Efficient synthesis of cyclic glycolipid analogues

Article abstract of DOI:10.1055/s-2007-973905

A straightforward approach to macrocyclic structures containing deoxysugar subunits was developed through the functionalization of a bishemiketal. The choice of the length and the nature of the linkers can provide macrocycles with diverse rigidities and p

Full text of DOI:10.1055/s-2007-973905

LETTER
1121
Efficient Synthesis of Cyclic Glycolipid Analogues
Analogues of
Cycé
rids ald Coste, Sandrine Gerber-Lemaire*
Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), Batochime, 1015 Lausanne,
Switzerland
Fax +41(21)6939355; E-mail: Sandrine.Gerber@epfl.ch
Received 11 January 2007
OP
PO
Abstract: A straightforward approach to macrocyclic structures
containing deoxysugar subunits was developed through the func-
tionalization of a bishemiketal. The choice of the length and the
nature of the linkers can provide macrocycles with diverse rigidities
and polarities.
ref. 8
55%
OH
PO
OH
threo-1
OP
P = BOM
Key words: cyclic glycolipid analogues, biscoupling reaction, cou-
pling reagent, C-glycosylation, ring-closing metathesis
O
OH OH
O
2
OH
OH
Carbohydrate-containing macrocycles and analogues
represent highly interesting molecules in view of their
diverse architectures and promising biological proper-
ties.1 For instance, rigid cyclic glycolipids containing a
phenylene-1,4-diamine subunit2 have been prepared and
may be used for modeling carbohydrate–carbohydrate
interactions at interfaces relevant to cell–cell adhesion
and communication. Butane-1,4-diol-linked cyclic neo-
oligoaminodeoxysaccharides3 have been synthesized for
studying the RNA–small molecules interactions and for
their ability to be superior binders for RNA than natural
aminoglycosides. Carbohydrate macrocycles may also be
useful as functional molecular pores.4 It has been reported
by Bundle et al.5 that tethered analogues of trisaccharide
epitopes display enhanced affinity for the binding to a
monoclonal antibody. Strained cyclic glycophanes
containing glucal subunits6 also represent potential cage
molecules for the complexation of cations and small
molecules.7 Recently, we disclosed8 the synthesis of
bishemiketal intermediate 2 through an ozonolysis–dia-
stereoselective reduction sequence on diolefin threo-1.9
NH2 OH NH2 OH OH OH OH NH2
3
Scheme 1 Preparation of amino-functionalized polyketides
ment of the substituents at C(2¢¢, 2¢¢¢), C(4¢¢, 4¢¢¢) and C(6¢¢,
6¢¢¢) was established by 2D NOESY experiment.
Transformation of diolefin 4 into the corresponding diol,
followed by coupling with biscarboxylic acids12 failed to
provide the corresponding cyclic bislactones. Alternative-
ly, ozonolysis of 4 followed by oxidation of the resulting
aldehyde moieties, in the presence of NaClO2, gave diacid
5 in 35% yield (three steps). A biscoupling reaction with
linear polyamines such as pentane-1,5-diamine and
nonane-1,9-diamine, using PyBOP (benzotriazol-1-yl-
oxytripyrrolidinophosphonium hexafluorophosphate) as
3
4''
1
PO
4''' OP
a, b
2
O
1''
OAc OAc
O
71%
1'''
6''
6'''
P = BOM
This derivative was then efficiently converted into several
amino-functionalized polyketides. Polyketide-like mac-
rolides were also efficiently prepared from diolefin 1
(Scheme 1).10 We report here the straightforward con-
version of 2 into analogues of carbohydrate-containing
macrocycles.
4
PO
OP
c–e
35%
f, g
O
OAc OAc
O
HO2C
O
CO2H
5
PO
OP
Our strategy for the preparation of macrocyclic structures
was based on the double functionalization of the hemi-
ketal moieties of 2 through a C-glycosylation reaction fol-
lowed by biscoupling with a linker to close the macrolide.
