A supramolecular ship in bottle strategy for enantiomeric selectivity in geminate radical pair recombination

Article abstract of DOI:10.1021/ol034362y

(Matrix presented) Reactions in which zeolites are modified with chiral inductors to serve as media for chiral induction are often limited by the propensity of both substrate and inductor to occupy the same supercage. Herein, we report a ship in bottle strategy utilizing the thermal decomposition of dioxetanes obtained from oxazolidinone-substituted enecarbamates for the enantioselective generation of methyl desoxybenzoin (MDB). Photoexcitation of the supramolecular geminate molecular pair results in enrichment of the opposite enantiomer of MDB.

Full text of DOI:10.1021/ol034362y

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2025-2028
A Supramolecular “Ship in Bottle”
Strategy for Enantiomeric Selectivity in
Geminate Radical Pair Recombination
,‡
Thomas Poon,† Nicholas J. Turro,* Jessica Chapman,† P. Lakshminarasimhan,‡
Xuegong Lei,‡ Waldemar Adam,§ and Sara G. Bosio§
Department of Chemistry and Department of Chemical Engineering,
Columbia UniVersity, 3000 Broadway, Mail Code 3119, New York, New York 10027,
Joint Science Department, W. M. Keck Science Center, 925 N. Mills AVe.,
Claremont McKenna, Pitzer, and Scripps Colleges, Claremont, California 91711,
Institut fu¨r Organische Chemie, UniVersita¨t Wu¨rzburg, 97074 Wu¨rzburg, Germany
turro@chem.columbia.edu
Received February 28, 2003
ABSTRACT
Reactions in which zeolites are modified with chiral inductors to serve as media for chiral induction are often limited by the propensity of both
substrate and inductor to occupy the same supercage. Herein, we report a “ship in bottle” strategy utilizing the thermal decomposition of
dioxetanes obtained from oxazolidinone-substituted enecarbamates for the enantioselective generation of methyl desoxybenzoin (MDB).
Photoexcitation of the supramolecular geminate molecular pair results in enrichment of the opposite enantiomer of MDB.
The past several decades have seen tremendous advances in
molecular stereochemistry, in particular with respect to
enantiomerically selective synthesis.1 In this report we
consider strategies for enantiomerically selective synthesis
involving reactive supramolecular geminate stereochemically
isomeric radical pairs.2 Control of stereochemistry in the
recombination reactions of reactive geminate radical pairs
is a challenge because of the inherently high reactivity of
the pair.
We have demonstrated that the confinement of a geminate
triplet radical pair to a zeolite supercage can lead to a small
degree of enantiomeric selectivity upon recombination of the
pair when a supramolecular chiral auxiliary is present in the
same supercage with the radical pair.3 However, available
strategies for creating a supercage that is occupied by both
a precursor to the radical pair and a chiral inductor involve
the random addition of both the chiral inductor and radical
pair precursor (i.e., a ketone) so that there is no control over
the initial supramolecular composition and stereochemistry
of the inductor/inductee pair or even any guarantee that the
inductor/inductee pair will occupy the same supercage.4 As
a result of this lack of control of the supramolecular
* To whom correspondence should be addressed. Tel: (+1) 212-854-
2175. FAX: (+1) 212-932-1289.
† Claremont McKenna, Pitzer, and Scripps Colleges.
‡ Columbia University.
§ Universita¨t Wu¨rzburg.
(1) (a) Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41, 1998. (b)
Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (c) Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2024.
(3) (a) Kaprinidis, N. A.; Landis, M. S.; Turro, N. J. Tetrahedron Lett.
1997, 38, 2609. (b) Lem, G.; Turro, N. J. Chem. Commun. 2000, 293.
(4) (a) Uppili, S.; Ramamurthy, V. Org. Lett. 2002, 4, 87. (b) Shailaja,
J.; Ponchot, K. J.; Ramamurthy, V. Org. Lett. 2000, 2, 937.
(2) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163.
10.1021/ol034362y CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/10/2003

