Synthesis of novel chiral crown ethers derived from D-glucose and their application to an enantioselective Michael reaction

Article abstract of DOI:10.1039/a905670j

New chiral monoaza-15-crown-5 derivatives anellated to methyl 4,6-di-O-butyl-α-D-glucopyranoside have been synthesized from 1 using the 4,6-O-benzylidene protecting group (removed by acetic acid) and 2,3-di-O-benzyl groups (removed by catalytic hydrogenolysis). The alkylation of the hydroxy groups in 1 and 5 with benzyl chloride and bis(2-chloroethyl) ether, respectively, were carried out in two-phase reactions using phase-transfer (PT) catalysts. These sugar-based crown ethers showed significant asymmetric induction as chiral PT catalysts in the Michael addition of 2-nitropropane to chalcone (90% ee). The substituent at the nitrogen atom of the crown ethers has a major influence on both the chemical yield and the enantioselectivity. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a905670j

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Synthesis of novel chiral crown ethers derived from D-glucose and
their application to an enantioselective Michael reaction
Péter Bakó,a Zoltán Bajora and László To´´ k e b*
a Department of Organic Chemical Technology, Technical University of Budapest,
H-1521 Budapest, P.O. Box 91, Hungary
b Organic Chemical Technology Research Group of the Hungarian Academy of Sciences
at the Technical University of Budapest, H-1521 Budapest, P.O. Box 91, Hungary
Received (in Cambridge, UK) 13th July 1999, Accepted 3rd November 1999
New chiral monoaza-15-crown-5 derivatives anellated to methyl 4,6-di-O-butyl-α--glucopyranoside have been
synthesized from 1 using the 4,6-O-benzylidene protecting group (removed by acetic acid) and 2,3-di-O-benzyl
groups (removed by catalytic hydrogenolysis). The alkylation of the hydroxy groups in 1 and 5 with benzyl chloride
and bis(2-chloroethyl) ether, respectively, were carried out in two-phase reactions using phase-transfer (PT) catalysts.
These sugar-based crown ethers showed significant asymmetric induction as chiral PT catalysts in the Michael
addition of 2-nitropropane to chalcone (90% ee). The substituent at the nitrogen atom of the crown ethers has a
major influence on both the chemical yield and the enantioselectivity.
N-unsubstituted compound) as chiral PT catalyst resulted in
Introduction
90% ee in the reaction of 2-nitropropane and chalcone.13 In this
One of the most attractive types of asymmetric synthesis is that
paper we report the full details of this work and additionally
in which chiral products are generated under the influence of
chiral crown ether catalysts. A number of chiral crown ethers
discuss the synthesis and properties of a series of N-substituted
analogues 8–11 (which in the event proved to be less effective
than the N-substituted original).
have been employed as chiral catalysts in phase-transfer reac-
tions.1 A variety of such macrocycles have been synthesized and
much attention was focussed on systems derived from carbo-
Results and discussion
The general synthetic procedures for compounds 2–7 are sum-
hydrates. Crown ethers anellated to different pyranosidic or
furanosidic carbohydrates have also been described.2 The
carbohydrate-containing chiral crown ethers have proved to be
suitable models for the study of chiral induction in enantio-
selective reactions. Although many chiral crown ethers having
different carbohydrate moieties have been synthesized in recent
years, only a few have successfully been applied as catalysts in
asymmetric reactions.1
marized in Schemes 1 and 2.
