Efficient dehydrative sialylation of C-4-aminated sialyl-hemiketal donors with Ph2SO/Tf2O

Full text of DOI:10.1021/jo802396a

Efficient Dehydrative Sialylation of C-4-Aminated
Sialyl-Hemiketal Donors with Ph2SO/Tf2O
Deju Ye, Wenfeng Liu, Dengyou Zhang, Enguang Feng,
Hualiang Jiang, and Hong Liu*
The Center for Drug DiscoVery and Design, State Key
Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences,
FIGURE 1. The structures of donors 1-5.
neighboring group participation;5 the modification of the amino
protective groups at the C-5 position;2d,6 the formation of 1,5-
lactam-Neu,7 5-N,4-O-carbonyl-Neu8 or 5-N,7-O-oxazinanone;9
and the development of new promoters. However, R-sialylation
remains a formidable challenge in that the reaction often
proceeds with low yields and poor R-stereoselectivity, and is
characterized by undesirable 2,3-elimination due to an electron-
withdrawing group at the anomeric center, the lack of a
participating auxiliary substituent adjacent to the anomeric
center, and a sterically hindered tertiary anomeric center.2f,g
Shanghai 201203, People’s Republic of China
hliu@mail.shcnc.ac.cn
ReceiVed October 27, 2008
Recently, Gin developed a new method for direct dehydrative
sialylation with C2-hemiketal sialyl donors (1, 2, Figure 1) using
the activation system Ar2SO/Tf2O.10 This was further extended
by Crich to the sialylation of thioglycoside donors (3-5) in
the presence of the hindered non-nucleophilic base 2,4,6-tri-
tert-butylpyrimidine (TTBP).11 It provides high yields and
moderate R-stereoselectivities for donors 1-3, and predominant
ꢀ-stereoselectivities for donors 4 and 5. With a view toward
augmenting R-stereoselectivity, we are interested in developing
rapid, low-temperature, R-stereoselective sialylations from C2-
hemiketal sialyl donors, avoiding the use of the base TTBP that
serves as a triflic acid scavenger for thioglycoside donors.
An efficient approach to the dehydrative sialylation of various
substrates with C-4-aminated sialyl-hemiketal donors by
using the reagent combination of diphenyl sulfoxide and
triflic anhydride is reported. By using a C-4-hindered non-
nucleophilic amine auxiliary, excellent yields and high
R-stereoselectivities were obtained for coupling with a wide
range of primary and secondary acceptors.
We report herein a series of C2-hemiketal sialyl donors in
which the C-4 position is substituted with cyclic secondary
amines as auxiliaries for the preparation of R-sialyl conjugates.
In this context, cyclic secondary amines were employed because
of their adaptations to the reaction of simultaneously stereose-
lective 2-O-deacetylation and 4-amination of peracetylated
Sialic acid residues are incorporated in a wide range of
oligosaccharides and glycoconjugates and are known to play
important biological roles in higher animals and humans.1 The
lead member of the series, N-acetylneuraminic acid (Neu5Ac),
is typically linked R-(2,3) or R-(2,6) to galactoside residues, or
is polymerized in the form of R-(2,8) or R-(2,9) linkages. Over
the years, a wide spectrum of sialylation methodologies for high
stereoselectivity and high yielding synthesis of these complex
sialoconjugates have been devised.2 These methodologies can
be characterized into several types: the introduction of various
leaving groups at the C-2 position;3 the incorporation of
participating auxiliaries at the C-3 position;4 the use of C-1
(5) (a) Takahashi, T.; Tsukamoto, H.; Yamada, H. Tetrahedron Lett. 1997,
38, 8223–8226. (b) Haberman, J. M.; Gin, D. Y. Org. Lett. 2001, 3, 1665–1668.
(c) Ishiwata, A.; Ito, Y. Synlett 2003, 1339–1343.
(6) (a) Demchenko, A. V.; Boons, G. J. Chem. Eur. J. 1999, 5, 1278–1283.
