Synthesis and application in asymmetric synthesis of azacrown ethers derived from D-glucose

Article abstract of DOI:10.1039/a802098a

New chiral monoaza-15-crown-5 derivatives and lariat ethers anellated to phenyl β-D-glucoside have been synthesized which show significant asymmetric induction as phase transfer catalysts in the Michael addition of 2-nitropropane to chalcone (84% ee) and

Full text of DOI:10.1039/a802098a

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Synthesis and application in asymmetric synthesis of azacrown ethers derived
from d-glucose
Pe´ter Bako´,a† Kristo´f Vizva´rdi,a Zolta´n Bajora and La´szlo´ To˜ke*b
a Department of Organic Chemical Technology, Technical University of Budapest, H-1521 Budapest, Hungary
b Organic Chemical Technology Research Group of the Hungarian Acadamy of Sciences at the Technical University of Budapest,
H-1521 Budapest, Hungary
Table 1 Yield and characterisation data of compounds 2–12
New chiral monoaza-15-crown-5 derivatives and lariat
ethers anellated to phenyl b-D-glucoside have been synthe-
[a]20
sized which show significant asymmetric induction as phase
Compound
Yield (%)a
(c 1, CHCl3) Mp/°C
transfer catalysts in the Michael addition of 2-nitropropane
to chalcone (84% ee) and in the Darzens condensation of
phenacyl chloride with benzaldehyde (74% ee).
2
3
4
5
6
7
8
9
29
95
44
32
39
32
42
48
48
54
45
235.5
228.6
243.0
235.4
239.2
241.1
234.9
244.3
235.2
240.1
244.9
74–75
58–59
105–106
58–60
oil
107–108
oil
153–55
oil
One of the most attractive types of asymmetric synthesis is that
in which chiral products are generated under the influence of
chiral crown ether catalysts. Although many optically active
crown ethers have been prepared, only a few have been used
successfully as catalysts in asymmetric reactions.1 Previously,
we reported the asymmetric Michael addition of phenyl acetate
to acrylate catalyzed by chiral crown ethers composed of two
glucose units (85% ee).1,2 The substituents on the sugar unit of
the macrocycle1,2 and the side arms at the nitrogen atom in the
crown ring3 play an important role in the catalytic activity of the
crown ethers. The latter compounds with heteroatoms in the
side arm, named lariat ethers or armed crown ethers, are known
to display special complexation, high lipophilic character and
unique guest specificity via macroring–side arm cooperativity.4
It is therefore reasonable to study the effect of using different
pendant arms on the chiral crown ether catalyst in asymmetric
reactions.
10
11
12
oil
oil
a After column chromatography.
(as a phase transfer catalyst) and 50% aq. NaOH to give
compound 2 (room temperature, 8 h, column chromatography).
The exchange of chlorine for iodine in 2 was carried out using
NaI in acetone (reflux, 24 h), resulting in the bis(iodide)
derivative 3. Compound 3 was cyclized with various primary
amines: n-butylamine, 2,4-dimethylpentan-3-ylamine, cyclo-
hexylamine, cyclohexylmethylamine, benzylamine, 2-phenyl-
ethylamine, ethanolamine, 2-methoxyethylamine and propa-
nolamine, respectively, according to the method described
previously,6 which requires dry Na2CO3 in MeCN as solvent
(reflux, 32–40 h, column chromatography). We thus obtained
the corresponding 15-membered macrocycles 4–12, the yields
of the ring closure steps after chromatography being in the range
32–54% (Table 1). All structures were ascertained by 1H NMR,
13C NMR, COSY, mass and elemental analysis.‡
We now report on the synthesis and application of new
monoaza-15-crown-5 compounds 4–12.
O
O
O
O
H
O
O
OR
OR
O
O
O
O
N
R1
H
O
H
O
Compounds 4–12 were then used as phase transfer catalysts
in different reactions in which enantiomeric mixtures can be
formed. These catalysts proved to be effective in two reactions:
the Michael addition of 2-nitropropane to chalcone (Scheme 1),
H
H
H
O
1 R = H
4 R1 = Bu
Me
2 R = (CH2)2O(CH2)2Cl
3 R = (CH2)2O(CH2)2I
5 R1 = Pri2CH
6 R1 = C6H11
7 R1 = C6H11CH2
8 R1 = Bn
9 R1 = Ph(CH2)2
10 R1 = HO(CH2)2
11 R1 = MeO(CH2)2
12 R1 = HO(CH2)3
H
C
NO2
Me
15
+
13
NaOBut
toluene
catalyst
O
Their synthesis starts from phenyl 4,6-O-benzylidene-b-d-
glucopyranoside 1. The vicinal free hydroxy groups in com-
pound 1 were alkylated using the method of Di Cesare and
Gross,5 with bis(2-chloroethyl) ether acting as solvent and
reagent, under liquid–liquid (LL) two-phase reaction condi-
tions, in the presence of tetrabutylammonium hydrogen sulfate
*
O2N
Me
Me
15
Scheme 1
Chem. Commun., 1998
1193