The Michael reaction is one of the most important C–C
bond-forming reactions, and stereoselective variants have been
extensively investigated in recent years.3 High asymmetric
inductions have been reported in the Michael addition of
methyl phenylacetate to methyl acrylate catalyzed by
carbohydrate-containing chiral crown ethers.4–8 We have
previously reported the synthesis of new 15-membered-ring
monoaza-crown ethers from glucose and galactose9 and their
application as chiral phase-transfer (PT) catalysts in an asym-
metric Michael addition and in a Darzens condensation.10,11
We first began investigating the Michael addition of 2-nitro-
propane to a chalcone catalyzed by chiral macrocyclic poly-
ethers under phase-transfer conditions. The best result achieved
in this reaction was 60% enantiomeric excess (ee) in the pres-
ence of monoaza-15-crown-5 ether containing a methyl 4,6-O-
benzylidene-α--glucopyranoside unit,11 and 82% ee generated
by the crown catalyst anellated to phenyl β--glucopyranoside,
respectively.12 The chiral nature of the crown ether, the rigidity
of the micro-environment of its cavity, the quality of the side
arm attached to the nitrogen atom and the substituents on the
sugar unit are all expected to play an important role. We have
found that the presence of butyl substituents on the gluco-
pyranose unit had an advantageous effect on both the chemical
yield and the enantioselectivity. We have reported, in a prelimin-
ary communication, that use of the monoaza-crown ether con-
taining a methyl 4,6-di-O-butyl-α--glucopyranoside unit (13,
Scheme 1 Synthesis of methyl 4,6-di-O-butyl-α--glucopyranoside 5
from methyl 4,6-O-benzylidene-α--glucopyranoside 1. Reagents and
conditions: i, benzyl chloride, 50% aq. NaOH, NBu4Br, rt; ii, 96%
CH3CO2H, reflux; iii, NaH, BuBr, DMF, rt; iv, 5% Pd/C EtOH, 50 ЊC.
The vicinal free hydroxy groups in methyl 4,6-O-benzylidene-
α--glucopyranoside 1 were treated with benzyl chloride, under
PT conditions, in the presence of tetrabutylammonium hydrox-
ide (PT catalyst). The reaction was carried out in a mixture of
benzyl chloride (as reagent and solvent) and 50% aq. sodium
hydroxide (10 h, room temp.) and we obtained the 2,3-di-O-
benzyl ether 2 in a better yield (85%) than that obtained by the
conventional method (in benzyl chloride, in the presence
of powdered potassium hydroxide).14 Removal of the 4,6-O-
benzylidene group in compound 2 was effected by aq. acetic
acid (2 h, 100 ЊC),15 yielding the derivative 3 in 78% yield.16
Alkylation of the two hydroxy groups in 3 with butyl bromide
J. Chem. Soc., Perkin Trans. 1, 1999, 3651–3655
This journal is © The Royal Society of Chemistry 1999
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Table 1 Addition of 2-nitropropane to chalcone catalyzed by crown
ethers 8–13a
Run
Catalyst
Yield(%)b
ee(%)c
1
2
3
4
5
6
8
9
10
11
12
13
49
53
40
43
35
82
45 (S)
55 (54d) (S)
27 (S)
42 (S)
10 (S)
Scheme 2 Synthesis of bisiodo podand 7 from compound 5. Reagents
and conditions: i, O(CH2CH2Cl)2, 50% aq. NaOH, NBu4Br, rt; ii, NaI,
acetone, reflux.
89 (90d) (S)
a Reaction time 24 h, base NaOBut, 20 ЊC. b Based on substance isolated
by preparative TLC. c Determined by optical rotation. d Determined by
1H NMR spectroscopy.
in DMF, in the presence of sodium hydride (48 h, room temp.)
afforded the 4,6-di-O-butyl derivative 4 in 74% yield. The
benzyl protecting groups in 4 were removed by catalytic
hydrogenolysis over palladium (5% Pd/C) in ethanol solution
(12 h; 50 ЊC), giving compound 5 in quantitative yield.
The hydroxy groups in 5 were alkylated by the method of
Gross17 with bis-(2-chloroethyl) ether as reagent and solvent
(Scheme 2). The liquid–liquid two-phase reaction using
tetrabutylammonium bromide as PT catalyst and 50% aq.
sodium hydroxide gave rise to the bischloro podand 6 (8 h,
room temp.) in 44% yield after chromatography. Exchange of
the chlorines in 6 by iodines was carried out using sodium
iodide in acetone (reflux, 40 h), yielding the bisiodo derivative 7.
