Diastereoselective epoxidation of oxazolidine-substituted alkenes by dimethyldioxirane and m-chloroperbenzoic acid: pi-facial control through hydrogen bonding by the urea functionality.

Article abstract of DOI:10.1021/ol006800w

[figure: see text] A high diastereoselectivity (up to > 98:2) is found for the DMD and m-CPBA epoxidations of chiral oxazolidine-substituted olefins with a urea group. The selectivity is explained in terms of hydrogen bonding between the remote NH group o

Full text of DOI:10.1021/ol006800w

ORGANIC
LETTERS
2001
Vol. 3, No. 1
79-82
Diastereoselective Epoxidation of
Oxazolidine-Substituted Alkenes by
Dimethyldioxirane and
m-Chloroperbenzoic Acid: π-Facial
Control through Hydrogen Bonding by
the Urea Functionality
Waldemar Adam* and Simon B. Schambony*
Institut fu¨r Organische Chemie, UniVersita¨t Wu¨rzburg, Am Hubland,
D-97074 Wu¨rzburg, Germany
adam@chemie.uni-wuerzburg.de
Received October 30, 2000
ABSTRACT
A high diastereoselectivity (up to >98:2) is found for the DMD and m-CPBA epoxidations of chiral oxazolidine-substituted olefins with a urea
group. The selectivity is explained in terms of hydrogen bonding between the remote NH group of the urea functionality and the epoxidizing
reagent. Methylation of the NH group prohibits hydrogen bonding, and a reversed selectivity is observed due to steric repulsion between the
reagent and the urea functionality.
Epoxidations are among the most useful oxidation reactions
in organic synthesis, since the epoxy functionality may be
transformed by ring opening stereoselectively into a large
number of highly functionalized products.1 For this purpose,
peracids2 and, more recently, dioxiranes3 have been used
extensively as effective and mild epoxidants. These versatile
reagents become particularly valuable when their epoxida-
tions are controlled stereoselectively; that is, the attack of
the epoxidant prefers one of the π faces of the olefinic
substrate.4 Besides reagent-controlled diastereoselectivity, the
influence of the olefin structure and especially directing
groups in controlling the attack of the oxygen-transferring
agent, both in experimental5 and theoretical6 studies, has
received much attention. In this context, the directing
propensity of allylic substituents is well documented,4b-d,7
but only relatively few examples are known for which the
* Address correspondence to W.A. Fax: +49(0)931/8884756. Internet:
http://www-organik.chemie.uni-wuerzburg.de.
(1) (a) Rao, A. S.; Paknokov, S. K.; Kirtane, J. G. Tetrahedron 1983,
39, 2323-2367. (b) Smith, J. G Synthesis 1984, 629-656. (c) Paterson, I.
Berrisford, D. J. Angew. Chem., Int. Ed. Engl. 1992, 31, 1179-1181. (d)
Erden, I. In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford, 1996; Vol. 1A, pp
105-117. (e) Hodgson, D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996,
52, 14361-14384. (f) Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421-
431.
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L., Eds.; Wiley: New York, 1973; Vol. 7, pp 93-251. (b) Rao, A. S. In
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Oxford, 1991; Vol. 7, pp 357-387. (c) Hoveyda, A. H.; Evans, D. A.; Fu,
G. C. Chem. ReV. 1993, 93, 1307-1370. (d) Adam, W.; Wirth, T. Acc.
Chem. Res. 1999, 32, 703-710.
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1986, 51, 1649-1653. (b) Koerner, T.; Slebocka-Tilk, H.; Brown, R. S. J.
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10.1021/ol006800w CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/06/2000

