Direct and stereoselective synthesis of α-linked 2-deoxyglycosides

Article abstract of DOI:10.1021/ol801833n

(Chemical Equation Presented) α-Linked 2-deoxyglycosides were conveniently obtained by employing a glycosyl donor having a participating (S)-(phenylthiomethyl)benzyl moiety at C-6, whereas 2,6-dideoxy-α- glycosides could be prepared by BF₃-Et₂O-promoted activation of allyl glycosyl donors.

Full text of DOI:10.1021/ol801833n

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4367-4370
Direct and Stereoselective Synthesis of
r-Linked 2-Deoxyglycosides
Jin Park, Thomas J. Boltje, and Geert-Jan Boons*
Complex Carbohydrate Research Center, The UniVersity of Georgia,
315 RiVerbend Road, Athens, Georgia 30602
gjboons@ccrc.uga.edu
Received August 6, 2008
ABSTRACT
r-Linked 2-deoxyglycosides were conveniently obtained by employing a glycosyl donor having a participating (S)-(phenylthiomethyl)benzyl
moiety at C-6, whereas 2,6-dideoxy-r-glycosides could be prepared by BF3·Et2O-promoted activation of allyl glycosyl donors.
Many medically important natural products are modified by
oligosaccharides composed of 2-deoxysugars, and examples
of such compounds include antibiotics such as erythromycin,
antiparasite agents such as amphotericin, insecticides such
as the avermectins, and anticancer drugs such as doxorubi-
cin.1-4 The sugar moiety of these compounds can wield a
remarkable influence on pharmacological and pharmacoki-
netic properties and can dictate the molecular recognition at
the drug target site. Not surprisingly, considerable efforts
are directed at the development of tools that make it possible
to diversify natural product glycosylation.5-7 This approach,
which has been coined glycodiversification or glycorandom-
ization, can be achieved by metabolic, enzymatic, and
chemical means.8-14
The stereochemical introduction of 2-deoxyglycosides is
a key step in chemical glycodiversification and has mainly
been achieved by indirect methods that employ a participat-
ing functionality as C-2 of a glycosyl donor such as halides
and aryl selenyl and sulfenyl derivatives.15-18 The drawback
of this approach is that the introduction and removal of the
participating functionality requires additional steps that need
to be performed in a stereoselective manner, often leading
(8) Zhang, G. S.; Shen, J.; Cheng, H.; Zhu, L. Z.; Fang, L. Y.; Luo,
S. Z.; Muller, M. T.; Lee, G. E.; Wei, L. J.; Du, Y. G.; Sun, D. X.; Wang,
P. G. J. Med. Chem. 2005, 48, 2600–2611
.
(9) Zhu, L.; Cao, X.; Chen, W.; Zhang, G.; Sun, D.; Wang, P. G. Bioorg.
Med. Chem. 2005, 13, 6381–6387
.
(10) Elchert, B.; Li, J.; Wang, J.; Hui, Y.; Rai, R.; Ptak, R.; Ward, P.;
Takemoto, J. Y.; Bensaci, M.; Chang, C. W. J. Org. Chem. 2004, 69, 1513–
1523
.
(11) Fu, X.; Albermann, C.; Zhang, C.; Thorson, J. S. Org. Lett. 2005,
7, 1513–1515
(12) Langenhan, J. M.; Peters, N. R.; Guzei, I. A.; Hoffmann, F. M.;
Thorson, J. S. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 12305–12310
(13) Zhang, G.; Shi, L.; Liu, Q.; Wang, J.; Li, L.; Liu, X. Tetrahedron
2007, 63, 9705–9711
(14) Rupprath, C.; Schumacher, T.; Elling, L. Curr. Med. Chem. 2005,
12, 1637–1675
(15) Durham, T. B.; Roush, W. R. Org. Lett. 2003, 5, 1871–1874
.
(1) Le, G. T.; Abbenante, G.; Becker, B.; Grathwohl, M.; Halliday, J.;
Tometzki, G.; Zuegg, J.; Meutermans, W. Drug DiscoV. Today 2003, 8,
.
701–709
.
.
(2) Butler, M. S. J. Nat. Prod. 2004, 67, 2141–2153
(3) Weymouth-Wilson, A. C. Nat. Prod. Rep. 1997, 14, 99–110
(4) Kirschning, A.; Bechthold, A. F. W.; Rohr, J. Top. Curr. Chem.
1997, 188, 1–84
(5) Griffith, B. R.; Langenhan, J. M.; Thorson, J. S. Curr. Opin.
Biotechnol. 2005, 16, 622–630
.
.
.
.
.
(16) Thiem, J.; Klaffke, W. In Synthesis of 2-deoxy glycosides; Kamer-
ling, J. P., Boons, G.-J., Lee, Y. C., Suzuki, A., Taniguchi, N., Voragen,
A. G. J., Eds.; Elsevier Ltd.: Oxford, 2007; Vol. 1, pp 313-335.
(17) De Lederkremer, R. M.; Marino, C. AdV. Carb. Chem. Biochem.
2008, 61, 143–216
(18) Roush, W. R.; Sebesta, D. P.; James, R. A. Tetrahedron 1997, 53,
8837–8852
.
(6) Blanchard, S.; Thorson, J. S. Curr. Opin. Chem. Biol. 2006, 10, 263–
271
.
.
(7) Thibodeaux, C. J.; Melancon, C. E; Liu, H. W. Nature 2007, 446,
1008–1016
.
.
10.1021/ol801833n CCC: $40.75
Published on Web 09/03/2008
2008 American Chemical Society

