Synthesis of (2S,2′S)-bimorpholine N,N′-quaternary salts as chiral phase transfer catalysts

Article abstract of DOI:10.1016/j.tetasy.2007.01.004

(2S,2′S)-Bimorpholine was synthesized starting from (R,R)-tartaric acid ester acetal in six steps in 50% of the total yield. Key steps include: cyanide catalyzed amidation and one-step cyclization with p-toluenesulfonyl imidazole. Derivatization of N,N′-d

Full text of DOI:10.1016/j.tetasy.2007.01.004

Tetrahedron: Asymmetry 18 (2007) 137–141
Synthesis of (2S,20S)-bimorpholine N,N0-quaternary
salts as chiral phase transfer catalysts
Kristin Lippur,a Tonis Kanger,a,* Kadri Kriis,a Tiiu Kailas,a Aleksander-Mati Muurisepp,a
˜
¨ ¨
Tonis Pehkb and Margus Loppa
˜
aDepartment of Chemistry, Faculty of Science, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia
bNational Institute of Chemical Physics and Biophysics, Akadeemia tee 23, Tallinn 12618, Estonia
Received 11 December 2006; accepted 8 January 2007
Abstract—(2S,20S)-Bimorpholine was synthesized starting from (R,R)-tartaric acid ester acetal in six steps in 50% of the total yield. Key
steps include: cyanide catalyzed amidation and one-step cyclization with p-toluenesulfonyl imidazole. Derivatization of N,N0-dibenzyl
bimorpholine afforded quaternary bimorpholinium salts, which were used as chiral phase transfer alkylation catalysts.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
R
R
R
R
R'
R'
O
O
N+ R'
N+ R'
Asymmetric organocatalysis has become an important
approach to stereoselective organic synthesis over the last
decade.1 The necessary organocatalysts are natural prod-
ucts selected from the chiral pool (such as amino acids,
especially proline)2 or are synthetic. There are practically
no limits to synthetic catalyst structure: one can design
and synthesize sterically and electronically tunable cata-
lysts.3 Compounds containing nitrogen have a special place
among catalysts because of their unique properties. Chiral
amines as donating ligands to metal catalysts are widely
applied in asymmetric hydrogenation and hydride transfer
reactions.4 Asymmetric aminocatalysis via enamine or
iminium intermediates has matured to become a widely
used methodology.5 Furthermore, quaternarization of the
enantiomerically pure amines gives rise to the chiral ammo-
nium compounds that are used as asymmetric phase trans-
fer catalysts (PTC).6
R
R
X-
N+
Br-
2
R'
R'
Figure 1.
We have now designed new dicationic catalysts 1a and 1b,
where the tartaric acid backbone is converted into a C2-
symmetric heterocycle (Fig. 2). In this new catalyst, nitro-
gen atoms are fixed into a more rigid cyclic two-centered
diammonium structure. We have previously shown that a
similar principle (incorporation of a nitrogen atom into a
R'
N+
R
N
N
O
O
R''
R'
O
O
O
O
HN
N
Alkylation of glycine imine ester in the presence of a PTC
as a model reaction has been investigated in detail. In addi-
tion to cinchonidine derivatives,7 spiro ammonium salts8
and two-centered tartaric acid derivatives9 are found to
be the most efficient catalysts for this reaction (Fig. 1).
X-
.
2
HX
R
N+
R''
R
1a R'=Me
R''=Bn
X=I
1b R'=R''=Bn
X=Br
2a R=H
2b R=Bn
3
*
Corresponding author. Tel.: +372 6204371; fax: +372 6202828; e-mail:
kanger@chemnet.ee
Figure 2.
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.01.004

138
K. Lippur et al. / Tetrahedron: Asymmetry 18 (2007) 137–141
O
cyclic compound and the remaining tartaric acid skeleton)
works efficiently in the case of some organocatalytic reac-
tions. Thus, 3,30-bimorpholine derivative 3 catalyzed
Michael addition and also intramolecular aldol
condensation proceed stereoselectively, affording the corre-
sponding products in high ee (up to 95%).10 Additionally,
3,30-bimorpholine has been used as a ligand in transition-
metal mediated asymmetric reductions.11 We expected that
the addition of sterically demanding substituents to the
nitrogen atoms in 2,20-bimorpholine 2a would afford
ammonium compounds with valuable asymmetric PTC
properties. Herein, we report a new efficient method for
the synthesis of (2S,20S)-bimorpholine 2a, its derivative
2b and their quaternarization and our preliminary results
of asymmetric alkylation of glycine imine ester in the pres-
ence of the new PTC.
