syn additions to 4α-epoxypyranosides: Synthesis of L-idopyranosides

Article abstract of DOI:10.1021/ol702185y

(Chemical Equation Presented) The syn-selective addition of organozinc compounds to 4α-epoxypyranosides (4α-EPs), generated from methyl β-D-glucoside or aminoglucoside, provides an efficient route to pyranosides with α-L-ido configurations, including L-id

Full text of DOI:10.1021/ol702185y

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4849-4852
syn Additions to 4
r-Epoxypyranosides:
Synthesis of
L
-Idopyranosides
Gang Cheng, Renhua Fan, Jesu´s M. Herna´ndez-Torres, Fabien P. Boulineau, and
Alexander Wei*
Department of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
alexwei@purdue.edu
Received September 5, 2007
ABSTRACT
The syn-selective addition of organozinc compounds to 4r-epoxypyranosides (4r-EPs), generated from methyl
â-D-glucoside or aminoglucoside,
provides an efficient route to pyranosides with
derivatives.
r
-L
-ido configurations, including L-iduronic acid, neosamine B, and higher monosaccharide
Unsaturated pyranosides such as glycals are used extensively
in carbohydrate and natural products synthesis.1 One wide-
spread application involves the formation of epoxyglycals
by stereoselective addition of dimethyldioxirane (DMDO),
which can be employed as glycosyl donor in the synthesis
of O- and C-glycosides.2 4-Deoxypentenosides (4-DPs) bear
a strong structural homology to glycals but retain a stereo-
genic anomeric center. The reactivity profile of 4-DPs is
similar to that of glycals but is somewhat more selective
with respect to stereocontrol. 4-DPs can be epoxidized by
DMDO in a highly facioselective manner,3,4 and 4â-
epoxypyranosides (4â-EPs) can undergo anti-selective (SN2)
ring opening to generate novel pyranosides with an L-altro
configuration.3 4R-Epoxypyranosides (4R-EPs), which can
also be obtained with high stereoselectivity,4 should be
equally valuable as precursors to L-pyranosides. Here we
demonstrate the utility of organozinc reagents for syn-
selective ring opening of 4R-EPs into pyranosides with an
L-ido configuration.
The efficient formation of R-C-glycosides via syn-selective
ring openings of R-epoxyglycals has been achieved with mild
organometallic reagents having a significant Lewis acid
character, namely, those derived from aluminum,5,6 boron,5
titanium,7 zirconium,8 or zinc.9 Syn delivery of the nucleo-
phile is assumed to proceed by coordination and simultaneous
activation of the epoxide by the metal center. Although many
of these reagents are likely to be useful for syn-selective
addition to 4-EPs,10 organozinc halides (RZnX) are most
appealing with respect to atom efficiency and functional
group compatibility and can be generated by several different
methods.9,11
4R-EPs 6 and 7 were derived in good yields from
â-methyl-D-glucoside 1 and â-methyl-D-glucosaminoside 2,
(5) (a) Rainier, J. D.; Cox, J. M. Org. Lett. 2000, 2, 2707-2709. (b)
Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson, W. B.; Rainier, J. D.
Tetrahedron 2002, 58, 1997-2009.
(6) Bailey, J. M.; Craig, D.; Gallagher, P. T. Synlett 1999, 132-134.
(7) Parrish, J. D.; Little, R. D. Org. Lett. 2002, 4, 1439-1442.
(8) Wipf, P.; Pierce, J. G.; Zhuang, N. Org. Lett. 2005, 7, 483-485.
(9) (a) Leeuwenburgh, M. A.; Timmers, C. M.; van der Marel, G. A.;
van Boom, J. H.; Mallet, J.-M.; Sinay¨, P. G. Tetrahedron Lett. 1997, 38,
6251-6254. (b) Steinhuebel, D. P.; Fleming, J. J.; Du Bois, J. Org. Lett.
2002, 4, 293-295. (c) Xue, S.; Han, K.-Z.; He, L.; Guo, Q.-X. Synlett
2003, 870-872.
(1) Ferrier, R. J.; Hoberg, J. O. In AdVances in Carbohydrate Chemistry
and Biochemistry; Horton, D., Ed.; Academic Press: New York, 2003; Vol.
58, pp 55-119.
(2) (a) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6661-6666. (b) Cheshev, P.; Marra, A.; Dondoni, A. Carbohydr. Res. 2006,
341, 2714-2716.
(10) Boulineau, F. P.; Wei, A. J. Org. Chem. 2004, 69, 3391-3399.
(11) (a) Knochel, P.; Almena, J. J.; Jones, P. Tetrahedron 1998, 54,
8275-8319. (b) Ikegami, R.; Koresawa, A.; Shibata, T.; Takagi, K. J. Org.
Chem. 2003, 68, 2195-2199. (c) Huo, S. Org. Lett. 2003, 5, 423-425. (d)
Kneisel, F. F.; Dochnahl, M.; Knochel, P. Angew. Chem., Int. Ed. 2004,
43, 1017-1021. (e) Huang, Z.; Negishi, E. Org. Lett. 2006, 8, 3675-3678.
(3) Boulineau, F. P.; Wei, A. Org. Lett. 2002, 4, 2281-2283.
(4) Cheng, G.; Boulineau, F. P.; Liew, S.-T.; Shi, Q.; Wenthold, P. G.;
Wei, A. Org. Lett. 2006, 9, 4545-4548.
10.1021/ol702185y CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/12/2007

