Flexible synthesis of 2-deoxy-C-glycosides and (1→2)-, (1→3)-, and (1→4)-linked C-glycosides

Article abstract of DOI:10.1002/anie.201209697

Link! Two, three, four! A rapid and flexible synthesis of native (1→n)-linked C-disaccharides (n=2, 3, 4; left) is possible. The configuration of the pseudoanomeric carbon was readily established by an epoxidation/ring-opening sequence. The synthesis of (1→n)-linked 2-deoxy-C-disaccharides (right) with high diastereoselectivity follows an even shorter route. Copyright

Full text of DOI:10.1002/anie.201209697

Angewandte
Chemie
DOI: 10.1002/anie.201209697
Carbohydrate Mimics
Flexible Synthesis of 2-Deoxy-C-Glycosides and (1!2)-, (1!3)-, and
(1!4)-Linked C-Glycosides**
Dennis C. Koester, Ella Kriemen, and Daniel B. Werz*
C-Glycosides are an important class of carbohydrate
mimics.[1] In these compounds the monosaccharide units are
linked by a methylene unit instead of an oxygen atom,
rendering the disaccharide highly stable towards enzymatic
and chemical hydrolysis. The conformational differences
between C- and O-glycosides have been the subject of
debate in the recent past because of the absence of exo and
endo anomeric effects in C-glycosides; however, a general
conclusion cannot be drawn to date.[2] The difficulties
associated with the synthesis of a C-glycosidic bond between
two monosaccharide moieties are readily apparent. Several
groups have addressed the synthesis of such structures in the
past decade.[3] Typically, methods have been developed only
for specific linkages[4,5] or have required elaborate building
blocks. Thus, a modular and robust approach for the synthesis
of a variety of different C-glycosidic linkages would be of high
synthetic and biochemical interest. Recently, we reported
a Sonogashira reaction to promote the synthesis of a- and b-
linked (1!6)-C-disaccharides.[3a] Herein we focus on the
preparation of more challenging C-glycosidic bonds and
present a strategy to build a- and b-linked (1!2)-, (1!3)-,
and (1!4)-C-disaccharides.
Our approach relies on the use of two monosaccharide
units. Starting from 1-stannylglucal 1 and exocyclic bromo-
olefins 2, a Stille cross-coupling would generate pseudo-
disaccharides 3 bearing a diene subunit (Scheme 1). The diene
subunit consisting of an endocyclic electron-rich and an
exocyclic less-electron-rich double bond sets the stage for
Scheme 1. Modular approach for the synthesis of 2-deoxy-C-glycosides
and (1!2)-, (1!3)-, and (1!4)-linked C-disaccharides.
several functionalization reactions. A global reduction leads
to (1!n)-linked 2-deoxy-C-glycosides of type 4, whilst an
oxidative–reductive functionalization of the endocyclic enol
ether would regenerate the native hydroxy group pattern of
the monosaccharide unit A (generation of 5). A further
reduction of the remaining exocyclic double bond forms the
methylene bridge between the two monosaccharide units and
completes the sequence. In the case of the (1!n)-linked
2-deoxy-C-glycosides 4 two stereocenters are generated. In
the synthesis of C-disaccharides 6 from dienes 3 three
stereocenters are installed, making the approach relatively
flexible in establishing the stereochemical configuration at
these centers.
1-Stannylglycals of type 1 are readily synthesized accord-
ing to established methods.[6] Exocyclic olefins 2 were
generated from the corresponding ketones by a Wittig-type
reaction using the phosphorus ylide Ph3PCHBr. However, the
bromo-substituted double bond in position 2 of the mono-
saccharide was preferentially obtained by means of a halo-
cyclopropanation of the respective glycals followed by the
opening of the three-membered ring.[7,8]
The subunits 1 and 2 were cross-coupled under standard
Stille conditions (Scheme 2).[9] As carbohydrate building
blocks, glucose-, galactose-, mannose-, and allose-based
systems were employed. Despite steric hindrance pseudo-
disaccharides 3 were synthesized in good yields ranging from
63% to 88%. The galactose- and mannose-based building
[*] Dipl.-Chem. D. C. Koester, M. Sc. E. Kriemen,
Priv.-Doz. Dr. D. B. Werz
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: dwerz@gwdg.de
Homepage: http://www.werz.chemie.uni-goettingen.de
[**] This work was supported by the German Research Foundation
(DFG) and the Fonds der Chemischen Industrie (Emmy Noether
Fellowship and Dozentenstipendium to D.B.W., Fonds-Doktoran-
denstipendium to D.C.K.). We thank Prof. Dr. Lutz F. Tietze for
generous support of our work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209697.
