Intramolecular benzyl protection delivery: A practical synthesis of DMDP and DGDP from D-fructose

Article abstract of DOI:10.1021/ol052668u

A two-step protection of 1,2-diols as the corresponding o-xylylene cyclic ethers, involving an intramolecular ring-closing O-benzylation reaction, has been developed to overcome the problems associated to regioselective benzylation reactions. The strategy has been applied to the high-yielding synthesis of the pyrrolidine glycosidase inhibitors DMDP and DGDP.

Full text of DOI:10.1021/ol052668u

ORGANIC
LETTERS
2006
Vol. 8, No. 2
297-299
Intramolecular Benzyl Protection
Delivery: A Practical Synthesis of
DMDP and DGDP from -Fructose
D
M. Isabel Garc´ıa-Moreno,† Matilde Aguilar,† Carmen Ortiz Mellet,*,† and
Jose´ M. Garc´ıa Ferna´ndez*,‡
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidad de SeVilla,
Apartado 553, E-41071 SeVilla, Spain, and Instituto de InVestigaciones Qu´ımicas,
CSIC, Ame´rico Vespucio s/n, Isla de la Cartuja, E-41092 SeVilla, Spain
mellet@us.es; jogarcia@iiq.csic.es
Received November 3, 2005
ABSTRACT
A two-step protection of 1,2-diols as the corresponding o-xylylene cyclic ethers, involving an intramolecular ring-closing O-benzylation reaction,
has been developed to overcome the problems associated to regioselective benzylation reactions. The strategy has been applied to the
high-yielding synthesis of the pyrrolidine glycosidase inhibitors DMDP and DGDP.
Benzyl ethers occupy a prominent position among the battery
of hydroxyl protecting groups currently employed in organic
chemistry. They can be introduced in high yield, remain
stable under the acidic or basic conditions used during
manipulation of other protecting groups such as esters, silyl
ethers, carbamates, or acetals, and can be removed in a later
step under mild conditions by catalytic hydrogenation.
O-Benzylation of polyol systems generally proceeds, how-
ever, with low regioselectivity, which is a quite serious
drawback frequently encountered in carbohydrate chemis-
try.1,2 The preparation of the natural polyhydroxylated
pyrrolidines 2,5-dideoxy-2,5-imino-D-mannitol (DMDP, 1)
and 2,5-dideoxy-2,5-imino-D-glucitol (DGDP, 2) from
D-fructose typically illustrates this limitation. Compounds 1
and 2 are potent inhibitors of several glycosidases3 and have
been used as starting materials for the preparation of other
polyhydroxyalkaloids of the pyrrolizidine family.4 A con-
venient synthetic strategy for accessing 1 and 2 has been
(1) Regioselective benzylation of carbohydrate derivatives has been
achieved, to a certain extent, via transient protection with silyl ether or
stannylidene acetal groups. See, for example: (a) Lee, J.-C.; Chang,
S.-W.; Liao, C.-C.; Chi, F.-C.; Chen, C.-S.; Wen, Y.-S.; Wangn, C.-C.;
Kulkarni, S. S.; Puranik, R.; Liu, Y.-H.; Hung, S.-C. Chem. Eur. J. 2004,
10, 399. (b) Halila, S.; Benazza, M.; Demailly, G. J. Carbohydr. Chem.
2001, 20, 467.
(2) Some remarkable preparations of partially benzylated carbohydrate
derivatives have been accomplished by an alternative strategy involving
regioselective O-debenzylation. See, for example: (a) Bistri, O.; Sinay¨, P.;
Sollogoub, M. Tetrahedron Lett. 2005, 46, 7757. (b) Lecourt, T.; Herault,
A.; Pearce, A. J.; Sollogoub, M.; Sinay¨, P. Chem. Eur. J. 2004, 10, 2960.
(c) Roizel, B. C.; Cabianca, E.; Rollin, P.; Sinay¨, P. Tetrahedron 2002, 58,
9579. (d) Pearce, A. J.; Sinay¨, P. Angew. Chem., Int. Ed. 2000, 39, 3610.
(3) Legler, G. In Iminosugars as Glycosidase Inhibitors; Stu¨tz, A. E.,
Ed.; Wiley-VCH: Weinheim, Germany, 1999; p 31.
(4) (a) Izquierdo, I.; Plaza, M. T.; Tamayo, J. A. Tetrahedron 2005, 61,
6527. (b) Izquierdo, I.; Plaza, M. T.; Franco, F. Tetrahedron: Asymmetry
2004, 15, 1465. (c) Garc´ıa-Moreno, M. I.; Rodr´ıguez-Lucena, D.; Ortiz
Mellet, C.; Garc´ıa Ferna´ndez, J. M. J. Org. Chem. 2004, 69, 3578.
† Universidad de Sevilla. Fax: +34 954624960. Tel: +34 954557150.
‡ Instituto de Investigaciones Qu´ımicas, CSIC. Fax: +34 954460565.
Tel: +34 954489559
10.1021/ol052668u CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/18/2005

