Chiral α,ω-diaminoethers derived from D-mannitol and L-treitol as building blocks for the synthesis of macrocyclic compounds possessing 1,3-benzenedicarboxamide or 2,6-pyridinedicarboxamide subunits

Article abstract of DOI:10.1016/S0957-4166(01)00309-3

Three new chiral α,ω-diaminoethers, derivatives of D-mannitol and L-treitol, possessing C₂ symmetry are prepared. The α,ω-diaminoethers were applied to the macrocyclization reaction under non-high-dilution conditions, which afforded chiral macrocyclic diamides possessing either 2,6-pyridinedicarboxamide or 1,3-benzenedicarboxamide moieties.

Full text of DOI:10.1016/S0957-4166(01)00309-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1763–1769
Chiral a,v-diaminoethers derived from
D
-mannitol and -treitol
L
as building blocks for the synthesis of macrocyclic compounds
possessing 1,3-benzenedicarboxamide or
2,6-pyridinedicarboxamide subunits
Piotr Pia˛tek,a Mariusz M. Gruzaa and Janusz Jurczaka,b,
*
aDepartment of Chemistry, University of Warsaw, Pasteura 1, PL-02-093 Warsaw, Poland
bInstitute of Organic Chemistry, Polish Academy of Science, Kasprzaka 44/52, PL-01-224 Warsaw, Poland
Received 5 June 2001; accepted 4 July 2001
Abstract—Three new chiral a,v-diaminoethers, derivatives of D-mannitol and L-treitol, possessing C2 symmetry are prepared. The
a,v-diaminoethers were applied to the macrocyclization reaction under non-high-dilution conditions, which afforded chiral
macrocyclic diamides possessing either 2,6-pyridinedicarboxamide or 1,3-benzenedicarboxamide moieties. © 2001 Elsevier Science
Ltd. All rights reserved.
1. Introduction
a,v-diaminoethers as substrates. Only few examples of
the preparative procedure for homochiral diamino-
ethers are reported in the literature.3a,9 Herein, we
report a useful method for synthesis of C2-symmetric
a,v-diaminoethers, containing three or five ethylene
units and their application in a non-high-dilution reac-
tion with dimethyl 1,3-benzenedicarboxylate or
dimethyl pyridine 2,6-dicarboxylate yielding chiral
macrocyclic diamides.
We have been interested for some time in using the
double-amidation reaction of methyl a,v-carboxylates
with primary a,v-diamines under non-high-dilution
conditions to obtain various macrocyclic amides.1 The
amide group exhibits dual complexing character (CꢀO
and N or NH) thus amide-based molecular receptors
can bind metal1e,2 and ammonium2d,3 cations, neutral
organic molecules4 as well as anionic species.5 In recent
years increasing attention has been paid to the interac-
tion of anions with both acyclic and cyclic synthetic
ligands.6 The hydrogen bond donor capacity of the
amide group, has been used as an anion binding ele-
ment in several molecular receptors.4a,5c,7 The 1,3-ben-
2. Results and discussion
1,2;5,6-Di-O-isopropylidene-
D
-mannitol 1 and 1,4-di-
O-benzyl- -threitol were selected as convenient
L
2
zene- or 2,6-pyridinedicarboxamide moiety is
a
sources of chirality. These readily available building
blocks were used previously for the synthesis of numer-
common structural feature of these molecular receptors.
Recently, we have found that achiral macrocyclic 2,6-
pyridine–amide based compounds bind halide and ace-
tate anions, as verified by 1H NMR titrations and
X-ray structural analyses.8 To expand our studies on
anion receptors, we decided to prepare chiral macro-
cyclic diamides based on 1,3-benzene- or 2,6-pyridinedi-
carboxamide subunits. In contrast to achiral
macrocyclic compounds of this type, the synthesis of
chiral analogs is more difficult due to use of chiral
ous chiral coronands.10 The synthesis of
D-mannitol
derived a,v-diaminoether 5, possessing five ethylene
bridges, began with preparation of 1,2;5,6-di-O-iso-
propylidene-3,4-bis-O-[(2-chloroethoxy)ethyl]-D-manni-
tol 3 (Scheme 1). The dichloride 3 was produced in 61%
yield under PTC conditions (ClCH2CH2OCH2CH2Cl,
NaOH, n-Bu4NHSO4) as reported in the literature.11
Compound 3 was then converted into the correspond-
ing diphthalimido derivative 4 by treatment with potas-
sium phthalimide in DMF. Hydrazinolysis of
4
afforded a,v-diaminoether 5 as a colorless oil. The
1
purity of diamine 5 (ꢀ95% based on H NMR) was
* Corresponding author. E-mail: jjurczak@che.uw.edu.pl
sufficient for further transformations.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00309-3

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Scheme 1. (i) ClCH2CH2OCH2CH2Cl, 50% NaOHaq, n-Bu4NHSO4; (ii) potassiophthalimide (PhtNK), DMF, 90°C; (iii) H2N–
NH2·H2O, EtOH, reflux.