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containing a free hydroxy group on the magnitude of the
enantioselectivity for the Darzens condensation is the reverse of
that for the Michael reactions (entries 7 and 8). The importance
of the chain-length at the N-atom in the catalytic activity is
reflected particularly in the experiment shown in entry 9:
catalyst 12 [R = (CH2)3OH] proved to be the most effective,
resulting in 74% ee at room temperature. With regard to the
effectiveness of the crown ether structure for enantiomeric
induction, we suppose that the substituent at the nitrogen atom
of the catalyst takes part in the complexation of the salt of the
anion by complexation of the cation in the third dimension,
working as a pseudo-lariat ether, and as a consequence increases
the effectiveness of the phase transfer process. Reactions
running in the absence of chiral catalyst give only racemic
products.
The authors gratefully acknowledge Professor Dr Suzanne
Toppet for NMR spectroscopic identification of the com-
pounds, Dr Erik Van der Eycken and Professor Dr Georges J.
Hoornaert for useful discussions (Laboratorium voor Orga-
nische Synthese, K. U. Leuven). This work was partly
supported by the Hungarian Academy of Sciences and the
National Science Foundation (OTKA T015677) and the Soros
Foundation.
O
O
H
O
catalyst
CH2Cl
H
*
*
O
H
+
aq. NaOH
toluene
16
17
18
Scheme 2
and the Darzens condensation of phenacyl chloride with
benzaldehyde (Scheme 2).
The Michael addition was carried out in a solid–liquid (SL)
system; in toluene, employing solid NaOBut as base (35 mol%)
and chiral catalyst (7 mol%) at room temperature.§ After the
usual work-up procedure the adduct was isolated by preparative
TLC, and the asymmetric induction, expressed in terms of the
enantiomeric excess (ee), was monitored by measuring the
optical rotation of the product 15 and comparing it with
literature values3 and by 1H NMR analysis using (+)-Eu(hfc)3 as
a chiral shift reagent. The results are shown in Table 2.
As can be seen, the substituents at the N-atom of the catalyst
have a significant influence on both the chemical yield and the
enentioselectivity. In all cases the (S)-(+)-adducts 15 were
found to be in excess. The catalyst having the bulky 2,4-di-
methylpentan-3-yl group at the N-atom gave the lowest
chemical yield and chiral induction (entry 2), and the crown
ether having a phenylethyl group (9) proved to be the best (entry
6). The methyl ether 11 showed a higher ee value than its free
hydroxy analogue 10 (entry 8 and 7). The length of the side arm
is decisive: catalyst 8 having a benzyl group shows poor chiral
induction (6% ee), while compound 9 containing a phenylethyl
group gives high enantioselectivity (84% ee).
The Darzens condensation (Scheme 2) was performed in a
binary LL system, using a toluene–30% aq. NaOH (5:1)
mixture.¶ The work-up procedure and determination of ee was
carried out in a similar manner to that mentioned for the Michael
addition. In all cases the epoxy ketone product 18 with a
negative optical rotation was found to be in excess, which on the
basis of the optical rotation of the pure enantiomer, corresponds
to an absolute configuration of (2R,3S).7 Low enantioselectiv-
ities were obtained using catalysts 4–8 (entries 1–5). The
macrocycle 10 [R = (CH2)2OH] having the hydrophilic
hydroxyethyl group at the N-atom gave 52% ee (entry 7) but this