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heterogeneous catalysts as well as the application of molec-
ular hydrogen not generated in situ did not result in the
desired C-disaccharides. Although in all cases four stereoiso-
mers have to be considered, we observed high substrate-
induced diastereoselectivity. Only two diastereomers in ratios
from 5:1 to 10:1 were detectable by NMR analysis. The
obtained products 4 have been characterized by 2D-NMR
and NOESY methods (see the Supporting Information).
In principle there are two conceivable strategies to access
the native hydroxy-group pattern starting from 3. The first
approach is a reductive–oxidative refunctionalization in
which first the less-electron-rich exocyclic double bond is
reduced and then the endocyclic enol ether oxidized to
regenerate the native hydroxy-group pattern of the carbohy-
drate. The second possibility is an inversion of this sequence,
first oxidizing the enol ether and then reducing the exocyclic
double bond to build the methylene bridge linking the two
monosaccharide units.
Recently, we found the reductive–oxidative approach to
be superior in the synthesis of (1!6)-C-disaccharides and
therefore we decided to pursue the first approach.[3a] How-
ever, pivotal differences cannot be ignored. In contrast to
(1!6)-linkages, the synthesis of (1!2)-, (1!3)-, and (1!4)-
linkages requires a diene subunit, which in terms of elec-
tronics differs from the enyne motif employed in the prior
case. A further major difference is that the reduction of the
exocyclic double bond generates a stereocenter, whereas in
the reduction of the exocyclic alkyne in (1!6)-C-disacchar-
ides there are no diastereoselectivity issues.
In our initial experiments we tried a Raney nickel
catalyzed reduction which had proved successful in the
synthesis of (1!6)-C-disaccharides.[3a] The application of
this heterogeneous catalyst in combination with molecular
hydrogen afforded 7ab in good yield (Scheme 4). We found
the diastereoselectivity to be surprisingly high and only the
allo configuration could be detected at C-3. A subsequent
hydroboration[3h,4g,11] led to the b-C-disaccharide in moderate
yield and high diastereoselectivity. However, this strategy
could not be transferred to other systems and we found
a reduced enol ether as the product of the first step. Hence, we
had to pursue the second strategy.
Scheme 2. Stille coupling of 1 and 2 to access (1!2)-, (1!3)-, and
(1!4)-linked C-glycosidic pseudodisaccharides 3. Reagents and con-
ditions: a) 1 (1.0 equiv), 2 (1.05 equiv), [Pd(PPh3)4] (10 mol%), CuI
(0.4 equiv), LiCl (2.5 equiv), DMF, 808C, 5.5–18 h. b) 1 (1.0 equiv), 2
(1.05 equiv), [Pd(PPh3)4] (10 mol%), MeCN/NMP (10:1), 95–1058C,
6–14 h.
blocks proved to be superb coupling partners for 1-stannyl-
glucal.
For a rapid and flexible route to (1!n)-linked 2-deoxy-
C-disaccharides 4, dienes 3 were subjected to a transfer
hydrogenation with ammonium formate and Pd on charcoal
(Scheme 3).[10] Such conditions provided 2-deoxy-C-disac-
charides with all conceivable linkages. The use of different
Scheme 3. Synthesis of (1!n)-linked 2-deoxy-C-disaccharides 4 (n=2,
Scheme 4. Refunctionalization of diene 3ab by means of a reduction–
oxidation sequence and subsequent deprotection to yield 6abb.
3, 4).
