral space
group could be transformed into local chirality by irradiation
of the crystal. The efforts of Scharf6 and Pete5,20 and their co-
workers have established the value of chiral auxiliaries in solution.
Following the initial observation by Hammond and Cole, Inoue
and co-workers have extensively explored the chiral sensitization
technique using cyclooctene photoisomerization as the model.
The elegant technique of transformation of chiral crystals
of achiral molecules into chiral products has been slow to
develop.21,22 Using an ionic chiral auxiliary approach, Scheffer
and co-workers,7,8,23 who introduced this new methodology, have
repeatedly crystallized achiral molecules in a chiral space group to
subsequently transform to chiral products.
Department of Chemistry, University of Miami, Coral Gables, Fl 33124,
USA
† Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b611387g
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understanding of how the cation–p interaction and confinement
provided by a zeolite bring about chiral induction remains elusive
to us. In this report, admitting that we have yet to develop a general
model for chiral induction within zeolites, we present our results
on chiral induction during the photocyclization of a-oxoamides
to b-lactams. There have been a considerable amount of studies
related to chiral induction during photocyclization of oxoamides
in crystals and in solid inclusion complexes. We believed that the
photobehavior of the same molecules in crystals would help us
understand the chiral induction process within zeolites. Examples
provided in this report further confirm the usefulness of zeolites
as media in performing chiral photochemistry.41
medium in which the photochemical reaction is conducted, can
occur either via direct transfer or through two steps—electron
transfer followed by proton transfer (Scheme 3).44–46 b-Lactam
was the major product (60–88%) from all a-oxoamide derivatives
investigated in this study although oxazolidinone was obtained
as the major product (>85%) in benzene solution (Table 1).
Despite the fact that the mechanism of hydrogen transfer has
yet to be resolved, we believe that the chiral induction could be
understood by either one of these two primary processes—electron
or hydrogen atom transfer. We focused our attention on the b-
lactam product and the enantiomeric/diastereomeric excess in this
product was monitored through HPLC. Since the oxazolidinone
product was formed in smaller amounts, no enantiomeric excess
(ee) or diastereomeric excess (de) measurements of this product
were made.
Results
In order to establish the value of zeolites as media for achieving
enantio- and diastereoselectivities during a photoreaction, we
have investigated thirty one a-oxoamide derivatives (1a–g, 4a–x;
Schemes 1 and 2). b-Lactams and oxazolidinones are the main
products of c-hydrogen transfer on excitation of a-oxoamides
(Scheme 1).42,43 The c-hydrogen transfer, depending upon the
In this article we show that reactions conducted within zeolites
are more selective both in terms of product distribution and chiral
induction, than those in solution. Two independent approaches
we have been exploring were utilized:13 (a) the ‘chiral inductor
approach’ where a chiral inductor adsorbed onto the zeolite
interior provides an asymmetric environment; (b) the ‘chiral
Scheme 1 Photochemical reaction of a-oxoamide derivatives 1a–1g.
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Scheme 2 Diastereoselective studies on covalent chiral auxiliary derivatives 4a–x.
auxiliary approach’ where the chiral information is covalently
attached to the reactant molecule. The absolute configurations
of the photoproducts except 5a were not determined due to
the relatively difficult conversion of the b-lactam products to
compounds with known absolute configuration. In the absence of
this information, we denote the two enantiomeric or diasteromeric
product peaks in GC and HPLC as A and B. The isomer
that eluted first was always assigned as A. Our main goal of
establishing the utility of zeolites as useful media for achieving
asymmetric induction in photochemical reactions was achievable
even without the absolute configurations of the enantiomeric
and diastereomeric products. However, our recent studies in the
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Scheme 3 Mechanism of photocyclization of a-oxoamides.
