Synthesis of 5,5'-disubstituted bimorpholines

Article abstract of DOI:10.1080/00397910902964874

A general method for the synthesis of 5,5'-disubstituted bimorpholines is proposed. According to the method, methyl-substituted and benzyl-substituted compounds were synthesized, starting from tartaric ester acetal. Target compounds were obtained in good

Full text of DOI:10.1080/00397910902964874

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Synthesis of 5,5′-Disubstituted
Bimorpholines
Kristin Lippur a , Cindy Elmers a , Tiiu Kailas a , Aleksander-Mati
Müürisepp a , Tõnis Pehk b , Tõnis Kanger a & Margus Lopp a
a Department of Chemistry, Faculty of Science, Tallinn University of
Technology, Tallinn, Estonia
b National Institute of Chemical Physics and Biophysics, Tallinn,
Estonia
Published online: 29 Dec 2009.
To cite this article: Kristin Lippur , Cindy Elmers , Tiiu Kailas , Aleksander-Mati Müürisepp , Tõnis
Pehk , Tõnis Kanger & Margus Lopp (2009): Synthesis of 5,5′-Disubstituted Bimorpholines, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:2, 266-281
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Synthetic Communications1, 40: 266–281, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902964874
SYNTHESIS OF 5,50-DISUBSTITUTED BIMORPHOLINES
Kristin Lippur,1 Cindy Elmers,1 Tiiu Kailas,1
1
Aleksander-Mati Mu¨u¨risepp, Tonis Pehk,
2
˜
Tonis Kanger, and Margus Lopp
1
1
˜
1Department of Chemistry, Faculty of Science, Tallinn University of
Technology, Tallinn, Estonia
2National Institute of Chemical Physics and Biophysics, Tallinn, Estonia
A general method for the synthesis of 5,50-disubstituted bimorpholines is proposed.
According to the method, methyl-substituted and benzyl-substituted compounds were
synthesized, starting from tartaric ester acetal. Target compounds were obtained in good
yield and high enantiomeric purity.
Keywords: Asymmetric synthesis; bimorpholine; cyclic diamines
INTRODUCTION
Enantiomerically pure nitrogen-containing heterocycles are of great
importance in organic chemistry. Their use as chiral auxiliaries, chiral reagents,
and chiral ligands in many organic reactions is well known.[1] Additionally, such
heterocycles are important building blocks for bioactive compounds.[2] Many
pharmaceutical agents contain morpholine derivatives as part of their structure.
The C-substituted morpholines have revealed antidepressant, appetite suppressant,
antioxidative, and antitumor biological activity.[3]
At the same time, the expanding scope of asymmetric aminocatalysis[4] has led
to the synthesis and wide use of a variety of diamines. These compounds are efficient
organocatalysts in many CꢀCꢀ and C-heteroatom bond-forming reactions.[5] C2-
symmetric bridged compounds that have a CꢀC bond between two heterocyclic
rings and possess both H donor and acceptor sites and a secondary amino group
are potential bifunctional catalysts (bimorpholines 1 and 2, Fig. 1). Substitution in
the morpholine rings makes them also attractive synthetic building blocks for
bioactive molecules.
In connection with our ongoing project of organocatalysis with diamines, we
have previously reported on the synthesis of (2S,20S)-bimorpholine 1 and
(3R,30R)-bimorpholine 2.[6] Derivatives of these bimorpholines have been used as
organocatalysts in several reactions.[7] The main idea of their preparation is to
Received March 5, 2009.
Address correspondence to To˜nis Kanger, Department of Chemistry, Faculty of Science, Tallinn
University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia. E-mail: kanger@chemnet.ee
266

SYNTHESIS OF 5,50-DISUBSTITUTED BIMORPHOLINES
267
Figure 1. 2,20-Bimorpholine 1 and 3,30-bimorpholine 2.
introduce the chiral structure of a readily available and cheap tartaric acid ester to
a backbone of a cyclic derivative. The key steps of the synthesis are the introduction
of nitrogen-containing functionality into tartaric acid derivatives and the intramo-
lecular cyclization.
Recently, we have reported on the synthesis of unsubstituted bimorpholine 1
via amidation of tartaric ester with 2-aminoethanol, followed by cyclization.[8] This
significant improvement of the preparation scheme increased the yield of the target
compound after the six-step sequence to 35%.
In the present work, we describe the synthesis of new 5,50-disubstituted bimor-
pholines as a general objective to functionalize the a-position of the nitrogen atom in
bimorpholines. The proposed scheme allows introduction of various substituents
and is based on the abovementioned route through amide formation. Thus, it is
an efficient synthesis of enantiomerically pure 5,50-dimethyl-2,20-bimorpholines 3
and 4 together with 5,50-dibenzyl derivative 5 (Fig. 2).
RESULTS AND DISCUSSION
Stereogenic centers in target compounds at bridgehead carbons were trans-
formed from tartaric ester and methyl or benzyl-substituted carbons from (S)-
aminoalcohol 7. Derivatives 3 and 5 were obtained from (R,R)-tartaric ester acetal
6, whereas its diastereoisomeric 4 was obtained from (S,S)-tartaric ester acetal.
The synthesis started with the cyanide-catalyzed amidation[9] of tartaric ester
acetal 6 with aminoalcohols 7 (a or b), which afforded amides 8 (a or b, respectively)
in more than 80% yield (Scheme 1). In a single step, the skeleton of the target
Figure 2. 5,50-Disubstituted bimorpholines.

268
K. LIPPUR ET AL.
Scheme 1. Synthesis of bimorpholine 5.
bimorpholine was formed. Reduction of amides with LiAlH4 gave rise to amines 9a,
b in good yield. The synthesis of bimorpholines 3 and 5 was completed analogously
to our previous preparation of unsubstituted bimorpholines (described by us
before).[8] Thus, secondary amino groups of compounds 9a, b were protected with
benzyl bromide in the presence of diisopropylethyl amine (DIPEA) in 80–98% yield.
When K2CO3 was used instead of DIPEA, the reaction was not complete in
2 days, and a mixture of starting material and monobenzylated and dibenzylated
products was detected. The acetal groups in compounds 10a, b were removed under
acidic conditions, which gave the desired tetraols 11a, b for the cyclization. So far, all
reactions were high-yielding. The final step of the sequence was intramolecular cycli-
zation. Tetraols 11a, b were cyclized in a one-step procedure with NaH and
1-(p-toluenesulfonyl)imidazole,[10] affording bimorpholines 12. Benzyl derivative
12b was obtained with a moderate yield (63%) and deprotection of it by ammonium
formate afforded the desired bimorpholine 5 in 90% yield.
Methyl substituted bimorpholine 12a was obtained via cyclization in an
unexpectedly poor yield—only 18%. A similar phenomenon was observed in the
synthesis of trans-2,5-disubstituted morpholines by Lanman and Myers[10]
—
N-benzyl-protected a-methyl substituted synthon gave a mixture of products in
the cyclization. The intermediate aziridinium ion was reversibly formed in
the course of the reaction. Nonregioselective opening of it led to several products,
lowering the yield of the target compound. Lanman and Myers showed that the
use of p-toluenesulfonamide protective group is critical to increase the yield of the
target compound. Therefore, we used the tosyl group instead of the benzyl group
to protect amine 9a (Scheme 2). The choice of the base played a crucial role in the

