Temperature and solvent control of the stereoselectivity in the reactions of singlet oxygen with oxazolidinone-substituted enecarbamates

Article abstract of DOI:10.1021/ja048438c

Oxazolidinone-functionalized enecarbamates react stereoselectively with singlet oxygen to give methyldesoxybenzoin (MDB) in moderate to high enantiomeric excess. The stereochemical outcome depends on the E/Z substrate geometry, temperature, and solvent variables. The analysis of the differential activation parameters suggests a large contribution from the entropy term in determining the enantioselectivity. We demonstrate the utility of the temperature and solvent variables in determining the degree of the photochemical kinetic resolution of the enecarbamates; for example, in the photooxygenation at -70 °C in methanol, MDB may be obtained in methanol. Copyright

Full text of DOI:10.1021/ja048438c

Published on Web 08/07/2004
Temperature and Solvent Control of the Stereoselectivity in the Reactions of
Singlet Oxygen with Oxazolidinone-Substituted Enecarbamates
Thomas Poon,† J. Sivaguru,‡ Roberto Franz,‡ Steffen Jockusch,‡ Claudia Martinez,‡
Ilyas Washington,‡ Waldemar Adam,§ Yoshihisa Inoue,| and Nicholas J. Turro*,‡
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 North Mills AVenue, Claremont McKenna, Pitzer, and Scripps Colleges, Claremont, California 91711,
Institut fu¨r Organische Chemie, UniVersita¨t Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg (Germany) and
Department of Chemistry, UniVersity of Puerto Rico, Rio Piedras, Puerto Rico 00931, and ICORP (JST) and
Department of Molecular Chemistry, Osaka UniVersity, Yamada-oka, Suita, Japan
Received March 18, 2004; E-mail: njt3@columbia.edu
Table 1. Stereoselectivity of the MDB Formation in the
Photooxygenationa of the Enecarbamates 1 in CDCl3
Oxazolidinone-substituted chiral enecarbamates 1 are mechanisti-
cally versatile systems for the study of conformational, electronic,
stereoelectronic, and steric effects on the stereoselectivity of
oxidation reactions at the alkene functionality.1 The photooxygen-
ation of the Z-isomers of 1 leads to diastereomerically pure
1
dioxetanes 2, which result from the attack of O2 exclusively on
the face anti to the isopropyl substituent of the oxazolidinone
stereogenic center at the C-4 position (Table 1).1e The rate of
addition is further governed by the configuration of the chirality
center at the C-3′ position of the alkenyl side chain, such that partial
conversion of 1 affords nonracemic methyldesoxybenzoin (MDB),
the decomposition product of 2.1b Thus, the enantiomeric excess
(ee) of MDB serves as a chemical probe for the reactivity of the
substrate diastereomers as a function of structure and environment.
We now report that the E-isomers 1c,d yield higher ee values
for MDB than their Z counterparts 1a,b. Thus, by simple modifica-
tion of the geometry of the alkene functionality, the directing
influence of the allylic chirality center is approximately doubled.
For example, a ca. 50:50 mixture of (3′R)-1c and (3′S)-1c reacts
with 1O2 to give 55(5% ee of R-MDB, i.e., about twice as high as
the corresponding Z substrate pair 1a. The reaction of the
diastereomeric pair (3′R,S)-1d, the enantiomeric complement to 1c,
gives similar ee values, but the opposite enantiomer of MDB is
favored. Furthermore, as we show in Table 2, the ee values for the
E-isomers 1c and 1d are remarkably sensitive to temperature and
solvent; i.e. we demonstrate control of enantioselectivity as has been
achieved in the enantiodifferentiating Z/E photoisomerization of
cyclooctene.2 The latter provides an exemplar for the solvent and
temperature dependence of the stereocontrol in the systems reported
here.