O
NH2(CH2)2OH
cat.NaCN
H
N
OH
OH
O
O
O
O
OMe
OMe
N
H
MeOH, 55 °C, 20 h
97%
O
O
4
5
BnBr
K2CO3
OH
OH
O
O
H
N
LiAlH4
N
H
THF, reflux, 2 h
82%
MeOH, 40 °C, 6 h
93%
6
Bn
Bn
OH
OH
O
OH
OH
HO
N
N
N
6M HCl
N
MeOH, 40 °C, 24 h
O
HO
82%
Bn
Bn
7
8
Bn
N
Bn
N
NaH
TsIm
2. Results and discussion
THF, RT, 20 h
82%
The synthesis of (2S,20S)-bimorpholine 2a has previously
been reported by our group.12 The key steps of the synthe-
sis are: introduction of nitrogen-containing functionality
into the tartaric acid derivative, chain lengthening via
O-alkylation of hydroxyl groups and intramolecular
cyclization. Nitrogen functionality was introduced into
the molecule using a two-step procedure, which involves
mesylation of the hydroxyl groups, followed by their azida-
tion with sodium azide (Scheme 1). The target compound
was obtained over 10 steps in a 15% overall yield.
O
O
2b
Scheme 2.
0.013 M led to the increase of the reaction yield from
23% to 82%. Thus N,N0-dibenzyl (2S,20S)-bimorpholine
2b was synthesized in five steps in 50% yield. (If unsubsti-
tuted bimorpholine is required, the debenzylation of 2b
with ammonium formate, affording desired (2S,20S)-bi-
morpholine 2a in a 70% yield, is used.)
Now we have developed a considerably shorter and more
efficient route to (2S,20S)-bimorpholine 2a, outlined in
Scheme 2. Cyanide-catalyzed amidation of (R,R)-tartaric
acid ester acetal 4 with 2-aminoethanol enables us to intro-
duce nitrogen and construct a necessary skeleton for cycli-
zation in one step in order to obtain the morpholine ring.
(2R,20R)-Bimorpholine 2b was synthesized according to the
same synthetic route starting from (S,S)-tartaric acid deriv-
ative. Chiral HPLC analysis on Chiralcel OD-H column of
both enantiomers revealed their high enantiomeric purity
(ee 99%).
First, cyanide-catalyzed amidation13 of acetal 4 with 2-
aminoethanol gave the desired amide 5 in an almost quan-
titative yield (97%). Amide 5 was reduced to amine 6 with
LiAlH4 in an 82% yield. Tertiary amine 7 was synthesized
via direct N-alkylation of secondary amine 6 with benzyl
bromide in a 93% yield. Deacetalization of compound 7
with 6 M HCl afforded tetraol 8 in an 82% yield. A key step
in the synthesis of dibenzyl bimorpholine 2b is cyclization
of tetraol 8. Mesylation or tosylation of the primary hydr-
oxyl groups in tetraol 8 led to a multicomponent mixture.
However, tetraol 8 was cyclized in a one-step procedure
with p-toluenesulfonyl imidazole in THF, affording N,N0-
dibenzyl (2S,20S)-bimorpholine 2b.14 The yield of this
intramolecular cyclization depends considerably on the
concentration. Decrease in the concentration from 0.1 to
In order to perform PTC assisted alkylation of glycine
imine ester 9, we synthesized quaternary ammonium salts
1a and 1b from N,N0-dibenzyl (2S,20S)-bimorpholine 2b
(Scheme 3). First, N-alkylation of tertiary amine 2b with
methyl iodide resulted in ammonium salt 1a in quantitative
yield as a single diastereoisomer (de >98% by NMR config-
urations at the two stereogenic N centres not determined).
PTC-mediated alkylation of imine 9 in the presence of cat-
alyst 1a gave a racemic product 10 (Scheme 4). Since the
efficient PTCs, which has been previously used7–9 is more
sterically hindered than catalyst 1a, we assumed that by
introducing more bulky groups into compound 2b, the
PTC-mediated alkylation of imine 9 could proceed with a
higher selectivity.
OMs
NH
H
O
O
O
O
HO
HO
OEt
OEt
HO
HO
N3
N3
NR
2a
NR
H
OMs
O
O
NH
Scheme 1.