SYNTHESIS OF 5,50-DISUBSTITUTED BIMORPHOLINES
269
Scheme 2. Synthesis of bimorpholine 3.
reaction. The selective N-protection in the presence of primary hydroxyl groups was
achieved by using MgO as the base[11] (Table 1). Although the selective N-protection
in the presence of Et3N is described in the literature,[12] in our case the reaction with
compound 9a resulted in a mixture of undetermined products (entry 1). The use of
sterically more hindered base (DIPEA) resulted in 24% yield (entry 2). When NaH
was added to the reaction, only the starting material was recovered (entry 3). The best
results were obtained by using MgO in THF=H2O (entries 4–6)––40% of the yield was
achieved within 24 h. Increasing the reaction time to 5 days increased the isolated yield
of the product to 52%. When the reaction was performed in the microwave reactor
during 1 h at 40–60ꢁC, it resulted in 22% yield together with a considerable amount
of by-products (entry 7). When dimethylformamide (DMF) was used as the solvent
in the microwave-assisted reaction, no reaction occurred (entry 8).
The synthesis with N-tosylated intermediate was similar to the method used in
the previous route. Thus, acetal 13a was deprotected under acidic conditions in 97%
yield. Using the present approach, the cyclization of tetraol 14a was efficient and
afforded bimorpholine 15a in 71% yield. It is likely that the formation of aziridinium
intermediate in the present case is retarded because of sulfoxonium ion character of
Table 1. Tosylation of amine 9a
Entry
Base
Solvent
Temp. (ꢁC)
Reaction time
13a yield (%)
1
2
3
4
5
6
7
8
Et3N
DIPEA
NaH
CH2Cl2
CH2Cl2
DMF
RT
48 h
19 h
5 h
n.d.a
24
0
0
n.r.b
40
MgO
MgO
MgO
MgO
MgO
THF=H2O
THF=H2O
THF=H2O
THF=H2O
DMF
RT
RT
24 h
3 d
48
52
RT
MWc 40–60
MW 100
5 d
1 h
22
n.r.
30 min
aNot determined.
bNo reaction.
cMicrowave reactor CEM Discover-S.

270
K. LIPPUR ET AL.
tosylamide. The target compound 3 was obtained by the reduction of tosyl amide
15 by LiAlH4 in 70% yield (Scheme 2).
The diastereoisomer 4 of bimorpholine 3 was synthesized according to the
same synthetic route as depicted in Scheme 2, starting from (S,S)-tartaric acid ester
acetal (see the experimental section for details). All the corresponding intermediates
are marked with the letter c. We have previously shown that this synthetic route led
to unsubstituted bimorpholines with high enantiomeric purity (ee 99%).[8] Now, the
NMR analysis of diastereomeric bimorpholines 3 and 4 revealed that no epimeri-
zation takes place in the course of the reactions. Diastereomeric purities of the
synthesized compounds were high (>98%), and the same can be concluded for
enantiomeric purity.
CONCLUSIONS
In summary, we have developed a general strategy for the synthesis of 5,50-
disubstituted bimorpholines. The substituents and the absolute configuration of
those positions are determined by the configuration and structure of the chosen
amino alcohol. Bimorpholines 3, 4, and 5 were all synthesized in good yield and high
enantiomeric purity over six steps. The investigation of catalytic properties of these
new compounds is currently under study.
EXPERIMENTAL
General
Chemicals were purchased from Aldrich Chemical Co. and were used as
received. Tetrahydrofuran (THF) was distilled over LiAlH4. Precoated silica-gel
60 F254 plates from Merck were used for thin-layer chromatography (TLC), whereas
for column chromatography silica gel KSK40–100 mm was used. Full assignment of
1H and 13C chemical shifts is based on the 1D and 2D FT NMR spectra measured
on a Bruker AMX500, Avance III 400 and Avance III 800 instruments. Solvent peaks
(CHCl3 d ¼ 7.27, CHD2OD d ¼ 3.30, CDCl3 d ¼ 77.00, CD3OD d ¼ 49.00) were used
as chemical shift references. Infrared (IR) spectra were measured on a Perkin-Elmer
Spectrum BX Fourier transform (FT)–IR spectrometer. Mass spectra (MS) were
recorded on a Shimadzu GCMS-QP2010 spectrometer using EI (70 eV). High-
resolution mass spectra (HRMS) were recorded on a Hitachi M80B spectrometer
using EI (70 eV) or on LTQ Orbitrap (Thermo Electron). Elemental analyses were
performed on a Perkin-Elmer C,H,N,S–Analyzer 2400. Optical rotations were
obtained using a Kruss Optronic GmbH Polarimeter P 3002. All reactions sensitive
¨
to moisture or oxygen were carried out under Ar atmosphere in oven-dried glassware.
(4R,5R)-N,N0-Bis[(1S)-2-hydroxy-1-methylethyl]-2,2-dimethyl-1,3-
dioxolane-4,5-dicarboxamide, 8a
(S)-Alaninol 7a (2.58 mL, 33.16 mmol) and sodium cyanide (81 mg, 1.66 mmol)
were added to a solution of (R,R)-tartaric acid ester acetal 6 (3.618 g, 16.58 mmol) in
MeOH (55 mL). The reaction mixture was refluxed for 48 h. MeOH was evaporated,

