Stereoselective synthesis of 2-deoxy-β-glycosides using Anomeric O-alkylation/arylation

Article abstract of DOI:10.1021/ol8022006

Anomeric O-alkylation/arylation is applied to the synthesis of 2-deoxy-β-glycosides. Treatment of lactols with NaH in dioxane followed by the addition of electrophiles leads to the formation of 2-deoxy-β- glycosides in high yield and high selectivity. The

Full text of DOI:10.1021/ol8022006

ORGANIC
LETTERS
2009
Vol. 11, No. 1
9-12
Stereoselective Synthesis of
2-Deoxy-ꢀ-glycosides Using Anomeric
O-Alkylation/Arylation
William J. Morris and Matthew D. Shair*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
shair@chemistry.harVard.edu
Received September 19, 2008
ABSTRACT
Anomeric O-alkylation/arylation is applied to the synthesis of 2-deoxy-ꢀ-glycosides. Treatment of lactols with NaH in dioxane followed by the
addition of electrophiles leads to the formation of 2-deoxy-ꢀ-glycosides in high yield and high selectivity. The high ꢀ-selectivity observed here
demonstrates a powerful stereoelectronic effect for the stereoselective formation of acetals under kinetic control.
2-Deoxy-ꢀ-glycosides are present in biologically active
natural products such as the lomaiviticins, olivomycin A,
OSW-1, and durhamycin. The stereoselective preparation of
2-deoxy-ꢀ-glycosides is difficult1 because substituents at C2
often serve as directing groups during the glycosylation
event. The synthesis challenge posed by 2-deoxy-ꢀ-glyco-
sides coupled with their presence in nature has inspired a
variety of approaches aimed at accessing these important
glycosides. The most common methods involve the use of a
heteroatom substituent at C2 of the glycosyl donor followed
by its reductive removal after glycosylation.2 Other methods
include the use of R-glycosyl phosphites,3 displacement of
R-glycosyl halides,4 palladium-catalyzed glycosylation reac-
tions,5 utilization of alkoxy-substituted anomeric radicals,6
and the use of glycosyl imidates as glycosyl donors under
oxidative conditions.7
We became interested in the synthesis of 2-deoxy-ꢀ-
glycosides because they are present in the lomaiviticins,
molecules we are targeting for synthesis (Figure 1). In
particular, our recent synthesis of the central ring system of
the lomaiviticins involves incorporation of the C4 and C4′
(1) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503.
(2) (a) Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541.
(b) Blanchard, N.; Roush, W. R. Org. Lett. 2003, 5, 81. (c) Thiem, J.;
Gerken, M. J. Org. Chem. 1985, 50, 954. (d) Ito, Y.; Ogawa, T. Tetrahedron
Lett. 1987, 28, 2723. (e) Grewal, G.; Kaila, N.; Franck, R. W. J. Org. Chem.
1992, 57, 2084. (f) Preuss, R.; Schmidt, R. R. Synthesis 1988, 694. (g)
Franck, R. W.; Marzabadi, C. H. J. Org. Chem. 1998, 63, 2197. (h)
Nicolaou, K. C.; Ladduwahetty, T.; Randall, J. L.; Chucholowski, A. J. Am.
Chem. Soc. 1986, 108, 2466. (i) Perez, M.; Beau, J.-M. Tetrahedron Lett.
1989, 30, 75. (j) Gervay, J.; Danishefsky, S. J. Org. Chem. 1991, 56, 5448.
(k) Tavecchia, P.; Trumtel, M.; Veyrieres, A.; Sinay, P. Tetrahedron Lett.
1989, 30, 2533. (l) Wiesner, K.; Tsai, T. Y. R.; Jin, H. HelV. Chim. Acta
1985, 68, 300.
(3) (a) Pongdee, R.; Wu, B.; Sulikowski, G. A. Org. Lett. 2001, 3, 3523.
(b) Hashimoto, S.; Yanagiya, Y.; Honda, T.; Ikegami, S. Chem. Lett. 1992,
1511.
(4) (a) Binkley, R. W.; Koholic, D. J. J. Org. Chem. 1989, 54, 3577.
(b) Toshima, K.; Misawa, M.; Ohta, K.; Tatsuta, K.; Kinoshita, M.
Tetrahedron Lett. 1989, 30, 6417.
(5) Zhou, M.; O’Doherty, G. A. J. Org. Chem. 2007, 72, 2485.
(6) (a) Crich, D.; Ritchie, T. J. J. Chem. Soc., Perkin Trans. 1 1990,
945. (b) Kahne, D.; Yang, D.; Lim, J. J.; Miller, R.; Paguaga, E. J. Am.
Chem. Soc. 1988, 110, 8716.
(7) Tanaka, H.; Yoshizawa, A.; Takahashi, T. Angew. Chem., Int. Ed.
2007, 46, 2505.
10.1021/ol8022006 CCC: $40.75
Published on Web 12/05/2008
2009 American Chemical Society

