Decoding stereocontrol during the photooxygenation of oxazolidinone- functionalized enecarbamates

Article abstract of DOI:10.1021/ol100174r

Figure presented Systematically designed oxazolidinone-derived enecarbamates reveal that solvent and temperature effects on the stereoselectivity during photooxygenation are likely due to the conformational flexibility of the chiral phenethyl side chain (entropy factors); the extent of enantiomeric excess in the photoproduct is dictated by the alkene geometry.

Full text of DOI:10.1021/ol100174r

ORGANIC
LETTERS
2
010
Vol. 12, No. 9
142-2145
Decoding Stereocontrol During the
Photooxygenation of
2
Oxazolidinone-Functionalized
Enecarbamates
†
Marissa R. Solomon, J. Sivaguru,* Steffen Jockusch, Waldemar Adam,*
and Nicholas J. Turro*
,‡
†
,§,⊥
,†
Department of Chemistry and Department of Chemical Engineering, Columbia
UniVersity, 3000 Broadway, New York, New York 10027, Department of Chemistry and
Molecular Biology, North Dakota State UniVersity, Fargo, North Dakota 58105,
Institut f u¨ r Organische Chemie, UniVersit a¨ t W u¨ rzburg, 97074 W u¨ rzburg, Germany, and
Department of Chemistry, UniVersity of Puerto Rico, Rio Piedras, PR 00931
njt3@columbia.edu; siVaguru.jayraman@ndsu.edu; wadam@adam.uprr.pr
Received March 19, 2010
ABSTRACT
Systematically designed oxazolidinone-derived enecarbamates reveal that solvent and temperature effects on the stereoselectivity during
photooxygenation are likely due to the conformational flexibility of the chiral phenethyl side chain (entropy factors); the extent of enantiomeric
excess in the photoproduct is dictated by the alkene geometry.
1,2
Considering that chirality is integrated into our very survival,
it is not remarkable that there is much focus on asymmetric
induction and absolute asymmetric synthesis. Traditionally,
enzymatic and thermal reactions have been employed to
(
1) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi,
†
Columbia University.
North Dakota State University.
Universit a¨ t W u¨ rzburg.
University of Puerto Rico.
T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932
.
‡
(2) (a) Inoue, Y.; Ramamurthy, V. Chiral Photochemistry; Marcel
Dekker: New York, 2004. (b) Inoue, Y. Chem. ReV. 1992, 92, 741. (c)
§
⊥
Rau, H. Chem. ReV. 1983, 83, 535.
10.1021/ol100174r  2010 American Chemical Society
Published on Web 04/12/2010

achieve high enantioselectivities in asymmetric transforma-
of interest to explore their individual control on the stereo-
chemical outcome during photooxygenation. To decipher
the factors responsible for stereoselection, we synthesized
the three enecarbamates 1a-c (Scheme 2). We chose the
2
,3
tions. Asymmetric photochemistry provides an attractive
alternative to these traditional routes to produce enantiose-
lectivity. The absorption of light is utilized to generate a
short-lived electronically excited state. The stereodifferen-
tiating factors must be able to influence stereoselectivity in
the photoproduct within the short lifetime of these excited
2
,3
Scheme 2. Photooxygenation of the Structurally Rich
Oxazolidinone-Functionlized Enecarbamates 1a-c
states.
Previously, we demonstrated
4-6
1
7
2
that singlet oxygen ( O ),
an electronically excited molecule, reacts with the oxazoli-
dinone-functionalized enecarbamates 1 to form chiral me-
thyldesoxybenzoin (MDB) as a photoproduct (Scheme 1).
Scheme 1
.
Photooxygenation of Oxazolidinone-Functionalized
Enecarbamate
R-configured C-4-methyloxazolidinone chiral auxiliary for
all three enecarbamates 1a-c. As established in our previous
4
-6
investigations,
the stereoselectivity does not depend on
The quite remarkable feature about this system is its
the size of this oxazolidinone C-4 substituent. The E-1a and
Z-1b enecarbamate diastereomers were prepared with phenyl
and (R/S)-phenethyl substituents at the C-3′ position of the
alkene funtionlity. We selected enecarbamate 1c with two
identical gem-alkene substituents viz., (R/S) phenylethyl
substituent at both the C-3′ and C-3′′ positions, to eliminate
the influence of the alkene geometry on the stereoselectivity
stereodifferentiating mechanism (diastereomeric cycloaddi-
1
tion of O
2
to 1 leading to the formation of the dioxetane 2;
Scheme 1) that results in notable enantiomeric excess (%
ee) in the MDB photoproduct with ee values as high as 97%.