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The new strategy relies on the refunctionalization of the
enol ether as the first step. To prove the viability of this
approach we initially examined the epoxidation of the (1!3)-
linked C-disaccharide 3ac. We found conditions that yielded
high chemo- and diastereoselectivity (Table 1, entry 3). The
utilization of only one equivalent of dimethyldioxirane
(DMDO) at ꢀ788C led to complete control of chemo-
selectivity: exclusively the enol ether double bond was
attacked. The epoxidation with DMDO proceeds with high
facial selectivity and solely leads to the gluco-configured
carbohydrate framework (d.r. > 20:1).[12] In the subsequent
ring-opening of the acetalic epoxide, the stereochemical
configuration of the pseudoanomeric carbon can be adjusted
by the choice of the nucleophilic hydride agent. Coordinating
hydrides such as diisobutylaluminum hydride (DIBAL) set
the stage for the b-anomer in high diastereoselectivities,
whereas strongly nucleophilic hydride sources such as super-
hydride (LiBHEt3) generated exclusively the a-product in an
SN2-type fashion.[3a,13,14]
Applying this strategy provides access to a variety of
different a- and b-linked C-disaccharides (Table 1). Even
under Shi conditions the generation of an epoxide with
manno configuration proved not to be feasible. Thus, the
newly generated 2-hydroxy group has to be inverted to
prepare manno-configurated C-disaccharides. A Mitsunobu
inversion failed, possibly because of high steric hindrance. To
access b-linked mannosyl derivatives a two-step sequence can
be employed. The oxidation of the 2-hydroxy group leads to
a ketone that can be easily reduced with sodium boro-
hydride[15] to obtain a b-manno-configurated C-disaccharide
Table 1: Synthesis of C-glycosidic disaccharides.
Entry Diene C-Glycosidic olefin
C-Disaccharide
Entry Diene C-Glycosidic olefin
C-Disaccharide
(1!2)-linked C-glycosidic disaccharides
1
2
3aa
3aa
5
6
3ad
3ad
3aaa (61%)[a]
6aaa (99%; Glc/Man =
5ada (58%)[a]
6ada (99%; Gal)[d]
3:1)[c]
5aab (61%)[b]
6aab (99%; Glc/Man =
5adb (53%)[b]
6adb (75%; Gal/Gul =
2:5)[c]
7:1)[d]
(1!3)-linked C-glycosidic disaccharides
(1!4)-linked C-glycosidic disaccharides
3
4
3ac
3ac
7
8
3ae
3ae
5acb (79%)[b]
6acb (99%; Man)[d]
5aea (65%)[a]
5aeb (60%)[b]
6aea (99%; All)[d]
5bcb (50% over three
6bcb (79%; Man/Tal =
6aeb (99%; All/Gul = 6:1)[d]
steps)[b,e]
4:1)[d]
Reagents and conditions: [a] 3 (1.0 equiv), DMDO (1.0 equiv), CH2Cl2, ꢀ788C, 1 h, !08C, 20 min, LiBHEt3 (15.0–40.0 equiv), THF, 08C, 3 h. [b] 3
(1.0 equiv), DMDO (1.0 equiv), CH2Cl2, ꢀ788C, 1 h, !08C, 20 min, DIBAL (5.0 equiv), CH2Cl2, ꢀ788C. [c] NH4HCOO (10.0 equiv), Pd/C, MeOH/
THF=1:1, 808C, 1.5–3 h. [d] Pd(OH)2/C, H2, MeOH/CH2Cl2/EtOAc=3:1:1, 258C, 18 h. [e] Inversion of the OH group for substrate 5acb over two
steps: 1) DMP (5.0 equiv), CH2Cl2, 258C, 18 h; 2) NaBH4 (18 equiv), MeOH/CH2Cl2 = 1:1, 08C, 3 h. DMP=Dess–Martin periodinane.
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Lett. 2004, 45, 7791 – 7794; e) G. Yang, J. Schmieg, M. Tsuji,
R. W. Franck, Angew. Chem. 2004, 116, 3906 – 3910; Angew.
Chem. Int. Ed. 2004, 43, 3818 – 3822; f) C. R. Bertozzi, D. G.