constitution and stereochemistry, we have devised a novel
strategy through which both the initial supramolecular
constitution and stereochemistry can be controlled.
The strategy involves (1) application of a variation of the
“ship in bottle” method that has been used for selective
reactivity of guests in zeolite supercages5 and (2) the
stereoselective formation of supramolecular stereoisomers as
the result of geminate molecular pair formation in a super-
cage. A specific example of this strategy is shown in Scheme
1 for the supramolecular enantiomeric selectivity of a radical
configuration) at position 1 and racemic (R,S) at position 5.
The strategy involves a diasteromer-differentiating oxidation
of the double bond of 1 to produce a supramolecular
geminate molecular pair 3. In the case of singlet oxygen
oxidation of 1, the formation of 3 probably occurs through
the intermediacy of a diastereomeric mixture of dioxetanes,
2.6 Decomposition of 2 results in the formation of a
supramolecular geminate pair of diastereomers, 3. The
photoexcitation of the MDB partner of the diastereomeric
geminate pair 3 will produce a prochiral radical pair as the
result of R-cleavage of the MDB molecule (Scheme 1).
Recombination of the prochiral geminate diastereomeric pair
4 occurs under the influence of the neighboring supramo-
lecular chiral inductor isopropyl oxazolidinone carbaldehyde.
The hypothesis behind the strategy is that geminate radical
pairs will be produced by photolysis of MDB, and because
the recombination of the geminate radical pair will occur in
a supercage under the influence of a supramolecular chiral
auxiliary, the supramolecular recombination will occur with
a degree of enantiomeric selectivity higher than that achieved
through the random addition of MDB and 3 to a host. The
supercage of the NaY zeolite was selected to test the
experimental feasibility of the strategy for supramolecular
enantiomeric selectivity outlined in Scheme 1.
Scheme 1
We have shown6 that the reaction of 1 with singlet oxygen
in solution is highly diastereoselective with respect to
producing dioxetanes (Scheme 1) from attack upon the less
hindered face of the enecarbamate 1. The thermal oxidation
of 1 was achieved by simply allowing a sample of 1 loaded
on NaY to stand in the dark. For example, the enecarbamate
1 (ca. 3 mg) was dissolved in isooctane and loaded on freshly
calcined NaY (ca. 300 mg). This loading corresponds to an
occupancy of ca. 1 molecule of 1 for 10 supercages of NaY.
Samples were washed 4× with fresh isooctane, and UV
spectroscopy confirmed that there was no 1 remaining in
the supernatant. Samples were immediately covered with Al
foil to maximize dark reaction and to minimize photochemi-
cal reaction of 1 resulting from room light. The samples were
allowed to stand at room temperature for 1-21 h and then
washed with isooctane and subjected to micro-Soxhlet
extraction with acetonitrile for 24 h. The products were
analyzed by both conventional GLC to determine the
conversion and by chiral GC to determine the ee. MDB was
identified as a product by both methods, and stereochemical
assignment was made by comparison with an authentic
sample of (S)-MDB.7
pair produced by the photolysis of methyl desoxybenzoin
(MDB) in the presence of a non-covalently attached chiral
oxazolidinone inductor, 3.
The enecarbamates 1a and 1b (Scheme 2) were designed
to provide an example of the proposed “ship in bottle”
strategy. Compound 1a is a mixture of molecular diastere-
omers that is enantiomerically pure (R configuration) at
position 1 and racemic (R,S) at position 5; 1b is a mixture
of molecular diastereomers that is enantiomerically pure (S
Scheme 2
The values of the enantiomeric excess of MDB produced
by dark oxidation of 1a and 1b are given in Scheme 2.
Starting with 1a an ee of 50 ( 7% of (R)-MDB is formed,
and starting with 1b an ee of ca. 47 ( 8% of (S)-MDB is
formed. A control was performed in which the isopropyl
group was absent from the oxazolidinone ring. This yielded
ca. 0% ee and supports the role of the oxazolidinone moiety
(5) Herron, N.; Stucky, G. D.; Tolman, C. A. Inorg. Chem. Acta 1985,
100, 135.
(6) Adam, W.; Bosio, S. G.; Turro, N. J. J. Am. Chem. Soc. 2002, 124,
8814.
(7) (S)-MDB was synthesized using the procedure of McKenzie, A.;
Roger, R.; Wills, G. O. J. Chem. Soc. 1926, 779.
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Org. Lett., Vol. 5, No. 12, 2003

