Effect of the medium on the oxaziridinium-catalyzed enantioselective epoxidation

Article abstract of DOI:10.1016/S0040-4039(02)02025-7

TRISPHAT salts of chiral iminium cations allow, in combination with 18-C-6, the use of biphasic CH₂Cl₂/water conditions, which can improve the enantioselectivity of the oxone-mediated epoxidation.

Full text of DOI:10.1016/S0040-4039(02)02025-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8257–8260
Effect of the medium on the oxaziridinium-catalyzed
enantioselective epoxidation
Jerome Lacour,* David Monchaud and Claire Marsol
De´partement de Chimie Organique, Universite´ de Gene`ve, quai Ernest Ansermet 30, CH-1211 Gene`ve 4, Switzerland
Received 20 August 2002; revised 22 August 2002; accepted 17 September 2002
Abstract—TRISPHAT salts of chiral iminium cations allow, in combination with 18-C-6, the use of biphasic CH2Cl2/water
conditions, which can improve the enantioselectivity of the oxone-mediated epoxidation. © 2002 Published by Elsevier Science
Ltd.
Stereoselective oxidative functionalization of unacti-
vated CꢀC double bonds is a topic of great interest in
today’s chemistry and much activity has been devoted
to the asymmetric transfer of oxygen atoms.1 Recently,
the epoxidation of olefins by oxaziridinium cations has
been studied because of the faculty of iminium ions—
formed along with the desired epoxides—to react with
Oxone® (potassium peroxymonosulfate) and regenerate
the reactive oxaziridinium species.2 Successful enan-
tioselective variants of this catalytic reaction have been
developed using as precatalysts non-racemic cyclic and
acyclic iminium salts (Fig. 1).3
cations to olefins happens in one step via charged spiro
transition states.6 We thus wondered whether the
stereoselectivity of the asymmetric reaction could
benefit from less polar solvent conditions as a ‘destabi-
lization’ of the diastereomeric transition states might
result in more discriminating stereoselective interac-
tions. Previously, the synthesis and resolution of
Generally, the chemical yields are good but the enan-
tioselectivities only moderate. Combinations of CH3CN
and water have been used as solvent mixtures, as the
reagents usually dissolve in these homogenous
(monophasic) conditions.4 Herein, we report that the
combined use of TRISPHAT counterions (1, Fig. 2)
and of catalytic amounts of 18-C-6 allows the use of
biphasic CH2Cl2/water conditions which can improve—
in the case of iminium precatalyst 2a—the enantioselec-
tivity of the epoxidation (enantiomeric ratio, e.r. from
2.4:1 to 7.2:1 for the epoxidation of 1-phenyl-dihy-
dronaphthalene 6). The recent report by Page et al. on
the synthesis and the use of iminium cation 2a for the
enantioselective epoxidation prompted us to disclose
our own results.5
Figure 1. Known chiral iminium precatalysts.
Mechanistic and computational studies have revealed
that the oxygen transfer reaction from oxaziridium
Figure 2. TRISPHAT anion
1 and iminium precatalyst
* Corresponding author. Tel.: +41 22 7026062; fax: +41 22 328 7396;
e-mail: jerome.lacour@chiorg.unige.ch
(4S,5S)-2a derived from -(+)-acetonamine.
L
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02025-7

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J. Lacour et al. / Tetrahedron Letters 43 (2002) 8257–8260
We decided to develop the chemistry of diphenyl-
azepinium cations of type 2, not yet reported at the
start of this study, as literature precedents indicated
that such derivatives would exhibit atropisomeric (aR)
and (aS) conformations, which would interconvert
freely in solution by rotation around the biphenyl
axis.10 Introduction of chiral substituents on the back-
bone and/or ion pairing with enantiopure anions would
lead to the formation of diastereomeric intramolecular
and/or intermolecular interactions, which could shift
the conformational equilibrium towards one preferred
(aR) or (aS) diastereomer (Fig. 3).10,11 If so, good
asymmetric efficiency was envisioned as the structure of
the precatalysts would resemble Aggarwal’s conforma-
tionally rigid dinaphthazepinium derivative, which is
one of the most efficient precatalyst.3b
Figure 3. Possible asymmetric induction from chiral sub-
stituents and counterions.