directing group is located further away from the double
bond.7 The observed stereoselectivity is significantly lower
than for allylic substituents due to less efficient alignment
of the substrate by the directing entity for a selective π-face
attack. Nonetheless, recently we discovered the directing
propensity of the remote urea NH functionality of chiral
oxazolidines in the singlet-oxygen ene reaction.8 As the
factors controlling singlet-oxygen reactions are often also
valid for DMD and m-CPBA epoxidations, these substrates
appeared to be promising for remote-functionality controlled
diastereoselective epoxidations. Herein we report that chiral
oxazolidine-substituted olefins undergo highly diastereo-
selective (up to >98:2) epoxidation with DMD and m-CPBA.
The diastereoselectivity is induced by a remote urea NH
group.
The synthesis of oxazolidine-substituted olefins 1a-c was
described previously,8 and derivative 1d was prepared by
condensation of tiglic aldehyde and S-phenylglycinol, fol-
lowed by acylation with phenylisocyanate (cf. the Supporting
Information). The substrates 1 were epoxidized with di-
methyldioxirane in acetone and m-chloroperbenzoic acid in
chloroform to yield the corresponding epoxides 2 (Table 1).
the epoxide lk-2a to the known allylic alcohol lk-3a,8,9 which
establishes the like configuration. Furthermore, the lk-2a
epoxide was converted to its lk-2c derivative through
methylation, which allowed us to assign the relative con-
figuration of the lk- and ul-2c epoxides (Scheme 1). The ul-
Scheme 1a
a Key: (i) NaH, MeI, DMSO, 20 °C, 15 h; (ii) activated Al2O3,
n-hexane, 20 °C, 16 h.
2d epoxide was synthesized independently from the optically
active aldehyde 2R,3S-310 (Scheme 2).
Scheme 2a
Table 1. Diastereoselective Epoxidation of
Oxazolidine-Substituted Olefins 1 by DMD and m-CPBA
a Key: (i) (1) K2CO3, CDCl3, 20 °C, 2 h; (2) PhNCO, CDCl3,
20 °C, 3 h.
convn
R1 R2 R3 oxidantb (%)a lk-2:ul-2
dra
entry
Ar
1a C6H5
1b p-NO2-C6H4
1c C6H5
1d C6H5
1a C6H5
1b p-NO2-C6H4
1c C6H5
1d C6H5
The exclusive like diastereoselectivity in the DMD ep-
oxidation of the 1a,b derivatives (entries 1 and 2) may be
explained in terms of the highly effective hydrogen bonding
1
2
3
4
5
6
7
8
H
H
Me
Me
H
H
DMD
DMD
>95 >98:2c
>95 >98:2c
H
Me
H
H
H
Me Me DMD
94
78
94
26:74
74:26
81:19
87:13
40:60
74:26
H
Me
Me
H
H
H
DMD
m-CPBA
m-CPBA >95
52
m-CPBA >95
(5) (a) Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1957, 1958-
1965. (b) Chamberlain, P.; Roberts, M. L.; Whitham, G. H. J. Chem. Soc.
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1999, 64, 3858-3860. (d) Freccero, M.; Gandolfi, R.; Sarzi-Amade`, M.;
Rastelli, A. J. Org. Chem. 2000, 65, 2030-2042. (e) Adam, W.; Bach, R.
D.; Dmitrenko, O.; Saha-Mo¨ller, C. R. J. Org. Chem. 2000, 65, 6715-
6728.
(7) (a) Kobayashi, Y.; Uchiyama, H.; Kanbara, H.; Sato, F. J. Am. Chem.
Soc. 1985, 107, 5541-5543. (b) Murray, R. W.; Singh, M.; Williams, B.
L.; Moncrieff, H. M. J. Org. Chem. 1996, 61, 1830-1841. (c) Adam, W.;
Bru¨nker, H.-G.; Kumar, A. S.; Peters, E.-M.; Peters, K.; Schneider, U.;
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Soc. 2000, 122, 7610-7611.
Me Me m-CPBAd
Me
H
H
a Determined by 1H NMR spectroscopy, error (5% of the stated values;
the mass balance was >90% in all cases. b DMD: acetone, 20 °C, 5 h;
m-CPBA: CDCl3, 20 °C, 2 h. c Not even traces of the corresponding unlike
epoxides were detected. d CH2Cl2/aqueous NaHCO3 buffer, 20 °C, 4 h (see
text).
The epoxidation of 1c with peracid was done in a buffered
two-phase system to avoid acid-catalyzed decomposition of
the product that was observed under standard reaction
conditions. For the substrates 1a,b (entries 1 and 2), the like
product is formed exclusively with DMD (not even traces
of the unlike diastereomer could be detected), but for the
derivative 1d (entry 4) a significantly lower like selectivity
is observed; in contrast, with the N-methylated urea 1c (entry
3) even the unlike epoxide is preferred. The stereochemical
assignment was made by base-catalyzed rearrangement of
(9) (a) Joshi, V. S.; Damodaran, N. P.; Dev, S. Tetrahedron 1968, 24,
5817-5830. (b) Va´zquez, J. T.; Chang, M.; Nakanishi, K. J. Org. Chem.
1988, 53, 4797-4800.
(10) (a) Mart´ın, T.; Rodr´ıguez, C. M.; Mart´ın, V. S. Tetrahedron:
Asymmetry 1995, 6, 1151-1164. (b) Tanaka, M.; Tomioka, K.; Koga, K.
Tetrahedron 1994, 50, 12843-12852.
80
Org. Lett., Vol. 3, No. 1, 2001

