A highly stereoselective synthesis of 2-deoxy-β-glycosides using 2- deoxy-2-iodo-glucopyranosyl acetate donors [7]

Full text of DOI:10.1021/ja984365j

J. Am. Chem. Soc. 1999, 121, 3541-3542
3541
that the sole product obtained in this reaction, 5, is in fact a latent
2-deoxy-â-glycoside, we sought to generalize and broaden the
scope of this reaction.
A Highly Stereoselective Synthesis of
2-Deoxy-â-glycosides Using
2-Deoxy-2-iodo-glucopyranosyl Acetate Donors
William R. Roush*,1 and Chad E. Bennett
Department of Chemistry, UniVersity of Michigan
Ann Arbor, Michigan 48109
Department of Chemistry, Indiana UniVersity
Bloomington, Indiana 47405
ReceiVed December 18, 1998
2-Deoxy glycosides are important structural components of
many natural products.2 Although 2-deoxy-R-glycosides are
generally easily prepared from glycals or activated 2-deoxysugar
precursors,3-5 the synthesis of 2-deoxy-b-glycosides has proven
to be a much more challenging undertaking.4,6-8 There are
relatively few methods for the synthesis of this important
glycosidic linkage directly from 2-deoxy glycosyl precursors, and
those procedures that have been reported lack generality and often
do not proceed with high selectivity.9-13 The most extensively
developed strategy for synthesis of 2-deoxy-â-glycosides utilizes
donors with equatorial C(2) heteroatom substituents (e.g., -Br,14
-SR,7,8,15-20 -SePh,21 -OAc,22 -NHCHO,22 and 1,2-epoxy23) that
are removed reductively after the glycosylation event. However,
most of these methods also lack broad generality, and highly
specialized syntheses of the donors are often required.7,8,14
We report herein a new, highly stereoselective synthesis of
2-deoxy-â-glucosides that utilizes 2-deoxy-2-iodo-glucopyran-
osyl acetates as the glycosyl donors, as illustrated by eq 1. This
Results of glycosidation reactions of donors 6-11 with
monosaccharide acceptors 4 and 12-15 are summarized in Table
1. These reactions were performed in CH2Cl2, usually in the
presence of activated 4 Å molecular sieves, using either TMS-
OTf or TBS-OTf as the promoter. Typically 2 equiv. of the less
reactive donors 8-11 are employed, while the more reactive
donors 6 and 7 may be used as the limiting reagent.25 Remarkably,
these glycosylations are highly stereoselective, and provide the
2-deoxy-2-iodo-â-disaccharides 16-29 in 62-92% yield. The
only cases in which R-glycosides were observed were experiments
using primary alcohol 12 as the acceptor, and the least selective
example (7 + 12) still proceeds with a 9:1 preference favoring
the â-disaccharide. Given the high selectivity of these glycosi-
dations and the ease with which the 2-iodo substituent is reduced
with Bu3SnH,24 we anticipate that 2-iodo-glycosyl donors will
find widespread application in the synthesis of 2-deoxy-â-
glycosides.
methodology evolved from earlier studies on the synthesis of the
R-L-olivomycoside linkage present in the aureolic acid antitumor
antibiotics. During these studies we examined a single example
of the glycosidation reaction of the â-L-2-iodo-olivomycosyl
acetate 3 using glucopyranose 4 as the acceptor.24 Recognizing
(1) Correspondence to this author should be sent to the University of
Michigan address.
(2) Kirschning, A.; Bechtold, A. F.-W.; Rohr, J. Top. Curr. Chem. 1997,
188, 1.
(3) Thiem, J.; Klaffke, W. Top. Curr. Chem. 1990, 154, 285.
(4) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503.
(5) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996,
35, 1380.
(6) Roush, W. R.; Lin, X.-F. J. Am. Chem. Soc. 1995, 117, 2236.
(7) Roush, W. R.; Sebesta, D. P.; Bennett, C. E. Tetrahedron 1997, 53,
8825.
(8) Roush, W. R.; Sebesta, D. P.; James, R. A. Tetrahedron 1997, 53, 8837.