graphic purification afforded diol 12 in a 55% overall
yield. According to Stodart et al.10b the yield of 12
could be increased to 82% if the chromatographic step
is omitted. However, in our case the purity of 12 was
insufficient for further application without chromato-
graphic purification.
The diaminoether 8, derived from 1,4-di-O-benzyl-L-
treitol, was prepared in a similar manner. Alkylation of
diol 2 by 1,2-bis-(2-chloroethoxy)ethane resulted in
dichloride 6, accompanied by substantial amounts (ꢀ
27%) of monoalkylated diol which was separated and
converted separately into dichloride 6. The overall yield
of compound 6 was 81%. Next, the reaction of dichlor-
ide 6 with potassium phthalimide afforded compound
7, which was readily recycled into diaminoether 8.
Finally, diol 12 was produced in a yield of 74% by
lithium aluminum hydride reduction of di-tert-butyl
ester 11. Ester 11 was prepared by reaction of 1,2;5,6-
A less direct pathway had to be followed for the
synthesis of three ethylene units possessing a,v-
diaminoether derived from D-mannitol. Straightforward
alkylation of diol 1 with 1,2-dichloroethane gave only
the 1,4-dioxane ring containing compound. Therefore,
we chose the C2-elongated diol 12 as a convenient
precursor of a,v-diaminoether.
di-O-isopropylidene-D-mannitol 1 with tert-butylbro-
moacetate, according to our own procedure described
previously for the synthesis of several other tert-butyl
esters derived from chiral diols.1c The overall yield of
the last two procedures is nearly the same but the
method based on reduction of di-tert-butyl ester 11 is
more practical due to the simplicity of the purification
processes.
Three independent synthetic routes were developed for
preparation of diol 12 (Scheme 2). The first one was
based on alkylation of 1 with O-(2%-tetrahydropyranyl)-
2-chloroethanol. The reaction carried out under PTC
conditions led to 1,2;5,6-Di-O-isopropylidene-3,4-bis-
Conversion of diol 12 into the appropriate diamide 14
was performed according to the Mitsunobu protocol.13
Treatment of diol 12 with phthalimide, in the presence
of triphenyl phosphine and di-iso-propyl azodicarboxyl-
ate (DIAD),14 led to diphthalimide 13 in a yield of 69%.
Finally hydrazinolysis of 13 afforded chiral a,v-
diaminoether 14 in 91% yield.
O-[(2%-tetrahydropyranyloxyethyl]- -mannitol 9 in 21%
D
yield. Although both the isopropylidene and tetra-
hydropyranyl (THP) ether protective groups are acid
sensitive, the reactivity of the THP ether is slightly
higher.12 Thus, di-THP-ether 9 was treated with cata-
lytic p-toluenesulfonic acid in methanol affording diol
12 (39%) accompanied by products resulting from iso-
propylidene cleavage. This route is clearly impractical
due to the low yield of both the alkylation and depro-
tection steps.
With the necessary a,v-diaminoethers 5, 8 and 14 at
hand we investigated the macrocyclization reactions.
Initially, however, some difficulties occurred: when we
treated diamines 5, 8 and 14 with dimethyl pyridine
2,6-dicarboxylate 15 or dimethyl 1,3-benzodicarboxyl-
ate 16 in methanol no reaction was observed. These
results indicated that dimethyl esters 15 and 16 were
inactive under such conditions. To overcome this prob-
lem we used two previously reported efficient methods
for activation of the double-amidation reaction,
namely: application of sodium methoxide as basic
mediator15 and high pressure1c–d,16 as a non-thermal
The second synthetic pathway used by us gave better
results. The reaction of 1 with allyl bromide provided
diallyl ether 10 in excellent yield, which was subse-
quently converted into diol 12 via ozonolysis followed
by reduction with sodium borohydride.10b Chromato-

P. Pia˛tek et al. / Tetrahedron: Asymmetry 12 (2001) 1763–1769
1765
Scheme 2. (i) ClCH2CH2OTHP, 50% NaOHaq, n-Bu4NHSO4; (ii) TsOH, MeOH; (iii) CH2ꢀCHCH2Br, KOH, toluene; (iv) O3,
NaBH4, MeOH; (v) BrCH2CO2But, n-Bu4NCl, 35% NaOHaq, toluene; (vi) LAH, dioxane; (vii) DIAD, PPh3, PhtNH, THF; (viii)
H2N–NH2·H2O, EtOH.
