Isolation and syn elimination of a peterson adduct to obtain optically pure product in the diastereoselective synthesis of oxazolidinone-functionalized enecarbamates

Article abstract of DOI:10.2174/157017809788681400

The Peterson reaction of (4R)-N-(trimethylsilyl)methyl-4-alkyloxazolidin-2- one gives (E/Z)-(4R)-N-(2', 3'- diphenylbut-1'-enyl)-4-alkyloxazolidin-2-ones (enecarbamates) with increasing (Z)-selectivity and moderate-to-high diastereoselectivity in the indi

Full text of DOI:10.2174/157017809788681400

362
Letters in Organic Chemistry, 2009, 6, 362-366
Isolation and syn Elimination of a Peterson Adduct to Obtain Optically
Pure Product in the Diastereoselective Synthesis of Oxazolidinone-
Functionalized Enecarbamates
Marissa R. Solomona, Hideaki Saitoa,b, J. Sivaguruc, Steffen Jockuscha, Yoshihisa Inoueb,d,
Waldemar Adame and Nicholas J. Turro*,a
aDepartment of Chemistry, Columbia University, New York, NY 10027, USA
bThe Department of Molecular Chemistry, Osaka University, 2-1 Yamada-oka, Suita 565-0871, Japan
cThe Department of Chemistry and Molecular Biology, North Dakota State University, Fargo, ND 58105
dEntropy Control Project, ICORP, JST, 4-6-3 Kamishinden, Toyonaka 560-0085, Japan
eDepartment of Chemistry, Facundo Bueso 110, University of Puerto Rico, Rio Piedras, PR 00931, USA, and the
Institute für Organische Chemie, Universität Würzburg, D-97074 Würzburg, Germany
Received January 17, 2009: Revised April 30, 2009: Accepted April 30, 2009
Abstract: The Peterson reaction of (4R)-N-(trimethylsilyl)methyl-4-alkyloxazolidin-2-one gives (E/Z)-(4R)-N-(2’,3’-
diphenylbut-1’-enyl)-4-alkyloxazolidin-2-ones (enecarbamates) with increasing (Z)-selectivity and moderate-to-high
diastereoselectivity in the individual E isomer as a function of increasing temperature. X-ray structure of the Peterson
adduct, (4R,3’S)-N-(2’,3’-diphenyl-2’-hydroxy-but-1’-enyl)-4-alkyloxazolidin-2-one (enecarbamates), reveals the
rationale for the formation of a single isomer through syn elimination. The optically pure enecarbamates obtained with the
Peterson adduct were further employed for photochemical and photophysical studies.
Keywords: Peterson reaction, diastereoselectivity, asymmetric synthesis, singlet oxygen.
Stereocontrol during the formation of carbon-carbon
bonds is an intriguing but challenging subject of research in
organic synthesis. During the last few decades, exploitation
of the Horner-Wadsworth-Emmons (HWE) and Wittig-type
reactions has afforded immense progress in this area [1, 2].
However, a widely known and potentially useful alternative
approach to asymmetric induction in C-C bond formation is
the Peterson reaction [3-7]. With precursors bearing a
trimethylsilyl (TMS) substituent, the generation and
subsequent olefination of the silyl carbanion with a carbonyl
partner was recently reported to give high enantioselec-
tivities for the ꢀ-trimethylsilanyl acetate [8], as well as high
Z-selectivities for a variety of ꢀ,ꢁ-unsaturated products [9-
11]
Enecarbamates, equipped with an oxazolidinone chiral
auxiliary, are mechanistically versatile systems to study
conformational, stereoelectronic, and steric effects on the
stereoselectivity of oxidation reactions [12-14], as well as
the diastereoselective photoisomerization at the alkene
functionality [15]. Herein we report (a) the role of
temperature on the diastereoselectivity in the Peterson
olefination of the oxazolidinone 2 with MDB (3) and (b) the
isolation and characterization of the intermediary (4R,3'S)-N-
(2',3'-diphenyl-2'-hydroxy-but-1'-enyl)-4-alkyloxazolidin-2-
one (5) (Schemes 1, 2 and Fig. 1). The precursors 2 for the
Peterson olefination were prepared from the corresponding
(4R)-alkyloxazolidinones (1) in good yields (Scheme 1) [16].
