Conformationally controlled (entropy effects), stereoselective vibrational quenching of singlet oxygen in the oxidative cleavage of oxazolidinone-functionalized enecarbamates through solvent and temperature variations

Article abstract of DOI:10.1016/j.tet.2006.01.119

On photooxygenation (methylene blue as sensitizer) of E/Z enecarbamates, equipped with the oxazolidinone chiral auxiliary, the oxidative cleavage of the alkenyl functionality releases the enantiomerically enriched methyldesoxybenzoin (MDB) product. The ex

Full text of DOI:10.1016/j.tet.2006.01.119

Tetrahedron 62 (2006) 6707–6717
Conformationally controlled (entropy effects), stereoselective
vibrational quenching of singlet oxygen in the oxidative
cleavage of oxazolidinone-functionalized enecarbamates
through solvent and temperature variations
a
J. Sivaguru, Marissa R. Solomon, Hideaki Saito,
a
a,c,d
e
Thomas Poon,
Steffen Jockusch, Waldemar Adam, Yoshihisa Inoue and Nicholas J. Turro
a
f,g
c,d
a,b,*
a
The Department of Chemistry, Columbia University, New York, NY 10027, USA
The Department of Chemical Engineering, Columbia University, New York, NY 10027, USA
b
c
The Department of Applied Chemistry, Osaka University, 2-1 Yamada-oka, Suita 565-0871, Japan
d
The Entropy Control Project, ICORP, JST, 4-6-3 Kamishinden, Toyonaka 560-0085, Japan
Joint Science Department, W. M. Keck Science Center, 925 North Mills Avenue, Claremont McKenna,
Pitzer, and Scripps Colleges, Claremont, CA 91711, USA
e
f
Institute f u€ r Organische Chemie, Universit a€ t W u€ rzburg, D-97074 W u€ rzburg, Germany
The Department of Chemistry, University of Puerto Rico, Facundo Bueso 110, Rio Piedras, PR 00931, USA
g
Received 8 November 2005; revised 3 January 2006; accepted 13 January 2006
Available online 5 June 2006
We dedicate this work to our appreciated friend and distinguished colleague, Professor Sigfried Huenig
(
University of Wuerzburg), on the occasion of his 85th birthday
Abstract—On photooxygenation (methylene blue as sensitizer) of E/Z enecarbamates, equipped with the oxazolidinone chiral auxiliary,
the oxidative cleavage of the alkenyl functionality releases the enantiomerically enriched methyldesoxybenzoin (MDB) product. The extent
(% ee) as well as the sense (R vs S) of the stereoselectivity in the MDB formation depends on the choice of the alkene configuration; the
efficacy of stereocontrol may be tuned by appropriate solvent and temperature conditions. Highlighted is the finding that the formation
of the preferred MDB enantiomer (R or S) depends for the E isomer on the chosen solvent and temperature, but not for the corresponding
Z isomer. The activation parameters for the various solvents disclose that differential entropy effects (DDS ) dominate the conformationally
z
more flexible E diastereomers. As mechanistic rationale for this unprecedented conformationally imposed stereochemical behavior, we pro-
pose the competitive action of stereoselective vibrational quenching of the attacking singlet oxygen by the enecarbamate versus sterically
controlled stereoselective oxidative cleavage of its double bond.
Ó 2006 Elsevier Ltd. All rights reserved.
1
–3
1. Introduction
formidable challenge.
In this regard, a novel concept,
which we have explored in the stereoselectivephotooxidative
cleavage of chiral enecarbamates, involves selective deacti-
vation (quenching) of one of the diastereomers in a pair of
The success in achieving a high enantioselectivity in photo-
1
–3
chemical reactions depends on how effectively the spatial
requirements of the process are manipulated within the short
lifetimes of the excited states. To imprint stereocontrol
1
1,12
chiral excited states.
Indeed, a high degree of stereocon-
4
trol may be imprinted in the photoproduct, but depending on
the oxidant and the reaction conditions, the sense of the
stereoselectivity may be reversed (Scheme 1).
5
–10
in the photoproduct, organized assemblies
have been
1
1–13
employed with varying degrees of success; however, obtain-
ing a high enantioselectivity in solution still constitutes a
1
4–16
Previously we have shown that such a photooxidative
cleavage of enecarbamates actually entails a photooxygena-
Keywords: Chiral auxiliary; Conformational effects; E/Z isomers; Mecha-
nism; Photooxygenation; Substituent effects; Stereoselectivity; Vibrational
quenching.
17–20
tion reaction,
[
in which the diastereomerically pure
1 S,2 S] dioxetane intervenes, as exemplified for the chiral
0
Z-configured enecarbamates in Figure 1. The salient reactiv-
0
*
Corresponding author. Tel.: +1 212 854 2175; fax: +1 212 932 1289;
e-mail: njt3@columbia.edu
ity feature in the exposed snapshot is the preferential
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.119

6708
J. Sivaguru et al. / Tetrahedron 62 (2006) 6707–6717
R
O
H
O
Ph
Ph
Ph
Ph
O
E
Ph
3'R
9
7% ee
R
O
N
R
4
R
H C
H C
3
3
Ph
S
S
R-MDB
iPr
R-MDB
1O2
1O2
6
4% ee
CD CN
CD OD
3
O
3
H
55.5 56.0 56.5 57.0 57.5 58.0
O
Ph
R
E
Ph
O
N
S
O
Ph
Ph
4
R
3
'S
Ph
H C
Ph
S-MDB
3
S
5
6.0 56.5 57.0 57.5 58.0 58.5
iPr
E(R)-2c
H C
3
S-MDB
Scheme 1. Stereoselective photooxidative cleavage of oxazolidinone-functionalized E-enecarbamates.
1
quenching of the electronically excited O as it attacks from
2
the kinetic resolution. These derivatives constitute versatile
and informative substrates for the study of conformational,
electronic, stereoelectronic, and steric effects on the stereo-
selectivity in the photooxidation of the alkene functional-
below, such that in addition to the steric preference for the
approach of O from above, the synergistic interplay of
quenching and steric hindrance dictates the observed
high diastereoselectivity. Moreover, the stereoselection in
the dioxetane formation is independent of the configuration
at the C-3 position of the alkyl side chain and the size of the
alkyl substituent at the C-4 position of the oxazolidinone
chiral auxiliary. Both, the methyl as well as the isopropyl
1
2
1
1,12,14–16,21
ity.
