Synthesis of chiral azacrown ethers derived from α-D-glucose and their catalytic properties on the asymmetric Michael addition

Article abstract of DOI:10.3987/COM-00-9098

Three types of chiral azacrown ethers have been synthesized from (+)(4,6-O-benzylidene)-O-methyl-α-D-glucopyranoside and their catalytic properties for the asymmetric Michael addition have been investigated; enantioselectivity switching which is dependent on the azacrown ether catalysts has been achieved.

Full text of DOI:10.3987/COM-00-9098

HETEROCYCLES, Vol. 55, No. 1, 2001, pp. 37 - 43, Received, 2nd November, 2000
α
SYNTHESIS OF CHIRAL AZACROWN ETHERS DERIVED FROM -D-
GLUCOSE AND THEIR CATALYTIC PROPERTIES ON THE
ASYMMETRIC MICHAELADDITION
Toshiyuki Itoh†* and Shohei Shirakami
Graduate School of Natural Science and Technology, Okayama University,
†Department of Chemistry, Faculty of Education, Okayama University, 3-1-1
Tsushima-naka, Okayama 700-8530, Japan. E-mail: titoh@cc.okayama-u.ac.jp
Abstract- Three types of chiral azacrown ethers have been synthesized from (+)-
(4,6-O-benzylidene)-O-methyl-α-D-glucopyranoside and their catalytic properties
for the asymmetric Michael addition have been investigated; enantioselectivity
switching which is dependent on the azacrown ether catalysts has been achieved.
Development of a natural environmentally friendly catalyst for the asymmetric reaction is one of the
1
current topics in recent organic synthesis; several types of efficient catalysts derived from alkaloids2 or
3
chiral crown ethers have been reported with their numerous applications.2,3 We are attracted by chiral
azacrown ethers which were derived from sugars reported by Töke and his colleagues.4 We have
previously demonstrated a simple method for resolving axially chiral biphenyldicarboxylic acids based on
the kinetic controlled cyclic ester formation of racemic biphenyldicarboxylic acids with (+)-(4,6-O-
benzylidene)-O-methyl-α-D-glucopyranoside.5 In the reaction, two adjacent hydroxyl groups at the 2-
and 3-positions on theglucoside had an important role in recognizing chirality.5b,6
Figure1. Results of MO(PM3) calculation of the optimized structure
of two azacrown ethers 1a and 2a derived from α-D-Glucose
OMe
O
O
OMe
OMe
O
MeO
MeO
MeO
O
O
O
O
O
O
O
N
N
H
H
1a (2,3-type)
2a (3,4-type)
Although no mechanistic detail for the origin of enantio-favoritism of Töke’s sugar-type azacrown ether
has been reported, we expected that opposite enantioselectivity could be seen between the 2,3-bridged