To assess any steric effect during the elimination process, the
(4R)-methyl- and (4R)-isopropyl-substituted oxazolidinone
derivatives were synthesized.
Despite its potential as a versatile synthetic tool in
manipulating stereocontrol during C-C double bond
formation, considerable effort has not been devoted to
studying asymmetric induction in the Peterson olefination to
date. In this context, we have investigated the diastereoselec-
tive Peterson olefination of (4R)-N-(trimethylsilyl)methyl-4-
alkyloxazolidin-2-one (2) with methyldesoxybenzoin
(MDB), (3), affording (E/Z)-(4R)-N-(2',3'-diphenylbut-1'-
enyl)-4-alkyloxazolidin-2-ones (enecarbamates (4)) by way
of syn elimination and have subsequently employed these
enecarbamates for photooxygenation reactions.
All Peterson reactions were carried out in an anhydrous
THF solution in the temperature range from –78 ºC to 20 ºC
(Scheme 2 and Table 1). A THF solution of the silyl
derivative (2) was stirred under a N2 atmosphere at -78 ºC
and n-BuLi was added. After the reaction mixture was stirred
for 1 h at -78 ºC, 0 ºC, or 20 ºC, a THF solution of (3) was
added drop wise and the stirring was continued for another 1
h. The work-up with an aqueous NH4Cl solution and
subsequent purification by column chromatography gave the
pair of (Z-4) or (E-4) diastereomers, each one as a pair of R/S
epimers at the C-3’ position, as displayed in Scheme 2.
*Address correspondence to this author at the Department of Chemistry,
Columbia University, New York, NY 10027, USA; Tel: 212-854-2175; Fax:
212-932-1289; E-mail: njt3@columbia.edu
The quantitative results of the chemical yields and
diastereoselectivities as a function of temperature are
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

Peterson Reaction to Obtain Oxazolidinone-Functionalized Enecarbamates
Letters in Organic Chemistry, 2009, Vol. 6, No. 5
363
O
O
(Iodomethyl)-
trimethylsilane
NaH/DMF
O
NH
O
N
SiMe3
90 min at r.t.
overnight
(R)
(R)
X
X
1
2
a: X = Me
b: X = iso-propyl
~80 %yield
Scheme 1. Synthesis of the (4R)-N-(trimethylsilyl)methyl-4-alkyl-oxazolidin-2-one (2) precursors for the Peterson olefination.
O
O
H
H
R
Ph
O
N
O
N
Ph
+
R
Ph
Ph
(R)
(R)
X
X
O
4(R),3'(R)-E-4
4(R),3'(R)-Z-4
1) n-BuLi, THF, -78 oC
O
N
SiMe3
2)
O
O
H
H
(R)
Ph
X
S
-78 to 20oC
Ph
Ph
Ph
O
N
O
N
Ph
+
+
2
O
Ph
3
(R)
(R)
X
a: X = Me
b: X = iso-propyl
X
S
4(R),3'(S)-E-4
4(R),3'(S)-Z-4
Scheme 2. Synthesis of enecarbamates (4) by Peterson olefination of (4R)-N-(trimethylsilyl)methyl-4-alkyloxazolidin-2-ones (2).
Table 1. Chemical Yields and Diastereoselectivity as a Function of Temperature in the Synthesis of Enecarbamates (4) via the
Peterson Olefination of (2)
X
Temp oC
%yielda of E [%de]b
%yielda of Z [%de]b
E:Zb
Me (4a)
20
0
6 [45(S)]
7 [71(S)]
2d
20 [10(R)]
44 [13(R)]
26 [64(S)]
15 [6(S)]
20 [5(S)]
24 [8(S)]
30 [10(R)]
20:80
13:87
2:98
-78
20
20c
0
iPr (4b)
7 [30(S)]
14 [38(S)]
12 [62(S)]
4 [98 (S)]
44:56
41:59
36:64
16:84
-78
aYields obtained by GC analysis (± 7%) with 4,4’-di-tert-butylbiphenyl (DTBP) as internal standard. bDiastereoselectivities (de) of the products (± 6%) and E:Z ratios (± 5%) obtained
by 1H NMR spectroscopy; the configuration of the epimer at the C-3’ position is shown in the parentheses. cChemical yields and diastereoselectivities of isolated products.
dDiastereoselectivity not determined.
displayed in Table 1. The low total yields (only 20-50%) of
the E/Z diastereomers are presumably due to the labile nature
of the intermediary carbanion and its slow addition to the
sterically encumbered carbonyl group of MDB (3) [17, 18].