O-alkylation have been performed with substituents in the
C2 position.10This has made it difficult to assess the
contribution of the ꢀ-effect versus steric (or electronic)
influences of C2 substitutents in the selective formation of
ꢀ-glycosides by anomeric O-alkylation. In this paper we
report the first examples of anomeric O-alkylation/arylation
in the absence of a C2 substituent, stereoselectively forming
2-deoxy-ꢀ-glycosides.
Before beginning our investigation into anomeric O-
alkylation/arylation, a synthesis of a protected form of the
N,N-dimethylpyrrolosamine sugar of lomaiviticin B was
accomplished (Scheme 2). Beginning from the known glycal
Scheme 2. Synthesis of Protected N,N-Dimethylpyrrolosamine
Figure 1. Lomaiviticin B.
carbinols by SN2 displacement of allylic sulfones with
methoxide anions.8 This raised the possibility that the
2-deoxy-ꢀ-glycosides at C4 and C4′ might be incorporated
via an anomeric O-alkylation using glycosyl-1-alkoxides.
Anomeric O-alkylation with glycosyl-1-alkoxides gener-
ally affords high levels of ꢀ-glycosides.9 An explanation for
this selectivity involves rapid equilibrium between axial and
equatorial alkoxides with the enhanced nucleophilicity of the
equatorial alkoxide leading to selective generation of ꢀ-gly-
cosides (Scheme 1). It has been proposed that the enhanced
1,11 triflation was followed by displacement with NaN3.12
The azido-glycal 2 was hydrated in a two-step procedure
involving addition of AcOH to 2 catalyzed by triphenylphos-
phine hydrogen bromide13 and cleavage of the resulting
anomeric acetate with Me2NH. Lactol 3 was isolated as a
4:1 (R:ꢀ) mixture of anomers.
Scheme 1. Kinetic Anomeric Effect
Our next goal was to establish general reaction conditions
to access 2-deoxy-ꢀ-glycosides directly from an anomeric
mixture of lactols (Table 1). During the course of our
Table 1. Optimization of Reaction Conditionsa
entry
condition
R:ꢀb
1
2
3
4
KHMDS, THF, -78 °C, allyl bromide
NaH, DMF, allyl bromide, 0 °C
NaH, DMF, LiBr, allyl bromide, 0 °C
NaH, dioxane, allyl bromide, 23 °C
95:5
1:1
1:1.5
5:95
nucleophilicity of the equatorial alkoxide (II), compared to
the axial alkoxide (I), is due to increased electron-electron
repulsion resulting from the alkoxide of II being gauche to
both electron lone pairs of the ring oxygen compared to a
single gauche interaction in I. This phenomenon has been
referred to as the kinetic anomeric effect,9 or the ꢀ-effect,
and may be similar to the R-effect, which is observed in
molecules where the nucleophilic atom is directly attached
to another heteroatom. To date, most examples of anomeric
a Performed at 0.1 M. As determined by H NMR (600 MHz)
b
1
optimization studies we found that treatment of lactol 3 with
KHMDS in THF at -78 °C followed by the addition of allyl
bromide led to the exclusive formation of the R-anomer
(entry 1).14 Changing the base to NaH and raising the
reaction temperature to 0 °C led to a 1:1 mixture of R and
(8) Krygowski, E. S.; Murphy-Benenato, K.; Shair, M. D. Angew. Chem.,
Int. Ed. 2008, 47, 1680.
10
Org. Lett., Vol. 11, No. 1, 2009