Compound 7 was cyclized with various primary amines: n-butyl-
amine, 3-methoxypropylamine, benzylamine and 2-phenylethyl-
amine according to the method described previously9 (Scheme
3). The method requires dry sodium carbonate in acetonitrile
(2–3%) solution] in the presence of dry potassium carbonate
(reflux, 32 h) in 52% yield after chromatography. Compound 12
was deprotected to 13 by 4% sodium amalgam in the presence
of dibasic sodium phosphate in methanol (reflux, 20 h) in a
yield of 85%, as reported for similar compounds.18 Our attempt
to form 13 by reductive removal of the N-tosyl group in 12 with
LiAlH4 in tetrahydrofuran (THF)19 was not successful and
caused the macrocyclic ring to open.The structure of products
1
8–13 was characterized by H NMR and mass spectroscopic
1
data. The H spectral parameters are similar to those of aza-
crown derivatives described earlier.9 The relative molecular
masses of new compounds were supported by CI-MS and FAB-
MS. The fragment at m/z 476 was of significant intensity in all
cases (see Experimental section) and is due to the (sugar-based-
aza-crown-N-CH2)ϩ fragment.
Compounds 8–13 proved to be effective as chiral PT catalysts
in the Michael addition of 2-nitropropane 15 to chalcone 14
(Scheme 5).
Scheme 3 Synthesis of crown ethers 8–11 from 7. Reagents and condi-
tions: i, primary amines (n-butylamine to 8, 3-methoxypropylamine to
9, benzylamine to 10, and 2-phenylethylamine to 11), Na2CO3, CH3CN,
reflux.
as solvent (reflux, 32–40 h). In dilute solutions (1–3%) poly-
condensation side-reactions are suppressed and the desired
intramolecular cyclization reaction takes place preferentially. In
this way we obtained the 15-membered monoaza-crown ethers
8–11 in moderate yields starting from 7 and the corresponding
primary amine. The yields of the ring-closure product, after
purification by chromatography, varied from 40–46%.
Scheme 5 The Michael addition of 2-nitropropane to chalcone.
Reagent and conditions: NaOBut, toluene, rt.
The unsubstituted monoaza-crown ether 13 was synthesized
by the method we described in our preliminary communi-
cation13 (Scheme 4). The chiral starting macrocycle 12 needed
for the preparation of the unsubstituted derivative 13 was
obtained from the bischloro podand 6 by treatment with one
molar equivalent of toluene-p-sulfonamide in DMF [in dilute
The Michael addition was carried out in toluene with solid
sodium tert-butoxide as base (35 mol%) and chiral catalyst
(7 mol%), at room temperature. After the usual work-up
procedure, the adduct 16 was isolated by preparative TLC;
the asymmetric induction, expressed in terms of the ee, was
monitored by measuring the optical rotation of the product 16
and comparing it with literature data for the preferred pure
1
enantiomer10 and by H NMR spectroscopy using europium
tris[3-(heptafluoropropylhydroxymethylene)-(ϩ)-camphorate]
[(ϩ)-Eu(hfc)3] as chiral shift reagent. The results, given in Table
1, show that the (S)-(ϩ)-adduct 16 is always in excess and,
moreover, that the substituent on the nitrogen atom of the
catalyst has a significant influence on both the chemical yield
and the asymmetric induction. It can be seen that the catalysts
8–11 resulted in moderate chemical yields from 40 to 53%;
however, the enantioselectivity of the catalysts was rather dif-
ferent. Among the crown amines 8–11 the weakest catalyst was
Scheme
4
Synthesis of crown ether 13 from 6. Reagents and
conditions: i, TsNH2, K2CO3, DMF, reflux; ii, 4% Na/Hgx, Na2HPO4,
MeOH, reflux.
3652
J. Chem. Soc., Perkin Trans. 1, 1999, 3651–3655

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the N-benzyl compound 10, which gave 27% ee. This value
increased in the presence of crown ether 11 having a phenylethyl
side arm (42% ee) and N-butyl compound 8 (45% ee); the N-
methoxypropyl derivative 9 (lariat ether) showed the highest
enantioselection of 55% ee. The results for catalysts 10 and 11
possessing benzyl and phenylethyl side groups indicate the
importance of the length of the side arm on the nitrogen atom.