means to drive the reaction forward. The reactions of
a,v-diaminoethers 5, 8 and 14 with diester 15 were carried
out in methanol in the presence of methoxide ion. This
methodfurnishedmacrocyclicdiamides17, 18and19with
yields of 18, 48 and 40%, respectively (Table 1). Using
high pressure conditions (MeOH, 10 kbar, rt) compounds
17–18 were procured with similar yields 39, 59 and 41%,
respectively. Reactions of dimethyl 1,3-benzodicarboxyl-
ate 16 with diamines 8 or 14 in the presence of MeO− or
under high pressure conditions gave compounds 21 and
22 with satisfactory yields, albeit lower than in the
reactions with component 15. Unfortunately, we failed
to form macrocyclic diamide 20 both in the presence of
MeO− ions and under high pressure conditions.

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P. Pia˛tek et al. / Tetrahedron: Asymmetry 12 (2001) 1763–1769
Table 1. Yields of diamides under various macrocyclization conditions
As a result of our investigations, two new and efficient
synthetic routes for the transformation of 1,2;5,6-di-O-
All chemical shifts are quoted in parts per million
relative to tetramethylsilane (l, 0.00 ppm), and coup-
ling constants (J) are measured in Hertz. High-resolu-
tion mass spectrometry (HRMS) experiments were per-
formed on an AMD-604 Intectra instrument using
LSIMS or EI technique. Column chromatography was
carried out on silica gel (Kieselgel-60, 200–400 mesh).
Methanol was freshly distilled from Mg/I2 under Ar.
THF and dioxane were also freshly distilled from Na/
benzophenone under Ar. Diesters 15 and 16 were pur-
chased commercially. Compounds 3, 10, 11 were
prepared according to the literature procedures.
isopropylidene-
D
-mannitol 1 and 1,4-di-O-benzyl-L-thre-
itol 2 to chiral a,v-diaminoethers 5, 8 and 14 have been
developed. Both strategies include elongation of the
diol, introduction of N-phthaloyl groups using Gabriel
or Mitsunobu protocols and liberation of amine
groups. The a,v-diaminoethers 5, 8 and 14 were suc-
cessfully applied to the macrocyclization reaction under
non-high-dilution conditions under which chiral macro-
cyclic diamides 17–19, 21 and 22, possessing 2,6-pyri-
dine- or 1,3-benzenedicarboxamide moiety, were
obtained in good to acceptable yields.
3.2. 2,3-Bis-O-(5-chloro-3-oxapentyl]-1,4-di-O-benzyl-L-
threitol 6
3. Experimental
Diol 2 (3 g, 10 mmol) and tetrabutylammonium hydro-
gensulfate (6.8 g, 20 mmol) were dissolved in bis(2-
chloroethyl) ether (50 mL), cooled to 5°C and added to
cooled 50% aqueous sodium hydroxide (50 mL). The
resulting mixture was stirred at 5°C for 4 h, and at rt
for 2 days. The mixture was diluted with water (50 mL)
and dichloromethane (50 mL), separated and the
aqueous phase was extracted with dichloromethane.
The combined extracts were washed with water, dried
(MgSO4) and concentrated. Excess chloroethyl ether
was evaporated and the resulting material was purified
3.1. General methods
Melting points were taken on a Ko¨fler type (Boetius)
hot-stage apparatus and are not corrected. Optical rota-
tions were measured using a Perkin–Elmer 241 polar-
1
imeter with a thermally jacketed 10 cm cell. H NMR
spectra were recorded with a Varian Gemini (200 or
500 MHz) spectrometers in CDCl3 using TMS as an
internal standard. 13C NMR spectra were also recorded
using a Varian Gemini (50 or 125 MHz) spectrometers.