to time-consuming synthetic procedures. On the other hand,
several methods are available for direct ꢀ-selective glyco-
sylation in which R-glycosyl halides, glycosyl phosphites,
and trichloroacetimidates are employed as glycosyl donors
in combination with a mild promoter.19-24 R-Glycosides of
2-deoxysaccharides have been obtained in moderate yield
by acid-catalyzed activation of glycals, anomeric esters, and
silyl ethers.25-28 Furthermore, diastereoselective Pd-promot-
ed glycosylations followed by reduction of a 2,3-double bond
of the resulting compound has been employed to prepare
unnatural 2,3-dideoxyglycosides.29,30 Reasonable anomeric
selectivities have also been achieved by remote assistance
of a p-methoxybenzoyl ester at C-3 of a glycosyl donor.
Remote particpiation has also been implicated in the stereo-
selective introduction of R-galactosides, R-glucosides, and
ꢀ-mannosides.31-37
Table 1. Glycosylations with Trichloroacetimidate Donors 1-3a
Recently, we demonstrated that glycosylations with gly-
cosyl donors modified at C-2 with a (S)-(phenylthiometh-
yl)benzyl moiety give exclusively R-anomeric selectivity due
to neighboring group participation resulting in an intermedi-
ate trans-fused 1,2-sulfonium ion.38-40 We were curious to
explore whether remote participation by a (S)-(phenylthi-
omethyl)benzyl moiety can be exploited in the stereochemical
synthesis of 2-deoxyglycosides. Thus, trichloroacetimidates
1-3 were prepared that have either a (S)-(phenylthiometh-
yl)benzyl, a benzyl ether, or an acetyl ester at C-6 (Table
1). Interestingly, a TMSOTf-mediated glycosylation of donor
1 with glycosyl acceptor 4 gave the expected disaccharide 8
donor
acceptor
product
yield (%)
R/ꢀ
1
1
1
1
2
2
2
2
3
4
5
6
7
4
5
6
7
4
8
94
93
95
92
96
95
92
93
90
15:1
12:1
10:1
8:1
1:1
1:1
5:1
4:1
4:1
11
13
15
9
12
14
16
10
(19) Pongdee, R.; Wu, B.; Sulikowski, G. A. Org. Lett. 2001, 3, 3523–
3525
.
(20) Arai, M.; Kaneko, S.; Konosu, T. Tetrahedron Lett. 2002, 43, 6705–
6708
.
(21) Nagai, H.; Sasaki, K.; Matsumura, S.; Toshima, K. Carbohydr. Res.
2005, 340, 337–353
(22) Tanaka, H.; Yoshizawa, A.; Takahashi, T. Angew. Chem., Int. Ed.
2007, 46, 2505–2507
.
.
(23) Zhou, M. Q.; O’Doherty, G. A. J. Org. Chem. 2007, 72, 2485–
2493
.
a All reactions were performed at -78 °C in DCM.
(24) Lam, S. N.; Gervay-Hague, J. Org. Lett. 2003, 5, 4219–4222
(25) Boivin, J.; Pais, M.; Monneret, C. Carbohydr. Res. 1980, 79, 193–
.
204
.
in good yield as almost exclusively the R-anomer. Similar
glycosylations employing glycosyl donors 2 and 3, having
a benzyl ether or acetyl ester at C-6, provided the disaccha-
rides 9 and 10, respectively, as mixtures of anomers. The
use of (R)-(phenylthiomethyl)benzyl ether at C-6 of the
glycosyl donor also led to excellent anomeric selectivity
indicating that the chirality of the auxiliary did not influence
the anomeric outcome of the glycosylation. We were unable
to identify the intermediate sulfonium ion by NMR experi-
ments in which 1 was activated with TMSOTf probably due
to the high reactivity of the intermediate. However, glyco-
sylations of 1 with 5-7 led to the isolation of the corre-
sponding disaccharides 11, 13, and 15 in excellent yields
with almost exclusively R-anomeric selectivity. The alterna-
tive use of benzylated derivative 2 gave the disaccharides
12, 14,and 16 as mixtures of anomers. Glycosylations of 2
and 3 promoted by BF3·Et2O did not lead to an improvement
of anomeric selectivity. Thus, it appears that a (phenylthi-
omethyl)benzyl ether at C-6 promotes high R-selectivity.
Next, attention was focused on anomeric control by
employing a glycosyl donor that has a (S)-(phenylthiometh-
(26) Kolar, C.; Kneissl, G. Angew. Chem., Int. Ed. Engl. 1990, 29, 809–
811
.
(27) Kolar, C.; Kneissl, G.; Wolf, H.; Kampchen, T. Carbohydr. Res.
1990, 208, 111–116
(28) Thiem, J.; Meyer, B. Chem. Ber. 1980, 113, 3067–3074
(29) Babu, R. S.; Zhou, M.; O’Doherty, G. A. J. Am. Chem. Soc. 2004,
126, 3428–3429
.
.
.
(30) Babu, R. S.; Guppi, S. R.; O’Doherty, G. A. Org. Lett. 2006, 8,
1605–1608
.
(31) Wiesner, K.; Tsai, T. Y. R.; Jin, H. HelV. Chim. Acta 1985, 68,
300–314
.
(32) Smid, P.; Deruiter, G. A.; van der Marel, G. A.; Rombouts, F. M.;
van Boom, J. H. J. Carbohydr. Chem. 1991, 10, 833–849
.
(33) Dejterjuszynski, M.; Flowers, H. M. Carbohydr. Res. 1975, 41,
308–312
.
(34) Demchenko, A. V.; Rousson, E.; Boons, G. J. Tetrahedron Lett.
1999, 40, 6523–6526
.
(35) Cheng, Y. P.; Chen, H. T.; Lin, C. C. Tetrahedron Lett. 2002, 43,
7721–7723
.
(36) Ustyuzhanina, N.; Komarova, B.; Zlotina, N.; Krylov, V.; Gerbst,
A.; Tsvetkov, Y.; Nifantiev, N. Synlett 2006, 921–923
(37) De Meo, C.; Kamat, M. N.; Demchenko, A. V. Eur. J. Org. Chem.
2005, 706–711
(38) Kim, J. H.; Yang, H.; Park, J.; Boons, G. J. J. Am. Chem. Soc.
2005, 127, 12090–12097
.
.
.
(39) Park, J.; Kawatkar, S.; Kim, J. H.; Boons, G. J. Org. Lett. 2007, 9,
1959–1962
.
(40) Kim, J. H.; Yang, H.; Boons, G. J. Angew. Chem., Int. Ed. 2005,
44, 947–949
.
4368
Org. Lett., Vol. 10, No. 19, 2008

