Conformational locking of the glycosyl acceptor for stereocontrol in the key step in the synthesis of heparin

Article abstract of DOI:10.1002/1521-3773(20020617)41:12<2128::AID-ANIE2128>3.0.CO;2-V

Complete control over the stereoselectivity of key coupling reactions in the synthesis of heparin can be exerted by conformationally locking the uronic acid acceptor (see scheme).

Full text of DOI:10.1002/1521-3773(20020617)41:12<2128::AID-ANIE2128>3.0.CO;2-V

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‡
[PPh4] ClÀ (300 mg, 0.8 mmol) in water (20 mL) was added to the mother
the same basis set as used in ref. [11] and analogous GIAO-
calculations of the shielding tensor of 4À were performed. Both
geometries performed almost equally well (maximum deviation from
experimental d(11B) data Æ 1 ppm). b) Coordinates for the B3LYP/6-
31G* structure of 4À are available from the authors (e-mail:
hnyk@iic.cas.cz).
liquor from this crystallization and a white precipitate was formed and
collected by filtration, washed with water (2 Â 10 mL), and dried in vacuum
at RT to give 277 mg of an anionic mixture. This mixture was separated by
multiple preparative TLC on silica gel, using 3% MeCN/CH2Cl2 as the
mobile phase (detection UV 254 nm). The second band, Rf ˆ 0.5 was
collected and washed out with MeCN. Evaporation of the solvent from
[13] Gaussian94 (RevisionB.2), M. J. Frisch, G. W. Trucks, H. B. Schlegel,
P. M. W. Gill, B. G. Johnson, M. A. Robb, J. R. Cheeseman, T. Keith,
G. A. Petterson, J. A. Montgomery, K. Raghavachari, M. A. Al-
Laham, V. G. Zahrzewski, J. V. Ortiz, J. B. Foresman, J. Cioslowski,
B. B. Stefanov, A. Nanayakkra, M. Challacombe, C. Y. Peng, P. Y.
Ayala, Y. Chen, M. W. Wong, J. L. Andres, E. S. Replogle, R.
Gomprets, R. L. Martin, D. J. Fox, J. S. Binkley, D. J. Defrees, L.
Baker, J. P. Stewart, M. Head-Gordon, C. Gonzales, J. A. Pople,
Gaussian, Inc., Pittsburgh, PA, 1995.
[14] S. Huzinaga, Approximate Atomic Wave Functions, University of
Alberta, Edmonton, Canada, 1971.
[15] W. Kutzelnigg, M. Schindler, U. Fleischer, NMR, Basic Principles and
Progress, Vol. 23, Springer, Berlin, 1990.
combined fractions gave pure 4À PPh4 (174 mg, 6%). White crystals were
‡
obtained by diffusion of Et2O into a concentrated CH2Cl2 solution of
4À PPh4 . M.p. 3508C, elemental analysis calcd (%) for C25H27B6P: B 15.33;
‡
found B 14.82.
‡
‡
4,5-I2-4À PPh4 : A solution of 4À PPh4 (35 mg, 0.083 mmol) in CH2Cl2
(10 mL) was treated with several portions of solid I2 (total 44 mg,
0.17mmol) in the presence of NEt 3 (0.5 mL) under stirring at RT for
0.5 h. The mixture was extracted with 5% aqueous Na2S2O3 (20 mL), the
CH2Cl2 layer collected and filtered through a short column of silica gel.
Evaporation of the filtrate gave pure 4,5-I2-4À PPh4 (52 mg, 93%). White
crystals were obtained by diffusion of Et2O vapors into a concentrated
CH2Cl2 solution of 4,5-I2-4À PPh4 . M.p. 2108C; elemental analysis calcd
‡
‡
[16] X. L. R. Fontaine, J. D. Kennedy, J. Chem. Soc. Dalton Trans. 1987,
1573.
(%) for C25H27B6PI2: B 9.62; found B 9.38.
Received: December 13, 2001 [Z18377]
[17] B. Brellochs in Contemporary Boron Chemistry (Eds.: M. G. David-
son, A. K. Hughes, T. B. Marder, K. Wade), Royal Society of
Chemistry, Cambridge, 2000, p. 212.
