Chiral-auxiliary-controlled diastereoselectivity in the epoxidation of enecarbamates with DMD and mCPBA

Article abstract of DOI:10.1021/ol0273194

(Matrix presented) Chiral oxazolidinone-substituted enecarbamates 1 are epoxidized in a diastereoselectivity up to 93:7 for both DMD and mCPBA. The diastereofacial differentiation depends on the steric interaction between the R¹ substituent on the oxazolidinone ring and the incoming electrophile. The stereochemical course of epoxidation was assessed by chemical correlation with the known optically active diols.

Full text of DOI:10.1021/ol0273194

ORGANIC
LETTERS
2
003
Vol. 5, No. 6
19-822
Chiral-Auxiliary-Controlled
Diastereoselectivity in the Epoxidation
of Enecarbamates with DMD and
mCPBA
8
Waldemar Adam, Sara G. Bosio,* and Barbara T. Wolff
Institut f u¨ r Organische Chemie, UniVersit a¨ t W u¨ rzburg, Am Hubland,
D-97074 W u¨ rzburg, Germany
adam@chemie.uni-wuerzburg.de
Received November 21, 2002
ABSTRACT
Chiral oxazolidinone-substituted enecarbamates 1 are epoxidized in a diastereoselectivity up to 93:7 for both DMD and mCPBA. The diastereofacial
1
differentiation depends on the steric interaction between the R substituent on the oxazolidinone ring and the incoming electrophile. The
stereochemical course of epoxidation was assessed by chemical correlation with the known optically active diols.
Besides the well-established stereoselective oxidations based
of the new stereogenic centers may be specified at will and
the desired enantiomerically enriched oxidation product may
be readily released by removal of the chiral inductor under
mild conditions. In favorable cases, the chiral auxiliary may
be recovered in high yield, which makes this methodology
economically feasible and preparatively attractive. In this
context, auxiliary-controlled epoxidations should be of
general synthetic interest, because the epoxy functionality
may be transformed into a great number of target molecules.
High diastereoselectivity may be achieved in the asym-
metric epoxidation of chiral oxazolidine-substituted olefins,5
in which hydrogen bonding of the remote urea functionality
with the oxidizing reagent directs the stereochemical course
of the oxygen transfer (Figure 1, transition structure A). A
remarkable competition was observed for related chiral
1
1b-e
2
on the steric, electronic,
stereoelectronic, and confor-
3
mational effects exerted by the functional group present in
the substrate or reagent, an alternative approach utilizes chiral
auxiliaries to control the stereochemical course of the
oxygen-transfer process.
Such diastereoselective control has become an important
4
strategy in asymmetric synthesis, because the configuration
(1) (a) Bovicelli, P.; Lupatelli, P.; Mincione, E.; Prencipe, T.; Curci, R.
J. Org. Chem. 1992, 57, 2182-2184. (b) Adam, W.; Br u¨ nker, H. -G.;
Kumar, A. S.; Peters, E. -M.; Peters, K.; Schneider, U.; Schering, H. J.
Am. Chem. Soc. 1996, 118, 1899-1905. (c) Murray, R. W.; Singh, M.;
Williams, B. L.; Moncrieff, H. M. J. Org. Chem. 1996, 61, 1830-1841.
(
1
d) Adam, W.; Paredes, R.; Smerz, A. K.; Veloza, L. A. Liebigs Ann./Recl.
997, 547-551. (e) Yang, D.; Jiao, G.-S.; Yip, Y.-C.; Wong, M.-K. J. Org.
Chem. 1999, 64, 1635-1639. (f) Tian, H.; She, X.; Yu, H.; Shu, L.; Shi,
Y. J. Org. Chem. 2002, 67, 2435-2446. (g) Wu, X.-Y.; She, X.; Shi, Y. J.
Am. Chem. Soc. 2002, 124, 8792-8793.
6
oxazolidine auxiliaries, in which steric repulsions dominated
for dimethyldioxirane (DMD) and hydrogen bonding for
(2) (a) Armstrong, A.; Draffan, A. G. J. Chem. Soc., Perkin Trans. 1
2
001, 21, 2861-2873. (b) Bach, R. D.; Glukhovtsev, M. N.; Gonzales, C.