Furthermore, the stereoselectivity does not depend on the
oxazolidinone substituent at the stereogenic C-4 position (Me,
i
t
4-6
Pr, or Bu give the same stereoselectivity).
In contrast,
in the photooxygenation process (Scheme 2).
the alkene geometry dictates the enantiomeric excess in
1
Photooxygenation of 1 with O
2
led to dioxetane 2, without
4
-6
MDB, with the E isomer giving a much larger enantiose-
any noticeable epimerization at the stereogenic centers.
The dioxetane 2 subsequently decomposed to chiral ketone
and the oxazolidinone aldehyde 4 (Scheme 1). In the case
5,6
lectivity than the corresponding Z diastereomer. Addition-
ally, the E enecarbamates are susceptible to solvent and
temperature effects, whereas the Z diastereomers show no
3
of E-isomer 1a and Z-isomer 1b, photooxygenation resulted
in the MDB photoproduct 3a (note that 3a and 3b are the
same). Similarly, photooxygenation of 1c (Scheme 2) led to
a mixture of meso-2,4-diphenyl-3-pentanone meso-DPP-3c),
along with the corresponding dl pair (dl-DPP 3c). The DPP
photoproduct from enecarbamate 1c allows determination of
both the diastereoselectivity (between the meso and dl pairs)
and enantioselectivity (between the dl pairs) as a function
of solvent and temperature (Scheme 2).
5
,6
solvent and temperature effects.
Given the marked influence of the alkene geometry and
the C-3′ phenethyl side chain in the enecarbamates, it was
(
3) Griesbeck, A. G.; Kramer, W.; Lex, J. Angew. Chem., Int. Ed. 2001,
0, 577
4) (a) Adam, W.; Bosio, S. G.; Turro, N. J. J. Am. Chem. Soc. 2002,
4
.
(
1
2
24, 14004. (b) Adam, W.; Bosio, S. G.; Turro, N. J. J. Am. Chem. Soc.
002, 124, 8814. (c) Adam, W.; Bosio, S. G.; Turro, N. J.; Wolff, B. T. J.
Org. Chem. 2004, 69, 1704. (d) Sivaguru, J.; Poon, T.; Franz, R.; Jockusch,
S.; Adam, W.; Turro, N. J. J. Am. Chem. Soc. 2004, 126, 10816. (e)
Sivaguru, J.; Saito, H.; Solomon, M. R.; Kaanumalle, L. S.; Poon, T.;
Jockusch, S.; Adam, W.; Ramamurthy, V.; Inoue, Y.; Turro, N. J.
Photochem. Photobiol. 2006, 82, 123. (f) Solomon, M.; Sivaguru, J.;
Jockusch, S.; Adam, W.; Turro, N. J. Photochem. Photobiol. Sci. 2009, 8,
ln[1 - c(1 + ee)]
ln[1 - c(1 - ee)]
s ) (k /k ) )
(1)
R
S
9
12. (g) Solomon, M.; Sivaguru, J.; Jockusch, S.; Adam, W.; Turro, N. J.
Photochem. Photobiol. Sci. 2008, 7, 531
5) Poon, T.; Sivaguru, J.; Franz, R.; Jockusch, S.; Martinez, C.;
Washington, I.; Adam, W.; Inoue, Y.; Turro, N. J. J. Am. Chem. Soc. 2004,
26, 10498
6) (a) Sivaguru, J.; Poon, T.; Hooper, C.; Saito, H.; Solomon, M.;
Jockusch, S.; Adam, W.; Inoue, Y.; Turro, N. J. Tetrahedron 2006, 62,
0647. (b) Sivaguru, J.; Saito, H.; Poon, T.; Omonuwa, T.; Franz, R.;
Jockusch, S.; Hooper, C.; Inoue, Y.; Adam, W.; Turro, N. J. Org. Lett.