SYNTHESIS OF 5,50-DISUBSTITUTED BIMORPHOLINES
271
and the crude mixture was purified by column chromatography on silica gel (7%
1
MeOH in CH2Cl2), affording amide 8a as a yellow oil (yield 4.029 g, 80%). H
NMR (CDCl3, 500 MHz) d: 7.16 (br d, J ¼ 7.8, 2H, NH), 4.54 (s, 2H, H-4,5), 4.08
(m, 2H, NHCH), 3.67 (dd, J ¼ 3.8, 11.2, 2H, CH2O), 3.51 (dd, J ¼ 6.3, 11.2, 2H,
CH2O), 3.39 (br s, 2H, OH), 1.49 (6H, s, 2-CH3), 1.19 (d, J ¼ 6.9, 6H, CH3). 13C
NMR (CDCl3, 125 MHz) d: 170.05 (CO), 112.51 (C-2), 77.46 (C-4,5), 66.25
(CH2OH), 47.59 (NHCH), 26.03 (2-CH3), 16.80 (CH3CH). IR: n¼3409, 3088,
2981, 2939, 2880, 1668, 1538, 1456, 1386, 1215, 1090, 1056 cmꢀ1. ½aꢂD ¼ ꢀ27.5
23
(c 1.45, MeOH). MS m=z: 305 (Mþ þ 1), 273, 255, 144, 114. HRMS calcd. for
C12H21N2O5 (Mþ ꢀCH3OH) 273.1449. Found 273.1440.
(4R,5R)-N,N0-Bis[(1S)-1-benzyl-2-hydroxyethyl]-2,2-dimethyl-1,3-
dioxolane-4,5-dicarboxamide, 8b
(S)-phenylalaninol 7b (7.287 g, 48.20 mmol) and sodium cyanide (118 mg,
2.41 mmol) were added to a solution of (R,R)-tartaric acid ester acetal 6 (5.258 g,
24.10 mmol) in MeOH (80 mL). The reaction mixture was refluxed for 24 h. MeOH
was evaporated, and the crude mixture was purified by column chromatography on
silica gel (7% MeOH in CH2Cl2), affording amide 8b as a yellow solid (yield 9.777 g,
1
89%). H NMR (CDCl3, 400 MHz) d: 7.36–7.25 (m, 10H, Bn), 7.22 (d, J ¼ 8.3, 2H,
NH), 4.35 (s, 2H, CHO), 4.32–4.23 (m, 2H, NCH), 3.75 (dd, J ¼ 3.7, 11.1, 2H,
13
CH2OH), 3.64 (dd, J ¼ 5.5, 11.1, 2H, CH2OH), 3.14 (br s, 2H, OH), 2.95 (m, 4H,
=
Bn CH2), 1.42 (s, 6H, CH3). C NMR (CDCl3, 100 MHz) d: 170.08 (C O), 137.40
(s-Bn), 129.21 (o-Bn), 128.52 (m-Bn), 126.64 (p-Bn), 112.43 (C(CH)3), 77.26 (CHO),
63.82 (CH2OH), 52.72 (NCH), 36.96 (Bn CH2), 25.81 (CH3). IR: n ¼ 3408, 3062,
2989, 2937, 1677, 1530, 1454, 1385, 1213, 1091, 1040, 746, 701 cmꢀ1. ½aꢂD ¼ ꢀ82.4
24
(c 1.18, MeOH). MS m=z: 456 (Mþ), 365, 347, 134, 120, 91. Anal. calcd. for
C25H32N2O6 (456.54): C, 65.77; H, 7.07; N, 6.14. Found: C, 65.50; H, 7.04; N, 6.10.
(2S,20S)-2,20-[[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-
diyl]bis(methyleneimino)]dipropan-1-ol, 9a
Amide 8a (2.589 g, 8.51 mol) in THF (60 mL) was added to a suspension of
LiAlH4 (1.937 g, 51.04 mol) in THF (50 mL) at 0ꢁC. After refluxing for 6 h, water
(1.9 mL), 15% NaOH solution (1.9 mL), and water (5.7 mL) were added at 0ꢁC.
The mixture was filtered and washed with EtOAc. The filtrate was dried over
Na2SO4. Solvents were evaporated, and the residue was purified by crystallization
(petroleum ether=EtOAc), affording amine 9a as white crystals (yield 2.225 g, 95%,
mp 47–49ꢁC). 1H NMR (CDCl3, 500 MHz) d: 3.94 (m, 2H, H-4,5), 3.57 (dd,
J ¼ 3.7, 10.8, 2H, CH2O), 3.29 (dd, J ¼ 7.0, 10.8, 2H, CH2O), 2.90 (dm, J ¼ 12.3,
2H, NHCH2), H-4,5), 2.79 (m, 2H, NHCH), 2.75 (dm, J ¼ 12.3, 2H, NHCH2), 2.6
(br s, 4H, NHþOH), 1.39 (6H, s, 2-CH3), 1.04 (d, J ¼ 6.5, 6H, CH3). 13C NMR
(CDCl3, 125 MHz) d: 108.63 (C-2), 78.81 (C-4,5), 65.71 (CH2OH), 54.59 (NHCH),
48.62 (CH2NH), 27.16 (2-CH3), 16.96 (CH3CH). IR: n ¼ 3293, 3119, 2989, 2968,
2934, 2852, 1443, 1379, 1230, 1082, 1056 cmꢀ1. ½aꢂD ¼ þ 4.9 (c 5.13, MeOH). MS
24
m=z: 277 (Mþ þ 1), 245, 187, 130, 88. HRMS calcd. for C12H25N2O3 (MþꢀCH3OH)
245.1863. Found 245.1869.

272
K. LIPPUR ET AL.
(2S,20S)-2,20-[[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]-
bis(methyleneimino)]bis(3-phenylpropan-1-ol), 9b
Amide 8b (9.746 g, 21.34 mmol) in THF (60 mL) was added to a suspension of
LiAlH4 (4.861 g, 128.09 mmol) in THF (150 mL) at 0ꢁC. After refluxing for 3 h, water
(4.8 mL), 15% NaOH solution (4.8 mL), and water (14.6 mL) were added at 0ꢁC. The
mixture was filtered and washed with EtOAc. The filtrate was dried over Na2SO4.
Solvents were evaporated, and the residue was purified by crystallization (EtOAc=
petroleum ether). The mother liquid was purified by column chromatography on
silica gel (3% MeOH=NH3 in CH2Cl2), affording amine 9b as white crystals (yield
1
8.372 g, 92%, mp 71–77ꢁC). H NMR (CDCl3, 400 MHz) d: 7.29–7.14 (m, 10H,
Bn), 3.85 (s, 2H, CHO), 3.60 (dd, J ¼ 3.6, 11.1, 2H, CH2OH), 3.34 (dd, J ¼ 5.6,
11.1, 2H, CH2OH), 2.87 (m, 2H, NCH), 2.81–2.75 (m, 4H, NCH2), 2.74–2.69 (m,
4H, Bn CH2), 1.29 (s, 6H, CH3). 13C NMR (CDCl3, 100 MHz) d: 138.40 (s-Bn),
129.16 (o-Bn), 128.54 (m-Bn), 126.40 (p-Bn), 108.49 [C(CH3)2], 78.43 (CHO), 62.76
(CH2OH), 60.68 (NCH), 48.25 (NHCH2), 37.86 (Bn CH2), 27.05 (CH3). IR:
n ¼ 3421, 3290, 3027, 2964, 2860, 1945, 1455, 1380, 1231, 1101, 1065, 743,
þ
700 cmꢀ1. ½aꢂD ¼ ꢀ31.6 (c 1.18, MeOH). MS m=z: 429 (M þ 1), 413, 397, 337,
23
206, 91. Anal. calcd. for C25H36N2O4 (428.58): C, 70.06; H, 8.47; N, 6.54. Found:
C, 69.74; H, 8.50; N, 6.50.
(2S,20S)-2,20-{[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]-
bis[methylene(benzylimino)]}dipropan-1-ol, 10a
To a solution of amine 9a (1.96 g, 7.09 mmol) in CH3CN (24 mL), DIPEA
(3.71 mL, 21.28 mmol) and benzyl bromide (2.53 mL, 21.28 mmol) were added.
The reaction mixture was stirred at 40ꢁC for 18 h. CH3CN was evaporated, water
(30 mL) was added, and the mixture was extracted with EtOAc (3 ꢃ 20 mL). The
organic phase was dried (Na2SO4), and solvent was evaporated. The residue was pur-
ified by crystallization (petroleum ether=EtOAc), affording benzylated amine 10a as
white crystals (yield 2.595 g, 80%, mp 91–92ꢁC). 1H NMR (CDCl3, 500 MHz) d: 7.30
(m, 4H, m-Bn), 7.26 (m, 4H, o-Bn), 7.25 (m, 2H, p-Bn), 3.85 and 3.39 (2d, J ¼ 13.7,
4H, Bn CH2), 3.59 (m, 2H, H-4,5), 3.33 and 3.30 (2 m, 4H, CH2O), 3.23 (br s, 2H,
OH), 3.04 (m, 2H, NCH), 2.59 and 2.51 (dm, 4H, J ¼ 14.0, NCH2), 1.36 (6H, s,
2-CH3), 0.88 (d, J ¼ 6.7, 6H, CH3). 13C NMR (CDCl3, 125 MHz) d: 139.29 (s-Bn),
128.92 (o-Bn), 128.41 (m-Bn), 127.11 (p-Bn), 109.10 (C-2), 80.41 (C-4,5), 63.18
(CH2OH), 56.28 (NCH), 54.32 (Bn), 51.41 (CH2N), 27.25 (2-CH3), 9.11 (CH3CH).
IR: n ¼ 3463, 3028, 2964, 2935, 2877, 1946, 1495, 1374, 1þ223, 1105, 1061, 736,
698 cmꢀ1. ½aꢂD ¼ þ 42.9 (c 1.18, MeOH). MS m=z: 456 (M ), 425, 232, 220, 178,
23
148, 91. Anal. calcd. for C27H40N2O4 (456.63): C, 71.02; H, 8.83; N, 6.13. Found:
C, 70.92; H, 8.87; N, 6.11.
(2S,20S)-2,20-{[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]-
bis[methylene(benzylimino)]}bis(3-phenylpropan-1-ol), 10b
To a solution of amine 9b (1.000 g, 2.33 mmol) in MeOH (8 mL), DIPEA
(1.22 mL, 7.00 mmol) and benzyl bromide (0.83 mL, 7.00 mmol) were added. The

