Conversion of D-Glucals into L-Glycals and Mirror-Image Carbohydrates

Article abstract of DOI:10.1021/ol036183m

(Equation presented) L-Glycals can be prepared in seven steps from readily available D-glucals, enabling the facile construction of mirror-image carbohydrates such as the L-lactosamine derivative shown above.

Full text of DOI:10.1021/ol036183m

ORGANIC
LETTERS
2004
Vol. 6, No. 1
119-121
Conversion of D-Glucals into L-Glycals
and Mirror-Image Carbohydrates
Fabien P. Boulineau and Alexander Wei*
Department of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
alexwei@purdue.edu
Received November 6, 2003
ABSTRACT
L-Glycals can be prepared in seven steps from readily available D-glucals, enabling the facile construction of mirror-image carbohydrates such
as the L-lactosamine derivative shown above.
Chiral intermediates derived from readily available D-glycals
are frequently employed as starting materials in the synthesis
of complex carbohydrates and other natural products.1 In
principle, compounds derived from these unsaturated D-
sugars represent only 50% of the available chiral space; the
remaining “left-handed” half can be routed by default through
the antipodal L-glycals. In addition to providing direct access
to a broad range of L-sugars and related glycoconjugates with
medicinal value (e.g., bleomycin2 and the aminoglycoside
antibiotics3), L-glycals can serve as the basis set for mirror-
image carbohydrates. Several intriguing hypotheses can be
developed around antipodal carbohydrate ligands in the
context of chiral biological systems: while their physico-
chemical properties would be essentially identical to those
of naturally occurring sugars, their interactions with proteins
and other biomacromolecules would not. In particular, the
unnatural enantiomers of carbohydrates and other bioorganic
structures may have the capacity to evade antibody detection
and enzymatic degradation.4 Wong and co-workers have
recently described a novel strategy involving synthetic
L-sugars based on this premise.5
While numerous synthetic routes toward L-sugars have
been developed, very few have been targeted at the synthesis
of L-glycals despite their broader synthetic utility. Some de
novo approaches have been reported: 6-deoxy- and C5
phenyl-substituted L-glycals have been prepared by Dan-
ishefsky and co-workers via cyclocondensation of activated
aldehydes and electron-rich dienes followed by enzymatic
resolution.6 6-Deoxy-L-glycals have also been synthesized
by McDonald and co-workers via endo-selective cyclization
of chiral alkynols.7 However, methods for preparing L-glycals
bearing C5 hydroxymethyl groups (e.g., L-glucal and L-
galactal) have so far depended on the degradation of rare or
unnatural L-sugars, with obvious economical drawbacks.8
Here we report an efficient synthesis of L-glycals from
readily available D-glucal 1 via pseudodesymmetrization of
(4) Schumacher, T. N. M.; Mayr, L. M.; Minor, D. L., Jr.; Milhollen,
M. A.; Burgess, M. W.; Kim, P. S. Science 1996, 271, 1854-1857.
(5) Kozlov, I. A.; Mao, S.; Xu, Y.; Huang, X.; Lee, L.; Sears, P. S.;
Gao, C.; Coyle, A. R.; Janda, K. D.; Wong, C.-H. ChemBioChem 2001, 2,
741-746.
(6) Berkowitz, D. B.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem.
Soc. 1992, 114, 4518-4529.
(7) (a) McDonald, F. E.; Reddy, K. S.; D´ıaz, Y. J. Am. Chem. Soc. 2000,
122, 4304-4309. (b) McDonald, F. E.; Wu, M. Org. Lett. 2002, 4, 3979-
3981.
(1) (a) Tolstikov, A. G.; Tolstikov, G. A. Russ. Chem. ReV. 1993, 62,
579-601. (b) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1380-1419.
(2) (a) Katano, K.; An, H.; Aoyagi, Y.; Overhand, M.; Sucheck, S. J.;
Stevens, W. C., Jr.; Hess, C. D.; Zhou, X.; Hecht, S. M. J. Am. Chem. Soc.
1998, 120, 11285-11296. (b) Boger, D. L.; Cai, H. Angew. Chem., Int.
Ed. 1999, 38, 448-476.
(8) Flekhter, O. B.; Baltina, L. A.; Tolstikov, G. A. J. Nat. Prod. 2000,
63, 992-994.
(3) Umezawa, S. AdV. Carbohydr. Chem. Biochem. 1974, 30, 111-182.
10.1021/ol036183m CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/09/2003