Cook, W. R. Kobertz, F. Gonzales-Scarano, M. Bednarski, J. Am.
Chem. Soc. 1992, 114, 10639 – 10641.
(Table 1, entry 4). The diastereoselectivity is controlled by
chiral induction of the substrate.
The stereochemistry of C-glycosidic olefins 5 could be
determined by analysis of the coupling constant of the
pseudoanomeric proton 1’-H to 2’-H. The signal of proton
1’-H is a doublet of doublets, in which one coupling addresses
7-H and the other coupling addresses 2’-H (for designation of
the protons, see Table 1, entry 1). The coupling constant to
7-H, which gives rise to a doublet with a characteristic
chemical shift, is easily extracted; thus, the other coupling
constant in the doublet of doublets results from the coupling
to 2’-H. A large coupling constant of J ꢁ 9 Hz indicates a
b-linkage, whilst J ꢂ 4 Hz suggests an a-configuration (for
details see the Supporting Information).
The formed C-glycosidic olefins were subsequently re-
duced. Attempts to hydrogenate the exocyclic double bond
with homogeneous catalysts such as Wilkinsonꢀs or Crabtreeꢀs
catalyst were in vain, even at high pressure.[16] The heteroge-
neously catalyzed reduction with Raney nickel did not lead to
the desired product under high pressure in a continuous-flow
hydrogen reactor. Finally, promising results were obtained by
using Pearlmanꢀs catalyst. The application of this catalyst has
a major advantage in that the double bond is reduced and all
of the protecting groups are removed simultaneously. In most
cases we observed high selectivities in the formation of
C-disaccharides 6. The stereochemical configuration of the
products was determined by careful analysis of the coupling
constants and by 1D-NOESY experiments (see the Support-
ing Information). In the case of the (1!2)-linkage we again
found the transfer hydrogenation to be the key to success.[10]
We did not observe the desired C-disaccharides when we
applied heterogeneous catalysis with molecular hydrogen not
generated in situ.
In conclusion, we have reported a rapid and flexible entry
to (1!2)-, (1!3)-, and (1!4)-C-disaccharides. The key step
is a Stille-type reaction of the functionalized subunits, in
which stannylglycals and exocyclic bromoolefins are
employed as coupling partners. The resulting highly substi-
tuted diene system can be either completely reduced to
2-deoxy-C-disaccharides or refunctionalized in an oxidative–
reductive manner to regenerate the native hydroxy-group
pattern of the respective carbohydrate moiety. The reported
approach should be applicable in the synthesis of complex
oligosaccharides and glycoconjugates. The generation of
amino sugars and the synthesis of more complex C-O-
glycosides are under investigation in our laboratory.
[2] a) L. M. Mikkelsen, M. J. Hernꢁiz, M. Martꢂn-Pastor, T.
Skrydstrup, J. Jimꢃnez-Barbero, J. Am. Chem. Soc. 2002, 124,
14940 – 14951; b) J. L. Asensio, F. J. CaÇada, X. Cheng, N. Khan,
D. R. Mootoo, J. Jimꢃnez-Barbero, Chem. Eur. J. 2000, 6, 1035 –
1041; c) Y. Wang, P. G. Goekjian, D. M. Ryckman, W. H. Miller,
S. A. Babirad, Y. Kishi, J. Org. Chem. 1992, 57, 482 – 489; d) T.
Haneda, P. G. Goekjian, S. H. Kim, Y. Kishi, J. Org. Chem. 1992,
57, 490 – 498; e) Y. Wang, P. G. Goekjian, D. M. Ryckman, Y.
Kishi, J. Org. Chem. 1988, 53, 4151 – 4153.
[3] Selected examples: a) D. C. Koester, M. Leibeling, R. Neufeld,
D. B. Werz, Org. Lett. 2010, 12, 3934 – 3937; b) T. Watanabe, G.
Hirai, M. Kato, D. Hashizume, T. Miyagi, M. Sodeoka, Org. Lett.
