Synthesis of spacer-linked tail to tail dimers derived from a conformationally rigid aminodeoxysugar by olefin metathesis

Article abstract of DOI:10.1055/s-2000-6328

The preparation of new tail to tail dimers of bridged aminodeoxysugars 2 and 11 is described. The first key step in the synthesis is the formation of the aminomethyl bridge in the carbohydrate-derived monomer 7 which is achieved by silver promoted ring closure of methyl 3-acetamido-6-bromo-2,3,6- trideoxy α-D-glucoside 6. Secondly, olefin metathesis of the corresponding 4-O-allyl glycoside 9 constitutes a powerful tool for dimerization, which allows synthesis of 1,4-butanediol-linked tail to tail neooligosaccharides 2 and 11.

Full text of DOI:10.1055/s-2000-6328

PAPER
1133
Synthesis of Spacer-Linked Tail to Tail Dimers Derived from a
Conformationally Rigid Aminodeoxysugar by Olefin Metathesis
Andreas Kirschning,* Guang-Wu Chen
Institut für Organische Chemie der Technischen Universität Clausthal, Leibnizstraße 6, D-38678 Clausthal-Zellerfeld, Germany
Fax (+)(0)5323722858; E-mail: andreas.kirschning@tu-clausthal.de
Received 14 February 2000; revised 21 March 2000
11 derived from a bridged aminodeoxysugar derivative.
By bridging5 the amino group-containing unit a confor-
mationally rigid structure is achieved while the linker
serves as a flexible spacer, helping to appropriately orien-
Abstract: The preparation of new tail to tail dimers of bridged ami-
nodeoxysugars 2 and 11 is described. The first key step in the syn-
thesis is the formation of the aminomethyl bridge in the
carbohydrate-derived monomer 7 which is achieved by silver pro-
moted ring closure of methyl 3-acetamido-6-bromo-2,3,6-trideoxy tate the rigidified amino groups in space. Based on our
previous results4 and recent work published by the groups
a-D-glucoside 6. Secondly, olefin metathesis of the corresponding
of Roy and Stütz,6 we envisaged olefin metathesis7 as a
4-O-allyl glycoside 9 constitutes a powerful tool for dimerization,
which allows synthesis of 1,4-butanediol-linked tail to tail neooli-
powerful method to dimerize allyl protected glycosides.
gosaccharides 2 and 11.
While it was known from earlier publications4,6 that allyl
glycosides are very well suited for this purpose, it is also
demonstrated in this paper that tail to tail dimerization can
Key words: neooligosaccharide, metathesis, aminodeoxysugar,
conformational restriction
be achieved by using a 4-O-allylated sugar monomer 9.
Methyl uloside 3, which was prepared in two steps from
Oligocationic
compounds,
namely
protonable
D-mannose,8 was the starting point for the synthesis of
spacer-linked homodimers 2 and 11 (Scheme 1). The se-
quence was initiated by stereoselective reduction of the
keto group (ribo/arabino = >15:1) followed by activation
of the alcohol group as a triflate9 and terminated by nu-
cleophilic attack of the azide anion to furnish arabino-
configured 3-azido methyl glycoside 4.10 Functional
group manipulations using two well established
reactions11 afforded the corresponding acetamido deriva-
tive 512 which paved the way for the oxidative opening of
the benzylidene group resulting in the formation of methyl
polyamines, have recently seen considerable attention be-
cause of their key role in biological processes. This in-
creased interest is particularly associated with their ability
to specifically bind to polynucleotides connected with the
possibility of inhibiting DNA duplication or RNA cataly-
sis, or the forcing of RNA into an alternate conforma-
tion.1,2 For example, nature has utilized aminodeoxy
sugars present in glycoconjugates like the anthracycline
antibiotic daunomycin as well as amino glycoside antibi-
otics like kanamycin A (1) to target polynucleotides.
These structures are ideally suited for binding as the rigid
character of the pyran ring along with the flexibility asso-
ciated with the glycosidic linkage give them the ability of
preorganization. In an elegant study, Tor and coworkers
showed that multivalent linker-modified dimers derived
from 1 also recognize RNA with enhanced binding along
with improved ribozyme inhibitory activity.1b,3 Recently,
we initiated a project on the preparation of new 1,4-bu-
tanediol-linked oligomeric aminodeoxysugars4 in order to
search for specific RNA-binders with new therapeutic
properties.