respectively, using an oxidation-decarboxylative elimination
sequence.3,10 Phthalimide 4 was transformed into azido
derivative 5 by diazo transfer onto the intermediate free
amine.12 DMDO oxidations of 4-DPs 3-5 were carried out
at -55 °C to produce 4R-EPs 6-8 with 10:1 R:â stereo-
selectivity and in quantitative yield (Scheme 1).4 The 4R-
EPs could be stored at -20 °C for several months without
concern for decomposition.
that ZnBr2 promotes syn addition by forming an active
complex with RZnBr (see below), rather than by direct
activation of the epoxide. The activation of organometallic
reagents by Lewis acids has been well documented over the
years.13
(δ-)R-(δ+)Zn-Br‚‚‚ZnBr2
The addition of RZnX species to 4R-EPs 6, 7, and 8
proceeded with high selectivity (syn:anti > 20:1) for a variety
of sp2- and sp-carbon nucleophiles, producing the corre-
sponding L-idopyranoside derivatives in good to high yields
(Table 2). For example, 4R-EP 6 was converted into
L-idopyranoside 9a in 84% isolated yield, accompanied by
a small amount of anti adduct and a product derived from
the minor 4â-EP isomer (<5% combined yield).14 4R-EP 6
also reacted efficiently with activated sp3-carbon nucleophiles
such as allylzinc bromide (entry 7) but was less receptive to
additions with (Z)-alkenylzinc agents (entries 10 and 13).
These derivatives could be obtained with higher overall yields
by partial hydrogenation of the corresponding alkynyl
derivatives.
Scheme 1. Synthesis of 4R-Epoxypyranosidesa
a Selected abbreviations: DMDO
)
dimethyldioxirane;
DMFDNpA ) dimethylformamide dineopentyl acetal; en )
ethylenediamine; Phth ) phthalimide; TEMPO ) tetramethyl-
piperidine oxide; TfN3 ) triflyl azide.
Several of the syn adducts in Table 2 were examined as
intermediates for preparing L-idopyranosides with natural or
unnatural configurations. In particular, we were interested
to develop novel routes to L-iduronic acid, a vital component
of heparin and heparan sulfate;15 neosamine B, a 2,6-
diaminopyranoside with L-ido configuration found in several
aminoglycoside antibiotics;16 and higher monosaccharides
with structural analogy to sialic acid and other biologically
active congeners.17,18 Syntheses of these sugars typically
involve manipulation of acyclic intermediates, either for
epimerization of the C5 stereocenter in the cases of L-iduronic
acid and neosamine B19,20 or for chain extension at the
reducing end in the case of higher monosaccharides.17,21 In
The most reliable syn additions were produced by generat-
ing RZnX species via the transmetallation of organolithium
or Grignard reagents (see Supporting Information). System-
atic examination of reaction conditions revealed that the
presence of excess ZnBr2 significantly improved the ef-
ficiency of addition (Table 1); adducts were produced in high
yields using 2 equiv of RZnBr, whereas stronger Lewis acids
such as Zn(OTf)2 or BF3-Et2O were often incompatible with
the epoxide. Furthermore, allyltrimethylsilane and other
electron-rich olefins tended to react poorly with 4R-EPs in
the presence of Lewis acids, in contrast to their efficacy as
nucleophiles in C-glycoside synthesis. These studies suggest
(12) Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996,
37, 6029-6033.
Table 1. Selected Conditions for syn Addition of 2-Furylzinc
Halides to 4R-Epoxypyranoside 7 in the Presence of ZnX2
(13) (a) Negishi, E.-i. Pur. Appl. Chem. 1981, 53, 2333-2356. (b) Olah,
G. A. Angew. Chem., Int. Ed. 1993, 32, 767-922. (c) Negishi, E.-i. Bull.
Chem. Soc. Jpn. 2007, 80, 233-257.
a
(14) Addition to the 4â-EP isomer is presumed also to proceed with high
syn selectivity.
(15) (a) Conrad, H. E. Heparin-Binding Proteins; Academic Press: San
Diego, 1998. (b) Linhardt, R. J. J. Med. Chem. 2003, 46, 2551-2564.
(16) Umezawa, S. AdV. Carbohydr. Chem. Biochem. 1974, 30, 111-
182.
(17) Danishefsky, S. J.; DeNinno, M. P. Angew. Chem., Int. Ed. Engl.
1987, 26, 15-23.
(18) (a) Unger, F. M. In AdVances in Carbohydrate Chemistry and
Biochemistry; Horton, D., Ed.; Academic Press: New York, 1982; Vol.
38, pp 323-388. (b) Stenutz, R.; Weintraub, A.; Widmalm, G. FEMS
Microbiol. ReV. 2006, 30, 382-403.
(19) (a) Blanc-Muesser, M.; Defaye, J. Synthesis 1977, 568-569. (b)
Jacquinet, J.-C.; Petitou, M.; Duchaussoy, P.; Lederman, I.; Choay, J.; Torri,
G.; Sinay¨, P. Carbohydr. Res. 1984, 130, 221-241. (c) Ojeda, R.; de Paz,
J. L.; Mart´ın-Lomas, M.; Lassaletta, J. M. Synlett 1999, 8, 1316-1318. (d)
Takahashi, H.; Hitomi, Y.; Iwai, Y.; Ikegami, S. J. Am. Chem. Soc. 2000,
122, 2995-3000.
(20) Usui, T.; Takagi, Y.; Tsuchiya, T.; Umezawa, S. Carbohydr. Res.
1984, 130, 165-177.
(21) (a) Gyo¨rgydea´k, Z.; Pelyva´s, I. Monosaccharide Sugars: Chemical
Synthesis by Chain Elongation, Degradation, and Epimerization; Academic
Press: San Diego, 1998. (b) Kru¨lle, T.; Holst, O.; Brade, H.; Schmidt, R.
R. Carbohydr. Res. 1993, 247, 145-158.
entry
furylZnX (equiv)
ZnX2 (equiv)
yield (%)b
1
2
3
4
5
6
7
2
2
4
10
2
2
ZnCl2 (2)
ZnCl2 (5)
ZnCl2 (2)
ZnCl2 (2)
ZnBr2 (0)
ZnBr2 (2)
ZnBr2 (5)
41
60
64
76
56
67
83
2
a Preparation of 2-furylzinc halide in THF: (i) furan, n-BuLi, THF, -78
°C, 30 min; (ii) ZnX2, THF, 0 °C, 30 min. Epoxide 7 was added as a CH2Cl2
solution at -78 °C, warmed to 0 °C, and then stirred for 2 h while warming
to rt. b Isolated yields.
4850
Org. Lett., Vol. 9, No. 23, 2007