The enantioselectivity of MDB is based on a critical balance of
the enthalpy and entropy terms, and the large contribution of the
entropy factor (Table 2, Figures S1 and S2 of the Supporting
Information) suggests that the conformational flexibility/rigidity of
the substrates/transition states and their solvation/desolvation
behavior are crucial in the stereodifferentiating component of the
mechanism for dioxetane (and MDB) formation. In such a case,
the ee value is directly related to the differential activation
parameters ∆∆Hq and ∆∆Sq through eqs 1 and 2.3 Enthalpic control
applies when the stereoselectivity is enhanced upon decreasing the
reaction temperature, a phenomenon common to many thermal
entry
substrate
convn (%)b
MDB (% ee)b
1
2
3
4
(Z,4R,3′R)-1a + (Z,4R,3′S)-1a
(Z,4S,3′S)-1b + (Z,4S,3′R)-1b
(E,4R,3′R)-1c + (E,4R,3′S)-1c
(E,4S,3′S)-1d + (E,4S,3′R)-1d
49 ( 12
47 ( 10
47 ( 3
50 ( 3
27 ( 4 (R)
11 ( 2 (S)
55 ( 5 (R)
40 ( 8 (S)
a Photooxygenations were performed using methylene blue as sensitizer.
b Values are an average of three determinations, and ranges are taken at
the 95% confidence level.
Table 2. Activation Parameters and Stereoselectivity Factors (s)
for the MDB Formation in the Oxidation of 1 by 1O2 as a Function
of Solvent and Temperature
b
c
q
q
temp MDB
(°C) (% ee)
convn
∆∆H
(kcal mol-1
∆∆S
(cal mol-1 K-1
)
substratea
solvent
(%)
sd
)
50 64 (S)
18 30 (S)
-15
-40 58 (R)
50 70 (R)
18 85 (R)
-15 90 (R)
-40 94 (R)
20 34 (S)
23
34
28
37
30
34
17
12
25
65
31
29
59
56
5
5.5
2.1
1.0
5.2
7.6
(3′R,S)-1c CD3CN
(3′R,S)-1c CD3OD
-4.5
-2.8
-17
0
19
23
37
-4.9
2.3
(3′R,S)-1c CD2Cl2 -20 27 (R)
-60 74 (R)
2.7
9.2
2.0
3.4
-4.0
-15
18 28 (R)
(3′R,S)-1d CD2Cl2 -20 36 (S)
-60 88 (S)
5.3
19
45
50
8 (S)
1.2
5.0
18 63 (R)
-15 78 (R)
-40 88 (R)
17
37
43
(3′R,S)-1c CDCl3
-4.5
-14
13
31
a A ca. 50/50 mixture of diastereomers (total concentration ) 3.0 × 10-3
M) in an NMR tube under O2 pressure was used, with methylene blue (3.7
× 10-4 M) as sensitizer. b Determined by GC using a Varian Chirasil-Dex
CB 25 m × 0.25 mm column. c Determined by 1H NMR analysis.
d Calculated from the equation6 s ) ln[1 - C(1 + eeMDB)]/ln[1 - C(1 -
eeMDB)], where C ) conversion.
asymmetric reactions.4 In CD3CN, CD2Cl2, and CDCl3, however,
the sense in the selectivity switches as the reaction temperature is
changed at the equipodal temperature, T0 (at T0, the % ee is zero).
These results suggest the formation of a reversible exciplex
intermediate in the stereodifferentiating step3a with the conforma-
tional mobility more pronounced in the E- than in the Z-isomer;
‡ Department of Chemistry and Department of Chemical Engineering, Columbia
University.
† Joint Science Department, Claremont McKenna, Pitzer, and Scripps Colleges.
§ Institut fu¨r Organische Chemie, Universita¨t Wu¨rzburg, and Department of
Chemistry, University of Puerto Rico.
| ICORP (JST) and Department of Molecular Chemistry, Osaka University.
9
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J. AM. CHEM. SOC. 2004, 126, 10498-10499
10.1021/ja048438c CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
A1,3 strain10 between the oxazolidinone auxiliary and the 3′-vinyl
substituent, which would magnify the conformational energy
difference between the diastereomers with opposite configurations
at the C-3′ position. Since previous studies1b have shown that for
Scheme 1. Preparation and Kinetic Resolution of R-MDB and
S-MDB by the Photooxidation of a 50/50 Diastereomeric Mixture of
the Enecarbamates (E,4R,3′R,S)-1c
1
each O2 molecule that is quenched, only about 1 in 10 substrate
molecules react, physical quenching of 1O2 to 3O2 is the major event.