The N-tosyl crown amide 12 proved to be the weakest catalyst
among all the crown ethers tested: chemical yield of 35% and
optical purity of 10% ee were obtained. It is probable that the
N-tosyl amide part in the crown ring reduces the complex-
forming properties, and its steric hidrance may play an essential
role too. The catalytic activity and enantioselectivity dramatic-
ally increased after the removal of the tosyl group: use of the
unsubstituted aza-crown catalyst 13 resulted in a yield of 82%
and enantioselectivity of 90% ee for the S-antipode. Therefore,
compared with the unsubstituted compound, the enantioselec-
tivity decreased in the case of N-substituted derivatives, most
probably because of steric reasons but also because of the free
NH group in the cycle making it probable that there is H-bond
involvement in the transition-state structures. This finding is
surprising in the light of our earlier findings with aza-crown
ethers containing a 4,6-O-benzylidene group on the sugar
moiety, when the substituents on the nitrogen mostly increased
the chemical yield and the enantioselectivity.10,11 The com-
pounds presented here show a different picture, which can be
explained by the structure of the molecule and which is differ-
ent from those presented earlier. The crown ethers have
no acetal ring and therefore they are more flexible. On the
other hand, the two butyl groups on the glucopyranoside
part considerably increase the lipophilicity of the molecule.
Further investigations including mechanistic studies are now
in progress.
added and stirring was continued for 1 h. After cooling, the
solution was evaporated to a syrup, water (2 × 40 cm3) and
toluene (2 × 60 cm3) were added, and the mixture was evapor-
ated to dryness again. The residue was dissolved in chloroform,
and the solution was washed successively with aq. sodium
bicarbonate and brine, dried (MgSO4), and concentrated.
Compound 3 was obtained as a syrup, which after crystalliz-
ation gave solid material (17.9 g, 78%), mp 75–76 ЊC (from
EtOH) (lit.,16a 73–74 ЊC); [α]D ϩ18.5 (c 1.5 CHCl3) {lit.,16a
[α]D ϩ 18.2 (c 1, CHCl3)}.
Methyl 2,3-di-O-benzyl-4,6-di-O-butyl-ꢀ-D-glucopyranoside 4
A mixture of 3 (22.0 g, 58.8 mmol) in dry DMF (150 cm3) and
60% NaH (6.0 g, 150 mmol) was stirred for 1 h under argon.
After cooling of the mixture to 0 ЊC, dry butyl bromide (63.0
cm3, 597.8 mmol) was added. The mixture was allowed to attain
room temperature and then was stirred for a further 48 h.
Excess of NaH was decomposed with methanol, and the solu-
tion was concentrated to a syrup. A solution of the residue
in chloroform (150 cm3) was washed with water (3 × 80 cm3),
dried (Na2SO4), and concentrated to give an oil, which was
purified by column chromatography on silica gel using hexane–
ethyl acetate (3:1) as eluent to afford syrupy title compound 4
(21.2 g, 74%), [α]D ϩ24.1 (c 1, CHCl3); νmax(neat)/cmϪ1 2957,
2871 (Me, methylene), 1726 (sugar ring), 1454, 1366 (alkyl
chain), 1094, 1057 (C–O), 1603, 737, 697 (Ar); δH (CDCl3) 0.89
(6H, t, CH3), 1.11–1.70 (12H, m, CH2), 3.35 (3H, s, OCH3),
3.38–3.86 (6H, m, CH and CH2), 4.52–4.77 (4H, m, CH2Ph),
4.82 (1H, d, J 3.5, anomer-H), 7.22–7.39 (10H, m, ArH);
CI-MS m/z 487 (Mϩ ϩ 1, 98%) (Found: C, 71.45; H, 8.53.
C29H42O6 requires C, 71.60; H, 8.64%).
Methyl 4,6-di-O-butyl-ꢀ-D-glucopyranoside 5
Experimental
General procedures
A suspension of palladium catalyst absorbed on charcoal (5%
Pd/C, 2.0 g) and compound 4 (29.1 g, 59.9 mmol) in absolute
ethanol (300 cm3) was shaken with hydrogen gas at 50 ЊC until
the absorption of the gas ceased (12 h). Removal of the catalyst
and concentration of the filtrate afforded the syrupy title prod-
uct 5 (18.2 g, 99%), [α]D ϩ114.5 (c 1, CHCl3); νmax(neat)/cmϪ1
3418br (OH), 2957, 2871 (Me, methylene), 1726 (sugar ring),
1464, 1367 (alkyl chain), 1126, 1053 (C–O); δH (CDCl3) 0.82–
0.98 (6H, m, CH3), 1.21–1.70 (12H, m, CH2), 3.38 (3H, s,
OCH3), 3.42–3.85 (8H, m, CH, CH2 groups and OH), 4.76
(1H, d, J 4.8, anomer-H) (Found: C, 58.71; H, 9.75. C15H30O6
requires C, 58.82; H, 9.80%).