published that involves the 3,4-di-O-benzylated D-fructopy-
ranose derivative 3 as a pivotal intermediate.5-7 Although
the hydroxyl group at position C-3 can be easily dis-
criminated at an early stage in the reaction sequence,
O-regioselective benzylation of the equatorial OH-4 in the
presence of the axial OH-5 in the monobenzylated precursor
4 is troublesome, affording the desired vicinal di-O-benzyl
ether in rather modest yield. Alternative preparations of 3
require multistep reaction sequences.8 This handicap in the
regioselective O-benzylation is largely responsible for the
low overall yields in the preparation of 1 and 2 from 3 (30%
and 14%, respectively; Scheme 1).
efficiency improvement in terms of atom economy11 (Scheme
2). The potential that this strategy holds for hydroxyl group
Scheme 2. Retrosynthetic Analysis of the Intramolecular
Benzyl Delivery Strategy for the Selective Protection of
1,2-Diols
manipulation is demonstrated here by its application to the
high yielding syntheses of 1 and 2.
Scheme 1. Synthesis of DMDP and DGDP from Selectively
Benzylated D-Fructose Derivativesa
Our synthetic route started from 1,2:4,5-di-O-isopro-
pylidene-â-D-fructopyranose 5,12 which was transformed into
the corresponding 3-O-(2-bromomethyl)benzyl ether 6 by
reaction with excess of commercial R,R′-dibromoxylene.
Selective acid-catalyzed hydrolysis of the 4,5-O-isopro-
pylidene group provided diol 7, which was activated by
treatment with sodium hydride in N,N-dimethylformamide.
Formation of a fused eight-membered ring involving OH-4,
to give the key intermediate 8, readily took place under these
conditions (Scheme 3). No traces of the 3,5-O-(o-xylylene)
a For reagents and conditions, see ref 5.
Scheme 3. Synthesis of DMDP via Intramolecular Benzyl
Delivery
Inspired by the concept of intramolecular delivery of
vicinal functionality,9 we conceived a strategy for the
selective O-xylylation of 1,2-diols involving an intramo-
lecular ring-closing O-benzylation reaction of a hydroxyl
group by a benzylating moiety previously installed at the
neighboring oxygen atom. We reasoned that this tactic would
enjoy improved regioselectivity compared to the correspond-
ing intermolecular O-benzylation reaction. Geometrical
considerations suggested that the o-xylylene tether would
provide the appropriate distance restriction to favor 1,2-
versus 1,3-O-(o-xylylene) protection.10 Moreover, protection
of a vicinal diol segment by a cyclic xylylene group, instead
of two independent benzyl ethers, results in a considerable
(5) (a) Izquierdo, I.; Plaza, M. T.; Franco, F. Tetrahedron: Asymmetry
2002, 13, 1503. (b) Izquierdo, I.; Plaza, M. T.; Robles, R.; Franco, F.
Carbohydr. Res. 2001, 330, 301.
(6) For selected examples of alternative recent syntheses, see: (a) Liu,
J.; Numa, M. M. D.; Liu, H.; Huang, S.-J.; Sears, P.; Shikhamn, A. R.;
Wong, C.-H. J. Org. Chem. 2004, 69, 6273. (b) Donohoe, T. J.; Headley,
C. E.; Cousins, R. P. C.; Cowley, A. Org. Lett. 2003, 5, 999. (c) Dondoni,
A.; Giovannini, P. P.; Perrone, D. J. Org. Chem. 2002, 67, 7023. (d)
Wrodnigg, T. M. Monatsh. Chem. 2002, 133, 393.
(7) For a very interesting approach to the synthesis of selectively
functionalized DMDP derivatives, see: (a) Wrodnigg, T. A.; Stu¨tz, A. E.;
Withers, S. G. Tetrahedron 1997, 38, 5463. (b) Wrodnigg, T. A.; Withers,
S. G.; Stu¨tz, A. E. Bioorg. Med. Chem. Lett. 2001, 11, 1063. (c) Wrodnigg,
T. A.; Dines, F.; Gruber, C.; Ha¨usler, H.; Lundt, I.; Rupitz, K.; Steiner, A.
J.; Stu¨tz, A. E.; Tarling, C. A.; Withers, S. G.; Wo¨lfrer, H. Bioorg. Med.
Chem. 2004, 38, 3485.
(8) Tatiboue¨t, A.; Lefoix, M.; Nadolny, J.; Martin, O. R.; Rollin, P.;
Yang, J.; Holman, G. D. Carbohydr. Res 2001, 333, 327.
(9) Knapp, S. Chem Soc. ReV. 1999, 28, 61.
positional isomer or intermolecular reaction products were
observed, which is in stark contrast with the low selectivity
of the classical intermolecular benzylation reaction.
298
Org. Lett., Vol. 8, No. 2, 2006