œ
[18] B. StÌbr, B. Wrackmeyer, J. Organomet. Chem., in press.
[1] a) T. Onak in Boron Hydride Chemistry (Ed.: E. L. Muetterties),
œ
Academic, New York, 1973, p. 349, and references therein; b) B. StÌbr,
Chem. Rev. 1992, 92, 225, and references therein.
œ
œ
œ
¬
[2] a) J. Plesek, T. JelÌnek, B. StÌbr, S. Hermanek, J. Chem. Soc. Chem.
œ
œ
Commun. 1988, 348; b) T. JelÌnek, B. StÌbr, J. Plesek, J. D. Kennedy, M.
Thornton-Pett, J. Chem. Soc. Dalton Trans. 1995, 431.
[3] T. JelÌnek, B. StÌbr, J. Holub, M. Bakardjiev, D. Hnyk, D. L Ormsby,
œ
C. A. Kilner, M. Thornton-Pett, H.-J. Schanz, B. Wrackmeyer, J. D
Kennedy, Chem. Commun. 2001, 1756.
[4] a) T. Onak, R. P. Drake, G. B. Dunks, J. Am. Chem. Soc. 1965, 87,
2505; b) S. R. Prince, R. Schaeffer, Chem. Commun. 1968, 451; c) T.
Onak, P. Matschei, E. Groszek, J. Chem. Soc. (A) 1969, 1990.
[5] a) W. H. Knoth, J. Am. Chem. Soc. 1967, 89, 1274; b) W. H. Knoth,
Inorg. Chem. 1971, 10, 598; W. H. Knoth, Inorg. Chem. 1973, 12, 785.
[6] a) C. Reed, Acc. Chem. Res. 1998, 31, 133; b) S. Strauss, Chem. Rev.
1993, 93, 927.
Conformational Locking of the Glycosyl
Acceptor for Stereocontrol in the Key Step in
the Synthesis of Heparin**
[7] P. Kaszynski, Collect. Czech. Chem. Commun. 1999, 64, 895.
Hernan A. Orgueira, Alessandra Bartolozzi,
Peter Schell, and Peter H. Seeberger*
œ
œ
œ
¬
[8] a) K. Base, S. Hermanek, B. StÌbr, Chem. Ind. (London) 1977, 951;
œ
œ
¬
b) K. Base, B. StÌbr, J. Dolansky, J. Duben, Collect. Czech. Chem.
Commun. 1981, 46, 2345.
Glycosaminoglycans (GAGs), including heparin (A), are
linear oligosaccharides that consist of amino sugars and uronic
acids.[1] Many glycosaminoglycans are involved in vital bio-
logical functions[2] but still, little is known about the molecular
mechanisms responsible for their action. Much progress
toward the synthesis of heparin fragments has been reported
[9] a) Crystal structure data for C25H25B6I2P: Mr ˆ 675.08, white crystal,
3
≈
size 0.2  0.18  0.10 mm , triclinic, space group P1, a ˆ 7.9841(6), b ˆ
13.2428(9), c ˆ 13.5646(9) ä, a ˆ 96.149(6), b ˆ 92.686(5), g ˆ
92.994(6)8, Vˆ 1422.02 ä3, Tˆ 293(2) K, Z ˆ 2, 1calcd ˆ 1.577 MgmÀ3
,
F(000) ˆ 652, m(MoKa) ˆ 2.28 mmÀ1, Data collected with a Siemens P4
four-circle diffractometer (MoKa radiation l ˆ 71.073 pm, graphite
monochromator); qmax ˆ 258. A total of 6152 reflections were meas-
ured, 4986 unique (Rint ˆ 0.0277). Absorption correction empirical (by
Y-scans), min./max. transmission coefficients 0.2453/0.2990, GoF on
F 2 was 1.125, R1 (I > 21(I)) ˆ 0.0358, wR2 ˆ 0.0924. Data/restrains/
parameters 4956/0/308. Largest difference Fourier peak and hole 1.511
and À1.173 eäÀ3. Refinement used SHELXTL V.5.1 (G. M. Shel-
drick, SHELXS-97, University of Gˆttingen, Gˆttingen (Germany),
[*] Prof. Dr. P. H. Seeberger, Dr. H. A. Orgueira, Dr. A. Bartolozzi,
Dr. P. Schell
Department of Chemistry, Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax : (‡1)617-253-2979
‡
1997). b) CCDC-175525 (4,5-I2-4À PPh4 ). contains the supplementary
E-mail: seeberg@mit.edu
crystallographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (‡44)1223-336-033; or deposit@ccdc.cam.
ac.uk).
