1,5-α-D-mannoseptanosides, ring-size isomers that are impervious to α-mannosidase-catalyzed hydrolysis

Article abstract of DOI:10.1021/ol8028065

1,5-D-Mannoseptanosyl di-and trisaccharide ring-size isomers of the corresponding mannopyranosyl oligosaccharides have been prepared. Remarkably, these compounds show no inhibition of the α-mannosidase-catalyzed hydrolysis of p-nitrophenyl-α-D-mannopyrano

Full text of DOI:10.1021/ol8028065

ORGANIC
LETTERS
2009
Vol. 11, No. 4
851-854
1,5-r-D-Mannoseptanosides, Ring-Size
Isomers That Are Impervious to
r-Mannosidase-Catalyzed Hydrolysis
Matthew A. Boone, Frank E. McDonald,* Joseph Lichter, Stefan Lutz, Rui Cao,
and Kenneth I. Hardcastle
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
fmcdona@emory.edu
Received December 4, 2008
ABSTRACT
1,5-D-Mannoseptanosyl di- and trisaccharide ring-size isomers of the corresponding mannopyranosyl oligosaccharides have been prepared.
Remarkably, these compounds show no inhibition of the r-mannosidase-catalyzed hydrolysis of p-nitrophenyl-r-D-mannopyranoside.
Seven-membered ring (septanose) oligosaccharides are un-
known in nature, as the thermodynamic preference of five-
and six-membered furanose and pyranose rings dominate the
structural motifs of natural sugars and their glycoconjugates.1
However, seven-membered ring sugars can be produced
using methods that utilize selective protective group trans-
formations of secondary alcohols of hexose sugars2,3 or by
rearrangements of appropriately protected furanoside deriva-
tives.4 Peczuh and co-workers have recently provided
considerable insights into other methods for preparation of
several stereoisomers of septanose carbohydrates.5
membered ring isomers of naturally occurring carbohydrate
structures, with particular emphasis on septanosyl isomers
of D-manno and D-gluco stereochemistry. Notwithstanding
the differences in hydroxyl positions for septanosides, we
anticipate that the biocompatibility of these substrates will
be quite high, as potential enzymatic or non-enzymatic
glycosidic hydrolysis will yield the biologically innocuous
hexose sugar. Furthermore, the absence of primary hydroxyl
groups and conformational differences for the seven-
membered ring isomer may result in novel enzymatic
reactivity or stability, which may be harnessed in applications
of septanose oligosaccharides as biomaterials or components
for drug delivery.6
Our laboratory has initiated a program to explore the
chemical, physical, and biological properties of the seven-
Our interest in this area began in 2004 when we reported
the synthesis of septanose (seven-membered ring) glycals
via alkynol cycloisomerization.7 The regioselectivity for
septanose glycal formation was dependent on a cyclic
protective group between adjacent alcohols (acetonide or
benzylidene acetal), but each diastereomer favored the
septanose glycal. Our initial synthesis of the alkynyl diol
substrates involved a one-carbon homologation of aldehyde
(1) Grindley, T. B.; Gulasekharan, V. J. Chem. Soc., Chem. Commun.
1978, 1073.
(2) (a) Stevens, J. D. J. Chem. Soc., Chem. Commun. 1969, 1140. (b)
Ng, C. J.; Stevens, J. D. Carbohydr. Res. 1996, 284, 241. (c) Tran, T. Q.;
Stevens, J. D. Aust. J. Chem. 2002, 55, 171
.
(3) Anet, E. F. L. Carbohydr. Res. 1968, 8, 164
.
(4) (a) Micheel, F.; Suckfu¨ll, F. Ann. 1933, 502, 85. (b) Ward, D. E.;
Liu, Y.; Rhee, C. K. Can. J. Chem. 1994, 72, 1429. (c) McAuliffe, J. C.;
Hindsgaul, O. Synlett 1998, 307. (d) Contour, M.-O.; Fayet, C.; Gelas, J.
Carbohydr. Res. 1990, 201, 150.
(5) (a) Peczuh, M. W.; Snyder, N. L.; Fyvie, W. S. Carbohydr. Res.
2004, 339, 1163. (b) Fyvie, W. S.; Morton, M.; Peczuh, M. W. Carbohydr.
Res. 2004, 339, 2363. (c) DeMatteo, M. P.; Snyder, N. L.; Morton, M.;
Baldisseri, D. M.; Hadad, C. M.; Peczuh, M. W. J. Org. Chem. 2005, 70,
24. (d) Castro, S.; Peczuh, M. W. J. Org. Chem. 2005, 70, 3312. (e) Castro,
S.; Fyvie, W. S.; Hatcher, S. A.; Peczuh, M. W. Org. Lett. 2005, 7, 4709.
(f) Snyder, N. L.; Haines, H. M.; Peczuh, M. W. Tetrahedron 2006, 62,
9301.
(6) Robinson, M. A.; Charlton, S. T.; Garnier, P.; Wang, X.; Davis,
S. S.; Perkins, A. C.; Frier, M.; Duncan, R.; Savage, T. J.; Wyatt, D. A.;
Watson, S. A.; Davis, B. G. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 14527.
(7) (a) Alca´zar, E. M.; Pletcher, J. M.; McDonald, F. E. Org. Lett. 2004,
6, 3877. (b) Koo, B.; McDonald, F. E. Org. Lett. 2007, 9, 1737.
10.1021/ol8028065 CCC: $40.75
Published on Web 01/20/2009
2009 American Chemical Society