005, 7, 2089. (c) Sivaguru, J.; Solomon, M. R.; Saito, H.; Poon, T.;
Jockusch, S.; Adam, W.; Inoue, Y.; Turro, N. J. Tetrahedron 2006, 62,
707. (d) Sivaguru, J.; Solomon, M. R.; Poon, T.; Jockusch, S.; Bosio, S. G.;
Adam, W.; Turro, N. J. Acc. Chem. Res. 2008, 41, 387
7) (a) Foote, C. S. Acc. Chem. Res. 1968, 1, 104. (b) Wasserman, H. H.;
.
ln(k /k ) ) ln[(100 + % ee)/(100 - % ee)]
(2)
(3)
R
S
(
1
.
q
q
q
ln(k /k ) ) ∆∆G ) ∆∆S
/R - ∆∆H
/RT
(
R
S
R-S
R-S
1
Photooxygenation of the enecarbamates 1a-c was per-
formed in three different solvents Viz., CDCl , CD OD and
CD CN at 15-18 °C. The results, tabulated in Table 1, reveal
that the E-isomer 1a favors R-MDB-3a as the photoproduct
in CDCl and CD OD (Table 1; entries 1 and 2), whereas in
2
3
3
6
3
.
(
3
3
Murray, R. W. Singlet Oxygen; Academic: New York, 1979. (c) Frimer,
A. A. Singlet Oxygen; CRC: Boca Raton, 1985; Vols. 1-4.
CD
3
CN (Table 1; entry 3) the optical antipode S-MDB-3a
Org. Lett., Vol. 12, No. 9, 2010
2143

Table 1. Solvent Effects during the Photooxygenation of
Enecarbamates 1a-c
Table 2. Temperature Effects during Photooxygenation of
a d
a
-
c
-
Enecarbamates 1c in Various Solvents
temp
entry compd solvent (°C) % ee (MDB, 3a) s (MDB, 3a)
temp
%
s
entry solvent (°C) convn
% de
% ee
(dl-DPP-3c)
1
2
3
4
5
6
1a
CDCl
3
18
18
18
15
15
15
67 (R)
75 (R)
28 (S)
8 (R)
15 (R)
5 (R)
5.9
8.1
0.5
1.4
2.0
2.2
1
2
3
4
5
6
7
8
CDCl
3
15
-15
-40
50
7
4
8
4
10
6
5
3
3
24 (meso) 77 (SS)
12 (meso) 89 (SS)
10 (meso) 90 (SS)
19 (meso) 68 (SS)
26 (meso) 71 (SS)
24 (meso) 76 (SS)
19 (meso) 79 (SS)
18 (meso) 87 (SS)
39 (meso) 35 (RR)
45 (meso) 22 (RR)
46 (meso) 2 (RR)
42 (meso) 1 (SS)
6.3
14
16
CD
CD
3
OD
CN
3
1b
CDCl
3
CD
3
OD
CN
6.2
4.8
4.2
6.9
11
2.7
1.8
1.8
1.4
CD
CD
3
OD
CN
15
3
-15
-40
-78
50
15
-15
-40
temp
(°C)
% ee
s
entry compd solvent
(dl-DPP, 3c) (dl-DPP-3c)
9
CD
3
7
8
9
a
1c
CDCl
3
15
15
15
77 (SS)
71 (SS)
22 (RR)
6.3
4.8
1.8
10
11
12
a
19
36
31
CD
CD
3
OD
CN
3
Concentration of 1a-c ) 3.0 mM; sensitizer (methylene blue) ) 0.37
Concentration of 1c ) 3.0 mM; sensitizer (methylene blue) ) 0.37
b
mM. The enantiomeric excess (% ee) of the MDB-3a and the dl-DPP-3c
photoproducts was determined by GC analysis on a chiral stationary phase
Varian GC3900; Varian CP-Chirasil-Dex CB column). Conversion of
enecarbamates (kept below 50%) was determined by GC analysis on an
achiral stationary phase (Varian GC3900; Varian Factor-4 VG-1 ms column)
or by H NMR spectroscopy with 4,4′-di-tert-butylbiphenyl as calibration
standard. All reported values are an average of a minimum of three runs
mM. The ratio of epimeric enecarbamate 1c with fixed C-4(R) configuration
as determined by H NMR spectroscopy was RS-5 (1)/SR-5 (1.6)/SS-5 (0.7)/
RR-5 (0.6). Conversion (% convn; kept below 50%) was determined by
GC analysis on an achiral stationary phase phase (Varian GC3900; Varian
Factor-4 VG-1 ms column) or by H NMR spectroscopy with 4,4′-di-tert-
butylbiphenyl as calibration standard. The diastereomeric excess (% de)
values were determined by GC analysis (meso-DPP-3c/dl-DPP-3c). The
1
c
b
(
1
1
c
d
within 3% error of the stated values. The stereoselectivity factor (s), which
represents the ratio of the rates of formation (k /k ) of the enantiomeric
R S
products, may be computed from the observed ee values at a given
conversion by means of eqs 1 and 2 (where c ) conversion and ee )
enantioselectivity in the photoproduct). The s factor is a quantitative measure
of the relative reaction rates for the two stereoisomers in question corrected
for the extent of conversion.
enantiomeric excess (% ee) of the dl-DPP product 3c was determined by
GC analysis on a chiral stationary phase (Varian GC3900; Varian CP-
Chirasil-Dex CB column). All reported values are an average of three runs,
reproduced within 3% error of the stated values. Temperature and solvent
effects in the case of 1a and 1b have been published (refs 5 and 6).