3-acetamido-6-bromo-2,3,6-trideoxy-a-D-glucoside
6.
Treatment of this bromide with anhydrous silver fluoride
led to activation of C-6, and intramolecular attack of the
acetamido group onto the highly electrophilic carbon af-
fording bridged deoxysugar 7. Prior to the ring closure, a
switch from the (4C1)- to (1C4)-conformation in 6 has to be
assumed (Scheme 2).13 Remarkably, formation of the ex-
pected elimination product 10 was not detected, which in
part has to be ascribed to the 3,5-cis substitution pattern
on the pyran ring.13 Benzoate 7 was hydrolyzed under ba-
sic conditions and the resulting alcohol 8 was finally allyl-
ated under standard conditions to afford the targeted 4-O-
allyl protected monomer 9.
NH2
H
O
At this point, allyl ether 9 was dimerized, using Grubbs
catalyst 12, the most insensitive metathesis catalyst to-
wards polar functionalities like the acetamido group. As
N
NH
O
HO
HO
OMe
H2N
MeO
O
HO
O
NH2
HO
O
O
O
1
expected, the H NMR and 13C NMR spectra of the
OH
OH
O
C2-symmetric homodimeric reaction product 11 (E/Z = 6:
1) showed only half the set of signals for all protons as
well as carbon atoms.14 Further structural support was
gained from proton integration and mass spectrometry.
Stütz and coworkers recently demonstrated that the stere-
oselectivity of the intermolecular metathesis reaction is
HO
Kanamycin A 1
NH2
2
In this paper, we describe the first synthesis of C2-sym-
metric 1,4-butanediol-linked neooligosaccharides 2 and
Synthesis 2000, No. 8, 1133–1137 ISSN 0039-7881 © Thieme Stuttgart · New York

1134
A. Kirschning, G.-W. Chen
PAPER
All temperatures quoted are uncorrected. Optical rotations were re-
Ph
O
a - c
f
Ph
O
O
O
O
O
corded on a Perkin-Elmer 141 polarimeter and are given in
X
1
10-1 deg cm2 g-1. 1H NMR, 13C NMR, H, 1H- and 1H, 13C-COSY
O
OMe
OMe
as well as NOESY spectra were recorded on a Bruker DPX 200-
NMR and a ARX 400-NMR spectrometer for solutions in CDCl3
using residual CHCl3 as internal standard (d = 7.26 ppm), unless
otherwise stated. Multiplicities are described using the following
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br = broad. Chemical shift values of 13C NMR spec-
tra are reported as values in ppm relative to residual CHCl3 (d = 77
ppm) as internal standard. The multiplicities refer to the resonances
in the off-resonance spectra and were elucidated using the distor-
tionless enhancement by polarisation transfer (DEPT) spectral edit-
ing technique, with secondary pulses at 90° and 135°. Multiplicities
are reported using the following abbreviations: s = singlet (due to
quaternary carbon), d = doublet (methine), q = quartet (methyl),
t = triplet (methylene). Mass spectra were obtained using a LCQ
Finnigan (ESI) instrument. Ion mass (m/z) signals are reported as
values in atomic mass units followed, in parentheses, by the peak in-
tensities relative to the base peak (100%). Combustion analyses
were performed by the Institut für Pharmazeutische Chemie, Tech-
nische Universität Braunschweig and Institut für Chemie, Hum-
boldt Universität zu Berlin. All solvents used were of reagent grade
and were further dried. Reactions were monitored by TLC on silica
gel 60 F254 (E. Merck, Darmstadt) and spots were detected either by
UV-absorption or by charring with H2SO4/4-methoxybenzaldehyde
in MeOH. Preparative column chromatography was performed on
silica gel 60 (E. Merck, Darmstadt). Ulose 3 was synthesized ac-
cording to the literature.8
3
4 X= N3
d, e
5 X= NHAc
Br
Ac
N
g
O
BzO
O
OMe
AcHN
OMe
OR
6
7 R= Bz
8 R= H
9 R= CH2-CH=CH2
h
i
Scheme 1 Reagents and conditions: (a) NaBH4, MeOH, 0 °C to r.t.,
2 h; (b) Tf2O, pyridine, CH2Cl2, r.t., 45 min; (c) NaN3, DMF, r.t., 1.5
h (87% for three steps); (d) LiAlH4, THF, 0 °C, 1 h; (e) Ac2O, pyrid-
ine, r.t., 2 h (91% for two steps); (f) CCl4, NBS, BaCO3, D, 6 h (76%);
(g) AgF, pyridine, r.t., 14 h (95%); (h) NaOMe, MeOH, r.t., 3 h;
(i) NaH, allyl bromide, r.t., 12 h (95% for two steps).