J. Am. Chem. Soc. 1998, 120, 9902-9910. (c) Armstrong, A.; Washington,
I.; Houk, K. N. J. Am. Chem. Soc. 2000, 122, 6297-6298.
(4) Jones, S. J. Chem. Soc., Perkin Trans. 1 2002, 95, 1-21.
(5) Adam, W.; Schambony, S. B. Org. Lett. 2001, 3, 79-82.
(3) Lucero, M. J.; Houk, K. N. J. Org. Chem. 1998, 63, 6973-6977.
1
0.1021/ol0273194 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/14/2003

Table 1. Diastereoselectivity in the Epoxidation of
Enecarbamate 1 by DMD and mCPBA
diastereoselectivity of epoxide 2b,c
1S:1R
entrya reagent substrate
1
2
3
3b
4
5
6
7
8
DMD
mCPBA (Z)-1a
DMD
DMDd
(Z)-1a
50:50
50:50
60:40
63:37
70:30
a
(Z)-1b
(Z)-1b
Figure 1. Transition structures for the addition of DMD and
mCPBA to oxazolidine-substituted olefins and perepoxide-like
transition structure for the addition of singlet oxygen to olefins.
mCPBA (Z)-1b
DMD (Z)-1c
mCPBA (Z)-1c
DMD (Z)-1d
mCPBA (Z)-1d
DMD (E)-1a
mCPBA (E)-1a
DMD (E)-1b
mCPBA (E)-1b
DMD (E)-1c
mCPBA (E)-1c
DMD (E)-1d
mCPBA (E)-1d
8 (10):92 (90)
8 (10):92 (90)
7 (6):93 (94)
7:93
m-chloroperbenzoic acid (mCPBA) to give diastereoselec-
tivities of opposite senses for these two oxygen-transferring
agents (Figure 1, structures B and B′).
9
50:50
50:50
53:47
50:50
1
1
1
13
14
0
1
2
Recently, we discovered the directing propensity of chiral
oxazolidinone-substituted ene-carbamates 1 in the [2 + 2]
40 (42):60 (58)
48:52e
25 (25):75 (75)
21:79
7
8
cycloaddition and ene reaction of singlet oxygen, which
gave very high (up to >95:5) diastereoselectivities. In this
case, the chiral auxiliary is directly connected to the reacting
1
1
5
6
9
a
double bond, and the π-facial attack of the oxidant may be
DMD epoxidation was run in acetone at ca. 20 °C, with mCPBA in
CHCl3 at ca. 20 °C, which gave the ester 3 by acid-catalyzed ring opening
of the intermediary epoxides 2; the diastereomeric ratio is given for the
epoxides 2; conversion > 95%, material balance > 95%. Only the
configuration at the C1 position of the epoxides 2 is specified, because it
expected to be guided by steric blocking caused through
conformational effects. In view of the perepoxide-like
b
10
transition structure (Figure 1, structure C), the factors that
control singlet oxygen reactions may also operate in the
DMD and mCPBA epoxidation.11 That this is, indeed, the
case for the oxazolidinone-substituted enecarbamates 1 is
demonstrated herein in their highly diastereoselective ep-
oxidation by DMD and mCPBA, provided that the appropri-
ate geometrical isomer, namely, the (Z)-enecarbamate, is
employed.
does not depend on the double-bond configuration of the starting material;
c
in the text, these descriptors are marked in bold. Diastereoselectivity
1
determined by H NMR spectroscopy (5% error of the stated value) directly
on the reaction mixture and by HPLC analysis (2% error, numbers in
parentheses) of the diol 5, prepared from epoxide 2 (DMD) and from the
ester 3 (mCPBA). d Run at -25 °C. e Also 50% epoxide (1S,2R)-2c and
2% ester (1R,2R)-3c.
and mCPBA acid in chloroform (Table 1). The epoxidation
The enecarbamates 1 were synthesized according to the
1
of the achiral (Z)-1a (R ) H) with DMD gave, as expected,
8
literature pocedure and epoxidized with DMD in acetone
a racemic mixture of the epoxides (1S,2S)-2a and (1R,2R)-
2
a (entry 1). In the epoxidation of the chiral (Z)-1b
(
6) Adam, W.; Pastor, A.; Peters, K.; Peters, E.-M. Org. Lett. 2000, 2,
019-1022.
