Asymmetric synthesis of novel C2-symmetric bimorpholines

Article abstract of DOI:10.1016/S0957-4166(02)00188-X

Novel heterocycles - (2S,2′S)-bimorpholine 1 and (3S,3′S)-bimorpholine 2 - were synthesised in >98% e.e. starting from tartaric acid ester.

Full text of DOI:10.1016/S0957-4166(02)00188-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 857–865
Asymmetric synthesis of novel C2-symmetric bimorpholines
To˜nis Kanger,a,* Kadri Kriis,b To˜nis Pehk,c Aleksander-Mati Mu¨u¨riseppa and Margus Loppb
aInstitute of Chemistry at Tallinn Technical University, Akadeemia tee 15, Tallinn 12618, Estonia
bFaculty of Chemistry, Tallinn Technical University, Ehitajate tee 5, Tallinn 19086, Estonia
cNational Institute of Chemical Physics and Biophysics, Akadeemia tee 23, Tallinn 12618, Estonia
Received 15 March 2002; accepted 18 April 2002
Abstract—Novel heterocycles—(2S,2%S)-bimorpholine 1 and (3S,3%S)-bimorpholine 2—were synthesised in >98% e.e. starting from
tartaric acid ester. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
We have now designed and synthesised two new chiral
bimorpholines 1 and 2 (Fig. 1) that combine the posi-
tive properties of the nitrogen atom with the positive
contribution of the oxygen chelating site. Additionally,
these compounds have the advantages of C2-molecular
symmetry.
Chiral heterocycles have become of great importance in
recent years because of their increasing use as essential
fragments of pharmaceuticals and because of their fre-
quent application as chiral ligands in asymmetric catal-
ysis. Nitrogen-containing compounds have several
advantageous properties over other analogous het-
eroatom-containing compounds, including good chelat-
ing ability, strong interaction with metals that usually
results in stable catalytic systems, easy separation from
non-basic products and the possibility of recycling in
chemical processes.1
Although the synthesis of other asymmetric bridged
heterocycles like bipyrrolidines,2–4 bipiperidines5 and
bisaziridines6 have been reported, no data regarding the
preparation of bimorpholines could be found in the
literature (except our preliminary communication on
the synthesis of 2,2%-bimorpholine 17).
2. Results and discussion
Retrosynthetic analysis of the target compounds is out-
lined on Scheme 1. The synthesis of both new com-
pounds is accomplished according to the same general
scheme starting from a tartaric acid ester and involving
the following key steps: introduction of the nitrogen-
containing functionality into the tartaric acid deriva-
Figure 1.
Scheme 1.
* Corresponding author. Fax: +372 6547524; e-mail: kanger@chemnet.ee
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00188-X

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T. Kanger et al. / Tetrahedron: Asymmetry 13 (2002) 857–865
tive, O-alkylation of hydroxyl groups with a function-
alised C2 unit, and subsequent intramolecular cyclisa-
tion. Substitution of either the primary or secondary
hydroxyl group by azide to give the intermediates 20
and 3, respectively, determines the position of the
bridging bond between the heterocyclic rings. Tartaric
acid ester is transformed with either retention or inver-
sion of configuration at the stereogenic centres to lead
to compound 1 and compound 2, respectively.
pound 7 and seven-membered ring compound 8 in
approximately a 1:1 ratio.
These negative results forced us to return to the general
synthetic Scheme 27 as the most reasonable approach
for obtaining the target compound. In order to over-
come the above complications we modified the cyclisa-
tion step using N-Boc derivative 13 as a synthon for the
cyclisation that reduces the hydrophilicity of the hetero-
cycle 14 and allows easily its isolation from water
solution.
2.1. Synthesis of (2S,2%S)-bimorpholine
In our previous communication we outlined a route to
bimorpholine 17 based on the alkylation of diazido diol
3 followed by reductive cyclisation of compound 4
(Scheme 2). The problems of using this route are con-
nected with the separation and purification of highly
hydrophilic target compound 1 from side product 1a
(formed in 10% yield). The complications with separa-
tion prompted us to search for a more practical syn-
thetic sequence.
The synthesis started with alkylation of diazido diol 3
with 2-benzyloxyethyl methanesulfonate (Scheme 4).
For the subsequent transformations of the benzyl and
azido groups a two-step procedure is needed.16 First,
the benzyl groups were cleaved with BBr3 followed by
catalytic hydrogenation of the azido groups, affording
diamino diol 11. The following standard transforma-
tions (protection with Boc2O and mesylation with
MsCl) led to the key intermediate 13. Although the
nucleophilicity of the amino groups of compound 13 is
reduced by the Boc-protection, the nucleophilicity is
still sufficient to enable sodium hydride induced cyclisa-
tion. The product 14 was easily worked-up and purified
and was also obtained in good yield (40% from 3).
Furthermore, no cross-coupling product analogous to
1a was formed. Deprotection of 14 with trifluoroacetic
acid gave the salt of the target compound, which was
isolated under basic conditions as the free amine.
A number of methods have been used for intramolecu-
lar heterocyclisation. Among them the Mitsunobu reac-
tion of amino alcohols is the most straightforward way
to obtain the target compounds.8 In this reaction, not
only acidic N-compounds (like Ns- and Ts-amides)9 but
also alkyl10 or arylamines11 and even primary amines12
form heterocycles. Our attempts to use the Mitsunobu
reaction in constructing the bimorpholine skeleton
under various reaction conditions were unsuccessful.