K. Lippur et al. / Tetrahedron: Asymmetry 18 (2007) 137–141
139
Bn
Bn
Bn
2400. Optical rotations were obtained using a Kruss Optro-
¨
Bn
MeI
N+
N
N
N
N+
Bn
nic GmbH Polarimeter P 3002. Chiral HPLC was per-
formed using an Agilent Technologies 1200 Series
chromatograph equipped with a Chiralcel OD-H column.
All the reactions sensitive to moisture or oxygen were car-
ried out under an Ar atmosphere in oven-dried glassware.
I-
CH3CN, 70 °C, 22 h
2
100%
O
O
O
O
O
O
2b
2b
1a
Bn
N+
Bn
N+
Bn
Bn
BnBr
4.2. (4R,5R)-N,N0-Bis(2-hydroxyethyl)-2,2-dimethyl-1,3-
dioxolane-4,5-dicarboxamide 5
Bn
N
Br-
CH3CN, 70 °C, 3 d
2
60%
O
O
2-Aminoethanol (1.42 mL, 23.5 mmol) and sodium cyanide
(58 mg, 1.17 mmol) was added to a solution of (R,R)-tar-
taric acid ester acetal 4 (2.561 g, 11.7 mmol) in MeOH
(25 mL). The reaction mixture was stirred at 55 ꢁC for
20 h. MeOH was evaporated and the crude mixture was
purified by the column chromatography on silica gel (15%
MeOH in CH2Cl2), to afford amide 5 as a yellow oil (yield
3.133 g, 97%). 1H NMR (DMSO-d6, 500 MHz): d 1.39
(6H, s, 2-CH3), 3.17 (4H, q, J = 3 · 5.8 Hz, CH2N), 3.41
(4H, dt, J = 5.4, 2 · 5.8 Hz, CH2OH), 4.49 (2H, s, H-4,5),
4.69 (2H, t, J = 5.4 Hz, OH), 7.97 (2H, t, J = 5.8 Hz,
NH). 13C NMR (DMSO-d6, 125 MHz) d: 26.21 (2-CH3),
41.37 (CH2N), 59.55 (CH2OH), 77.60 (CHO), 111.73 (C-
1b
Scheme 3.
Ph2C=N
CO2C(CH3)3
10 mol% catalyst 1a or 1b
Ph2C=N
CO2C(CH3)3
15M aq KOH
PhMe, 20 h 0 ºC, 4 h RT
BnBr
Bn
H
9
10
Scheme 4.
Derivatization of compound 2b with benzyl bromide affor-
ded quaternary tetrabenzyl bimorpholinium salt 1b (in a
60% yield after crystallization). The sterically hindered salt
was thereafter used in the PTC-mediated alkylation of
imine 9. Catalyst 1b revealed certain enantioselection in
the alkylation; however, the selectivity was quite low and
compound 10 was obtained with 18% ee. The catalyst
might need further modification in order to increase steric
hinderance at the ammonium site.
2), 169.11 (CO). IR: m = 3338, 3092, 2990, 2940, 2881,
22
1670, 1537, 1385, 1260, 1214, 1082 cmꢀ1. ½aꢁD ¼ ꢀ20:9 (c
2.40, MeOH). MS m/z: 277 (M++1), 246, 218, 188, 130.
Anal. Calcd for C11H20N2O6 (276.29): C, 47.82; H, 7.30;
N, 10.14. Found: C, 47.60; H, 7.29; N, 9.94.
4.3. 2,20-{[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-
diyl]bis(methyleneimino)}diethanol 6
3. Conclusions
Amide 5 (9.097 g, 0.033 mol) in THF (100 mL) at 0 ꢁC was
added to a suspension of LiAlH4 (7.50 g, 0.20 mol) in THF
(50 mL). After refluxing for 2 h, water (7.7 mL), 15%
NaOH solution (7.7 mL) and water (23 mL) were added
at 0 ꢁC. The mixture was filtered and washed with THF.
The inorganic precipitate was extracted with THF
(200 mL) in a Soxhlet apparatus. The combined THF ex-
tracts were dried over Na2SO4. After filtration, the solvents
were evaporated and the residue was purified by column
chromatography on silica gel (7% MeOH/NH3 in CH2Cl2),
A high-yield synthetic scheme in six steps, starting from
tartaric ester, to obtain the enantiomeric 2,20-bimorpholine
2b was developed. Although the corresponding bimorpho-
linium salts were found to be inefficient catalysts for the
alkylation of the glycine imine ester, further investigations
to widen the synthetic scope of this potential organocata-
lyst in other reactions are in progress.