7) Adam, W.; Bosio, S. G.; Turro, N. J. J. Am. Chem. Soc. 2002, 124,
814-8815.
8) Adam, W.; Bosio, S. G.; Turro, N. J. J. Am. Chem. Soc. 2002, 124,
4004-14005.
9) Baumstark, A. L.; McCloskey C. J. Tetrahedron Lett. 1987, 28,
311-3314.
1
i
(
R d Pr) at ca. 20 °C, the epoxide 2b was formed in a
1
8
1
3
12
(
1S:1R diastereomeric ratio (dr) of only 60:40 (entry 3a);
at -25 °C, no significant increase in the dr value was
observed (entry 3b). An increase in the size of the R1
substituent on the oxazolidinone ring caused a significant
increase in the diastereoselectivity of the epoxidation. For
(
(
(
10) (a) Inagaki, S.; Fukui, K.J. Am. Chem. Soc. 1975, 97, 7480-7484.
(
(
5
b) Dewar, M. J. S.; Thiel, W. J. Am. Chem. Soc. 1977, 99, 2338-2339.
c) Hotokka, M.; Roos, B.; Siegbahn, P. J. Am. Chem. Soc. 1983, 105,
(12) In Table 1, only the configuration at the C1 position is given for
the two diastereomers, namely, the stereochemical descriptors 1S and 1R,
because this position does not depend on the initial double-bond configura-
tions of the enecarbamates (Z)-1 and (E)-1; for clarity and convenience,
the 1S and 1R desriptors are marked in bold in the text when in combination
with the C2 position.
263-5269. (d) Yoshioka, Y.; Yamada, S.; Kawakami, T.; Nishino, M.;
Yamaguchi, K.; Saito, I. Bull. Chem. Soc. Jpn. 1996, 69, 2683-2699.
11) Adam, W.; Br u¨ nker, H.-G.; Kumar, A. S.; Peters, E.-M.; Peters,
K.; Schneider, U.; von Schnering, H. G. J. Am. Chem. Soc. 1996, 118,
899-1905.
(
1
820
Org. Lett., Vol. 5, No. 6, 2003

1
1
t
the enecarbamates (Z)-1c (R ) Ph) and (Z)-1d (R ) Bu),
high dr values (92:8) were obtained with DMD, the major
epoxide isomers being (1R,2R)-2c (entry 5) and (1R,2R)-2d
Scheme 1. Transformation of Epoxide 2c and Ester 3c to
Common Diol 5
(entry 7).
The epoxidation of the (E)-1 isomers by DMD shows the
1
same trend: for the achiral (E)-1a (R ) H), no selectivity
is observed (entry 9), whereas the diastereofacial differentia-
1
tion increases with the size of the R substituent. The 1S:1R
1
i
ratios range from 53:47 for (E)-1b (R ) Pr, entry 11) to
1
4
1
0:60 for (E)-1c (R ) Ph, entry 13) and to 25:75 for (E)-
1
t
d (R ) Bu, entry 15). Notable, and mechanistically
pertinent, are the much lower dr values for the DMD
epoxidation of the (E)-configured chiral enecarbamates 1
(entries 11, 13, and 15) compared to the (Z)-1 diastereomers
(entries 3, 5, and 7).