Peracetylation of 2, followed by treatment with allyltri-
methylsilane and BF3·OEt2, under diluted conditions,11 af-
forded the bisallyl derivative 4 in 71% yield (two steps),
as a single isomer (Scheme 2). The equatorial arrange-
OH OH
O
6 n = 1, 37%
7 n = 5, 46%
O
O
N
N
(
)
n
H
H
Scheme 2 Synthesis of macrocyclic diamides. Reagents and condi-
tions: (a) Ac2O, pyridine, DMAP (cat.); (b) H2C=CHCH2SiMe3,
BF3·OEt2, 4 A MS, MeCN, 0 °C; (c) O3, CH2Cl2, –78 °C; (d) Me2S,
–78 °C; (e) NaClO2, NaH2PO4, 2-methylbut-2-ene, t-BuOH–H2O;
(f) H2N(CH2)5NH2 or H2N(CH2)9NH2, (i-Pr)2NEt, PyBOP, DMF;
(g) K2CO3, MeOH.
SYNLETT 2007, No. 7, pp 1121–1123
2
4.
0
4.
2
0
0
7
Advanced online publication: 13.04.2007
DOI: 10.1055/s-2007-973905; Art ID: G02407ST
© Georg Thieme Verlag Stuttgart · New York

1122
G. Coste, S. Gerber-Lemaire
LETTER
coupling reagent under diluted conditions, afforded metathesis or Cu(I)-catalyzed 1,3-dipolar cycloadditions.
macrocyclic bisamides 6 and 7, in 37% and 46% yields, The bidirectional strategy disclosed here provides an
respectively, after methanolysis of the acetyl groups.
alternative pathway, using synthon 2 as a template to in-
troduce nitrogen-containing linkers for generating macro-
cyclic structures. These molecules represent interesting
scaffolds for the preparation of biologically active com-
pounds.
We also envisaged the use of ring-closing metathesis13 for
the formation of macrocycles containing deoxysugars.
Esterification of diol 814 with methanesulfonyl chloride,
followed by displacement of the intermediate dimesylate
with allylamine and cleavage of the acetyl groups, provid-
ed diamine 9 in 42% yield (three steps). Upon treatment
with Grubbs’ II catalyst at low concentration (0.003 M),
compound 9 underwent a ring-closing metathesis reac-
tion. Contrarily to our previous studies on the cyclization
of linear polyketides10 which led to a cross-metathesis
process prior to ring closure, no traces of cross-coupling
derivatives were observed with bisallyl intermediate 9.
Subsequent reduction of the double bond by catalytic
hydrogenation afforded the macrocyclic diamine 1014 in
48% yield (two steps; Scheme 3).
Acknowledgment
We are grateful to the Swiss National Foundation for financial sup-
port (grant no. 200020-100028/1). We thank Mr. Martial Rey, Mr.
Alain Razaname and Mr. Francisco Sepulveda for technical help.
References and Notes
(1) (a) Furukawa, J.; Sakairi, N. Trends Glycosci. Glycotechnol.
2001, 13, 1. (b) Wessjohann, L. A.; Ruijter, E.; Garcia-
Rivera, D.; Brandt, W. Mol. Diversity 2005, 9, 171.
(2) (a) Velasco-Torrijos, T.; Murphy, P. V. Org. Lett. 2004, 6,
3961. (b) Murphy, P. V.; Müller-Bunz, H.; Velasco-
Torrijos, T. Carbohydr. Res. 2005, 340, 1437. (c) Velasco-
Torrijos, T.; Murphy, P. V. Tetrahedron: Asymmetry 2005,
16, 261.
(3) (a) Chen, G. W.; Kirschning, A. Chem. Eur. J. 2002, 8,
2717. (b) Jaunzems, J.; Oelze, B.; Kirschning, A. Org.
Biomol. Chem. 2004, 2, 3448.
(4) Bodine, K. D.; Gin, D. Y.; Gin, M. S. Org. Lett. 2005, 7,
4479.
(5) McGavin, R. S.; Gagne, R. A.; Chervenak, M. C.; Bundle, D.
R. Org. Biomol. Chem. 2005, 3, 2723.
(6) Belghiti, T.; Joly, J. P.; Didierjean, C.; Dahaoui, S.;
Chapleur, Y. Tetrahedron Lett. 2002, 43, 1441.