1
4. Experimental
affording amine 6 as a yellow oil (yield 6.688 g, 82%). H
NMR (CDCl3, 500 MHz): d 1.37 (6H, s, 2-CH3), 2.75
and 2.78 (4H, m, OCHCH2N), 2.80 and 2.82 (4H, m,
NCH2CH2), 2.9 (4H, br s, OH and NH), 3.63 (4H, br t,
J = 5.2 Hz, CH2OH), 3.87 (2H, br t, J = 3.0 Hz, CHO).
13C NMR (CDCl3, 125 MHz): d 27.10 (2-CH3), 51.54
(OCHCH2N), 51.58 (NCH2CH2), 60.86 (CH2OH), 78.96
4.1. Materials and methods
Chemicals were purchased from either Aldrich Chemical
Co. or Alfa Aesar and used as received. THF was distilled
over LiAlH4. Precoated silica gel 60 F254 plates from
Merck were used for TLC, whereas for column chromato-
graphy silica gel KSK40-100 lm was used. Full assignment
(C-4,5), 108.74 (C-2). IR: m = 3310, 2932, 2985, 1674,
23
1456, 1375, 1080 cmꢀ1. ½aꢁD ¼ ꢀ28:0 (c 2.63, MeOH).
of H and 13C chemical shifts is based on the 1D and 2D
MS (10 eV) m/z: 249 (M++1), 233, 217, 188, 144, 116.
1
FT NMR spectra on a Bruker AMX500 instrument. Sol-
vent peaks (CHCl3 d = 7.27, DMSO-d5 d = 2.50,
CHD2OD d = 3.30, CDCl3 d = 77.00, DMSO-d6
d = 39.50, CD3OD d = 49.00) were used as chemical shift
references. IR spectra were measured on a Perkin–Elmer
Spectrum BX FTIR spectrometer. Mass spectra were
recorded on a Hitachi M80B spectrometer using EI (70 eV)
or CI (isobutane) mode or on a Shimadzu GCMS-
QP2010 spectrometer using EI (70 eV). Elemental analyses
were performed on a Perkin–Elmer C, H, N, S-Analyzer
4.4. 2,20-{[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-
diyl]bis[methylene(benzylimino)]}diethanol 7
Amine 6 (399 mg, 1.61 mmol) was dissolved in MeOH
(15 mL), K2CO3 (666 mg, 4.82 mmol) and benzyl bromide
(573 lL, 4.82 mmol) were added. The reaction mixture
was stirred at 40 ꢁC for 6 h. MeOH was evaporated and
the crude mixture was purified by column chromatography
on silica gel (5% MeOH/NH3 in CH2Cl2), affording benzyl-

140
K. Lippur et al. / Tetrahedron: Asymmetry 18 (2007) 137–141
ated amine 7 as a yellow oil (yield 643 mg, 93%). 1H NMR
(CDCl3, 500 MHz): d 1.36 (6H, s, 2-CH3), 2.63 (4H, d,
J = 3.0 Hz, OCHCH2N), 2.66 and 2.72 (4H, td,
J = 2 · 5.3 and 13.4 Hz, NCH2CH2), 3.45 (2H, br s, OH),
3.58 (4H, br t, J = 5.3 Hz, CH2OH), 3.63 and 3.70 (4H, both
d, J = 13.5 Hz, BnCH2), 3.73 (2H, br t, J = 3.0 Hz, CHO),
7.24–7.33 (10H, m, Ar). 13C NMR (CDCl3, 125 MHz): d
27.07 (2-CH3), 56.01 (OCHCH2N), 56.26 (NCH2CH2),
59.23 (CH2OH), 59.50 (BnCH2), 78.37 (C-4,5), 109.10 (C-
2), 127.18 (p-Ar), 128.27 (m-Ar), 129.05 (o-Ar), 138.29 (s-
d, J = 11 Hz, H-3e,30e,5e,50e), 3.48 and 3.52 (4H, d,
J = 13.0 Hz, BnCH2), 3.52 (2H, br m, H-2,20), 3.64 (2H,
br t, J = 11 Hz, H-6a,60a), 3.91 (2H, br d, J = 11 Hz, H-
6e,60e), 7.27 (2H, m, p-Ar), 7.32 (8H, m, o,m-Ar). 13C
NMR (CDCl3, 125 MHz): d 52.82 (C-5,50), 54.61 (C-
3,30), 63.30 (BnCH2), 66.97 (C-6,60), 76.48 (C-2,20),
127.07 (p-Ar), 128.20 (m-Ar), 129.06 (o-Ar), 137.72 (s-
Ar). IR: m = 3027, 2909, 2857, 2816, 1602, 1494, 1453,
23
1349, 1118, 1088, 1047, 1019 cmꢀ1. ½aꢁD ¼ þ49:4 (c 6.36,
MeOH). MS m/z: 352 (M+), 261, 206, 175, 164, 134, 91.