Figure 2. Representative chiral GC traces for the enantiomeric
pair of MDB recovered from the irradiation of 3@NaY formed
from the thermal oxidation of 1@NaY. Products from the irradiation
of 3a@NaY and 3b@NaY, are shown in traces a and b, respec-
tively. Trace c is the MDB product from irradiation of the
enecarbamate lacking a stereocenter at position 1.
Figure 1. Representative chiral GC traces for the enantiomeric
pair of MDB recovered from the dark oxidation of 1@NaY.
Products from the oxidation of 1a@NaY and 1b@NaY, are shown
in traces a and b, respectively. Trace c is the MDB product from
the dark oxidation of the enecarbamate lacking a stereocenter at
position 1.
with those for random supramolecular chiral-inductor/
inductee pairs, 3ran@NaY (Scheme 2) was examined. Samples
of racemic MDB(R,S) and enantiomerically pure 4(R) or 4(S)
were loaded on NaY to produce samples of 3ran[4(R)/MDB-
(R,S)]@NaY and 3ran[4(S)/MDB(R,S)]@NaY, respectively.
Photolysis of these samples resulted in the conversion of a
racemic mixture of [4(R) + MDB(R,S)]@NaY to a mixture
that was enantiomerically enriched in either MDB(R) or
MDB(S) by only a few %, a value close to the experimental
uncertainty in the evaluation of the ee. However, since the
enantiomerically favored MDB “flipped” in going from 4(R)-
to 4(S) as a random chiral auxiliary, the small selectivity is
outside of the experimental error.
as a chiral inductor in the reaction (Figure 1). The yields of
MDB are low (less than 1%) and quickly build up to a
maximum and then do not change with time. These results
indicate that there is a limiting amount of an oxidizing agent
(e.g., molecular oxygen included in the zeolite or a fixed
number of oxidizing defects in the zeolite framework)
contained by the zeolite that is not replenished. Since the
oxygen available for the oxidation is small and the conversion
of the enecarbamate will run to only a few percent conver-
sion, only the more reactive diastereomer will react, leading
to an ee:diastereomer-differentiating reaction.
The next issue to be explored was the effect of photolysis
on the enantiomerically enriched supramolecular geminate
pairs 3a@NaY and 3b@NaY produced by oxidation of
1a@NaY and 1b@NaY. It has been shown previously3a that
low ee’s of the order of ca. 5-10% are achieved in the
photolysis of racemic MDB@NaY that is coloaded with
ephedrin (or diethyl tartrate) as a random supramolecular
chiral auxiliary. In the case of an enriched sample of 3[3(R)/
MDB(R)]@NaY an hour of photolysis produces 3[3(R)/
MDB(S)]@NaY in ca. 35-40% ee of (S)-MDB. The
photolysis of 3[3(S)/MDB(S)]@NaY produces 3[3(S)/MDB-
(R)]@NaY in ca. 35-40% ee of (R-)MDB. The control in
which the isopropyl group is absent, producing racemic MDB
upon thermal oxidation, yields racemic MDB after photolysis
(Figure 2).
The products of 1 with singlet oxygen have been inves-
tigated in solution.6 It was found that a dioxetane is formed
with essentially complete diastereoselectivity; the singlet
oxygen reacting from the least hindered face of the molecule
(Scheme 3) to diastereoselectively form a dioxetane, which
then decomposes to form MDB. Although the source of the
oxygenation in the thermal reaction (Scheme 1) of 1@NaY
is not known, the high ee of the process is consistent with
molecular oxygen (either ground state or singlet oxygen)
being the reagent responsible for the oxidation. Another
possibility is that oxygen atoms from the zeolite framework
add to a radical cation formed from loss of an electron from
1 to the zeolite,9 followed by a framework oxygen atom
transfer.
Remarkably, an initial ee of ca. 50% of (R)-MDB (or (S)-
MDB) is converted to an ee of ca. 40% of (S)-MDB (or (R)-
MDB), corresponding to a reversal of the ee of nearly 100%!
The values of the ee are among the highest reported for
enantiomerically selective recombination of geminate radical
pairs under any conditions.8 This result indicates the potential
power of the strategy to produce enantiomeric excesses of
either enantiomer of MDB depending on the reaction
conditions.
The photolyses of ketones that undergo reversible R-cleav-
age have been extensively investigated.10 When a racemic
ketone such as MDB undergoes R-cleavage to form a
geminate radical pair in the presence of a chiral auxiliary in
a zeolite supercage, the geminate pair undergoes enantio-
(8) (a) Greene, F. D.; Berwick, M. A.; Stowell, J. C. J. Am. Chem. Soc.
1970, 92, 867. (b) Hutton, R. S.; Roth, H. D.; Kraeutler, B.; Cherry, W. R.;
Turro, N. J. J. Am. Chem. Soc. 1979, 101, 2227. (c) Inoue, Y. Chem. ReV.
1992, 92, 741.
(9) Lakshminarasimhan, P.; Thomas, K. J.; Johnston, L. J.; Ramamurthy,
V. Langmuir 2000, 16, 9360.
A comparison of the results of the geminate supramolecu-
lar chiral inductor/inductee pairs, 3gem@NaY (Scheme 2),
Org. Lett., Vol. 5, No. 12, 2003
2027

