2-C-branched glycosides from 2′-carbonylalkyl 2-O-Ms(Ts)-C- glycosides. A tandem SN2-SN2 reaction via 1,2-cyclopropanated sugars

Article abstract of DOI:10.1021/ol0486627

(Chemical Equation Presented) Under basic conditions, 2′-aldehydo (acetonyl) 2-O-Ms(Ts)-α-C-glycosides undergo an intramolecular S _N2 reaction to form 1,2-cyclopropanated sugars, which react with nucleophiles (alcohols, thiols, and azide) at the anomeric carbon to give 2-C-branched glycosides. By way of contrast, the 1,2-cyclopropanes derived from 2′-ketones only react with thiols to give 2-C-branched thioglycosides.

Full text of DOI:10.1021/ol0486627

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3497-3499
2-C-Branched Glycosides from
-Carbonylalkyl
2-O-Ms(Ts)-C-Glycosides. A Tandem
SN2 SN2 Reaction via
2′
−
1,2-Cyclopropanated Sugars
Huawu Shao,† Sanchai Ekthawatchai,† Shih-Hsiung Wu,‡ and Wei Zou*,†
Institute for Biological Sciences, National Research Council of Canada,
100 Sussex DriVe, Ottawa, Ontario K1A 0R6, Canada, and Institute of Biological
Chemistry, Academia Sinica, Taipei, Taiwan
wei.zou@nrc-cnrc.gc.ca
Received July 12, 2004
ABSTRACT
Under basic conditions, 2
sugars, which react with nucleophiles (alcohols, thiols, and azide) at the anomeric carbon to give 2-C-branched glycosides. By way of contrast,
the 1,2-cyclopropanes derived from 2 -ketones only react with thiols to give 2-C-branched thioglycosides.
′-aldehydo (acetonyl) 2-O-Ms(Ts)-r-C-glycosides undergo an intramolecular SN2 reaction to form 1,2-cyclopropanated
′
C-Branched sugars in natural antibiotics, bacterial polysac-
charides, and macrolides are often associated with specific
biological functions.1 Unnatural 2-C-branched sugars also
serve as metabolic substrates, e.g., Bertozzi et al. tested 2-C-
acetonylsugars, derived from 2-iodosugars, as mimics of 2-N-
acetylsugars for cell surface engineering2 and Hindsgaul et
al. prepared a 2-C-acetamide sugar from a 2,3-epoxide as
an inhibitor of the biosynthesis of lipid A.3
Most 2-C-branched sugars are synthesized from glycals
through 1,2-cyclopropanation followed by selective ring-
opening via solvolysis,4,5 which often provides an anomeric
mixture of glycosides because of the involvement of an
oxocarbonium-like intermediate, with R-glycosides being
(4) For reviews, see: (a) Cousins, G. S.; Hoberg, J. O. Chem. Soc. ReV.
2000, 29, 165-174. (b) Lebel, H.; Marcoux, J.-F.; Malinaro, C.; Charette,
A. B. Chem. ReV. 2003, 103, 977-1050. (c) Reissig, H.-U.; Zimmer, R.
Chem. ReV. 2003, 103, 1151-1196. (d) Doyle, M. P.; Protopopova, M. N.
Tetrahedron 1998, 54, 7919-7946. (e) Wong, H. N. C.; Hon, M.-Y.; Tse,
C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. ReV. 1989, 89, 165-
198.
† National Research Council of Canada.
‡ Academia Sinica.
(1) (a) Chapleur, Y.; Che´tien, F. In PreparatiVe Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker: New York, 1997; pp 207-262. (b)
Yoshima, J. AdV. Carbohydr. Chem. Biochem. 1984, 42, 69-134. (c)
Lindberg, B. AdV. Carbohydr. Chem. Biochem. 1987, 48, 279-318. (d)
Celmer, W. D. Pure Appl. Chem. 1971, 28, 413-453.