Table 1 Photoreaction of 1a–g in solution and within NaY: percentages
of the two photoproducts, b-lactam (2) and a-oxazolidinone (3)a
above chiral inductors on their internal surfaces were used as
reaction media. The experimental section provides details for
the inclusion of the reactants and the chiral inductors within a
zeolite, irradiation procedure, extraction and analysis. The loading
level (represented as ꢀSꢁ and defined as the average number of
molecules per supercage) of 1 and 0.01 of the chiral inductor and
the substrate, respectively, were maintained. A higher ratio of the
chiral inductor was employed to maximize the chances of the
substrate molecule being adjacent to the chiral inductor within
the supercage. Sample handling was carried out under laboratory
conditions (temperature, 20 ◦C; humidity, 50%). Since the external
surface of the NaY zeolites constitutes less than 1% of the total
surface area, in the absence of any specific interactions, adsorption
of molecules would be expected to be on the internal surface
thereby leading to photoreaction within and not on the external
surface of a zeolite.
Benzene
NaY
Substratesb
2
3
2
3
1a
1b
1c
1d
1e
1f
11
9
7
6
89
91
93
94
88
85
87
80
12
15
13
20
5
95
60
40
2 (f1)
3 (f2)
11
45 (f1)
50 (f2))
89
48 (f1)
37 (f2)
78
10 (f1)
4 (f2)
22
1g
a Based on GC analysis, the relative ratios of the product peaks are
presented; the reported values represent averages of three independent
runs. b All irradiations were conducted at room temperature.
Photoreaction of 1a in solution in the presence of a chiral
inductor and within NaY in the absence of a chiral perturber
resulted only in racemic 2a. Photoreaction of 1a within chirally
modified NaY using (−)norephedrine as a chiral inductor gave the
b-lactam 2a with 44% ee (Table 2). Moderate enantioselectivities
ranging between 10–23% (maximum) depending upon the chiral
inductor used were obtained with substrates 1b–d (Table 2).
Irradiations of 1a–d included within Li+, Na+, K+, Rb+ and Cs+
exchanged Y zeolites were conducted to investigate the role of
alkali ions in asymmetric induction showed enantioselectivities
varying with the alkali ion with all substrates proving their
importance (Table 2).
crystalline state of one of the systems enabled us to assign
the absolute configuration of the newly formed chiral center
in the photoproduct 5a.47
Chiral inductor approach
The major products upon irradiation of zeolite included a-
oxoamides 1a–g were the b-lactams 2a–g (Scheme 1). Among
the various chiral inductors explored, ephedrine, norephedrine
and pseudoephedrine gave better results (Table 2). Alkali ion
exchanged Y type zeolites rendered chiral by adsorption of the
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Table 2 Enantioselective studies on b-lactam photoproductsa
Medium/chiral inductora,b
2a ee (%)
2b ee (%)
2c ee (%)
2d ee (%)
2e ee (%)
2f1 ee (%)
2g ee (%)
Benzene
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Benzene/(−)ephedrine
NaY
LiY/(−)-ephedrine
NaY/(−)-ephedrine
KY/(−)-ephedrine
RbY/(−)-ephedrine
NaY/(−)-ephedrine/50◦ C
NaY/(−)-ephedrine/−60 ◦
NaY/(+)-ephedrine
NaY/(−)-norephedrine
NaY/(+)-norephedrine
NaY/(−)-pseudoephedrine
3A
18B
3A
3B
18B
17B
20B
44B
40A
10B
10B
6A
27A
7A
3A
27A
27A
23B
4A
6B
1A
13A
3A
0
7A
25B
12B
6A
5B
—
4A
10A
13A
5A
11A
8A
11B
5A
7B
—
1A
5A
2A
0
—
—
5B
3B
2A
10A
3B
1A
4A
3A
0
—
—
5B
20B
19A
5B
23A
4A
10A
13A
5A
11A
8A
11B
5A
7B
C
10A
10A
—
15A
NaY/(−)-phenylethylamine
—
—
a All irradiations unless stated were conducted at room temperature. b The A’s and B’s refer to the first and second peak that elute from the HPLC column.