Mps were determined with a Büchi 510 apparatus and are
uncorrected. Specific rotations were determined with a Perkin-
Elmer 241 polarimeter at 20 ЊC, and [α]D--values are given in units
of deg cm2 gϪ1. IR spectra were recorded with a Perkin-Elmer
1
237 spectrophotometer. H NMR spectra were recorded on a
Bruker WM 250 instrument for solutions in CDCl3. J-Values
are given in Hz. Mass spectra were obtained on a JEOL JMS-01
SG-2 instrument. Chemical ionization was applied as the
ionization technique. Elemental analysis was performed on a
Perkin-Elmer 240 automatic analyzer. Analytical and prepar-
ative TLC was performed on silica gel (60 GF-254, Merck);
column chromatography was carried out using 70–230 mesh
silica gel (Merck).
Methyl 4,6-di-O-butyl-2,3-bis-O-[2-(2-chloroethoxy)ethyl]-ꢀ-D-
glucopyranoside 6
A solution of compound 5 (16.1 g, 52.6 mmol) and tetrabutyl-
ammonium bromide (16.7 g, 52.6 mmol) in bis(2-chloroethyl)
ether (92 cm3, 831.4 mmol) was vigorously stirred with 50% aq.
NaOH (92 cm3) at room temp. for 10 h. The reaction mixture
was then poured into a mixture of dichloromethane (330 cm3)
and water (330 cm3) and the resulting solution was separated.
The aqueous portion was washed with dichloromethane
(2 × 200 cm3); the combined organic layer and washings were
then washed with water (3 × 180 cm3), dried (Na2SO4), and
evaporated to dryness. The syrup remaining was shaken with
hexane (3 × 100 cm3). The precipitate (Bu4NBr) was filtered off,
and the filtrate was evaporated to give a syrup, which was
chromatographed on a column of silica gel (220 g) using diethyl
ether–methanol (10:0.5) as eluent to give syrupy product 6
(12.1 g, 44%); [α]D ϩ61.5 (c 1, CHCl3); νmax(neat film)/cmϪ1
2957, 2871 (Me, methylene), 1726 (sugar ring), 1460, 1357 (alkyl
chain), 1100, 1051 (C–O), 749 (C–Cl); δH (CDCl3) 0.90–0.94
(6H, m, CH3), 1.34–1.40 (6H, m, CH2), 1.52–1.64 (6H, m,
CH2), 3.38 (3H, s, OCH3), 3.59–3.98 (22H, m, CH and CH2
groups), 4.82 (1H, d, J 4.8, anomer-H) (Found: C, 53.02; H,
Methyl 2,3-di-O-benzyl-4,6-O-benzylidene-ꢀ-D-glucopyranoside
2
A solution of methyl 4,6-O-benzylidene-α--glucopyranoside 1
(20.0 g, 70.9 mmol) and tetrabutylammonium bromide (23.0 g,
71.4 mmol) in benzyl chloride (140.0 cm3, 1.22 mol) was vigor-
ously stirred with 50% aq. NaOH (140.0 cm3, 2.67 mol) at room
temperature for 10 h. The reaction mixture was added to a
mixture of dichloromethane (450 cm3) and water (450 cm3). The
organic layer was decanted and the aqueous one was washed
with dichloromethane. The organic phases were combined,
washed with water, dried (Na2SO4), and concentrated; the
residue was crystallized from ethanol to give 2 (27.9 g, 85%),
mp 97–98 ЊC (lit.,14 99 ЊC); [α]D ϩ23.3 (c 1, acetone) {lit.,14 [α]D
ϩ23.5 (c 1, acetone)}.
Methyl 2,3-di-O-benzyl-ꢀ-D-glucopyranoside 3
Compound 2 (29.5 g, 63.7 mmol) was stirred with 96% acetic
acid (300 cm3) at 100 ЊC for 2 h. Water (100 cm3) was then
J. Chem. Soc., Perkin Trans. 1, 1999, 3651–3655
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8.55; Cl, 13.36. C23H44O8Cl2 requires C, 53.18; H, 8.47; Cl,
13.48%).