5
,6
insensitive to solvent and temperature variations. Quite
striking are the similar stereoselectivity trends observed upon
varying the solvent and temperature during photooxygenation
of E-1a and 1c.
is preferred as the photoproduct. In contrast, the Z-isomer
1
b affords R-MDB-3a irrespective of the employed solvent
Table 1; entries 4-6). In the case of 1c, the SS-DPP-3c
photoproduct dominated in CDCl and CD OD (Table 1;
entries 7 and 8), while the optical antipode RR-DPP-3c
photoproduct was favored in CD CN. For the gem-disubsti-
(
As we have employed an epimeric mixture of enecarbam-
ates (50:50 mixture of R/S-configured phenethyl substituent),
the relative reactivity of epimers would dictate the enanti-
oselectivity in the photoproduct. This relative reactivity is
empirically defined as the stereoselectivity factor “s”, given
3
3
3
tuted enecarbamate 1c and E-enecarbamate 1a, it is quite
striking to observe a similar switch in the enhanced optical
8
antipode of the photoproduct in CD
and CD OD.
To ascertain the role of temperature, the photooxygenation
of 1c was carried out at different temperatures in CDCl
CD OD and CD CN as listed in Table 2. Inspection of Table
reveals that the enantioselectivity between the dl-DPP-3c
3
CN compared to CDCl
3
by eq 1 That relation exposes the relative rate of formation
3
of the enantiomers from their corresponding diastereomeric
transition states of epimeric substrates. Additionally, the
stereoselectivity factor “s” adjusts for the extent conversion
in the photoproduct. A high “s” factor (s > 50) enables
complete kinetic resolution of the photoproduct (at around
3
,
3
3
2
depends on the reaction temperature. Two distinct trends are
displayed, which in turn depend on the employed solvent.
5
0% conversion). We previously demonstrated the practical
advantage of high s factors, by kinetically resolving the
In CDCl
the temperature, to favor the SS-DPP-3c enantiomer. In
contrast, for CD CN, the ee values decrease upon lowering
3 3
and CD OD, the ee values increase upon lowering
MBD-3a enantiomer during the photooxidation of E-1a with
1
5
O
2
(s)72). This implies that in the case of 1c, for which
3
the maximum s factor is 16 in CDCl at -40 °C, the
maximum ee value of the dl-DPP-3c photoproduct would
3
the temperature, with the RR-DPP-3c enantiomer preferred
at the higher temperatures of 50 and 15 °C. The enantiose-
lectivity was near zero at the low temperatures of -15 and
8
be ∼80% at 50% conversions. Thus, complete kinetic
resolution of the epimeric enecarbamate 1c is not feasible.
-
40 °C. With respect to diastereoselectivity (de values), the
To understand the solvent and temperature effects in the
meso-DPP-3c diastereomer was favored over the dl pair,
photooxygenation of 1a-c, the differential activation pa-
rameters (∆∆S R-S and ∆∆H R-S) were computed from the
irrespective of the solvent and the temperature. Our previous
‡
‡
5
,6
investigation
with the E-isomer 1a and Z-isomer 1b
revealed that the enantioselectivity in the MDB-3a photo-
product depends on the temperature and the solvent in the
case of the E isomer (similar to 1c), while the Z isomer was
(
8) (a) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249. (b)
Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. AdV. Synth. Catal. 2001, 343,
5.