(2) Hang, H. C.; Bertozzi, C. R. J. Am. Chem. Soc. 2001, 123, 1242-
1243.
(3) (a) Jackman, J. E.; Fierke, C. A.; Tumey, L. N.; Pirrung, M.;
Uchiyama, T.; Tahir, S. H.; Hindsgaul, O.; Raetz, C. R. H. J. Biol. Chem.
2000, 275, 11002-11009. (b) Li, X.; Uchiyama, T.; Raetz, C. R. H.;
Hindgaul, O. Org. Lett. 2003, 5, 539-541.
(5) For solvolysis conditions, see: (a) Scott, R. W.; Heathcock, C. H.
Carbohydr. Res. 1996, 291, 205-208. (b) Collum, D. B.; Still, W. C.;
Mohamadi, F. J. Am. Chem. Soc. 1986, 108, 2094-2096. (c) Kim, C.;
Hoang, R.; Theodorakis, E. A. Org. Lett. 1999, 1, 1295-1297. (d) Hoberg,
J. O.; Claffey, D. J. Tetrahedron Lett. 1996, 37, 2533-2536. (e) Ramana,
C. V.; Murali, R.; Nagarajan, M. J. Org. Chem. 1997, 62, 7694-7703. (f)
Ramana, C. V.; Nagarajan, M. Synlett 1997, 763-764. (g) Bertinato, P.;
Sorensen, E. J.; Meng, D.; Danishefsky, S. J. J. Org. Chem. 1996, 61, 8000-
8003. (h) Beyer, J.; Skaanderup, P. R.; Madsen, R. J. Am. Chem. Soc. 2000,
122, 9575-9583. (i) Beyer, J.; Madsen, R. J. Am. Chem. Soc. 1998, 120,
12137-12138.
10.1021/ol0486627 CCC: $27.50
© 2004 American Chemical Society
Published on Web 08/31/2004

Scheme 1. Base-Mediated Rearrangements
Scheme 2 Tandem SN2-SN2 Mechanism
favored due to the anomeric effect. A recent ring-opening
of sugar cyclopropanecarboxylates mediated by NIS provided
1,2-trans 2-C-branched glycosides.6 We report herein a
tandem SN2-SN2 reaction involving a base-mediated 1,2-
cyclopropanation from 2′-carbonylalkyl 2-O-Ms(Ts)-C-gly-
cosides and subsequent nucleophilic substitution at the
anomeric carbon leading to 1,2-trans 2-C-branched â-O- and
â-S-glycosides and â-glycosyl azides.
It is known that 2′-carbonylalkyl R-C-glycosides epimerize
to their â-anomers under basic conditions through â-elimina-
tion to an acyclic R,â-conjugated aldehyde (ketone) inter-
mediate followed by an intramolecular hetero-Michael
addition.7 However, this cyclization is poorly stereoselective
in C-furanosides. Fleet et al. have developed an intramo-
lecular SN2 reaction to form furan esters via base treatment
of 2-O-Tf (Ms) sugar lactones.8 Following the same rationale,
we decided to place a leaving group at the O(2)-position of
2′-carbonylalkyl C-glycopyranosides to see if the C-furano-
side would be formed stereoselectively after â-elimination
and subsequent intramolecular SN2 substitution at C(2) by
C(5)-OH.
The results indicate that the cyclopropanation (1,2-
substitution) was favored over the â-elimination due to the
1,2-trans configurations of R-C-mannoside. This mechanism
resembles one observed by Danishefsky et al. involving 1,2-
migration of the N-sulfonamide from 2-iodo-1-N-sulfonamide
to 2-N-sulfonamide glycosyl compounds.11
Although highly â-selective, the reaction will not be
practically useful unless better chemical selectivity is achieved
and other substrates and nucleophiles can be incorporated.
Thus, 2′-aldehydo 2-O-Ts-C-glycoside (6) and 2′-acetonyl
2-O-Ms-C-glycoside (7) were included as substrates, and
alcohols, thiols, and sodium azide were used as nucleophiles.