oxidation to carboxylic acid 4 and decarboxylative elimina-
tion to 3*,6*-O-dibenzyl-L-glucal 5 using N,N-dimethylfor-
mamide dineopentyl acetal (DMFDNA).18 The latter proce-
dure has been used previously to introduce ∆4,5-unsaturation
into the pyranose ring of O-glycosides.19,20 Overall, the
conversion of D-glucal 1 to L-glucal 5 was accomplished in
seven steps and 36% yield.
Scheme 1. Synthesis of L-Glucal 5a
With respect to the mechanism of decarboxylative elimi-
nation, we note that the temperature required for the
decomposition of â-C-glucuronide intermediate 4 (150 °C)
is considerably higher than that for R-O-glucuronides, whose
elimination is complete after 1 h at 120 °C.21 This suggests
that the glucuronides must first adopt geometries with trans
1
diaxial C4 and C5 substituents such as C4 or twist-boat
conformations (see Figure 1), as opposed to the formation
a Reagents and conditions: (a) DMDO, CH2Cl2/acetone, 0 °C.
(b) (iPrO)Me2SiCH2MgCl (3.5 equiv), CuI (0.5 equiv), THF, -10
°C. (c) 30% H2O2, KOH, MeOH/THF, rt (66% over three steps).
(d) (n-Bu)2SnO, BnBr, TBAI, toluene, reflux. (e) AcOH/THF/H2O,
45 °C (90% over two steps). (f) TEMPO (5 mol %), bleach,
saturated aq NaHCO3, CH2Cl2, 0 °C. (g) N,N-Dimethylformamide
dineopentyl acetal, xylenes, 150 °C (61% over two steps). PMP )
p-methoxyphenyl.
an intermediate C-glycoside (see Scheme 1).9 This method
takes advantage of latent symmetry elements that are present
in D-glucose to produce L-glucal and L-galactal.10 In addition,
our approach is complementary to methods that epimerize
D-hexoses at the C5 stereocenter to produce other isomeric
L-sugars such as L-idose and L-altrose (starting from D-
glucose and D-galactose, respectively).11-13
D-Glucal derivative 1 (prepared from â-D-glucose pen-
taacetate in five steps and 47% overall yield)14 was trans-
formed into â-C-glycoside 2 on a multigram scale in 66%
yield by dimethyldioxirane (DMDO) oxidation15 and CuI-
mediated addition of (iPrO)Me2SiCH2MgCl, followed by
Tamao-Kumada oxidation (see Scheme 1).16,17 The unsym-
metrically protected C-glycoside 2 was converted in two
steps to partially benzylated triol 3, followed by TEMPO
Figure 1. Possible trans diaxial conformations adopted during the
decarboxylative elimination of 4.
of a cyclic orthoamide intermediate.22 In the case of 4, the
benzyloxymethyl group at C1 raises the barrier to intercon-
version and may destabilize transition-state geometries by
introducing sterically unfavorable interactions.
L-Glucal 5 can be readily transformed into the antipodal
isomers of several common pyranoside derivatives, and is
an ideal precursor for constructing mirror-image carbohy-
drates. As a demonstration, we have synthesized the methyl
glycoside of N-acetyl-L-lactosamine (L-Gal-(â1f4)-L-GlcNAc-
â-OMe), whose antipode is the core disaccharide found in
human blood group antigens and serves as a substrate for a
number of glycosyltransferases (see Scheme 2).23,24
3*,6*-O-dibenzyl-L-glucal 5 was oxidized using the Dess-
Martin periodinane and treated immediately with NaBH4,
affording the corresponding dibenzyl-L-galactal as the major
isomer (84% yield, L-Gal/L-Glc > 30:1). Tribenzyl-L-galactal
6 was isolated in diastereomerically pure form after benzy-
(9) Pseudosymmetry of hydroxymethyl C-glycosides has been appreciated
by others: Hoffmann, H. M. R.; Dunkel, R.; Mentzel, M.; Reuter, H.; Stark,
C. B. W. Chem. Eur. J. 2001, 7, 4772-4789.
(10) L-Glucose has been previously synthesized by oxidative decarboxy-
lation of â-C-glucuronides, in low to fair yields: (a) Shiozaki, M. J. Org.
Chem. 1991, 56, 528-532. (b) Smid, P.; Noort, D.; Broxterman, H. J. G.;
van Straten, N. C. R.; van der Marel, G. A.; van Boom, J. H. Recl. TraV.
Chim. Pays-Bas 1992, 111, 524-528.
(11) Takahashi, H.; Hitomi, Y.; Iwai, Y.; Ikegami, S. J. Am. Chem. Soc.
2000, 122, 2995-3000.
(12) Blanc-Muesser, M.; Defaye, J. Synthesis 1977, 568-569.
(13) Rochepeau-Jobron, L.; Jacquinet, J.-C. Carbohydr. Res. 1997, 303,
395-406.
(14) D-Glucal 1 was prepared according to literature protocols: Fernan-
dez-Mayoralas, A.; Marra, A.; Trumtel, M.; Veyrie`res, A.; Sinay¨, P.
Carbohydr. Res. 1989, 188, 81-95.
(15) (a) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989,
111, 6661-6666. (b) Lee, G. S.; Min, H. K.; Chung, B. Y. Tetrahedron
Lett. 1999, 40, 543-544.
(18) To maintain a consistent nomenclature, the carbons of L-glycals and
derivatives thereof have been numbered 1* through 6*.
(19) Philips, K. D.; Zˇemlicˇka, J.; Horwitz, J. P. Carbohydr. Res. 1973,
30, 281-286.
(20) Boulineau, F. P.; Wei, A. Org. Lett. 2002, 4, 2281-2283.
(21) We have observed that decarboxylative elimination of â-O-
glucuronides also requires 1 h at 150 °C.
(22) (a) Hara, S.; Taguchi, H.; Yamamoto, H.; Nozaki, H. Tetrahedron
Lett. 1975, 19, 1545-1548. (b) Mulzer, J.; Bru¨ntrup, G. Chem. Ber. 1982,
115, 2057-2075.
(16) Tamao, K.; Ishida, N.; Kumada, M. J. Org. Chem. 1983, 48, 2120-
2122.
(17) The stereoselectivity of this transformation is noteworthy, as
reactions between Grignard reagents and 1,2-epoxyglycals do not always
proceed in high yield or with complete SN2 selectivity: (a) Smoliakova, I.
P. Curr. Org. Chem. 2000, 4, 589-608. (b) Allwein, S. P.; Cox, J. M.;
Howard, B. E.; Johnson, W. B.; Rainier, J. D. Tetrahedron 2002, 58, 1997-
2009.
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Org. Lett., Vol. 6, No. 1, 2004