...
F
Ag
Br
H
Br
H
NHAc
O
O
O
BzO
AcHN
OMe
BzO
AcHN
OMe
OBz
OMe
10
(4C1)- 6
(1C4)- 6
Methyl 3-azido-4,6-O-benzylidene-2,3-dideoxy-a-D-arabino-
hexopyranoside (4)
Scheme 2
To a solution of ulose 3 (11.4 g, 43.1 mmol) in dry MeOH (400 mL)
was added NaBH4 (3.3 g, mmol) at 0 °C in one portion and the sus-
pension was stirred at r.t. for 2 h. After addition of a mixture of H2O/
CH2Cl2 (1:1; 440 mL), the layers were separated and the organic
phase was washed with brine (100 mL), dried (MgSO4) and concen-
trated in vacuo. The crude product (11.4 g) was dissolved in CH2Cl2
(200 mL) and added dropwise to a solution prepared by dissolving
highly dependent on the configuration and the nature of
protecting groups present in carbohydrate derived termi-
nal olefins.6c Our synthesis was completed by catalytic
hydrogenation of the double bond followed by deacetyla- (CF3SO2)2O (16.8 g, 10 mL, 59.6 mmol) in CH2Cl2 (200 mL) at
-5 °C to which a mixture of dry pyridine (13.4 g, 170 mmol) in
CH2Cl2 (200 mL) had been added. The reaction mixture was stirred
for 45 min at r.t. and poured into an ice cold aq bicarbonate solution.
The aqueous layer was extracted with CH2Cl2 (2 ¥ 200 mL) and the
combined organic extracts were washed with brine (100 mL), dried
(MgSO4) and concentrated in vacuo to afford a red oil. After co-dis-
tillation with toluene a crystalline material was obtained which was
recrystallized in Et2O/hexane (2:1) to give colorless crystals (mp
65-70 °C dec.). However, the red oil can directly be used for the
next step by dissolving it at r.t. in dry DMF (260 mL) and treating
it with NaN3 (10.9 g, 167.7 mmol) in one portion. The solution was
stirred at at r.t. for 1.5 h, cooled to ambient temperature and hydro-
lyzed by adding a mixture of H2O/Et2O (1:1, 300 mL). The aqueous
layer was extracted with Et2O (3 ¥ 150 mL) and the combined or-
ganic extracts were washed with brine (150 mL), dried (MgSO4)
and concentrated in vacuo. DMF was removed by Kugelrohr distil-
lation to afford a yellow oil. This was further purified by flash col-
umn chromatography (Et2O/hexane, 2: 1) to afford colorless
needles (10.9 g, 37.4 mmol; 87%): mp 114-115 °C (EtOH/hexane,
10:1). [a]D21 +108.9 (c 1.5, CHCl3).
tion under standard conditions furnishing the desired
spacer-linked dimer 2.
N
Ac
NAc
O
OMe
MeO
a
b, c
9
O
2
O
O
11
PCy
Ru
3 Ph
Cl
Cl
PCy3
12
Scheme 3 Reagents and conditions: (a) 12 (8 mol%), C6H6, 50 °C,
18 h (88%); (b) H2, PtO2, CH2Cl2/MeOH (3: 1), r.t., 16 h (99%); (c)
Ba(OH)2 8 H2O, D, 24 h (84%).
In summary, we have described an efficient synthetic
route towards 1,4-butanediol linked tail to tail dimers de-
rived from a conformationally rigidified, bridged amin-
odeoxy sugar derivative. Studies on the biological
properties of these new neooligosaccharides are under-
way.