Table 3 Influence of para- and meta-amide, amino alcohol and amino
acid derivatives on % de of the b-lactam photoproducts (5a–5x)a,b
The isopropyl groups of the amide moiety of the substrate 1a
were replaced with two methyl, one isopropyl and one cyclohexyl,
and two cyclohexyl groups (1e–g respectively) to determine the
influence of the structure of the substrate on enantioselectivity.
The best ee obtained within an MY zeolite for the photoproducts
(2e–2g) using a specific chiral inductor is presented in Table 2.
Examination of the effect of temperature on systems 1a–d
showed it had no effect on the enantioselectivity of b-lactam
products 2a, 2b, and 2d (Table 2). Product 2c showed variation
Substrates
Solution
LiY
NaY
KY
RbY
CsY
4a
4p
4b
4q
4c
4r
4d
4s
4e
4t
2A
0
2A
7A
2A
0
5A
13A
30A
14A
19A
5A
17A
3A
2B
62A
45A
54A
38A
22A
25A
30B
40A
83B
35B
40A
43B
22A
49A
60B
83A
20A
45A
20A
25B
68A
50B
9B
25A
19A
16A
1A
30A
1A
19B
19A
54A
9B
47B
12B
17B
40A
11A
42A
5B
19A
60B
24B
74B
9A
10B
16B
16A
5A
15A
1A
12A
40B
14B
1A
16A
5B
12B
20A
20B
35A
40A
3A
30B
10A
25B
8A
—
—
—
—
5A
33B
3B
44B
—
◦
6B
2A
2B
6B
3B
5B
6A
0
1B
7A
1A
2A
5A
3A
5A
5B
5B
15B
in ee with temperature (RT to −60 C; Table 2) and a switching
of enantiomer was observed from 13% (A) at 23◦ to 25% (B) at
−60 ◦C.
10B
6A
8B
—
4f
10B
5A
25B
16A
47A
0
—
5A
—
5A
5B
10A
—
4g
4h
4u
4i
4v
4j
4w
4k
4x
4l
4m
4n
4o
Chiral auxiliary approach
9A
12A
12B
1A
29A
0
5A
9B
40A
41B
2B
It is evident from the presentation above that photoreaction of
a-oxoamides 1a–g within chirally modified zeolites produced only
low to moderate enantioselectivity. Hence we explored a strategy
in which the chiral influence on the reactant is brought forth by
a chiral substituent covalently linked to the reactant at a location
remote to the reaction site. A variety of chiral auxiliaries such
as amines, amino acid methyl esters and amino alcohols were
examined by covalently linking them via the carboxyl group at
the para or meta position of the phenyl unit of the a-oxoamide
(Scheme 2). Attempts to synthesize ortho substituted a-oxoamides
were unsuccessful.
30B
30A
8A
20A
9B
5B
4B
a All irradiations unless stated were conducted at room temperature. b The
A’s and B’s refer to the first and second peak that elute from the HPLC
column.
Excitation of the chiral auxiliary coupled oxoamides 4a–x
within zeolites gave b-lactams 5a–x as major products (Scheme 2).
The oxazolidine product 6a–x was formed only in 15–20%
within zeolites. The percentage de’s obtained on the b-lactam
photoproduct with various covalently linked chiral amines, amino
acids, and amino alcohols as chiral auxiliaries at para (4a–
o) and meta (4p–x) positions of the phenyl moiety of N,N-
diisopropylglyoxylamides are presented in Table 3. In all cases,
higher de’s were obtained within a zeolite than in solution.
Examples 4e and 4v are particularly noteworthy. Both 4e and 4v
photolyzed in NaY zeolite resulted in a maximum 83% de of 5e and
5v. It is important to note that the same compounds in solution
(CH3CN) gave 2% and 7% de. Additionally, the diastereoselectivity
in all examples (Table 3) varied with the alkali ion in the zeolite.