Methylene blue was used to generate the
singlet oxygen for the photooxidative cleavage of the alkenyl
functionality in these chiral enecarbamates to produce the
optically active MDB product.
0
0
0
0
i
0
derivatives 1 Z,4R(Me),3 S-2b and 1 Z,4R( Pr),3 R-2c afford
The extent of and the sense in the enantioselectivity were as-
sessed for the E geometry of the alkene as function of (a) the
alkyl substituent at the C-4 position of the oxazolidinone
chiral auxiliary (see Chart 1), (b) the configuration of the
alkyl substituent at the C-4 position of the oxazolidinone
chiral auxiliary, (c) the solvent, and (e) the reaction temper-
ature. Herewith we report the results of this extensive inves-
tigation, which evidently show that the difference in the
spatial arrangement offered by the E versus Z diastereomers
of the enecarbamates is crucial. Furthermore, for achieving
the observed high stereoselectivity in the formation of
the MDB product during the photooxygenation of the E
enecarbamates, we conjecture that the singlet oxygen is pref-
0
0
the corresponding [1 S,2 S] dioxetanes in diastereomeric
ratios (dr) of about 95:5. For comparison, the enecarbamate
Z-2a without a substituent at the C-4 position of the oxazo-
lidinone, i.e., the parent ring, displays no diastereoselectivity
whatsoever in the dioxetane formation of the [2+2] cyclo-
1
14–16
addition with O .
2
In the present work, for comparison with the Z diastereomer,
we have explored the photooxidative cleavage of the E-2
enecarbamates (see thestructurematrixofChart 1). These are
equipped with the oxazolidinone chiral auxiliary for asym-
metric induction, to yield MDB and 3 as photoproducts
Analogous to the previously studied Z
ca. 50:50 diastereomeric mixtures of the R/S
isomers at the C-3 position in the alkene side chain were
used, to assess how effective the stereocontrol would be in
1
1,12
(
isomer,
Scheme 2).
erentially deactivated (quenched) in one of the epimeric
transition structures for the E-enecarbamate/ O encounter
1
4–16,21
1
2
0
complexes. Such selective quenching of diastereomeric
excited states constitutes a promising stereochemical tool
O
O
H
O
4R
1
O2
N O
H
i
Pr
'S
1'S
Ph
2
O
H
3'R
CH3
O
4R
N
1'
H
i
3'R
Pr 2'
Ph
O
i
1
'Z,4R( Pr),3'R-2
O
H
CH3
4
R
N
1
'R
H
i
Pr
2'R
Ph
3'R
CH3
1
O2
O
O
1
2
Figure 1. Preferred p-facial attack of O from above controlled by the steric shielding of the 4-isopropyloxazolidinone substituent in the Z enecarbamates.

J. Sivaguru et al. / Tetrahedron 62 (2006) 6707–6717
6709
O
H
CH3
3'(R/S)
O
H
O
O
O
1
'
1
'
2
'
Ph
2'
O
NH
N
Ph
O
N
O
O
N
H
E
Z
4
4
3'(R/S)
Ph
Ph
1
a
Z-2a
'Z,4(H),3'(R/S)-2a
3a
E-2a
1'E,4(H),3'(R/S)-2a
1
O
H
CH3
O
H
O
O
O
1
'
3'(R/S)
1'
2
'
2' Ph
O
NH
Me
O
N
O
N
Ph
O
N
H
E
Z
4R
4R
4R
4R
3'(R/S)
Ph
Ph
Me
Me
Z(R)-2b
'Z,4R(Me),3'(R/S)-2b
Me
(
R)-1b
E(R)-2b
1'E,4R(Me),3'(R/S)-2b
(R)-3b
1
H
CH3
O
O
O
H
1'
O
O
1
'
3'(R/S)
Ph
2
'
2' Ph
O
NH
Me
O
O
O
N
O
N
O
N
E
H
Z
4S
4S
4S
4S
3
'(R/S)
Ph
Ph
Me
Z(S)-2b
'Z,4S(Me),3'(R/S)-2b
Me
Me
(
S)-1b
E(S)-2b
1'E,4S(Me),3'(R/S)-2b
(S)-3b
1
CH3
O
O
H
H
O
O
O
1
'
3'(R/S)
Ph
1'
2'
Ph
'
2
O
NH
N
O
N
O
N
H
E
Z
4R
4R
4R
3'(R/S)
Ph
4R
Ph
i
i
Pr
i
Pr
Pr
i
Pr
(
R)-1c
Z(R)-2c
'Z,4R( Pr),3'(R/S)-2c
E(R)-2c
(R)-3c
i
i
1
1'E,4R( Pr),3'(R/S)-2c
CH3
H
O
O
O
H
O
1
'
3'(R/S)
O
2
'
1'
Ph
2'
N
Ph
O
NH
O
N
O
N
H
Z
E
4S
4S
4S
Ph
4S
3'(R/S)
Ph
i
i
i
Pr
Pr
Pr
i
Pr
Z(S)-2c
'Z,4S( Pr),3'(R/S)-2c
(
S)-1c
E(S)-2c
i
'E,4S( Pr),3'(R/S)-2c
(
S)-3c
i
1
1
Chart 1. Structure matrix.
to effect the enantioselective photooxidative cleavage of
chiral alkenes.
2.2. Methods
.2.1. General procedure for the synthesis of the E ene-
carbamates E-2. A sample of 0.150 mmol of Z-2 (see
2
2
. Experimental
Chart 1, Scheme 2) was dissolved in 20 mL of CH Cl and
2
2
placed into a quartz test tube, fitted with a rubber septum, gas
delivery needle, and vent needle. The solution was purged for
2
.1. Materials
20 min with dry N gas and then irradiated at 254 nm in
a Rayonet photochemical reactor for 20–30 min under a pos-
itive N pressure. GC analysis of the photolysate showed that
2
2
All regular solvents were purchased from Aldrich and the deu-
terated solvents from Cambridge Isotope Labs and used as
received. CDCl was stored over sodium bicarbonate prior to
use. Flash chromatography was carried out on silica gel, while
2-mm thick silica gel plates (EMD 60F) were employed for pre-
parative TLC. Commercially available compounds were puri-
the photostationary state (Z/E¼52:48) was reached after
3
ꢀ
20 min. The solvent was removed at ca. 25 C and 15 Torr
on a rotatory evaporator. The residue was loaded onto a pre-
parative TLC plate and eluted with a 2:1 mixture of hexane
and methyl tert-butyl ether (MTBE). The faster running frac-
tion was extracted with a 1:1 mixture of CH Cl and EtOAc
fied by standard procedures. The Z-2 enecarbamates were
synthesized by a previously published procedure.