SYNTHESIS OF 5,50-DISUBSTITUTED BIMORPHOLINES
273
reaction mixture was stirred at 40ꢁC for 16 h. MeOH was evaporated, water (30 mL)
was added, and the mixture was extracted with CH2Cl2 (2 ꢃ 25 mL). The organic
phase was dried (Na2SO4), and solvent was evaporated. The residue was purified
by column chromatography on silica gel (33% EtOAc in petroleum ether), affording
benzylated amine 10b as a white solid (yield 1.392 g, 98%, mp 101–103ꢁC). 1H NMR
(CDCl3, 400 MHz) d: 7.43–7.16 (m, 20H, Ar), 4.04 (d, J ¼ 13.6, 2H, N-Bn CH2),
3.70–3.61 (m, 2H, CHO), 3.52 (d, J ¼ 13.6, 2H, N-Bn CH2), 3.40 (d, J ¼ 7.4, 4H,
CH2OH), 3.28 (m, 2H, NCH), 3.20 (br s, 2H, OH), 3.04 (dd, J ¼ 4.0, 13.3, 2H, Bn
CH2), 2.79–2.65 (m, 4H, NCH2), 2.39 (dd, J ¼ 9.9, 13.3, 2H, Bn CH2), 1.47 (s,
6H, CH3). 13C NMR (CDCl3, 100 MHz) d: 139.12 and 139.10 (s-Bn), 128.99,
128.92, 128.53 and 128.47 (o-Bn, m-Bn), 127.29 and 126.17 (p-Bn), 109.36
[C(CH3)2], 80.51 (CHO), 63.12 (NCH), 60.80 (CH2OH), 54.48 (N-Bn CH2), 52.05
(NCH2), 31.74 (Bn CH2), 27.30 (CH3). IR: n ¼ 3454, 3027, 2984, 2933, 2856, 1496,
1455, 1371, 1215, 1030, 735, 699 cmꢀ1. ½aꢂD ¼ ꢀ18.0 (c 1.05, MeOH). MS m=z:
23
608 (Mþ), 577, 517, 254, 91. Anal. calcd. for C39H48N2O4 (608.83): C, 76.94; H,
7.95; N, 4.60. Found: C, 76.87; H, 8.00; N, 4.57.
(2S,3S)-1,4-Bis{benzyl[(1S)-2-hydroxy-1-methylethyl]amino}-
butane-2,3-diol, 11a
HCl solution (6 N) (2 mL) was added to a solution of N-benzyl amine 10a
(103 mg, 0.23 mmol) in MeOH (3 mL), and the mixture was heated at 40ꢁC for
22 h. Then 10 N NaOH solution was added in an ice-water bath until pH 8–9. After
the addition of brine (5 mL), MeOH was evaporated, and the mixture was extracted
with CH2Cl2 (4 ꢃ 10 mL). The organic phase was dried (Na2SO4), and solvent was
evaporated. The residue was purified by column chromatography on silica gel (5%
MeOH=NH3 in CH2Cl2), affording tetraol 11a as a white solid (yield 85 mg, 90%,
1
mp 88–89ꢁC). H NMR (CDCl3, 400 MHz) d: 7.33–7.22 (m, 10H, Bn), 3.75 (d,
J ¼ 13.6, 2H, Bn CH2), 3.59 (t, J ¼ 6.3, 2H, CHOH), 3.52–3.38 (m, 6H, Bn CH2,
CH2OH), 2.99–2.89 (m, 2H, CHCH3), 2.70 (dd, J ¼ 6.8, 13.4, 2H, NCH2), 2.57
(dd, J ¼ 6.3, 13.4, 2H, NCH2), 0.93 (d, J ¼ 6.7, 6H, CH3). 13C NMR (CDCl3,
100 MHz) d: 139.44 (s-Bn), 128.77 (o-Bn), 128.50 (m-Bn), 127.19 (p-Bn), 69.26
(CHOH), 64.00 (CH2OH), 57.18 (CHCH3), 55.39 (Bn), 52.25 (NCH2), 9.71 (CH3).
IR: n ¼3339, 3024, 2964, 2930, 2831, 1494, 1451, 1369, 1164, 1113, 1062, 726,
þ
696 cmꢀ1. ½aꢂD ¼ þ 65.8 (c 1.71, MeOH). MS m=z: 417 (M þ 1), 385, 238, 220,
23
178, 148, 130, 91. Anal. calcd. for C24H36N2O4 (416.57): C, 69.20; H, 8.71; N,
6.72. Found: C, 69.12; H, 8.72; N, 6.71.
(2S,3S)-1,4-Bis{benzyl[(1S)-1-benzyl-2-hydroxyethyl]amino}-
butane-2,3-diol, 11b
HCl solution (6 N) (10 mL) was added to a solution of N-benzyl amine 10b
(1.392 g, 2.29 mmol) in MeOH (15 mL) and the mixture was heated at 60ꢁC for
19 h. Then 10 N NaOH solution was added in an ice-water bath until pH 8–9. After
evaporation of MeOH, brine (30 mL) was added, and the mixture was extracted
with CH2Cl2 (2 ꢃ 25 mL). The organic phase was dried (Na2SO4) and solvent was
evaporated. The residue was purified by column chromatography on silica gel

