A comparative mechanistic analysis of the stereoselectivity trends observed in the oxidation of chiral oxazolidinone-functionalized enecarbamates by singlet oxygen, ozone, and triazolinedione

Article abstract of DOI:10.1016/j.tet.2006.07.105

The stereoselectivity in the reactions of the E/Z enecarbamates 1, equipped with the oxazolidinone chiral auxiliary, has been examined for singlet oxygen (¹O₂), ozone (O₃), and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) in

Full text of DOI:10.1016/j.tet.2006.07.105

Tetrahedron 62 (2006) 10647–10659
A comparative mechanistic analysis of the stereoselectivity trends
observed in the oxidation of chiral oxazolidinone-functionalized
enecarbamates by singlet oxygen, ozone, and triazolinedione
J. Sivaguru,a Thomas Poon,b Catherine Hooper,b Hideaki Saito,a,c,d Marissa R. Solomon,a
Steffen Jockusch,a Waldemar Adam,e,f Yoshihisa Inouec,d and Nicholas J. Turroa,g,
*
aThe Department of Chemistry, Columbia University, New York, NY 10027, USA
bJoint Science Department, W.M. Keck Science Center, 925 N. Mills Ave., Claremont McKenna, Pitzer, and Scripps Colleges,
Claremont, CA 91711, USA
cThe Department of Applied Chemistry, Osaka University, 2-1 Yamada-oka, Suita 565-0871, Japan
dThe Entropy Control Project, ICORP, JST, 4-6-3 Kamishinden, Toyonaka 560-0085, Japan
eInstitute fu€r Organische Chemie, Universita€t Wu€rzburg, D-97074 Wu€rzburg, Germany
fThe Department of Chemistry, University of Puerto Rico, Facundo Bueso 110, Rio Piedras, PR 00931, USA
gThe Department of Chemical Engineering, Columbia University, New York, NY 10027, USA
Received 30 May 2006; revised 26 July 2006; accepted 31 July 2006
Available online 29 September 2006
Abstract—The stereoselectivity in the reactions of the E/Z enecarbamates 1, equipped with the oxazolidinone chiral auxiliary, has been
examined for singlet oxygen (1O2), ozone (O3), and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) in a variety of solvents as a function of tem-
perature. The oxidative cleavage of the alkenyl functionality by O2 and O3 releases the enantiomerically enriched methyldesoxybenzoin
1
(MDB) product. The extent (% ee) as well as the sense (R vs S) of the stereoselectivity in the MDB formation depends on the electronic nature
of the oxidant. A high stereoselectivity, substantially dependent on solvent and temperature, is displayed for the reactions with 1O2, whereas
the ground-state reactants O3 and PTAD are rather unaffected by solvent and temperature variations. The present comparative analysis clearly
substantiates our hypothesis of stereoselective vibrational quenching of the attacking 1O2, whereas O3 and PTAD are only subject to steric
impositions. The electronically excited 1O2 is sensitive to all three stereochemically relevant structural characteristics embodied in the chiral
enecarbamates, namely the R/S configuration at the C4 position of the oxazolidinone chiral auxiliary, the Z/E geometry of the ‘alkene’
0
functionality, and R/S configuration at the C3 position of the enecarbamate side chain.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
(Scheme 1) with related reactive species viz. singlet oxygen
(1O2),14–17 ozone (O3),18 and 4-phenyl-1,2,4-triazoline-3,5-
dione (PTAD).19–23 Indeed, the high stereoselectivity was
observed in the formation of the product MDB 3 (Scheme 1)
in the reactions with 1O2. The observed high stereoselectivity
was hypothesized to result from a combination of steric inter-
actions and selective deactivations of the excited state
(Scheme 1).11,24
High enantioselectivity in photochemical reactions1–3 de-
pends on effective manipulation of chiral/prochiral faces of
the reactant within the short lifetimes of the excited states.4
To imprint stereocontrol in the photoproduct, confined
media5–10 has been employed with considerable success;
however, to obtain a high enantioselectivity in solution still
constitutes a formidable challenge.1–3 In this regard, a novel
concept, which we have explored in the stereoselective pho-
tooxidative cleavage of chiral enecarbamates, involves selec-
tive deactivation (quenching) of one of the diastereomers in
a pair of chiral excited states.11–13 To demonstrate this
concept, we have compared the reaction of enecarbamates 1
Previously we have shown24–26 that the photooxidation of
enecarbamates by 1O2 leads to diastereomerically pure
dioxetanes (complete conversion), as exemplified for the
chiral Z-configured enecarbamate 10Z,4R(iPr),30(R/S)-1
(Fig. 1).
The salient reactivity feature in the exposed snapshot in
Figure 1 is the approach of 1O2 on to the double bond, where
in addition to the steric hindrance imposed on the O2, the
Keywords: Kinetic resolution; Ozonolysis; Photooxygenation; Substituent;
Solvent and temperature effects; Vibrational quenching.
* Corresponding author. Tel.: +1 212 854 2175; fax: +1 212 932 1289;
e-mail: njt3@columbia.edu
1
possible synergistic stereoselective vibrational quenching
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.105

10648
J. Sivaguru et al. / Tetrahedron 62 (2006) 10647–10659
(A)
1O2
H
O
Ph
3'(R/S)
CH3
O
O
N
O
O
+
3'(R/S)
Ph
Z / E
Ph
(B)
O3
N
O
3
2
4(R/S)
Ph
Ph
N
O
O
1
N
N
ene products + cycloaddition products
(C)
PTAD
(1O2 Analogue)
Scheme 1. Reactions of oxazolidinone-functionalized Z/E-enecarbamates 1 with (A) 1O2, (B) O3, and (C) PTAD.
O
O
H
O
4R
1O2
O
N
H
i
1'S
Pr
2'S
Ph
O
3'R
H
1'
2'
N
H
O
4R
CH3
i
Pr
3'R
Ph
O
i
H
1'Z,4R(Pr),3'(R)-1
O
CH3
4R
N
1'R
H
i
Pr
Ph
3'R
1O2
2'R
O
CH3
O
Figure 1. Preferred p-facial attack of 1O2 from above, controlled by the steric shielding of the 4-isopropyl substituent of the oxazolidinone chiral auxiliary in
Z enecarbamates.
1
of the O2 from the bottom face could dictate the observed
high diastereoselectivity. Moreover, the stereoselection in
the dioxetane formation is independent from the configura-
In the present work, we compare the reactivity of singlet
oxygen (1O2, Scheme 1A) for both E and Z diastereomers
of the enecarbamates (Chart 1) with O3, an electrophilic
oxidant akin to 1O2 (Scheme 1B) and PTAD, a ground-state
analogue of 1O2 (Scheme 1C). If, indeed, our hypothesis of
stereoselective vibrational quenching in the photooxidative
cleavage of the enecarbamates by 1O2 proves to be correct,
then PTAD would constitute a good test reagent, as it is con-
sidered analogous19–23 in its chemical reactivity to 1O2, but
as a ground-state molecule PTAD, is not subject to vibra-
tional deactivation.28 Moreover, in view of its much larger
0
tion of the alkyl side chain at the C3 position and the size
of the alkyl substituent at the C4 position (Me, Pr, Ph) of
i
the oxazolidinone chiral auxiliary.24–26 For example, the dia-
stereomer 10Z,4R(iPr),30R-1 (Fig. 1) that possesses the R
configuration at the C4 position affords the corresponding
[10S,20S] dioxetane with complete stereocontrol [diastereo-
meric ratios (d.r.) of >95:5]. Further, the stereoselection in
the MDB product 3 (Scheme 1) upon photooxidative cleav-
age of these oxazolidinone-functionalized enecarbamates by
1O2 depends not only on the alkene geometry (Z/E), the size
of the C4 alkyl substituent (H, Me, iPr) in the oxazolidinone
1
size than O2, this bulkier species would be more sensitive
to steric effects. Similarly, the highly reactive O3 oxidant
is also a ground-state species and is not subjected to vibra-
tional quenching as in the case of 1O2. Thus, the electrophilic
O3, a highly reactive ground-state oxidant would provide an
opportunity to probe the importance of the excited-state
character in the photooxygenation process. An additional
advantage of O3 over PTAD is the fact that like 1O2, oxida-
tion of both Z and E enecarbamates 1 by O3 affords the same
MDB product 3,29 which should facilitate the direct compar-
ison of the stereoselection of these two oxidants.
0
ring, and the configuration (R/S) at the C3 stereogenic center
of the phenethyl side chain, but also on the nature of the sol-
vent and the reaction temperature.11,27 The stereoselectivity
of oxidation of the conformationally more flexible E dia-
stereomer responds sensitively to such reaction conditions
(ee values of up to 97%), whereas the conformationally
more rigid Z diastereomer behaves less sensitively to such
manipulation (ee values of up to 30%).11,27 We proposed
that conformational effects (entropy control) are responsible
for stereoselective quenching of 1O2 by vibrational deactiva-
tion (a new concept!), in concert with the steric interactions
leading to stereoselective oxidative cleavage of the double-
bond by the attacking 1O2.11,27
In the present work, analogous to previous reports,11,27 we
shall employ both E and Z oxazolidinone-functionalized
enecarbamates as 50:50 diastereomeric mixtures of the R/S
0
isomers at the C3 position. Thus, for the purpose of this