between the urea NH functionality of the olefinic substrate
and the oxygen atom of the DMD oxidant in the lower-
energy transition structure like-TS (Scheme 3). The impor-
hydrogen bonding is obstructed. The hydrogen-bonding
conformer 4a′ is favored by 3.2 kcal/mol over 4a′′; thus,
this conformer is preferentially populated and epoxidation
by assistance through hydrogen bonding leads to the observed
high like diastereoselectivity (path a in Scheme 4). In
contrast, the conformers 4d′ and 4d′′ are nearly equal in
energy (the conformer 4d′′ is even favored by 0.36 kcal/
mol over 4d′) and both conformers will be essentially equally
populated. Since for the conformer 4d′′ effective hydrogen
bonding is difficult, the epoxidation along this reaction
channel (path b in Scheme 4) is expected to be unselective.
Thus, the moderate selectivity (74:26) for the substrate 1d
results from the 50:50 superposition of the exclusively like-
selective epoxidation of the conformer 1d′ and the totally
unselective epoxidation of conformer 1d′′. Application of
the computational results for 4a,d on the experimental cases
1a,b,d (Scheme 4), the overall diastereoselectivity for 1d
should be lower than for 1a and 1b, as manifested by the
data in Table 1 (entries 1, 2 and 4).
Scheme 3
tance of the free NH functionality for the like diastereo-
selectivity is emphasized by the reversal of selectivity upon
capping of this group by methylation (entry 3). For substrate
1c, hydrogen bonding is not possible and steric repulsion
between the urea functionality and DMD disfavors the like
attack and, therefore, a reversal of the diastereoselectivity is
observed to favor the unlike epoxide ul-2c.
For m-chloroperbenzoic acid a similar trend is observed.
Thus, the oxazolidines with a free NH group and a properly
aligned olefin conformation as in the substrates 1a,b
predominantly afford the corresponding like epoxides (entries
5 and 6). N methylation as in substrate 1c (entry 7) expresses
a slight preference for the unlike epoxide (control by steric
effects), while for the tiglyl derivative 1d (entry 8) a slightly
reduced like diastereoselectivity is observed. As in the DMD
epoxidations, hydrogen bonding between the oxidant and the
NH functionality lowers the energy of the like transition state
and, thus, this attack is preferred (Scheme 5).
The importance of proper conformational alignment of the
double-bond functionality in the substrate is demonstrated
in the epoxidation of cis-dimethyl derivative 1d (entry 4).
Although this substrate bears a urea NH group, the like
selectivity for the DMD epoxidation is significantly lower
than that of the oxazolidines 1a,b. The reason for the reduced
like diastereoselectivity is to be sought in the steric interac-
tions between the additional R-methyl group of the double
bond and the oxazolidine. To assess this, DFT calculations
(B3LYP/6-31G*) of the model substrates 4a and 4d were
carried out, in which the aryl group of the urea moiety was
replaced by a hydrogen atom and the phenyl substituent of
the oxazolidine ring by a methyl group. Two conformational
energy minima were found for the derivatives 4a and 4d
(Scheme 4). In the conformers 4a′ and 4d′, the π system is
oriented favorably for hydrogen bonding with the urea NH
functionality, whereas in the conformers 4a′′ and 4d′′, the
double bond is located directly above the NH2 group and
Scheme 5
Usually hydrogen bonding is more effective for m-CPBA
compared to DMD epoxidations7c and, therefore, it was
unexpected, that the diastereoselectivity for m-CPBA was
lower than for DMD, especially since the reaction medium
is less polar for the peracid (chloroform) than for dioxirane
(acetone) and stronger hydrogen bonding should operate for
m-CPBA. Inspection of molecular models suggests that the
lower diastereoselectivity of the peracid compared to the
dioxirane may be explained in terms of the higher steric
constraints for a proper alignment of the hydrogen bonding
between the urea NH functionality and the carbonyl group
of the peracid in the spiro transition structure of the peracid
epoxidation (Scheme 5).
Scheme 4
It is instructive to compare the present results with the
DMD epoxidation of chiral allylic alcohols.11 In the reaction
of mesitylol (5) with DMD, a preference of the threo attack
Org. Lett., Vol. 3, No. 1, 2001
81