P. Pia˛tek et al. / Tetrahedron: Asymmetry 12 (2001) 1763–1769
1767
by column chromatography, using hexane/ethyl acetate
(3:1) as eluent. The dichloride 6 (3.15 g, Rf=0.65,
hexane/AcOEt 1:1) and monochloride (1.1 g, Rf=0.45,
hexane/AcOEt 1:1) were obtained as colorless oils. The
monoalkylated compound was converted into dichlor-
ide 6 by the same procedure. The total yield of dichlor-
ide 6 was 4.14 g (81%). [h]2D0=+5.2 (c=1.1, CHCl3);
1H NMR (200 MHz, CDCl3), l 7.4–7.2 (10H, m, -Ph);
4.51 (4H, s, -CH2Ph); 3.8–3.5 (22H, m); 13C NMR (50
MHz, CDCl3), l 138.5; 128.5; 127.8; 127.7; 79.5; 73.5;
71.4; 71.0; 70.9; 69.9; 43.0 (-CH2NH2); HR LSIMS m/z
calcd for C26H36O6Na35Cl2 [M+Na]+: 537.1787; found
537.1794.
evaporated to give diamine 5, 8 or 14 as an oil. (The
diaminoethers were stored under argon.)
3.4.1. 3,4-Bis-O-(5-amino-3-oxapentyl)-1,2;3,4-di-O-iso-
propylideno-D-mannitol 5. Yield 93%, colorless oil,
[h]2D4=+6.2 (c=2.6, CHCl3); 1H NMR (200 MHz,
CDCl3), l 4.30–3.96 (6H, m); 3.85–3.75 (4H, m); 3.65–
3.53 (6H, m); 3.48 (4H, t, J=5, -CH2CH2NH2); 2.85
(4H, t, J=5, -CH2NH2); 1.60 (4H, bs, -NH2); 1.41 (6H,
s, -CH3); 1.34 (6H, s, -CH3); 13C NMR (50 MHz,
CDCl3), l 108.5; 80.6; 75.7; 73.4; 72.2; 70.4; 66.50; 41.9;
26.7; 25.3; HR LSIMS m/z, calcd for C20H40O8N2Na
[M+Na]+: 459.2682; found 459.2706.
3.3. General procedure for the synthesis of diphthalimide
ethers 4 and 7
3.4.2. 2,3-Bis-O-(5-amino-3-oxapentyl)-1,4-di-O-benzyl-
L
-threitol 8. Yield 90%, yellowish oil, [h]2D0=+7.9 (c=
2.2, CHCl3); 1H NMR (200 MHz, CDCl3), l 7.31 (10H,
s); 4.51 (4H, s); 3.88–3.50 (14H, m); 3.45 (4H, t, J=5.2,
-CH2CH2NH2); 2.80 (4H, t, J=5.2, -CH2NH2); 1.47
(4H, bs, -NH2); 13C NMR (50 MHz, CDCl3), l 138.4;
128.4; 127.7; 127.6; 79.3; 73.4; 73.3; 70.8; 70.6; 69.8;
41.9 (-CH2NH2); HR LSIMS m/z, calcd for
C26H41O6N2 [M+H]+: 477.2965; found 477.2978.
A solution of dichloride 3 or 6 (3 mmol) and potassium
phthalimide (1.3 g, 7.2 mmol) in dry DMF (50 mL) was
stirred for 24 h at 90°C under argon. The solvent was
evaporated under reduced pressure. The resulting mate-
rial was dissolved in water (50 mL) and
dichloromethane (50 mL), phases were separated and
the aqueous one was extracted with dichloromethane
(3×30 mL). The organic extracts were combined, dried
(MgSO4) and concentrated to afford crude diphthal-
imide ether, which was purified by column chromatog-
raphy using hexane/ethyl acetate (1:1) as eluent.
3.4.3. 3,4-Bis-O-(2-aminoethyl)-1,2;3,4-di-O-isopropyli-
deno-D
-mannitol 14. Yield 91%, yellowish oil, [h]2D4=
1
+14.8 (c=2.0, CHCl3); H NMR (200 MHz, CDCl3), l
4.3–3.9 (6H, m); 3.7–3.6 (6H, m); 2.84 (4H, t, J=5.2
Hz, -CH2NH2); 1.41 (6H, s, -CH3); 1.34 (6H, s, -CH3);
13C NMR (50 MHz, CDCl3), l 108.4; 80.3; 75.2; 75.1;
66.60; 42.2; 26.5; 25.1; HR LSIMS m/z, calcd for
C16H33O6N2 [M+H]+: 349.2329; found 349.2351.