[**] Financial support from the National Institutes of Health (HL-64799
and HL-62598), The Research Corporation (Research Innovation
Award to P.H.S.), CaP CURE (Research Awards to P.H.S.), FOMEC
(Postdoctoral Fellowship for H.A.O.), CNRI (Italian National Re-
search Center, Postdoctoral Fellowship for A.B.), and the DAAD
(German Academic Exchange Service, Postdoctoral Fellowship for
P.S.) is gratefully acknowledged. Funding for the MIT-DCIF Varian
500 MHz NMR was provided by NSF (Award CHE-9808061).
Funding for the MIT-DCIF Bruker 400 MHz NMR was provided by
NIH (Award 1S10RR13886-01). Funding for the MIT-DCIF Varian
300 MHz was provided by NSF (Award DBI-9729592).
[10] R. E. Williams, Adv. Inorg. Chem. Radiochem. 1976, 18, 67 .
[11] P. v. R. Schleyer, K. Najafian, Inorg. Chem. 1998, 37, 3454.
[12] a) All calculations used the Gausian94 program package[13] and were
performed on the Power Challenge XL computer of the Super-
computing Center of the Charles University in Prague (Czech
Republic). The calculations were carried out at the self-consistent
field (SCF) level and employed a II Huzinaga basis set,[14] well-suited
for the calculations of magnetic properties.[15] Additionally, the
structure of 4À was optimized using a hybrid functional B3LYP with
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
2128
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1433-7851/02/4112-2128 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 12

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–
The reaction of C2-azido glucose trichloroacetimidate 1
and fluoride donors 4 and 5[11] with glucuronic acid acceptor
2[11] yielded anomeric mixtures of disaccharides 3 and 6
(Scheme 1). Better ratios of a-linked disaccharides were
obtained with the slower reacting glycosyl fluorides. Similar
results had been reported previously with other glucuronic
acid acceptors.[4a,c, 12] Interestingly, glycosylations that involve
iduronic acid 8,[13] resulted exclusively in the formation of a-
glucosamine linkages, in accordance with previous reports.[14]
To rationalize the markedly different behavior of glucuronic
and iduronic acid acceptors, we analyzed the conformational
differences of the two monosaccharides. Glucuronic acids
preferentially adopt a 4C1 conformation with an equatorial C4
OSO3
O
O
–
–O3SO
OSO3
–O3SHN
O
O
O
HO
O
–O3SO
OH
–O3SHN
–
–
CO2
CO2
O
O
HO
A
O
OH
and may provide useful tools for the identification of specific
recognition sequences.[3, 4] The most difficult task faced during
the assembly of the heparin backbone is the selective
installation of the a-glycosidic linkage by coupling glucos-
amine units and uronic acids. The installation of a-glucos-
amine linkages, ubiquitous in nature,[5] remains challenging.
The C2 amino group of glucosamine is typically masked in the
form of a nonparticipating azide[4d, 6] to reduce b-glucoside
formation. Anomeric selectivities vary greatly and often
require difficult separations. Electronic effects[7] and confor-
mational constraint[8] of the glycosidating agent have been
utilized to control the stereochemical outcome of glycosyla-
tions. Manipulation of the steric and electronic nature of the
glycosyl acceptor to direct glycosylations have received less
attention. Two features of the acceptor are known to influence
the stereochemical course of the reaction: the intrinsic
reactivity of the hydroxy group that functions as nucleophile
(axial hydroxy groups are generally less reactive than
equatorial hydroxy groups)[9] and steric factors, which result
in matched/mismatched pairs of glycosyl donors and accept-
ors.[10]
1
hydroxyl group. Iduronic acid in contrast adopts either a C4
conformation with a C4 axial hydroxy group or a skewed-boat
2S0 conformation in oligosaccharide sequences, depending on
the substituents on the ring.[15, 16] Apparently, the stereo-
chemical outcome of these glycosylations is related to the
conformation of the acceptor.