11,12,14–16
2
2

6710
J. Sivaguru et al. / Tetrahedron 62 (2006) 6707–6717
H
CH3
O
(
R/S)
Ph
,3-diphenyl-1-butanal
Ph
2
O
H
O
N
4
TsOH
H
toluene
(R/S)
reflux, 48 h
X
1
hν
or
CH3
O
H
O
Z
3'(R/S)
Ph
hν / 3Sens.
E
Ph
O
N
4
O
N
3
'(R/S)
Ph
(R/S)
4(R/S)
H C
Ph
3
X
X
1
Z-2
E-2
O2
Ph
O
O
O
N
4
H
(R/S)
(
R/S)
+
H3C
Ph
X
3
MDB
Scheme 2. Synthesis and photooxygenation of 4-oxazolidinone-functionalized Z and E enecarbamates.
to recover the starting material (Z-2). The slower running
fraction was extracted with a 1:1 mixture of CH Cl and
EtOAc, to give 0.07 mmol of the corresponding E-2.
J¼7.20, 3H), 2.00–2.12 (m, 1H), 3.65 (ddd, J¼8.10, 4.23,
3.66, 1H), 4.04 (dd, J¼8.95, 4.33, 1H), 4.10 (t, J¼8.68,
1H), 4.32 (q, J¼7.20, 1H), 5.89 (s, 1H), 6.96–7.01 (m,
2
2
1
3
2
H), 7.10–7.22 (m, 8H); C NMR (75 MHz, CDCl )
3
ppm
2.2.1.1. E(R)-2b. E(R)-2b was obtained in 95% yield
according to the above general procedure. The two dia-
d
127.5, 127.6 (2C), 127.7 (2C), 128.2 (2C), 129.0 (2C),
¼14.6, 17.8, 18.4, 28.2, 39.2, 62.7, 63.1, 121.0, 126.3,
0
were separated on a preparative TLC plate by eluting with
0
0
0
+
stereomers 1 E,4R(Me),3 R-2b and 1 E,4R(Me),3 S-2b
138.9, 143.1, 146.1, 157.1; MS (FAB): M+H Calcd
336.1958, Exptl 336.1972.
2
:1 hexane/methyl-tert-butyl ether mixture.
0
i
0
1
2
.2.1.6. 1 E,4R( Pr),3 S-2c.
H
NMR (300 MHz,
0
0
1
ppm
2
.2.1.2. 1 E,4R(Me),3 R-2b.
H
NMR (300 MHz,
CDCl ) d ¼0.87 (d, J¼6.92, 6H), 1.39 (d, J¼7.20,
3
ppm
CDCl ) d ¼1.45 (d, J¼6.10, 3H), 1.55 (d, J¼7.14, 3H),
3H), 2.01–2.15 (m, 1H), 3.75 (ddd, J¼8.70, 4.78, 3.92,
3
4
7
d
.00 (m, 1H), 4.11 (m, 1H), 4.49 (m, 2H), 5.90 (s, 1H),
.06 (m, 2H), 7.32 (m, 8H); C NMR (75 MHz, CDCl3)
1H), 4.08 (dd, J¼8.95, 4.88, 1H), 4.19 (t, J¼8.80, 1H),
13
1
3
4.28 (q, J¼7.20, 1H), 5.88 (s, 1H), 6.84–6.87 (m,
ppm
ppm
¼16.9, 18.0, 39.4, 54.4, 120.7, 126.7, 127.4, 127.9,
2H), 7.07–7.27 (m, 8H); C NMR (75 MHz, CDCl )
3
1
(
28.3, 128.6, 129.4, 138.8, 143.6, 148.6, 157.1, 158.9; MS
FAB): M+H Calcd 308.1572, Exptl 308.1644.
d
126.7, 127.9, 128.0 (4C), 128.7 (2C), 129.4 (2C), 138.4,
¼15.6, 17.3, 18.6, 29.5, 39.5, 63.2, 63.9, 121.9,
+
+
142.2, 144.9, 157.1; MS (FAB): M+H Calcd 336.1958,
Exptl 336.1961.
0
0
1
2
.2.1.3. 1 E,4R(Me),3 S-2b. H NMR (300 MHz, CDCl )
3
ppm
d
¼1.42 (d, J¼5.93, 3H), 1.51 (d, J¼7.23, 3H), 3.89 (m,
1
2
1
1
H), 4.01 (m, 1H), 4.49 (m, 2H), 5.93 (s, 1H), 7.08 (m,
H), 7.28 (m, 8H); C NMR (75 MHz, CDCl ) d ¼17.4,
2.2.1.7. E(S)-2c. E(S)-2c was obtained in 95% yield
according to the above general procedure. The two dia-
stereomers 1 E,4S( Pr),3 R-2c and 1 E,4S( Pr),3 S-2c were
on preparative TLC plate by eluting with 2:1 hexane/
methyl-tert-butyl ether mixture.
1
3
ppm
3
0
i
0
0
i
0
8.3, 54.6, 69.6, 121.2, 126.7, 127.5, 127.9, 128.2, 128.7,
29.5, 139.0, 143.6, 148.6, 159.0, 162.7; MS (FAB):
+
M+H Calcd 308.1572, Exptl 308.1656.
0
i
0
1
2.2.1.4. E(R)-2c. E(R)-2c was obtained in 95% yield
according to the above general procedure. The two dia-
stereomers 1 E,4R( Pr),3 R-2c and 1 E,4R( Pr),3 S-2c were
separated on preparative TLC plate by eluting with 2:1
hexane/methyl-tert-butyl ether mixture.