3.3.1. 3,4-Bis-O-(5-phthalimido-3-oxapentyl)-1,2;3,4-di-
O-isopropylideno-D-mannitol 4. White crystals, yield
1
81%, mp 109–111°C, [h]2D4=+11.4 (c=1.05, CHCl3); H
NMR (500 MHz, CDCl3), l 7.86–7.82 (4H, AB/2,
-NPht); 7.73–7.69 (4H, AB/2, -NPht); 4.14 (2H, m);
4.08 (2H, dd, J=6, J=8.5); 3.92 (2H, dd, J=6, J=8.5);
3.88 (4H, m); 3.73 (4H, t, J=5); 3.69 (4H, t, J=6); 3.56
(4H, t, J=5); 3.52 (2H, m); 1.36 (6H, s, -CH3); 1.29
(6H, s, -CH3); 13C NMR (250 MHz, CDCl3), l 168.2;
133.9; 132.2; 123.2; 108.6; 80.6; 75.6; 72.1; 70.2; 67.8;
66.6; 37.4; 26.7; 25.3; HR LSIMS m/z, calcd for
C36H44O12N2Na [M+Na]+: 719.2792; found 719.2805.
3.5. 3,4-Bis-O-(2-O-tetrahydropyranyloxyethyl)-1,2;5,6-
di-O-isopropylidene-D-mannitol 9
To a solution of 1 (2.0 g, 7.63 mmol) and tetra-
butylammonium hydrogen sulfate (0.24 g, 0.69 mmol)
in THPOCH2CH2Cl (6.8 mL, 7.51 g, 45.8 mmol)
aqueous sodium hydroxide (50%, 17 mL) was added
dropwise. The resulting two-phase system was vigor-
ously stirred at 65°C for 2 days under argon. The
mixture was then diluted with dichloromethane, washed
with water, dried over MgSO4, filtered and concen-
trated under reduced pressure. The resulting oil was
eluted through a silica column (hexane/ethyl acetate
4:2) to give the pure product as a colorless oil (0.83 g,
21%). [h]2D0=+5.9 (c=2.85, CHCl3); 1H NMR (200
MHz, CDCl3), l 4.64 (2H, t, J=2.7); 4.21 (2H, m);
4.14–3.46 (18H, m); 1.94–1.42 (12H, m); 1.41 (3H, s,
-CH3); 1.38 (3H, s, -CH3); 1.35 (3H, s, -CH3); 1.34 (3H,
s, -CH3); 13C NMR (50 MHz, CDCl3), l 109.05; 108.56;
98.71; 98.67; 79.18; 78.84; 75.72; 75.36; 72.28; 72.22;
67.50; 66.72; 65.91; 62.06; 61.94; 30.39; 30.30; 26.64;
26.41; 25.21; 19.23; 19.17; HR LSIMS m/z, calcd for
C26H46O10Na [M+Na]+: 541.2989; found 541.2979.
3.3.2. 2,3-Bis-O-(5-phthalimido-3-oxapentyl)-1,4-di-O-
benzyl-
L
-threitol 7. Colorless oil, yield 75%, [h]2D0=+4.0
1
(c=1.0, CHCl3); H NMR (200 MHz, CDCl3), l 7.85–
7.62 (8H, AB, -NPht); 7.32–7.20 (10H, m); 4.46 (4H, s,
-CH2Ph); 3.90–3.78 (4H, m); 3.78–3.42 (18H, m); 13C
NMR (50 MHz, CDCl3), l 168.2; 138.4; 133.9; 132.1;
128.3; 127.6; 127.5; 123.2; 79.2; 73.2; 70.7; 70.3; 69.8;
67.8; 37.4; HR LSIMS m/z, calcd for C42H44O8N2Na
[M+Na]+: 759.2893; found 759.2867.