1H NMR (400 MHz): d = 7.35-7.52 (m, 5H, ArH), 5.62 (s, 1H,
PhCH), 4.78 (dd, 1H, J = 1.0, 4.0, Hz, 1-H), 4.28 (dd, 1H, J = 4.6,
9.6 Hz, 6-Heq), 4.05 (ddd, 1H, J = 5.0, 9.6, 12.0 Hz, 3-H), 3.85 (ddd,
1H, J = 4.6, 9.6, 12.0 Hz, 5-H), 3.76 (dd, 1H, J = 9.6, 12.0 Hz, 6-
Hax), 3.58 (t, 1H, J = 9.6 Hz, 4-H), 3.35 (s, 3H, OCH3), 2.17 (ddd,
1H, J = 1.0, 5.0, 13.4 Hz, 1H, 2-Heq), 1.72 (ddd, 1H, J = 4.0, 12.0,
13.4 Hz, 2-Hax).
Synthesis 2000, No. 8, 1133–1137 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Spacer-Linked Tail to Tail Dimers
1135
13C NMR (100 MHz): d = 137.0 (s, Ph), 125.9-129.3 (Ph), 101.5 (d,
CHPh), 98.1 (d, C-1), 82.1, 69.0 (2d, C-4, C-5), 63.1 (t, C-6), 56.4
(q, OCH3), 54.8 (d, C-3), 35.5 (t, C-2).
1H NMR (400 MHz): d = 8.09-7.42 (m, 5H, Ph), 4.96 and 4.92 (dd,
1H, J = 2.8, 5.4 Hz, 4-H), 4.87-4.78 (m, 1H, 1-H), 4.76 (m, 1H,
5-H), 4.69 and 4.44 (2 br t, 1H, 3-H), 3.89-3.55 (m, 2H, 6-H, 6´-H),
3.50 and 3.49 (2s, 3H, OCH3), 2.35-1.98 (m, 2H, 2-Hax, 2-Heq),
2.15 and 2.09 (2s, 3H, NCOCH3).
Anal. Calcd for C14H17N3O4: C, 57.72; H, 5.88; N, 14.43. Found: C,
57.69; H, 5.94; N, 14.01.
Each carbon appeared as a pair of signals due to the presence of two
stereoisomers.
13C NMR (100 MHz): d = 169.0, 168.6 (q), 165.9, 165.8 (q), 133.7,
133.5 (q), 130.0, 129.9 (d), 129.4, 129.2 (q), 128.6, 128.5 (d), 98.3,
97.5 (d), 73.3, 72.2 (d), 70.7, 70.1 (d), 56.9, 56.7 (q), 54.1, 51.6 (d),
50.2, 48.2 (t), 32.1, 30.4 (t), 21.7, 21.6 (q).
Methyl 3-Acetamido-4,6-O-benzylidene-2,3-dideoxy-a-D-arabi-
no-hexopyranoside (5)
To a solution of compound 4 (5.4 g, 18.5 mmol) in dry THF
(300 mL) was added LiAlH4 (3.5 g, 92 mmol) at 0 °C and stirring
was continued for 1 h. EtOH was added (25 mL) followed by an
aqueous solution of sodium-potassium tartrate (150 mL) and CHCl3
(300 mL). The aqueous layer was extracted with CHCl3 (3 ¥ 100
mL) and the combined organic extracts were washed with brine
(150 mL), dried (MgSO4) and evaporated in vacuo. The crude oil
was dissolved in dry pyridine (75 mL) and acetic anhydride (30 mL)
at 0 °C. After 2 h at r.t., a mixture of H2O/CH2Cl2 (1:1, 50 mL) was
added. The aqueous layer was extracted with CH2Cl2 (3 ¥ 30 mL)
and the combined organic extracts were washed with brine (150
mL), dried (MgSO4) and concentrated in vacuo. Pyridine was re-
moved by co-distillation using toluene to afford colorless crystals
Anal. Calcd for C16H19NO5 (305.33): C, 62.94; H, 6.27; N, 4.59.
Found: C, 63.05; H, 6.37; N, 4.29.
Methyl 3-Acetamido-4-O-allyl-3,6-anhydro-2,3,6-trideoxy-a-D-
arabino-hexopyranoside (9)
To a solution of compound (7) (300 mg, 1.02 mmol) in dry MeOH
(10 mL) was added sodium methoxide (10.5 mg, 0.19 mmol,
0.2 equiv). The mixture was stirred at r.t. for 3 h (TLC: toluene/ac-
etone, 1:6) and the solvent was removed under reduced pressure.