Based on these observations we intended to use glucuronic
acid acceptors in a 1C4 conformation. NMR spectroscopic
analysis of glucuronic acids 12 and 14 and iduronic acids 17
and 19, which carry cyclic isopropylidene protecting groups
1
revealed that these monosaccharides adopt a C4 conforma-
tion, as judged by the coupling constants (J4,5 ꢀ 3.5 Hz (4C1:
J
4,5 > 8 Hz) and J1,2 ꢀ 2.7Hz). Differentially protected uronic
acid monomers 12, 14, 17, and 19 were prepared from triols 11
and 16 by formation of isopropylidene[17] or cyclopentyl-
idene[18] acetals upon reaction with 2-methoxypropene or
methoxycyclopentene under kinetic control (Scheme 2). In
addition to the desired compounds, the corresponding furano-
sides 13, 15, 18, and 20 were obtained and were resubmitted to
1,2 acetal formation after cleavage of the acetal protective
group.
Herein we discuss a new method for the stereoselective
installation of a-glucosamine linkages by locking the con-
formation of the monosaccharide acceptor. Several key
disaccharide building blocks, previously obtained as anomeric
mixtures, were prepared by utilizing this approach.
With conformationally constrained glucuronic acid accept-
ors 12 and 14 in hand, we began to investigate the stereo-
chemical outcome of the coupling reactions (Scheme 3).
glucuronic acid acceptors
R1O
R1O
CO2Me
a or b
CO2Me
O
O
O
TBSO
BnO
HO
BnO
TBSO
BnO
O
+
O
OR2
O
O
BnO
N3
OBz
N3
OBz
1: R1 = Ac, R2 = CNHCCl3
4: R1 = Ac, R2 = F
5: R1 = Bn, R2 = F
3: R1 = Ac (α/β 3:1, 57% from 1
2
α/β 7:1, 77% from 4)
6: R1 = Bn α/β 5:1 (43%)
iduronic acid acceptors
AcO
OBn
O
OBn
O
AcO
TBSO
AcO
MeO2C
O
a or b
OTDS
MeO2C
O
OTDS
TBSO
+
OR1
AcO
OH
N3
OH
OH
N3
O
7: R1 = CNHCCl3
10: R1 = F
8
9 completely α selective
(47% from 7, 30% from 10)
Scheme 1. Synthesis of disaccharides by using uronic acid acceptors. a) For 1 and 7: TBSOTf, CH2Cl2, À208C !RT; b) for 4, 5, and 10: AgClO4, SnCl2,Et2O,
molecular sieves (4 ä), 08C !RT. TBSOTf ˆ tert-butyldimethylsilyl trifluoromethanesulfonate, Bz ˆ benzoyl, TDS ˆ dimethylthexylsilyl.
Angew. Chem. Int. Ed. 2002, 41, No. 12
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2129

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reactions greatly simplifies access to disaccharide
modules for heparin assembly and purification of the
reaction products.
CO2Me
OBn
O
CO2Me
O
CO2Me
O
HO
a or b
HO
OH
O
+
BnO
BnO
OH
R
O
In addition to their use as molecular locks, 1,2-
acetals are convenient for the differential protection of
monosaccharides and were applied to iduronic acid
acceptors. Coupling of glycosyl donors 1 and 28 with
iduronic acid acceptors 17 and 19 furnished disacchar-
ides 32 (1‡17), 33 (28‡17), and 34 (28‡19). After the
cyclic acetal protecting groups served their purpose
they were readily removed to yield disaccharide diols
23 (from 21 and 22), 27 (from 25 and 26), 35 (from 32),
and 36 (from 33 and 34), ready for further function-
alization and incorporation as key building blocks into
the modular assembly of heparin oligosaccharides
(Scheme 4).