J. Sivaguru et al. / Tetrahedron 62 (2006) 10647–10659
10649
H
H
O
O
O
H
O
H
1'
3'(R/S)
1'
3'(R/S)
1'
2'
1'
2'
Ph
2'
Ph
Ph
N
2'
Ph
O
N
O
O
N
O
N
E
Z
Z
E
4R
4S
4S
3'(R/S)
Ph
4R
3'(R/S)
Ph
i
i
Ph
Pr
Z(R)-1
Ph
Pr
Z(S)-1
i
i
Pr
Pr
E(R)-1
E(S)-1
i
i
i
i
1'Z,4R(Pr),3'(R/S)-1
1'E,4R(Pr),3'(R/S)-1
1'Z,4S(Pr),3'(R/S)-1
1'E,4S(Pr),3'(R/S)-1
O
O
O
O
O
N
N
O
H
Ph
O
3'(R/S)
Ph
H
S
R
i
i
Pr
Pr
(R)-2
(S)-2
3
Chart 1. Structure matrix.
study, stereoselectivity will be defined as selective consump-
tion (kinetic resolution) of enecarbamaes (upon reaction
C4 stereogenic center of the oxazolidinone chiral auxiliary.
O3 was generated by means of an OL100 Ozone Generator.
1
0
with O2, O3, and PTAD) based upon the C3 stereochemis-
try.11 The chemical reactivity of 1O2, O3, and PTAD toward
the diastereomeric enecarbamates shall be examined as
a function of (i) E/Z alkene geometry, (ii) the R/S configura-
tion at the C4 position of the oxazolidinone chiral auxiliary,
2.2. 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, df¼0.25 mm) was
employed for the separation on the achiral stationary phase,
with a program of 50 ꢀC for 4 min, raised to 225 ꢀC at
10 ꢀC/min, and kept at 225 ꢀC for 10 min. A Varian CP-
Chirasil-DEX CB column (l¼25 m, id¼0.25 mm, df¼
0.25 mm) was used for the separations on the chiral stationary
phase, with a program of 135 ꢀC for 70 min, raised to 200 ꢀC
0
(iii) the R/S configuration of the alkyl substituent at the C3
position of the oxazolidinone chiral auxiliary, (iv) the sol-
vent, and (v) the reaction temperature. The stereoselectivity
1
for the reactions with PTAD19–23 (vs O2) is based on the
comparison of diastereomeric composition of the enecarba-
mates 1 before and after the reaction. On the other hand, for
the comparison of O2 with O3, the enantiomeric excess in
1
the MDB product 3 was examined (Scheme 1).29
at 15 ꢀC/min, and kept at 200 ꢀC for 30 min. The H NMR
1
and 13C NMR spectra were recorded on BRUKER spectro-
meters (Model DPX300 or DRX300). For the reaction with
PTAD, all H NMR spectra were obtained in CDCl3 on an
Herein we report the results of an extensive investigation,
which for the first time compares the stereochemical behav-
ior of such chemically diverse reactive species (1O2, O3, and
PTAD), whose reactivity are analogous in their reaction with
the diastereomeric E and Z enecarbamates 1. Evidently, the
observed difference in the stereocontrol of these reactive
species validates our hypothesis of significant vibrational de-
activation (physical quenching) of the electronically excited
1O2 as a factor for the observed stereoselectivity in the for-
mation of the MDB product. Such selective quenching of
diastereomeric excited states constitute a promising stereo-
chemical tool to effect enantioselective photoreactions.
1
AC360 Bruker spectrometer, supplied with NTNMR soft-
ware version 1.3 and processed with Mestre-C 4.1.1.0.
2.3. Photooxygenation of Z and E enecarbamates
The appropriate Z or E enecarbamate epimeric pair 1 (see
Chart 1) and the methylene blue sensitizer were dissolved
in 0.7 mL of the desired deuterated solvent (the enecarba-
mate concentration was 3.0ꢁ10ꢂ3 M and that of methylene
blue 3.7ꢁ10ꢂ4 M), placed into the NMR tube, sealed with
a rubber septum, fitted with a gas delivery needle, and
a vent needle. Dry O2 gas was purged through the sample
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 1H NMR spectroscopy to de-
termine the conversion (kept below 50%). The mass balance
(based on unreacted enecarbamate and formed MDB prod-
uct) and the conversion (based on unreacted enecarbamate)
were determined by GC analysis on an achiral stationary
phase, with 4,40-di-tert-butylbiphenyl as calibration stan-
dard. The enantioselectivity (% ee) of the MDB product
was determined by GC analysis on a chiral stationary phase.
2. Experimental
2.1. Materials
All regular solvents were purchased from Aldrich and the
deuterated solvents from Cambridge Isotope Labs and
used as received. CDCl3 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 em-
ployed for preparative TLC. Commercially available com-
pounds were purified by standard procedures. The Z and E
enecarbamates were synthesized by previously published
methods.11,12,24–26 The Z and E enecarbamates 1 were
2.4. Reaction of enecarbamates with PTAD
0
used as 50:50 mixture of R and S enantiomers at the C3 po-
sition (Chart 1), but the epimeric pair is optically pure at the
The respective enecarbamate pair (0.013 mmol) in CDCl3
was placed in the NMR tube followed by the addition of