ꢀ anomers. The addition of LiBr, an additive known to
enhance ꢀ-selectivity in anomeric O-alkylation,15 provided
only minor improvements in selectivity (entry 3). Gratify-
ingly, we found that changing the solvent from DMF to
dioxane and increasing the reaction temperature to 23 °C
led to a dramatic increase in selectivity. These conditions
afforded the 2-deoxy-ꢀ-glycoside 5 exclusively in 91% yield.
Table 3. Lactol and Electrophile Scopea
With optimal reaction conditions in hand, the scope of
this reaction was evaluated (Table 2). We considered
Table 2. Electrophile Scopea
a Reactions performed at 0.1 M. b Isolated yield after chromatographic
c
1
purification. As determined by H NMR (600 MHz)
nucleophilic aromatic substitution as a valuable application
of this methodology due to its potential use in the synthesis
of the aureolic acid family of natural products. Toward that
end, when lactol 3 was treated with NaH in dioxane followed
by 1-bromo-2,4-dinitrobenzene, the 2-deoxy-ꢀ-glycoside
a Reactions performed at 0.1 M. b Isolated yield after chromatographic
purification. As determined by H NMR (600 MHz)
c
1
(9) (a) Schmidt, R. R. Angew. Chem., Int. Ed. 1986, 25, 212. (b) Klotz,
W.; Schmidt, R. R. Liebigs Ann. Chem. 1993, 683. (c) Schmidt, R. R.;
Michel, J. Tetrahedron Lett. 1984, 25, 821. (d) Box, V. G. S. Heterocycles
1982, 19, 1939.
product 8 was isolated as an 18:1 mixture of anomers
favoring the ꢀ-anomer. Primary triflates such as 916 proved
to be suitable electrophiles for anomeric O-alkylation, as
(10) Schmidt, R. R.; Esswein, A. Angew. Chem., Int. Ed. 1988, 27, 1178.
This alkylation affords the R-glycoside.
(11) Halcomb, R. L.; Wittman, M. D.; Olson, S. H.; Danishefsky, S.
J. Am. Chem. Soc. 1991, 113, 5080.
(14) Xiong, X.; Ovens, C.; Pilling, A. W.; Ward, J. W.; Dixon, D. J.
Org. Lett. 2008, 10, 565.
(12) Werz, D. B.; Seeberger, P. H. Angew. Chem., Int. Ed. 2005, 44,
6315.
(15) Vauzeilles, B.; Dausse, B.; Palmier, S.; Beau, J.-M. Tetrahedron
Lett. 2001, 42, 7567.
(13) Bolitt, V.; Mioskowski, C.; Lee, S.-G.; Falck, J. R. J. Org. Chem.
1990, 55, 5812.
(16) Yadav, J. S.; Reddy, B. V. S.; Reddy, K. B.; Satyanarayana, M.
Tetrahedron Lett. 2002, 43, 7009.
Org. Lett., Vol. 11, No. 1, 2009
11