Scheme 1. Synthesis of D-Arabinoseptanose Glycals 9-13
to alkyne8 of an appropriately protected pentose. Unfortu-
nately, preparation of the alkynol substrate for the D-arabino
glycal (precursor to D-manno- and D-glucoseptanosides) was
much more difficult than for the other three diastereomers.
We now report asymmetric syntheses of the alkynyl diols 7
and 8 that provide gram-scale quantities of the D-arabinosep-
tanose glycals, while offering flexibility in protective group
patterns. Key features of this synthesis include the lipase-
catalyzed enzymatic resolution of (()-2 (Scheme 1),9 which
was more easily conducted on multigram scale than enan-
tioselective alkynylation10 or Sharpless kinetic resolution of
(()-2.11 From compound 4, the chiral secondary alcohols
were introduced with Sharpless epoxidation12 to 5, followed
by Mitsunobu inversion13 and Ti(O-i-Pr4)-promoted regi-
oselective addition of benzoic acid14 to alkynyl diol 6. After
introduction of the required cyclic protective group as
acetonide 7 or as benzylidene acetal 8, tungsten-catalyzed
alkynol cycloisomerization15 provided the respective sep-
tanose glycals 9 and 10, which were isolated after protection
of the 5-hydroxyl as the glycals 11-13.16
methanolysis of the mixture of epoxides afforded a 1:1
mixture of the D-glucoseptanosyl epoxide 14 and the
methanol addition product 15 arising from the D-mannosep-
tanosyl epoxide (Scheme 2). The epoxide 14 was remarkably
stable to a variety of nucleophilic addition conditions. On
the other hand, the reaction of 12 with DMDO resulted in a
complex mixture, consistent with competitive oxidation of
the benzylidene acetal.17 Thus reductive cleavage of the
benzylidene acetals 12 and 13 was followed by O-benzylation
to afford the septanose glycals 17 and 18 in excellent yield.
DMDO epoxidations of glycals 17 and 18 were stereose-
lective, so that addition of sodium methoxide to the epoxide
intermediate 19 provided the partially protected D-mannosep-
tanoside 20, whereas lithium thiophenoxide addition resulted
in the formation of thioglycosides 22-23. Thus epoxidation
occurred cis to the allylic C3 benzyloxy substituent but trans
to both C4 and C5 substituents, consistent with observations
in several six-membered ring glycals.18 The protective group
manipulations of 20 to 21 and 22-23 to 24-25 were
straightforward, other than the observation that deprotection
of the trimethylsilylethoxymethyl (SEM) group to the free
C5-alcohol of methyl R-mannoseptanoside acceptor synthon
21 was possible only with DMPU solvent in conjunction with
molecular sieves.19,20
Our original intention was to functionalize the glycal by
dimethyldioxirane (DMDO) epoxidation, followed by nu-
cleophilic addition at C1. Unfortunately, epoxidation of
acetonide glycal 11 was not stereoselective. Moreover, basic
(8) Thie´ry, J.-C.; Fre´chou, C.; Demailly, G. Tetrahedron Lett. 2000, 41,
6337.
(9) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113, 6129.
(10) (a) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
9687. (b) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855.
(11) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(12) Woodard, S. S.; Finn, M. G.; Sharpless, K. B. J. Am. Chem. Soc.
1991, 113, 106.
(17) Hayes, C. J.; Sherlock, A. E.; Selby, M. D. Org. Biomol. Chem.
2006, 4, 193.
(18) (a) Cheng, G.; Boulineau, F. P.; Liew, S.-T.; Shi, Q.; Wenthold,
P. G.; Wei, A. Org. Lett. 2006, 8, 4545. For other studies on dioxirane
epoxidations of seven-membered cyclic enol ethers, see: (b) Orendt, A. M.;
Roberts, S. W.; Rainier, J. D. J. Org. Chem. 2006, 71, 5565. (c) Markad,
S. D.; Xia, S.; Snyder, N. L.; Surana, B.; Morton, M. D.; Hadad, C. M.;
Peczuh, M. W. J. Org. Chem. 2008, 73, 6341.
(13) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Martin, S. F.; Dodge, J. A.
Tetrahedron Lett. 1996, 61, 2967. (c) Hughes, D. L.; Reamer, R. A. J.
Org. Chem. 1996, 61, 2967.
(19) Lipshutz, B. H.; Miller, T. A. Tetrahedron Lett. 1989, 30, 7149
.
(20) (a) The stereochemistry of septanoside 25 was confirmed by
conversion into the known R-1,6-diacetyl-2,3,4-tri-O-benzyl-D-
mannopyranose,20b in three steps: (1) TFA, CH2Cl2; (2) NBS, H2O, THF;
(3) Ac2O, Et3N, cat. DMAP, CH2Cl2. (b) Tennant-Eyles, R. J.; Davis, B. G.;
(14) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557.
(15) McDonald, F. E.; Reddy, K. S.; D´ıaz, Y. J. Am. Chem. Soc. 2000,
122, 4304.
(16) Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343.
Fairbanks, A. J. Tetrahedron: Asymmetry 2000, 11, 231
.
852
Org. Lett., Vol. 11, No. 4, 2009