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J. Sivaguru et al. / Tetrahedron 62 (2006) 10647–10659
0.003 mmol of the PTAD dissolved in chloroform-d. The
amount of PTAD was chosen to give a maximum of 25%
conversion. The reaction was allowed to proceed at 24, 7,
or ꢂ20 ꢀC until the disappearance of the characteristic
red color of the PTAD indicated that the reaction had
terminated. The samples were then subjected to H NMR
spectroscopy to record the conversion and diastereomeric
excess.
3. Results
The reaction between the chiral enecarbamates 1 and the
three different reactive species O2, O3, and PTAD was
1
carried out to assess the difference in their reactivity and
stereoselectivity. The Evans chiral auxiliary31–33 in the ene-
carbamate diastereomer Z-1 serves as the essential stereo-
chemical director, whereas the 1-phenylethyl substituent at
1
0
the C3 position of the double bond minimizes the ene reac-
2.5. General procedure for the ozone oxidation of the
enecarbamates
tion during photooxygenation24–26 as the required coplanar
alignment of the only allylic hydrogen atom is encumbered.
The E-1 enecarbamate was prepared from the Z-1 diastereo-
mer by direct or sensitized photochemical isomerization,34
followed by chromatographic separation. Photooxygenation
of the enecarbamate 1 gave quantitatively the expected oxa-
zolidinone aldehyde 2 and the chiral methyldesoxybenzoin
(MDB) 3 on complete conversion of the substrate. In previ-
ous experiments,24–26 the thermally labile dioxetane was de-
tected at ꢂ35 ꢀC and shown to decompose readily at room
temperature (ca. 20 ꢀC) into aldehyde 2 and MDB 3
(Scheme 1, Chart 1).
An aliquot of the appropriate enecarbamate epimeric pair
was taken from a standard solution in dichloromethane
and transferred to a NMR tube. Most of the solvent was
removed by means of a gentle stream of N2, the residual
solvent removed by placing the open NMR tube into a
vacuum (w12 in. Hg) oven at room temperature for at least
2 h. To each NMR tube was added 0.7 mL of the desired
deuterated solvent. The NMR tube with the enecarbamate
was kept in a cooling bath at the required temperature. A
separate test tube with the deuterated solvent of interest
was placed into the cooling bath at the required tempera-
ture, and saturated with O3 (generated by OL100 Ozone
Generator) by purging with O3 gas for a minimum of
15–20 min. The required amount of an O3-saturated solu-
tion was added to the NMR tube and the conversion
The reactivity of chiral Z and E enecarbamates 1 with 1O2,
O3, and PTAD, was compared by examining the selectivity
observed with the three different reactants. The product stud-
ies for the reactions of Z and E enecarbamates 1 with
PTAD19–23 are presented in Table 1. The comparable results
for reactions with O329 and 1O2,11,27 which have been previ-
ously published are summarized in Tables 2 and 3, respec-
tively. The reactions with PTAD as with the previous
1
monitored by H NMR spectroscopy (conversion <20%).
The amounts of O3-saturated solution used in the case of
CD2Cl2/CDCl3 were 50 mL at +20 ꢀC, 40 mL at ꢂ15 ꢀC,
30 mL at ꢂ45 ꢀC, and 25 mL at ꢂ70 ꢀC. For CD3OD, the
amounts of O3-saturated solution were 90 mL at +20 ꢀC,
50 mL at ꢂ15 ꢀC, 40 mL at ꢂ45 ꢀC, and 35 mL at ꢂ70 ꢀC.
Because of the lower solubility of ozone in CD3OD,30 larger
amounts of O3-saturated solution were used in the CD3OD
experiments. After addition of the O3, the reaction was
allowed to proceed at the desired temperature for 15 min,
0
work, employed a 50:50 mixture of C3 epimers and were
conducted to conversions less than 25% to minimize forma-
tion of side products.
Examination of Table 1 shows that there is no significant
effect of the alkene geometry in the PTAD reaction with
the chiral Z and E enecarbamates 1. As exemplified in Entry
1 of Table 1, the addition of PTAD to E(R)-1 in CDCl3 at
24 ꢀC accumulated a 14% diastereomeric excess of the
1
and then analyzed by H NMR spectroscopy, with conver-
sion calculated by integration of the aldehyde (decompo-
sition product) and the unreacted enecarbamates signals.
The samples were then subjected to GC analysis on a chiral
stationary phase.
Table 1. Diastereomeric excess in enecarbamate 1 after reaction with PTAD
in CDCl3
Entry Enecarbamatea Temp (ꢀC) % de enecarbamateb–d % Convnc
2.6. General procedure for the oxidation of the enecar-
bamates by triphenyl phosphite ozonide
0
14 [C3 S]
0
8 [C3 S]
0
11 [C3 S]
1
2
3
E(R)-1
24
7
ꢂ20
24
17
20
16
A 0.5 mL aliquot of triphenyl phosphite (1.72ꢁ10ꢂ6 M) in
dichloromethane was pipetted into a colorless 1-dram vial,
and placed into a cooling bath kept at ꢂ70 ꢀC. The O3 gas
was bubbled through the chilled solution for a minimum of
10 min until the solution acquired the characteristic purple
color of O3 saturation (O3 generated by OL100 Ozone
Generator), followed by N2 gas to remove excess O3 (ca.
5 min). To the colorless triphenyl phosphite ozonide solu-
tion was added a pre-cooled solution (kept in the same
cooling bath) of Z(R)-1 in dichloromethane, and the mix-
ture was allowed to react for 40 min in the cooling bath
at ꢂ70 ꢀC. After 40 min, the vial was removed from the
cooling bath and the contents allowed to warm up to
room temperature (ca. 20 ꢀC). The reaction mixture was
concentrated and submitted to GC analysis on a chiral
and an achiral stationary phase, with di-tert-butylbiphenyl
as calibration standard.
0
13 [C3 R]
0
10 [C3 R]
4
5
E(S)-1
Z(R)-1
13
11
7
0
10 [C3 S]
0
13 [C3 S]
0
14 [C3 S]
6
7
8
24
7
ꢂ20
24
7
ꢂ20
19
13
19
9
10
11
Z(S)-1
0
4 [C3 R]
16
13
18
0
0
4 [C3 R]
a
A ca. 50:50 mixture of diastereomers (total concentration 0.1 M) was
used.
b
c
Average of three runs (error ꢃ4%).
Conversion was monitored by 1H NMR spectroscopy; the conversion
(error ꢃ3%) was kept low to prevent side reactions.19–23
d
0
It is important to note that the C3 isomer of the enecarbamate substrate is
observed in excess in the product mixture, since it is the less reactive
epimer of the starting enecarbamate pair; for example, in entry 1,
0
PTAD is relatively more reactive with the C3 (R) epimer and, hence, the
0
C3 (S) epimer of E(R)-1 accumulates.