Previous results by Page et al. on the use of (4S,5S)-5-
amino-2,2-dimethyl-6-phenyl-1,3-dioxane (or -(+)-ace-
L
tonamine) as a source of asymmetric induction in
oxaziridinium-catalyzed epoxidations, convinced us to
use this primary amine in conjunction with the diphenyl-
azepinium skeleton.3c Synthesis of derived iminium
cation 2a was realized in two steps (Scheme 1). Reduc-
tive amination of biphenyl-2,2%-dicarbaldehyde 312 in
Scheme 1. Synthesis of iminium precatalysts 2a (R=
D-(−) or
L
-(+)-acetonamine) and 2b (R=n-Pr): (i) NaBH3CN, RNH2,
the presence of
D
-(−) or -(+)-acetonamine, NaBH3CN
L
AcOH, CH3CN, 4a (77%) and 4b (94%); (ii) a. I2, AcOK,
EtOH, reflux, b. [R3NH][1], chromatography over SiO2:
[2a][1] (60–68%) and [2b][1] (62%).
and AcOH afforded desired
D
-(−)- and -(+)-4a in 77%
L
yield.13 Finally, treatment of compounds 4a with I2/
AcOK in boiling EtOH afforded the desired iminium
species as their iodide salts.14
tris(tetrachlorobenzenediolato)phosphate(v) 1, known
as TRISPHAT, was reported.7 This chiral anion (D and
L enantiomers) is an efficient NMR chiral shift and
resolving agent for cationic organic and organometallic
derivatives.8 More importantly for this study, its
lipophilicity confers to its salts an affinity for organic
solvents and, once dissolved, the ion pairs do not
partition in aqueous layers (AL).9 It was thus expected,
in biphasic solvent conditions, that the TRISPHAT
salts of iminium and oxaziridinium cations would react
in the less polar organic layer (OL, CH2Cl2) rather than
in the polar aqueous one.
In situ association with TRISPHAT anions was real-
ized by chromatography under previously reported con-
ditions. To take into account a possible influence of the
chirality of the anion, all four diastereomeric ion pairs
[L
-2a][D-1], [
L
-2a][L-1], [
D
-2a][D-1] and [ -2a][L-1] were
D
prepared and afforded in moderate overall yields (60–
68%).15 Cation 2b made from achiral 1-propyl-amine
was also synthesized following the same conditions and
salt [2b][D-1] was afforded in decent yield (62% from 3).
Initial experiments were performed with 1-phenyl-cyclo-
hexene 5 as substrate (Table 1). Under classical acetoni-
Table 1. Asymmetric epoxidation of 1-phenyl-cyclohexene 5 by diphenylazepinium precatalysts
Entrya
Iminium
Anion
Solvent medium
Additive
Conversion
(%)b
Yield
(%)c
E.e.
E.r.d
Conf.e
(%)d
1f
2
3
4
5
6
7
8
9
L
L
-2a
-2a
BPh4
L-1
D-1
L-1
D-1
D-1
L-1
D-1
L-1
D-1
CH3CN:H2O 1:1
CH3CN:H2O 1:1
CH3CN:H2O 1:1
CH2Cl2:H2O 3:2
CH2Cl2:H2O 3:2
CH2Cl2:H2O 3:2
CH2Cl2:H2O 3:2
CH2Cl2:H2O 3:2
CH2Cl2:H2O 3:2
CH2Cl2:H2O 3:2
–
–
–
–
100
100
100
0
0
90
100
100
100
97
–
–
69
0
60
61
0
–
–
69
69
70
69
0
4:1
4.1:1
–
–
–
5.4:1
5.4:1
5.7:1
5.4:1
–
(S,S)
(S,S)
–
–
–
(S,S)
(S,S)
(R,R)
(R,R)
–
2b
L
-2a
2b
L
–
0
-2a
-2a
-2a
-2a
18-C-6 (2.5 mol%)
18-C-6 (2.5 mol%)
18-C-6 (2.5 mol%)
18-C-6 (2.5 mol%)
18-C-6 (2.5 mol%)
78
77
88
82
89
L
D
D
10
2b
a Unless otherwise indicated, all epoxidations were carried out at rt for 3 h with 0.2 mmol of 1-phenyl-cyclohexene, 0.2 mmol of Oxone®, 0.8 mmol
of NaHCO3 and 5 mol% of precatalyst.