Therefore, we turned to another possible alternative
(Scheme 3). It is known that lactams can be synthesised
from corresponding esters via intramolecular attack of
an amino group13,14 or via reductive cyclisation of azido
esters.15 In our case the corresponding azides in the
course of reduction of azido group in compound 5
should give the desired bimorpholine 1. However, we
found that the in situ cyclisation of the diamine 6
results in a mixture of the six-membered ring com-
2.2. Synthesis of (3S,3%S)-bimorpholine
The synthesis of the bimorpholine 2 followed the same
general scheme as for the previous compound 1, involv-
ing inversion of the configuration of the stereogenic
centres in the synthesis of diazide 20 (Scheme 5). The
following steps are basic functional group or protective
group transformations (cleavage of benzyl group, cata-
Scheme 2.
Scheme 3.

T. Kanger et al. / Tetrahedron: Asymmetry 13 (2002) 857–865
859
Scheme 4. Reagents and conditions: (a) BnOCH2CH2OMs, Bu4NI, cis-dicyclohexano-18-crown-6, dioxane, NaOH/H2O, 80°C,
86%; (b) BBr3, CH2Cl2, −78°C, 71%; (c) H2, Pd/C, MeOH, 100% (crude); (d) Boc2O, dioxane/H2O/KOH, 0°C to rt, 88%; (e)
MsCl, Et3N, CH2Cl2, 0°C to rt, 76%; (f) NaH, THF, 0°C to rt, 99%; (g) CF3COOH, CH2Cl2; (h) 3.0 M NaOH, Et2O, 29% (for
two steps).
Scheme 5. Reagents and conditions: (a) BnOCH2CH2OMs, Bu4NI, cis-dicyclohexano-18-crown-6, dioxane, NaOH/H2O, 80°C,
69%; (b): 0.5N HCl, MeOH, 86%; (c) MsCl, Et3N, CH2Cl2, 0°C to rt, 100% (crude); (d) NaN3, DMF, 80°C, 77%; (e) BBr3,
CH2Cl2, −78°C, 70%; (f) H2, Pd/C, MeOH, 99%; (g) Boc2O, dioxane/H2O/KOH, 0°C to rt, 84%; (h) MsCl, Et3N, CH2Cl2, 0°C
to rt, 90%; (i) NaH, THF, 0°C to rt, 91%; (j) CF3COOH, CH2Cl2, 94%; (k) 3.0 M NaOH, Et2O, 50%.
lytic hydrogenation of azide, protection of amino group
and mesylation), which usually proceed in high yield.
amides 27 and 28 with (S)-(−)-a-methoxy-a-(trifluoro-
methyl)phenylacetic acid (MTPA) and (R)-(−)-a-
methoxyphenylacetic acid (MPA) (Fig. 2). The use of
MTPA or MPA for the derivatisation of the unsymmet-
rical secondary amines at room temperature results in
The key intermediate 24 was obtained from tartaric
acid derivative 16 in the multistep procedure in 24%
yield. Similarly to the previous scheme the cyclisation
reaction was also effective and led to protected bimor-
pholine 25 in 91% yield. Deprotection of 25 with tri-
fluoroacetic acid gave the corresponding salt 26. The
target compound 2 was obtained after basic treatment
of 26 in 32% yield starting from compound 22.
2.3. Determination of the enantiomeric excess of
bimorpholines
For the determination of the enantiomeric purity of
bimorpholine 1, it was converted into diastereomeric
Figure 2.

860
T. Kanger et al. / Tetrahedron: Asymmetry 13 (2002) 857–865
NMR spectra with different signals from the (E)- and
(Z)-conformers of the amides. Usually, more profound
differences are observed for MTPA derivatives, and
that was also observed in the present case. Two sec-
ondary amino groups in the bimorpholine structure
result, in the case of enantiomerically pure compounds,
four sets of signals, from (EE)-, (ZZ)- and (EZ)-iso-
mers correspondingly, with the (EZ)-isomer giving sep-
arate signals from the (E)- and (Z)-rings. Thus, an
enantiomeric impurity in such compounds should result
in additional sets of signals from the diastereoisomers.
We have found that both 27 and 28 gave only four sets
of signals, which are most clearly seen from the 13C
NMR spectra (Table 1). A detailed analysis of the
spectra was carried out in the case of diastereoisomers
from compound 27, where larger differences in chemi-
cal shifts and in their relative concentrations of isomers
were observed. The isomers had the relative concentra-
tions 51:37:12 (the first of them being the (EZ)-isomer).