For example, the de obtained on compound 5e within MY zeolites
were: LiY, 2%; NaY, 83%; KY, 54%; and RbY, 16%. Apart from the
alkali ion dependent de, in some cases, the diastereomer formed
in excess was dependent on the alkali ion present in zeolites. For
example, compounds 4e and 4l gave 83% and 74% B respectively
within NaY and 54% and 68% respectively of A within KY. Unlike
the para substituted derivatives, most meta substituted oxoamides
did not show an alkali ion dependent diastereomer switch on
the b-lactam products. Our desire to investigate the asymmetric
induction with the chiral auxiliaries appended at the ortho position
of the N,N-diisopropylglyoxylamide could not be realized owing
to the difficulties in their synthesis.
The dependency of diastereoselectivity on the nature of the
alkali ion when various alkali ion exchanged zeolites were used
as listed in Table 3 clearly points out that no single alkali ion
is in general more effective than others and that it varies with
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the different compounds. There was a drastic reduction in de to
2% when irradiation of silica gel-adsorbed 4a was conducted (no
alkali ion and no supercage). Furthermore, even when irradiation
was conducted in NaY with increases in the silicon content (with
a corresponding adjustment of the alkali ion content), the de
decreased. For example an increase in Si–Al ratio from 2.4 to
40 resulted in the de of product 5a changing from 62% to 7%
respectively. Similarly, changes in moisture content of the zeolite
that would alter alkali ion concentration were reflected in changes
in de. For example, 4a within dry and wet (alkali ion exposed to
normal laboratory humidity) NaY resulted in 62% and 18% de
respectively in the product 5a. All these observations emphasize
the importance of the alkali ion in the chiral induction process. In
addition to the effect observed due to the absence of both alkali
ion and supercage when silica gel was used the importance of the
confined space became apparent when irradiation of 4a in LiClO4
or NaClO4 saturated acetonitrile produced 5a with 5% de. Thus
the above observations lead us to conclude that both the alkali ion
and the confined space of zeolites are crucial to chiral induction
during c-hydrogen transfer in a-oxoamides.
usefulness of zeolites as reaction media to bring about chiral
induction in photochemical reactions. In the following paragraphs
a brief discussion of the observations on the photocyclization of
a-oxoamides is presented.
Photoreaction of a-oxoamides 1a–g using the chiral inductor
approach gave enantioselectivities ranging between 4–44% on b-
lactam products within zeolites (Table 2). It is important to note
that in solution, even in the presence of chiral inductors, only
a racemic product mixture was obtained. The best results were
obtained with 1a. Photoreaction of 1a within NaY using (−)-
norephedrine as a chiral inductor gave ee (44%, B) on the b-
lactam photoproduct. As expected, the enhanced isomer switched
when (+)-norephedrine was used confirming the observed chiral
induction to be no artifact. Unfortunately, this observation could
not be extended to 1b–g where the same chiral inductor gave the
b-lactams with very low ee (3–20%). As indicated in Table 2, the
chiral inductor that gave the best ee in each case was different.
Based on our experience with a-oxoamides as well as the systems
investigated earlier, we conclude that the best chiral induction
is usually obtained with ephedrine, norephedrine and/or pseu-
doephedrine. In our hands, depending on the system, one of these
compounds works best though the exact one can’t be predicted.
We visualize chiral induction to be the result of close interaction
between the reactant and the chiral inductor enforced by the
alkali ion present within a zeolite. Our computational and solid-
state NMR results in the case of phenyl cyclohexyl ketones were
recently presented.33 In this example, we showed that the alkali
ion enforces an interaction between the chiral inductor and the
ketone. We believe that the same phenomenon plays a role in a-
oxoamides as well. If this was true one would expect that any
variation of the structure of the ternary supramolecular complex
made up of an alkali ion, chiral inductor and a-oxoamide would
have a consequence on the ee within a zeolite. This was found
to be the case. As seen in Table 2, the ee was dependent on the
nature of the alkali ion, and the structures of the a-oxoamide and
the chiral inductor. Even though prediction of the structure of
the ternary complex and its chiral outcome might be possible,
we at this time are unable to do so. Since the flexibility of the
ternary complex would depend on the temperature, one would
expect the ee also to depend on the temperature of irradiation.