(100) (Found: C, 65.00; H, 9.28; N, 2.52. C30H51NO8 requires C,
65.09; H, 9.22; N, 2.53%).
Methyl 4,6-di-O-butyl-2,3-bis-O-[2-(2-iodoethoxy)ethyl]-ꢀ-D-
glucopyranoside 7
N-(2-Phenylethyl)-2,3,5,6,8,9,11,12,14,15-decahydro(methyl
4,6-di-O-butyl-2,3-dideoxy-ꢀ-D-glucopyranosido)[2,3-e]-1,4,7,
10-tetraoxa-13-azacyclopentadecine 11. Column chromato-
graphy afforded syrupy 11 (1.2 g, 45%), [α]D ϩ51.3 (c 1, CHCl3);
νmax (neat film)/cmϪ1 2932, 2862 (Me, methylene), 1462, 1360
(alkyl chain), 1120, 1097, 1056 (C–O), 1600, 738, 700 (Ar); δH
(CDCl3) 0.84–0.97 (6H, m, CH3), 1.32–1.44 (6H, m, CH2),
1.52–1.66 (6H, m, CH2), 2.62–2.91 (8H, m, NCH2 and CH2Ph),
3.38 (3H, s, OCH3), 3.44–3.92 (18H, m, CH and CH2 groups),
4.82 (1H, d, J 4.8, anomer-H), 7.15–7.32 (5H, m, ArH); EI-MS
m/z 567 (Mϩ, 13%), 536 (Mϩ Ϫ OCH3, 54), 476 (Mϩ Ϫ CH2Ph,
95), 105 (100) (Found: C, 65.38; H, 9.36; N, 2.42. C31H53NO8
requires C, 65.60; H, 9.34; N, 2.47%).
A mixture of bischloro derivative 6 (6.0 g, 11.55 mmol) and
anhydrous NaI (6.9 g, 47.1 mmol) in dry acetone (150 cm3) was
stirred under reflux for 40 h. After cooling, the precipitate was
filtered off and washed with acetone. The combined acetone
solution was evaporated. The residue was dissolved in dichloro-
methane (100 cm3), and the solution was washed with water
(3 × 50 cm3) and dried (Na2SO4) to give compound 7 (7.8 g,
96%) as a syrup, [α]D ϩ46.3 (c 1, CHCl3); νmax(neat film)/cmϪ1
2957, 2871 (Me, methylene), 1726 (sugar ring), 1105, 1052
(C–O), 1460, 1357 (alkyl chain), 545 (C–I); δH (CDCl3) 0.85–
0.96 (6H, m, CH3), 1.32–1.40 (6H, m, CH2), 1.52–1.64 (6H, m,
CH2), 3.27 (4H, t, CH2I), 3.38 (3H, s, OCH3), 3.45–4.10 (18H,
m, CH and CH2 groups), 4.82 (1H, d, J 4.8, anomer-H).
N-Tosyl-2,3,5,6,8,9,11,12,14,15-decahydro(methyl 4,6-di-O-
butyl-2,3-dideoxy-ꢀ-D-glucopyranosido)[2,3-e]-1,4,7,10-tetra-
oxa-13-azacyclopentadecine 12
General method for preparation of crown ethers 8–11
A mixture of bischloro podand 6 (2.6 g, 5.0 mmol),
toluene-p-sulfonamide (0.86 g, 5.0 mmol) and anhydrous
K2CO3 (3.5 g, 25.3 mmol) was stirred and refluxed in dry DMF
(150 cm3) for 32 h. After the reaction was complete, the precipi-
tate was filtered off and washed with chloroform. The com-
bined filtrate and washings were evaporated under reduced
pressure, and the residue was dissolved in chloroform, washed
with water, and dried (MgSO4). After removal of the solvent,
column chromatography of the residue on silica gel with
toluene–methanol (10:1) as the eluent gave the N-tosyl macro-
cycle 12 as a yellow oil (1.6 g, 52%), [α]D ϩ33.4 (c 1.8, CHCl3);
δH (CDCl3) 0.80–0.96 (6H, m, CH3), 1.32–1.42 (6H, m, CH2),
1.52–1.66 (6H, m, CH2), 2.41 (3H, s, ArCH3), 2.72–2.98 (4H, m,
NCH2), 3.40 (3H, s, OCH3), 3.45–3.90 (18H, m, CH and CH2
groups), 4.88 (1H, d, J 4.8, anomer-H), 7.22–7.70 (4H, m,
ArH); MS (FAB) m/z 618 (MHϩ) (Found: C, 58.44; H, 8.28;
N, 2.21. C30H51NO10S requires C, 58.34; H, 8.26; N, 2.26%).