b Conversion was calculated from the ratio of 1-phenyl-cyclohexene and 1-phenyl-cyclohexene-oxide in GC and/or by 1H NMR.
c Yield based on conversion after flash column chromatography.
d Determined by chiral HPLC (Chiracel OD-H).
e The configuration of the major enantiomer of the epoxide is indicated as (S,S) or (R,R).
f See Ref. 5.

J. Lacour et al. / Tetrahedron Letters 43 (2002) 8257–8260
8259
trile/water conditions, compound
5
reacted with
between the AL and OL, and permit the oxidation in
the OL of the iminium cation into its reactive oxaziri-
dinium derivative (Scheme 2). Reactions were thus per-
formed again with a catalytic amount of 18-C-6 (2.5
mol%) and yielded the desired epoxide in decent iso-
lated yields (77–89%) and higher enantiomeric purity
(e.e. 69–70%). The influence of the chiral nature of
TRISPHAT was tested and little or no effect was
Oxone®, NaHCO3 and salt [
L
-2a][L-1] (5 mol%) to give
(1S,2S)-1-phenylcyclohex-1-ene oxide in high yield
(entry 2). The enantiomeric excess of the epoxide (e.e.
61%) was virtually identical to the one observed by
Page et al. (e.e. 60%) with salt [ -2a][BPh4] as precata-
L
lyst (Table 1, entry 1). This result seemed logical as ion
pairs are separated by the solvent in polar media:16
iminium ion
L
-2a reacts on its own with little influence
monitored as reactions with diastereomeric salts [
L-
from the chemical or chiral nature of the counterion.17
2a][D-1], [ -2a][L-1], [ -2a][D-1] and [ -2a][L-1] led
L
D
D
essentially to the same enantiomeric excesses (Table 1,
entries 6–9). With [2b][D-1], no selectivity was observed
(Table 1, entry 10). One possibility to explain this lack
of influence displayed by the chiral anion is to consider
the poor asymmetric induction of anion 1 onto the (aS)
and (aR) conformational equilibrium.18,11
Biphasic CH2Cl2/water conditions were then tried and
initial attempts were disappointing as no epoxide could
be found in the crude mixtures from reactions per-
formed with precatalysts [ -2a][L-1] and [2b][D-1]
L
(entries 4 and 5). We reasoned that this lack of reactiv-
ity was not the result of the biphasic conditions per se
but rather the consequence of the tight containment of
the reagents in two separate liquid phases: the organic
TRISPHAT salts in the OL and Oxone® in the AL. If
so, addition of 18-C-6 to the mixture would be suffi-
cient to establish a transport mechanism of KHSO5
Other prostereogenic di- and trisubstituted olefins (6–9)
were tested with this novel biphasic protocol and the
results are summarized in Table 2. Epoxide formation
was observed with usually quantitative conversion (1H
NMR, GC) and good overall isolated yields (64–85%).
Generally, enantioselectivities for the reactions per-
formed under biphasic conditions were higher than
those reported by Page et al. for the homogenous
conditions.5 In the case of 6, 1-phenyl-3,4-dihydronaph-
thalene oxide was obtained in much higher enan-
tiomeric excess (76% versus 41%). Interestingly, a
reversal of the absolute configuration—(+)-(1R,2S)
instead of (−)-(1S,2R) in homogenous conditions—was
observed for product 1-phenyl-3,4-dihydronaphthalene
oxide.19
In conclusion, we have shown that the ion pairing of an
iminium cation with TRISPHAT anions allows the use
of strict biphasic conditions, which can lead to higher
enantioselectivities. Although most results have
remained modest in the case of precatalyst 2a, we
Scheme 2. Plausible mechanism for the biphasic oxaziri-
dinium-catalyzed epoxidation.