274
K. LIPPUR ET AL.
(50% EtOAc in petroleum ether), affording tetraol 11b as a white solid (yield 1.095 g,
84%, mp 44–49ꢁC). 1H NMR (CDCl3, 400 MHz) d: 7.37–7.12 (m, 20H, Ar), 3.89 (d,
J ¼ 13.7, 2H, N-Bn CH2), 3.69 (m, 4H, N-Bn CH2, CHOH), 3.60 (m, 2H, CH2OH),
3.55–3.48 (m, 2H, CH2OH), 3.21 (br s, 4H, OH), 3.10–3.01 (m, 2H, NCH), 2.97 (dd,
J ¼ 5.2, 13.4, 2H, Bn CH2), 2.89 (dd, J ¼ 6.7, 13.3, 2H, NCH2), 2.79 (dd, J ¼ 6.9,
13.3, 2H, NCH2), 2.62 (dd, J ¼ 9.2, 13.4, 2H, Bn CH2). 13C NMR (CDCl3,
100 MHz) d: 139.38 and 139.26 (s-Bn), 129.02, 128.72, 128.53 and 128.50 (o-Bn,
m-Bn), 127.25 and 126.15 (p-Bn), 69.00 (CHOH), 63.80 (NCH), 62.10 (CH2OH),
55.98 (N-Bn CH2), 52.88 (NCH2), 32.33 (Bn CH2). IR: n ¼ 3368, 3026, 2933, 2838,
1495, 1454, 1118, 1075, 1029, 738, 699 cmꢀ1. MS m=z: 567 (Mþꢀ1), 537, 477, 314,
296, 284, 254, 224, 264, 91. Anal. calcd. for C36H44N2O4 (568.76): C, 76.02; H,
7.80; N, 4.93. Found: C, 75.73; H, 7.81; N, 4.88.
(2S,20S,5S,50S)-4,40-Dibenzyl-5,50-dimethyl-2,20-bimorpholine, 12a
Tetraol 11a (85 mg, 0.20 mmol) in THF (20 mL) was added to NaH (41 mg,
1.02 mmol) at 0ꢁC under an Ar atmosphere. The mixture was stirred at 0ꢁC for
5 min and at rt for 1 h. The reaction mixture was cooled to 0ꢁC, and
1-(p-toluenesulfonyl)imidazole (91 mg, 0.40 mmol) was added. After stirring for
15 min at 0ꢁC, the reaction mixture was allowed to warm to rt and stirred for
42 h. The suspension was cooled to 0ꢁC, and the reaction was quenched by dropwise
addition of sat. NH4Cl solution (5 mL). THF was evaporated, brine was added, and
the mixture was extracted with EtOAc (4 ꢃ 20 mL). The organic phase was dried
(Na2SO4) and solvent was evaporated. The residue was purified by column chroma-
tography on silica gel (2% MeOH=NH3 in CH2Cl2), affording dibenzyl bimorpholine
1
12a as a yellow oil (yield 14 mg, 18%). H NMR (CDCl3, 400 MHz,) d: 7.35–7.25
(m, 10H, Bn), 4.12 (d, J ¼ 13.3, 2H, Bn CH2), 3.80 (dd, J ¼ 3.3, 11.2, 2H, OCH2),
3.42–3.36 (m, 2H, OCH), 3.29–3.22 (m, 2H, OCH2), 3.05 (d, J ¼ 13.3, 2H, Bn
CH2), 2.43 (m, 4H, NCH2, NCH), 2.12 (dd, J ¼ 10.4, 11.6, 2H, NCH2), 1.05 (d,
J ¼ 6.2, 6H, CH3). 13C NMR (CDCl3, 100 MHz) d 138.56 (s-Bn), 129.00 (o-Bn),
128.16 (m-Bn), 126.83 (p-Bn), 73.16 (OCH2), 58.04 (Bn), 55.34 (NCH), 53.15
(NCH2), 15.32 (CH3). IR: n ¼3028, 2963, 2892, 2841, 1494, 1453, 1377, 1106, 734,
þ
699 cmꢀ1. ½aꢂD ¼ þ 128.1 (c 2.50, MeOH). MS m=z: 380 (M ), 289, 217, 202,
23
188, 178, 91. Anal. calcd. for C24H32N2O2 (380.53): C, 75.75; H, 8.48; N, 7.36.
Found: C, 75.57; H, 8.45; N, 7.33.
(2S,20S,5S,50S)-4,40,5,50-Tetrabenzyl-2,20-bimorpholine, 12b
Tetraol 11b (486 mg, 0.85 mmol) in THF (45 mL) was added to a suspension of
NaH (171 mg, 4.27 mmol) in THF (40 mL) at 0ꢁC under an Ar atmosphere. The
mixture was stirred at 0ꢁC for 5 min and at rt for 1 h. The reaction mixture was
cooled to 0ꢁC, and 1-(p-toluenesulfonyl)imidazole (380 mg, 1.71 mmol) was added.
After stirring for 15 min at 0ꢁC, the reaction mixture was allowed to warm to rt
and stirred for 43 h. The suspension was cooled to 0ꢁC, and the reaction was
quenched by dropwise addition of sat. NH4Cl solution (10 mL). THF was evapo-
rated, brine was added, and the mixture was extracted with EtOAc (2 ꢃ 20 mL).
The organic phase was dried (Na2SO4), and solvent was evaporated. The residue

SYNTHESIS OF 5,50-DISUBSTITUTED BIMORPHOLINES
275
was purified by column chromatography on silica gel (30% EtOAc in petroleum
ether), affording dibenzyl bimorpholine 12b as a white solid (yield 287 mg, 63%,
1
mp 47–55ꢁC). H NMR (CDCl3, 800 MHz) d: 7.31 (m, 8H, m, o- 4,40Bn), 7.26 (m,
2H, p-4,40Bn), 7.23 (t, J ¼ 7.5 Hz, 4H, m-5,50Bn), 7.18 (t, J ¼ 7.5 Hz, 2H, p-5,50Bn),
7.14 (d, J ¼ 7.5 Hz, 4H, o-5,50Bn), 4.30 and 3.10 (2d, J ¼ 13.3 Hz, 4H, 4,40Bn
CH2), 3.67 (dd, J ¼ 3.0 and 11.7 Hz, 2H, H-6,60e), 3.33 (d, J ¼ 10.5 Hz, 2H,
H-2,20a), 3.24 (dd, J ¼ 10.1 and 11.7 Hz, 2H, H-6,60a), 3.17 (dd, J ¼ 4.2 and
14.2 Hz, 2H, 5,50Bn), 2.64 (m, 2H, H-5,50a), 2.48 (d, J ¼ 12.0 Hz, 2H, H-3,30e),
2.44 (dd, J ¼ 8.8 and 14.2 Hz, 2H, 5,50Bn), 2.20 (dd, J ¼ 10.5 and 12.0 Hz,
13
H-3,30a). C NMR (CDCl3, 201 MHz) d: 138.79 (s-4,40Bn), 138.59 (s-5,50Bn),
129.23 (o-5,50Bn), 129.11 (o-4,40Bn), 128.53 (m-5,50Bn), 128.47 (m-4,40Bn), 127.14
(p-4,40Bn), 126.44 (p-5,50Bn), 76.35 (C-2,20), 71.51 (C-6,60), 61.29 (C-5,50), 58.45
(4,40Bn), 53.70 (C-3,30), 36.51 (5,50Bn). IR: n ¼ 3026, 2952, 2890, 2826, 149þ4, 1453,
1119, 740, 697 cmꢀ1. ½aꢂD ¼ þ 146.7 (c 1.05, EtOAc). MS m=z: 532 (M ), 441,
23
292, 266, 254, 91. Anal. calcd. for C36H40N2O2 (532.73): C, 81.17; H, 7.57; N,
5.26. Found: C, 80.95; H, 7.61; N, 5.23.
(2S,20S,5S,50S)-5,50-Dibenzyl-2,20-bimorpholine, 5
To a solution of N-benzyl-bimorpholine 12b (250 mg, 0.47 mmol) in THF
(5 mL), 10% Pd=C (375 mg) and ammonium formate (148 mg, 2.35 mmol) were
added under an Ar atmosphere. After heating the reaction mixture at 60ꢁC for
6 h, the mixture was filtrated and washed with MeOH. MeOH was evaporated,
and the crude mixture was purified by column chromatography (5% MeOH=NH3
in CH2Cl2), affording bimorpholine 5 as a yellow oil (yield 149 mg, 90%). 1H
NMR (CDCl3, 400 MHz) d: 7.31–7.25 (m, 4H, m-Bn), 7.24–7.18 (m, 2H, p-Bn),
7.18–7.14 (m, 4H, o-Bn), 3.92 (dd, J ¼ 3.0, 11.1, 2H, CH2O), 3.44–3.38 (m, 2H,
CHO), 3.31–3.25 (m, 2H, CH2O), 3.02–2.94 (m, 2H, NHCH), 2.76–2.68 (m, 4H,
NHCH2), 2.64 (dd, J ¼ 4.6, 13.4, 2H, Bn CH2), 2.40 (dd, J ¼ 9.2, 13.4, 2H, Bn
CH2), 1.71 (br s, 2H, NH). 13C NMR (CDCl3, 100 MHz,) d: 137.67 (s-Bn), 129.09
(o-Bn), 128.58 (m-Bn), 126.53 (p-Bn), 76.68 (CHO), 72.66 (CH2O), 55.55 (NHCH),
47.38 (NHCH2), 38.56 (Bn CH2). IR: n ¼3285, 3028, 2907, 2851, 1496,þ1454,
1339, 1105, 746, 701 cmꢀ1. ½aꢂD ¼ ꢀ8.5 (c 2.24, MeOH). MS m=z: 353 (M þ 1),
24
261, 204, 178, 128, 117, 91. Anal. calcd. for C22H28N2O2 (352.48): C, 74.97; H,
8.01; N, 7.95. Found: C, 74.71; H, 8.07; N, 7.89.
N,N0-[[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]di(methylene)]bis{N-
[(1S)-2-hydroxy-1-methylethyl]-4-methylbenzenesulfonamide}, 13a
MgO (654 mg, 16.23 mmol) was added to a solution of amine 9a (897 mg,
3.25 mmol) in THF (10 mL) and H2O (2.5 mL) and the mixture was stirred at rt
for 30 min. TsCl (1.238 g, 6.49 mmol) was added, and the mixture was stirred for
5 d. The mixture was filtered through celite, and the filtrate was washed with EtOAc.
After the evaporation of solvents, the precipitate was dissolved in EtOAc (30 mL)
and washed with H2O (2 ꢃ 20 mL). The organic phase was dried (Na2SO4), and
solvent was evaporated. The residue was purified by column chromatography on
silica gel (50% EtOAc in petroleum ether), affording tosylamide 13a as an