This was found to be so in the case of 1c where a difference in
ee was observed when irradiations were conducted at different
temperatures (Fig. 1). Not only was there a variation in ee
but also the isomer being enhanced switched between high and
Discussion
As presented above, we have experimented with two approaches
to achieve chiral induction during the photocyclization of a-
oxoamides to b-lactams within zeolites. We discuss the ‘chiral
inductor approach’ first. The ideal approach to achieve chiral
induction within zeolites would be the use of ‘chiral zeolites’
as reaction media. In the absence of stable chiral zeolites, we
have resorted to modifying an achiral zeolite to a chiral one by
physical adsorption of optically pure organic molecules (chiral
inductors) within zeolites. The chiral inductors were selected based
on their availability, size, functionality and inertness to irradiation
conditions. Recently we succeeded in achieving moderate enan-
tioselectivity by this approach in diverse reactions including (1)
photocyclization of tropolone and pyridone derivatives,32 (2) light
initiated geometric isomerization of 1,2-diphenylcyclopropanes
and 2,3-diphenyl-1-benzoyl cyclopropanes,35,36 (3) Norrish type II
reaction of phenyl adamantyl ketones, phenyl norbornyl ketones
and phenyl cyclohexyl ketones34,38 and (4) oxa-di-p-methane re-
arrangement of naphthalenones and cyclohexenones.48,49 Despite
the extensive list, we are unable to formulate rules that would
allow prediction of the chiral outcome of a photoreaction within
a zeolite. Nevertheless we have established, unequivocally, the
Fig. 1 HPLC traces showing the temperature effect on enantioselectivity of b-lactam (2c) within NaY; reactant: 1c, chiral inductor: (−)-ephedrine.
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low temperatures. Such a temperature dependent enantiomer
switch has been noted during the geometric isomerization of
cis-cyclooctene in solution.50 We anticipate that the temperature
dependent enantioselectivity might be due to the rigidity of the
substrate–cation–CI complex on lowering the temperature. This
rigidity results in better interaction between the CI and the
substrate. The above mentioned argument is supported by the
observation that during the high temperature (50◦ C) photolysis
of substrate 1c within NaY/(−)-ephedrine, the % ee reduced to
7(A) owing to an increase in the mobility of the substrate and
the chiral inductor. Whereas at RT or higher, the molecule is still
flexible and therefore favors a different conformation from which
hydrogen abstraction might result in enantiomeric excess of the
opposite isomer A. Since the temperature effect was not uniform
with other substrates, it was not pursued in detail. We do not have a
clear explanation why only 1c showed the temperature dependence
but not the others.
Having obtained partial success with chiral inductor method-
ology, we decided to explore the chiral auxiliary approach. In
this approach with an achiral Y zeolite as the reaction medium,
the chiral influence is provided by an optically pure substituent
covalently linked to the reactant molecule. In the case of a-
oxoamides, to examine the influence of the location as well as
the nature of the chiral auxiliary on the extent of chiral induction,
we covalently linked various chiral auxiliaries at the para and meta
positions of the aryl ring of the a-oxoamide (Table 3).
In order to gain an insight into the role of the cation
during the chiral induction process, structures of the cation–
reactant supramolecular complexes were computed at HF/3–
21G* level.51 We find gas phase computational data useful as
a guide in formulating a preliminary working model for the
chemical behavior of molecules within a zeolite. We recognize
that the above computations refer to a naked cation whereas the
chemistry relates to the cation bound to the walls of the zeolite.
Therefore, conclusions drawn using the computational results are
expected to be only approximate. The substrates chosen for the
study were para substituted S(−)-phenyl ethyl amide and S(−)-
cyclohexylethylamide of N,N-diisopropylglyxylamide. Geometry
optimization of the above structures in the presence of Na+ gave
four cation–reactant bound complexes for (S(−)-4a and S(−)-4d).