yl)benzyl ether at C-4. Surprisingly, an attempt to introduce
the auxiliary at C-4 by treatment of sugar alcohol 17 with
(S)-(phenylthiomethyl)benzyl acetate 18 in the presence of
BF3·Et2O led to the formation of disaccharide 19 (Scheme
1). Thus, unexpected activation of the allyl glycoside of 17
Table 2. Glycosylations with Allyl Glycosyl Donors 20-22a
Scheme 1. Direct Activation of a 2,6-Dideoxy Allyl Glycoside
led to self-condensation. However, the allyl glycoside of
disaccharide 19 did not undergo further activation indicating
that 17 (or its auxiliary modified counterpart) is more reactive
than 19.
donor
acceptor
T (°C)
product
yield (%)
R/ꢀ
Allyl glycosides are attractive building blocks in glycoside
chemistry because the allyl moiety provides convenient
protection of the anomeric center but can easily be removed
by isomerization to a vinyl glycoside, which can be
hydrolyzed under mild conditions to give a lactol. The latter
compound can be converted into various glycosyl donors
such as trichloroacetimidates, phosphites, and halides. The
intermediate vinyl glycoside can also directly be employed
as a glycosyl donor in TMSOTf-promoted glycosyla-
tions.41,42
20
20
20
20
21
21
21
21
22
22
22
22
4
5
6
7
4
5
6
7
4
5
6
7
-78
-78
-78
23
26
29
32
24
27
30
33
25
28
31
34
85
80
68
62
83
82
68
65
85
82
73
72
8:1
5:1
7:1
5:1
10:1
8:1
11:1
10:1
14:1
13:1
15:1
10:1
-78
-30-0
-30-0
-30-0
-30-0
0 to rt
0 to rt
0 to rt
0 to rt
We envisaged that allyl 2-deoxyglycosides would be
interesting building blocks for oligosaccharide assembly
because the results presented here indicate that these
compounds can be employed in direct glycosylations using
BF3·Et2O as the promoter or converted into various conven-
tional glycosyl donors using standard procedures. To explore
the direct glycosylation of allyl 2-deoxyglycosides in more
detail, compounds 20, 21, and 22, which have either benzyl
ether or ester at C-3 and C-4, were employed in BF3·Et2O-
mediated glycosylations with glycosyl acceptors 4-7 to give
the corresponding disaccharides 23-34 (Table 2). Interest-
ingly, the highly activated glycosyl donor 20 having benzyl
ethers at C-3 and C-4 could be activated at -78 °C to provide
the expected disaccharides 23, 26, 29, and 32 in excellent
yields (Table 2). The somewhat less reactive glycosyl donor
21, having a benzoyl ester C-4, required a temperature of
-30 °C for activation, whereas the least reactive derivative
22 was only reactive at 0 °C. Importantly, each glycosylation
resulted in the formation of the expected disaccharide
(23-34) as mainly the R-anomer. Thus, these results
indicated that the high R-anomeric selectivity observed in
the formation of disaccharide 19 is not due to participation
by the C-4 (S)-(phenylthiomethyl)benzyl ether but probably
a result of the BF3·Et2O-promoted activation of the allyl
glycoside. Furthermore, it was observed that the correspond-
a All reactions were performed in DCM.
ing methyl glycosides of 20-22 were less reactive than allyl
glycosides because higher reaction temperatures and a larger
excess of BF3·Et2O (4 equiv) was required for activation.
The use of catalytic TMSOTf as the promotor to activate
20-22 led to good anomeric selectivities; however, the yields
were significantly lower compared to BF3·Et2O-promoted
glycosylations.
Attempts were also made to introduce ꢀ-glycosides by
treatment of compounds 20-22 with TMSI or TMSBr to
form the intermediate halides, which can then be displaced
by a sugar alcohol to form ꢀ-glycosides.24 However, these
attempts led to formation of disaccharides in good yields
but with poor anomeric selectivities (see the Supporting
Information).
Finally, the direct activation of allyl 2-deoxyglycosides
was employed in an armed-disarmed strategy to synthesize
more complex compounds.43-45 Thus, it was envisaged that
benzylated 2,6-dideoxyglycoside 20 would be more reactive
(43) Boons, G. J. Tetrahedron 1996, 52, 1095–1121
(44) Douglas, N. L.; Ley, S. V.; Lucking, U.; Warriner, S. L. J. Chem.
Soc., Perkin Trans. 1 1998, 51–65
(45) Koeller, K. M.; Wong, C. H. Chem. ReV. 2000, 100, 4465–4493
.
(41) Boons, G. J.; Isles, S. Tetrahedron Lett. 1994, 35, 3593–3596
.
.
(42) Boons, G. J.; Isles, S. J. Org. Chem. 1996, 61, 4262–4271
.
.
Org. Lett., Vol. 10, No. 19, 2008
4369