After examining various base/solvent combinations, we were
able to obtain 2-C-branched glycosides (2, 9, and 10) from
2-O-Ms 1 in good yields with triethylamine as base, and no
byproduct 3 was isolated (see Scheme 3 and entries 1, 4,
Thus, 2′-aldehydo 2-O-Ms-C-glycoside (1) was prepared
from the respective allyl C-glycoside by ozonolysis.9 Upon
treatment of 1 with 4% NaOMe, two major products were
obtained, namely, the 2-C-branched methyl â-glucopyrano-
side 2 (40-50%) and the bicyclic product 3 (10-15%), but
no C-furanoside was isolated (Scheme 1). Both structures
were unambiguously characterized by NMR analysis.10 On
the basis of the products obtained, we believe that the enolate
4 reacted to give the 1,2-cyclopropanated sugar 5, which in
turn underwent ring-opening with methoxide at the anomeric
carbon to afford 2; presumably an intramolecular rearrange-
ment afforded 3 (Scheme 2).
Scheme 3. Synthesis of 2-C-Branched Glycosides
(6) Sridhar, P. R.; Ashalu, K. C.; Chandrasekaran Org. Lett. 2004, 6,
1777-1779.
(7) (a) Shao, H.; Wang, Z.; Lacroix, E.; Wu, S.-H.; Jennings, H.; Zou,
W. J. Am. Chem. Soc. 2002, 124, 2130-2131. (b) Wang, Z.; Shao, H.;
Lacroix, E.; Wu, S.-H.; Jennings, H.; Zou, W. J. Org. Chem. 2003, 68,
8097-8105. (c) Zou, W.; Lacroix, E.; Wang, Z.; Wu, S.-H. Tetrahedron
Lett. 2003, 44, 4431-4433.
(8) (a) Sanjayan, G. J.; Stewart, A.; Hachisu, S.; Gonzalez, R.; Watterson,
M. P.; Fleet, G. Tetrahedron Lett. 2003, 44, 5847-5851. (b) Watterson,
M. P.; Edwards, A. A.; Leach, J. A. Smith, M. D.; Ichihara, O.; Fleet, G.
Tetrahedron Lett. 2003, 44, 5853-5857.
and 6 in Table 1). The same selectivity but lower yields were
obtained from 2-O-Ts 6 with K2CO3/CH3CN as the base and
solvent (entries 2, 3, and 5). Under both sets of conditions,
the 2-C-branched glycosyl azide 11 was also produced in
moderate yield (entry 7). The best results, however, were
obtained when 1, 6, and 7 were treated with thiols; this
(9) (a) Zou, W.; Wang, Z.; Lacroix, E.; Wu, S.-H.; Jennings, H.
Carbohydr. Res. 2001, 334, 223-231. (b) Uchiyama, T.; Vassilev, V. P.;
Kajimoto, T.; Wong, W.; Huang, H.; Lin, C.-C.; Wong, C.-H. J. Am. Chem.
Soc. 1995, 117, 5395-5396. (c) Minehan, T. G.; Kishi, Y. Tetrahedron
Lett. 1997, 38, 6815-6818. (d) Praly, J.-P.; Chen, G.-R.; Gola, J.; Hetzer,
G.; Raphoz, C. Tetrahedron Lett. 1997, 38, 8185-8188. (e) Roe, B. A.;
Boojamra, C. G.; Griggs, J. L.; Bertozzi, C. R. J. Org. Chem. 1996, 61,
6442-6445.
(11) (a) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112,
5811-5819. (b) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1991,
113, 5863-5864. (c) Danishefsky, S. J.; Koseki, K.; Griffith, D. A.; Gervay,
J.; Peterson, J. M.; McDonald, F. E.; Oriyama, T. J. Am. Chem. Soc. 1992,
114, 8331-8333.