The most stable structure (−74.8 kcal mol−1) obtained for S(−)-4a
is the one where Na+ is bound to the carbonyl and the phenyl
moiety of the chiral auxiliary through cation-dipolar and cation-p
interactions (Fig. 2a). In such a structure, the chiral auxiliary has
very little conformational flexibility. On the other hand, in the case
of S(−)-4d, the structure with the cation-dipolar (with the carbonyl
group) interaction with energy of only −58 kcal mol−1 (Fig. 2b)
that would allow free rotational mobility of the chiral auxiliary was
obtained. Based on the above results, we believe that ‘rigidification’
of the chiral auxiliary through a cation–chromophore interaction
plays a role in the chiral induction process within a zeolite. One
should note that the zeolite supercage contains several cations
and even though visualization of structures with more than one
alkali ion interacting with the reactant molecule within a zeolite
is possible, we did not perform computation in the presence of
multiple cations. From our above computational data, we wish
to draw attention only to the fact that an interaction between the
alkali ion and the chiral auxiliary, depending on the chromophores
present, could restrict the conformational flexibility of the chiral
auxiliary that would influence the extent of chiral induction.
We observed, in the case of 2,3-diphenyl-1-benzoyl cyclo-
propane derivatives, that the chiral auxiliary functions better at
The greater efficiency of chiral auxiliaries containing aromatic
or carbonyl groups as noted in our earlier studies proved true
in this study as well.13 For example S(−)-phenyl ethyl amide
as the chiral auxiliary (4a) gave the product with a de of 55%
while cyclohexyl ethyl amide as the chiral auxiliary (4d) gave only
30%. Similar differences were observed between 4e containing an
aryl substituent and 4h, 4i and 4j that contain alkyl substituents.
Perusal of Table 3 reveals that 4e yields a maximum de of 83% in
NaY while 4h, 4i and 4j gave the products in 22%, 60% and 20%
de respectively in NaY.
Fig. 2 Binding affinity of Na+ with (a) S (−)-phenyl ethyl amide of N,N-diisopropyl-a-oxoamide (4a) and (b) S(+)-cyclo hexyl ethyl amide of
N,N-diisopropyl-a-oxoamide (4d), optimized using Gaussian-98 software [HF, 3–21G*].
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the meta than at the para position.35 We ascribe this effect to the
proximity of the chiral auxiliary to the reaction site. The results
of examination of the influence of a chiral auxiliary linked at the
para and meta positions of the aryl ring of an a-oxoamide as shown
in Table 3 are not clear-cut with the chiral auxiliary functioning
better at the para position in some cases and at the meta position
in others. For example, bulkier chiral auxiliaries such as phenyl
ethyl amide, naphthyl ethyl amide and phenyl alanine methyl ester
functioned better at the para position while slightly smaller chiral
auxiliaries such as 3-methyl-2-butyl amide, valine methyl ester,
leucine methyl ester and isolecuine methyl ester functioned better
at the meta position. Results with a-oxoamides suggest that the
conclusion drawn based on 2,3-diphenyl-1-benzoyl cyclopropane
derivatives, namely that a chiral auxiliary works better when it is
closer to the reaction site, is not general and that the mechanism
by which a chiral auxiliary functions within a zeolite is yet to be
understood.
solvent and the cation present within a zeolite plays an important
role in the process, at this stage we do not have an insight into how
the cation within the supercage influences the chiral outcome.
Among the 24 para and meta substituted compounds studied
within zeolites, 15 compounds (4d–o, 4r, 4s, and 4x) showed an
alkali ion dependent diastereomer switch on the b-lactam products
upon variation of cations occupying the zeolite framework.
Among the 15 compounds, 13 of them are para substituted
derivatives and 2 are meta substituted derivatives. It is particularly
revealing in the case of product 4e which gave 83% of the B
isomer with NaY but switched to the 54% of A diastereomer
in KY. Though the exact reason for this behavior has not been
understood we believe that the probable reason for the switch could
be the difference in site to which the two alkali metal ions (Na or K)
bind. This suggestion, although in our case has no experimental
support, has literature precedence.52–55 Based on density functional
calculations and low energy collisionally activated and thermal
radiative dissociation experiments, a difference in binding pattern
between Li+ and K+ ions with valine and glycine 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. Such a phenomenon could be involved within a zeolite
and responsible for the observed cation controlled diastereomer
switch within a zeolite. It is important to recognize that it is
not only the cation size that controls the extent and direction of
diastereoselectivity but also the binding ability and charge density
of cations play an important role. Overall, too many factors control
the chiral induction process within a zeolite making prediction a
bit risky.