(b) Meijer, A.; Ellervik, U. J. Org. Chem. 2004, 69, 6249–6256. (c) De Meo,
C.; Priyadarshani, U. Carbohydr. Res. 2008, 343, 1540–1522. (d) Demchenko,
A. V.; Boons, G. J. Tetrahedron Lett. 1998, 39, 3065–3068. (e) De Meo, C.;
Demchenko, A. V.; Boons, G. T. J. Org. Chem. 2001, 66, 5490–5497. (f) Lin,
C. C.; Wong, C. H. Angew. Chem., Int. Ed. 2001, 40, 2900–2903. (g) Mukaiyama,
T.; Mandai, H.; Jona, H. Chem. Lett. 2002, 31, 1182–1183. (h) Tanaka, H.;
Adachi, M.; Takahashi, T. Chem. Eur. J. 2005, 11, 849–862. (i) Ando, H.; Koike,
Y.; Ishida, H.; Kiso, M. Tetrahedron Lett. 2003, 44, 6883–6886. (j) Tanaka, K.;
Goi, T.; Fukase, K. Synlett 2005, 2958–2962.
(7) Ando, H.; Koike, Y.; Koizumi, S.; Ishida, H.; Kiso, M. Angew. Chem.,
Int. Ed. 2005, 44, 6759–6763.
(8) (a) Tanaka, H.; Nishiura, Y.; Takahashi, T. J. Am. Chem. Soc. 2006,
128, 7124–7125. (b) Farris, M.; De Meo, C. Tetrahedron Lett. 2007, 48, 1255–
1227.
(1) (a) Schauer, R. Sialic Acids: Chemistry, Metabolism and Function;
Springer-Verlag: New York, 1982; Vol. 10. (b) Simanek, E. E.; McGarvey, G. J.;
Jablonwski, J. A.; Wong, C. H. Chem. ReV. 1998, 98, 833–862.
(2) (a) Kiefel, M. J.; von Itzstein, M. Chem. ReV. 2002, 102, 471–490. (b)
Ye, X. S.; Huang, X. F.; Wong, C.-H. Chem. Commun. 2001, 974–975. (c) Wang,
Y. H.; Ye, X. S.; Zhang, L. H. Org. Biomol. Chem. 2007, 5, 2189–2200. (d)
Lin, C.-C.; Huang, K.-T.; Lin, C.-C. Org. Lett. 2005, 7, 4169–4172. (e)
Hanashima, S.; Castagner, B.; Nokami, T.; Seeberger, P. H. Org. Lett. 2007, 9,
1777–1779. (f) Boons, G.-J.; Demchenko, A. V. Chem. ReV. 2000, 100, 4539–
4565. (g) Ando, H.; Imamura, A. Trends Glycosci. Glycotechnol. 2004, 16, 293–
303.
(9) Tanaka, H.; Ando, H.; Ishihara, H.; Koketsu, M. Carbohydr. Res. 2008,
343, 1585–1593.
(3) (a) Zhang, Z.; Ollmann, I. R.; Ye, X.; Wischnat, R.; Baasov, T.; Wong,
C.-H. J. Am. Chem. Soc. 1999, 121, 734–753. (b) Cai, S. T.; Yu, B. Org. Lett.
2003, 5, 3827–3830.
(4) (a) Okamoto, K.; Kondo, T.; Goto, T. Tetrahedron 1987, 43, 5909–5918.
(b) Ito, Y.; Ogawa, T. Tetrahedron 1990, 46, 89–102. (c) Hossain, N.;
Magnusson, G. Tetrahedron Lett. 1999, 40, 2217–2220.
(10) (a) Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997, 119,
7597–7598. (b) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122, 4269–
4279. (c) Haberman, J. M.; Gin, D. Y. Org. Lett. 2003, 5, 2539–2541.
(11) (a) Crich, D.; Li, W. Org. Lett. 2006, 8, 959–962. (b) Crich, D.; Li, W.
J. Org. Chem. 2007, 72, 2387–2391. (c) Crich, D.; Wu, B. L. Tetrahedron 2008,
64, 2042–2047.
10.1021/jo802396a CCC: $40.75
Published on Web 01/16/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1733–1735 1733

TABLE 1. Sialylation of C-4-Aminated Sialyl-Hemiketal Donors
with MeOH
SCHEME 1. Synthesis of Donors 6a-f
SCHEME 2. A Hypothetical Mechanism
a Isolated yields. b Determined by LC/MS. c Reported in ref 10c:
sialylation of donor 1 with 2-propanol as acceptor. d Reported in ref
11a: sialylation of donor 2 with methanol as acceptor.