Anal. Calcd for C22H28N2O2 (352.48): C, 74.97; H, 8.01;
N, 7.95. Found: C, 74.80; H, 8.11; N, 7.89.
Ar). IR: m = 3426, 3029, 2985, 2936, 2825, 1602, 1495,
23
1454, 1371, 1251, 1214, 1170, 1046 cmꢀ1. ½aꢁD ¼ ꢀ8:4 (c
2.37, MeOH). MS m/z: 413 (M+ꢀCH3), 410, 319, 262,
206, 164, 134, 91. Anal. Calcd for C25H36N2O4 (428.58):
C, 70.06; H, 8.47; N, 6.54. Found: C, 69.83; H, 8.58; N, 6.48.
4.7. (2R,20R)-4,40-Dibenzyl-2,20-bimorpholine 2b
Compound 2b was synthesized using the same synthetic
4.5. (2S,3S)-1,4-Bis[(2-hydroxyethyl)(benzyl)amino]butane-
2,3-diol 8
scheme, starting from (S,S)-tartaric acid derivative 4.
22
½aꢁD ¼ ꢀ47:9 (c 1.84, MeOH). HPLC analysis: tR for
(R,R)-2b 9.8 min; tR for (S,S)-2b 19.3 min (hexane/iPrOH
To a solution of benzylated amine 7 (6.615 g, 15.4 mmol) in
MeOH (50 mL) 6 M HCl solution (40 mL) was added and
the mixture was heated at 40 ꢁC for 21 h. In an ice-water
bath 10 M NaOH solution was added until pH ꢂ 8–9.
After the addition of satd NaCl solution (30 mL), the mix-
ture was extracted with CH2Cl2 (4 · 20 mL). The organic
phase was dried over Na2SO4 and the solvent was evapo-
rated. The residue was purified by column chromatography
on silica gel (5% MeOH/NH3 in CH2Cl2), affording tetraol
8 as a yellow oil which solidifies in a freezer (yield 4.893 g,
82%). 1H NMR (CD3OD, 500 MHz): d 2.59 and 2.67 (4H,
m, NCH2CH2), 2.64 (4H, m, OCHCH2N), 3.57 and 3.58
(4H, m, CH2OH), 3.63 and 3.71 (4H, both d,
J = 14.0 Hz, BnCH2), 3.67 (2H, br t, J = 3.0 Hz, H-2,3),
7.29 (2H, m, p-Ar), 7.27 (4H, m, m-Ar), 7.32 (4H, m, o-
Ar). 13C NMR (CD3OD, 125 MHz): d 57.69 (OCHCH2N),
58.58 (NCH2CHO), 60.84 (CH2OH), 60.97 (BnCH2), 70.87
(C-4,5), 128.10 (p-Ar), 129.29 (m-Ar), 130.23 (o-Ar), 140.34
95:5, 0.8 mL/min).
4.8. (2S,20S)-2,20-Bimorpholine 2a
To a solution of bimorpholine 2b (294 mg, 0.83 mmol) in
MeOH (10 mL) 10% Pd/C (441 mg) and ammonium for-
mate (263 mg, 4.17 mmol) was added under an Ar atmo-
sphere. After heating the reaction mixture at 60 ꢁC for
7 h, the mixture was filtered and washed with MeOH.