value was dramatically reduced (13% ee) for its methyl ether 11
(entry 8). It is interesting to note that the effect of the compound
Notes and References
† E-mail: p-bako@chem.bme.hu
‡ Selected data for 2: dH(250 MHz, CDCl3, SiMe4) 7.50–7.06 (m, 10 H,
ArH), 5.56 (s, 1 H, Benzylidene-CH), 5.06 (d, J 7.6, 1 H, anomer-H), 4.36
(dd, J 10.5, 4.3, 1 H, H-6), 4.09–3.53 (m, 21 H, 8 CH2O, 5 CH). For 3:
7.50–7.05 (m, 10 H, ArH), 5.56 (s, 1 H, benzylidene-CH), 5.06 (d, J 7.6, 1
H, anomer-H), 4.38–4.36 (dd, J 10.5, 4.3, 1 H, H-6), 4.02–3.52 (m, 18 H, 8
CH2O, 2 CH), 3.21–3.18 (m, 3 H, H-2, H-3, H-5). For 9: 7.37–7.02 (m, 15
H, ArH), 5.54 (s, 1 H, benzylidene-CH), 5.06 (d, J 7.6, 1 H, anomer-H), 4.36
(dd, J 10.5, 4.3, 1 H, H-6), 4.10–3.57 (m, 15 H, 6 CH2O and 3 CH),
3.54–3.47 (m, 2 H, H-2, H-5), 2.89–2.76 (m, 8 H, 3 NCH2, CH2Ph).
§ The Michael addition was performed as follows: 1.44 mmol of chalcone
and 3.36 mmol of 2-nitropropane were dissolved in 3 ml of anhydrous
toluene, and then 0.1 mmol of crown ether and 0.5 mmol of base were
added. The mixture was stirred under an Ar atmosphere. After completing
the reaction (8–40 h) a mixture of 7 ml of toluene and 10 ml of water was
added. The organic phase was processed in the usual manner. The product
was purified on silica gel by preparative TLC with hexane–ethyl acetate
(10:1) as eluent; mp 146–148 °C, [a]2D0 + 68 (c 1, CH2Cl2) (84% ee) (lit.,3
+80.8, for pure enantiomer), dH 7.85 (m, 2 H, Ph), 7.52 (m, 3 H, Ph), 7.25
(m, 5 H, Ph), 4.18–3.25 (m, 3 H, CH2, CH), 1.62 (s, 3 H, CH3), 1.54 (s, 3
H, CH3).
¶ Typical experimental procedure for the asymmetric Darzens condensa-
tion: a toluene solution of 1.3 mmol of phenacyl chloride (3 ml) was treated
with 1.9 mmol of benzaldehyde and 0.1 mmol of catalyst in 0.6 ml of 30%
NaOH solution. The mixture was stirred under Ar atmosphere. After
completing the reaction 7 ml of toluene were added, the organic phase
washed with water, dried over MgSO4 and the solvent evaporated. The
Table 2 Effect of chiral crown catalysts 4–12 on the asymmetric Michael
addition and Darzens condensation
Michael addition
Darzens condensation
residue was chromatographed on preparative silica gel of 2 mm thickness
20
578
(Kieselgel 60 GF254), using CH2Cl2 as eluent; (a] 2111 (c 1, CH2Cl2)
(52% ee) (lit.,7 2214, for pure enantiomer); dH 8.01 (m, 2 H, Ph), 7.60 (t,
1 H, Ph), 7.48 (t, 2 H, Ph), 7.40–7.30 (m, 5 H, Ph), 4.29 (d, J 2, 1 H), 4.08
(d, J, 1 H).
Entry
Catalyst Yield (%)a Ee (%)b Yield (%)
Ee (%)b
1
2
3
4
5
6
7
8
9
4
5
6
7
8
61
15
50
53
56
78
71
65
42
27
4
23
24
6
92
33
94
70
88
4
3
4
8
1 L. To˜ke, P. Bako´, Gy. M. Keseruˆ, M. Albert and L. Fenichel,
Tetrahedron, 1998, 54, 213 and references cited therein.
4
30
52 (53)c
13
2 L. To˜ke, L. Fenichel and M. Albert, Tetrahedron Lett., 1995, 36, 5951.
´
9
82 (84)c 72
3 P. Bako´, A. Szo¨llo˜sy, P. Bombicz and L. To˜ke, Heteroatom Chem., 1997,
10
11
12
45
60
6
86
72
68
8, 333.
4 G. W. Gokel, Chem. Soc. Rev., 1992, 21, 39.
5 P. Di Cesare and B. Gross, Synth. Commun., 1979, 4581.
6 P. Bako´ and L. To˜ke, J. Inclusion Phenom., 1995, 23, 195.
7 B. Marsman and H. Wynberg, J. Org. Chem., 1979, 44, 2312.
74
a Based on isolation by preparative TLC. b Determined by optical rotation.
c Determined by 1H NMR spectroscopy in the presence of Eu(hfc)3 as chiral
shift reagent.
Received in Liverpool, UK, 16th March 1998; 8/02098A
1194
Chem. Commun., 1998