Neu5Ac (Scheme 1),12 and their likelihoods to serve as triflic
acid scavengers that promote direct dehydrative sialylation. It
was reported that in situ generation of a diphenyl sulfoxide
bi(triflate) intermediate 7 would lead to rapid activation of the
C2-hemiketal within 6 to afford the C2-sialyloxosulfonium
species 8, which was subsequently converted to the sialyl
conjugate 11 with an appropriate nucleophilic acceptor (Scheme
2).10 We postulate that the sialyl donor 8, which has a hindered
non-nucleophilic tertiary amine, can subsequently trap the
anionic byproduct of activation, triflate, to give two covalent
double ion-pair intermediates 9 and 10. Of these two putative
reactive intermediates, the axial (ꢀ) orientation 9 is likely to
predominate due to donor 6 being a ꢀ-anomer. More impor-
tantly, the repulsive interaction on the double ion-pair is also
likely to make 9 adopt an axial (ꢀ) orientation, thus resulting
in the preferred formation of the desired R-sialoside.
FIGURE 2. X-ray crystal structure of sialoside 11a.
This hypothetical mechanism was initially exemplified by the
coupling of a series of C-4-aminated sialyl-hemiketal donors
with the model sialyl acceptor methanol by utilizing the Ph2SO/
Tf2O activation system. The resulting yields and anomeric
selectivities of the sialylation reactions are summarized in Table
1. It is clear that using the standard protocol, the C-4 cyclic
amine auxiliary exerts a dramatic effect in favoring the
R-sialylation of the methanol acceptor.13 For example, the
coupling of a sialyl-hemiketal donor incorporating the C-4
morpholin-4-yl (Table 1, entry 1, 6a) amine with methanol
proceeded with excellent yield and high R-selectivity (98%
yield, R:ꢀ ) 97:3) compared with the donors without the C-4
cyclic amine auxiliary (donors 1 and 3) with a similar coupling
protocol (Table 1, entry 7, 11g; 98%, yield, 1:2, R:ꢀ;10 entry 8,
11h; 94% yield, 1.5:1, R:ꢀ11a). The structure of the R-sialoside
11a was initially confirmed by COSY and HSQC NMR
experiments, and the anomeric configuration was assigned on
2.10-2.30), H4 (R-anomer: δ ) 2.30-2.60 ppm; ꢀ-anomer: δ
) 2.80-3.10), and H9a (|R-anomer δ Η9a - δ H9b| < |ꢀ-
anomer δ Η9a - δ H9b|; R-anomer: H9a, δ ) 4.20-4.40 ppm;
ꢀ-anomer: δ ) 4.50-4.80).5b,10c,11a,b,14a The R-anomeric con-
figuration of 11a was further confirmed by X-ray crystal-
lographic analysis (Figure 215). More dramatic illustrations of
the favorable stereochemical influence of the C-4 cyclic amine
auxiliary arise in the sialylation examples shown in Table 1
(entries 2-6, sialosides 11b-f; R predominant).
Next, with 6a as the model sialyl-hemiketal donor, a variety
of alcohols (12a-i) were examined as acceptors under the same
reaction conditions, and the results are summarized in Table 2.
Sialylation of primary and secondary alcohols with donor 6a
proceeded smoothly with excellent yields and a high level of
R-selectivities (Table 2, entries 1-4). For the hindered tertiary
14
1
the basis of empirical H NMR rules. Thus, the most useful
characteristic parameters for a particular anomer are the chemical
shifts of H3eq (R-anomer: δ ) 2.40-2.60; ꢀ-anomer: δ )
(14) The commonly used empirical 1H NMR rules are based on differences
among H3, H4, and H9 chemical shifts, as well as coupling constants between
3
H7 and H8, and, preferably, the sialic acid JCl, H3ax. For details, see: (a)
Dabrowski, U.; Friebolin, H.; Brossmer, R.; Supp, M. Tetrahedron Lett. 1979,
20, 4637–4640. (b) Hori, H.; Nakajima, T.; Nishida, Y.; Ohrui, H.; Meguro, H.
Tetrahedron Lett. 1988, 29, 6317–6320. (c) Atsufumi, N.; Tohru, T.; Nobuaki,
M.; Kenji, M. Org. Lett. 2007, 9, 4742–4744.
(15) CCDC 687283 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(12) (a) Ye, D. J.; Li, J.; Zhang, J.; Liu, H.; Jiang, H. L. Tetrahedron Lett.
2007, 48, 4023–4027. (b) Ye, D. J.; Deng, G. H.; Liu, W. F.; Feng, E. G.; Liu,
H.; Jiang, H. L. Tetrahedron 2008, 64, 6544–6550.