The MeOH was evaporated and the crude mixture was
purified by column chromatography on silica gel (7%
MeOH/NH3 in CH2Cl2), affording bimorpholine 2a as a
white solid (yield 101 mg, 70%). The spectroscopic data
were in agreement with the published data.12
4.9. (2S,20S)-4,40-Dibenzyl-4,40-dimethyl-2,20-bimorpholin-
ium diiodide 1a
(s-Ar). IR: m = 3369, 3062, 3028, 2829, 1602, 1494, 1453,
To a solution of bimorpholine 2b (206 mg, 0.58 mmol) in
CH3CN (6 mL) methyl iodide (364 lL, 5.84 mmol) was
added. The mixture was stirred at 70 ꢁC for 22 h. CH3CN
was evaporated and the crystals were washed with EtOAc,
affording quaternary ammonium salt 1a as yellow crystals
(yield 372 mg, 100%). 1H NMR (CD3OD, 500 MHz): d
3.24 (6H, s, NCH3), 3.42 (2H, br d, J = 12.5 Hz, H-
5e,50e), 3.56 (2H, br d, J = 12.5 Hz, H-3e,30e), 3.67 (2H,
br t, J = 12.5 Hz, H-5a,50a), 3.77 (2H, br t, J = 12.5 Hz,
H-3a,30a), 4.09 (2H, br d, J = 12.5 Hz, H-6e,60e), 4.18
(2H, br t, J = 12.5 Hz, H-6a,60a), 4.36 (2H, br d,
J = 12.5 Hz, H-2a,20a), 4.79 (4H, br s, BnCH2), 7.51–7.57
(6H, m, m,p-Ar), 7.67 (4H, m, o-Ar). 13C NMR (CD3OD,
125 MHz): d 45.48 (NCH3), 59.83 (C-5,50), 60.51 (C-3,30),
61.75 (C-6,60), 70.21 (C-2,20), 73.32 (BnCH2), 127.54 (s-
Ar), 130.39 (m-Ar), 132.02 (p-Ar), 134.55 (o-Ar). IR:
22
1372, 1132, 1028 cmꢀ1. ½aꢁD ¼ ꢀ25:2 (c 4.87, MeOH).
MS m/z: 389 (M++1), 224, 206, 194, 164, 134, 91. Anal.
Calcd for C22H32N2O4 (388.51): C, 68.01; H, 8.30; N,
7.21. Found: C, 67.98; H, 8.33; N, 7.21.
4.6. (2S,20S)-4,40-Dibenzyl-2,20-bimorpholine 2b
Tetraol 8 (2.127 g, 5.47 mmol) in THF (400 mL) was added
to NaH (1.095 g, 27.37 mmol) at 0 ꢁC, under an argon
atmosphere. The mixture was stirred at 0 ꢁC for 5 min
and at rt for 1 h. The reaction mixture was cooled to
0 ꢁC
and
1-(p-toluenesulfonyl)imidazole
(2.434 g,
10.95 mmol) was added. After stirring for 15 min at 0 ꢁC
the reaction mixture was allowed to warm to rt and stirred
for 20 h. The reaction suspension was cooled to 0 ꢁC, and
the reaction was quenched by the dropwise addition of satd
NH4Cl solution (20 mL). THF was evaporated, satd NaCl
and satd NaHCO3 solutions were added and the mixture
was extracted with EtOAc (3 · 15 mL). The organic phase
was dried over Na2SO4 and solvent was evaporated. The
residue was purified by column chromatography on silica
gel (1.5% MeOH/NH3 in CH2Cl2), affording 2b as a yellow
m = 4042, 3449, 2965, 2883, 1989, 1623, 1497, 1472, 1430,
22
1357, 1257, 1102 cmꢀ1. ½aꢁD ¼ þ41:2 (c 4.74, MeOH).
MS m/z: 637 (M++1). Mp 165–168 ꢁC.
4.10. (2S,20S)-4,4,40,40-Tetrabenzyl-2,20-bimorpholinium
dibromide 1b
1
oil (yield 1.573 g, 82%). H NMR (CDCl3, 500 MHz): d
To a solution of bimorpholine 2b (225 mg, 0.64 mmol) in
CH3CN (6 mL), benzyl bromide (456 lL, 3.83 mmol) was
2.19 (4H, br t, J = 11 Hz, H-3a,30a,5a,50a), 2.63 (4H, br

K. Lippur et al. / Tetrahedron: Asymmetry 18 (2007) 137–141
141
3. (a) Chen, J.-R.; Li, X.-Y.; Xing, X.-N.; Xiao, W.-J. J. Org.