type of azacrown ethers (1a) and 3,4-bridged type azacrown ethers (2a), both of which are derived from
the same source of α-D-glucose; the computational chemistry suggest that 2a is a pseudo-enatiomeric
form of 1a and addition reaction of a nucleophile to a suitable acceptor would take place from the
opposite side in the reactions catalyzed by azacrown ether (1a) or (2a) (Figure 1).7
Scheme 1. Synthesis of various types of chiral azacrown ethers derived from
(4,6-O-benzylidene)-O-methyl- α-D-glucopyranoside (4)
MeO
O
MeO
O
MeO
O
MeO
O
OBn
O
OBn
OH
OH
OH
c
OBn
OAc
d
a
b
TrO
O
O
O
O
O
O
O
OAc
TrO
Ph
Ph
5
4
6
Cl
7
Cl
MeO
O
g
b
f
e
OBu
OBu
MeO
O
OBn
O
MeO
O
MeO
O
OBn
O
c
O
O
OBu
OBu
g
BuO
O
O
O
O
O
HO
O
O
O
OHOH
HN
h
Cl
N
Cl
9
10
Ts
2b: 3,4-Type
e
8
MeO
O
MeO
O
OBu
OBu
OBu
OBu
MeO
O
O
O
O
h
O
O
N H
O
O
O
O
O
O
O
BuO
OBu
H
N
N
Ts
11
1b: 2,3-Type4a
3b: 4,6-Type
N
13a
MeO C4F9
N
13b
MeO
MeO
O
I
O
O
O
O
O
O
i
O
N R
O
O
I
O
O
O
O
C4F9
13c
OH
12
13
Ph
Ph
OMe
13e
13d
a) Bu2SnO, MeOH, reflux, 1 h, then BnBr, 110°C,11 h, 83%. b) 0.5 N-HCl, THF, MeOH, reflux, 4 h,
95~100%. c) TrCl, pyridine, 40°C, 8 h, then Ac2O, rt, 2 h, >90%. d) (ClCH2CH2)2O, 50% aq. NaOH,
NBu4·HSO4 , rt, 12 h, 83%. e) TsNH2, K2CO3, DMF, 120°C, 36 h, 72%. f) TMSCl, NaI, MeCN, rt, 5 min,
97%. g) BuBr, NaH, DMF, 40°C, 10 h, >90%. h) Na·Naphthalenide DME, -60°C, 1 h, 59%. i) RNH2,
,
Na2CO3 or Cs2CO3, MeCN, reflux, 36~48 h, 54~87%.

We thus decided to synthesize various types of chiral azacrown ethers systematically, and to investigate
their catalytic properties on the asymmetric reaction. We synthesized two types of novel chiral azacrown
ethers (2b) and (3b) from glucopyranoside (4) following Scheme 1. Glucoside (4) was converted to 2-
benzyl ether through a cyclic stannyl ester to give glucoside (5) in 63% yield,8 then deprotection and
regioselective protection at the 6-position as trityl ether to afford 6. Bisalkylation of 6 at 3- and 4-
positions was successfully accomplished under a phase-transfer reaction condition9 to lead to 7;
cyclization of 7 and alkylation at 6-position and final detosylation gave 2b in good overall yield. Through
the similar pathway, 4,6-bridged type azacrown ether (3b) was also synthesized successfully. Because a
substituent at the nitrogen atom of the azacrown ether seems to affect the enantio-favoritism of the
reaction by MO calculation, we also synthesized seven types of N-alkylated azacrown ethers (13a-13e).
Using chiral azacrown ether (1b)4a, we initially tested enantioselective alkylation of glycine derivative
(14),2h however, only poor enantioselective reaction was observed. On the other hand, enantioselective
Michael addition of an enolate derived from 14 to methyl vinyl ketone gave the addition product (15) in
good yield with acceptable enantioselectivity (Eq. 1) and the results are summarized in Table 1.
(3 eq)
Azacrown (20 mol%)
E
Ph
Ph
Ph
Ph
CO2But
E
(1)
N
CO2But
N
*
t
NaOBu (20 mol%)
14
15
Solvent
Table 1. Results of asymmetric Michael reaction mediated by chiral azacrown ethers
15
15
Temp.
(°C)
Time
(h)
Entry
Acceptor Crown
Solvent
Yield(%) a ee(%)b, c
O
1b
1
2
3
4
5
Toluene
Et2O
-78
-78
-78
-78
-78
3
14
7
75
77
82
79
28
64(S)
70(S)
72 (S)
60 (R)
2 (R)
Me
O
Me
O
1b
1b Toluene:Et2O=1:1
2b Toluene:Et2O=1:1
3b Toluene:Et2O=1:1
Me
O
Me
O
5.5
39
Me
a) Isolated yield. b) Enantiomeric excess was determined by HPLC Analysis (CHIRALCEL OD),
Hexane: i-PrOH= 200:1 ~ 350:1. c) The absolute configuration was determined by comparison of
specific rotation value with that of the authentic sample. 2p,y
The optical purity of product (15) was strongly dependent on the solvent system, the mixed solvent
system (toluene to ether = 1:1) gave a better result than that in toluene or ether. A mixture of 14, azacrown