276
K. LIPPUR ET AL.
amorphous white solid (yield 980 g, 52%). 1H NMR (MeOD, 400 MHz) d: 7.82–7.78
(m, 4H, o-Ts), 7.35 (dd, J ¼ 0.6, 8.6, 4H, m-Ts), 3.97–3.88 (m, 4H, CHO, CHCH3),
3.69 (d, J ¼ 14.9, 2H, NCH2), 3.54 (dd, J ¼ 7.1, 11.5, 2H, CH2OH), 3.45 (dd, J ¼ 6.2,
11.5, 2H, CH2OH), 3.34–3.27 (m, 2H, NCH2), 2.41 (s, 6H, para-CH3), 1.35 (s, 6H,
CCH3), 1.17 (d, J ¼ 6.9, 6H, CHCH3). 13C NMR (MeOD, 100 MHz) d: 144.81 (p-
Ts), 139.13 (s-Ts), 130.70 (m-Ts), 128.48 (o-Ts), 110.97 [C(CH3)2], 81.55 (CHO),
64.38 (CH2OH), 57.03 (CHCH3), 47.40 (NCH2), 27.33 [C(CH3)2], 21.45 (p-CH3),
16.75 (CHCH3). IR: n ¼ 3522, 2984, 2936, 1599, 1375, 1329, 1244, 1156, 817 cmꢀ1
.
þ
23
½aꢂD ¼ ꢀ108.6 (c 0.66, MeOH). MS m=z: 585 (M þ 1), 569, 553, 509, 495, 284,
242, 212, 155, 91. Anal. calcd. for C27H40N2O8S2 (584.76): C, 55.46; H, 6.89; N,
4.79; Found: C, 55.15; H, 6.92; N, 4.76.
N,N0-[(2S,3S)-2,3-Dihydroxybutane-1,4-diyl]bis{N-[(1S)-2-hydroxy-1-
methylethyl]-4-methylbenzenesulfonamide}, 14a
To a solution of tosylamide 13a (980 mg, 1.68 mmol) in MeOH (8 mL), 6 N HCl
solution (5 mL) was added, and the mixture was heated at 55ꢁC for 48 h. In an
ice-water bath, 10 N NaOH solution was added until pH 8–9. After addition of brine
(10 mL), MeOH was evaporated, and the mixture was extracted with CH2Cl2
(4 ꢃ 25 mL). The organic phase was dried (Na2SO4), and solvent was evaporated.
The residue was purified by column chromatography on silica gel (3% MeOH in
CH2Cl2), affording tetraol 14a as a white solid (yield 838 mg, 92%, mp 56–61ꢁC).
1H NMR (MeOD, 400 MHz) d: 7.77 (d, J ¼ 8.0, 4H, o-Ts), 7.39 (d, J ¼ 8.0, 4H, m-
Ts), 4.00 (t, J ¼ 6.3, 2H, CHOH), 3.90 (dt, J ¼ 6.9, 13.6, 2H, CHCH3), 3.58 (dd,
J ¼ 6.9, 11.4, 2H, CH2OH), 3.48 (dd, J ¼ 6.1, 11.4, 2H, CH2OH), 3.34–3.19 (m, 4H,
NCH2), 2.42 (s, 6H, p-CH3), 0.96 (d, J ¼ 6.9, 6H, CHCH3). 13C NMR (MeOD,
100 MHz) d: 145.04 (p-Ts), 138.53 (s-Ts), 130.85 (m-Ts), 128.58 (o-Ts), 71.11
(CHOH), 65.55 (CH2OH), 57.54 (NCH), 48.00 (NCH2), 21.47 (p-CH3), 14.75
(CHCH3). IR: n ¼ 3430, 2978, 2938, 1598, 1330, 1155, 817 cmꢀ1. ½aꢂD ¼ þ 37.5
23
(c 0.66, MeOH). MS m=z: 513 (MþꢀCH2OH), 469, 242, 155, 91. Anal. calcd. for
C24H36N2O8S2 (544.69): C, 52.92; H, 6.66; N, 5.14. Found: C, 52.63; H, 6.69; N, 5.10.
(2S,20S,5S,50S)-5,50-Dimethyl-4,40-bis[(4-methylphenyl)sulfonyl]-2,20-
bimorpholine, 15a
Tetraol 14a (1.304 g, 2.39 mmol) in THF (60 mL) was added to a suspension of
NaH (479 mg, 11.97 mmol) in THF (180 mL) at 0ꢁC under an Ar atmosphere. The
mixture was stirred at 0ꢁC for 5 min and at rt for 1 h. The reaction mixture was
cooled to 0ꢁC, and 1-(p-toluenesulfonyl)imidazole (1.064 g, 4.79 mmol) was added.
After stirring for 15 min at 0ꢁC, the reaction mixture was allowed to warm to rt
and stirred for 90 h. The suspension was cooled to 0ꢁC, and the reaction was
quenched by dropwise addition of sat. NH4Cl solution (15 mL). THF was evapo-
rated, brine was added, and the mixture was extracted with EtOAc (3 ꢃ 30 mL).
The organic phase was dried (Na2SO4), and solvent was evaporated. The residue
was purified by column chromatography on silica gel (40% EtOAc in petroleum
ether), affording ditozyl bimorpholine 15a as a white solid (yield 862 mg, 71%,
mp 62–68ꢁC). 1H NMR (CDCl3, 400 MHz) d: 7.68 (d, J ¼ 8.0, 4H, o-Ts), 7.35

