Phase transfer catalysed asymmetric epoxidation of chalcones using chiral crown ethers derived from D-glucose and D-mannose

Article abstract of DOI:10.1055/s-2004-817751

New chiral monoaza-15-crown-5 lariat ethers synthesized from D-mannose and the glucose-based crown ethers of similar type generated significant asymmetric induction as phase transfer catalysts in the epoxidation of chalcones with tert-butyl-hydroperoxide

Full text of DOI:10.1055/s-2004-817751

LETTER
643
Phase Transfer Catalysed Asymmetric Epoxidation of Chalcones Using Chiral
Crown Ethers Derived from D-Glucose and D-Mannose
Phase Transfe
é
Catalysed
t
A
symm
e
e
tric
E
pox
r
idation of Cha
B
lcones akó,*a Tibor Bakó,a Attila Mészáros,a György Keglevich,a Áron Szöllősy,b Sándor Bodor,a Attila Makó,a
László Tőkec
a
Department of Organic Chemical Technology, Budapest University of Technology and Economics, 1521 Budapest, P. O. Box 91,
Hungary
Fax +36(1)4633648; E-mail: pbako@mail.bme.hu
b
NMR Laboratory of the Institute for General and Analytical Chemistry, Budapest University of Technology and Economics,
1521 Budapest, P. O. Box 91, Hungary
c
Organic Chemical Technology Research Group of the Hungarian Academy of Sciences at the Budapest University of Technology and
Economics, 1521 Budapest, P. O. Box 91, Hungary
Received 18 November 2003
The glucose-based crown ethers (1) were available by
Abstract: New chiral monoaza-15-crown-5 lariat ethers synthe-
earlier methods,6 while the mannose-based compounds 2
have been synthesized in analogous manner, via inter-
mediates 3–5 (Scheme 1).
sized from D-mannose and the glucose-based crown ethers of simi-
lar type generated significant asymmetric induction as phase
transfer catalysts in the epoxidation of chalcones with tert-butyl-hy-
droperoxide (80–92% ee).
The vicinal hydroxy groups of the 4,6-O-benzylidene-a-
D-mannopyranoside 3 were alkylated with bis(2-chloro-
ethyl) ether in liquid-liquid two-phase system, in the pres-
ence of tetrabutylammonium hydrogen sulfate and 50%
aqueous NaOH to give intermediate 4 after chromato-
graphy.7
Key words: chiral crown ethers, asymmetric phase transfer cataly-
sis, lariate ether, asymmetric epoxidation
One of the most attractive approaches in catalytic asym-
metric syntheses is the phase transfer catalytic technique
in which the enantioselectivity is generated by a chiral
crown ether catalyst.1 A prominent group of optically ac-
tive crown ethers contains carbohydrate moiety as the
source of chirality. Although a number of chiral crown
ethers have been prepared from monosaccharides,2 only a
few of them have been successfully used as catalysts in
asymmetric reactions.3 Recently, we have reported an
asymmetric Michael addition and a Darzens condensa-
tion, in which the glucose-based chiral lariat ethers of type
1 generated high enantioselectivity (95% and 72%, re-
spectively).3,4 Now, we describe a new model reaction, in
which the macrocycle 1 proved to be an effective catalyst,
namely the epoxidation of chalcones under phase transfer
conditions. New crown ethers of similar type incorporat-
ing a mannopyranoside unit (2) have been synthesized
that could also be used in the above reaction.
Recently, efficient methods have been developed for the
enantioselective epoxidation of a,b-enones applying
poliamino acid catalysts,5a,b chiral phase transfer cata-
lysts,5c–e chiral ligand-metal peroxide systems,5f,g and
lanthanide-BINOL systems.5h,i
In this communication, the asymmetric epoxidation of
chalcone is investigated in the presence of glucose- and
mannose-based lariat ether catalysts 1 and 2 respectively.