is observed (threo/erythro ) 76:24), which was explained
by beneficial hydrogen bonding between the oxygen atom
of the oxidant and the allylic hydroxy functionality, the latter
properly aligned by 1,3-allylic strain (Scheme 6). This
clear that the urea moiety is more acidic and, therefore, the
better hydrogen donor.15 Additionally, the hydrogen-donating
NH functionality of the urea substrate is located directly
opposite of the double bond, in optimal juxtaposition for
interaction with the oxygen atom of the epoxidant. Thus,
the urea-substituted olefin hydrogen bonds more strongly
with the dioxirane and exhibits a much higher diastereo-
selectivity than the allylic alcohol.
Scheme 6
In summary, the present results show that a favorably
disposed urea NH functionality not only induces a very high
diastereoselectivity in the epoxidation by DMD (>98:2), but
it surpasses in efficacy that for m-CPBA (up to 87:13), which
is remarkable in view of the fact that peracids are generally
more effective than dioxiranes.7c Although the directing
group is located four bonds away from the reacting site,
namely the π bond to be attacked, the perfect stereoselectivity
is caused by the optimal conformational alignment of the
olefin functionality for beneficial hydrogen bonding between
the urea NH group of the substrate and the oxygen atom of
the reagent. The directing ability of the urea NH group should
find valuable applications in the control of stereoselectivity.
diastereoselectivity is substantially lower than for the urea
derivative 1a (>98:2), although both possess structurally the
same double-bond functionality. This impressive difference
in the diastereoselectivity between the allylic alcohol and
the substrates demands an explanation. For a high diastereo-
selectivity, two prerequisites must be fulfilled: First, the
directing group must be fixed sufficiently on one side of the
double bond; second, there must be an efficient interaction
between the directing group and the reagent. For the allylic
alcohol and the urea substrates the alignment of the directing
functionality is similar in energy (1,3-allylic strain favors
one conformer by 3-4 kcal/mol12) since both possess the
same π system and, thus, the difference in the diastereo-
selectivity must arise from more effective hydrogen bonding
in the urea case. Since the ability to act as hydrogen donor
correlates with the acidity of a molecule, the stronger acid
should form the stronger hydrogen bond. From a comparison
of the acidities of 2-propanol (pKa ) 30.3)13 and N,N-
dimethyl-N′-phenylurea (pKa ) 21.2)14 in DMSO it becomes
Acknowledgment. The generous financial support by the
Deutsche Forschungsgemeinschaft (Schwerpunktprogramm
“Peroxidchemie: Mechanistische und pra¨parative Aspekte
des Sauerstofftransfers”) and the Fonds der Chemischen
Industrie (doctoral fellowship 1998-2000 for S.B.S.) is
gratefully appreciated. We thank Prof. Dr. K.-H. Drauz and
Dr. M. Schwarm (Degussa-Hu¨ls AG, Hanau) for generous
gifts of optically active phenylglycinol.
Supporting Information Available: Experimental Sec-
tion with the details for the preparation of 1d, the epoxidation
of oxazolidines 1a-d, and the calculations for the preferred
conformations of the oxazolidines 4a and 4d. This material
is available free of charge via the Internet at http://pubs.acs.org.
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Lett. 1993, 34, 8427-8430. (b) Adam, W.; Smerz, A. K. J. Org. Chem.
1996, 61, 3506-3510.
OL006800W
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(15) DMSO rather than water was chosen for comparison of the acidities,
because like the actual reaction medium (acetone), it is an aprotic polar
solvent.
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1991, 113, 5006-5017.
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82
Org. Lett., Vol. 3, No. 1, 2001