OH
O
R
O
11
R
R
13: R = Me (32%)
15: R =
12: R = Me (48%)
14: R =
(57%)
(29%)
CO2Me
OBn
OBn
O
HO
a or b
MeO2C
OH
O
MeO2C
OH
O
O
+
BnO
O
R
O
OH OH
R
O
16
R
R
18: R = Me (20%)
20: R =
17: R = Me (68%)
19: R =
In summary, we have demonstrated a new concept
for stereochemical control in the key step in the
synthesis of heparin. Locking the conformation of the
glucuronic acid acceptor allowed the completely
selective preparation of the desired cis glycosides. This
approach greatly simplified the preparation of disac-
charide modules for the stereoselective assembly of
heparin oligosaccharides. Work in this area is underway and
will be reported in due course.
(56%)
(18%)
Scheme 2. Installation of 1,2-acetal protecting groups as molecular locks of uronic
acid monosaccharides. a) 2-Methoxypropene, DMF, CSA; b) methoxycyclopentene,
DMF, CSA. DMF ˆ N,N-dimethylformamide, CSA ˆ camphor sulfonic acid.
Coupling of glycosyl trichloroacetimidate 1 or glycosyl
fluoride 4 with acceptors 12 and 14 resulted exclusively in
the formation of a-linked disaccharides 21 (from 12) and 22
(from 14) in very good yields (Scheme 3). The exact nature of
the cyclic protecting group (isopropylidene or cyclopentyl-
idene) and the anomeric leaving group did not influence the
selectivity of the coupling reaction. Since glycosyl trichloro-
acetimidates performed slightly better than glycosyl fluorides,
further coupling reactions were performed with these donors.
The coupling reactions of donor 24 with acceptors 12 and 14
and the coupling reactions of donors 28 and 29 with acceptor
12 were completely a-selective, as expected, and produced 25
(24‡12), 26 (24‡14), 30 (28‡12), and 31 (29‡12) as the only
products (Scheme 3). Complete a-selectivity of the coupling
Experimental Section
21: Glucosamine 1 (1.87g, 3.14 mmol) and glucuronic acid 12 (850 mg,
2.51 mmol) were coevaporated with toluene and then dissolved in
anhydrous CH2Cl2 (31 mL) before freshly activated powdered molecular
sieves (4-ä, 700 mg) were added. TBSOTf (72 mL, 0.314 mmol) was added
dropwise at À788C, and the mixture was then warmed to room temper-
ature over 2.5 h. Triethylamine (0.5 mL) was added, the mixture was
filtered through a pad of celite, and the solvent was removed under reduced
pressure. Flash chromatography on silica gel (hexanes/EtOAc 85:15)
afforded 21 (1.68 g, 86%) as a colorless foam. [a]2D4 ˆ ‡97.2 (c ˆ 2.55,
CH2Cl2); IR (thin film on NaCl): nÄ ˆ 3032, 2953, 2930, 2858, 2106, 1746,
1455, 1250 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.40 7.27 (m, 10H; H ),
ar
glucuronic acid acceptors
AcO
CO2Me
OBn
O
1
or
4
12
or
14
a (for 1)
O
N
AcO
TBSO
c or d
TBSO
BnO
+
CO2Me
O
O
or
O
BnO
3 O
BnO
b (for 4)
OH
R
N3
O
O
OH
R
21: R = Me (86% (a); 80% (b))
23: (81% from 21;
90% from 22)
22: R =
(80% (a); 79% via (b))
R1O
R2O
R3O
CO2Me
OBn
R1O
R1O
R2O
R3O
NH
CCl3
O
12
or
14
R2O
a
O
c or d
O
O
CO2Me
+
R3O
O
O
N3
O
O
R
N3
OH
BnO
N3
O
O
OH
R
24: R1 = Ac, R2 = Bn, R3 = Bn
25: R1 = Ac, R2 = Bn, R3 = Bn, R4 = Me (83%)
26: R1 = Ac, R2 = Bn, R3 = Bn, R4 =
27: R1 = Ac, R2 = Bn, R3 = Bn
(84% from 25; 81% from 26)
28: R1 = Ac, R2 = TBS, R3 = Ac
29: R1 = Bn, R2 = TBS, R3 = Bn
(82%)
30: R1 = Ac, R2 = TBS, R3 = Ac, R4 = Me (92%)
31: R1 = Bn, R2 = TBS, R3 = Bn, R4 = Me (77%)
Scheme 3. Synthesis of disaccharides by using ™locked∫ glucuronic acid acceptors. a) TBSOTf, molecular sieves (4 ä), CH2Cl2, À788C !RT; b) AgClO4,
SnCl2, Et2O, molecular sieves (4 ä), 08C !RT; c) for 21 and 25: dichloroacetic acid (aqueous, 75%); d) for 22 and 26: dichloroacetic acid (aqueous,
50%).