3.4. General procedure for the synthesis of diamines 5,
8 and 14
To a solution of the diphthalimide 4, 7 or 13 (1.5
mmol) in 96% ethanol (50 mL) was added hydrazine
monohydrate (1 mL), and the solution was stirred
under reflux for 24 h. Ethanol was evaporated, the
white residue was dissolve in aqueous sodium hydrox-
ide (20%, 30 mL), and extracted with dichloromethane
(3×30 mL). The combined extracts were washed with
water (30 mL) and dried (Na2SO4). The filtrate was
3.6. 3,4-Bis-O-(2-hydroxyethyl)-1,2;5,6-di-O-isopropyli-
dene-D-mannitol 12
From 9: To a solution of the bis(tetrahydropyranyl)
compound 9 (0.49 g, 0.95 mmol) in MeOH–CH2Cl2
(1:1) mixture (100 mL) p-toluenesulfonic acid (10 mg)

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P. Pia˛tek et al. / Tetrahedron: Asymmetry 12 (2001) 1763–1769
Method B (under high pressure): An equimolar solution
of the dimethyl a,v-dicarboxylate (0.5 mmol) and the
appropriate a,v-diamine (0.5 mmol) in methanol (5
mL) was filled into a Teflon ampoule, placed in a
high-pressure vessel filled with ligroine as a trans-
mission medium and compressed (12 kbar) at room
temperature for 48 h. After decompression, the reaction
mixture was transferred quantitatively to a round-bot-
tomed flask and the solvent was evaporated. The
residue was chromatographed on a silica gel column
using 0.5–3% mixtures of methanol in chloroform.
was added. The solution was stirred overnight at 40°C
and NaHCO3 (2 g) was added, and the mixture stirred
for 1 h. The mixture was filtered and the filtrate evapo-
rated. The oil residue was purified by column chro-
matography using hexane/ethyl acetate (2:3) as eluent
giving diol 12 as a colorless oil (0.13 g, 39%).
From 10: The compound was prepared according to
literature procedure.
From 11: To a solution of diester 11 (2.45 g, 5 mmol)
in dry dioxane (40 mL) LiAlH4 (0.4 g, 10.5 mmol) was
added. The mixture was stirred under reflux under
argon for 12 h. After cooling, water (5 mL), aqueous
NaOH (20%, 10 mL) and water (50 mL) were sequen-
tially added. The mixture was extracted with
dichloromethane (3×50 mL), and the combined extracts
were dried over MgSO4. After filtration, the solvent was
evaporated to yield diol 12 as a colorless oil or semi-
solid. Crude product was purified by column chro-
matography using gradient eluation with toluene/
chloroform–chloroform/methanol to yield diol 12 (1.42
g, 81%). White crystals, mp 76–77°C, [h]2D0=+15.3 (c=
3.8.1. (7R,8R)-7,8-Bis((4R)-2,2-dimethyl-1,3-dioxalan-
4-yl)-6,9-dioxa-3,12,18-triazabicyclo[12.3.1]octadeka-
1(17),14(18),15-triene-2,13-dione 17. Method A. Reac-
tion time 6 days. Yield 18.8%. Method B. Yield 39.0%.
White solid, [h]2D4=−2.1 (c=1.2, CHCl3); 1H NMR (500
MHz, CDCl3), l 8.93 (2H, bt, -NHCO-); 8.27 (2H, d,
J=7.5); 8.06 (1H, t, J=7.5); 4.20 (2H, m); 4.12 (2H,
dd, J=6, J=8.5); 3.92 (2H, dd, J=6, J=8.5); 3.89–
3.83 (4H, m); 3.76–3.65 (4H, m); 3.65–3.58 (2H, m);
1.40 (6H, s, -CH3); 1.32 (6H, s, -CH3); 13C NMR (125
MHz, CDCl3), l 162.59; 148.34; 139.64; 123.93; 108.76;
78.91; 75.46; 68.13; 67.13; 38.62; 26.68; 25.30; HR EI
m/z, calcd for C23H33O8N3 [M]+: 479.2268; found
479.2243.
1
1.1, CHCl3); H NMR (200 MHz, CDCl3), l 4.3–3.65
(16H, m); 3.53 (2H, bs, -OH); 1.44 (6H, s, -CH3); 1.35
(6H, s, -CH3); 13C NMR (50 MHz, CDCl3), l 109.5;
108.6; 78.2; 76.6; 75.2; 74.1; 72.7; 67.5; 65.7; 62.7; 26.8;
26.4; 25.7; HR LSIMS m/z, calcd for C16H30O8Na
[M+Na]+: 373.1838; found 373.1841.