2.2.1.8. 1 E,4S( Pr),3 S-2c. H NMR (300 MHz, CDCl )
3
dppm¼0.85 (d, 3H), 0.92 (d, 3H), 1.42 (d, 3H), 2.11–2.18 (m,
1H), 3.71–3.76 (ddd, 1H), 4.12 (dd, 1H), 4.19 (t, 1H), 4.41
(q, 1H), 5.97 (s, 1H), 7.06–7.11 (m, 2H), 7.20–7.34 (m,
0
i
0
0
i
0
1
3
ppm
8H); C NMR (75 MHz, CDCl ) d ¼15.1, 18.5, 19.0,
3
28.2, 39.9, 62.9, 63.2, 121.4, 126.7, 127.9, 128.1 (4C),
128.7 (2C), 129.5 (2C), 138.9, 143.3, 146.6, 157.1; MS
(FAB): M+H Calcd 336.1958, Exptl 336.1952.
0
i
0
1
2
.2.1.5. 1 E,4R( Pr),3 R-2c. H NMR (300 MHz, CDCl )
3
ppm
+
d
¼0.76 (d, J¼7.03, 3H), 0.86 (d, J¼6.85, 3H), 1.33 (d,

J. Sivaguru et al. / Tetrahedron 62 (2006) 6707–6717
6711
0
i
0
1
2
.2.1.9. 1 E,4S( Pr),3 R-2c. H NMR (300 MHz, CDCl )
3
aldehyde 3 (see Scheme 2) quantitatively on complete
conversion of the substrate. To recall, the thermally labile
dioxetane intermediate was previously detected at ꢁ35 C
ppm
d
3
5
¼0.96 (d, 6H), 1.42 (d, 3H), 2.12–2.22 (m, 1H), 3.81–
ꢀ
and was shown to decompose readily at room temperature
(ca. 20 C) into MDB and aldehyde 3.
.87 (ddd, 1H), 4.16 (dd, 1H), 4.28 (t, 1H), 4.37 (q, 1H),
.96 (s, 1H), 6.93–6.97 (m, 2H), 7.16–7.35 (m, 8H);
1
3
C
ppm
ꢀ
13–15
NMR (75 MHz, CDCl ) d ¼15.6, 17.3, 18.6, 29.5, 39.5,
3
6
1
3.2, 63.9, 121.9, 126.7, 127.9, 128.0 (4C), 128.7 (2C),
29.4 (2C), 138.4, 142.2, 144.9, 157.1; MS (FAB): M+H
+
To assess the diastereoselectivity in the oxidative cleavage of
the chiral enecarbamate substrate E-2 as a function of tem-
perature and solvent, the photooxygenation under a variety
of conditions was examined. The new results for the E-2
diastereomers are collected in Table 1, together (for compar-
ison purposes) with the relevant data of the already published
Calcd 336.1958, Exptl 336.1950.
2
.3. Instrumentation
GC analyses were carried out on a Varian 3900 gas chromato-
graph, equipped with an auto-sampler. A Varian Factor-4
VG-1ms column (l¼25 m, id¼0.25 mm, and df¼0.25 mm)
was employed for the separation on the achiral stationary
1
3–15
Z-2 diastereomers.
diastereomers,
As for the previously studied Z-2
we employed a ca. 50:50 diastereomeric
1
3–15
0
mixture of the R and S isomers at the C-3 position also in
the photooxygenations of the E-2 enecarbamates. The con-
version was kept below 50% to avoid overoxidation, which
would therewith distort the ee values.
ꢀ
ꢀ
phase, with a program of 50 C for 4 min, raised to 225 C
ꢀ
ꢁ1
ꢀ
at 10 C min , and kept at 225 C for 10 min. A Varian
CP-Chirasil-DEX CB column (l¼25 m, id¼0.25 mm, and
df¼0.25 mm) was used for the separation on the chiral
ꢀ
stationary phase, with a program of 135 C for 70 min, raised
The negligible effect of the alkyl substituent at the oxazoli-
dinone C-4 position in the photooxidative cleavage of the
chiral enecarbamates 2 is exemplified for the E diastereomer
ꢀ
ꢀ
13
ꢁ1
ꢀ
to 200 C at 15 C min , and kept at 200 C for 30 min. The
H NMR and C NMR spectra were recorded on BRUKER
spectrometers (Model DPX300 or DRX300).
1
with the methyl [E(R)-2b] and the isopropyl [E(R)-2c]
ꢀ
groups (Table 1). In CDCl at 18 C the E(R)-2b (entry 2)
3
2
.3.1. Photooxygenation of Z and E enecarbamates (see
gave the R-MDB enantiomer with an ee value of 67% at
19% conversion (s¼5.9) and the E(R)-2c (entry 2) an ee
value of 63% at 17% conversion (s¼5.0). The respective s
factors (see Eq. 1) convincingly express the relatively low
response to the steric factors of the oxazolidinone chiral
auxiliary. For this reason, hereafter we shall concentrate
on the isopropyl derivative E-2c.
Chart 1). The appropriate Z or E enecarbamate 2 (see
Scheme 2) and methylene blue sensitizer in 0.7 mL of the
desired deuterated solvent (the enecarbamate concentration
ꢁ
3
was 3.0ꢂ10 M and that of methylene blue was 3.7ꢂ
ꢁ
4
1
rubber septum, and fitted with a gas delivery needle and
0
M) were placed into the NMR tube, sealed with a
a vent needle. Dry O gas was purged through the sample
2
for 20 min, while irradiating with a 500-W halogen lamp,
equipped with a cutoff filter (<500 nm). After irradiation,
the samples were submitted to H NMR spectroscopy to
As already demonstrated previously for the Z series of dia-
stereomers,
1
3–15
the sense of the enantioselectivity in the
1
MDB product is opposite, while the extent of diastereomeric
control in the photooxidative cleavage of the E enecarba-
mates is the same (within the experimental error) for the
R and S antipodes at the C-4 position (Table 1). This is
clearly evident in the % ee data for the E(R)-2c and E(S)-
2c isomers, as exemplified by their photooxygenation in
determine the conversion (kept below 50%). The mass bal-
ance (based on unreacted enecarbamate and formed MDB
product) and the conversion (based on unreacted enecarba-
mate) were determined by GC analysis on an achiral station-
0
ary phase, with 4,4 -di-tert-butylbiphenyl as calibration
standard. The enantioselectivity (% ee) of the MDB product
was determined by GC analysis on a chiral stationary phase.
ꢀ
CD Cl at 20 C. As expected, the reversal in the enantio-
2
2
selectivity sense was also seen for E(R)-2c (entries 5–7)
and affords the S-MDB (34% ee at 25% convn), whereas
E(S)-2c (entries 17–19) leads to the R-MDB (28% ee at
29% convn) enantiomer as final oxidation products.