ether (1b) (20 mol%), and methyl vinyl ketone in the presence of 20 mol% of sodium t-butoxide at -78°C
for 7 h gave the Michael adduct (15) in 82% yield with 72% ee (Entry 3 in Table 1). The absolute
configuration of the product was found to be (S) by comparison of the specific rotation value of 15 with
that of the authentic sample.2p,y As suggested by the result of MO calculation, desired “enantioselectivity
switching” was realized; the Michael adduct ((R)-15) was obtained in 79% yield with 60% ee when the
reaction was carried out using azacrown ether (2b) as catalyst (Entry 4). The reaction using 4,6-bridged
type azacrown ether (3b) as catalyst, on the other hand, gave 15 in poor enantioselectivity (Entry 5).
Because “enantioselectivity switching” was obtained for 1b and 2b, we assume that the most important
factor determining the enantioselectivity was the difference in the torsion of the molecular flame of the
azacrown ether ring; this should control the direction of the Michael acceptor attack to the enolate on the
azacrown ring.
Table 2. Results of asymmetric Michael reaction mediated by chiral azacrown ethers
15
Yield(%) a ee(%)b
15
Temp.
(°C)
Time
(h)
Entry
Acceptor Crown
O
Solvent
68 (S)
62 (S)
12 (S)
20 (S)
21 (S)
60 (S)
47 (S)
---
1
2
3
4
5
6
7
8
9
13a Toluene:Et2O=1:1
13b Toluene:Et2O=1:1
13c Toluene:Et2O=1:1
13d Toluene:Et2O=1:1
13e Toluene:Et2O=1:1
1b Toluene:Et2O=1:1
-78
-78
0.5
0.4
8
72
75
79
61
53
52
63
0d
Me
O
Me
O
Me
O
Me
O
Me
-78
-78
5.5
1.5
39
-78
-50
CN
O
1b
Et2O c
-50
17
OMe
O
1b Toluene:Et2O=2:1
1b Toluene:Et2O=1:1
-78~25
-40
24
Ph
Ph
NMe2
O
48 (S)
28
83
O
a) Isolated yield. b) Enantiomeric excess was determined by HPLC Analysis (CHIRALCEL OD),
Hexane: i-PrOH= 200:1 ~ 350:1. c) Reaction in ether gave better result than those in the standard mixed
solvent system. d) No reaction took place and the strating compound was recovered quantitatively.
Michael addition was next investigated in the presence of various types N-substituted azacrown ethers
(Table 2). Remarkable acceleration was observed when the reactions were carried out in the presence of
N-2-pyridylmethyl-substituted azacrown ether (13a) or (13b); only 0.4~0.5 h reaction provided (S)-15
with 68% ee (Entry 1) and 62% ee (Entry 2), respectively. Significant reduction of enantioselectivity was
observed when 13c and 13d were used as catalysts (Entries 4 and 5), though the same (S)-enantio-