Scheme 1 Reagents and conditions: a) O(CH2CH2Cl)2, 50% aq
NaOH, NBu4HSO4, 89%; b) NaI, acetone, reflux; c) RNH2, Na2CO3,
CH3CN, reflux, 44–53%; d) TsNH2, K2CO3, DMF, reflux, 55%; e)
4% Na/Hgx, Na2HPO4, MeOH, reflux, 92%.
SYNLETT 2004, No. 4, pp 0643–0646
Advanced online publication: 10.02.2004
DOI: 10.1055/s-2004-817751; Art ID: G31703ST
© Georg Thieme Verlag Stuttgart · New York
0
9.
0
3.
2
0
0
4

644
P. Bakó et al.
LETTER
The exchange of chlorine for iodine in 4 was accom-
plished by NaI in acetone resulting in bis-iodo derivative
5. Compound 5 was cyclized with various primary amines
such as: ethanolamine, propanolamine and 3-methoxy-
propanolamine, in MeCN, in the presence of dry Na2CO3
to give 2a, 2b and 2c, respectively by the extension of the
method described.6 After chromatography, the 15-mem-
bered macrocycles 2a–c were obtained in 44–53%.
Scheme 2
(7a, R1 = R2 = Ph) and comparing it with literature values
1
and by H NMR analysis using (+)-Eu(hfc)3 as a chiral
The N-tosyl macrocycle 2d needed for the preparation of
the unsubstituted derivative 2e was obtained from dichlo-
ro intermediate 4 by treatment with one equivalent of
para-toluene-sulfonamide in diluted DMF solution in the
presence of dry K2CO3 in a yield of 55%. The tosyl group
of 2d was removed by 4% sodium amalgam in MeOH to
give 2e in a yield of 92% (Scheme 1). All new products
shift reagent (7a–m). The trans-epoxyketone 7 was
obtained in all experiments.
Table 1 summarizes the results obtained in the presence of
glucose- and mannose-based lariat ethers 1a–i and 2a–e,
respectively, as catalyst. It can be seen that the yields and
the enantioselectivities are significantly affected by the N-
substituents. With respect to the activity of the glucose-
based lariat ethers (1a–i, entries 1–9), one observes that
the lowest enantiomeric excess values (ca 8–11%) were
recorded in the case of catalysts 1b, 1c and 1i containing
a n-butyl, a benzyl and a diphenylphosphinobutyl N-sub-
stituent, respectively. The best results (92% and 81% ee)
were obtained applying catalysts with g-hydroxypropyl
and b-hydroxyethyl substituents (1f and 1d, respectively),
but the 41% of ee detected using the d-hydroxybutyl de-
rivative (1h) is also considerable. It can be concluded that
the length of the chain connecting the hydroxy group to
the nitrogen atom plays an important role in the asym-
metric induction and the optimum length is of three
1
and intermediates were characterised by H NMR and
mass spectroscopy. The elemental composition was sup-
ported by elemental analysis.
The epoxidation of chalcones 6 with tert-butyl hydroper-
oxide (TBHP, 2 equiv) was carried out in a liquid-liquid
two-phase system in toluene, employing 20% aq NaOH
(3.5 equiv) as the base and 7 mol% of chiral crown cata-
lyst at a temperature of 5–6 °C (Scheme 2).
After the usual work-up procedure the product was isolat-
ed by preparative TLC. The asymmetric induction, ex-
pressed in terms of the enantiomeric excess (ee), was
monitored by measuring the optical rotation of the product
Table 1 Effect of Chiral Crown Catalysts 1 and 2 on the Asymmetric Epoxidation of Chalcone (6a, R1 = R2 = Ph) by t-BuOOH, at 5 °C
Yielda of 7a (%)
[a]D
eec (%)
b
Entry
Time (h)
Catalyst
Compound
R
1
2
1a
1b
1c
1d
1e
1f
H
4
10
10
1
47
59
33
65
58
82
61
65
64
25
70
72
67
+59
28
Butyl
–24.3
–16
11
3
Benzyl
8
4
(CH2)2OH
(CH2)2OCH3
(CH2)3OH
(CH2)3OCH3
(CH2)4OH
(CH2)4P(O)Ph2
H
–173
–43
81 (82)d
20
5
3
6
1
–196
–49
92 (94)d
23
7
1g
1h
1i
2
8
1
–88
41
9
2
–23
11
10
11
12
13
2e
2a
2b
2c
9
+20
9
(CH2)2OH
(CH2)3OH
(CH2)3OCH3
3
+154
+171
+66
72 (71)d
80 (82)d
31
2
6
a Based on isolation by preparative TLC.