The geometry optimized structures (HF/3–21G*) of the
para and meta substituted phenyl ethyl amide of N,N-
diisopropylglyoxylamide (4a and 4p) shown in Fig. 3 are larger
than the dimensions of the supercage (dia 13 A).51 We believe that
˚
it is quite likely that the reactant molecule is stationed between
˚
the two supercages through the window (∼8 A dia). Under such a
condition, it is possible that two cations are holding the reactant
molecule in two different cages by interacting with the chiral
auxiliary in one cage and with the reactant chromophore, diketone,
in the other cage. Although we are confident that the chiral
induction within a zeolite is far more effective than in an organic
The final part of the presentation deals with the identification
of the absolute configuration of the b-lactam product from 4a.
Knowledge of the absolute configuration of the newly formed
chiral center allows us to speculate the mechanism of chiral
induction within zeolite Y. Using the data obtained from our
recent studies on single crystal to single crystal transformation of
4a to 5a, we were able to identify the b-lactam 5a that is enhanced
within NaY to have the R configuration at the newly formed chiral
center. As illustrated in Scheme 3 upon excitation of a-oxoamide
either an electron transfer (followed by proton transfer) or a
hydrogen abstraction (the exact nature of it being dependent on
the medium and the substituents attached to the amide nitrogen)
is believed to be the primary process. Independent of the primary
step, the 1,4-biradical intermediate is involved in the formation
of b-lactam and 1,3-zwitterion in the formation of oxazolidinone
products (Scheme 3). In general, the absolute configuration of
the newly formed chiral center in the b-lactam product is decided
at the stage of the ring closure of the 1,4-biradical intermediate
(Scheme 3), i.e., to which face of the prochiral benzylic radical
center the c-carbon radical adds. In media where the equilibrium
between the two rotomers of the biradical (biradicals A and B
in Scheme 3) is not established, the chirality would be decided at
the hydrogen abstraction (or proton transfer) stage. Both crystal
structure determination47 on 4a and computation of 4aꢂ suggest
that the dicarbonyl part of 4a and 4aꢂ is twisted with respect to
Fig. 3 a) Geometry optimized meta-substituted phenyl ethyl amide
of a-oxoamide (4a); b) geometry optimized para-substituted phenyl
ethyl amide of a-oxoamide (4d), optimized using Gaussian-98 software
[HF, 3–21G*].
=
the aryl ring. As illustrated in Fig. 4 the torsion angle O C–Ca–
Nb in 4a could be either positive or negative, i.e., the carbonyl
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Fig. 4 Positive or negative torsion angles based on carbonyl group facing
above or below the aromatic p-plane.
Fig. 5 X-Ray crystal structure of oxoamide derivative 4c; note the
two c-hydrogens are placed at different distances from the carbonyl
chromophore.
could be above or below the aryl p-plane. Under these conditions
the hydrogen abstraction could occur from either the top or
the bottom prochiral face of the carbonyl group leading to two
biradical rotomers A and B (Scheme 3).
was taken in a Pyrex test tube and dissolved in methanol or ethyl
acetate solution.