J. Sivaguru et al. / Tetrahedron 62 (2006) 10647–10659
10651
Table 2. Determination of the stereoselectivity factor (s) for the formation of (R/S)-MDB product in the oxidationa of 1 by O3 as a function of solvent and
temperature29
Entry
Enecarbamatea
Solvent
CD2Cl2
Temp (ꢀC)
% ee MDBb
% Convnc
sd
DDHz (kcal molꢂ1 d
)
DDSz (cal molꢂ1 Kꢂ1 d
)
1
2
3
4
E(R)-1
20
ꢂ15
ꢂ45
ꢂ70
22 (S)
24 (S)
16 (S)
18 (S)
6
15
18
27
1.6
1.7
1.4
1.5
0.16
1.49
5
6
7
E(R)-1
E(R)-1
CDCl3
20
ꢂ15
ꢂ70
20
ꢂ15
ꢂ45
ꢂ70
18 (S)
20 (S)
29 (S)
12
17
25
1.5
1.6
2.0
ꢂ0.48
ꢂ0.97
8
9
10
11
CD3OD
4 (S)
2 (S)
0
4
6
4
5
1.1
1.1
1.0
1.1
0.12
0.16
4 (S)
12
13
14
Z(R)-1
Z(S)-1
CD2Cl2
CD2Cl2
20
ꢂ15
ꢂ78
20
20
ꢂ15
ꢂ15
ꢂ45
ꢂ70
ꢂ70
31 (R)
30 (R)
36 (R)
10
12
9
2.0
1.9
2.2
ꢂ0.14
0.79
2.98
15
16
17
18
19
20
21
33 (S)
27 (S)
38 (S)
12 (S)
6 (S)
6
9
7
20
27
9
2.0
1.8
2.3
1.3
1.2
2.2
1.1
0.6
36 (S)
4 (S)
36
22
23
24
Z(S)-1
Z(S)-1
CDCl3
20
ꢂ15
ꢂ70
20
ꢂ15
ꢂ45
ꢂ70
20 (S)
16 (S)
18 (S)
16
17
14
1.6
1.4
1.5
0.08
1.03
0.62
25
26
27
28
CD3OD
20 (S)
21 (S)
22 (S)
22 (S)
3
4
16
7
1.5
1.5
1.6
1.6
ꢂ0.05
A 50:50 mixture of diastereomers (total concentration 2.3ꢁ10ꢂ3 M) was used.
Average of three runs (error ꢃ6%).
a
b
c
d
Conversion monitored by 1H NMR spectroscopy the conversion was kept low to prevent side reactions.18
Calculated from Eqs. 1–3.
Table 3. Determination of the stereoselectivity factor (s) for the formation of (R/S)-MDB product in the photooxygenationa of 1 as a function of solvent and
temperature11,27
Entry
Enecarbamatea
Solvent
CDCl3
Temp (ꢀC)
MDBb (% ee)
Convnc (%)
sd
1.2
5
13
31
DDHz (kcal molꢂ1 d
)
DDSz (cal molꢂ1 Kꢂ1 d
)
1
2
3
4
E(R)-1
50
18
8 (S)
63 (R)
78 (R)
88 (R)
5
17
37
43
ꢂ4.5
ꢂ14
ꢂ15
ꢂ40
5
6
7
E(R)-1
E(R)-1
CD2Cl2
CD3CN
20
ꢂ20
ꢂ60
50
18
ꢂ15
ꢂ40
34 (S)
27 (R)
82 (R)
25
65
54
2.3
2.7
40
ꢂ4.0
ꢂ4.5
ꢂ15
ꢂ17
8
9
10
11
64 (S)
30 (S)
0
23
34
28
37
5.5
2.1
1.0
5.2
58 (R)
12
13
14
15
16
E(R)-1
CD3OD
50
18
ꢂ15
ꢂ40
ꢂ70
70 (R)
85 (R)
90 (R)
94 (R)
97 (R)
30
34
17
12
8
7.6
19
23
37
72
ꢂ2.5
ꢂ4.9
17
18
19
E(S)-1
Z(R)-1
CD2Cl2
CD2Cl2
20
ꢂ20
ꢂ60
20
ꢂ20
ꢂ60
28 (R)
36 (S)
88 (S)
29
59
56
2.0
3.4
45
5.3
19.0
1.2
20
21
22
22 (R)
22 (R)
30 (R)
29
59
56
1.7
2.1
2.6
ꢂ0.7
The E enecarbamate concentration is 3.0ꢁ10ꢂ3 M and that for the methylene blue sensitizer is 3.7ꢁ10ꢂ4 M.
Conversion (convn) of enecarbamates determined by GC analysis on an achiral stationary phase with 4,40-di-tert-butylbiphenyl as calibration standard, and by
1H NMR spectroscopy; averages of three runs, within 5% error of the stated values.
Calculated from Eqs. 1–3.
a
b
c
Determined by GC analysis on a chiral stationary phase.
d

10652
J. Sivaguru et al. / Tetrahedron 62 (2006) 10647–10659
0
C3 (S)-epimer of E(R)-1 after the reaction; thus, the C3 (R)-
epimer of E(R)-1 is more reactive. By changing the alkene
0
geometry to the Z enecarbamate, the C3 (S)-epimer of
Z(R)-1 accumulated in a 10% diastereomeric excess under
identical conditions (Entry 6), which indicates that the
0
C3 (R)-epimer of Z(R)-1 is more reactive. Thus, when the
R configuration at the C4 position of the oxazolidinone chiral
0
lnðkR=kSÞ ¼ ln½ð100 þ % eeÞ=ð100 ꢂ % eeÞꢄ
ð2Þ
ð3Þ
ꢂ DDGz =RT ¼ lnðkR=kSÞ
RꢂS
¼ DDSzRꢂS=R ꢂ DDHzRꢂS=RT
The effect of the solvent type and polarity was examined
by conducting the ozonolysis in the polar, protic solvent
CD3OD, and the low-polarity halogenated solvents CD2Cl2
and CDCl3. For the oxidative cleavage of the E(R)-1 sub-
strate by O3, the solvent dependence of the stereoselectivity
follows the order (the ee values are given in parentheses)
CD3OD (4%)<CDCl3 (18%)<CD2Cl2 (22%) at the com-
mon temperature of about 20 ꢀC (Table 2; Entries 8, 5, and
1). Similarly, for the O3 cleavage of the Z isomer [Z(S)-1],
the solvent dependence of the stereoselectivity follows the
order CD3OD (20%)zCDCl3 (20%)<CD2Cl2 (33%), also
at about 20 ꢀC (Table 2; Entries 25, 22, and 15). Evidently,
the best diastereoselectivity is obtained for CD2Cl2, whereas
the lowest stereocontrol is displayed by the hydrogen-
bonded solvent methanol at the same temperature. Since
the stereoselectivity in CDCl3 and CD3OD is similar (Table
2; compare Entries 22–24 and 25–28), the solvent polarity
alone cannot be the responsible factor for the stereocontrol
in the oxidative cleavage of the Z(S)-1 enecarbamates by O3.
0
auxiliary was used, the C3 (R)-epimer was more reactive ir-
respective of the alkene Z/E geometry. For example (Table 1;
0
Entries 1–3), PTAD is more reactive for the C3 (R)-epimer of
0
E(R)-1 and, hence, the C3 (S)-epimer of E(R)-1 was observed
in excess after the reaction. Similarly, PTAD is more reactive
0
0
for the C3 (R)-epimer of Z(R)-1 and, thus, the C3 (S)-epimer
of Z(R)-1 results in excess (Table 1; Entries 6–8). The low
selectivity observed in the reaction (<15%) indicates that
0
the C3 stereocenter is not playing a dominant role. Since the
sense in the stereoselection was reversed upon changing
the configuration at the C4 position of the oxazolidinone
chiral auxiliary from R to S (Table 1; Entries 4,5 and
9–11), the PTAD reaction is well behaved.
The enantiomeric excesses in the MDB product upon oxida-
tive cleavage of the epimeric pairs of oxazolidinone-derived
E and Z enecarbamates by O3 are given in Table 2 for three
different solvents (CD2Cl2, CDCl3, and CD3OD) and at
various temperatures. The conversion was kept low to avoid
side reactions18 and the enantiomeric excess (ee) was ob-
tained by GC analysis of the methyldesoxybenzoin (MDB)
product on a chiral stationary phase. Inspection of Table 2
reveals the following features: (i) The same MDB enantio-
mer is formed preferentially irrespective of the solvent,
that is, employed, but the ee values for both E and Z enecar-
bamates change notably, when compared at the same
temperature; for example, the ee value for the O3 oxidation
of E(R)-1 in CD2Cl2 is 18% (Entry 4), in CDCl3 it is 29%
(Entry 7), and in CD3OD it is 4% (Entry 11) at ꢂ70 ꢀC.
(ii) The sense of the preferentially generated MDB enantio-
mer depends on the configuration at the C4 position of the
oxazolidinone ring, as well as the alkene Z/E geometry;
for example, E(R)-1 substrate gave the S-MDB product in
excess, whereas the corresponding Z(R)-1 enecarbamate
afforded R-MDB in excess. (iii) The same MDB enantiomer
is produced irrespective of the temperature. (iv) The change
in the configuration at the C4 position of the oxazolidinone
reverses the sense of the MDB enantiomer to the same
extent, which indicates that the O3 oxidation is also well
behaved. (v) The observed ee values depend on the extent
of conversion; thus, the ee values were moderate at low
conversions and small at high conversions.
In contrast, the ozonolysis of the E(R)-1 diastereomer in
CDCl3 and CD3OD displays significant differences in the
observed stereoselectivity (Table 2; compare Entries 5–7
and 8–11). Although not as dramatic as observed for the
1O2 oxidation, the effect is attributed to the differing alkene
geometry (Z vs E enecarbamate) and the various confor-
mations that these diastereomers may adopt in the two
solvents.11,27,29 To be noted is the comparatively high ee
values for the Z versus the E enecarbamates. Mechanistically
mostrevealingisthefindingthattheR-MDBenantiomeristhe
favored product for Z(R)-1 (Table 2; Entries 12–14), but the S-
MDB isomer dominates for E(R)-1 (Table 2; Entries 1–11).
For example, in CD2Cl2 at 20 ꢀC E(R)-1 favors the S-MDB
product (Table 2; Entry 1), whereas Z(R)-1 prefers the
R-MDB (Table 2; Entry 12) under the identical conditions.
Our previous results on the photooxygenation of Z and E
enecarbamate (Table 3) showed that there is negligible effect
of the alkyl substituent (methyl or isopropyl group) at the
oxazolidinone C4 position.11–13,24–27 Further, upon employ-
ing R or S antipodes at the C4 position (Table 3), the sense of
the enantioselectivity in the MDB product is reversed, while
the extent of the stereocontrol in the photooxidative cleavage
of the E enecarbamates is the same (within the experimental
error). This is clearly displayed by the % ee data for the
E(R)-1 and E(S)-1 diastereomers, as exemplified by their
photooxygenation in CD2Cl2 at 20 ꢀC (s factor ca. 2 for
both; Entries 5 and 17 in Table 3). Thus, E(R)-1 (Table 3; En-
tries 5–7) favors the S-MDB enantiomer (34% ee at 25%
convn), whereas E(S)-1 (Entries 17–19) favors the R-MDB
(28% ee at 29% convn) enantiomer as the final oxidation
products; the reversal in the enantioselectivity sense is
expected.
The stereoselectivity factor (s), which represents the ratio of
the rates of formation (kR/kS) of the enantiomeric products,
may be computed from the observed ee values at a given
conversion by means of Eqs. 1 and 2.35–38 The computed
s values for the O3 oxidation are given in Table 2, and are
quite low, i.e., at best w2. Consequently, the stereocontrol
in the ozonolysis reaction is relatively poor.
kR ln½1 ꢂ Cð1 þ eeMDBÞꢄ
s ¼
¼
ð1Þ
kS ln½1 ꢂ Cð1 ꢂ eeMDBÞꢄ
The effect of the solvent type and polarity was examined
by conducting the photooxygenation in the polar, aprotic
solvent CD3CN, the polar, protic solvent CD3OD, and the
where C is the conversion and eeMDB the ee value of the
MDB product