disaccharide 10 was isolated in 90% yield exclusively as the
ꢀ diastereomer. Following the successful anomeric O-
alkylation of a C6 triflate, we set out to determine if
secondary triflates were competent electrophiles for this
reaction. Despite previous reports by Schmidt of anomeric
O-alkylations on similar systems,17 triflates 11 and 12 failed
to undergo displacement (entries 4 and 5). In each case,
addition of the alkoxide took place at sulfur resulting in
detriflation of 11 and 12.
was purified by flash column chromatography yielding 81%
of 5 and quantitative recovery of trans-4-tert-butylcyclo-
hexanol. This experiment is the best support to date that the
high ꢀ-selectivity in anomeric O-alkylations/arylations is due
to the increased nucleophilicity of the ꢀ-configured anomeric
alkoxides.
Scheme 3. Competition Experiment
The methodology proved to be general with respect to the
starting lactol component (Table 3). Lactol 13, derived from
glucose, was allylated in high yield and provided exclusively
the ꢀ-anomer (15). Nucleophilic aromatic substitution with
16 took place in high yield, albeit with slightly diminished
stereoselectivity. The displacement of primary triflate 18
furnished 2-deoxy-ꢀ-glycoside 19 in 75% yield.18 The lactol
derived from galactose (14) also provided 2-deoxy-ꢀ-
glycosides in high yields and with high levels of sterocontrol
(entries 4 and 5). Galactose- and mannose-derived C6 triflates
were found to be suitable electrophiles for this reaction
(entries 6 and 7). The ability to utilize lactols and C6 triflates
with varying substitution patterns is a key feature of this
methodology. This compares favorably to traditional glyco-
sylation reactions where subtle changes to either the glycosyl
donor or acceptor can have a dramatic impact on the
stereoselectivity of the reaction.19
We next devised a competition experiment between lactol
3 and trans-4-tert-butylcyclohexanol20 to determine whether
the increased reactivity of equatorial alkoxides derived from
lactols (II, Scheme 1) can be attributed to steric effects or
the aforementioned ꢀ-effect. An equimolar mixture of lactol
3 and trans-4-tert-butylcyclohexanol (26) was dissolved in
dioxane and treated with 2 equiv of NaH (Scheme 3). After
10 min, 1 equiv of allyl bromide was added to the reaction
mixture. After workup, 1H NMR of the crude reaction
mixture showed only two products: 2-deoxy-ꢀ-glycoside 5
and unreacted trans-4-tert-butylcyclohexanol 26. The mixture
In conclusion, we report that anomeric O-alkylation/
arylation can be used to form 2-deoxy-ꢀ-glycosides with high
stereoselectivity. The high ꢀ-selectivity afforded with 2-deoxy-
1-lactols supports the theory that the ꢀ-effect, rather than
the substituent at C2, is the stereocontrol element in anomeric
O-alkylations/arylations. This conclusion has been obscured
in previous reports concerning anomeric O-alkylations/
arylations because they all involved substrates with C2
substituents, which may have influenced the stereoselectivity.
The competition experiment reported here demonstrates that
the nucleophilicity of ꢀ-configured anomeric alkoxides is
enhanced over similar cyclohexyl alkoxides, presumably due
to the proximity of the alkoxide and the lone pair electrons
of the ring oxygen. These results suggest that the ꢀ-effect is
a powerful stereoelectronic effect that may be useful in
designing other stereoselective reactions.
Acknowledgment. Financial support for this project was
provided by the NIH (CA125240), Merck Research Labo-
ratories, Novartis, and AstraZeneca.
(17) Tsvetkov, Y. E.; Klotz, W.; Schmidt, R. R. Liebigs Ann. Chem.
1992, 371.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) This methodology has been applied in an iterative manner to access
polysaccharides. See Supporting Information.
(19) (a) Durham, T. B.; Roush, W. R. Org. Lett. 2003, 5, 1871. (b)
Hashimoto, S.; Yanagiya, Y.; Honda, T.; Ikegami, S. Chem. Lett. 1992,
1511.
(20) Spiniello, M.; White, J. M. Org. Biomol. Chem. 2003, 17, 3094.
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