(7) Fukudome, M.; Shiratani, T.; Nogami, Y.; Yuan, D. Q.;
Fujita, K. Org. Lett. 2006, 8, 5733.
In summary, we have described an efficient synthetic
route toward novel macrocyclic derivatives containing
deoxysugar subunits and diamino- or diamidoalkyl link-
ers. In particular, ring-closing metathesis and peptide cou-
pling reactions under diluted conditions have proven to be
suitable transformations for the construction of these de-
rivatives. The methods reported so far for the preparation
of glycolipids analogues often rely on the synthesis of
sugar units appended with alkenyl, alkynyl and azido
functionalities for further cyclization through ring-closing
PO
OP
O
OAc OAc
O
a–c
4
(8) Coste, G.; Gerber-Lemaire, S. Eur. J. Org. Chem. 2006,
3903.
60%
P = BOM
8
(9) (a) Schwenter, M. E.; Vogel, P. Chem. Eur. J. 2000, 6, 4091.
(b) Csákÿ, A. G.; Vogel, P. Tetrahedron: Asymmetry 2000,
11, 4935. (c) Schwenter, M. E.; Vogel, P. J. Org. Chem.
2001, 66, 7869. (d) Gerber-Lemaire, S.; Vogel, P. Eur. J.
Org. Chem. 2003, 2959. (e) Meilert, K. M.; Schwenter, M.
E.; Shatz, Y.; Dubbaka, S. R.; Vogel, P. J. Org. Chem. 2003,
68, 2964. (f) Vogel, P.; Gerber-Lemaire, S.; Carmona
Asenjo, A. T.; Meilert, K.; Schwenter, M. E. Pure Appl.
Chem. 2005, 131.
OH
O
OH
PO
OP
OH OH
O
d–f
42%
N
N
H
H
9
(10) Coste, G.; Gerber-Lemaire, S. Synlett 2006, 685.
(11) Kagawa, N.; Ihara, M.; Toyota, M. Org. Lett. 2006, 5, 875.
(12) Muthusamy, S.; Gnanaprakasam, B.; Zurres, E. Org. Lett.
2006, 5, 1913.
(13) For the synthesis of cyclic glycolipids using ring-closing
metathesis, see: (a) Fürstner, A.; Müller, T. J. Am. Chem.
Soc. 1999, 121, 7814. (b) Fürstner, A. Eur. J. Org. Chem.
2004, 943. (c) Dörner, S.; Westermann, B. Chem. Commun.
2005, 2852.
g, h
48%
HO
O
OH
PO
OP
O
(14) Preparation and Data for 4: A solution of 2 (176 mg, 0.305
mmol) in pyridine–Ac2O (1:1, 6 mL) was treated with
DMAP (15 mg, 0.122 mmol, 0.4 equiv) at 25 °C for 3 h.
After completion of the reaction, solvents were evaporated
in vacuo. Purification of the residue by flash chromatog-
raphy (60% EtOAc in pentane) afforded the resulting
peracetylated bishemiketal as a yellow oil (205 mg, quant.).
To a solution of this intermediate in MeCN (68 mL) was
added 4 Å MS (1.4 g) and the mixture was stirred for 30 min.
Allyltrimethylsilane (525 mL, 3.303 mmol, 12 equiv) was
introduced and the solution was stirred for an additional 30
HN
NH
10
Scheme 3 Synthesis of a macrocyclic diamine through ring-closing
metathesis. Reagents and conditions: (a) O3, CH2Cl2, –78 °C; (b)
Me2S, –78 °C; (c) NaBH4, MeOH; (d) MsCl, Et3N, CH2Cl2, 0 °C;
(e) allylamine–DMF (1:3), K2CO3, 40 °C; (f) MeOH; (g) Grubbs’ II
catalyst (0.2 equiv), CH2Cl2 (0.003 M), 50 °C; (h) H2, Pd/C, EtOAc–
MeOH.