Anhydrous Na2CO3 (3.8 g, 36.2 mmol) was suspended in a solu-
tion of the corresponding primary amine (4.60 mmol) and the
bisiodo compound 7 (3.45 g, 4.60 mmol) in dry acetonitrile (100
cm3) under argon. The stirred reaction mixture was refluxed for
32–40 h and monitored by TLC. After cooling, the precipitate
was filtered off and washed with acetonitrile. The combined
acetonitrile solution was concentrated; the residual oil was dis-
solved in chloroform, amd the solution was washed with water,
dried (Na2SO4), and concentrated. The residue was purified
by column chromatography on silica gel with chloroform–
methanol (10:0.5–10:2) to afford the title compounds.
N-Butyl-2,3,5,6,8,9,11,12,14,15-decahydro(methyl 4,6-di-O-
butyl-2,3-dideoxy-ꢀ-D-glucopyranosido)[2,3-e]-1,4,7,10-tetra-
oxa-13-azacyclopentadecine 8. Column chromatography gave
syrupy 8 (1.1 g, 46%), [α]D ϩ57.4 (c 1, CHCl3); νmax(neat film)/
cmϪ1 2930, 2862 (Me, methylene), 1462, 1359 (alkyl chain),
1120, 1097, 1056 (C–O); δH (CDCl3) 0.84–0.96 (9H, m, CH3),
1.22–1.78 (16H, m, CH2), 2.47–2.88 (6H, m, NCH2), 3.38 (3H,
s, OCH3), 3.43–3.83 (18H, m, CH and CH2 groups), 4.82 (1H,
d, J 4.8, anomer-H); EI-MS; m/z 519 (Mϩ, 17%), 488
(Mϩ Ϫ OCH3, 67), 476 (Mϩ Ϫ C3H7, 91), 105 (100) (Found: C,
62.29; H, 10.12. C27H53NO8 requires C, 62.42; H, 10.21%).
2,3,5,6,8,9,11,12,14,15-Decahydro(methyl 4,6-di-O-butyl-2,3-
dideoxy-ꢀ-D-glucopyranosido)[2,3-e]-1,4,7,10-tetraoxa-13-aza-
cyclopentadecine 13
Compound 12 (1.4 g, 2.27 mmol), anhydrous disodium hydro-
gen phosphate (1.3 g, 9.10 mmol), and 4% sodium amalgam
(11.0 g, 19.1 mmol) were placed in dry methanol (20 cm3). The
mixture was heated at reflux under a nitrogen atmosphere for
20 h while being stirred rapidly. After cooling to room temper-
ature, the resulting slurry was decanted into water (80 cm3) and
extracted with chloroform (30 cm3 × 4). The organic layers were
combined, dried (MgSO4), and evaporated under reduced pres-
sure to yield compound 13 (0.89 g, 85%) as a yellow oil, [α]D
ϩ58.9 (c 1.5, CHCl3); δH (CDCl3) 0.84–0.96 (6H, m, CH3),
1.32–1.42 (6H, m, CH2), 1.52–1.66 (6H, m, CH2), 2.45 (1H, br s,
NH), 2.82–2.98 (4H, m, NCH2), 3.40 (3H, s, OCH3), 3.44–3.92
(18H, m, CH and CH2 groups), 4.83 (1H, d, J 4.8, anomer-H);
MS (FAB) m/z 464 (MHϩ) (Found: C, 59.50; H, 9.68; N, 3.08.
C23H45NO8 requires C, 59.61; H, 9.72; N, 3.02%).