J. Sivaguru et al. / Tetrahedron 62 (2006) 10647–10659
10653
1
low-polarity halogenated solvents CD2Cl2 and CDCl3. For
the photooxidative cleavage of the E-1 substrate, the solvent
dependence of the diastereoselectivity follows the order
CD3CN (30%)wCD2Cl2 (34%)<CDCl3 (63%)<CD3OD
(85%) at the common temperature of about 18–20 ꢀC (Table
3; Entries 9, 5, 2, and 13); the ee values are given in parenthe-
ses. Evidently, the best stereoselectivity is obtained for the
hydrogen-bonding solvent methanol (Table 3; Entry 13),
whereas the lowest stereoselectivity is displayed by the apro-
tic acetonitrile (Table 3; Entry 9) at the same temperature of
18 ꢀC. To be noted is the relatively high ee value in chloro-
form-d (Table 3; Entries 1–4). Again, mechanistically most
revealing is the finding that the R-MDB enantiomer is the
favored product in CDCl3 and CD3OD (Table 3; Entries 2
and 13), but the S-MDB isomer dominates in CD2Cl2 and
CD3CN (Table 3; Entries 5 and 9). Thus, also for the photo-
oxidative cleavage of the E(R)-1 enecarbamates, the stereo-
selectivity cannot be attributed to the solvent polarity alone.
trends for the three oxidants O2, O3, and PTAD, we will
rely on the previously published structural details of the
chiral Z24 and E27 enecarbamates.
4. Discussion
Before entering into a mechanistic analysis of the stereo-
chemical control exercised by O2, O3, and PTAD with
Z/E enecarbamates 1, the established reaction pathways
must be recalled. Both O2 and PTAD approach the alkene
1
1
double bond (on the XY-plane) perpendicularly (Z-axis),
as shown in Figure 2 for the transition structures A (1O2)
and C (PTAD),19–23 whereas O3 adds to the double bond
18
laterally, as displayed by the transition structure B in
Figure 2. Additionally, the major differences and similarities
between the three reagents are:
(i) Both O3 and PTAD are ground-state molecules and will
not experience any excited-state vibrational deactiva-
tion as observed for the electronically excited 1O2; their
stereoselectivity is expected to be controlled mainly by
steric effects, whereas for 1O2 also physical quenching
may play a role.28
Still more intriguing for mechanistic considerations is the
temperature dependence of the ee values upon photooxyge-
nation of the E(R)-1 substrate (Table 3). Only in methanol
is the extent of the diastereoselectivity relatively constant
(note the high ee value of 97% at ꢂ70 ꢀC, i.e., nearly perfect
stereocontrol!); moreover, the same enantiomer, namely
R-MDB, is formed over the entire temperature range
from ꢂ70 to +50 ꢀC (Table 3; Entries 12–16). In the other
solvents, a temperature-dependent change in the sense of
stereoselection is observed from the usual R-MDB to the S-
MDB isomer. For example, very good stereocontrol (ee value
of 88%) in favor of R-MDB is found in chloroform-d at
ꢂ40 ꢀC (Table 3; Entry 4), but the S-MDB isomer is favored
with only poor diastereoselectivity (ee value of only 8%) at
+50 ꢀC (Table 3; Entry 1). This inflection in the enantioselec-
tivity sense (R to S isomer) occurs in CDCl3 above +18 ꢀC
(Table 3; Entries 1 and 2), whereas in CD2Cl2 it takes place
between +20 and ꢂ20 ꢀC (Table 3; Entries 5 and 6). In the
case of CD3CN, the change in the sense takes place at
ꢂ15 ꢀC (Table 3; Entry 10), as indicated by the 0% ee value
in the MDB product.
1
(ii) PTAD19–23 is a much larger enophile than O2 and if
0
steric control at the C3 position is the deciding factor,
then a higher stereoselectivity should be expected for
PTAD compared to 1O2.14–17
18
1
(iii) O3 is similar in size to O2 and should be subject to
similar steric interactions,29 but differences may arise
from its lateral attack on the double bond versus the
perpendicular one for 1O2.
Based on this mechanistic background, we shall now analyze
the factors that underlay the stereoselectivity in the oxida-
tion of both Z and E enecarbamates with O3 and PTAD,
and compare the present results with our previously pub-
1
lished ones11,24–27 for O2. A brief summary of the salient
features of our experimental data is given below:
(i) A high stereoselectivity is observed in the formation of
MDB for the O2 oxidation of E-1; whereas a low
1
The present stereoselectivity data indicate that the solvent
and temperature effects are just confined to the reaction of
1O2 with E-1. Both the O3 and PTAD reactions do not
show any noticeable dependence of the stereocontrol on
either temperature or solvent. These remarkable stereoselec-
tivity trends require careful mechanistic scrutiny, to under-
stand the details of the enecarbamate oxidation. To enable
a detailed comparative mechanistic rationalization of these
stereoselectivity is observed for both O3 and PTAD
reactions with E-1.
(ii) O2 is sensitive to all the stereochemical structural fea-
1
tures inherent with the chiral enecarbamate substrate
(the alkene Z/E geometry, the R/S configuration at the
C4 position in the oxazolidinone chiral auxiliary, and
0
the R/S configuration at the C3 position of the
Figure 2. Plausible transition structures for the reactions of 1O2 (A), O3 (B), and PTAD (C) with the chiral enecarbamates Z-1.