2008, 10, 4167 – 4170; c) G. Kirai, T. Watanabe, K. Yamaguchi, T.
Miyagi, M. Sodeoka, J. Am. Chem. Soc. 2007, 129, 15420 – 15421;
d) M. H. D. Postema, J. L. Piper, V. Komanduri, L. Lei, Angew.
Chem. 2004, 116, 2975 – 2978; Angew. Chem. Int. Ed. 2004, 43,
2915 – 2918; e) J. L. Piper, M. H. D. Postema, J. Org. Chem. 2004,
69, 7395 – 7398; f) G. D. McAllister, D. E. Paterson, R. J. K.
Taylor, Angew. Chem. 2003, 115, 1425 – 1429; Angew. Chem. Int.
Ed. 2003, 42, 1387 – 1391; g) M. H. D. Postema, J. L. Piper, L.
Liu, J. Shen, M. Faust, P. Andreana, J. Org. Chem. 2003, 68,
4748 – 4754; h) L. Liu, M. H. D. Postema, J. Am. Chem. Soc.
2001, 123, 8602 – 8603; i) B. Patro, R. R. Schmidt, J. Carbohydr.
Chem. 2000, 19, 817 – 826; j) B. A. Johns, Y. T. Pan, A. D. Elbein,
C. R. Johnson, J. Am. Chem. Soc. 1997, 119, 4856 – 4865; k) H.
Streicher, A. Geyer, R. R. Schmidt, Chem. Eur. J. 1996, 2, 502 –
510; l) A. T. Khan, P. Sharma, R. R. Schmidt, J. Carbohydr.
Chem. 1995, 14, 1353 – 1367; m) J.-A. Mahling, R. R. Schmidt,
Synthesis 1993, 325 – 328; n) Y. Wang, S. A. Babirad, Y. Kishi, J.
Org. Chem. 1992, 57, 468 – 481; o) R. Preuss, R. R. Schmidt, J.
Carbohydr. Chem. 1991, 10, 887 – 900; p) K. Wallimann, A.
Vasella, Helv. Chim. Acta 1991, 74, 1520 – 1532; q) R. R.
Schmidt, R. Preuss, Tetrahedron Lett. 1989, 30, 3409 – 3412;
r) B. Giese, M. Hoch, C. Lamberth, R. R. Schmidt, Tetrahedron
Lett. 1988, 29, 1375 – 1378; s) B. Giese, T. Witzel, Angew. Chem.
1986, 98, 459 – 460; Angew. Chem. Int. Ed. Engl. 1986, 25, 450 –
451; t) P. Lesimple, J. M. Beau, P. G. Sinaꢄ, Chem. Soc. Chem.
Commun. 1985, 894 – 895.
[4] a) T. Kikuchi, J. Takagi, H. Isou, T. Ishiyama, N. Miyaura, Chem.
Asian J. 2008, 3, 2082 – 2090; b) J. S. Potuzak, D. Tan, Tetrahe-
dron Lett. 2004, 45, 1797 – 1801; c) V. Jeanneret, L. Meerpoel, P.
Vogel, Tetrahedron Lett. 1997, 38, 543 – 546; d) P. Lesimple, J.-M.
Beau, Bioorg. Med. Chem. 1994, 2, 1319 – 1330; e) E. Dubois, J.-
M. Beau, Carbohydr. Res. 1992, 228, 103 – 120; f) R. W. Friesen,
R. W. Loo, J. Org. Chem. 1991, 56, 4821 – 4823; g) S. Hanessian,
M. Martin, R. C. Desai, J. Chem. Soc. Chem. Commun. 1986,
926 – 927.
[5] Selected examples of recently published methods accessing
simple arylated and alkylated C-glycosides: a) R. S. Andrews,
J. J. Becker, M. R. Gagnꢃ, Angew. Chem. 2010, 122, 7432 – 7434;
Angew. Chem. Int. Ed. 2010, 49, 7274 – 7276; b) H. Gong, M. R.
Gagnꢃ, J. Am. Chem. Soc. 2008, 130, 12177 – 12183; c) S.