N-(3-Methoxypropyl)-2,3,5,6,8,9,11,12,14,15-decahydro-
(methyl 4,6-di-O-butyl-2,3-dideoxy-ꢀ-D-glucopyranosido)[2,3-e]-
1,4,7,10-tetraoxa-13-azacyclopentadecine 9. Compound 9 (0.84
g, 42%) was obtained as a syrup after chromatography, [α]D
ϩ55.1 (c 1, CHCl3); νmax (neat film)/cmϪ1 2930, 2862 (Me,
methylene), 1462, 1360 (alkyl chain), 1120, 1100, 1056 (C–O);
δH (CDCl3) 0.84–0.96 (6H, m, CH3), 1.32–1.42 (6H, m, CH2),
1.52–1.66 (6H, m, CH2), 2.47–2.88 (6H, m, NCH2), 3.32 (3H, s,
OCH3), 3.39 (3H, s, OCH3), 3.45–3.92 (22H, m, CH and CH2
groups), 4.82 (1H, d, J 4.8, anomer-H); EI-MS m/z 535 (Mϩ,
8%), 504 (Mϩ Ϫ OCH3, 58), 476 (Mϩ Ϫ CH2CH2OCH3, 89),
105 (100) (Found: C, 60.48; H, 9.94; N, 2.58. C27H53NO9
requires C, 60.56; H, 9.90; N, 2.61%).
General procedure for the Michael addition
N-Benzyl-2,3,5,6,8,9,11,12,14,15-decahydro(methyl 4,6-di-O-
butyl-2,3-dideoxy-ꢀ-D-glucopyranosido)[2,3-e]-1,4,7,10-tetra-
oxa-13-azacyclopentadecine 10. Column chromatography
afforded syrupy 10 (1.0 g, 40%); [α]D ϩ56.2 (c 1.2, CHCl3); νmax
(neat film)/cmϪ1 2932, 2862 (Me, methylene), 1462, 1360 (alkyl
chain), 1120, 1097, 1056 (C–O), 1600, 738, 700 (Ar); δH (CDCl3)
0.84–0.97 (6H, m, CH3), 1.32–1.44 (6H, m, CH2), 1.52–1.66
(6H, m, CH2), 2.62–2.90 (6H, m, NCH2 and CH2Ph), 3.38 (3H,
s, OCH3), 3.44–3.92 (18H, m, CH and CH2 groups), 4.82 (1H,
d, J 4.8, anomer-H), 7.15–7.32 (5H, m, ArH); EI-MS m/z 553
(Mϩ, 13%), 536 (Mϩ Ϫ OCH3, 54), 476 (Mϩ Ϫ CH2Ph, 95), 105
This was performed as follows: Chalcone 14 (0.3 g, 1.44 mmol)
and 2-nitropropane 15 (0.3 cm3, 3.36 mmol) were dissolved in
dry toluene (3 cm3), and crown ether catalyst (0.1 mmol) and
sodium tert-butoxide (0.05 g, 0.5 mmol) were added. The mix-
ture was stirred under an argon atmosphere at room temper-
ature. After completion of the reaction (20–24 h) a mixture of
toluene (7 cm3) and water (10 cm3) was added. The organic
phase was processed in the usual manner. The product was
purified by preparative TLC on silica gel using hexane–ethyl
acetate (10:1) as eluent, and had mp 146–148 ЊC, [α]D ϩ80.8
3654
J. Chem. Soc., Perkin Trans. 1, 1999, 3651–3655

View Article Online
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(c 1, CH2Cl2) for pure (S)-(ϩ)-enantiomer;10 δH (CDCl3) 1.54
(3H, s, CH3), 1.63 (3H, s, CH3), 3.27 (1H, dd, J 17.2 and 3.2,
CH2), 3.67 (1H, dd, J 17.2 and 10.4, CH2), 4.15 (1H, dd, J 10.4
and 3.2, CH), 7.18–7.32 (5H, m, ArH), 7.42 (2H, t, COPh
H-m), 7.53 (1H, t, COPh H-p), 7.85 (2H, d, COPh H-o).
Acknowledgements
This work was supported by the National Science Foundation
(OTKA T 029253 and T 026478) and Hungarian Academy of
Sciences.
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Paper 9/05670J
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