The ratio of two minor isomers corresponds to 0.666
kcal/mol difference in DG and from that the conforma-
tional energy for the (EZ)-isomer (0.333 kcal/mol) may
be calculated from simple additivity. The calculated
value of relative concentrations of three isomers (taking
into account that (EZ)-isomer can be formed in two
ways) is 46:41:13, which is quite close to the observed
ratio for the isomers of compound 27. The assignment
of the (EE)- and the (ZZ)-isomers (and (E)- and (Z)-
rings of the (EZ)-isomer) was made on the basis of
1
comparison of H differential shielding effects in these
isomers with the published data on the conformers of
(R)-MTPA
amides
of
(R)-3-methylpiperidine.17
Table 1. 1H and 13C NMR chemical shifts of bimorpholines and their derivativesa
Atoms
Compound
Isomer
2
3
5
6
Other
1H
13C
1H
13C
1H
13C
1H
13C
1H
13C
1
3.42
77.57
69.66
75.18
74.90
75.28
74.69
66.66
67.36
66.81
66.99
65.87
73.75
75.83
74.48
75.12
69.25
67.01
2.76
2.68
47.11
55.71
43.42
44.82
43.49
44.87
46.90
48.80
46.60
48.60
54.44
45.63
45.76
46.39
45.54
61.72
59.09
2.86
2.76
2.89
2.91
2.90
3.75
2.80
3.82c
2.92
3.75
2.81
3.82c
3.43
3.63
3.30
3.95
3.44
3.69
3.55
3.83
3.30
3.43
2.68
4.51
2.87
4.46
2.86
4.58
2.16
3.95
2.41
2.68
2.75
2.78
45.69
45.59
43.44
42.12c
43.54
42.01c
40.10
38.45
40.08
38.68
44.59
41.88
43.30
42.14
42.90
48.33
45.19
3.58
3.92
3.47
3.76
3.42
3.84
3.44
3.89c
2.92
3.75
3.43
3.88c
3.78
3.82
3.55
3.89
3.43
3.82
3.52
3.84
3.83
3.98
3.32
3.86
3.49
3.76
3.44
3.95
3.31
3.65
3.48
3.82
3.63
3.76
68.21
67.79
66.39
66.61c
66.45
66.52c
66.81
67.39
66.87
67.22
64.95
66.26
66.46
66.64
66.17
66.64
65.66
2
3.30
3.75
3.30
(EE)-14b
(ZZ)-14b
(EZ,E)-14b
(EZ,Z)-14b
(EE)-25b
(ZZ)-25b
(EZ,E)-25b
(EZ,Z)-25b
26
2.83
3.80
2.88
3.67
2.82
3.83
3.03
3.69
4.60
1.37
1.37
1.37
1.37
1.43
1.44
1.40
1.47
154.57, 80.04, 28.18
154.46, 80.05c, 28.18
154.41, 79.99c, 28.18
154.46, 79.93c, 28.18
154.26, 79.73, 28.16
153.86, 80.49, 28.19
153.97, 80.08, 28.06
153.78, 80.14, 28.25
3.29
3.31
3.34
3.65
3.98
3.60
4.39
4.60
4.38
3.72
3.58
4.00
3.49
3.83
3.76
4.11
2.04
(EE)-27
(ZZ)-27
(EZ,E)-27
(EZ,Z)-27
29 ring Ad
29 ring B
2.05
3.25
2.30
3.74
3.06
3.82
2.13
3.65
2.40
3.69
3.72
3.69
3.71
164.02, 134.04, 126.61, 128.43, 129.59
164.47, 133.31, 126.43, 128.50, 129.43
164.25, 134.14, 126.71, 128.51, 129.80
164.44, 133.18, 126.35, 128.54, 129.48
3.48
2.33
2.82
3.39
3.86
3.41
3.79
2.89
a In CDCl3, for 26 in CD3OD.
b At 243 K.
c Unambiguous assignment of isomers within the columns.
d Substituent on five-membered ring trans to the C(3)H of 2. 13C and 1H chemical shifts in 28 from 6,6-dimethyl bicyclo[3.3.1]-2-heptene part of
molecule, from atoms 1 to 7: 42.47 (2.32), 147.42, 123.98 (5.57), 31.39 (2.28), 40.82 (2.09), 37.96, 32.25 (1.01 and 2.42). Methyl groups at 21.62
(0.86) and 26.29 (1.30) and CHN(N) at 85.93 (3.74) ppm.

T. Kanger et al. / Tetrahedron: Asymmetry 13 (2002) 857–865
861
Although, the 3-methylpiperidine MTPA amides are a
very rough model for the investigated bimorpholine 1
(having an anomeric effect from the connection of
two rings), the observed regularities in differential
shieldings of 1H nuclei show that the (EE)-isomer
should be more stable than the (ZZ)-isomer and the
compound 1 has (S,S)-configuration.
rated solution of NH4Cl was added. The aqueous
layer was extracted with EtOAc (3×20 mL) and dried
over MgSO4. Evaporation of the solvent and purifica-
tion of the crude product by chromatography on sil-
ica gel (petroleum ether/EtOAc, 10:0.5 to 10:2)
afforded 9 as a colourless liquid (2.6 g, 86%); [h]D21
+7.6 (c 2.73, CH2Cl2). IR (film): 3010, 2955, 2920,
2085, 1590, 1445, 1275, 1195. MS (CI) m/z: 441 [M+
1
For determination of the enantiomeric excess of
bimorpholine 2, the compound was converted into
diastereomeric aminal derivative 29 with (1R)-(−)-
myrtenal18 (Fig. 2). Only one set of 1H and 13C
chemical shifts was observed with different chemical
shifts for the two morpholine rings (Table 1). Mutual
assignment of the two rings is based on the gauche
interactions of the substituent with carbons C(3),
C(3%), C(5) and C(5%) of 2.
H]+, 413, 385, 356, 91. H NMR (500 MHz, CDCl3)
l 3.37 (dd, 2H, J=6.4 and 12.9 Hz, CH2N), 3.47
(dd, 2H, J=2.8 and 12.9 Hz, CH2N), 3.61 and 3.62
(m, 4H, CH2OCH2Ph), 3.71 (m, 2H, CHO), 3.75 and
3.82 (m, 4H, CH2OCH), 4.53 (s, 4H, OCH2Ph), 7.30
(m, 2H, p-Ph), 7.34 (m, 8H, o-,m-Ph); 13C NMR (125
MHz, CDCl3) l 50.70 (CH2N), 69.84 (CH2OCH2Ph),
70.82 (CH2OCH), 73.25 (OCH2Ph), 79.21 (CHO),
127.63 (p-Ph), 127.70 (o-Ph), 128.35 (m-Ph), 138.06
(s-Ph).