Table 2. Asymmetric epoxidation of olefins using salt [ -2a][L-1] as precatalyst
L
Entrya
Alkene
Precatalyst
Yield (%)b
E.e.c (%)
E.r.
Conf.
MonoFe.e.d
1
2
3
4
5
5
6
7
8
9
[L
[L
[L
[L
[L
-2a][L-1]
-2a][L-1]
-2a][L-1]
-2a][L-1]
-2a][L-1]
67
85
85
82
64
69
76
17
23
42
5.4:1
7.2:1
1.4:1
1.6:1
2.4:1
(S,S)
(1R,2S)
(S,S)
(S)
(1S,2S)
60
41e
15
59
37
a Unless otherwise indicated, all epoxidations were carried out at rt for 3 h with 0.2 mmol of alkene, 0.2 mmol of Oxone®, 0.8 mmol of NaHCO3,
2.5 mol% of 18-C-6, 5 mol% of [ -2a][L-1] and a 3:2 mixture of CH2Cl2:H2O as solvent.
L
b Yield based on conversion after flash column chromatography.
c Determined by chiral HPLC (Chiracel OD-H) and GC (Lipodex-E).
d Established by Page et al. in homogenous solvent conditions (CH3CN:H2O 1:1) using [
e Major enantiomer: (−)-(1S,2R)-1-phenyl-3,4-dihydronaphthalene oxide.
L
-2a][BPh4] as precatalyst; see Ref. 5.

8260
J. Lacour et al. / Tetrahedron Letters 43 (2002) 8257–8260
believe that these new conditions can be applied to
already reported iminium salts and might lead to better
results. Further studies are performed to match anion
and cation structures to benefit from the asymmetric
ion pairing.
7. (a) Lacour, J.; Ginglinger, C.; Favarger, F. Tetrahedron
Lett. 1998, 4825–4828; (b) Lacour, J.; Ginglinger, C.;
Grivet, C.; Bernardinelli, G. Angew. Chem., Int. Ed. Engl.
1997, 36, 608–609.
8. Lacour, J.; Jodry, J. J.; Monchaud, D. Chem. Commun.
2001, 2302–2303 and references cited therein.
9. This property has led to successful applications of 1 as a
chiral selector in asymmetric extraction processes:
Lacour, J.; Goujon-Ginglinger, C.; Torche-Haldimann,
S.; Jodry, J. J. Angew. Chem., Int. Ed. 2000, 39, 3695–
3697; Jodry, J. J.; Lacour, J. Chem. Eur. J. 2000, 6,
4297–4304.
Acknowledgements
We thank Roche Diagnostics for a generous gift of
L
-acetonamine. We are grateful for financial support of
this work by the Swiss National Science Foundation,
the Federal Office for Education and Science (COST
D11), the Socie´te´ Acade´mique de Gene`ve, the Schmid-
heiny Foundation as well as the Sandoz Family Foun-
dation (C.M., J.L.).
10. Ooi, T.; Uematsu, Y.; Kameda, M.; Maruoka, K. Angew.
Chem., Int. Ed. 2002, 41, 1551–1554 and references cited
therein.
11. In principle, D3-symmetric 1 is suitable for the chiral
recognition of C2-symmetric organic cations, although in
practice, low induction is usually observed: Lacour, J.;
Londez, A.; Goujon-Ginglinger, C.; Buß, V.; Bernar-
dinelli, G. Org. Lett. 2000, 2, 4185–4188; Pasquini, C.;
Desvergnes-Breuil, V.; Jodry, J. J.; Dalla Cort, A.;
Lacour, J. Tetrahedron Lett. 2002, 43, 423–426 and this
paper.
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4. To the noticeable exception of some olefins, see: Aggar-
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L
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L
wal, V. K. WO. 9 706 147, 1997.
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