The crude product was directly employed in the next step without
any further purification. The residue was dissolved in anhyd THF
(10 mL) at r.t. and sodium hydride (55-65% in oil, 0.1 g, 2.5 mmol)
was added. After generation of H2 ceased, the mixture was treated
with allyl bromide (0.21 mL, 2.5 mmol, 2.5 equiv). Stirring was
continued for 12 h at r.t. After addition of MeOH (5 mL), stirring
was continued for 3 h and the solvent was removed in vacuo. The
oily residue was dissolved in H2O (20 mL) and extraction was car-
ried out using CH2Cl2 (4 ¥ 20 mL). The combined organic extracts
were washed with H2O and dried (MgSO4). Concentration under re-
duced pressure afforded a crude oil (288 mg) which was purified by
column chromatography (20 g silica gel; EtOAc with 3% of Et3N)
which afforded the title compound 9 as a 1.2:1 mixture of isomers
(226 mg, 0.94 mmol; 95% for two steps).
22
(5.16 g, 16.8 mmol, 91%): mp 271-273 °C (subl.). [a]D +66 (c
1.8, CHCl3). Lit.12a: mp 272-274 °C (subl.), [a]D23 +65.
Methyl 3-Acetamido-4-O-benzoyl-6-bromo-2,3,6-trideoxy-a-D-
arabino-hexopyranoside (6)
To a solution of compound 5 (17.2 g, 56.0 mmol) in dry CCl4
(430 mL) were added N-bromosuccinimide (11.87 g, 66.7 mmol)
and barium carbonate (16.0 g, 81.1 mmol). The mixture was re-
fluxed for 6 h (bath temperature 105 °C). After cooling of the faint
yellow reaction mixture, the solvent was removed under reduced
pressure. The residue was extracted with CH2Cl2 (250 mL), the
clear extract was successively washed with 5% aq sodium hydrogen
sulfite, aq sodium bicarbonate, dried (MgSO4) and evaporated in
vacuo. The resultant residue (20 g) was purified by column chroma-
tography (silica gel; petroleum ether/EtOAc, 1: 2) to afford the title
compound (16.4 g, 42.5 mmol, 75.9%) as colorless crystals: mp
147 °C.
1H NMR (400 MHz): d = 8.08-7.40 (m, 5H, Ph), 6.05 (d, 1H,
J = 8.6 Hz, N-H), 5.02 (dd, 1H, J = 9.6, 9.6 Hz, 4-H), 4.85 (d, 1H,
J = 3.2 Hz, 1-H), 4.66 (dddd, 1H, J = 4.8, 8.6, 9.6, 13.2 Hz, 3-H),
4.18 (ddd, 1H,J = 2.6, 6.2, 9.6 Hz, 5-H), 3.56 (dd, 1H, J = 2.6, 9.8
Hz, 6-H), 3.49 (dd, 1H, J = 6.2, 9.8 Hz, 6´-H), 3.40 (s, 3H, OCH3),
2.26 (ddd, 1H, J = 0.6, 4.8, 13.2 Hz, 2-Heq), 1.80 (s, 3H, OAc), 1.74
(ddd, 1H, J = 3.2, 13.2, 13.2 Hz, 2-Hax).
1H NMR (400 MHz): d = 5.98-5.85 (m, 1H, CH= ), 5.31-5.16 (m,
2H, CH2=CH-), 4.75-4.67 (m, 1H, 1-H), 4.54 and 4.07 (m, 1H, 3-
H), 4.45 and 4.42 (s, 1H, 5-H), 4.20-4.00 (m, 2H, =CHCH2), 3.73-
3.45 (m, 2H, 6-H), 3.60-3.50 (m, 1H, 4-H), 3.43 (s, 3H, OMe), 2.06
and 2.00 (s, 3H, NCOCH3), 2.14-1.97 (m, 2H, 2-Hax and 2-Heq).
Each carbon appeared as a pair of signals due to the presence of two
stereoisomers.
13C NMR (100 MHz): d = 169.0, 168.5 (s, O=CN), 134.0 (d, =CH),
117.9, 117.8 (t, CH2= ), 98.1, 97.4 (d, C-1), 75.3, 74.5 (d, C-4), 73.5,
71.8 (d, C-5), 70.6 (t, =CH-CH2), 56.6, 56.4 (q, OMe), 54.4, 51.3 (d,
C-3), 50.0, 48.2 (t, C-6), 31.3, 29.6 (t, C-2), 21.5, 21.3 (q, OCCH3).