In the epoxidations with mCPBA, the epoxide was
1
observed directly in the H NMR spectrum of the reaction
mixture at low (only ca. 10%) conversion of the enecar-
bamates 1. In all cases, the major diastereomer epoxide is
the same as in the DMD reaction; however, the epoxide was
opened exclusively at the C1 position to the ester 3 by the
acid generated from mCPBA. When the mCPBA epoxidation
3
of the (E)-1a enecarbamate was conducted in a NaHCO -
buffered two-phase system to avoid the acid-catalyzed ring
opening of the epoxide product, the formation of the ester
(1R*,2S*)-3a could not be avoided (not shown in Table 1)
under these conditions either.
common diol 5 gave the same enantiomeric ratio as the
diastereomeric ratios of the epoxide 2c and the ester 3c
1
As in case of DMD, the achiral (Z)-1a (R ) H, entry 9)
is epoxidized also unselectively by mCPBA in the unbuffered
reaction, whereas the diastereomeric ratios of the chiral
(within the experimental error). Moreover, the absolute
configuration of the major enantiomer was found to be R by
comparison with an authentic reference sample of enantio-
merically enriched diol 5, prepared independently according
1
enecarbamates (Z)-1b-d increase as the size of the R
substituents on the oxazolidinone ring is increased. Thus,
for the isopropyl-substituted enecarbamate (Z)-1b (entry 4),
the diastereomeric ratio is substantially lower than for the
phenyl-substituted derivative (Z)-1c (entry 6) and the tert-
butyl one (Z)-1d (93:7, entry 8). Again, the (E)-configured
enecarbamates are epoxidized by mCPBA in lower diaste-
reoselectivity than the (Z)-configured counterparts (entries
13
to the literature. From the (R)-configuration of the major
enantiomer of diol 5, the configuration at the C2 position in
the major isomer of the epoxide 2c and the ester 3c, both
derived from encarbamate (Z)-1c, may also be assigned as
R, provided that the C2 site is not involved in the ring-
opening hydrolysis 2c f 4c and esterification 2c f 3c. That
this is so could be unequivocally established for the latter
process, because NMR analysis of the reaction mixture
revealed that exclusively the regioisomer with nucleophilic
attack on the C1 position had been formed. Consequently,
the absolute configuration of the ester 3c is 1S,2R and, hence,
that of the epoxide 2c is 1R,2R.
12, 14, and 16), as was the case for DMD (entries 11, 13,
and 15). In fact, for the substrate with the large tert-butyl
substituent (E)-1d, an appreciable dr value of 71:29 was
observed, in favor of the (1S,2S)-3d isomer (entry 16). An
exceptional case is the mCPBA epoxidation of the (E)-1c
1
(
R ) Ph) enecarbamate. This substrate also affords a mixture
of the two diastereomeric epoxides, but only the (1R,2S)-2c
diastereomer is converted to the ester (1S,2S)-3c, while the
With the absolute configuration of epoxides 2 assessed,
the stereochemical course of the oxygen-transfer process may
be now scrutinized. The diastereoselectivity is controlled by
(1S,2R)-2c epoxide resists esterification. Presumably, nu-
cleophilic attack on the C1 position is sterically hindered.
The absolute configurations of the epoxides 2 and esters
1
the R substituent in the oxazolidinone ring, because for the
1
parent enecarbamate 1a (R ) H) an unselective epoxidation
3
were determined by their transformation to the common
1
occurs and the dr ratio depends on the size of R . Moreover,
diol 5 (Scheme 1). For this purpose, the hydrolysis of the
epoxide 2c derived from the enecarbamate (Z)-1c was
catalyzed by p-toluensulfonic acid (p-TsOH) in an acetone/
water mixture, followed by reductive cleavage of the chiral
the configuration of stereogenic center in the oxazolidinone
ring determines the absolute configuration of the epoxide
product; that is, the (R)-configuration in the enecarbamate
(Z)-1b (entries 3 and 4) leads mainly to the (1S,2R)-2b,
4
auxiliary with NaBH /DBU. The chiral auxiliary could be
whereas the (S)-configuration in substrates (Z)-1c (entries 5
recovered in amounts up to 67%. Similarly, the mixture of
the ester 3c derived from the mCPBA epoxidation of the
enecarbamate (Z)-1c was readily reduced in one step to the
(13) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Joeng, K. S.; Kwong, H. L.; Morika, A. K.; Wang, Z. M.; Xu,
diol 5 by NaBH
4
. The chiral HPLC analysis of the resulting
D. Q.; Zhang, X. L. J. Org. Chem. 1992, 57, 2768-2771.
Org. Lett., Vol. 5, No. 6, 2003
821

Figure 2. Preferred π-facial attack of the DMD epoxidation as a
function of the substituent R size in the enecarbamates (Z)-1b,c (R
)
3
H, CH ).
and 6) and (Z)-1d (entries 7 und 8) affords mainly the
corresponding (1R,2R)-epoxides. To account for the fact that
1
the size and the location of the R substituent dictate the
extent and the sense of the diastereoselectivity, we propose
the mechanism in Figure 2 for the oxygen transfer.