10654
J. Sivaguru et al. / Tetrahedron 62 (2006) 10647–10659
phenethyl side chain), as reflected in the vastly different
stereoselectivities (Table 3) observed for the Z and E
enecarbamates. This is highlighted by the observation
that the photooxidative cleavage of the E-1 isomer
affords the MDB product in high (up to 97%) enantio-
selectivity (Table 3), whereas the ee value for the Z-1
isomer is low (only 30% at best) under comparable
reaction conditions.11,24–27 In contrast, both PTAD
(Table 1) and O3 (Table 2), display a very low stereo-
selectivity for both Z and E enecarbamates.
Since we have employed a 50:50 diastereomeric mixture of
0
enecarbamates E-1 (actually, R/S epimers at the C3 stereo-
genic site of the alkyl side chain), the stereoselection in
the present case entails kinetic resolution.11,27 Thus, the
enantiomeric excess in the MDB product 3, which is formed
in the double-bond cleavage by 1O2 and O3, reflects the dif-
ferentiation in the relative reaction rates of the enecarbamate
oxidation (Fig. 3). For such kinetic resolution, the so-called
selectivity factor (s),35–38 which is a quantitative measure
(corrected for the extent of conversion) of the relative reac-
tion rates for the two stereoisomers in question (Eqs. 1 and 2)
come to prominence. In the present case, the s factor may be
(iii) The sensitivity of the three different reactive species
1
0
towards C3 stereochemistry follows the order O2>>
O3>PTAD; thus, PTAD reacts preferentially with the
0
computed for the two-epimeric enecarbamates [C3 (R) and
0
C3 (R)-epimer irrespective of the alkene Z/E geometry,
0
C3 (S) epimers] from the substrate conversion and the
0
whereas the C3 (S)-epimer of the E enecarbamate and
0
the C3 (R)-epimer of the Z enecarbamate are more reac-
tive for O3.
MDB enantiomeric excess by using Eqs. 1 and 2. A large
s value translates to high enantiomeric excess in the MDB
product (see Figs. 3 and 4).
(iv) The enantiomeric excess in the MDB product for the
1O2 oxidation of the E-1 diastereomer depends substan-
tially on the employed solvent and the temperature con-
ditions, but not for the corresponding Z-1 enecarbamate
(Table 3);11,24–27 no significant solvent and temperature
effects are evident for the reaction of PTAD (Table 1)
and O3 (Table 2) with both Z and E enecarbamates.
(v) Not only does the extent of stereoselection (% ee value)
for the E-1 diastereomer vary extensively as a function
of solvent and temperature (Table 3), but the favored
configuration (R vs S enantiomers of MDB) changes,
i.e., there is an inversion in the sense of the stereoselec-
tivity for the 1O2 oxidation (Table 3), but not for PTAD
(Table 1) or O3 (Table 2).
For illustration purposes, under identical conditions, the
oxidation of E(R)-1 by 1O2 gave an ee value of 97%
100
s=72.0
80
60
40
s=2.0
This divergent behavior in the stereochemical control dis-
played by O2, O3, and PTAD in their reactivity towards 1
needs to be mechanistically rationalized in terms of the tra-
jectory for the attack on the double bond of the chiral enecar-
20
1
s=1.08
0
0
20
40
Conversion (%)
60
80
100
0
bamate substrate. The configuration at the C3 position is of
particular interest in regard to steric blocking (ground-state
reactivity) versus vibrational deactivation (excited-state re-
activity) by the methyl versus phenyl substituents for attack
of the reagent on the double bond.
Figure 4. The dependence of the enantiomeric excess of the MDB product
on the conversion of the chiral oxazolidinone-functionalized enecarbamates
to illustrate the consequences of the difference in the s factor.35–38
H
O
Conversion = 8%
O
Ph
ee = 97% (R-MDB)
s factor = 72
N
R
O
+
O
3'(R/S)
Ph
CH3
1O2
3
2
(A)
O
E
Ph
-70°C
CD3OD
N
O
3'(R/S)
4R
CH3
Ph
O3
E(R)-1
H
O
Conversion = 5%
ee = 4% (S-MDB)
s factor = 1.1
O
Ph
N
R
O
+
O
3'(R/S)
Ph
CH3
3
2
(B)
Figure 3. The GC traces of the MDB product for the oxidation of E(R)-1 by 1O2 (A) and O3 (B) at ꢂ70 ꢀC in CD3OD.