Synlett 2007, No. 7, 1121–1123 © Thieme Stuttgart · New York

LETTER
min. At 0 °C, BF3·OEt2 (210 mL, 1.651 mmol, 6 equiv) was
Analogues of Cyclic Glycolipids
1123
1.65 (m, 6 H), 1.20–1.50 (m, 10 H). 13C NMR (100 MHz,
MeOD): d = 176.4, 175.7, 142.0, 131.9, 131.5, 131.2, 96.2,
75.7, 73.3, 73.2, 72.7, 71.7, 68.9, 73.1, 73.7, 73.5, 47.8, 47.1,
46.9, 42.7, 42.5, 42.2, 42.1, 42.0, 39.8, 39.1, 32.5, 32.2, 27.2.
ESI–HRMS: m/z [M + Na] calcd for C40H58N2O10:
added. After stirring for 1 h at 0 °C the reaction mixture was
poured into a sat. aq NaHCO3 solution (40 mL) and filtered
through a pad of celite®. The filtrate was extracted with
EtOAc (3 × 40 mL). The combined organic extracts were
washed with brine (70 mL), dried over MgSO4 and
749.3989; found: 749.3995.
concentrated in vacuo. Purification of the residue by flash
chromatography (30% EtOAc in pentane) afforded 4 as a
colorless oil (153 mg, 71% over two steps). IR (film): 3410,
2100, 1450, 1370, 1240, 1190, 1140, 1060, 960, 830, 780
cm–1. 1H NMR (400 MHz, MeOD): d = 7.25–7.35 (m, 10 H),
5.74–5.80 (m, 2 H), 4.98–5.10 (m, 6 H), 4.78 (s, 4 H), 4.60
(s, 4 H), 3.95–4.02 (m, 4 H), 3.73–3.80 (m, 2 H), 2.32–2.48,
2.13–2.24 (2 × m, 2 × 2 H), 1.96–2.07, 1.53–1.72 (2 × m, 4
H), 1.83–1.96, 1.27–1.36 (2 × m, 4 H), 1.73–1.83, 1.53–1.72
(2 × m, 6 H), 1.98 (s, 6 H). 13C NMR (100 MHz, MeOD):
d = 171.5, 171.4, 142.2, 135.5, 135.4, 128.4, 128.0, 127.7,
116.4, 116.3, 92.9, 70.8, 70.7, 69.9, 69.8, 69.6, 69.5, 69.0,
66.8, 66.0, 39.9, 39.5, 38.6, 37.4, 37.3, 37.2, 37.1, 34.9, 20.4,
20.3. ESI–MS: m/z = 709.3 [M + H]. MALDI–HRMS: m/z
[M + Na] calcd for C41H56O10: 731.3771; found: 731.3769.
Preparation and Data for 5: O3 was passed through a
solution of 4 (200 mg, 0.282 mmol) in CH2Cl2 (9 mL) during
5 min at –78 °C. After persistence of a blue coloration, O2
was passed through the solution to eliminate the excess of
O3. Dimethyl sulfide (83 mL, 1.128 mmol, 4 equiv) was
added and the mixture was stirred for an additional 10 min.
The solvent was evaporated in vacuo at 0 °C. The residual oil
was dissolved in t-BuOH–H2O (1:1, 4 mL) and treated with
KH2PO4 (461 mg, 3.385 mmol, 12 equiv), NaClO2 (383 mg,
231 mmol, 15 equiv) and 2-methylbut-2-ene (200 mL, 231
mmol, 15 equiv) at 25 °C for 12 h. The mixture was poured
into brine (20 mL) and extracted with EtOAc (3 × 20 mL).