3. Results
To assess the diastereoselectivity in the oxidative cleavage of
the chiral enecarbamate substrate E-2 as a function of tem-
perature and solvent, the photooxygenation under a variety
The effect of the solvent type and polarity was examined by
comparing the polar aprotic solvent CD CN, the polar protic
3
solvent CD OD, and the halogenated solvents CD Cl and
2
3
2
2
2,23
of conditions was examined. Evans’ chiral auxiliary
CDCl , which are of relatively low polarity. For the photo-
3
was chosen as the essential stereochemically directing entity
and was introduced into the enecarbamate substrate Z-2 by
condensing the 4-alkyl-substituted oxazolidinones with the
oxidative cleavage of the E-2c substrate, the solvent depen-
dence of the diastereoselectivity follows the order CD CN
3
(30% )w CD Cl (34%)<CDCl (63%)<CD OD (85%) at
2
2
3
3
ꢀ
2,3-diphenyl-1-butanal (see Scheme 2). The 1-phenylethyl
substituent at the C-3 position of the double bond was
the required
the common temperature of about 18–20 C (Table 1, entries
9, 5, 2 and 13, respectively); the ee values are given in paren-
theses. Evidently, the best diastereoselectivity is obtained for
the hydrogen-bonding solvent methanol (entry 13), whereas
the lowest control is displayed by the aprotic acetonitrile
(entry 9) at the same temperature. The relatively high ee
value in chloroform-d (entries 1–4) is quite striking. Mech-
anistically most revealing is the finding that the R-MDB
enantiomer is the favored product in CDCl and CD OD
0
selected to minimize the ene reaction;
1
1,12,14–16
coplanar alignment of the only allylic hydrogen atom is
encumbered. The E-2 diastereomer was prepared by direct
or sensitized photochemical isomerization of Z-2, followed
2
4
by chromatographic separation (Scheme 2). Analogous
1
3–15
to the previously studied Z diastereomer, the photo-
oxygenation of the E-2 enecarbamate gave the expected
chiral methyldesoxybenzoin (MDB) and the oxazolidinone
3
3
(entries 2 and 13, respectively), but the S-MDB isomer

6712
J. Sivaguru et al. / Tetrahedron 62 (2006) 6707–6717
a
Table 1. Determination of the stereoselectivity factor (s) for the formation of (R/S)-MDB product in the photooxygenation of E(R)-2b, E(R)-2c, and E(S)-2c as
a function of solvent and temperature
ꢀ
b
MDB (% ee)
c
Convn (%)
d
s
b
MDB (% ee)
c
Convn (%)
d
s
Entry
Temp ( C)
Solvent
E(R)-2b
E(R)-2c
1.
2.
3.
4.
50
18
CDCl
3
—
—
19
14
52
—
5.9
14.0
45.0
8 (S)
63 (R)
78 (R)
88 (R)
5
17
37
43
1.2
5.0
13.0
31.0
67 (R)
85 (R)
86 (R)
ꢁ15
ꢁ40
5
6
7
.
.
.
20
ꢁ20
ꢁ60
50
18
ꢁ15
ꢁ40
50
18
CD
2
3
Cl
2
7 (S)
62 (R)
95 (R)
10
23
31
0.9
5.1
59.0
34 (S)
27 (R)
82 (R)
25
65
54
2.3
2.7
40.0
8
9
1
1
.
.
0.
1.
CD
CN
OD
—
—
18
55
33
—
64 (S)
30 (S)
0
23
34
28
37
5.5
2.1
1.0
5.2
28 (S)
0
45 (R)
0.5
1.0
3.3
58 (R)
12.
13.
14.
15.
16.
CD
3
—
—
17
13
13
—
8.1
10.0
15.0
70 (R)
85 (R)
90 (R)
94 (R)
97 (R)
30
34
17
12
8
7.6
19.0
23.0
37.0
72.0
75 (R)
80 (R)
86 (R)
ꢁ15
ꢁ40
ꢁ70
E(S)-2c
1
1
1
7.
8.
9.
20
ꢁ20
ꢁ60
CD
2
Cl
2
28 (R)
36 (S)
88 (S)
29
59
56
2.0
3.4
45.0
a
b
c
ꢁ3
ꢁ4
The E enecarbamate concentration is 3.0ꢂ10 M and 3.7ꢂ10 M for the methylene blue sensitizer.
The enantiomeric excess (% ee) of the MDB product, determined by GC analysis on a chiral stationary phase.
0
Conversion (convn) of enecarbamates determined by GC analysis on an achiral stationary phase with 4,4 -di-tert-butylbiphenyl as calibration standard, and by
H NMR spectroscopy; averages of three runs, within 5% error of the stated values.
Calculated from Eq. 1.
1
d
dominates in CD Cl and CD CN (entries 5 and 9, respec-
2
same enantiomer, namely R-MDB, is formed over the entire
ꢀ
2
3
tively). Thus, the selectivity cannot be attributed to the
solvent polarity alone in the photooxidative cleavage of
the E-2 enecarbamates.
temperature range from ꢁ70 to +50 C (entries 12–16). In
the other solvents, depending on the temperature, a change
in the sense from the usual R-MDB to the S-MDB isomer
is observed. For example, very good stereocontrol (ee value
of 88%) in favor of R-MDB is found in chloroform-
Still more intriguing for mechanistic considerations is the
temperature dependence of the ee values for the E-2c sub-
strate (Table 1). Only in methanol the extent of the diastereo-
ꢀ
d at ꢁ40 C (entry 4), but the S-MDB isomer is preferred
with very poor diastereoselectivity (ee value of only 8%)
at +50 C (entry 1). This inflection in the enantioselectivity
ꢀ
sense (R to S isomer) occurs in CDCl above +18 C (entries
selectivity is relatively constant (note the high ee value of
ꢀ
ꢀ
9
7% at ꢁ70 C, i.e., nearly perfect stereocontrol!) and the
3
0
0
0
0
Figure 2. X-ray crystal structure (Ref. 25) of 1 E,4S(Me),3 R-2b and 1 E,4S(Me),3 S-2b.