The above results show that the enantiomeric excess
of both of the synthesised bimorpholines 1 and 2 is
very high (e.e. >98%).
4.2. (4S,5S)-4,5-Diazidomethyl-3,6-dioxa-1,8-octanediol
10
3. Conclusion
To a solution of dibenzyl ether 9 (1.13 g, 2.58 mmol)
in anhydrous CH2Cl2 (20 mL) BBr3 (500 mL, 5.29
mmol) was added dropwise at −78°C under an Ar
atmosphere. The mixture was stirred at −65 to −40°C
until the reaction was complete (6 h). The reaction
was quenched with a saturated solution of NaHCO3
and was extracted several times with CH2Cl2. After
drying over MgSO4 the filtrate was concentrated
affording a crude diazido diol 10 as a brown liquid.
The crude product was chromatographed on silica gel
(petroleum ether/EtOAc, 1:1 to 0:1) affording the
target compound as a yellow oil (475 mg, 71%). MS
In summary, novel heterocyclic C2-symmetric bimor-
pholines with high e.e. were synthesised. These com-
pounds may be used as ligands for chiral metal
catalysts. It is assumed that unique structure of the
obtained bridged compounds may result in more rigid
chelates with metals increasing the conformational
influence of the stereodifferentiation in various reac-
tions. The synthesis of different chiral catalysts based
on the ligands obtained in this study is currently
under investigation.
1
(EI) m/z: 259 [M−H]+, 231, 201, 142. H NMR (500
MHz, CDCl3) l 3.00 (s, 2H, OH), 3.33 (dd, 2H, J=
5.5 and 12.9 Hz, CH2N), 3.52 (dd, 2H, J=3.4 and
12.9 Hz, CH2N), 3.67 (m, 2H, CHO), 3.70 and 3.80
(m, 4H, CH2OCH), 3.75 and 3.77 (m, 4H, CH2OH);
13C NMR (125 MHz, CDCl3) l 50.57 (CH2N), 61.92
(CH2OH), 72.80 (CH2OCH), 79.36 (CHO).
4. Experimental
Full assignment of 1H and 13C chemical shifts is
based on the 1D and 2D FT NMR spectra on a
Bruker AMX500 instrument. Solvent peaks (CHCl3
l=7.27, CD2HOD l=3.30, CDCl3 l=77.00, CD3OD
l=49.00) were used as chemical shift references. The
mass spectra were recorded on a Hitachi M80B spec-
trometer using electron ionisation (EI) at 70 eV or
chemical ionisation (CI) with isobutane. IR spectra
were recorded on Hitachi 270-30 infrared spectropho-
tometer. Optical rotations were measured using a
Kru¨ss Optronic GmbH automatic digital polarimeter
P 3002. Elemental analyses were performed on a
Perkin–Elmer C, H, N, S–Analyzer 2400.
4.3. (4S,5S)-4,5-Diaminomethyl-3,6-dioxa-1,8-
octanediol 11
To a solution of diazido diol 10 (440 mg, 1.69 mmol)
in MeOH (15 mL) was added 10% Pd/C (90 mg,
0.085 mmol). The mixture was hydrogenated under a
hydrogen atmosphere for 4 h. The catalyst was
removed by filtration through Celite® and the filtrate
was evaporated affording a crude product (350 mg,
100%) which was used in the next step without purifi-
cation. [h]1D9 −35.3, (c 1.89, MeOH). IR (film): 3360,
2936, 1596, 1458, 1348, 1110, 1032. MS (CI) m/z: 209
[M+H]+, 192, 148, 130, 101. HRMS M/2 104.0716
4.1. (2S,3S)-2,3-Bis[(2%-benzyloxy)ethoxy]-1,4-
diazidobutane 9
To a solution of diazido diol 3 (1.2 g, 6.97 mmol) in
dioxane (15 mL) and a 50% NaOH aqueous solution
(15 mL), Bu4NI (268 mg, 0.73 mmol), cis-dicyclohex-
ano-18-crown-6 (63 mg, 0.17 mmol) and 2-benzyl-
oxyethyl methanesulfonate (4.0 g, 17.4 mmol) were
added. After stirring for 42 h at 80°C, the reaction
mixture was cooled to room temperature and a satu-
1
(calcd for C4H10NO2 104.0712) H NMR (500 MHz,
CDCl3+CD3OD) l 2.44 (dd, 2H, J=6.7 and 12.9 Hz,
CH2N), 2.63 (dd, 2H, J=2.9 and 12.9 Hz, CH2N),
3.25 (m, 2H, CHO), 3.38–3.45 (m, 8H, CH2O); 13C
NMR (125 MHz, CDCl3+CD3OD) l 40.42 (CH2N),
61.09 (CH2OH), 72.06 (CH2OCH), 80.43 (CHO).

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T. Kanger et al. / Tetrahedron: Asymmetry 13 (2002) 857–865
4.4. (2S,3S)-Di-tert-butyl-2,3-bis[(2%-hydroxy)ethoxy]-
centration in vacuum and purification of the crude
product by chromatography on silica gel (hexane/2-
propanol, 5:1 to 4:1) afforded compound 14 (443 mg,
99%). [h]2D1 +15.3 (c 1.78, CH2Cl2). MS (CI) m/z: 373
[M+H]+, 317, 261. The NMR spectrum shows at room
temperature exchange broadening. Detailed analysis
was performed at 243 K in a CDCl3 solution with the
help of data from tert-butoxycarbonyl effects on mor-
pholine and sarcosine. 1H and 13C NMR chemical shifts
of individual conformers are given in Table 1. Anal.
calcd: C, 58.05; H, 8.66; N, 7.52. Found: C, 58.18; H,
8.61; N, 7.77%.