13C NMR (100 MHz): d = 169.8 (s, O=CN), 166.8 (s, O=CO), 133.7
(s, Ph), 129.9 (d, Ph), 128.9 (s, Ph), 128.6 (d, Ph), 97.9 (d, C-1),
73.1, 69.3 (2d, C-4, C-5), 55.0 (q, OCH3), 46.7 (d, C-3), 36.2 (t, C-
6), 32.6 (t, C-2), 23.3 (q, Ac).
Anal. Calcd for C12H19NO4 (241.13): C, 59.73; H, 7.94; N, 5.81.
Found: C, 59.81; H, 7.88; N, 5.70.
Anal. Calcd for C16H20BrNO5 (386.24): C, 49.75; H, 5.22; Br,
20.69; N, 3.63. Found: C, 49.69; H, 5.30; Br, 20.87; N, 3.31.
1,4-Bis[methyl 3´-acetylamido-3´,6´-anhydro-2´,3´,6´-trideoxy-
a-D-arabino-hexopyranos-4´-yl]-2-butene-1,4-diol (11)
Compound 9 (74 mg, 0.31 mmol) was kept in vacuo (10-2 Torr) for
5 h and dissolved in dry benzene (10 mL) under N2. To this solution
was added catalyst 12 (12 mg, 4.8 mol%). The purple solution was
stirred at r.t. for 2 h, at which time the starting material had reacted
only sluggishly. A second portion of the metathesis catalyst (8 mg,
3.2 mol%, total 8 mol%) was added. After stirring at 50 °C under N2
for 18 h, the reaction mixture was concentrated under reduced pres-
sure. The residue was dissolved in Et2O (30 mL) and Et3N
(1 mL) and stirred for 2 h. Removal of the solvent under reduced
pressure afforded an oil, which was purified by column chromatog-
raphy (CH2Cl2/MeOH, 15:1) to afford the title compound 11 (61
mg, 0.134 mmol; 88%) as a mixture of four inseparable stereoiso-
mers (trans:cis = 6:1). The spectroscopic data for both of the major
Methyl 3-Acetamido-3,6-anhydro-4-O-benzoyl-2,3,6-trideoxy-
a-D-arabino-hexopyranoside (7)
To a solution of compound 6 (16.0 g, 41.4 mmol) in dry pyridine
(320 mL) was added silver fluoride (16 g, 126.1 mmol). The mix-
ture was stirred at r.t. for 14 h and the dark suspension was poured
into Et2O (800 mL). After filtration over Celite®, the filtrate was
washed with CH2Cl2 (3 ¥ 300 mL) and the combined extracts were
concentrated in vacuo. Addition of toluene (6 ¥ 40 mL) to the resi-
due was used to remove traces of pyridine by co-distillation. Final
purification was achieved by column chromatography (silica gel;
Et2O/CH2Cl2,1:1) to afford the title compound (11.94 g, 39.1 mmol,
94.5%) as colorless crystals: mp 125 °C (Et2O).
Synthesis 2000, No. 8, 1133–1137 ISSN 0039-7881 © Thieme Stuttgart · New York

1136
A. Kirschning, G.-W. Chen
PAPER
(b) Michael, K.; Tor, Y. Chem. Eur. J. 1998, 4, 2091.
trans-isomers are close to identity. Spectroscopic data for the trans-
isomers:
(c) Pearson, N. D.; Prescott, C. D. Chem. Biol. 1997, 4, 409.
(d) Wilson, W. D.; Ratmeyer, L.; Zhao, M.; Ding, D.;
McConnaughie, A. W.; Kumar, A.; Boykin, D. W. J. Mol.
Rec.1996, 9, 187.
1H NMR (400 MHz): d = 5.90-5.84 (m, 2H, 2 ¥ CH= ), 4.73-4.68
(m, 2H, 2 ¥ 1-H), 4.55 and 4.09 (m, 2H, 2 ¥ 3-H), 4.46 and 4.44 (2s,
2H, 2 ¥ 5-H), 4.20-4.05 (m, 4H, 2 ¥ CH2CH= ), 3.75-3.48 (m, 4H,
2 ¥ 6-H, 6´-H), 3.62-3.53 (m, 2H, 2 ¥ 4-H), 3.44 (s, 6H, 2 ¥ OMe),
2.08 and 2.02 (s, 6H, 2 ¥ NCOCH3), 2.14-1.84 (m, 4H, 2 ¥ 2-Hax,
2-Heq).