J. Sivaguru et al. / Tetrahedron 62 (2006) 10647–10659
10655
with a s factor of 72, compared to only 4% for the O3
oxidation with an s factor of about 1.1 (compare Entry
16 in Table 3 and Entry 11 in Table 2). As a practical uti-
lization of such a high s factor in a kinetic resolution, we
previously demonstrated11 that we may photochemically
between ꢂ0.5 to +0.6 kcal molꢂ1 and the DDSz values be-
tween ꢂ1.0 and +3.0 cal molꢂ1 Kꢂ1 over the entire variation
of reaction conditions (Table 2). In contrast, a pronounced
temperature dependence is displayed for the 1O2 oxidation,
since the DDHz term varies between ꢂ5.0 and
+5.0 kcal molꢂ1 and the DDSz term between ꢂ17 and
+19 cal molꢂ1 Kꢂ1 (Table 3). Clearly, the major contribution
derived from the differential activation entropy term (DDSz),
in comparison with the differential activation enthalpy term
(DDHz), cannot be ignored.
1
resolve the two epimers with O2 by running the photo-
oxygenation of E(R)-1 in CD3OD at ꢂ70 ꢀC to nearly
50% conversion. The R-MDB product was separated from
the reaction mixture by chromatography and an ee value of
97% was obtained. The unreacted 10E,4R(iPr),30S-1 ene-
carbamate was then quantitatively photooxidized at room
temperature to afford the S-MDB product with an ee value
The experimental trends in the temperature dependence of
the enantioselectivity for the O3 and O2 oxidations of the
1
1
of 97%. This remarkable case of stereoselection for O2
was previously coined as photochemical Pasteur-type
enecarbamates as a function of the solvent nature is given
in the Eyring plots for the E(R)-1 diastereomer in Figure 5.
The slope of nearly zero in the Eyring plot for the O3 oxida-
tion in the investigated solvents indicates that this reaction is
insensitive to solvent and temperature variations, since the
differential activation enthalphy (DDHz) contributes negligi-
bly.41,42 Since the behavior of PTAD parallels that of O3, we
presume that PTAD also exhibits similar Eyring plots. Also
kinetic resolution.11
The plot of % ee versus conversion in Figure 4 displays that
the dependence of the enantioselectivity as a function of
conversion for various s factors, as observed for the O3 oxi-
dation (Table 2), for which the ee values are moderate at low
and small at high conversions. For example, 36% ee was ob-
served at 9% conversion and only 4% ee at 36% conversion
(Table 2; Entries 20 and 21) for the oxidation of Z(S)-1 by O3
in CD2Cl2 at ꢂ70 ꢀC. The consequence of the difference in
the s factors is best illustrated in Figure 3, where an ee value
of 97% was obtained for 1O2 (s factor of 72) compared to an
ee value of only 4% for O3 (s factor of 1.1) in CD3OD. When
stereoselectivity results are rationalized mechanistically in
the kinetic-resolution studies, instead of the ee values the s
factor should be employed.35–38 The reason for this is that
the ee value refers to the amount of the enhanced MDB enan-
tiomer uncorrected for the extent of conversion, whereas the
s factor reflects the variation in the ee value corrected for
the extent of conversion (Eq. 1; Fig. 4).35–38 For example,
in the case of the O3 oxidation of Z(S)-1 at ꢂ70 ꢀC, in
CD2Cl2 the ee value is 4% S-MDB at 36% conversion and
the s factor 1.1 (Table 2; Entry 21), while for CD3OD the
ee value is 22% S-MDB at 7% conversion and the s factor
1.6 (Table 2; Entry 28); clearly, there is a large difference
in the ee values, but the s factors are almost the same. In
1
note the nearly parallel lines (similar slopes) for the O2
oxidation, which indicate that the enthalpic contribution
(DDHz) is about the same in the diverse solvents; thus, the
stereoselectivity is controlled by the entropic term (DDSz).
Most significant is the crossing of the zero % ee line, which
constitutes the inversion point in the sense of the enantio-
selectivity, i.e., opposite configurations are selected as the
favored MDB enantiomer.
The contrasting temperature and solvent dependence of the
stereoselectivity observed for the O2 and O3 reactants (by
1
inference, PTAD is similar to O3) in their oxidation of the
chiral enecarbamate substrates is convincingly exposed by
the DDSz and DDHz parameters.2,39,40 Thus, the stereoselec-
tion is a critical balance of the enthalpy and entropy, which
are interrelated by Eqs. 1 and 2. Consequently, the large con-
tribution from the differential activation parameters for the
1O2 oxidation (Table 3) suggests that the transition state is
conformationally flexible and its solvation–desolvation
behavior is crucial. Expectedly, the temperature and solvent
variations influence the stereo-differentiating step.2,39,40
Such entropy effects are indicative of conformational fac-
tors,2,39,40 which in the present case are dictated, presum-
1
the case of the O2 oxidation of the E enecarbamate, there
is a significant variation in the s factor upon changing the
solvent from CD2Cl2 (the s factor varies from 2.3 to 40) to
CD3OD (the s factor varies from 7.6 to 72), but not for the
Z isomer. Comparison of the stereoselectivity of PTAD,
O3, and 1O2 in the various solvents at different temperatures,
it is clear that PTAD (Table 1) and O3 (Table 2), exhibits es-
sentially no temperature effect or solvent effect for both Z/E
enecarbamates, whereas 1O2 (Table 3) displays a substantial
temperature effect and solvent effect for the E enecarba-
mates and not for the Z enecarbamates. The differential
activation parameters (DDSz and DDHz) were determined
for the reactivity of O3 and 1O2. Since the temperature profile
of the stereoselectivity for PTAD is quite similar to that of
O3, we shall consider only the O3 and 1O2 oxidants, but infer
for PTAD from the O3 results. The DDSz and DDHz values
0
ably, by the stereogenic center at the C3 position of the
phenethyl side chain. In contrast, the low contribution
from the differential activation parameters for the O3 oxida-
tion indicates that the transition state is more rigid and not
affected by the variation of the external factors of the system.
As expected, there is no significant temperature and solvent
dependence in the sense of the stereoselectivity for the O3
and PTAD oxidations.
These conspicuously complex temperature and solvent ef-
fects in the stereoselectivity observed for the oxidation of
the E and Z enecarbamates by O2, O3, and PTAD can be
1
1
for the O2 and O3 oxidation of E(R)-1 diastereomer in
mechanistically rationalized in terms of the structural fea-
tures inherent within the chiral substrate and the electronic
nature of the oxidants. We previously proposed11,24–27 that
the high stereocontrol in the photooxidative cleavage of the
enecarbamates by the electronically excited 1O2 is the conse-
quence of selective p-facial quenching by the enecarbamate
substrate. In this context, it is well known that the lifetime of
CDCl3, CD2Cl2, and CD3OD were computed with the help
of the Eyring relation (Eq. 3) and the data are given in Table
2 for O3 and in Table 3 for 1O2.2,27,39,40 The DDSz and DDHz
values for the O3 oxidation of the enecarbamate 1 Z/E dia-
stereomers reveal a negligible temperature effect in the
MDB enantiomeric excess; e.g., the DDHz values range

10656
J. Sivaguru et al. / Tetrahedron 62 (2006) 10647–10659
T, °C
60
13
-23
-51
3
2
3
2
91
ee(R)[%]
76
46
0.0
1
1
0
0
-1
-2
-3
-1
-2
-3
46
ee(S)[%]
E(R)-1 O3/CD3OD
E(R)-1 O3/CDCl3
E(R)-1 O3/CD2Cl2
E(R)-1 1O2/CD3OD
E(R)-1 1O2/CDCl3
E(R)-1 1O2/CD2Cl2
76
91
3.0
3.5
4.0
103/T, K-1
4.5
3.0
3.5
4.0
103/T, K-1
4.5
Figure 5. Eyring plots for the stereoselective photooxygenation of E(R)-1 by O3 (left) and 1O2 (right) in a variety of solvents.
1O2 in deuterated solvents is much longer than non-deuter-
(Scheme 2), which is reported44–46 to add at ꢂ70 ꢀC
1
ated ones,14–17 since C–H bond vibrations deactivate O2
directly to alkenes through a perepoxide-like transition
state, i.e., it displays O2 reactivity, but does not involve
genuine O2.
to its triplet ground state.28 In view of the higher flexibility
of enecarbamates, conformations may be populated, in
which one p face of the double bond exposes a larger number
of C–H bonds for selective quenching28 of the incoming elec-
tronically excited 1O2 (see Panel A in Fig. 6). Further, deute-
rium substitution (CD3 vs CH3) at the alkene geometry
(cis- vs trans-) in the ene-reaction involving 1O2 shows a sub-
stantial isotope-effect (kH/kD for cis-: 1.04–1.09 and kH/kD
for trans-: 1.38–1.41).43 If this hypothesis is valid, the
ground-state reactive species like PTAD and O3 will not be
1
1
As shown in Scheme 2, an ee value of 83% (R-MDB) was
observed for the triphenyl phosphite ozonide [(PhO)3PO3]
oxidation of Z(R)-1,29,45,46 compared to only 36% (R-
MDB) for O3. Due to the bulkiness of the (PhO)3PO3 oxidant
and its ground-state character, the stereoselectivity dis-
played in the O3 (and by inference also PTAD) reactions
may be attributed to the steric interference experienced by
these reactants with the enecarbamate substrate. Evidently,
1
vibrationally deactivated like O2. Thus, for O3 and PTAD
1
only steric hindrance reflects the observed selectivity. Our
analyses of O3 and PTAD reactivity with the Z(R)-1 empha-
sizes this aspect. As shown in Panel B (O3) and Panel C
(PTAD) of Figure 6, the approach of reactant onto the double
bond is hindered from the bottom by the isopropyl group,
such that O3 as well as PTAD are forced to attack from the
top. Additionally, kinetic resolution by the stereogenic center
the much higher stereoselection exhibited by O2 than for
O3 and PTAD suggests that factors other than steric imped-
1
iments control the stereoselectivity of the O2 oxidations,
possibily quenching of the exited state nature of O2 by
vibrational interactions.
1
To understand the intricacies of the complex stereoselectiv-
ity trends observed for the 1O2, O3, and PTAD, the structural
characteristics in regard to the stereochemical aspects of the
chiral enecarbamates needs to be considered in detail. As
shown in Figure 7, the oxazolidinone-functionalized enecar-
bamate are composed of three distinct stereochemically per-
tinent structural features, namely the R/S configuration at the
C4 position in the oxazolidinone chiral auxiliary, the Z/E
geometry of the alkenyl double bond (labeled alkene), and
0
at the C3 position of the phenethyl side chain plays a role in
enriching one of the MDB enantiomers (Fig. 6).27 For exam-
ple, in the O3 oxidation of the 50:50 mixture of the 30R/S di-
0
astereomers of Z(R)-1, the C3 (R)-epimer is more reactive
0
than C3 (S)-epimer, such that the R-MDB enantiomer is
0
formed in excess and the C3 (S)-epimer of the Z enecarba-
mate accumulates (see Panel B in Fig. 6). Similar arguments
apply also to the reactivity of PTAD with the 50:50 mixture
of the 30R/S diastereomers of Z(R)-1 (see Panel C in Fig. 6),
which is corroborated in the observed selectivity (Table 1).
0
the R/S configuration at the C3 position of the alkyl side
chain on the double bond. The following implications on
the control of the stereoselectivity imposed by these struc-
tural features on the attacking oxidants may be anticipated:
Indeed, if steric effects play a dominant role in the O3 oxi-
dation, then the observed ee values should be higher when
a bulkier ozone-like oxidant is employed in the kinetic
0
resolution of the R/S epimers at the C3 position. This ex-
pectation was tested with the triphenyl phosphite ozonide
(i) The reactant may be sterically sensitive to the C4
position and distinguish between its R/S configurations
but unable to sense any differences for the Z/E