Figure 3. DFT-calculated (B3LYP-3-21G*) preferred conforma-
tions for the diastereomeric pair of tert-butyl enecarbamates (E)-
1d and (Z)-1d as a function of the double-bond configuration.
When the R1 substituent is below the plane of the
enecarbamate double bond, as shown in Figure 2, steric
hindrance obstructs the syn attack (syn with respect to the
1
R substituent of the oxazolidinone auxiliary) and the anti
epoxidation. In this case, the same steric interactions operate
for both DMD and mCPBA because hydrogen-bonding
effects are not involved for the latter. If hydrogen bonding
between the carbonyl group in the oxazolidinone and the
proton of the mCPBA were taking place, a higher diaste-
reoselectivity would be expected for mCPBA, because the
1
attack is favored. For R a tert-butyl group (R ) CH
3
in
Figure 1), as in the enecarbamate (Z)-1d (entries 7 and 8),
the highest anti diastereoselectivity (dr 7:93) is obtained, such
that the (1R,2R)-2d epoxide is formed almost exclusively
for both oxidants DMD and mCPBA.
The preferred π-face that is attacked remains the same
for the (Z)- or (E)-configured enecarbamates; however, the
extent of the diastereofacial differentiation depends decisively
on the double-bond configuration, because the epoxidation
of the (Z)-isomer is more selective than that of the (E)-
isomer. This difference is due to conformational effects in
the (Z)- and (E)-isomers, which express the efficacy of
shielding of one side of the double bond in the enecarbamate
1
steric repulsion with the substituent R should be enhanced.
In summary, we have shown that the chiral encarbamate
1 may be epoxidized in a diastereoselectivity up to 93:7 for
both DMD and mCPBA. The diastereofacial differentiation
has been rationalized in terms of the steric interaction
1
between the R substituent on the oxazolidinone ring and
the incoming electrophile on account of conformational
1
effects, such that anti attack (opposite to the R substituent)
(
Figure 3).
is favored. Chemical correlation of epoxides 2 and esters 3
to the known optically active common diol 5 established the
π-facial stereochemical course of this unprecedented oxygen-
transfer process.
As can be seen from the DFT-calculated lowest-energy
conformations for the (E)-1d and (Z)-1d isomers in Figure
, the shielding of the syn face of the double bond by the
3
t
Bu group is more effective for the (Z)- than for the (E)-
diastereomer, such that anti attack should be facilitated for
the former, as is documented by the higher dr values for
these substrates (entries 7 and 8 for (Z)-1d versus entries 15
and 16 for (E)-1d). Thus, only the large steric demand of a
tert-butyl group is sufficient to shield the double bond
effectively in the (E)-configured enecarbamate 1d and then
induce an appreciable diastereoselectivity. In the case of
enecarbamate (E)-1c, the phenyl group is smaller than the
tert-butyl group and is not effective in shielding the double
bond.
Acknowledgment. This work was generously supported
by the Deutsche Forschungsgemeinschaft (Schwerpunkt-
programm “Peroxidchemie”) and the Fonds der Chemischen
Industrie. We thank M. Schwarm (Degussa H u¨ ls AG, Hanau)
for a generous gift of the optically active oxazolidinones and
alaninol, J. Bialas for the synthesis of DMD, and H. Ihmels
for helpful discussion.
Supporting Information Available: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
6
In contrast with previous findings, the same π-facial
selectivity is observed for mCPBA and DMD in the present
OL0273194
822
Org. Lett., Vol. 5, No. 6, 2003