1,4-butanedicarbamate 12
To a cooled solution of diamino diol 11 (350 mg, 1.69
mmol) in dioxane:H2O (15 mL:7 mL) di-tert-butyl
dicarbonate (810 mg, 3.72 mmol) was added at 0°C.
The reaction mixture was allowed to warm up to room
temperature and an aqueous solution of KOH (1.2
mmol) was added. The reaction mixture was stirred
overnight. After concentration of the reaction mixture,
brine was added and the resulting mixture was
extracted with EtOAc (4×15 mL). The combined
organic layers were dried over MgSO4 and concen-
trated. Purification by chromatography on silica gel
(hexane/2-propanol, 10:2) afforded compound 12 (608
mg, 88%). [h]1D9 −12.1 (c 2.22, CH2Cl2). IR (film): 3480,
3005, 2960, 1705, 1380, 1265, 1180, 1120. MS (CI) m/z:
409 [M+H]+, 309, 279, 253. 1H NMR (500 MHz,
CDCl3, exchange broadened spectrum) l 1.44 (s, 18H,
Boc), 3.17 and 3.48 (m, 4H, CH2N), 3.40 (bs, 2H, OH),
3.53 (m, 2H, CHO), 3.65 and 3.74 (m, 4H, CH2O), 3.72
(m, 4H, CH2OH), 5.32 (bs, 2H, NH); 13C NMR (125
MHz, CDCl3) l 28.36 (Boc), 40.52 (CH2N), 62.03
(CH2OH), 72.74 (CH2OCH), 79.47 (CHO), 79.60 (Boc),
156.38 (Boc).
4.7. (2S,2%S)-Bimorpholine 1
Compound 14 (443 mg, 1.19 mmol) was dissolved in
CH2Cl2 (8 mL) and trifluoroacetic acid (3 mL) was
added. After stirring for 0.5 h at room temperature
reaction was complete. The solution was evaporated
and the residue was triturated with Et2O to give white
solid of trifluoroacetate salt 15. The solid product was
isolated by filtration, washed with Et2O and dried in
vacuum to dryness. Salt 15 was dissolved in a 3.0 M
NaOH aqueous solution (3 mL) and stirred for 15 min
followed by evaporation of water in vacuum. The
obtained slurry was triturated with Et2O several times.
Evaporation of Et2O gave product 1 (59 mg, 29%, mp
115–120°C). An analytical sample was chro-
matographed on basic aluminium oxide (CH2Cl2/
MeOH, 90:10) for spectroscopic analysis. [h]2D0 +18.0 (c
4.89, MeOH). GC–MS (EI) m/z: 172 [M]+, 116, 86, 57.
HRMS m/z 172.1245 (calcd for C8H16N2O2 172.1211).
1H and 13C NMR chemical shifts see Table 1.
4.5. (4S,5S)-4,5-Bis-(N-tert-butoxycarbonyl)amino-
methyl-3,6-dioxaoctane-1,8-dimethanesulfonate 13
Methanesulfonyl chloride (340 mL, 4.40 mmol) was
slowly added to a cooled solution of diol 12 (641 mg,
1.57 mmol) and triethylamine (660 mL, 4.71 mmol) in
anhydrous CH2Cl2 (15 mL) at 0°C. The mixture was
allowed to warm to room temperature during 3 h,
water was added, the organic layer was separated and
the aqueous layer was extracted with EtOAc (3×20
mL). The combined organic layers were washed with
brine, dried over MgSO4 and evaporated. The crude
product was purified by chromatography on silica gel
(hexane/2-propanol, 10:2) affording compound 13 (670
mg, 76%). [h]1D9 −8.5 (c 2.67, MeOH). MS (CI) m/z: 565
4.8. (4S,5S)-4,5-Bis-[(2%-benzyloxy)ethoxymethyl]l-2,2-
dimethyl-1,3-dioxolane 17
To a solution of diol 16 (1.15 g, 7.09 mmol) in dioxane
(15 mL) and a 50% NaOH aqueous solution (15 mL),
Bu4NI (262 mg, 0.71 mmol), cis-dicyclohexano-18-
crown-6 (66 mg, 0.18 mmol) and 2-benzyloxyethyl
methanesulfonate (4.07 g, 17.7 mmol) were added. The
mixture was stirred for 42 h at 80°C, was cooled to
room temperature and a saturated solution of NH4Cl
was added. The aqueous layer was extracted with
EtOAc (3×20 mL) and dried over MgSO4. Evaporation
of the solvent and purification of the crude product by
chromatography on silica gel (petroleum ether/EtOAc,
10:1 to 10:4) afforded 17 as a colourless liquid (2.1 g,
69%). [h]1D9 −3.7 (c 6.33, CH2Cl2). IR (film): 3035, 2985,
2870, 1495, 1455, 1215, 1140, 1095, 735. MS (CI) m/z:
415 [M−CH3]+, 339, 263, 91. 1H NMR (500 MHz,
CDCl3) l 1.43 (s, 6H, CH3), 3.64 (m, 4H, CH2OBn),
3.65 (m, 4H, CH2CHO), 3.70 (m, 4H, CH2O), 4.02 (m,
2H, CHO), 4.56 and 4.57 (both d, 4H, J=12.1 Hz,
1
[M]+, 503, 465, 409, 238. H NMR (500 MHz, CDCl3,
exchange broadened spectrum) l 1.43 (s, 18H, Boc),
3.07 (s, 6H, Ms), 3.18 and 3.45 (m, 4H, CH2N), 3.53
(m, 2H, CHO), 3.83 and 3.90 (m, 4H, CH2O), 4.33 and
4.37 (m, 4H, CH2OMs), 5.12 (bs, 2H, NH); 13C NMR
(125 MHz, CDCl3) l 28.30 (Boc), 37.62 (Ms), 40.15
(CH2N), 68.55 (CH2OCH), 68.88 (CH2OMs), 79.25
(CHO), 79.48 (Boc), 156.05 (Boc).