2144
Org. Lett., Vol. 12, No. 9, 2010

9
‡
‡
Eyring plots (Table 3, Figure 1). As may be seen from the
is enhanced (the ∆∆S and ∆∆H contributions compensate
each other upon temperature variations due to the opposite
sign), but in modest preference. As a consequence of the
low entropy and enthalpy contributions (as in the case of
‡
eqs 2 and 3, the change in the % ee values (or ∆∆G R-S
)
CD
3
OD for 1c, where the ee values increase from 71% at
q
q
Table 3. Activation Parameters ∆∆H and ∆∆S for the
1
5 °C to 79% at -40 °C), on decreasing the temperature,
a
Photooxygenation of 1a-c Enecarbamates
‡
the contribution from ∆∆H increases slightly. The response
to temperature on the enantioselectivity is nominal such that
the sense of the enantioselectivity does not change. Thus,
q
∆∆S R-S (cal·mol-1·K-1
q
∆
∆H R-S (kcal·mol-1
)
)
entry solvent
1a
1b
1c
1a
1b
1c
‡
‡
the ∆∆H R-S and ∆∆S R-S terms expose the conformational
factors. In the present case, presumably, such conformational
1
2
3
CDCl
3
-4.9 -0.2 -2.2
OD -1.5 -0.2 -0.7
CN -4.4 -0.1 -1.4
-14
-1.0
-17
0.2
0.4
0.1
-3.7
0.8
-6.4
9
CD
CD
3
factors are dictated by the stereogenic center at the C-3′
position of the phenethyl side chain. For substrate 1c (gem-
di-substituted alkene), the alkene geometry (E or Z) cannot
exert an influence on the stereoselctivity, such that temper-
ature and solvent effects dominate.
3
a
Activation parameters were computed by using eqs 2 and 3 from the
data of the Eyring plots.
Our investigation of the enecarbamate 1c, which negates
the influence of the alkene geometry due to gem-di-
substitution, exposes the stereoselectivity of the chiral
phenethyl substituent in the photooxidation of E-1a and Z-1b
enecarbamates (Figure 2). This provides support for our
Figure 2. Entropic control and the role of phenethyl substituent
during the photooxygenation of 1a-c.
Figure 1
a-c (red, 1a; green, 1b; blue, 1c) at various temperatures in CDCl
O), CD OD (2), and CD CN (9).
. Eyring plot for the photooxygenation of enecarbamates
6
initial suspicion that the greater conformational flexibility
1
(
3
3
3
of the C-3′ phenethyl substitution is intimately linked to the
greater entropic control. This mechanistic insight is pivotal
in understanding entropic factors for the design of molecular
systems to exploit stereocontrol during light-induced trans-
depends both on the entropic and enthalpic terms. Since the
‡
10
∆
∆H R-S/RT term is proportional to the reciprocal temper-
formations.
ature (eq 3), the ln(k /k ) value is determined mostly by the
R
S
enthalpic contribution at low temperatures; however, as
the temperature increases, the relative contribution from the
Acknowledgment. The authors at Columbia thank the
NSF (CHE-07-17518) for generous support of this research.
J.S. (NDSU) thanks the National Science Foundation for
generous support through the CAREER award (CHE-
0748525). W.A. gratefully acknowledges previous financial
support from the Deutsche Forschungsgemeinschaft,
Alexander von Humboldt-Stiftung, and the Fonds der Che-
mischen Industrie.
‡
‡
∆
S
∆S R-S/R term increases and begins to override the ∆∆H R-
/RT term at some temperature. Eventually, the sign of the
ln(k /k ) value inverts and the sense of the enantioselectivity
R
S
‡
‡
switches, provided that the ∆∆H R-S and ∆∆S R-S terms
possess the same sign (Table 3). This is the case here for
the photooxygenation of the E-1a and 1c (e.g., the switch in
3
the chiral sense occurs at -40 °C in CD CN for 1c). In
Supporting Information Available: Synthesis and ir-
radiation procedures and Eyring plots This material is
available free of charge via the Internet at http://pubs.acs.org.
contrast, the corresponding Z-1b isomer is insensitive to
temperature, as convincingly exposed by the near-zero
‡
‡
∆
∆H R-S and ∆∆S R-S terms with opposite signs (Table 3;
Figure 1 green lines). Consequently, irrespective of what
OL100174R
temperature is chosen, the same enantiomeric MDB product
(
10) (a) Ayitou, A. J.-L.; Jesuraj, J. L.; Barooah, N.; Ugrinov, A.;
(
9) (a) Leffler, J. E. J. Org. Chem. 1955, 20, 1202. (b) Leffler, J. E. J.
Sivaguru, J. J. Am. Chem. Soc. 2009, 131, 11314. (b) Ayitou, A. J.-L.;
Sivaguru, J. J. Am. Chem. Soc. 2009, 131, 5036.
Org. Chem. 1966, 31, 533.
Org. Lett., Vol. 12, No. 9, 2010
2145