J. Sivaguru et al. / Tetrahedron 62 (2006) 6707–6717
6713
ꢀ
20 C (entries 5 and 6). In the case of CD CN, the temper-
ature at which the change of sense takes place is ꢁ15 C
1
and 2), while in CD Cl it takes place between +20 C and
2
kinetic resolution, the so-called stereoselectivity factor (s)
applies (Eq. 1),
2
ꢀ
26–29
ꢁ
which is a quantitative measure (cor-
3
ꢀ
entry 10), as indicated by the 0% ee value in the MDB prod-
rected for the extent of conversion) of the relative reaction
rates for the two stereoisomers in question. In the present
photooxygenation of the enecarbamates 2, the s factor for
the two epimers from the substrate conversion and the
MDB enantiomeric excess. A large value will translate
into high enantiomeric excess in the MDB product even at
50% conversion (see Fig. 3). This is the case, for example,
(
uct (see Table 1). These profound selectivity trends require
careful mechanistic scrutiny, to understand the details of
the photocleavage pathway.
To enable a detailed mechanistic rationalization of the
favored attack by O on the double bond of the enecarba-
1
in the photooxidation of the E(R)-2c substrate in CD OD
3
2
ꢀ
mate, the structural details of the chiral enecarbamate must
be known reliably. Fortunately, we succeeded in crystalliz-
ing the methyl derivative E(S)-2b from ether/hexane and ob-
tained its solid-state structure by X-ray crystallography
at ꢁ70 C with the s factor of 72 (see Table 1, entry 16).
k
R
ln½1 ꢁ Cð1+eeMDBÞꢃ
MDB
s ¼
¼
ð1Þ
kS ln½1 ꢁ Cð1 ꢁ ee
Þꢃ
2
5
(
Fig. 2).
where C is the conversion and eeMDB is the ee value of the
MDB product.
0
b and 1 E,4S(Me),3 S-2b are contained in the same unit cell.
0
AsdisplayedinFigure2, bothdiastereomers 1 E,4S(Me),3 R-
0 0
2
Inspection of the crystal structure reveals that the oxazolidi-
none carbonyl is almost perpendicular to the plane of the
double bond, such that the nitrogen lone pair is contained
within that plane for conjugation with the carbonyl group.
The phenyl substituent on the double bond is also twisted
out of conjugation, to minimize the steric interactions with
the phenethyl side chain. Presumably, polarity factors of the
oxazolidinone functionality and steric interactions with the
alkyl side chain are minimized in the observed conformation.
As a practical utilization of such a high s factor for the
kinetic resolution with O , the photooxygenation of E(R)-
1
2
ꢀ
sion. The R-MDB product was separated from the reaction
2c was run in CD OD at ꢁ70 C up to nearly 50% conver-
3
mixture by chromatography and an ee value of 97% was ob-
tained. The unreacted 1 E,4R( Pr),3 S-2c enecarbamate was
0
then quantitatively photooxidized at room temperature to
i
0
afford the S-MDB product with an ee value of 97%. This re-
markable case of O stereoselection was previously coined
as photochemical Pasteur-type kinetic resolution.
1
2
1
1,13,26–29
4
. Discussion
To understand the temperature dependence of the enantio-
meric excess in the MDB product for the photooxygenation
of E(R)-2c in the various solvents, the differential activation
The salient features of photooxygenation of the E-2 and the
Z-2 diastereomers of the enecarbamates are three-fold:
z
z
parameters (DDS and DDH ) were computed with the help
of Eyring relation (Eq. 2):
2
,30,31
(
i) While the photooxidative cleavage of the E-2 isomer
affords the MDB product in high (up to 97%) enantio-
selectivity (Table 1), the ee value for the Z-2 isomer is
quite low (only 30% at best) under comparable reaction
lnðk
R
=k
S
Þ ¼ DDSz =R ꢁ DDHz =RT
ð2Þ
RꢁS
RꢁS
z
z
The DDS and DDH data for the E(R)-2b and E(R)-2c dia-
stereomers are collected in Table 2, together with the previ-
ously investigated Z(R)-2c in CD Cl for comparison.
2
1
1,12,14–16
conditions;
1
0
(
ii) The enantiomeric excess in the MDB product depends
substantially on the solvent and the temperature of the
photooxygenation for the E-2 isomer (Table 1), but that
is not the case for the corresponding Z-2 enecarba-
2
1
1,12,14–16
mate;
100
s=100
(
iii) Not only does the extent of stereoselection (% ee value)
of the E-2 diastereomer vary extensively as a function
of solvent and temperature (Table 1), but also the
favored configuration (R vs S enantiomers of MDB)
changes, i.e., there is an inversion point in the sense
of the stereoselectivity.
s=72.0
80
60
40
s=10.0
s=5.0
This divergent behavior in the stereocontrol displayed by the
two geometrical isomers E and Z needs to be mechanistically
rationalized in terms of the trajectory of the O attack onto
2
s=2.0
1
the double bond during the photooxidative cleavage of the
enecarbamate substrate. Since we have employed for the
photooxygenation a ca. 50:50 diastereomeric mixture of
20
s=1.08
0
0
enecarbamates E-2 (R/S epimers at the C-3 stereogenic
0
20
40
60
80
100
site of the alkyl side chain), the stereoselection in the present
study entails a case of kinetic resolution. Thus, the enantio-
meric excess in the MDB product, which is formed in the
double-bond cleavage, reflects the differentiation in the reac-
tion rates of the enecarbamate photooxidation. For such
conversion (%)
Figure 3. The dependence of the enantiomeric excess of the MDB product
on the conversion of chiral oxazolidinone-functionalized enecarbamates as
a function of the stereoselectivity factor (s).
2
6–29

6714
J. Sivaguru et al. / Tetrahedron 62 (2006) 6707–6717
a
Table 2. Solvent dependence of the differential activation parameters for
the photooxygenation of E(R)-2b, E(R)-2c, E(S)-2c, and Z(R)-2c in different
solvents
z
z
z
z
Entry Solvent DDH
(
DDS
kcal mol ) (cal mol
DDH
) (kcal mol ) mol
DDS (cal
ꢁ
1
ꢁ1 ꢁ1
ꢁ1
ꢁ1 ꢁ1
K
K )
E(R)-2b
E(R)-2c
1
2
3
4
CDCl
3
ꢁ4.9
ꢁ6.6
ꢁ14
ꢁ23
ꢁ17
ꢁ4.5
ꢁ4.0
ꢁ4.5
ꢁ2.5
ꢁ14
ꢁ15
ꢁ17
CD
CD
CD
2
3
3
Cl
2
CN ꢁ4.4
OD ꢁ1.5
ꢁ1.0
ꢁ4.9
E(S)-2c
19.0
Z(R)-2c
5
CD
Cl
2 2
5.3
6
CD
2
Cl
2
ꢁ0.2
0.4
a
z
z
DDH and DDS were computed from Eq. 2.