SYNTHESIS OF 5,50-DISUBSTITUTED BIMORPHOLINES
277
(d, J ¼ 8.0, 4H, m-Ts), 3.83–3.73 (m, 4H, CHO, CH2O), 3.64 (dd, J ¼ 2.1, 12.3, 2H,
NCH2), 3.30 (dd, J ¼ 7.5, 11.7, 2H, CH2O), 3.09–3.00 (m, 2H, NCH), 2.85 (dd,
J ¼ 7.3, 12.3, 2H, NCH2), 2.45 (s, 6H, p-CH3), 1.23 (d, J ¼ 6.5, 6H, CH3). 13C
NMR (CDCl3, 100 MHz) d: 143.82 (p-Ts), 134.47 (s-Ts), 129.84 (m-Ts), 127.48
(o-Ts), 72.99 (CHO), 70.64 (CH2O), 51.53 (NCH), 45.89 (NCH2), 21.53 (para-
CH3), 15.52 (CH3). IR: n ¼ 2977, 2926, 2870, 1598, 1349, 1166, 1112, 817 cmꢀ1
.
þ
24
½aꢂD ¼ þ22.2 (c 1.58, MeOH). MS m=z: 509 (M þ 1), 353, 254, 240, 198, 155,
139, 100, 91.
(2S,20S,5S,50S)-5,50-Dimethyl-2,20-bimorpholine, 3
Tosylamide 15a (777 mg, 1.53 mmol) in THF (30 mL) was added to a suspen-
sion of LiAlH4 (464 mg, 12.22 mmol) in THF (20 mL) at 0ꢁC. After refluxing for
29 h, water (464 mL), 15% NaOH solution (464 mL), and water (1.4 mL) were added
at 0ꢁC. The mixture was filtered and washed with EtOAc. The filtrate was dried over
Na2SO4. After filtration, solvents were evaporated, and the residue was purified by
column chromatography on silica gel (7% MeOH=NH3 in CH2Cl2), affording bimor-
1
pholine 3 as a white solid (yield 164 mg, 54%, mp 81–86ꢁC). H NMR (CDCl3,
400 MHz) d: 3.86 (dd, J ¼ 3.1, 11.1, 2H, CH2O), 3.39–3.33 (m, 2H, CHO),
3.15–3.08 (m, 2H, CH2O), 2.93–2.78 (m, 6H, CH2NH, CHNH), 1.67 (br s, 2H,
NH), 0.94 (d, J ¼ 6.4, 6H, CH3). 13C NMR (CDCl3, 100 MHz) d: 76.92 (CHO),
74.09 (CH2O), 49.85 (CHNH), 47.34 (CH2NH), 17.51 (CH3). IR: n ¼3308, 3272,
2970, 2898, 2860, 1444, 1377, 1105 cmꢀ1. ½aꢂD ¼ þ 11.3 (c 2.76, MeOH). MS
23
m=z: 200 (Mþ), 169, 141, 128, 113, 102, 97, 70, 56. HRMS calcd. for C10H20N2O2
(MþþH) 201.15975; found 201.15991.
(4S,5S)-N,N0-Bis[(1S)-2-hydroxy-1-methylethyl]-2,2-dimethyl-1,3-
dioxolane-4,5-dicarboxamide, 8c
(S)-Alaninol 7a (1.98 mL, 25.42 mmol) and sodium cyanide (62 mg, 1.27 mmol)
were added to a solution of (S,S)-tartaric acid ester acetal 6c (2.773 g, 12.71 mmol) in
MeOH (42 mL). The reaction mixture was refluxed for 21 h. MeOH was evaporated,
and the crude mixture was purified by column chromatography on silica gel (7%
MeOH in CH2Cl2), affording amide 8c as an amorphous white solid (yield 3.169 g,
82%). 1H NMR (CDCl3, 400 MHz) d: 7.07 (d, J ¼ 8.2, 2H, NH), 4.58 (s, 2H,
CHO), 4.13–4.01 (m, 2H, NHCH), 3.81 (t, J ¼ 5.5, 2H, OH), 3.66 (m, 2H, CH2OH),
3.47 (m, 2H, CH2OH), 1.46 (s, 6H, CCH3), 1.17 (d, J ¼ 6.8, 6H, CHCH3). 13C NMR
=
(CDCl3, 100 MHz) d: 170.34 (C O), 112.76 (C(CH3)2), 77.67 (CHO), 65.96
(CH2OH), 47.65 (NHCH), 26.28 (CCH3), 17.01 (CHCH3). IR: n ¼3408, 3086,
2980, 2938, 2878, 1667, 1535, 1457, 1385, 1219, 1090, 1054 cmꢀ1. ½aꢂD ¼ þ 16.5 (c
24
3.68, MeOH). MS m=z: 305 (Mþ þ 1), 273, 255, 144, 114, 154. Anal. calcd. for
C13H24N2O6 (304.35): C, 51.31; H, 7.95; N, 9.20. Found: C, 50.93; H, 7.97; N, 9.16.
(2S,20S)-2,20-[[(4R,5R)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]-
bis(methyleneimino)]bis(3-phenylpropan-1-ol), 9c
Amide 8c (3.057 g, 10.04 mol) was added in THF (60 mL) to a suspension of
LiAlH4 (2.287 g, 60.27 mol) in THF (40 mL) at 0ꢁC. After refluxing for 4 h, water

278
K. LIPPUR ET AL.
(2.3 mL), 15% NaOH solution (2.3 mL), and water (6.9 mL) were added at 0ꢁC. The
mixture was filtered and washed with EtOAc. The filtrate was dried over Na2SO4.
After filtration, solvents were evaporated, and the residue was purified by column
chromatography on silica gel (10–20% MeOH=NH3 in CH2Cl2), affording amine
9c as an amorphous yellow solid (yield 1.909 g, 69%). 1H NMR (CDCl3,
400 MHz) d: 3.88–3.81 (m, 2H, CHO), 3.57 (dd, J ¼ 3.9, 10.8, 2H, CH2OH), 3.28
(dd, J ¼ 7.0, 10.8, 2H, CH2OH), 2.93 (ddd, J ¼ 1.9, 4.6, 11.9, 2H, NHCH2), 2.76
(pd, J ¼ 3.9, 6.5, 2H, NHCH), 2.67 (dd, J ¼ 4.1, 11.9, 2H, NHCH2), 1.39 (s, 6H,
CCH3), 1.05 (d, J ¼ 6.5, 6H, CHCH3). 13C NMR (CDCl3, 100 MHz) d: 108.84
[C(CH3)2], 79.58 (CHO), 65.53 (CH2OH), 54.85 (NHCH), 49.73 (NHCH2), 27.14
(CCH3), 17.01 (CHCH3). IR: n ¼ 3307, 2933, 1459, 1380, 1250, 1057 cmꢀ1
.
þ
23
½aꢂD ¼ þ 56.8 (c 3.55, MeOH). MS m=z: 277 (M þ 1), 261, 245, 187, 158, 144,
130, 100, 88. HRMS calcd. for C12H25N2O3 (MþꢀCH3OH) 245.1863; found
245.1860.
N,N0-[[(4R,5R)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]di(methylene)]bis{N-
[(1S)-2-hydroxy-1-methylethyl]-4-methylbenzenesulfonamide}, 13c
MgO (1.094 g, 27.14 mmol) was added to a solution of amine 9c (1.500 g,
5.43 mmol) in THF (18 mL) and water (4.5 mL) and the mixture was stirred at rt
for 30 min. TsCl (2.069 g, 10.85 mmol) was added, and the mixture was stirred for
4 d. The mixture was filtered through celite, and the filtrate was washed with EtOAc.
After the evaporation of solvents, the precipitate was dissolved in EtOAc (30 mL)
and washed with water (3 ꢃ 30 mL). The organic phase was dried (Na2SO4), and sol-
vent was evaporated. The residue was purified by column chromatography on silica
gel (50% EtOAc in petroleum ether), affording tosylamide 13c as an amorphous
1
white solid (yield 2.005 g, 63%). H NMR (CDCl3, 400 MHz) d: 7.78 (d, J ¼ 8.1,
4H, o-Ts), 7.34 (d, J ¼ 8.1, 4H, m-Ts), 4.32–4.24 (m, 2H, CHO), 4.02–3.91 (m, 2H,
CHCH3), 3.71 (d, J ¼ 15.6, 2H NCH2), 3.59–3.42 (m, 4H, CH2OH), 3.38 (dd,
J ¼ 5.5, 9.2, 2H, OH), 3.08–2.97 (m, 2H, NCH2), 2.44 (s, 6H, para-CH3), 1.43 (s,
6H, CCH3), 0.78 (d, J ¼ 6.8, 6H, CHCH3). 13C NMR (CDCl3, 100 MHz) d: 143.79
(p-Ts), 136.88 (s-Ts), 129.84 (m-Ts), 127.25 (o-Ts), 110.63 [C(CH3)2], 80.27 (CHO),
64.49 (CH2OH), 55.49 (CHCH3), 44.88 (NCH2), 26.82 [C(CH3)2], 21.53 (p-CH3),
12.84 (CHCH3). IR: n ¼3510, 2981, 2938, 1598, 1384, 1325, 1246, 1156, 815 cmꢀ1
.
þ
23
½aꢂD ¼ þ 125.3 (c 2.37, MeOH). MS m=z: 553 (M ꢀCH2OH), 509, 495, 284, 242,
212, 155, 91. Anal. calcd. for C27H40N2O8S2 (584.76): C, 55.46; H, 6.89; N, 4.79;
Found: C, 55.47; H, 6.93; N, 4.74.
N,N0-[(2R,3R)-2,3-Dihydroxybutane-1,4-diyl]bis{N-[(1S)-2-hydroxy-1-
methylethyl]-4-methylbenzene-sulfonamide}, 14c
To a solution of tosylamide 13c (2.085 g, 3.57 mmol) in MeOH (15 mL), 6 N
HCl solution (10 mL) was added, and the mixture was heated at 60ꢁC for 22 h. In
an ice-water bath, 10 N NaOH solution was added until pH 8–9. After addition of
sat. NaCl solution (20 mL), MeOH was evaporated, and the mixture was extracted
with CH2Cl2 (5 ꢃ 25 mL). The organic phase was dried (Na2SO4), and solvent was
evaporated. The residue was purified by column chromatography on silica gel