b In CH2Cl2 at 22 °C.
c Determined by optical rotation.
d Determined by 1H NMR spectroscopy in the presence of Eu(hfc)3 as chiral shift reagent.
Synlett 2004, No. 4, 643–646 © Thieme Stuttgart · New York

LETTER
Phase Transfer Catalysed Asymmetric Epoxidation of Chalcones
645
carbon atoms as in 1f. It is also important to see that me- The epoxidation of a series of chalcones (6a–m, Table 2)
thylation of the hydrophilic functions in 1d and 1f resulted was examined in the presence catalyst 1f that seemed to be
in a dramatic decrease in the enantioselectivity as demon- the most efficient in the enantioselective epoxidation of
strated by the ee of 20% and 23% obtained with 1e and 1g, chalcone 6a.
respectively. It is clear that the hydrophilic substituents
ensure a better transport of the catalyst between the
Due to solubility problems, the experiments were carried
out at room temperature. The trans epoxy-ketones 7a–m
toluene–water two-phase system, while the lipophilic
were formed in all cases and as the enantiomer with neg-
(CH2)nOMe substituents prevent the transport between the
ative optical rotation. The oxidation of monosubstituted
derivatives (7b–d and 7g,h) took place with a higher
enantioselectivity (77–82%, entries 2–4, 7 and 8), as com-
pared with that of the unsubstituted chalcone (7a, 73%
phases. The discrimination between the prochiral plane of
the chalcone is the most efficient when catalyst 1f assists
the formation of the transient complex.
Remarkably, the use of catalysts 1b–i promoted the for- ee). Among the disubstituted chalcones, the epoxidation
mation of an excess of epoxyketone 7a with negative op- of the derivatives containing 4-chloro or 4-methyl group
tical rotation that is of 2R,3S configuration.8 At the same in both phenyl rings (7j and 7l) led to an ee of ca 77% (en-
time, in the unsubstituted case 1a, the formation of the tries 10 and 12). Presumably, the significant differences
antipode with positive rotation was formed in excess observed in the enantioselectivities are the consequences
(entry 1).
of steric and electronic effects. The substitution pattern in-
fluences the solubility and lipophilicity of the substrates.
In the experiments using lariat ethers bearing a mannose
unit (2a–c, 2e) as catalyst, the epoxyketone 7a with a pos- To explain the efficiency of the chiral crown ether in this
itive optical rotation (2S,3R) was formed in excess. With oxidation, one should assume the formation of the t-
regard to the impact of the length of chain and the nature BuOO– anion,9 which is accompanied by the crown-sodi-
of the substituent in lariat ethers 2a–c on the ee values, a um cation and this tert-butylhydroperoxide anion attacks
similar tendency can be observed as with glucose-based the electron-deficient alkene. With respect to the efficien-
catalysts 1d,f,g.
cy of the crown ether in asymmetric induction, it is
assumed that the substituent on the nitrogen atom assists
the complexation of the cation of the salt in the third di-
mension. The complexing interaction is optimum with the
hydroxypropyl substituent. Hence, we could achieve a
fine tuning regarding the structure of the catalyst and the
highest enantioselectivity.
The catalyst with hydrophilic hydroxyethyl substituent,
and especially that with a hydroxypropyl arm 2a and 2b
were efficient chiral inductors providing 7g with an ee of
72% and 80%, respectively.