The combined organic extracts were dried over MgSO4 and
concentrated in vacuo. Purification of the residue by flash
chromatography (5–20% of MeOH in CH2Cl2) afforded 5 as
a yellow oil (74 mg, 35% over three steps). IR (film): 3440,
2940, 1740, 1715, 1680, 1375, 1245, 1100, 1140, 740, 700
cm–1. 1H NMR (400 MHz, MeOD): d = 7.24–7.34 (m, 10 H),
5.10–5.16 (m, 2 H), 4.78 (d, 4 H), 4.61 (s, 4 H), 4.49–4.57
(m, 2 H), 3.93–4.04 (m, 2 H), 3.83–3.91, 3.67–3.78 (2 × m,
2 × 1 H), 2.54–2.65, 2.27–2.35 (2 × m, 2 × 2 H), 2.05, 2.03
(2 × s, 6 H), 1.87–1.98, 1.61–1.86 (3 × m, 14 H). 13C NMR
(100 MHz, MeOD): d = 181.7, 181.6, 174.2, 173.3, 139.4,
129.4, 128.9, 128.7, 93.8, 71.3, 70.9, 70.9, 70.6, 70.6, 70.3,
69.8, 68.2, 67.6, 42.2, 41.7, 41.6, 39.8, 39.3, 38.5, 37.8, 36.7,
36.6, 21.6, 21.5. ESI–HRMS: m/z [M + K] calcd for
Data for 7: IR (film): 3365, 2960, 1610, 1570, 1410, 1335,
1070, 740, 700 cm–1. 1H NMR (400 MHz, MeOD): d = 7.28–
7.37 (m, 10 H), 4.84 (br s, 4 H), 4.64 (s, 4 H), 4.40–4.59 (m,
2 H), 3.85–4.07 (m, 6 H), 2.97–3.15, 2.75–2.85 (2 × m, 2 ×
2 H), 1.97–2.21 (m, 4 H), 1.66–1.82 (m, 4 H), 1.46–1.64 (m,
10 H), 1.23–1.43 (m, 14 H). 13C NMR (100 MHz, MeOD):
d = 176.3, 176.0, 142.0, 131.9, 131.5, 131.2, 96.4, 73.8, 73.2,
72.0, 71.7, 70.1, 69.6, 73.4, 73.1, 48.0, 46.8, 46.7, 42.9, 42.5,
42.4, 41.9, 41.4, 39.6, 39.4, 32.8, 32.7, 32.6, 30.2, 29.9. ESI–
HRMS: m/z [M + Na] calcd for C44H66N2O10: 805.4615;
found: 805.4620.
Preparation and Data for 9: To a solution of 8 (70 mg,
0.097 mmol) dissolved in CH2Cl2 (1 mL) were added Et3N
(122 mL, 0.879 mmol, 9 equiv) and methanesulfonyl
chloride (28 mL, 0.293 mmol, 3 equiv) at 0 °C. After stirring
for 2 h at 0 °C, the reaction mixture was poured into a sat. aq
NaHCO3 solution (20 mL) and extracted with EtOAc (3 × 20
mL). The combined organic extracts were washed with brine
(40 mL), dried over MgSO4 and concentrated in vacuo. The
residual oil was dissolved in a mixture of DMF–allylamine
(3:1, 4 mL) and treated, at 40 °C, with K2CO3 (120 mg, 0.879
mmol, 9 equiv) for 12 h. The solvents were evaporated in
vacuo. The residual oil was taken up in MeOH (3 mL) and
the solution was stirred for 3 h. The reaction mixture was
poured into H2O (20 mL) and extracted with EtOAc (3 × 20
mL). The combined organic extracts were washed with brine
(40 mL), dried over MgSO4 and concentrated in vacuo.
Purification of the residue by flash chromatography (4%
NH4OH in MeCN) afforded 9 (28 mg, 42% over three steps)
as a colorless oil. IR (film): 3440, 2950, 1740, 1715, 1455,
1370, 1240, 1165, 1100, 1040, 740, 700 cm–1. 1H NMR (400
MHz, MeOD): d = 7.26–7.34 (m, 10 H), 5.85–5.99 (m, 2 H),
4.31, 5.28 (2 × d, 4 H), 4.82 (s, 4 H), 4.61 (s, 4 H), 3.87–4.15
(m, 8 H), 3.37, 3.35 (2 × d, 4 H), 2.74–2.92 (m, 4 H), 2.13–
2.50 (3 × m, 14 H), 1.22–1.50 (m, 4 H). 13C NMR (100 MHz,
MeOD): d = 139.4, 134.3, 134.2, 129.4, 128.9, 128.7, 119.9,
119.8, 93.9, 93.8, 71.4, 70.9, 70.8, 70.7, 70.0, 69.4, 67.7,
66.6, 70.6, 52.4, 52.3, 47.0, 46.8, 45.7, 44.3, 43.8, 39.3, 38.3,
37.1, 37.0, 31.8, 31.3. ESI–HRMS: m/z [M + H] calcd for
C41H62N2O8: 711.4584; found: 711.4588.