Lemaire, I. N. Houpis, T. Xiao, J. Li, E. Digard, C. Gozlan, R.
Liu, A. Gavryushin, C. Diꢅne, Y. Wang, V. Farina, P. Knochel,
Org. Lett. 2012, 14, 1480 – 1483.
Received: December 4, 2012
Published online: February 10, 2013
Keywords: carbohydrate mimics · C-disaccharides ·
.
C-glycosides · epoxide opening · Stille reaction
[6] K. Jarowicki, C. Kilner, P. Kocienski, Z. Komsta, J. Milne, A.
Wojtasiewicz, V. Coombs, Synthesis 2008, 2747 – 2763.
[7] a) H. Lu, R. B. Silverman, J. Med. Chem. 2006, 49, 7404 – 7412;
b) K. Sato, T. Sekiguchi, T. Hozumi, T. Yamazaki, S. Akai,
Tetrahedron Lett. 2002, 43, 3087 – 3090; c) D. Seyferth, J. K.
Heeren, S. O. Grim, J. Org. Chem. 1961, 26, 4783 – 4784.
[1] Review articles: a) D. C. Koester, A. Holkenbrink, D. B. Werz,
Synthesis 2010, 3217 – 3242; b) P. Sears, C.-H. Wong, Angew.
Chem. 1999, 111, 2446 – 2471; Angew. Chem. Int. Ed. 1999, 38,
2300 – 2324; c) M. H. D. Postema, Tetrahedron 1992, 48, 8545 –
8599. Other important contributions: d) M. R. Chaulagain,
M. H. D. Postema, F. Valeriote, H. Pietraszkewicz, Tetrahedron
2988 www.angewandte.org
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[8] a) C. V. Ramana, R. Murali, M. Nagarjan, J. Org. Chem. 1997,
62, 7694 – 7703; b) R. J. Hewitt, J. E. Harvey, J. Org. Chem. 2010,
75, 955 – 958.
[9] a) K. Pchalek, M. P. Hay, J. Org. Chem. 2006, 71, 6530 – 6535;
b) X. Han, B. M. Stoltz, E. J. Corey, J. Am. Chem. Soc. 1999, 121,
7600 – 7605; c) A. X. Huang, Z. Xiong, E. J. Corey, J. Am. Chem.
Soc. 1999, 121, 9999 – 10003.
[13] U. Majumder, J. M. Cox, H. W. B. Johnson, J. D. Rainier, Chem.
Eur. J. 2006, 12, 1736 – 1746.
[14] a) M. Inoue, S. Yamashita, A. Tatami, K. Miyazaki, M. Hirama,
J. Org. Chem. 2004, 69, 2797 – 2804; b) S. Krishnamurthy, R. M.
Schubert, H. C. Brown, J. Am. Chem. Soc. 1973, 95, 8486 – 8487.
[15] F. W. Lichtenthaler, T. Schneider-Adams, S. Immel, J. Org.
Chem. 1994, 59, 6735 – 6738.
[10] X. Li, L. Li, Y. Tang, L. Zhong, L. Cun, J. Zhu, J. Liao, J. Deng, J.
Org. Chem. 2010, 75, 2981 – 2988.
[11] R. R. Schmidt, R. Preuss, R. Betz, Tetrahedron Lett. 1987, 28,
6591 – 6594.
[16] a) Y. Zhu, K. Burgess, Acc. Chem. Res. 2012, 45, 1623 – 1636;
b) R. Crabtree, Acc. Chem. Res. 1979, 12, 331 – 337; c) J. A.
Osborn, F. H. Jardine, J. F. Young, G. Wilkinson, J. Chem. Soc. A
1966, 1711 – 1732.
[12] a) L. Alberch, G. Cheng, S.-K. Seo, X. Li, F. P. Boulineau, A.
Wei, J. Org. Chem. 2011, 76, 2532 – 2547; b) R. L. Halcomb, S. J.
Danishefsky, J. Am. Chem. Soc. 1989, 111, 6661 – 6666.
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