3.8.2. (9R,10R)-9,10-Bis((4R)-2,2-dimethyl-1,3-dioxalan-
4-yl)-6,9,12,15-tetraoxa-3,18,24-triazabicyclo[18.3.1]-
tetracoza-1(23),20(24),21-triene-2,19-dione 18. Method
A. Reaction time 5 days. Yield 48.8%. Method B. Yield
59.7%. White solid, [h]2D4=+7.6 (c=2.5, CHCl3); 1H
NMR (200 MHz, CDCl3), l 9.23 (2H, bt, -NHCO-);
8.33 (2H, d, J=7.6 Hz); 8.00 (1H, t, J=7.6); 4.3–3.5
(24H, m); 1.39 (6H, s, -CH3); 1.32 (6H, s, -CH3); 13C
NMR (50 MHz, CDCl3), l 164.0; 148.7; 138.4; 124.6;
108.8; 80.0; 74.4; 71.6; 71.4; 70.2; 67.1; 39.7; 26.8; 25.3;
HR EI m/z, calcd for C27H41O10N3 [M]+: 567.2792;
found 567.2799.
3.7. 3,4-Bis-O-(2-phthalimidoethyl)-1,2;5,6-di-O-iso-
propylidene-D-mannitol 13
To a solution of diol 12 (1 g, 2.86 mmol), phthalimide
(1 g, 6.86 mmol) and triphenylphosphine (1.8 g, 6.86
mmol) in dry THF (50 mL) was added dropwise di-iso-
propyl azadicarboxylate (DIAD) (1.35 mL, 6.86 mmol).
The mixture was stirred at rt under argon for 3 days
and the solvent was evaporated. The crude oil was
purified by column chromatography using hexane/ethyl
acetate (3:2) as an eluent to afford the diphthalimide as
white crystals (1.27 g, 73%), mp 131–135°C. [h]2D4=
3.8.3. (9S,10S)-9,10-Bis(benzyloxymethyl)-6,9,12,15-tet-
raoxa-3,18,24-triazabicyclo[18.3.1]tetracoza-1(23),
20(24),21-triene-2,19-dione 19. Method A. Reaction time
2 days. Yield 40.2%. Method B. Yield 41.9%. White
solid, [h]2D0=+42.3 (c=1.97, CHCl3); 1H NMR (500
MHz, CDCl3), l 8.95 (2H, bt, -NHCO-); 8.32 (2H, d,
J=7.5); 7.97 (1H, t, J=7.5); 7.34–7.25 (10H, m); 4.49
(2H, dAB, J=12); 4.44 (2H, dAB, J=12); 3.85–3.79 (2H,
m); 3.77–3.52 (20H, m); 13C NMR (125 MHz, CDCl3),
l 164.0; 148.9; 138.5; 138.0; 128.4; 127.7; 124.8; 78.5;
73.4; 70.8; 70.7; 70.6; 69.1; 39.8; HR LSIMS m/z, calcd
for C33H41O8N3Na [M+Na]+: 630.2791; found
630.2795.
1
+12.8 (c=1.0, CHCl3); H NMR (200 MHz, CDCl3), l
7.90–7.65 (8H, AB, -NPht); 4.20–3.50 (16H, m); 1.32
(6H, s, -CH3); 1.23 (6H, s, -CH3); 13C NMR (50 MHz,
CDCl3), l 168.0; 133.9; 132.0; 123.2; 108.6; 80.7; 76.2;
75.2; 69.2; 66.4; 37.9; 26.5; 25.0; HR LSIMS m/z, calcd
for C32H36O10N2Na [M+Na]+: 631.2267; found
631.2279.
3.8. General procedures for synthesis of bisamides 17–22
Method A (in the presence of MeO−): The solution of
ester (0.35 mmol) in dry methanol (5 mL) was cooled to
5°C and sodium (8 mg, 0.35 mmol) was added. A
solution of diamine (0.35 mmol) in dry methanol (5
mL) was added. The mixture was left at rt for a period
of 2–26 days (monitored by TLC). The solvent was
evaporated and the residue was purified by column
chromatography using gradient eluation with toluene/
chloroform, chloroform and chloroform/methanol mix-
tures as eluent.
3.8.4. (9R,10R)-9,10-Bis((4R)-2,2-dimethyl-1,3-dioxalan-
4-yl)-6,9,12,15-tetraoxa-3,18-diazabicyclo[18.3.1]tetra-
coza-1(23),20(24),21-triene-2,19-dione 21. Method A.