favoritism was obtained in all reactions. Generally, results of the Michael reaction are strongly dependent
on the species of Michael acceptor. The reaction with acrylonitrile (Entry 7) gave the Michael product
with moderate enantioselectivity (60% ee), while poor enantioselectivity was obtained in the reactions of
acrylate derivatives (Entries 8 and 10), and no Michael adduct was obtained for chalcone (Entry 9).
In conclusion, we have accomplished enantioselectivity switching of the Michael addition using three
types of chiral azacrown ethers derived from the same origin of α-D-glucose. 3,4-Bridged types of
azacrown ether gave (R)-adduct, while 2,3-bridged type of crown ether afforded (S)-adduct. It should be
noted that the enantioselectivity can also be modified by the N-substituent group of the azacrown ether,
though the major factor determining the enantioselectivity was the asymmetrical environment due to the
crown ether ring. Although the enantioselectivity remained at an insufficient level, these results provide
very important information for considering the transition state structure of the present azacrown ether
mediated asymmetric reaction. Further investigations on optimization of the substrate using various types
of N-substituted azacrown ethers are now in progress.
ACKNOWLEDGMENT
This work was supported by a grant from the Venture Business Laboratory of the Graduate School of
Okayama University. The authors are grateful to the SC-NMR Laboratory of the Okayama University for
the NMR measurements.
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7. MacSpartan Pro was employed for MO (PM3) calculation. Results of MO (PM3) calculation (Heat of
formation): 1a; -271.63 Kcal/mol, 2a; -270.10 Kcal/mol.
8. M. J. Eis, and B. Ganem, Carbohydrate Res., 1988, 316.
9. P. D. Cesare, and B. Gross, Synthesis, 1979, 458.
10. Physical constant and NMR data of 2b: colorless syrup; Rf 0.46 (CHCl3 / MeOH = 3:1); [α]D23 +28.4°
(c1.38, CHCl3); 1H NMR (200 MHz, δ, CDCl3) 0.90 (3H, t, J=7.3 Hz), 1.26-1.68 (4H, m), 1.97 (1H,
br s), 2.68-2.92 (4H, m), 3.33 (3H, s), 3.28-4.16 (20H, m), 4.56 (1H, d, J=3.5 Hz), 4.61 (1H, d, J=12.2
Hz), 4.73 (1H, d, J= 12.2 Hz), 7.27-7.33 (5H, m); 13C NMR (50 MHz, ppm, CDCl3) 13.9, 19.3, 31.7,
47.5, 47.9, 55.0, 69.1, 69.4, 69.6, 69.8, 70.0, 70.4, 71.4, 72.6, 73.1, 73.2, 80.0, 81.4, 98.1, 127.9,
128.0, 128.4, 138.1; IR (neat, cm-1) 3384, 2921, 1459, and 1100.
3b: colorless solid; mp 76~78°C (recrystallization from CHCl3); Rf 0.48 (CH2Cl2 / MeOH = 3:1);
[α]D29 +70.3° (c 0.76, CHCl3); 1H NMR (200 MHz, δ, CDCl3) 0.91 (6H, t, J= 7.3 Hz), 1.26-1.63 (8H,
m), 2.33 (1H, br s), 2.83-2.86 (4H, m), 3.12-4.10 (22H, m), 3.40 (3H, s), 4.78 (1H, d, J= 3.5 Hz); 13C
NMR (50 MHz, ppm, CDCl3) 13.8, 13.9, 19.1, 19.3, 32.1, 32.6, 48.4, 55.0, 69.2, 69.8, 70.4, 70.8, 71.2,
71.3, 72.2, 72.3, 73.1, 78.6, 80.8, 81.6, 97.7; IR (neat, cm-1) 3333, 2923, 1462, 1365, 1106, and 796.
23
Michael adduct (15): colorless syrup; Rf 0.23 (hexane / ethyl acetate = 2:1); [α]D -47.9° (c 1.15,
CHCl3), 72%ee(S); 1H NMR (200 MHz, δ, CDCl3) 1.43 (9H, s), 2.11(3H, s), 2.15 (2H, t, J= 7.3 Hz),
2.52 (2H, dt, J= 7.3, 6.1 Hz), 3.95 (1H, t, J= 6.1 Hz), 7.13-7.64 (10H, m); 13C NMR (50 MHz, ppm,
CDCl3) 27.7, 28.0, 29.9, 39.8, 64.7, 77.2, 81.1, 127.7, 128.0, 128.4, 128.6, 128.7, 130.3, 136.4, 139.4,
170.5, 170.9, 208.3; IR (neat, cm-1) 3060, 2974, 1728, 1710, 1627, and 1154.