13C NMR (100 MHz): d = 169.1, 168.6 (s, O = CN), 129.3, 129.2
(d, = CH), 98.3, 97.6 (d, C-1), 75.7, 74.7 (d, C-4), 73.5, 71.7 (d,
C-5), 69.3 (t, CH2-CH = ), 56.8, 56.7, (q, OCH3), 54.4, 51.3 (d, C-
3), 50.1, 48.3 (t, C-6), 31.4, 29.7 (t, C-2), 21.6, 21.4 (q, OCCH3).
(2) Bailly, C.; Hénichart, J. -P. In Molecular Aspects of
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Angew. Chem., Int. Ed. Engl. 1992, 31, 340.
Tokuda, M.; Fujiwara, K.; Gomibuchi, T.; Hirama, M.;
Uesugi, M.; Sugiura, Y. Tetrahedron Lett. 1993, 34, 669.
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Ikemoto, N.; Danishefsky, S. J.; Crothers, D. M. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2797.
LRMS (ES): m/z (%) = 477.1 (22) [M+Na+], 455.4 (100) [M+H+].
NMR data of alkenic double bond of cis-isomers:
1H NMR (400 MHz): d = 5.80-5.74 (m, 2H, CH = ), 4.65-4.61 (m,
2H, 2 ¥ 1-H).
(3) Wang, H.; Tor, Y. Bioorg. Med. Chem. Lett. 1997, 7, 1951.
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(4) Kirschning, A.; Chen, G. -W. Tetrahedron Lett. 1999, 40,
4665.
(5) For some recent examples on the preparation of spacer
modified oligosaccharides see:
13C NMR (100 MHz): d = 129.1 (d, = CH).
1,4-Bis[methyl 3´-amino-3´,6´-anhydro-2´,3´,6´-trideoxy-a-D-
arabino-hexopyranos-4´-yl]-1,4-butanediol (2)
Homodimer (11) (61 mg, 0.134 mmol) was dissolved in CH2Cl2/
MeOH (3:1, 8 mL) and to the solution, PtO2 was added (3 mg). The
suspension was stirred under H2 atm at r.t. for 16 h, after which time
the reduction was complete (TLC: CH2Cl2/MeOH, 10:1). After fil-
tration, the reaction mixture was concentrated under reduced pres-
sure to afford an oil, which was purified by flash column
chromatography (CH2Cl2/MeOH, 20:1). The hydrogenated inter-
mediate (61 mg, 0.134 mmol) was dissolved in H2O (20 mL) at r.t.
and treated with barium hydroxide octahydrate (3.0 g, 9.5 mmol).
The solution was heated under reflux (130-140 °C) for 24 h. After
cooling to r.t., dry ice was added and the suspension was filtered.
The filtrate was treated with Amberlite IRA-904 (OH--form,
20 mL) for 30 min. The solution was filtered again and concentrated
in vacuo. The residue still contained some traces of barium salts and
was taken up in CHCl3. Filtration and removal of the solvent afford-
ed the title compound 2 (42 mg, 0.113 mmol; 84.3%).
Patch, R. J.; Chen, H.; Pandit, C. R. J. Org. Chem. 1997, 62,
1543.
Kieburg, C.; Dubber, M.; Lindhorst, Th. K. Synlett 1997,
1447.
Ramza, J.; Descotes, G.; Basset, J. -M.; Mutch, A. J.
Carbohydr. Chem. 1996, 15, 125.
Descotes, G.;Ramza, J.; Basset, J. -M.; Pagano, S.
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Ats, S. -C.; Lehmann, J.; Petry, S. Carbohydr. Res. 1994, 252,
325.
Lehmann, J.; Petry, S. Carbohydr. Res. 1990, 204, 141.
(6) (a) Dominique, R.; Das, S. K.; Roy, R. Chem. Commun. 1998,
2437.
(b) Roy, R.; Dominique, R.; Das, S. K. J. Org. Chem. 1999,
64, 5408.
[a]D23.5 +16.9 (c 0.64, CHCl3/MeOH, 5:1).