(9) Wiesner, K.; Tsai, T. Y. R.; Jin, H. HelV. Chim. Acta 1985, 68, 300.
(10) Crich, D.; Ritchie, T. J. Carbohydr. Res. 1989, 190, C3.
(11) Kahne, D.; Yang, D.; Lim, J. J.; Miller, R.; Paguaga, E. J. Am. Chem.
Soc. 1988, 110, 8716.
(12) Binkley, R. W.; Sivik, M. R. J. Carbohydr. Chem. 1991, 10, 399 and
references therein.
(13) Hashimoto, S.-i.; Sano, A.; Sakamoto, H.; Nakajima, M.; Yanagiya,
Y.; Ikegami, S. Synlett 1995, 1271.
(14) Thiem, J.; Gerken, M. J. Org. Chem. 1985, 50, 954 and references
therein.
(15) Nicolaou, K. C.; Ladduwahetty, T.; Randall, J. L.; Chucholowski, A.
J. Am. Chem. Soc. 1986, 108, 2466.
(16) Ito, Y.; Ogawa, T. Tetrahedron Lett. 1987, 28, 2723.
(17) Preuss, R.; Schmidt, R. R. Synthesis 1988, 694.
(18) Grewal, G.; Kaila, N.; Franck, R. W. J. Org. Chem. 1992, 57, 2084.
(19) Hashimoto, S.; Yanagiya, Y.; Honda, T.; Ikegami, S. Chem. Lett. 1992,
1511.
(20) Franck, R. W.; Marzabadi, C. H. J. Org. Chem. 1998, 63, 2197 and
references therein.
(21) Perez, M.; Beau, J.-M. Tetrahedron Lett. 1989, 30, 75.
(22) Trumtel, M.; Tavecchia, P.; Veyrie´res, A.; Sinay¨, P. Carbohydr. Res.
1989, 191, 29.
10.1021/ja984365j CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/26/1999

3542 J. Am. Chem. Soc., Vol. 121, No. 14, 1999
Communications to the Editor
Table 1. Glycosidation Reactions of 2-Deoxy-2-iodo-glucopyranosyl Acetates
product
glycoside
isolated
â:R
â:R donor
glycosyl donor
acceptor
promoter (equiv)
reaction conditionsa
yieldb (%)
selectivityc
â
6 (0.8 equiv)
7 (0.8 equiv)
8 (2 equiv)
10 (2 equiv)
11 (2 equiv)
6 (0.7 equiv)
7 (0.5 equiv)
8 (2 equiv)
12
12
12
12
12
4
4
4
4
4
TMS-OTf (0.5 eq)
TMS-OTf (0.5 eq)
TMS-OTf (0.15 eq)
TBS-OTf (0.25 eq)
TMS-OTf (0.15 eq)
TMS-OTf (0.5 eq)
TMS-OTf (0.5 eq)
TMS-OTf (0.15 eq)
TMS-OTf (0.15 eq)
TMS-OTf (0.25 eq)
TMS-OTf (0.05 eq)
TMS-OTf (0.5 eq)
TMS-OTf (0.05 eq)
TMS-OTf (0.2 eq)
-78 °C, 40 min
-78 °C to -30 °C, 2 h
-35 °C, 25 mind
0 °C, 0.5 h
16
17
18
19
25e
20
21
22
23
24
26e
27
28
29
92
83
93
74
86
90
93
89
81
62
78
82
80
74
95:5
90:10
98:2
92:8
98:2
â only
â only
â only
â only
â only
â only
â only
â only
â only
â
87:13
60:40
96:4
â
-35 °C, 0.5 hd
-78 °C, 5 min
-78 °C to -45 °C, 2 h
-35 °C, 0.75 hd
-35 °C, 1 hd
â
87:13
88:12
60:40
96:4
â
9 (2 equiv)
10 (2 equiv)
11 (2 equiv)
6 (0.7 equiv)
6 (0.8 equiv)
6 (0.7 equiv)
0 °C, 0.25 h
4
-35 °C, 2.25 hd
-78 °C, 10 min
-78 °C, 10 min
-78 °C, 10 min
13
14
15
â
â
a All reactions were performed in CH2Cl2 in the presence of activated 4 Å molecular sieves, unless indicated otherwise. b Yield of product(s)
isolated chromatographically, calculated based on the limiting component of the reaction. c Product ratios determined by 500 MHz 1H NMR analysis
of the crude reaction products. The detection limit of these determinations is such that ca. 2-3% of the R-anomer could have escaped detection in
those experiments where only the â anomer was observed. d Molecular sieves were not used in this experiment. e These experiments were quenched
with Et3N (10 equiv), and then Et3N‚3HF (10 equiv, 3 h, 0 °C) was added to deprotect the TES ether, which was partially cleaved under the original
reaction conditions.