4.6. (2S,2%S)-N,N%-Di-(tert-butoxycarbonyl)bimorpholine
14
To a solution of dimesylate 13 (670 mg, 1.19 mmol) in
anhydrous THF (14 mL) was added NaH (285 mg, 7.13
mmol, 60% suspension in mineral oil) portionwise at
0°C. The reaction mixture was stirred overnight at
room temperature and quenched with a saturated solu-
tion of NH4Cl at 0°C. The aqueous layer was extracted
with EtOAc (3×15 mL) and dried over MgSO4. Con-
CH2Ph), 7.29 (m, 2H, p-Ph), 7.35 (m, 8H, o-,m-Ph); 13
NMR (125 MHz, CDCl3) 26.95 (Me), 69.34
C
l
(CH2OBn), 70.99 (CH2O), 71.96 (OCH2CH), 73.19
(OCH2Ph), 77.32 (CHO), 109.63 (OCO), 127.54 (p-Ph),
127.65 (o-Ph), 128.30 (m-Ph), 138.15 (s-Ph). Anal.
calcd: C, 69.74; H, 7.96. Found: C, 69.39; H, 7.86%.

T. Kanger et al. / Tetrahedron: Asymmetry 13 (2002) 857–865
863
4.9. (2S,3S)-1,4-Bis-[(2%-benzyloxy)ethoxy]butane-2,3-
afforded diazide 20 (1.305 g, 77%). [h]1D9 −26.0 (c 5.67,
CH2Cl2). IR (film): 3035, 2868, 2104, 1496, 1454, 1270,
1104, 738. MS (CI) m/z: 441 [M+H]+, 413, 385, 261, 91.
1H NMR (500 MHz, CDCl3) l 3.65 (m, 4H, CH2OBn),
3.69 (m, 4H, CH2O), 3.74 (m, 4H, CH2CHN3), 3.75 (m,
2H, CHN3), 4.58 (s, 4H, CH2Ph), 7.30 (m, 2H, p-Ph),
7.36 (m, 8H, o-,m-Ph); 13C NMR (125 MHz, CDCl3) l
60.74 (CHN3), 69.37 (CH2OBn), 70.87 (OCH2CH),
70.93 (CH2O), 73.27 (OCH2Ph), 127.64 (p-Ph), 127.69
(o-Ph), 128.37 (m-Ph), 138.05 (s-Ph). Anal. calcd: C,
59.99; H, 6.41; N, 19.08. Found: C, 59.47; H, 6.51; N,
18.63%.
diol 18
To solution of dibenzyl ether 17 (1.93 g, 4.5 mmol) in
methanol (25 mL) 0.5N HCl (5 mL) was added and the
reaction mixture was stirred overnight. The mixture
was diluted with a saturated NaHCO3 solution. After
evaporation of methanol and acetone, the aqueous
layer was extracted with EtOAc (3×30 mL) and dried
over MgSO4. Filtration and concentration to dryness in
vacuum afforded the crude product. Purification of the
crude product by chromatography on silica gel
(petroleum ether/2-propanol, 10:1 to 10:5) afforded diol
18 (1.51 g, 86%). [h]D18 −2.0 (c 9.78, CH2Cl2). IR (film):
3444, 3036, 2868, 1606, 1496, 1454, 1096, 738. MS (CI)
m/z: 391[M+H]+, 299, 239, 149, 91. 1H NMR (500
MHz, CDCl3) l 3.15 (d, 2H, J=4.6 Hz, OH), 3.63 (m,
4H, CH2OBn), 3.64 (m, 4H, CH2CHO), 3.69 (m, 4H,
CH2O), 3.86 (m, 2H, CHO), 4.57 (s, 4H, CH2Ph), 7.30
(m, 2H, p-Ph), 7.34–7.35 (m, 8H, o-,m-Ph); 13C NMR
(125 MHz, CDCl3) l 69.16 (CH2OBn), 70.37 (CHO),
70.76 (CH2O), 73.03 (OCH2CH), 73.18 (OCH2Ph),
127.64 (p-Ph), 127.71 (o-Ph), 128.35 (m-Ph), 137.92
(s-Ph). Anal. calcd: C, 67.67; H, 7.74. Found: C, 67.90;
H, 7.89%.
4.12. (5S,6S)-5,6-Diazido-3,8-dioxadecane-1,10-diol 21
To a solution of compound 20 (169 mg, 0.38 mmol) in
anhydrous CH2Cl2 (3 mL), BBr3 (1.0 M in CH2Cl2, 780
mL, 0.78 mmol) was added dropwise at −78°C under an
argon atmosphere. The mixture was stirred at −65 to
−45°C until reaction was complete (5 h). Purification of
the crude product by chromatography on silica gel
(petroleum ether/2-propanol, 10:2 to 10:5) afforded
diazido diol 21 (69 mg, 70%). [h]2D0 −38.4 (c 4.44,
CH2Cl2). IR (film): 3388, 2872, 2100, 1264, 1052, 736.
MS (CI) m/z: 261 [M+H]+, 233, 205, 115. Anal. calcd:
C, 36.92; H, 6.20; N, 32.29. Found: C, 36.41; H, 6.02;
N, 31.97%.