than compound 35, which has a deactivating acetyl ester at
C-3. Indeed, a BF3·Et2O-mediated glycosylation of 20 with
35 in DCM at -20 °C gave clean formation of disaccharide
36, which was isolated in a yield of 56% (R/ꢀ ) 6/1) and
led to the recovery of a small amount of starting materials
(Scheme 2). However, further activation of allyl glycoside
coupling with glycosyl acceptor 35 and in this case disac-
charide 37 was obtained in a yield of 62% (R/ꢀ ) 8/1). The
successful formation of this compound indicates that the
benzoyl ester at C-4 of 21 is less deactivating than the acetyl
ester at C-3 of 35. Fortunately, the allyl glycoside of 37 could
be activated with BF3·Et2O at 0 °C, and coupling with
cyclohexanol, which was used as a mimic of the aglycon of
compounds such as avermectin B1a, gave disaccharide 38 as
mainly the R-anomer.
Scheme 2. Armed-Disarmed Glycosylation Strategy
In conclusion, it has been demonstrated that 2-deoxygly-
cosyl donors having a (S)-(phenylthiomethyl)benzyl moiety
at C-6 can be employed for the chemical synthesis of
R-linked glycosides. In addition, it was found that allyl 2,6-
dideoxyglycosides could easily be activated with BF3·Et2O
and couplings with a variety of sugar alcohol provided mainly
R-glycosides. It is to be expected that the methodology will
be attractive for glycorandomization of medically important
natural products.
Acknowledgment. This research was supported by a grant
from the NIH (NIGM 2R01GM065248).
36 at a higher reaction temperature led to decomposition of
the disaccharide. It is possible to convert the allyl glycoside
of the latter compound into another leaving group for
conventional glycosylation. We aimed, however, to minimize
manipulations during oligosaccharide assembly, and there-
fore, the less reactive glycosyl donor 21 was employed in a
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra. This information is
available free of charge via the Internet at http://pubs.acs.org.
OL801833N
4370
Org. Lett., Vol. 10, No. 19, 2008