The 2-deoxy-2-iodo-glucosyl acetate donors can be prepared
by two different routes. One approach, illustrated here by the
synthesis of 6, involves the reaction of a glucal (30) with NIS
and HOAc in toluene at reflux. Although this method provided a
ca. 1:1 mixture of the â-gluco (6) and R-manno (31) isomers,26
the R-manno isomer can be reduced back to the starting glycal
30 by treatment with LiI in THF. The second route is stereo-
specific at C(2), and originates from the readily available iodo
ether 32.27,28 The two hydroxyl groups of 32 are easily differenti-
ated, with monosilylation or benzylation occurring selectively at
C(4). Application of this method to the synthesis of 8 and 11 is
summarized in the Supporting Information.
The factors that cause the 2-iodo substituent to be such a powerful
stereodirecting group, far superior to the extensively studied C(2)-
SAr and -SePh substituents,8,15-19,21 remain to be clarified.
However, an observation that may have mechanistic significance
is that donors 6 and 8 containing C(3) and C(4) silyl ether
protecting groups are considerably more reactive than 9 and 10
(comparable entries for 6 vs 9 and 8 vs 10). Donors 6 and 8 (as
well as 7 and 11) exist in twist-boat conformations, as determined
by 1H NMR analysis which reveals J1,2 ) 7.4 Hz, J3,4 ) 3.7 Hz,
and J2,3 ) J4,5 < 1 Hz. This conformation is adopted in order to
minimize the gauche interactions between the bulky silyl sub-
stituents.29,30 On the other hand, donors 9 and 10 adopt the usual
4C1 chair conformation. Although the ground-state conformational
preferences of the donors strikingly influences their reactivity,
the reaction stereoselectivity is independent of this feature.
Applications of the 2-deoxy-2-iodo-glucopyranosyl glycosida-
tion methodology reported herein to the synthesis of biologically
important 2-deoxyoligosaccharides is in progress and will be
reported in due course.
Acknowledgment. This research was supported by a grant from the
NIH (GM 38907).
Supporting Information Available: Experimental procedures and
tabulated spectroscopic data for new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
The remarkable stereoselectivity of these glycosylation reac-
tions is virtually unparalleled in the 2-deoxy-â-glycoside arena.
JA984365J
(23) Gervay, J.; Danishefsky, S. J. Org. Chem. 1991, 56, 5448.
(24) Roush, W. R.; Briner, K.; Sebesta, D. P. SynLett 1993, 264.
(25) The â-glycosyl acetates equilibrate with the R-acetate anomers, which
are less reactive glycosylating agents. Although the R-acetates can be used as
substrates for these reactions, glycosylation reactions of these compounds
generally require temperatures 20-30 °C warmer than for the â-glycosyl
acetate anomers. Consequently, we have found it advantageous to use 2 equiv
of donors 8-11 in these glycosylation reactions.
(26) These reactions are selective for the R-manno isomers when performed
at lower temperatures.
(27) Leteux, C.; Veyrieres, A.; Robert, F. Carbohydr. Res. 1993, 242, 119.
(28) Tailler, D.; Jacquinet, J.-C.; Noirot, A.-M.; Beau, J.-M. J. Chem. Soc.,
Perkin Trans. 1 1992, 3163.
(29) Tius, M. A.; Busch-Peterson, J. Tetrahedron Lett. 1994, 35, 5181.
(30) Hosoya, T.; Ohashi, Y.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett.
1996, 37, 663.