comparison, 4-EPs enable the stereoselective installation of
carbon fragments at C5 with retention of the pyranose ring
and anomeric configuration.
Table 2. syn Additions to 4R-Epoxypyranosides 6-8a
Scheme 2. Synthesis of L-Iduronic Acid and Neosamine B
Methyl Glycosides
L-Iduronic acid methyl glycoside 12 was prepared in 73%
yield from 2-furyl adduct 9a by ozonolysis with Me2S
workup (Scheme 2). Neosamine B methyl glycoside 14 was
derived in 3 steps from 11e (the C5 vinyl adduct of 4R-EP
derivative 8) by ozonolysis, reductive amination, and hy-
drogenation, and fully characterized as peracetate 15.
Scheme 3. Addition of Mono- and Dialkylzinc Species to
4R-Epoxypyranoside 6
a Epoxide 6 added as a CH2Cl2 solution at -78 °C to
PhCH2CH2ZnBr (4 equiv) and ZnBr2 (3 equiv) in THF, slowly
warmed to -30 °C, and then stirred for 12 h at -30 °C. bEpoxide
6 added at -78 °C to (PhCH2CH2)2Zn (4 equiv) in THF, slowly
warmed to -30 °C, and then stirred for 4 h at 0 °C.
Reactions involving unactivated alkylzinc halides and
dialkylzincs did not proceed as smoothly under comparable
reaction conditions. For example, phenethylzinc bromide and
diphenethylzinc gave low to fair yields of expected L-
idopyranoside 16 accompanied by significant amounts of C5
phenethoxy adducts 17 (Scheme 3), an indication of the
oxidative sensitivity of alkylzinc species.22 Rigorous removal
of oxygen from the reaction mixture did not improve the
ratio of C- to O-addition products, implying that alkylzincs
a See Supporting Information for reaction conditions. b A: (i) RH (4
equiv), n-BuLi (2 equiv), THF, -78 °C; (ii) ZnBr2 (7 equiv), THF, 0 °C.
B: RMgBr (2 eq), ZnBr2 (7 equiv), 0 °C. C: (i) RBr or RI (2 equiv),
t-BuLi (4 equiv), Et2O, -78 °C; (ii) ZnBr2 (7 equiv). D: RI (2 equiv), Zn
(activated powder), THF, 45 °C. c Isolated yields. d 9f formed as a byproduct
(40% yield). e Yield in 2 steps via 9f. f Yield in 4 steps via 9i.
(22) Katritzky, A. R.; Luo, Z. Heterocycles 2001, 55, 1467-1474.
Org. Lett., Vol. 9, No. 23, 2007
4851