The data for the E-2 isomer in the aprotic solvents CDCl3,
CD Cl , and CD CN display (Table 2, entries 1–3) a pro-
2
2
3
nounced temperature dependence of the MDB enantiomeric
excess, namely, a relatively high contribution by the differen-
z
ꢁ1
ꢁ1
tial activation entropy term (jDDS jꢄ14 cal mol mol ), as
well as an appreciable contribution by the differential
activation enthalpy term (jDDH jw4 kcal mol ). As may
z
ꢁ1
be seen from the differential Eyring relation (Eq. 2), the
change in the % ee values (or DDG ) depends both on the
Figure 4. Eyring plots for the stereoselective photooxygenation of E(R)-2c
and E(S)-2c enecarbamates in various solvents.
z
z
entropic and enthalpic terms. Since the DDH
is proportional to the reciprocal temperature (Eq. 2), the
/RT term
RꢁS
nearly parallel lines (similar slopes) bring out the fact that
the extent of enthalpic contribution (DDH ) is about the
z
ln(k /k ) value is determined mostly by the enthalpic contri-
S
R
bution at low temperatures; however, as the temperature in-
creases, the relative contribution from the DDS
increases and begins to override the DDH
same as that in the diverse solvents, but the crossing of the
0% ee line reflects the change in the sense of specification
of the favored configuration for the MDB enantiomer.
Another point that is focused well in Figure 4, is the mirror
imaging of the two lines for the E(R)-2c [ ] and E(S)-2c
z
/R term
/RT term at
RꢁS
z
RꢁS
some temperature. Eventually, the sign of the ln(k /k ) value
inverts and the enantioselectivity sense switches, provided
R
S
z
z
that the DDH
and DDS
terms possess the same
sign, as is the case here for the photooxygenation of the
[
] diastereomers upon photooxygenation in CD Cl ,
2 2
RꢁS
RꢁS
which conveys the stereocontrol by the stereogenic center
at the C-4 position of the oxazolidinone chiral auxiliary.
The similar magnitudes but opposite signs of the DDS and
E-2 isomer (Table 2, entries 1–3). Such entropy effects are
indicative of conformational factors, which in the
present case are dictated, presumably, by the stereogenic
2
,30,31
z
z
DDH terms for the oppositely configured E(R)-2c and
E(S)-2c diastereomers in CH Cl (Table 2; entries 2 and 5,
0
center at the C-3 position of the phenethyl side chain.
2
2
respectively) are dictated by mirroring of the two lines
in Figure 4. The intersection of the two lines signifies the
In contrast, the corresponding Z-2c isomer is insensitive
to temperature, as convincingly exposed by the near-zero
ꢀ
temperature (inversion temperature, ꢁ3 C for CD Cl ) at
2
2
z
z
DDS and DDH terms in CD Cl with opposite sign
2
which the entropic contribution equals the enthalpic contri-
bution, which will be reflected in the 0% ee value in the
MDB product.
2
2
,30,31
( consequently, irrespective of what
temperature is chosen, the R-enantiomeric MDB product is
enhanced (as DDS and DDH compensate each other upon
temperature variations due to the opposite sign), but in mod-
Table 2, entry 6);
z
z
These conspicuously complex temperature and solvent
effects on the stereoselectivity of the E and Z enecarbamate
photooxygenation shall now be mechanistically scrutinized.
As already anticipated, conformational factors may be
responsible for the difference in the sensitivity response be-
tween the E and Z oxazolidinone-functionalized enecarba-
mates toward solvent and temperature variations. To assess
such conformational factors, detailed X-ray crystal struc-
tures of the E and Z diastereomers should be helpful; how-
ever, such structures are not necessarily definitive, since
our photooxygenations are conducted in the solution phase
and not in the solid state, for which the actual conformations
may differ appreciably. The pertinent crystal structures are
given in Figure 5, which disclose some significant conforma-
tional differences.
est preference. Similarly, in the protic CD OD solvent, also
3
for the E-2 isomer a small temperature dependence is ob-
served (Table 1, entries 12–16), again corroborated by the
z
z
small DDS and DDH values (Table 2, entry 4). As a conse-
quence of the low entropy and enthalpy contributions, in the
z
z
protic methanol (notice the same sign for DDS and DDH ;
upon decreasing the temperature the contribution from
DDH will increase slightly), the response of the E-2 isomer
to temperature is nominal; certainly the sense of the enantio-
selectivity is not changed.
z
An effective visual display of these experimental trends in
the temperature dependence of k /k as a function of the sol-
vent nature is given in Eyring plots for E-2c (Fig. 4). The
R
S

J. Sivaguru et al. / Tetrahedron 62 (2006) 6707–6717
6715
0
i
Figure 5. Comparison of the favored conformers for the E-4S(Me),3 S-2b (A) and Z-4S( Pr),3 S-2c (B) enecarbamates, as revealed by the corresponding solid-
0
0
i
0
0
state structures, of the E-4S(Me),3 S-2b (A) and Z-4S( Pr),3 S-2c (B) enecarbamates (for clarity, only the 4R,3 S epimers are shown), which disclose some
pertinent conformational differences. It should, however, be emphasized that in (A) we are using the methyl derivative, whereas in (B) the isopropyl one;
unfortunately, the crystal structures are not available for the same alkyl group at the C-4 position of the oxazolidinone chiral auxiliary; nevertheless, for the
present discussion it is not the substituent in the oxazolidinone chiral auxiliary that counts, but the E and Z geometries of the double bond.