The ratio of E : Z diastereomers (the last column in Table 1)
varied appreciably over the employed temperature range, i.e.,
it increased in favor of the Z isomer with decreasing
temperature. For example, with the methyl derivative (4a),
the E : Z ratio went from 20 : 80 at 20 ºC to 2 : 98 at -78 ºC.
A similar temperature-dependent trend for the stereoselec-
tivity of the C-3'-R/S epimers was observed. In particular,
with the (E-4b), the diastereomeric excess (de) increases
substantially in favor of the S epimer with decreasing
temperature and, in fact, at -78 ºC the de value is as high as
98%. Contrastingly, the epimeric differentiation is low for
the (Z-4b) isomer with the de values varying only 5-10% and
the selectivity inverting from S to R as the temperature
decreased [19].
When one equivalent of the n-BuLi base was used, one of
the Peterson adducts (5) was isolated as a colorless
crystalline solid and subjected to X-ray crystallographic
analysis (Fig. 1). The configuration at the C-3' position of the
phenethyl side chain in the adduct was inferred from the
known configuration at the C-4 position of the chiral
oxazolidin-2-one. As additional confirmation of the assign-
ment, the enecarbamate obtained from the syn elimination of
the Peterson adduct (Fig. 2) afforded a single MDB product
on photooxygenation [12-14] (Scheme 3).

364 Letters in Organic Chemistry, 2009, Vol. 6, No. 5
Solomon et al.
Me3Si
OH
O
N
H
Me
3'S
Ph
H
Ph
Fig. (1). The X-ray crystallographic structure (deposition number CCDC 652101) of the Peterson adduct (4R,3’S)-N-(2’,3’-diphenyl-2’-
hydroxy-but-1’-enyl)-4-isopropyloxazolidin-2-one, the isopropyl derivative of (5).
SiMe3
O
O
O
a
H
syn-elimination
(basic condition)
O
N
O
N
H
4R
4R
Ph
Ph
Me
Me
3'R
Ph
3'R
Ph
H
H
large steric hindrance
E-(4R3'R)-isomer
High Preference for E-(4R3'S)-isomer
SiMe3
O
O
O
H
H
O
N
O
N
syn-elimination
(basic condition)
4R
4R
Ph
Ph
Ph
H
H
3'S
3'S
Me
Ph
Me
small steric hindrance
E-(4R3'S)-isomer
SiMe3
O
O
small steric hindrance
b
O
H
syn-elimination
Me
O
N
O
N
H
4R
4R
Me
(basic condition)
3'S
Ph
Ph
3'S
Ph
Ph
H
H
Z-(4R3'S)-isomer
Moderate Selectivity
SiMe3
O
O
small steric hindrance
O
H
H
syn-elimination
(basic condition)
O
N
O
N
H
4R
4R
H
3'R
Me
Ph
Ph
3'R
Me
Z-(4R3'R)-isomer
Ph
Ph
Fig. (2). The proposed mechanism of stereo-control for the formation of the (E-4b) (a) and (Z-4b) (b) diastereomers in the Peterson
olefination of oxazolidinone (2b).
The X-ray structural analysis (Fig. 1) of (5) clearly
shows that the oxazolidinone ring points perpendicularly to
the newly formed C-C bond, to minimize steric interactions
with the phenethyl substituent at the C-3' position.
Presumably, this steric interaction is responsible for the high
diastereoselectivity of 98% at -78 ºC for the (E-4b)
diastereomer. The syn elimination of adduct (5) under a basic
condition gave exclusively and quantitatively the C-3'S
epimer of the (E-4b) isomer (see Supplementary data). This
result unambiguously demonstrates that the elimination

Peterson Reaction to Obtain Oxazolidinone-Functionalized Enecarbamates
Letters in Organic Chemistry, 2009, Vol. 6, No. 5
365
O
O
H
O
O
Ph
Ph
1O2
Ph
O
N
O
N
Ph
Ph
Ph
R
R
O
(R)
(R)
R
X
X
3
4
1
Scheme 3. Photooxygenation of enecarbamate (4) with O2 to yield the dioxetane which then decomposes to MDB (3) isomer and the
oxazolidinone aldehyde.
process is not reversible; only one C-3' epimer is formed
from the Peterson adduct.