could be oxidized by the 4-EPs or an unidentified byproduct
of the DMDO reaction (Scheme 1).23
L-Idopyranosides with C5 alkyl substituents can be pre-
pared with considerable structural diversity and in syntheti-
cally useful yields via the syn addition of alkenyl groups.
We illustrate this with the stereoselective syntheses of several
octopyranoside derivatives, all with L-ido configuration but
stereochemically divergent at C6 and C7. Compounds 20
and 21 were prepared respectively from trans-allylic ether
9h and cis-allylic ether 18 (via reduction of propargylic ether
9i) by catalytic osmylation, with diastereomeric ratios of 5:1
and 6:1 favoring the desired product (Scheme 4). The
configurations of octopyranosides 20 and 21 were tentatively
assigned as D-threo-L-ido and L-erythro-L-ido with the
stereochemical relationship of C5 and C6 being erythro in
each case, according to the empirical rule developed by Kishi
and co-workers.24 The stereochemical assignments were
Scheme 4. Stereoselective Synthesis of Octopyranosides with
L-ido Configurationa
Figure 1. Stereochemical assignments of bicyclic lactones 20-
23. Conformations are drawn to emphasize NOE interactions.
confirmed by nuclear Overhauser enhancement (NOE)
measurements (Figure 1). The osmylation of R,â-unsaturated
lactone 9m, which was expected to proceed with selectivity
opposite to that of 18, yielded a single diastereomer that was
assigned as D-erythro-L-ido by NOE analysis of diacetate
22. Compound 9m could also be oxidized stereoselectively
into epoxide 19 by hypochlorite oxidation25 and converted
cleanly by phenylselenol reduction26 into 7-deoxyocto-
pyranoside 23, whose C6 configuration was assigned to be
L-glycero by NOE measurements.
In conclusion, ZnBr2-mediated syn additions to 4R-
epoxypyranosides provide a general and efficient route to
natural and unnatural L-idopyranosides.
Acknowledgment. This work was supported by the
National Institutes of Health (GM-06982). The authors also
gratefully acknowledge support from the Purdue Cancer
Center and the Purdue interdepartmental NMR facility, and
Mr. Zhihong Huang (Purdue Univ.) for helpful discussions
on organozinc chemistry.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization of compounds
9a-23. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL702185Y
(23) In some instances the deoxygenated reactant (4-DP 3) could be
recovered in low yield.
(24) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247-
a Selected abbreviations: BAIB ) bisacetoxyiodobenzene; CSA
) camphorsulfonic acid; MP ) methoxypropene; NMO ) mor-
pholine N-oxide; TBS ) tert-butyldimethylsilyl; TEMPO ) tetra-
methylpiperidinoxy radical.
55.
(25) Zhu, L.; Kedenburg, P. J.; Xian, M.; Wang, G. P. Tetrahedron Lett.
2005, 46, 811-813.
(26) Ding, F.; Jennings, P. M. Org. Lett. 2005, 7, 2321-2324.
4852
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