Preparation and Data for 10: To a solution of 9 (25 mg,
0.035 mmol) dissolved in CH2Cl2 (15 mL) was added
Grubbs’ II catalyst (6 mg, 0.007 mmol, 0.2 equiv) and the
mixture was stirred at 50 °C for 9 h. The solvent was
evaporated in vacuo. The crude oil was dissolved in
MeOH–EtOAc (1:3, 3 mL) and was treated at 25 °C for 4 h
with a catalytic amount of Pd(OH)2 on activated charcoal
under 1 atm of H2. The reaction mixture was filtered through
a pad of celite®. The filtrate was concentrated in vacuo.
Purification of the residue by flash chromatography (5%
NH4OH in MeCN) afforded 10 as a pale yellow oil (18 mg,
48%). IR (film): 3405, 2955, 1730, 1605, 1510, 1450, 1370,
1250, 1170, 1110, 1030, 850, 775 cm–1. 1H NMR (400 MHz,
MeOD): d = 7.27–7.35 (m, 10 H), 4.82 (s, 4 H), 4.62 (s, 4 H),
3.85–4.15 (m, 8 H), 3.21–3.83 (2 × m, 8 H), 1.91–2.12, 1.50–
1.90 (2 × m, 18 H), 1.23–1.52 (m, 4 H). 13C NMR (100 MHz,
MeOD): d = 130.0, 128.4, 127.9, 126.9, 93.0, 92.9, 69.7,
69.6, 70.0, 69.9, 69.6, 69.5, 69.2, 68.5, 66.3, 65.6, 49.8, 49.7,
46.3, 45.8, 45.3, 42.9, 42.2, 38.0, 36.3, 35.9, 26.6, 26.5, 26.3.
ESI–HRMS: m/z [M + Na] calcd for C39H60N2O8: 707.4247;
found: 707.4234.
C39H52O14: 783.2994; found: 783.3040.
Preparation and Data for 6: To a solution of 5 (25 mg,
0.033 mmol) in DMF (1.4 mL) were added (i-Pr)2NEt (15
mL, 0.081 mmol, 2.4 equiv), and PyBOP (40 mg, 0.081
mmol, 2.4 equiv). Pentane-1,5-diamine (3 mL, 0.033 mmol,
1 equiv) solution in DMF (1 mL) was added dropwise, at
0 °C, over 6 h. The mixture was stirred at 25 °C for 6 h. After
completion of the reaction, the solvent was evaporated in
vacuo. The crude oil was taken up in MeOH (1.5 mL) and
treated with K2CO3 (20 mg, 0.145 mmol, 4 equiv) at 25 °C
for 4 h. The reaction mixture was poured into H2O (20 mL)
and extracted with EtOAc (3 × 20 mL). The combined
organic extracts were washed with brine (40 mL), dried over
MgSO4 and concentrated in vacuo. Purification of the
residue by flash chromatography (2–4% MeOH in CH2Cl2)
afforded 6 (7 mg, 37% over two steps). IR (film): 3440,
2930, 1740, 1715, 1410, 1355, 1245, 1180, 1100, 1140, 740,
700 cm–1. 1H NMR (400 MHz, MeOD): d = 7.25–7.50 (m,
10 H), 4.86 (br s, 4 H), 4.60 (br s, 4 H), 4.53–4.59, 4.44–4.49
(2 × m, 2 H), 3.92–4.07 (m, 6 H), 2.97–3.12, 2.78–2.87 (2 ×
m, 2 × 2 H), 1.94–2.20 (m, 4 H), 1.66–1.78 (m, 4 H), 1.52–
Synlett 2007, No. 7, 1121–1123 © Thieme Stuttgart · New York

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