(13) This protocol, employing 1.0 equiv of donor, 2.0 equiv of Ph2SO, and
1.4 equiv of Tf2O, is similar to that reported in ref 10c.
1734 J. Org. Chem. Vol. 74, No. 4, 2009

TABLE 2. Sialylation of C-4 Morpholin-4-yl Sialyl-Hemiketal
Donor 6a with Acceptor Alchoholsa
substrate-dependent situation was also observed when sialylating
with the sialyl donor 3.11a
In summary, we have demonstrated that the challenging
R-sialylation with C-4-aminated sialyl-hemiketal donors can be
efficiently performed by using the Ph2SO/Tf2O promotion
system. The introduction of a hindered non-nucleophilic cyclic
amine at the C-4 position is demonstrated to be important in
these couplings and is anticipated to function in the formation
of a double ion-pair intermediate by trapping the anionic triflate.
Sialylation of a series of alcohol nucleophiles produced excellent
yields and anomeric selectivities. With this new procedure, a
series of 4-aminated Neu5Ac R-(2,6) Gal glycosidic linkages
can be installed efficiently, which can be further explored to
prepare a variety of biologically relevant sialyl-conjugated
derivatives.
Experiment Section
General Experimental Procedure for the Sialylation Reac-
tions. To a solution of C-4-aminated sialyl-hemiketal donor 6 (0.10
mmol) and diphenyl sulfoxide (Ph2SO, 0.20 mmol, 2.0 equiv) in
anhydrous CH2Cl2 (2 mL) at -78 °C under positive argon pressure
was added trifluoromethanesulfonic anhydride (Tf2O, 23.2 µL, 0.14
mmol, 1.4 equiv). The reaction was stirred for 1 h, followed by
the addition of a solution of acceptor 12 (0.25 mmol, 2.5 equiv) in
anhydrous CH2Cl2 (0.5 mL) at -78 °C. The resulting solution was
warmed to -50 °C and stirred for 2 h, then dry triethlamine (139.2
µL, 1.0 mmol, 10.0 equiv) was added. The resulting mixture was
concentrated, and the residue was dissolved with EA (100 mL),
then washed with water (2 × 20 mL) and brine. The organic layer
was dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The sialosides were isolated by flash column chromatog-
raphy (see the Supporting Information for details).
Acknowledgment. We gratefully acknowledge financial
support from the State Key Program of Basic Research of China
(Grant 2006BAI01B02), the National Natural Science Founda-
tion of China (Grants 20721003 and 20472094), the Basic
Research Project for Talent Research Group from the Shanghai
Science and Technology Commission, and the 863 Hi-Tech
Program of China (Grants 2006AA020602).
Supporting Information Available: Experimental details and
characterization data for all compounds, and crystallographic
information files (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
a 6a was chosen as the model donor. b Isolated yields. c Determined
by LC/MS. d No coupling sialosides but only the 2,3-glycal derivative
was detected. e Isolated ratios.
JO802396A
(16) Determined by LC-Ms and 1H NMR.
alcohols 12e and 12f, no coupling sialosides but only the
undesired 2,3-glycal derivative16 was detected. This may be due
to the steric hindrance of a cyclic amine at the C-4 position
that prevents the nucleophilic attack on the R-face of intermedi-
ate 9. Optimal R-selectivities were obtained for the important
galactose 6-OH derivatives (Table 2, entries 7-9). Interestingly,
however, considerably lower selectivity was obtained with a
glucose 6-OH derivative (Table 2, entry 10, 1.5:1, R:ꢀ). This
1H NMR (300 MHz, CDCl3, ppm) δ 1.92 (s, 3H), 2.02 (s, 3H), 2.04 (s, 3H),
2.10 (s, 3H), 2.51-2.57 (br, 2H), 2.68-2.74 (br, 2H), 3.21 (m, 1H), 3.55-3.68
(br, m, 4H), 3.77 (s, 3H), 4.08-4.18 (m, 1H), 4.26-4.34 (m, 2H), 4.62 (dd, J
) 12.3, 3.3 Hz, 1H), 5.32-5.36 (m, 1H), 5.55 (t, J ) 4.2 Hz, 1H), 6.09 (d, J )
2.7 Hz, 1H); LC-Ms m/z 501 [M + H]+ 100%.
J. Org. Chem. Vol. 74, No. 4, 2009 1735