Table 2 Epoxidation of Substituted Chalcones by t-BuOOH in the Presence of Catalyst 1f at Room Temperature
b
Entry
1
R1
R2
Time [h]
Yielda [%]
7a, 78
7b, 62
7c, 53
7d, 57
7e, 82
7f, 61
[a]D
eec [%]
73
81
82
80
47
66
77
79
27
77
3
Ph
Ph
1
–155.1
–169.7
–167.9
–156.1
–91.1
2
Ph
p-Me-Ph
p-OMe-Ph
p-Cl-Ph
o,p-di-Cl-Ph
m,p-di-Cl-Ph
Ph
3
3
Ph
3
4
Ph
1
5
Ph
1
6
Ph
0.5
3
–129.3
–183.4
–195.9
–45.2
7
p-Me-Ph
p-NO2-Ph
p-OMe-Ph
p-Cl-Ph
p-F-Ph
p-Me-Ph
p-Me-Ph
7g, 57
7h, 38
7i, 29
8
Ph
2
9
p-NO2-Ph
p-Cl-Ph
o-Cl-Ph
p-Me-Ph
o,p-di-Cl-Ph
4
10
11
12
13
1
7j, 66
–154.7
–6.6
1
7k, 77
7l, 64
3
–171.9
–87.8
76
42
0.5
7m, 82
a Based on isolation by preparative TLC.
b In CH2Cl2 at 22 °C.
c Determined by 1H NMR spectroscopy in the presence of Eu(hfc)3 as chiral shift reagent.
Synlett 2004, No. 4, 643–646 © Thieme Stuttgart · New York

646
P. Bakó et al.
LETTER
H-6), 3.55–3.98 (m, 18 H, OCH2, H-2, H-3, H-4, H-5), 3.37
(s, 3 H, OCH3), 2.78 (t, 6 H, CH2N). FAB–MS: 484 [M+ +
H], 506 [M+ + Na]. For 2b: [a]D20 +15.0 (c = 1, CHCl3).
Acknowledgement
This work was supported by the National Science Foundation (OT-
KA T 042514).
20
FAB–MS: 498 [M+ + H], 520 [M+ + Na]. For 2c: [a]D
+19.6 (c = 1, CHCl3). 1H NMR: d = 7.39 (d, 2 H, ArH), 7.27
(t, 3 H, ArH), 5.52 (s, 1 H, benzylidene-CH), 4.67 (s, 1 H,
anomer-H), 4.16 (q, J = 10.1 Hz, 1 H, H-6), 4.02 (t, J = 9.6
Hz, 1 H, H-6), 3.45–3.95 (m, 18 H, OCH2, H-2, H-3, H-4, H-
5), 3.31 (s, 3 H, OCH3), 3.24 (t, 3 H, OCH3), 2.72 (t, 4 H,
CH2N), 2.56 (t, 2 H, CH2N), 1.69 (m, 2 H, CH2). FAB–MS:
512 [M+ + H], 534 [M+ + Na]. For 2d: [a]D20 +18.8 (c = 1,
CHCl3). 1H NMR: d = 7.71 (d, 2 H, tosyl-ArH), 7.49 (d, 2 H,
tosyl-ArH), 7.38 (d, 2 H, ArH), 7.32 (t, 3 H, ArH), 5.62 (s, 1
H, benzylidene-CH), 4.74 (s, 1 H, anomer-H), 4.26 (q, J =
10.1 Hz, 1 H, H-6), 4.12 (t, J = 9.6 Hz, 1 H, H-6), 3.51–4.00
(m, 16 H, OCH2, H-2, H-3, H-4, H-5), 3.40 (s, 3 H, OCH3),
3.20–3.26 (m, 4 H, CH2N), 2.44 (s, 3 H, CH3). FAB–MS:
594 [M+ + H], 616 [M+ + Na]. For 2e: [a]D20 +26.3 (c = 1,
CHCl3). 1H NMR: d = 7.47 (d, 2 H, ArH), 7.35 (t, 3 H, ArH),
5.60 (s, 1 H, benzylidene-CH), 4.78 (s, 1 H, anomer-H), 4.25
(q, J = 10.1 Hz, 1 H, H-6), 4.14 (t, J = 9.6 Hz, 1 H, H-6),
3.55–4.08 (m, 16 H, OCH2, H-2, H-3, H-4, H-5), 3.39 (s, 3
H, OCH3), 2.85 (t, 2 H, CH2N), 2.76 (t, 2 H, CH2N), 2.55 (m,
1 H, NH). FAB–MS: 440 [M+ + H], 462 [M+ + Na].
References
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Chalcone (1.44 mmol) and the crown ether (0.1 mmol) were
dissolved in 3 mL of toluene and 1 mL of 20% aq NaOH was
added maintaining the temperature at 5 °C with ice water.
Then 0.5 mL of tert-butylhydroperoxide (5.5 M decane
solution, 2.88 mmol) was added and the mixture stirred at 5
°C. After completing the reaction (1–48 h), a mixture of 7
mL of toluene and 10 mL of water was added. The organic
phase was dried (Na2SO4) and concentrated in vacuo. The
crude product was purified on silica gel by preparative TLC
with hexane–EtOAc (10:1) as eluent, for 7a [a]D = –196 (c =
1, CH2Cl2, 20 °C) with 92% ee (lit., [a]D –214 for the pure
enantiomer);10 mp 64–66 °C (EtOH). 1H NMR (CDCl3): d =
8.02 (d, 2 H, o-COPh-H), 7.63 (t, 1 H, p-COPh-H), 7.50 (t, 2
H, m-COPh-H), 7.38–7.44 (m, 5 H, CHPh-H), 4.30 (d, J =
1.9 Hz, 1 H, COCH), 4.09 (d, J = 1.9 Hz, 1 H, PhCH). For
7c: [a]D = –167.9 (c = 1, CH2Cl2, 20 °C) with 82% ee; mp 81
°C (EtOH). 1H NMR: d = 8.01 (d, 2 H, o-COPh-H), 7.39 (m,
5 H, CHPh-H), 6.95 (d, 2 H, m-COPh-H), 4.25 (d, J = 1.7 Hz,
1 H, COCH), 4.07 (d, J = 1.3 Hz, 1 H, PhCH), 3.87 (s, 3 H,
OCH3). For 7d: [a]D = –156.1 (c = 1, CH2Cl2, 20 °C) with
80% ee; mp 121 °C (EtOH). 1H NMR: d = 7.96 (d, 2 H, o-
COPh-H), 7.46 (d, 2 H, m-COPh-H), 7.40 (t, 3 H, m,p-
CHPh-H), 7.36 (d, 2 H, o-CHPh-H), 4.23 (d, J = 1.6 Hz, 1 H,
COCH), 4.07 (d, J = 1.3 Hz, 1 H, PhCH).
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(11) Selected data for 5: [a]D20 +18.0 (c = 1, CHCl3). 1H NMR:
d = 7.47 (d, 2 H, ArH), 7.36 (t, 3 H, ArH), 5.59 (s, 1 H,
benzylidene-CH), 4.78 (s, 1 H, anomer-H), 4.24 (q, J = 10.1
Hz, 1 H, H-6), 4.06 (t, J = 9.6 Hz, 1 H, H-6), 3.66–4.00 (m,
16 H, OCH2, H-2, H-3, H-4, H-5), 3.38 (s, 3 H, OCH3), 3.26
(t, 2 H, CH2I), 3.18 (t, 2 H, CH2I). For 2a: [a]D20 +16.0 (c =
1, CHCl3). 1H NMR: d = 7.48 (d, 2 H, ArH), 7.35 (t, 3 H,
ArH), 5.30 (s, 1 H, benzylidene-CH), 4.75 (s, 1 H, anomer-
H), 4.24 (q, J = 10.1 Hz, 1 H, H-6), 4.11 (t, J = 9.6 Hz, 1 H,
Synlett 2004, No. 4, 643–646 © Thieme Stuttgart · New York