(10) â-Configuration of 2 was determined on the basis of the observation
of NOE between H1 and H3 and the large coupling constant J1,2 ) 8.8 Hz.
3498
Org. Lett., Vol. 6, No. 20, 2004

of 17 in comparison to 5 is probably due to the acetyl group
being less electron-withdrawing than the aldehyde.4e,13
Consequently, cyclopropane 17 only reacted with strong
nucleophiles. To the best of our knowledge, these are the
first examples of an SN2 reaction at the anomeric carbon of
1,2-cyclopropanated sugars.
In summary, we have developed an alternative method for
the synthesis of 2-C-branched glucosides with exclusive
â-anomeric selection. 2′-Aldehydo (acetonyl) 2-O-Ms(Ts)-
R-C-mannosides undergo an intramolecular SN2 reaction to
form 1,2-cyclopropanated sugars. The cyclopropane inter-
mediates from the 2′-aldehydes then react with nucleophiles
(alcohols, thiols, and azide) by an SN2 reaction at the
anomeric carbon leading to 2-C-branched glycosides, while
1,2-cyclopropanes derived from 2′-ketones only react with
thiols to give 2-C-branched thioglycosides. Further studies
on the application of this reaction and the utilities of the
intermediates are currently in progress.
Table 1. Synthesis of 2-C-Branched Glycosidesa
entry substrate nucleophile base/solventb product (yield %)
1
2
3
4
5
1
6
6
1
6
6
MeOH
MeOH
PhOH
EtOH
EtOH
AllylOH
A
B
B
C
B
A
2 (72%)
2 (52%)
8 (62%)
9 (71%)
9 (51%)
6
10 (76%)
7
8
9
10
11
12
13
1 and 6 NaN3
1 and 6 PhSH
1 and 6 4-MeOPhSH
1 and 6 4-ClPhSH
A and B
B and D
B and D
B and D
D
11 (50-52%)
12 (67-86%)
13 (70-85%)
14 (72-83%)
15 (83%)
7
7
7
4-MeOPhSH
4-ClPhSH
MeOH
D
D
16 (85%)
17 (81%)
a Reaction was conducted at room temperature overnight. b Base/solvent
combinations: A,TEA/MeOH; B, K2CO3/MeCN; C, TEA/EtOH; D, K2CO3/
MeOH.
Acknowledgment. The work was supported in part by
National Research Council of Canada (to W.Z.) and by
National Science Council of Taiwan (to S.H.W.). We are
also grateful to Suzon Larocque for the assistance in NMR
analysis and Lisa Morrison for mass spectroscopic analysis.
produced 2-C-branched â-thioglycosides (12-16) in excel-
lent yields (entries 8-12). Surprisingly, when 7 was treated
with base in methanol, rather than the 2-C-branched methyl
â-glycoside being isolated, we obtained the stable 1,2-
cyclopropanated sugar 17, an intermediate predicted by the
mechanism illustrated in Scheme 2, as the major product
(entry 13).12 Treatment of 17 with thiols in K2CO3/MeOH
produced the expected 2-C-branched thioglycosides, but its
reaction with alcohols (MeOH and PhOH) was very sluggish
and yielded multiple byproducts. The diminished reactivity
Supporting Information Available: Experimental pro-
cedures and NMR spectra (1H, 13C, COSY, NOESY,
TOCSY, and HSQC) for products (2, 3, 6-17). This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0486627
(12) An attempt to isolate 1,2-cyclopropanated 5 was unsuccessful. For
17: δH 1.98 ppm (H-2, J1,2 ) 7.2 Hz), 2.34 (H-1′, J1,1′ ) 1.6), and 3.86
(H-1, J2,1′ ) 5.6 Hz). For complete assignment, see Supporting Information.
(13) Nucleophilic addition only takes place on cyclopropanes substituted
with electron-withdrawing groups, see: Danishefsky, S. J. Acc. Chem. Res.
1979, 12, 66-72.
Org. Lett., Vol. 6, No. 20, 2004
3499