The remarkable stereoselectivity of this photooxidation may be due
to the relatively small number of 1O2 trajectories that are available
for chemical reaction with the alkene compared to those for physical
quenching. This postulate implies a remarkable selective vibrational
1
control in the O2 reactivity, a novel concept that merits further
investigation.
We have shown that the chiral-auxiliary functionalized enecar-
bamates 1 react in high diastereoselectivity to give the enantiomeric
R-MDB and S-MDB in ee values of up to 97% (isolated products).
The stereochemical control depends on the E/Z substrate geometry,
temperature, and solvent as internal and external variables. Through
the optimization of these variables, we demonstrate that a “photo-
chemical” Pasteur-type kinetic resolution is achieved, with a high
degree of stereoselectivity.
the latter is quite insensitive to temperature-based switching.
ln(kR/kS) ) ln[(100 + % ee)/(100 - % ee)]
ln(kR/kS) ) ∆∆SqR-S/R - ∆∆HqR-S/RT
(1)
(2)
Acknowledgment. For the work in Wuerzburg, the financial
support from the Deutsche Forschungsgemainschaft, Alexander von
Humboldt-Stiftung, and the Fonds der Chemischen Industrie is
gratefully appreciated. T.P. acknowledges the support of the W.M.
Keck Foundation. I.W. thanks the NIH for a postdoctoral fellowship.
We at Columbia thank the NSF (CHE 01-10655) for generous
support of this research.
The reactions of E-1c with 1O2 were performed in four different
solvents at various temperatures.5 The values that were extracted
from the data in Table 2 reveal these striking features: (1) A
significant solvent effect on the ee values is observed for comparable
temperatures, (2) the sense of the enantioselectivity is switched
within the temperature range in CD3CN, CD2Cl2, and CDCl3, of
which CD3CN shows the widest range in the ee values, and (3) the
reaction in CD3OD at -40 °C gives an ee value of 94%, the highest
enantioselective formation of MDB that has been reported to date.6
In contrast, the reaction of the Z-1a diastereomer with 1O2 in various
solvents resulted in a minimal effect and no switching of enantio-
selectivity sense. The conformational features of the Z-isomers and
their role in the mechanism of the 1O2 reaction have been previously
reported,1 but similar studies (2D and variable temperature NMR)
on the E-isomers are silent on the mechanistic details (computational
data are forthcoming).
The stereoselectivity factor (s) is the ratio of the rates of
formation of the enantiomeric products (s ) kR/kS).7 The photo-
oxidation of 1c in CD3OD at -40 °C has an s value of 37, which
predicts that an ee value as high as 97% is possible below -70 °C.
To validate this prediction, the photooxidation of (3′R,S)-1c was
run at -70 °C in CD3OD, and indeed, an ee value of 97(0.7% for
R-MDB was obtained, which corresponds to s ) 72 at an average
of 8% conversion (Scheme 1).
By taking advantage of the high s-factor, the photooxidation of
(3′R,S)-1c was run to nearly 50% conversion. The R-MDB product
was removed from the reaction mixture by silica-gel chromatog-
raphy and analyzed on a chiral stationary phase (ee ) 97(0.7%).8
The CD spectrum of the R-MDB obtained in Scheme 1 possesses
an opposite configurational sense to that of the independently
synthesized S-MDB,9 as expected (Figure S2, Supporting Informa-
tion). The remaining reaction mixture was again photooxidized to
consume the unreacted (3′R)-1c, the pure (3′S)-1c isomer was
isolated by chromatography and then quantitatively photooxidized
at room temperature to give the S-MDB product with an ee value
of 97% (Scheme 1).
Supporting Information Available: Experimental procedures,
NMR spectra of 1, and figures. This material is available free of charge
via the Internet at http://pubs.acs.org.
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