Compound 8 is well-suited for further elaboration at C-5
in order to access polyhydroxylated pyrrolidines.13 Thus,
double inversion involving iodination with the iodine-
imidazole-triphenylphosphine system, followed by nucleo-
philic displacement of the halogen atom in the L-sorbo
intermediate 9 with azide anion, afforded the corresponding
5-azido-5-deoxy-â-D-fructopyranose derivative 10. Cleavage
of the anomeric acetonide group by treatment with 90%
aqueous trifluoroacetic acid provided the reducing azidosugar
11, possessing a substitution profile of stereochemical
complementarity to DMDP. Catalytic hydrogenation of 11
at 4 bar in the presence of HCl provoked simultaneous
removal of the cyclic o-xylylene protecting group, reduction
of the azido group into the corresponding amine, intramo-
lecular addition of the amino group to the latent aldehyde
group of the monosaccharide and steroselective reduction
of the resulting imine, to give the target C2-symmetric
pyrrolidine 1 as the corresponding hydrochloride in a one-
pot transformation (Scheme 3).
sulfonylation of OH-5 in 8 and subsequent nucleophilic
displacement by azide provided the requested azidosugar 12
in 83% yield (to be compared with a 72.5% yield for a similar
two-step transformation in 3).14 Trifluoroacetic acid catalyzed
cleavage of the anomeric isopropylidene group to give the
reducing derivative 13 followed by catalytic hydrogenation
afforded the target compound 2, as the corresponding
hydrochloride, in six steps and 55% overall yield from 5
(Scheme 4).
Scheme 4. Synthesis of DGDP
It is noteworthy that, in addition to the expected increase
in the regioselectivity of the vicinal diol protection step, the
use of the cyclic o-xylylene protecting group results in a
dramatic improvement of the nucleophilic substitution reac-
tions at the neighboring C-5 center as compared with the
di-O-benzyl derivative 3. Thus, using identical reaction
conditions, the iodination yield goes up from 48% to 98%
(for 9) and the subsequent azide anion displacement increases
from 85% to 91% (for 10). Probably, in the cyclic arrange-
ment the aromatic ring is forced to occupy the space between
the positions involved in the benzyl ether linkages, therefore
releasing steric hindrance at the vicinity of this region. The
preparation of 1 from the diacetonide D-fructose precursor
5 was accomplished in seven steps and 61% overall yield.
In summary, the concept of intramolecular delivery of
benzyl protection is here demonstrated by the regioselective
preparation of the 3,4-O-(o-xylylene)-D-fructose derivative
8 from the monobenzyl-protected diol 7. The new methodol-
ogy provides alternative opportunities for selective diol
protection and for reactivity control. These favorable features
have been translated into highly efficient preparations of the
natural glycosidase inhibitors DMDP and DGDP.15
The synthesis of the epimeric pyrrolidine 2 requires a
precursor having the L-sorbo configuration. Trifluoromethane-
Acknowledgment. We thank the Spanish Ministerio de
Educacio´n y Ciencia for financial support (contracts number
BQU2003-00937 and CTQ2004-05854/BQU).
(10) The o-xylylene tether has been previously used as a rigid spacer to
connect two different monosaccharide moieties during the stereocontrolled
synthesis of spirodisaccharides. See: (a) Rubio, E. M.; Garc´ıa-Moreno, M.
I.; Balbuena, P.; Ortiz Mellet, C.; Ferna´ndez Garc´ıa, J. M. Org. Lett. 2005,
7, 729. (b) Rubio, E. M.; Ortiz Mellet, C.; Garc´ıa Ferna´ndez, J. M. Org.
Lett. 2003, 5, 873.
Supporting Information Available: Experimental details
and characterization data for compounds 6-13. This material
is available free of charge via the Internet at http://pubs.acs.org.
(11) Trost, B. M. Science 1991, 247, 1471.
OL052668U
(12) Compound 5 can be prepared in one step from commercially
available D-fructose by reaction with acetone in the presence of sulfuric
acid (45% yield). See: Lichtenthaler, F. W. Carbohydr. Res. 1998, 313,
69.
(13) For early, but remarkable, examples on the manipulation of
D-fructose at C-5, see: (a) Murphy, D. J. Chem. Soc. C 1967, 1732. (b)
Armenakian, A.; Mahmood, M.; Murphy, D. J. Chem. Soc., Perkin I 1972,
63. (c) Chmielewski, M.; Whistler J. Org. Chem. 1975, 40, 639.
(14) For a discussion on the influence of polar and steric factors on the
nucleophilic displacement of sulfonate esters, see: Richardson, A. C.
Carbohydr. Res. 1969, 10, 395.
(15) The fact that efficient methods to access L-fructose have been recent-
ly reported additionally broadens the scope of this approach to access un-
natural polyhydroxypyrrolidine derivatives. See: Franke, D.; Machajewski,
T.; Hsu, C.-C.; Wong, C.-H. J. Org. Chem. 2003, 68, 6828.
Org. Lett., Vol. 8, No. 2, 2006
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