4.10. (1S,2S)-1,2-Bis-[(2%-benzyloxy)ethoxymethyl]-
ethane 1,2-dimethanesulfonate 19
4.13. (5S,6S)-5,6-Diamino-3,8-dioxadecane-1,10-diol 22
Methanesulfonyl chloride (0.75 mL, 9.36 mmol) was
slowly added to a solution of diol 18 (1.51 g, 3.89
mmol) and triethylamine (1.65 mL, 11.86 mmol) in
anhydrous CH2Cl2 (20 mL) at 0°C. Temperature was
allowed to rise to room temperature during 3 h, water
was added and the organic layer was separated. The
aqueous layer was extracted with EtOAc (3×40 mL).
The combined organic layers were washed with brine
and dried over MgSO4. Concentration in vacuum
afforded crude dimesylate 19 (2.12 g, 100%). [h]1D8 −14.6
(c 9.56, CH2Cl2). IR (film): 3032, 2872, 1604, 1496,
1454, 1362, 1174, 1102, 914, 740. MS (CI) m/z: 546
To a solution of diazido diol 21 (514 mg, 1.98 mmol) in
MeOH (15 mL) 10% Pd/C (105 mg, 0.10 mmol) was
added. The mixture was hydrogenated overnight under
a hydrogen atmosphere. The catalyst was removed by
filtration through Celite® and the filtrate was evapo-
rated under vacuum affording a crude diamino diol 22
(410 mg, 99%). [h]2D0 +11.6 (c 3.78, MeOH). IR (film):
3356, 2872, 1598, 1458, 1358, 1122, 1072, 892. MS (CI)
m/z: 209 [M+H]+, 104. HRMS M/2 104.0714 (calcd for
C4H10NO2 104.0712). 1H NMR (500 MHz, CDCl3+
CD3OD) l 2.89 (m, 2H, CHNH2), 3.37 (dd, 2H, J=5.8
and 9.6 Hz, CH2CHN), 3.44 (dd, 2H, J=4.0 and 9.6
Hz, CH2CHN), 3.46 (m, 2H, CH2O), 3.60 (m, 2H,
CH2O), 3.60 (m, 4H, CH2OH); 13C NMR (125 MHz,
CDCl3+CD3OD) l 52.38 (CHNH2), 61.01 (CH2OH),
72.50 (CH2O), 73.45 (OCH2CH).
1
[M]+, 454, 366, 91. H NMR (500 MHz, CDCl3) l 3.06
(s, 6H, Ms), 3.63–3.65 (m, 4H, CH2OBn), 3.67–3.69 (m,
4H, CH2O), 3.77 (dd, 2H, J=3.5 and 11.0 Hz,
CH2CHO), 3.82 (dd, 2H, J=6.9 and 11.0 Hz,
CH2CHO), 4.52 (s, 4H, CH2Ph), 4.96 (m, 2H, CHO),
7.29–7.36 (m, 10H, Ph); 13C NMR (125 MHz, CDCl3)
l 38.65 (Ms), 69.12 (CH2OBn), 69.82 (OCH2CH), 70.72
(CH2O), 73.16 (OCH2Ph), 79.03 (CHO), 127.74 (p-Ph),
127.76 (o-Ph), 128.40 (m-Ph), 137.82 (s-Ph). Anal.
calcd: C, 52.73; H, 6.23. Found: C, 52.39; H, 6.37%.
4.14. (1S,2S)-Di-tert-butyl-1,2-bis[(2%-hydroxyethoxy)-
methyl-1,2-ethanedicarbamate 23
To a cooled solution of diamino diol 22 (410 mg, 1.97
mmol) in dioxane:H2O (15 mL:5 mL) di-tert-butyl
dicarbonate (945 mg, 4.34 mmol) was added at 0°C.
The reaction mixture was allowed to warm up to room
temperature and an aqueous solution of KOH (1.2
mmol) was added. The reaction mixture was stirred
overnight. After concentration of the reaction mixture,
brine was added and the resulting mixture was
extracted with EtOAc (4×30 mL). Combined organic
layers were dried over MgSO4 and concentrated. Purifi-
cation by chromatography on silica gel (hexane/2-
propanol, 10:2) afforded compound 23 (675 mg, 84%).
MS (CI) m/z: 409 [M+H]+, 353, 309, 279, 253. 1H
4.11. (1S,2S)-1,2-Diazido-1,2-bis-[(2%-benzyloxy)ethoxy-
methyl]ethane 20
A mixture of dimesylate 19 (2.12 g, 3.88 mmol) and
sodium azide (0.89 g, 13.65 mmol) in anhydrous DMF
(12 mL) was stirred for 48 h at 80°C. After cooling to
room temperature the suspension was diluted with a
water/brine mixture, was extracted with EtOAc (3×50
mL) and dried over MgSO4. Concentration in vacuum
and purification of the crude product by chromatogra-
phy on silica gel (petroleum ether/EtOAc, 10:1 to 10:4)

864
T. Kanger et al. / Tetrahedron: Asymmetry 13 (2002) 857–865
NMR (500 MHz, CDCl3, exchange broadened spec-
trum) l 3.36 (bs, 2H, OH), 3.51 (dd, 2H, J=4.1 and 9.3
Hz, CH2CHN), 3.56 (t, 4H, J=4.3 Hz, CH2O), 3.59
(dd, 2H, J=3.0 and 9.3 Hz, CH2CHN), 3.71 (dt, 4H,
J=3.6 and 5.3 Hz, CH2OH), 4.01 (m, 2H, CHN), 5.30
(bs, 2H, NH); 13C NMR (125 MHz, CDCl3) l 28.35
(Boc), 51.27 (CHN), 61.48 (CH2OH), 71.17 (OCH2CH),
72.81 (CH2O), 79.80 (Boc), 156.39 (Boc).