As illustrated in Figure 5, the oxazolidinone carbonyl of the
E isomer (C-3 S epimer) is oriented above the plane of the
20
0
double bond (for the other C-3 R epimer, the oxazolidinone
carbonyl is oriented below), compared to the coplanar
0
2
5
10
1
3–15
alignment of the Z isomer (see Fig. 5).
molecular models and quantum-chemical computations sug-
gest that the Z diastereomer
Moreover,
1
3–15
is conformationally more
0
rigid than the E one. The greater flexibility of the E con-
former appears to be due to less steric encumbrance between
the imposing phenyl and oxazolidinone groups. Therefore,
we speculate that the more mobile E conformer is more sus-
ceptible to solvent and temperature variations, as confirmed
y = 1.3203 + 3.5864 x
E(R)-2b
-
-
10
20
E(R)-2c
Z(R)-2c
E(S)-2c
z
by the larger DDS contribution (Table 2). Correspondingly,
the greater rigidity of the Z conformer makes it less sensitive
to solvent and temperature variations, as reflected by the
lower DDS values (Table 2). Further work would be re-
quired, to confirm the higher flexibility of the E conformer,
e.g., NOESY and NOE NMR spectroscopy as well as theo-
retical studies would be helpful.
z
-6
-4
-2
0
2
4
∆∆ H‡
z
z
Figure 6. Plot of DDS versus DDH for the photooxygenation of E(R)-2b,
E(R)-2c, E(S)-2c, and Z(R)-2b.
The enthalpy–entropy plot for both the E and Z enecarba-
mates is shown in Figure 6. The differential activation
parameters fall on a single straight line passing through the
origin, which indicates that the same diastereo-differentiat-
ing mechanism operates, irrespective of (a) the configuration
of the double bond [E or Z], (b) the alkyl substituent at the
onto the double bond of the chiral enecarbamate, to reveal
the critical oxidant/substrate interactions in the attack. As
0
tion, i.e., 3 R versus 3 S, plays an important role in aligning
exemplified in Figure 2, the configuration at the C-3 posi-
0
0
the oxazolidinone carbonyl with respect to the face of
i
0
0
C-4 position [Me or Pr], (c) the configuration of the C-4 sub-
stituent [R or S isomer], and (d) the solvent that is employed.
the double bond. In 1 E,4S(Me),3 R-2b, the oxazolidinone
carbonyl is oriented toward the top face of the double
0
0
bond, whereas in the 1 E,4S(Me),3 S-2b epimer it is steered
toward the bottom face. Although it is well known that polar
groups may facilitate the facial selectivity of singlet oxy-
A pertinent aspect to be rationalized is the higher stereo-
selectivity of the E compared to the Z enecarbamate. It is
truly remarkable that the smallest possible oxidant, namely
singlet oxygen, is subject to such high stereocontrol. To un-
3
2
gen, in the present case, this alone does not explain the
high selectivity for the E isomer. The reason is that the rela-
tive spatial arrangement of the carbonyl and the phenethyl
groups is the same in both the structures and, thus, equal
derstand the higher stereocontrol for the E isomer, we shall
explore now the details of the trajectory for the incoming O
1
2

6716
J. Sivaguru et al. / Tetrahedron 62 (2006) 6707–6717
amounts of the R- and S-MDB enantiomers would be ex-
pected. Evidently, besides conformational and steric factors,
additional interactions must be involved.
The stereoselection of the kinetically preferred MDB enan-
tiomer depends not only on the alkene geometry (Z/E), the
i
size of the C-4 alkyl substituent (H, Me, Pr) in the oxazo-
lidinone ring, and the configuration (R/S) at the C-3 stereo-
0
We propose that the high stereocontrol in the R-MDB versus
S-MDB formation for the photooxidative cleavage of the
E isomer is the consequence of selective p-facial quenching
of the electronically excited singlet oxygen by the enecarba-
mate substrate. In this context, it is well known that the life-
time of singlet oxygen in deuterated solvents is much higher
genic center of the phenethyl side chain, but also on the
nature of the solvent and the reaction temperature. The con-
formationally more flexible E diastereomer responds sensi-
tively to such reaction conditions (ee values of up to 97%),
whereas the conformationally more rigid Z diastereomer
behaves impervious to such manipulation (ee values of up
to 30%). We argue that the stereochemical consequences
1
7–20
than non-deuterated ones,
deactivate O to its triplet ground state. In view of the
since C–H bond vibrations
1
33
of such conformational effects (entropy control) are stereo-
selective quenching of O by vibrational deactivation (a
2
1
higher flexibility of E enecarbamates, conformations may
be populated, in which one p face of the double bond ex-
poses a larger number of C–H bonds for selective quench-
2
novel concept), in competition with stereoselective oxidative
double-bond cleavage subject to steric interactions on the
3
3
1
1
ing of the incoming excited O . In the present case of
2
attacking O .
2
kinetic resolution, to generate selectively the R-MDB enan-
0
0
0
tiomer in excess from the 3 R/3 S diastereomeric pair, the 3 S
epimer must be preferentially quenched and thereby accu-
mulates. We have previously shown low selectivity in the
MDB product for photooxidation of both E and Z enecarba-
Acknowledgements
The authors at Columbia thank the NSF (CHE 01-10655
and CHE-04-15516) for generous support of this research.
W.A. is grateful for the financial support from the Deutsche
Forschungsgemeinschaft, Alexander-von-Humboldt Stif-
tung, and the Fonds der Chemischen Industrie. T.P. acknowl-
edges the support of the W.M. Keck Foundation. H.S. and
Y.I. gratefully acknowledge a JSPS research for fellowship
for young scientists (08384) for young scientists to H.S.
The authors thank Dr. Sara G. Bosio for initiating the work
on the photooxygenation of Z enecarbamates.
3
4
mates with ozone—a reactive ground state species. A more
careful inspection of the solid-state structures for the 3 R/3 S
0
diastereomeric pair in Figure 2 reveals that in the 3 R epimer,
0
0
the methyl groups of the oxazolidinone ring and the phen-
ethyl side chain are located on opposite p faces of the double
bond, whereas in the 3 S epimer these methyl groups are on
the same side (in the shown structure, above the plane of the
double bond). If such conformationally imposed structural
differences apply also in the solution phase, the attacking
0
1
0
O is more efficiently deactivated by the 3 S epimer and
2
the R-MDB enantiomer is favored, as observed in aprotic
solvents at subambient temperature (Table 1). The more
efficient stereocontrol (higher % ee values in favor of the
R-MDB enantiomer) as the temperature is decreased
References and notes
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(
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0
0
3. Rau, H. Chem. Rev. 1983, 83, 535–547.
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2
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1
2
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1
2
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5
. Conclusion
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0
oxazolidinone ring, the chirality center at the C-3 position
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