In conclusion, the Peterson olefination of the oxazolidin-
ones (2a) and (2b) with racemic MDB (3) affords the chiral
enecarbamates (4a) and (4b) in high stereoselectivity,
especially at low temperature. The stereo-control of the E/Z
diastereomers and of the R/S epimers in the enecarbamates
(4a) and (4b) is dictated by the steric interactions between
the oxazolidinone ring and the phenethyl side chain in the
transition states for the C-C bond formation. The X-ray
crystal structure of the intermediary Peterson adduct (5)
substantiates these mechanistic speculations. This Peterson
olefination is not reversible, which strongly indicates that the
stereoselectivity is determined at the stage of the C-C bond
formation. In this unique approach to kinetic resolution
utilizing the combination of chiral auxiliary and the Peterson
olefination, the chiral enecarbamates were subjected to
photooxidation with singlet oxygen to yield the MDB
product in high enantioselectivities. Taken altogether, these
results demonstrate the usefulness of the Peterson olefination
reaction in controlling the cis-trans geometry about double
bonds and, more significantly, as a potentially valuable tool
to include in our still sparse repertoire of asymmetric
induction methods. Succinctly, the steric and directing
effects of the oxazolidinone chiral auxiliary in concert with
the Peterson olefination reaction can serve to effect
stereocontrol when forming chiral C-C bonds. We were able
to employ the optical pure isomers, obtained though the
isolation of the Peterson adduct, to study both the chemical
and physical quenching of singlet oxygen and the factors that
lead to stereoselectivity and kinetic resolution.19 Thus
synthesizing optically pure enecarbamates via Peterson’s
olefination enabled us to better understand the reactivity of
excited state molecular oxygen (singlet oxygen).
These remarkable stereochemical findings for the present
Peterson olefination require a mechanistic rationalization in
terms of appropriate transition structures. A mechanism
consistent with the stereoselectivity observed in the case of
substrate (2b) is proposed in Fig. (2), which is based on the
established syn elimination under basic conditions [5]. Fig.
(2a) reveals that in the adduct leading to the (E-4b) isomer,
there is a severe steric hindrance between the isopropyl
group of the oxazolidinone and the phenethyl substituent at
the C-3' position for the 3'(R) than for the 3'(S) epimer. Thus,
the transition state for the formation of the 3'(S) epimer of
the (E-4b) diastereomer is energetically favored, which
accounts for the high diastereoselectivity obtained especially
at low temperatures (Table 1). In the case of (Z-4b),
however, the difference in the steric hindrances between the
3'R and 3'S epimers is much less pronounced, since the
phenethyl substituent points away from the isopropyl group
in the adduct. Consequently, only a moderate diastereoselec-
tivity is observed for the (Z-4b) isomer even at low
temperature. The reversal in the chiral sense of the preferred
epimer (3'R versus 3'S) for the (Z-4a) isomer is difficult to
rationalize reliably for such low stereo-control, but subtle
structural and environmental factors likely play an important
role [20, 21].
The optically pure enecarbamates thus synthesized were
invaluable for the elucidation of the reaction mechanism of
photooxygenation and for ascertaining the role of vibrational
deactivation [22] in such processes. For the experiment it
was necessary to obtain compounds that were optically pure
and the isolation of the Peterson adduct allowed us to do so
in great quantities. The optically pure (E-4b) isomers
showed that the rate of physical quenching is substantially
different in the diastereomers that differ in the C-3' position
(Table 2) [22]. This difference in the quenching efficiency
was reflected in the enantiomeric excess (63% [R-MDB])
upon photooxygen-ation in the MDB product that was
rationalized in our previous investigations [12-14, 19].
ACKNOWLEDGEMENTS
The authors at Columbia thank the NSF (CHE-04-15516,
CHE-07-17518) for generous support of this research. W.A.
gratefully acknowledges previous financial support from the
Deutsche
Forschungsgemeinschaft,
Alexander
von
Humboldt-Stiftung, and the Fonds der Chemischen Industrie.