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Angew. Chem. Int. Ed. 2002, 41, No. 12

COMMUNICATIONS
iduronic acid acceptors
OBn
O
OBn
O
AcO
TBSO
R1O
AcO
TBSO
R1O
NH
CCl3
MeO2C
O
AcO
TBSO
R1O
MeO2C
O
17
or
19
OH
a
O
b or c
O
+
R
O
O
OH
N3
O
N3
R
N3
O
32: R1 = Bn; R = Me (91%)
33: R1 = Ac; R = Me (90%)
34: R1 = Ac; R =
1: R1 = Bn
28: R1 = Ac
35: R1 = Bn (92%)
36: R1 = Ac (89% from 33)
(88% from 34)
(88%)
Scheme 4. Synthesis of disaccharides by using iduronic acid acceptors. a) TBSOTf, molecular sieves (4 ä), CH2Cl2, À788C !RT; b) for 32 and 33:
dichloroacetic acid (aqueous, 75%); c) for 34: dichloroacetic acid (aqueous, 50%).
5.78 (d, J ˆ 3.7Hz, 1H; H1B), 5.17(d, J ˆ 3.7Hz, 1H; H1A), 4.88 (d, J ˆ
11.0 Hz, 1H; ArCH2), 4.78 (d, J ˆ 11.0 Hz, 1H; ArCH2), 4.68 (s, 2H;
ArCH2), 4.59 (d, J ˆ 6.1 Hz, 1H; H5B), 4.38 (dd, J ˆ 2.1, 11.9 Hz, 1H;
H6Aa), 4.25 4.21 (m, 2H; H-2B, H4B), 4.09 4.05 (m, 2H; H6Ab, H3B),
3.89 3.85 (m, 1H; H5A), 3.74 (dd, J ˆ 8.5, 10.4 Hz, 1H; H3A), 3.71 (s, 3H;
OCH3), 3.63 (dd, J ˆ 8.5, 9.8 Hz, 1H; H4A), 3.25 (dd, J ˆ 3.7, 10.4 Hz, 1H;
H2A), 2.08 (s, 3H; COCH3), 1.63 (s, 3H; isopropylidene CH3), 1.39 (s, 3H;
isopropylidene CH3), 0.89 (s, 9H; tBu), 0.02 (s, 3H; CH3), 0.00 ppm (s, 3H;
CH3); 13C NMR (125 MHz, CDCl3): d ˆ 170.9, 170.1, 138.1, 137.3, 128.6,
128.4, 128.2, 128.0, 127.7, 127.5, 111.0, 98.2, 95.7, 80.0, 76.0, 75.6, 75.1, 73.9,
72.3, 71.9, 71.3, 71.2, 63.6, 62.9, 52.5, 27.6, 26.0, 25.9, 21.0, 18.1, À3.6,
À4.8 ppm; MS (FAB): calcd for C38H53N3O12Si: 771.3399; found: 771.3386
[9] a) G.-J. Boons, Carbohydrate Chemistry, Blackie Academic and
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[13] R. Ojeda, J. L. de Paz, M. MartÌn Lomas, J. M. Lassaletta, Synlett
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‡
[M] .
Received: September 24, 2001 [Z17964]
Revised: February 15, 2002
[14] a) T. Chiba, J.-C. Jacquinet, P. Sinay
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