Scheme 2. Preparation of Various D-Mannoseptanoside Derivatives
Encouraged by Peczuh’s report of glycosylations of other
septanose thioglycosides,5ewe first studied the glycosylation
of septanoside acceptor synthon 16 with the thioglycoside
donor synthon 24. This transformation provided fully pro-
tected disaccharide 26 (Scheme 3), for which the crystal
structure confirmed the stereochemical assignments for the
compounds arising from epoxidation and ring-opening
products 15 and 19. A more practical combination of O5-
SEM-protected thioglycoside 25 with C5-alcohol 21 provided
the disaccharide 27 (Scheme 4), again with alpha stereose-
lectivity despite the absence of a participating group at C2.
After removal of the SEM protective group, disaccharide
alcohol 28 was glycosylated again with 25 to provide
trisaccharide 29. Each mannoseptanoside was fully depro-
tected by global debenzylation via Pd(OH)2/C-catalyzed
hydrogenolysis. The crude polyols 31 and 32 were purified
by forming the peracetate derivatives and silica gel chro-
matography, followed by ammoniacal methanolysis, whereas
the trisaccharide 33 was obtained analytically pure without
further purification.
Scheme 3. Synthesis and Crystal Structure of Disaccharide 26
Although the seven-membered ring isomers of the natu-
rally occurring pyranosides exhibit substantially different
arrangements of the hydroxyls, including the incorporation
of the primary C6 carbon into the ring, we still wondered if
the common arrangement of hydroxyls at C2, C3, and C4
would be sufficient for 31-33 to serve as substrates for
glycosidase hydrolysis. Thus we evaluated the jack bean
R-mannosidase-catalyzed hydrolysis of p-nitrophenyl R-D-
mannopyranoside (PNP-Man) in the presence of varying
concentrations of R-mannoseptanosides 31-33 (Table 1).21
Remarkably, none of our mannoseptanosides showed sig-
nificant inhibition of PNP-Man hydrolysis, suggesting that
these seven-membered ring-size isomers did not interact with
the matched enzyme for R-mannopyranoside hydrolysis.
Given the different conformations of mannoseptanosides and
mannopyranosides, future enzyme inhibition studies might
Org. Lett., Vol. 11, No. 4, 2009
853