In the isotropic media, the chiral auxiliary has little or no
influence on the reactant a-oxoamide and therefore there is
no preference for either of the rotomers leading to very low
diastereoselectivity on the b-lactam (Table 3). Clearly within a
zeolite this is not the case and enhanced formation of an RR
diastereomer (5a)15 during photoreaction of 4a suggests that the
hydrogen abstraction occurs preferentially from one rotomer of
the reactant a-oxoamide. Based on formation of the R isomer, the
same one formed during crystal irradiation, we believe that 4a
adopts a structure similar to that in a crystal where the torsion
Loading and photolysis of achiral a-oxoamides (1a–g) in the
presence of chiral inductors in MY zeolites
In order to activate the zeolite, commercially available NaY (300
mg) was kept in a furnace maintained at 500 ◦C for 12 h prior to
use. The activated NaY was added to the hexane–dichloromethane
(4 : 1) solution of the substrate, being careful not to add it too fast
which would result in charring of the sample, and not too slow
as the moisture in the atmosphere would hydrate the zeolite. a-
Oxoamides (∼4 mg) and the chiral inductor (25 mg) were stirred
with activated NaY (300 mg) in 5 mL of dichloromethane–hexane
(1 : 4) for 12 h at room temperature. The loading level of the chiral
inductor was maintained at one molecule in every supercage, while
the loading level of the substrate was kept at one molecule in every
ten supercages. A higher ratio of the chiral inductor is employed to
maximize the chances of the substrate molecule being adjacent to
the chiral inductor within a supercage. The zeolite containing both
the reactant and the chiral inductor was collected by filtration,
washed with hexane and irradiated (450 W medium pressure Hg
lamp, Pyrex filter) as a hexane slurry for 1–3 h. Sample handling
was carried out under laboratory conditions (temperature = 20 ◦C,
humidity 55%). The product was extracted with dichloromethane
and analyzed by GC or HPLC.
=
angle O C–Ca–Nb is positive. In this structure, of the two c-
hydrogens present in two isopropyl groups, one is expected to
be closer to the carbonyl chromophore. Based on comparing the
isomer (A or B) enhanced during irradiation of eight oxoamide
molecules included within zeolites or as crystals we believe that the
majority of molecules have a conformation in which the reactive
carbonyl chromophore has a positive tilt with respect to the aryl
p-plane within zeolites (Fig. 5). The comparative study presented
in Table 4 reveals six out of eight molecules (except 4c and 4p)
adopt a positive tilt within the NaY zeolite with respect to the
aryl p-plane. Understanding how the chiral auxiliary controls the
=
torsion angle O C–Ca–Nb of the diketoamide part might get us
closer to uncovering the mechanism of chiral induction within a
zeolite.
Loading and irradiation of a-oxoamide derivatives (4a–x)
Experimental
The a-oxoamide derivative (4 mg), was dissolved in a mixture of
Loading and photoreaction of a-oxoamides
dry methylene chloride–hexane (1 : 4). NaY (300 mg), dried at
◦
All photoreactions were performed by using a 450 W medium
pressure mercury lamp placed in a water-cooled Pyrex immersion
well (transmits l > 290 nm). For solution photolysis, the sample
500 C was added to the above. The slurry was stirred for 12 h,
filtered and washed with hexane (3 × 5 ml). The supernatant
hexane layer was tested for complete loading by removing hexane
Table 4 Comparison of isomers enhanced within the NaY zeolite and in the crystalline state
Substrate
Torsion angle in crystalline state/deg
% de (in crystals)
% de (within NaY)
4a
4c
4e
4f
4m
4n
4p
4q
90.36
89.55
−89.51
−86.99
86.48
>99A
96B
82A
99B
91B
95B
80A
99B
60A
54A
83B
40A
50B
9B
88.12
−69.12
45A
45A
−100
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under a positive pressure of nitrogen. The zeolite complexed with
the guest was dried under vacuum (3 × 10−3 Torr) at 65 ◦C for 6 h
and irradiated (450 W medium pressure Hg lamp) in dry hexane
(5 ml) for 45 min. The products were extracted from the zeolite by
stirring with 5 mL of acetonirile.
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Acknowledgements
V. R. thanks the NSF for financial support (CHE-0212042)
and J. R. Scheffer for a long-standing collaboration and insightful
discussions on various aspects of chiral photochemistry.
34 A. Natarajan, V. Ramamurthy and J. T. Mague, Mol. Cryst. Liq. Cryst.,
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