SYNTHESIS OF 5,50-DISUBSTITUTED BIMORPHOLINES
279
(3% MeOH in CH2Cl2), affording tetraol 14c as an amorphous white solid (yield
1
1.942 g, 100%). H NMR (CDCl3, 400 MHz) d: 7.76 (d, J ¼ 8.1, 4H, o-Ts), 7.33 (d,
J ¼ 8.1, 4H, m-Ts), 4.22–4.14 [m, 2H, CHOH)], 4.03–3.93 (m, 2H, CHCH3),
3.63–3.44 (m, 4H, CH2OH), 3.40 (dd, J ¼ 3.6, 15.3, 2H, NCH2), 3.12 (dd, J ¼ 9.1,
15.3, 2H, NCH2), 2.43 (s, 6H, p-CH3), 0.83 (d, J ¼ 6.8, 6H, CHCH3). 13C NMR
(CDCl3, 100 MHz) d: 143.76 (p-Ts), 136.79 (s-Ts), 129.88 (m-Ts), 127.21 (o-Ts),
71.08 (CHOH), 64.41 (CH2OH), 55.48 (NCH), 45.94 (NCH2), 21.54 (p-CH3),
24
13.11 (CHCH3). IR: n ¼ 3421, 2978, 2930, 1598, 1333, 1155, 816 cmꢀ1. ½aꢂD
¼
þ 73.4 (c 1.97, MeOH). MS m=z: 513 (MþꢀCH2OH), 495, 469, 242, 155, 91. Anal.
calcd. for C24H36N2O8S2 (544.69): C, 52.92; H, 6.66; N, 5.14. Found: C, 52.52; H,
6.63; N, 5.07.
(2R,20R,5S,50S)-5,50-Dimethyl-4,40-bis[(4-methylphenyl)sulfonyl]-2,20-
bimorpholine, 15c
Tetraol 14c (1.916 g, 3.52 mmol) in THF (80 mL) was added to NaH (704 mg,
17.59 mmol) in THF (270 mL) at 0ꢁC under Ar atmosphere. The mixture was stirred
at 0ꢁC for 5 min and at rt for 1 h. The reaction mixture was cooled to 0ꢁC, and
1-(p-toluenesulfonyl)imidazole (1.564 g, 7.04 mmol) was added. After stirring for
15 min at 0ꢁC, the reaction mixture was allowed to warm to rt and stirred for
22 h. The suspension was cooled to 0ꢁC, and the reaction was quenched by dropwise
addition of sat. NH4Cl solution (50 mL). THF was evaporated, brine was added, and
the mixture was extracted with EtOAc (3 ꢃ 30 mL). The organic phase was dried
(Na2SO4). After filtration, solvents were evaporated, and the residue was purified
by crystallization (in boiling MeOH). The mother liquid was purified by column
chromatography on silica gel (50% EtOAc in petroleum ether), affording ditozyl
1
bimorpholine 15c as white crystals (yield 1.510 g, 84%, mp 174–177ꢁC). H NMR
(CDCl3, 400 MHz) d: 7.69 (d, J ¼ 8.0, 4H, o-Ts), 7.32 (d, J ¼ 8.0, 4H, m-Ts),
4.01–3.93 (m, 2H, NCH), 3.61 (m, 4H, CH2O), 3.50 (dd, J ¼ 1.8, 12.7, 2H,
NCH2), 3.44–3.38 (m, 2H, CHO), 3.09 (dd, J ¼ 10.6, 12.7, 2H, NCH2), 2.44 (s,
6H, p-CH3), 1.07 (d, J ¼ 6.8, 6H, CH3). 13C NMR (CDCl3, 100 MHz) d: 143.54
(p-Ts), 137.30 (s-Ts), 129.87 (m-Ts), 127.05 (o-Ts), 75.51 (CHO), 71.41 (CH2O),
48.37 (NCH), 40.29 (NCH2), 21.52 (para-CH3), 13.65 (CH3). IR: n ¼2982, 2932,
2874, 1600, 1341, 1157, 1123, 809 cmꢀ1. ½aꢂD ¼ þ 94.9 (c 2.37, CHCl3). MS m=z:
24
353 (Mþ- Ts), 254, 198, 155, 100, 91. Anal. calcd. for C24H32N2O6S2 (508.66): C,
56.67; H, 6.34; N, 5.51. Found: C, 56.67; H, 6.31; N, 5.49.
(2R,20R,5S,50S)-5,50-Dimethyl-2,20-bimorpholine, 4
Tosylamide 15c (432 mg, 0.85 mmol) in THF (10 mL) was added to a suspen-
sion of LiAlH4 (258 mg, 6.79 mmol) in THF (18 mL) at 0ꢁC. After refluxing for
10 h, water (260 mL), 15% NaOH solution (260 mL), and water (780 mL) were added
at 0ꢁC. The mixture was filtered and washed with EtOAc. The filtrate was dried over
Na2SO4. After filtration, solvents were evaporated, and the residue was purified
by column chromatography on silica gel (3–10% MeOH=NH3 in CH2Cl2), affording
bimorpholine 4 as a yellow oil, which solidifies in the freezer (yield 133 mg, 78%).
1H NMR (CDCl3, 400 MHz) d: 3.73–3.61 (m, 6H, CHO, CH2O), 3.02–2.90 (m,

280
K. LIPPUR ET AL.
4H, CHNH, CH2NH), 2.80 (dd, J ¼ 2.7, 12.6, 2H, CH2NH), 2.14 (br s, 2H, NH),
1.18 (d, J ¼ 6.7, 6H, CH3). 13C NMR (CDCl3, 100 MHz) d: 74.46 (CHO), 70.47
(CH2O), 47.99 (CHNH), 42.71 (CH2NH), 16.88 (CH3). IR: n ¼ 3304, 3235, 2955,
2897, 2852, 1456, 1382, 1097 cmꢀ1. ½aꢂD ¼ ꢀ2.2 (c 8.82, MeOH). MS m=z: 200,
22
141, 128, 114, 102, 97, 70.
ACKNOWLEDGMENTS
The authors thank the Estonian Science Foundation (Grant Nos. 6662 and
6778), the Ministry of Education and Research (Grant No. 0142725S06), and EU
European Regional Development Fund (3.2.0101.08–0017) for financial support.
The authors are grateful to Lauri Peil (Ph.D.), University of Tartu, Institute of
Technology proteomics core facility, for HRMS analysis.
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