Chem. 2006, 71, 8198–8202; (b) Chen, J.-R.; Lu, H.-H.; Li,
X.-Y.; Cheng, L.; Wan, J.; Xiao, W.-J. Org. Lett. 2005, 7,
4543–4545; (c) Ibrahem, I.; Zou, W.; Engqvist, M.; Xu, Y.;
added. The mixture was refluxed for 31 h. CH3CN was
evaporated and the crude product was crystallized in
CH3CN, affording quaternary ammonium salt 1b as white
crystals (yield 267 mg, 60%). 1H NMR (CD3OD,
500 MHz): d 3.21 (2H, br t, J = 13 Hz, H-5a,50a), 3.37
(2H, br t, J = 13 Hz, H-3a,30a), 3.47 (2H, br d,
J = 13 Hz, H-5e,50e), 3.74 (2H, br d, J = 13 Hz, H-
3e,30e), 3.97 (2H, br d, J = 13 Hz, H-6e,60e), 4.54 (2H, br
t, J = 13 Hz, H-6a,60a), 4.55 and 4.60 (4H, d,
J = 12.8 Hz, BnCH2), 4.55 (2H, br d, J = 13 Hz, H-
2a,20a), 5.20 and 5.23 (4H, d, J = 13.3 Hz, BN0CH2),
7.45–7.52 (10H, m, o,m,p-Ar), 7.60 (6H, m, m0,p0-Ar),
7.75 (4H, m, o0-Ar). 13C NMR (CD3OD, 125 MHz): d
54.75 (C-5,50), 55.88 (C-3,30), 61.44 (C-6,60), 63.27 (BN0
CH2), 68.53 (BnCH2), 69.87 (C-2,20), 127.57 (s-Ar),
128.23 (s0-Ar), 130.40 (m-Ar), 130.78 (m0-Ar), 132.06 (p-
Ar), 132.15 (p0-Ar), 134.69 (o0-Ar), 135.04 (o-Ar). IR:
m = 3629, 3411, 3033, 2978, 2950, 2892, 2709, 2613, 1985,
´
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1616, 1496, 1454, 1214, 1102, 760, 734, 704 cmꢀ1
.
22
½aꢁD ¼ ꢀ53:7 (c 2.5, MeOH). Mp 170–173 ꢁC.
4.11. Alkylation of imine 9
A solution of quaternary salt 1b (13 mg, 0.019 mmol) and
imine 9 (55 mg, 0.19 mmol) in toluene (6 mL), was cooled
to 0 ꢁC, degassed and placed under an argon atmosphere.
Benzyl bromide (27 lL, 0.22 mmol) and degassed 15 M
KOH were added. The mixture was stirred for 20 h. In
addition, to complete the reaction, the mixture was stirred
at rt for 4 h. H2O (10 mL) was added and the mixture was
extracted with EtOAc (2 · 7 mL) and dried (Na2SO4). Sol-
vent was evaporated and the residue was purified by col-
umn chromatography (3% EtOAc in petroleum ether),
affording imine 10 as a colourless oil (yield 21 mg, 29%).
24
22
½aꢁD ¼ þ40 (c 1.84, CH3Cl) (½aꢁD ¼ ꢀ185:3 (c 1.0, CH3Cl)
for 85% ee imine 10).7c Ee of the product was also deter-
mined by chiral HPLC (column Chiralcel OD-H, eluent:
hexane–iPrOH = 99.5:0.5, 0.6 mL/min).
´
10. (a) Mosse, S.; Laars, M.; Kriis, K.; Kanger, T.; Alexakis, A.
Org. Lett. 2006, 8, 2559–2562; (b) Kriis, K.; Kanger, T.;
Laars, M.; Kailas, T.; Muurisepp, A.-M.; Pehk, T.; Lopp, M.
¨ ¨
Synlett 2006, 1699–1702.
Acknowledgements
11. (a) Kriis, K.; Kanger, T.; Muurisepp, A.-M.; Lopp, M.
¨ ¨
The authors thank the Estonian Science Foundation
(Grants Nos. 6662, 5628 and 6778) and the Ministry of
Education and Research (Grant No. 0142725s06) for finan-
cial support.
Tetrahedron: Asymmetry 2003, 14, 2271–2275; (b) Kriis, K.;
Kanger, T.; Lopp, M. Tetrahedron: Asymmetry 2004, 15,
2687–2691.
12. (a) Kriis, K.; Kanger, T.; Pehk, T.; Lopp, M. Proc. Estonian
Acad. Sci. Chem. 2001, 50, 173–179; Kriis, K.; Kanger, T.;
Pehk, T.; Lopp, M. Chem. Abstr. 2002, 136, 118420; (b)
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