Scheme 4. Iterative Glycosylation Synthesis of D-Mannopyranosyl Di- and Trisaccharides
Table 1. Kinetic Parameters for p-Nitrophenyl Mannopyranoside (PNP-Man) Hydrolysis by R-Mannosidase in the Absence and
Presence of Septanosyl Oligosaccharides 31-33a
controlb
0.75 mM 31
6.0 mM 31
0.75 mM 32
6.0 mM 32
0.75 mM 33
6.0 mM 33
Km (mM)
Kcat (s-1
3.8 ( 0.5
44 ( 1
3.1 ( 0.3
38 ( 1
3.6 ( 0.3
41 ( 1
2.7 ( 0.2
45 ( 1
4.3 ( 0.4
41 ( 1
2.1 ( 0.2
44 ( 1
2.4 ( 0.3
46 ( 2
)
a Inhibition of jack bean R-mannosidase-catalyzed hydrolysis of PNP-Man (0-30 mM) in the absence of mannoseptanosides (control) or in the presence
of 0.75 or 6.0 mM mannoseptanosides 31, 32, and 33. b The literature reports Km values for jack bean R-mannosidase-catalyzed hydrolysis of PNP-Man
ranging from 2.5 to 4.67 mM (ref 21a,b).
benefit from testing additional members of the glycosidase
family, in order to cover a broader range of substrate
specificity.
chain oligoseptanosides via larger fragment coupling strate-
gies.
Acknowledgment. M.A.B. is an Achievement Rewards
for College Scientists (ARCS) Foundation fellow (2007-
present). We also acknowledge the use of shared instru-
mentation provided by the National Institutes of Health,
National Science Foundation, the Georgia Research Al-
liance, and the University Research Committee of Emory
University.
In conclusion, tungsten-catalyzed cycloisomerizations of
alkynyl alcohols have ultimately permitted access to a unique
family of non-natural septanosyl oligosaccharide ring-size
isomers of R-mannopyranosides. As the 1,5-linked D-
mannoseptanosyl di- and trisaccharides have not previously
been reported in the literature, the demonstration of this
glycosylation strategy involving more complex glycosyl
acceptors and donors is an important achievement toward
future applications of this concept to the synthesis of long-
Supporting Information Available: Detailed experimen-
tal procedures and characterization for all synthetic com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) (a) Li, Y.-T. J. Biol. Chem. 1967, 242, 5474. (b) Mari, S.; Posteri,
H.; Marcou, G.; Potenza, D.; Micheli, F.; Can˜ada, F. J.; Jimenez-Barbero,
J.; Bernardi, A. Eur. J. Org. Chem. 2004, 5119.
OL8028065
854
Org. Lett., Vol. 11, No. 4, 2009