26 (113 mg, 0.28 mmol, 94%) was dissolved in a 3.0 M
NaOH aqueous solution (1 mL) and stirred for 15 min
followed by evaporation of water. The obtained slurry
was triturated with Et2O several times. Evaporation of
Et2O afforded product 2 (24 mg, 50%, mp 66–68°C).
[h]2D0 −29.4 (c 2.0, MeOH). MS (EI) m/z: 172 [M]+, 114,
86, 58. HRMS m/z 172.1234 (calcd for C8H16N2O2
1
172.1211). For H and 13C NMR chemical shifts see
Table 1.
4.15. (5S,6S)-5,6-Bis-(N-tert-butoxycarbonyl)amino-3,6-
dioxadecane 1,10-dimethanesulfonate 24
4.18. Preparation of (S)-(−)-a-methoxy-a-(trifluoro-
methyl)phenylacetic acid diamide 27 and (R)-(−)-a-
methoxyphenylacetic acid diamide 28 from
(2S,2%S)-bimorpholine 1
Methanesulfonyl chloride (50 mL, 0.65 mmol) was
slowly added to a solution of diol 22 (90 mg, 0.22
mmol) and triethylamine (95 mL, 0.68 mmol) in anhy-
drous CH2Cl2 (3 mL) at 0°C. The crude product was
purified by chromatography on silica gel (hexane/2-
propanol, 10:3 to 10:5) affording compound 24 as a
colourless syrup which solidifies in the fridge (110 mg,
90%). [h]2D1 −7.7 (c 3.78, CH2Cl2). IR (film): 3384, 2980,
2940, 1708, 1352, 1248, 1172. MS (CI) m/z: 565 [M+
A solution of (S)-(−)-MTPA (46 mg, 0.20 mmol) and
DCC (42.5 mg, 0.21 mmol) in anhydrous CH2Cl2 (0.5
mL) was stirred 0.5 h at 0°C. Bimorpholine 1 (15 mg,
0.087 mmol) in anhydrous CH2Cl2 (0.5 mL) was added
and stirring was continued overnight. The reaction
mixture was filtered, the filtrate was washed with water,
brine and dried over Na2SO4. After concentration in
vacuum the crude product was purified by chromatog-
raphy affording diamide 27 (26 mg, 50%). Diamide 28
was synthesised from (R)-MPA analogously. 1H and
13C NMR chemical shifts of individual conformers at
room temperature are given in Table 1.
1
H]+, 509, 465, 409. H NMR (500 MHz, CDCl3) l 1.43
(s, 18H, Boc), 3.06 (s, 6H, Ms), 3.55 (dd, 2H, J=3.5
and 9.7, CH2CHN), 3.64 (dd, 2H, J=2.2 and 9.7 Hz,
CH2CHN), 3.73–3.74 (m, 4H, CH2O), 3.92 (m, 2H,
CHN), 4.34–4.37 (m, 4H, CH2OMs), 5.20 (d, 2H, J=
5.7, NH); 13C NMR (125 MHz, CDCl3) l 28.32 (Boc),
37.63 (Ms), 51.39 (CHN), 68.69 (CH2OMs), 68.96
(CH2O), 70.98 (OCH2CH), 79.56 (Boc), 156.18 (Boc).
Anal. calcd: C, 42.55; H, 7.14; N, 4.96. Found: C,
42.52; H, 7.23; N, 4.88%.
4.19. Preparation of aminal 29 with (1R)-(−)-myrtenal
from (3S,3%S)-bimorpholine 2
To a solution of bimorpholine 2 (18 mg, 0.10 mmol)
4.16. (3S,3%S)-N,N%-Di-(tert-butoxycarbonyl)bi-
,
and 4 A MS in anhydrous Et2O (1R)-(−)-myrtenal (32
morpholine 25
mL, 0.21 mmol) was added via syringe under an argon
atmosphere and the mixture was stirred overnight. The
molecular sieves were removed by filtration through
Celite® and the filtrate was evaporated under vacuum
affording a crude aminal. Purification by chromatogra-
phy on silica gel (hexane/EtOAc, 10:2, 1% Et3N)
To a solution of dimesylate 24 (778 mg, 1.38 mmol) in
anhydrous THF (15 mL) was added NaH (393 mg, 9.83
mmol, 60% suspension in mineral oil) portionwise at
0°C. The reaction mixture was stirred overnight at
room temperature and quenched with a saturated solu-
tion of NH4Cl at 0°C. The aqueous layer was extracted
with EtOAc (3×30 mL) and dried over MgSO4. Con-
centration in vacuum and purification of the crude
product by chromatography on silica gel (hexane/2-
propanol, 10:0.7 to 10:1) afforded compound 25 (465
mg, 91%). [h]2D0 +86.2 (c 5.33, CH2Cl2). IR (film): 3010,
2965, 2890, 1710, 1470, 1435, 1380, 1250, 1185, 1130.
MS (CI) m/z: 373[M+H]+, 317, 261. NMR spectra at
room temperature show exchange broadening, but the
interconversion barrier is somewhat higher than in 14.
Results of measured spectra (at 243 K) with the assign-
ment of individual conformers are given in Table 1.
1
afforded compound 29 (17 mg, 57%). For H and 13C
NMR chemical shifts see Table 1.
Acknowledgements
This research was supported by Estonian Science Foun-
dation, Grant Nos. 4976, 5133 and 3781.
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