Reaction time 26 days. Yield 24.0%. Method B. Yield
25.1%. Colorless crystals, mp 109–116°C, [h]2D0=−28.5
1
(c=2.2, CHCl3); H NMR (500 MHz, CDCl3), l 8.38
(1H, s); 8.21 (2H, dd, J=7.5, J=1.5); 7.62 (2H, bt,
J=5, -NHCO-); 7.56 (1H, t, J=7.5); 4.25–4.20 (2H, m);
4.14 (2H, dd, J=5.5, J=8.5); 3.97–3.89 (6H, m); 3.80–
3.74 (2H, m); 3.71–3.50 (14H, m); 1.41 (6H, s, -CH3);

P. Pia˛tek et al. / Tetrahedron: Asymmetry 12 (2001) 1763–1769
1769
1.34 (6H, s, -CH3); 13C NMR (125 MHz, CDCl3), l
166.3; 133.6; 131.8; 129.1; 123.2; 109.1; 80.46; 74.6;
72.4; 71.2; 70.5; 67.0; 39.8; 26.9; 25.4; HR LSIMS m/z,
calcd for C48H42O10N2Na [M+Na]+: 589.2737; found
589.2744.
3. (a) Nazarenko, A. Y.; Huszthy, P.; Bradshaw, J. S.;
Lamb, J. D.; Izatt, R. M. J. Incl. Phenom. 1995, 20,
13–22; (b) Huszthy, P.; Bradshaw, J. S.; Zhu, Y. C.;
Wang, T.; Dalley, N. K.; Curtis, J. C.; Izatt, R. M. J.
Org. Chem. 1992, 57, 5383–5394.
4. (a) Tellado, F. G.; Goswami, S.; Chang, S. K.; Geib, S.
J.; Hamilton, A. D. J. Am. Chem. Soc. 1990, 112, 7393–
7394; (b) Chang, S. K.; Hamilton, A. D. J. Am. Chem.
Soc. 1988, 110, 1318–1319.
5. (a) Davis, A. P.; Perry, J. J.; Wiliams, R. P. J. Am. Chem.
Soc. 1997, 119, 1793–1794; (b) Kelly, T. R.; Kim, M. H.;
Hamilton, A. D. J. Am. Chem. Soc. 1994, 116, 7072–
7080; (c) Fan, E.; Van Arman, S. A.; Kincaid, S.; Hamil-
ton, A. D. J. Am. Chem. Soc. 1993, 115, 369–370.
6. For recent reviews see: (a) Beer, P. D.; Gale, P. A.
Angew. Chem., Int. Ed. 2001, 40, 486–516; (b) Antonisse
M. M. G., Reinhoudt, D. N. J. Chem. Soc., Chem.
Commun. 1998, 443–448; (c) Schmidtchen, F. P.; Berger,
M. Chem. Rev. 1997, 1609–1646.
3.8.5. (9S,10S)-9,10-Bis(benzyloxymethyl)-6,9,12,15-tet-
raoxa-3,18-diazabicyclo[18.3.1]tetracoza-1(23),20(24),21-
triene-2,19-dione 22. Method A. Reaction time 26 days.
Yield 11.0%. Method B. Yield 28%. White solid, [h]2D0=
1
+33.4 (c=1.44, CHCl3); H NMR (500 MHz, CDCl3),
l 8.26 (1H, s); 8.18 (2H, dd, J=1.5, J=7.5); 7.54 (1H,
t, J=7.5); 7.49 (2H, bt, -NHCO-); 7.33–7.25 (10H, m);
4.49 (2H, dAB, J=12); 4.44 (2H, dAB, J=12); 3.86–3.80
(2H, m); 3.79–3.70 (6H, m); 3.69–3.52 (14H, m); 13C
NMR (125 MHz, CDCl3), l 166.4; 137.8; 133.8; 131.8;
129.1; 128.4; 127.82; 127.78; 123.1; 78.3; 73.4; 70.8;
70.7; 70.6; 68.9; 39.9; HR LSIMS m/z, calcd for
C34H42O8N2Na [M+Na]+: 629.2839; found 629.2835.
7. Kavallieratos, K.; Bertao, C. M.; Crabtree, R. H. J. Org.
Chem. 1999, 64, 1675–1683.
8. Szumna, A. Ph.D. Thesis, Institute of Organic Chemistry,
Polish Academy of Sciences, Warsaw, 2000.
Acknowledgements
9. (a) Anantanarayan, A.; Fyles, T. F. Can. J. Chem. 1990,
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This work was supported by the State Committee for
Scientific Research (Project 3T09A 127 15). The
authors wish to thank the Polish Science Foundation
for additional financial support.
1
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