(c) Hadwiger, P.; Stütz, A. E. Synlett 1999, 1787.
(7) Alkene Metathesis in Organic Synthesis; Fürstner, A., Ed.;
Springer Verlag: Berlin, Heidelberg, 1999.
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
Ivin, K. J. J. Mol. Catal. A-Chem. 1998, 133, 1.
Randall, M. L.; Snapper, M. L. J. Mol. Catal. A: Chem. 1998,
133, 29.
1H NMR (400 MHz): d = 4.85 (dd, 2H, J = 9.2, 3.8 Hz, 2 ¥ 1-H),
4.27 (t, 2H, J = 3.2 Hz, 2 ¥ 5-H), 3.60-3.40 (m, 6H, 2 ¥ OCH2 and
2 ¥ 4-H), 3.42 (s, 6H, 2 ¥ OMe), 3.42-3.32 (m, 2H, 2 ¥ 3-H), 3.16
(d, 2H, J = 12.8 Hz, 2 ¥ 6-H), 3.08 (dd, 2H, J = 12.8, 4.0 Hz, 2 ¥
6´-H’), 2.12-2.07 (m, 2H, 2 ¥ NH), 1.92 (ddd, 2H, J = 12.8, 9.4, 1.4
Hz, 2 ¥ 2-Hax), 1.69 (m, 4H, CH2CH2), 1.64 (dt, 2H, J = 12.8, 3.8
Hz, 2 ¥ 2´-H).
13C NMR (100 MHz): d = 98.1 (d, 2 ¥ C-1), 78.8 (d, 2 ¥ C-4), 73.4
(d, 2 ¥ C-5), 69.3 (t, 2 ¥ OCH2), 56.3 (q, 2 ¥ OMe), 52.4 (d, 2 ¥
C-3), 47.5 (t, 2 ¥ C-6), 32.6 (t, 2 ¥ C-2), 26.3 (t, CH2-CH2O).
Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2036.
Armstrong, S. K. J. Chem. Soc., Perkin Trans I 1998, 371.
Fürstner, A. Topics in Catalysis 1997, 4, 285.
Randall, M. L.; Snapper, M. L. J. Mol. Catal. A: Chem. 1998,
133, 29.
LRMS (ES): m/z (%) = 395.5 (52) [M+Na+], 373.4 (100) [M+H+].
Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995,
28, 446.
(8) Klemer, A.; Rodemeyer, D. Chem. Ber. 1974, 2612.
(9) Meyer zu Reckendorf, W.; Spohr, U. Liebigs Ann. Chem.
1982, 137.
(10) Replacement of the corresponding mesylate by azide has been
achieved in boiling DMF by Richardson (71%) as well as
Guthrie and co-workers (see references 12). We found that
under these conditions a substantial amount of the elimination
product (22%) was formed.
(11) Greene, T. W. Protective Groups in Organic synthesis; Wiley:
New York, Chichester, Brisbane, Toronto, Singapore, 1981.
(12) (a) Richardson, A. C. Carbohydr. Res. 1967, 4, 422.
(b) Guthrie, R. D.; Murphy, D. J. Chem. Soc. 1965, 6956.
Acknowledgement
We thank the Deutsche Forschungsgemeinschaft (SFB 416) as well
as the Fonds der Chemischen Industrie for financial support. Prepa-
rative assistance by S. Domann, M.-R. Fischer, and S. Pollmann is
gratefulley acknowledged.
References
(1) For reviews see:
(a) Hermann, T.; Westhof, E. Curr. Opin. Biotechnol. 1998, 9,
66.
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Synthesis of Spacer-Linked Tail to Tail Dimers
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(13) Treatment of the lyxo-configured 3-epimer of 6 with silver
fluoride exclusively affords the corresponding enol ether:
Horton, D.; Weckerle, W. Carbohydr. Res. 1975, 44, 227.
(14) Assignment of the trans- and cis- stereoisomers was based on
chemical shifts in the 13C NMR spectra: Breitmaier, E.;
Voelter, W. 13Carbon NMR Spectroscopy. High Resolution
Methods and Applications in Organic Chemistry and
Biochemistry; VCH: New York, 1987; p 192.
Diver, S. T.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119,
5106.
Article Identifier:
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Synthesis 2000, No. 8, 1133–1137 ISSN 0039-7881 © Thieme Stuttgart · New York