cal reactions produce only minor enantiomeric excesses of
the recombination products, although significant de’s have
been observed.2 The nature of the thermal oxidation of
1@NaY is not clear and warrants further study. Whatever
the mechanism, the enantiomeric selectivity is one of the
highest achieved today with a noncovalent supramolecular
inductor/inductee pair in a zeolite supercage.11 Remarkably,
the enantioselectivity produced in the creation of a geminate
supramolecular pair can be reversed by photolysis of an
enriched geminate noncovalent supramolecular inductor/
inductee pair in a zeolite supercage. These initial studies
demonstrate the potential power of generating supramolecular
geminate chiral inductor/inductee pairs. It is to be noted that
the precursor structure 1 can exist as eight completely
independent stereoisomers, each of which can be stereo-
selectively oxidized to four completely independent su-
pramolecular geminate isomeric inductor/inductee pairs,
which upon photolysis will, in principle, produce different
enantiomeric selectivity. The investigation and correlation
of the initial supramolecular stereochemistry with the final
photochemically induced enantioselectivity opens the door
to a novel field for the investigation of supramolecular
stereochemical issues.
Scheme 3
selective recombination. However, in the reactions in which
the probability of a chiral inductor and a geminate radical
pair being in the same supercage is not controlled, the
limiting enantiomeric excesses are typically low (<10%).
According to Scheme 1, enantiomerically pure 3 is produced
along with MDB as a geminate molecular pair. This
guarantees that the prochiral radical pair produced in the
photolysis of MDB will be produced in a supercage with a
chiral inductor.
In conclusion, we have demonstrated that the recombina-
tion reactions of supramolecular geminate inductor/inductee
radical pairs in zeolite photochemical reactions produce
significant enantiomeric excesses through a “ship in bottle”
strategy. The recombination reactions of random supramo-
lecular inductor/inductee radical pairs in zeolite photochemi-
Acknowledgment. This work was funded by the National
Science Foundation through Grant CHE-01-10655. T.P.
thanks The W.M. Keck Foundation and Claremont McKenna,
Pitzer, and Scripps Colleges for sabbatical funding. J.C.
thanks the NSF and Columbia University for REU support.
The authors thank Roberto Franz for discussions and
assistance in checking several results.
OL034362Y
(10) (a) Tarasov, V. F.; Ghatlia, N. D.; Avdievich, N. I.; Turro, N. J. Z.
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A. L.; Turro, N. J. J. Phys. Chem. 1993, 97, 363. (c) Step, E. N.;
Buchachenko, A. L.; Turro, N. J. J. Org. Chem. 1992, 57, 7018. (d) Tarasov,
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