from 6. Galactosyl donor 7 was coupled with L-glucal 5 (1.5
equiv) using the thioglycoside activation conditions described
by Seeberger et al. to furnish protected L-lactal 8 in 73%
yield.25 After surveying several different conditions for
installing the acetamido group at C2*, we used a slightly
modified version of the sulfonamidoglycosylation procedure
developed by Danishefsky and co-workers.26 L-Lactal 8 was
transformed into its 2*-â-iodo-1*-R-phenylsulfonamido de-
rivative and then treated with NaOMe in MeOH to give
methyl N-phenylsulfonyl-â-L-lactosaminoside, followed by
acetylation to afford 9 in 80% yield after three steps.
Desulfonylation with sodium naphthalenide at -78 °C
cleanly produced N-acetyl derivative 10, which was globally
deprotected to methyl N-acetyl-â-L-lactosaminoside 11 in
79% overall yield from 9.27
Scheme 2. Synthesis of N-Acetyl-L-lactosaminoside 11a
In summary, we have developed an expedient route to
L-glycals and mirror-image oligosaccharides from D-glucals.
We anticipate that in addition to preparing L-sugars such as
those described here, the decarboxylative elimination of
pyranosides may have broad utility in the stereocontrolled
synthesis of highly substituted dihydro- and tetrahydropyrans.
a Reagents and conditions: (a) Dess-Martin periodinane, NaH-
CO3, 4A molecular sieves, CH2Cl2, rt. (b) NaBH4, MeOH/CH2Cl2,
-5 °C. (c) NaH, BnBr, DMF, rt (81% over three steps). (d) DMDO,
CH2Cl2/acetone, -55 °C. (e) EtSLi, THF, 0 °C. (f) Ac2O, pyridine,
rt (63% over three steps). (g) 7 (1.0 equiv), 5 (1.5 equiv), MeOTf,
2,6-di-tert-butyl-4-methylpyridine, 4A molecular sieves, CH2Cl2
(73%). (h) I(collidine)2ClO4, PhSO2NH2, 4A molecular sieves, 0
°C. (i) NaOMe, MeOH, rt. (j) Ac2O, Et3N, DMAP, CH2Cl2, rt (80%
over three steps). (k) Na naphthalenide, THF, -78 °C. (l) NaOMe,
MeOH, 45 °C (80% over two steps). (m) H2, Pd(OH)2/C, MeOH,
rt (99%).
Acknowledgment. This work was supported by donors
of the American Cancer Society (CDD-106244) and the
American Heart Association (30399Z).
Supporting Information Available: Experimental details
and analytical data for the preparation of L-glucal 5 from
D-glucal 1. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL036183M
(24) Mong, T., K.-K.; Huang, C.-Y.; Wong, C.-W. J. Org. Chem. 2003,
68, 2135-2142.
(25) Seeberger, P. H.; Eckhardt, M.; Gutteridge, C. E.; Danishefsky, S.
J. J. Am. Chem. Soc. 1997, 119, 10064-10072.
lation and treated with anhydrous DMDO to yield the desired
R-epoxide, which was then reacted with EtSLi and acetylated
to produce thioethyl â-L-galactoside donor 7 in 63% yield
(26) (a) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112,
5811-5819. (b) Danishefsky, S. J.; Hu, S.; Cirillo, P. F.; Eckhardt, M.;
Seeberger, P. H. Chem. Eur. J. 1997, 3, 1617-1628.
(27) Methyl N-acetyl-â-L-lactosamine 11 was found to be spectroscopi-
(23) Wang, Z.-G.; Zhang, X.; Visser, M.; Live, D.; Zatorski, A.; Iserloh,
U.; Lloyd, K. O.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 1728-
1732.
cally identical to its enantiomer but opposite in optical activity. 11: [R]20
D
+24.0° (c 0.5, MeOH). ent-11 (synthesized from the corresponding
D-glycals): [R]20 -23.4° (c 0.5, MeOH).
D
Org. Lett., Vol. 6, No. 1, 2004
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