Table 2. Ratio of Physical Quenching (kpQ) and Chemical Quenching (kpQ) Obtained in CDCl3 Using trans-4-Octene as a Standard.
Optically Pure Enecarbamates were Obtained via syn Elimination of the Peterson Olefination Adduct
a
X
Stereochemistry
kpQ/kcQ
C-4
C-3'
iPr (E-4b)
R
S
S
S
0.13
0.21b
aBased on reactive and physical quenching rate constants (Reference [22]).
bThe C-4R,C3’R and C-4S,C3’S enecarbamates are optical antipodes.

366 Letters in Organic Chemistry, 2009, Vol. 6, No. 5
Solomon et al.
[9]
Kojima, S.; Fukuzaki, T.; Yamakawa, A.; Murai, Y. Org. Lett.,
2004, 6, 3917.
Kojima, S.; Inai, H.; Hidaka, T.; Ohkata, K. Chem. Commun.,
2000, 1795.
Fuerstner, A.; Brehm, C.; Cancho-Grande, Y. Org. Lett., 2001, 3,
3955.
Adam, W.; Bosio, S. G.; Turro, N. J.; Wolff, B. T. J. Org. Chem.,
2004, 69, 1704.
J.S. thanks NDSU for Faculty Start-up award and the
National Science Foundation for the CAREER award (CHE-
0748525). H.S. is grateful for a JSPS research fellowship
(No. 08384) given to young scientists, to conduct part of this
work in Professor Turro’s laboratory at the Columbia
University. The authors thank Professor Gerald Parkin,
Columbia University, for the X-ray structure determination
of the Peterson adduct.
[10]
[11]
[12]
[13]
Poon, T.; Sivaguru, J.; Franz, R.; Jockusch, S.; Martinez, C.;
Washington, I.; Adam, W.; Inoue, Y.; Turro, N. J. J. Am. Chem.
Soc., 2004, 126, 10498.
[14]
[15]
Sivaguru, J.; Poon, T.; Franz, R.; Jockusch, S.; Adam, W.; Turro,
N. J. J. Am. Chem. Soc., 2004, 126, 10816.
Saito, H.; Sivaguru, J.; Jockusch, S.; Inoue, Y.; Adam, W.; Turro,
N. J. Chem. Commun., 2005, 3424.
Vedejs, E.; Larsen, S.; West, F. G. J. Org. Chem., 1985, 50, 2170.
Barrett, A. G. M.; Hill, J. M.; Wallace, E. M.; Flygare, J. A.
Synlett, 1991, 764.
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publishers
Web site along with the published article.
[16]
[17]
[18]
[19]
Waschbusch, R.; Carran, J.; Savignac, P. Tetrahedron, 1996, 52,
14199.
Sivaguru, J.; Solomon, M. R.; Poon, T.; Jockusch, S.; Bosio, S. G.;
Adam, W.; Turro, N. J. Acc. Chem. Res., 2008, 41, 387.
Inoue, Y. Chem. Rev., 1992, 92, 741.
Inoue, Y.; Ramamurthy, V. Chiral Photochemistry. Marcel Dekker:
New York, 2004.
Solomon, M. R.; Sivaguru, J.; Jockusch, S.; Adam. W.; Turro, N. J.
Photochem. Photobiol. Sci., 2009, 8, doi: 10.1039/ b903848e.
REFERENCES
[1]
[2]
[3]
[4]
[5]
[6]
Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev., 1997, 97, 2341.
Rein, T.; Pedersen, T. M. Synthesis, 2002, 579.
Ager, D. J. Synthesis, 1984, 384.
[20]
[21]
Ager, D. J. Org. React., 1990, 38, 1.
Peterson, D. J. J. Org. Chem., 1968, 33, 780.
van Staden, L. F.; Gravestock, D.; Ager David, J. Chem. Soc. Rev.,
2002, 31, 195.
[22]
[7]
[8]
Murai, T.; Fujishima, A.; Iwamoto, C.; Kato, S. J. Org. Chem.,
2003, 68, 7979.
Iguchi, M.; Tomioka, K. Org. Lett., 2002, 4, 4329.