J. Sivaguru et al. / Tetrahedron 62 (2006) 10647–10659
10657
More vibrational deactivation due to
increased C-H bond encounters
(A)
Less vibrational deactivation from
fewer C-H bond encounters
O2
1
1
O2
O
O
Less reactive
Z(R)-1 3'S isomer
H
More reactive
Z(R)-1 3'R isomer
H
H
H
O
N
O
N
CH3
4R
4R
H
H
H
3'R
Ph
H3C
Ph
H3C
CH3
3'S
H
CH
CH3H
3H
H
H
Vibrational
Deactivation
Vibrational
Deactivation
1
1
O2
O2
O2
O2
(B)
O3
More steric hindrance
O
O3
Less steric hindrance
O
Less reactive
Z(R)-1 3'S isomer
H
More reactive
Z(R)-1 3'R isomer
H
H
H
O
N
O
N
CH3
4R
4R
H
H
H
3'R
Ph
H3C
Ph
H3C
CH3
3'S
H
CH
CH3H
3H
H
H
Attack from bottom face not
possible due to steric blocking
O3
(C)
O
O
Ph
Ph
O
N
N
N
N
More steric hindrance
O
Less steric hindrance
O
N
O
N
H
Less reactive
Z(R)-1 3'S isomer
More reactive
Z(R)-1 3'R isomer
H
H
H
O
N
O
N
CH3
4R
4R
H
H
H
3'R
Ph
H3C
Ph
H3C
CH3
3'S
H
CH
3H
CH3H
H
H
Attack from bottom face not
possible due to steric blocking
N
N
O
O
N
Ph
Figure 6. The favored p-facial attack on the alkene double bond of the chiral enecarbamate Z(R)-1 by 1O2 (A), O3 (B), and PTAD (C).
O
O
O
H
O
O
O
Z
3'(R/S)
Ph
(R/S)
Ph
O
H
O
N
O
N
(PhO)3P
+
4R
4R
Ph
CH2Cl2, -70 °C
Ph
MDB
Z(R) -1
(A)
(B)
H
O
3'(R/S)
Ph
Z
ee: 83%(R)
R-MDB
ee: 36%(R)
R-MDB
O
N
4R
Ph
O
O
S-MDB
Z(R)-1
O3
O
(PhO)3P
S-MDB
(R/S)
O
Ph
Ph
MDB
Scheme 2. Oxidation of the Z(R)-1 diastereomer by O3 (A) and by (PhO)3PO3 (B); for comparison, the corresponding GC traces (chiral stationary phase) are
displayed.

10658
J. Sivaguru et al. / Tetrahedron 62 (2006) 10647–10659
Figure 7. The stereochemically relevant structural composition of the chiral oxazolidinone-functionalized enecarbamates and their implications in regard to
stereocontrol.
configurations of the alkene geometry nor the R/S con-
0
figurations of the C3 position; a low stereoselectivity
5. Conclusion
should be expected, as displayed by PTAD.
(ii) The reactant may be sensitive to the C4 position and the
The current comparative study involving 1O2, O3, and PTAD
with enecarbamates 1 provides detailed insights into the
intricate nature of the steric and electronic interactions re-
quired to achieve a high selectivity in the photooxygenation
of chiral alkenes. The extensive stereochemically relevant
structural properties embodied in the chiral oxazolidinone-
substituted enecarbamates (i.e., the chiral centers at the C4
0
alkene geometry, but insensitive to the C3 position; up
to a moderate stereoselectivity should be expected, as
observed O3.
(iii) The reactant may be sensitive to all three stereo-
chemical features, namely the C4 position, the alkene
0
0
position of the oxazolidinone ring and at the C3 position
geometry, and the C3 position; a high stereoselectivity
should result, as found for 1O2.
of the phenethyl side chain, as well as the E/Z configurations
of the alkene functionality) make these substrates informa-
tive molecular probes to explore the mechanistic intricacies
of the oxidative cleavage of alkenyl double bonds. The
stereoselection depends not only on the alkene geometry
From the above analysis of the stereochemically relevant
structural characteristics of the chiral enecarbamate sub-
strate and the electronic nature of the three reactants, we
speculate that the vibrational deactivation (physical quench-
ing) is responsible for the high stereocontrol exhibited by
i
(Z/E), the size of the C4 alkyl substituent (H, Me, Pr) in
0
the oxazolidinone ring, the configuration (R/S) at the C3
1
electronically excited O2 (w97% ee at ꢂ70 ꢀC; CD3OD,
stereogenic center of the phenethyl side chain, the solvent,
and temperature, but also on the electronic nature (excited
vs ground state) of the oxidant. The most dramatic effects
on the stereocontrol have been seen for the conformationally
more flexible E diastereomer, which responds to the
electronic characteristics of the reactive species, possibly
through the selective vibrational quenching by the substitu-
Table 2).28 In contrast, the ground-state O3 and PTAD oxi-
dants are only subject to classical steric effects, which are
relatively ineffective for stereoselection. Thus, the prod-
uct-generating chemical pathway competes with the physi-
cal quenching process through vibrational deactivation by
C–H bonds.28,47 In the vibrational deactivation scenario,
the isopropyl group at the C4 position of the oxazolidinone
chiral auxiliary is apparently responsible for the excited-
state deactivation of 1O2. To compare directly the influence
of vibrational deactivation encountered in [2+2] cycloaddi-
tion with that of ene reaction should be of pertinent mecha-
nistic interest. In our case, such comparison with the same
substrates will not be possible as the phenethyl side chain
exclusively gives the [2+2] cycloaddition product. The phen-
ethyl group would need to be replaced with a methyl group,
to study the influence of vibrational deactivation for the ene
reaction. Previously we have demonstrated that the oxazoli-
dinone chiral auxiliary provides high p-facial selectivity
through the C4 substituent for both the ene and the [2+2] re-
action in the case of substrates that have the methyl instead
of the phenethyl group.25 It was also shown that the mode se-
lectivity (ene vs [2+2]) depends on the alkene E versus Z ge-
ometry, which was explained in terms of an orbital-directing
effect of the enamine-type functionality.25 Again, deuterated
substrates would be necessary to examine the influence of
vibrational deactivation in the ene reaction. A promising
mechanistic probe to validate this novel phenomenon of
0
ents at the C3 position of the chiral enecarbamates as a func-
tion of their configuration. The stereochemical consequence
of this novel phenomenon deserves further exploration in
photochemical transformations.
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 For-
schungsgemeinschaft, Alexander-von-Humboldt Stiftung,
the Fonds der Chemischen Industrie, and the hospitality of
the University of Puerto Rico. T.P. acknowledges the support
of the W.M. Keck Foundation. H.S. and Y.I. gratefully ac-
knowledge a JSPS research fellowship for young scientists
(08384). The oxidative work with 1O2 and O3 was carried out
at the Columbia University, and the PTAD studies were con-
ducted at Claremont McKenna, Pitzer, and Scripps Colleges.
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