Supporting Information © Wiley-VCH 2006

69451 Weinheim, Germany

1

Three-Step Synthesis of Sialic Acids and Derivatives [**]

Zhangyong Hong, Lei Liu, Che-Chang Hsu, and Chi-Huey Wong*

General. Reactions were monitored with analytical thin-layer chromatography (TLC) on

silica gel 60 F254 plates and visualized under UV (254 nm) and/or by staining with 5%

sulfuric acid or acidic ceric ammonium molybdate. 1H NMR spectra were recorded on a

Bruker DRX 500 MHz NMR spectrometer at 20 ºC. Chemical shifts (in ppm) were

determined relative to residual undeuterated solvent as an internal reference. Coupling

constant(s) in hertz (Hz) were measured from one-dimensional spectra. 13C Attached

Proton Test (C-Apt) spectra were obtained with Varian Mercury 300 MHz spectrometer

and were calibrated with CD3OD (δ 49.0 ppm) or uncalibrated in D2O. Mass spectra (ESI

and ESI-TOF High Accuracy Mass) were obtained by the analytical services of this

department.

Ethyl glyoxylate was purchased from Fluka as 50% solution in toluene. It exists partly in

the polymerized form, but can be used directly without any pretreatment. Di-p-

anisylmethylamine 10 was prepared according to the published procedure (Y. Ito, Y.

Kobayashi, T. Kawabata, M. Takase, S. Terashima, Tetrahedron 1989, 45, 5767-90).

Nitrone was prepared by a modified version of the published procedures (C. M.

Dicken, P. DeShong, J. Org. Chem. 1982, 47, 2047-2051; Y. Inouye, K. Takaya, H.

Kakisawa, Bull. Chem. Soc. Jpn. 1983, 56, 3541-3542): N-alkylhydroxylamine

hydrochloride or acetate (10.0 mmol), ethyl glyoxylate (2.04 g, 50% in toluene, 10.0

mmol), and sodium bicarbonate (1.68 g, 20.0 mmol) in toluene (20 ml) was stirred at

room temperature overnight. The solid was filtered and the filtrate was concentrated to

2

afford the nitrone whose 1H NMR and 13C NMR were the same as the published data.

This nitrone was then used directly without any purification.

General procedure for “one pot” synthesis of 9, 22, 25 and 28 through the modified

petasis coupling. Aldose sugar (20.0 mmol), di-p-anisylmethylamine (4.86 g, 20.0

mmol), and vinyl boronic acid dibutyl ester (7.36 g, 40.0 mmol) in aqueous ethanol (100

ml, ethanol:H2O = 4:1) was stirred at 50 oC for 72 hrs. Then TFA (6.0 ml) was added and

stirred for further 16 hrs. The solvent was evaporated and MeOH (50 ml) was added to

dissolve the residue. Sodium bicarbonate (3.36 g, 40.0 mmol) and Ac2O (2.55 g, 25.0

mmol) (for the preparation of 22, the activated ester of 2-acetoxyacetic acid was added

instead of Ac2O) was added and stirred for 1 hr at room temperature. The solid was

filtered and the filtrate was dried and the residue was purified through silica gel flash

chromatography (eluted with CH2Cl2 and MeOH) to afford the product in 50-60% based

on aldose sugar.

OH

OH

OH

OH

NHAc

1H NMR (500 MHz, CD3OD) 5.96 (ddd, J = 17.0 Hz, 10.5 Hz and 6.0 Hz, 1H, H-2), 5.18

(dt, J = 17.5 Hz and 1.5 Hz, 1H, H-1), 5.13 (dt, J = 10.5 Hz and 1.5 Hz, 1H, H-1), 4.46

(m, 1H, H-3), 3.72 (dd, J = 11.0 Hz and 3.5 Hz, 1H, H-7), 3.66 (dd, J = 8.5 Hz and 1.5

Hz, 1H, H-4), 3.63 (ddd, J = 8.5 Hz, 6.0 Hz and 3.5 Hz, 1H, H-6), 3.56 (dd, J = 11.0 Hz

and 5.5 Hz, 1H, H-7), 3.45 (dd, J = 8.0 Hz and 1.5 Hz, 1H, H-5), 1.94 (s, 3H, H-Ac); 13C-

APT NMR (75 MHz, CD3OD) 172.1, 135.9, 115.4, 71.3, 71.1, 70.4, 63.8, 54.1, 21.5;

ESI-MS (m/z): 242.0 [M+Na]+.

OH

OH

OH

OH

HN

OOAc

3

1H NMR (500 MHz, CD3OD) 5.91 (ddd, J = 17.0 Hz, 10.5 Hz and 5.5 Hz, 1H, H-2), 5.17

(dt, J = 17.5 Hz and 1.5 Hz, 1H, H-1), 5.14 (dt, J = 10.5 Hz and 1.5 Hz, 1H, H-1), 4.57

(m, 1H, H-3), 4.52 (s, 2H, H-Gc), 3.82 (dd, J = 7.0 Hz and 1.0 Hz, 1H, H-4), 3.72 (dd, J =

11.0 Hz, and 4.0 Hz, 1H, H-7), 3.64 (ddd, J = 9.0 Hz, 5.5 Hz and 3.0 Hz, 1H, H-6), 3.55

(dd, J = 11.0 Hz and 5.5 Hz, 1H, H-7), 3.53 (dd, J = 8.0 Hz and 1.0 Hz, 1H, H-5), 2.09 (s,

3H, H-Ac); 13C-APT NMR (75 MHz, CD3OD) 171.8, 170.1, 136.5, 116.6, 72.6, 71.8,

71.2, 64.9, 63.5, 56.1, 20.5; ESI-MS (m/z): 300.1 [M+Na]+.

OH

OH

NHAc

1H NMR (500 MHz, CD3OD) 5.86 (ddd, J = 17.0 Hz, 10.5 Hz and 7 Hz, 1H, H-2), 5.16

(dt, J = 17.5 Hz and 1.5 Hz, 1H, H-1), 5.13 (dt, 10.5 Hz and 1.5 Hz, 1H, H-2), 4.40 (m,

1H, H-3), 3.55 (ddd, J=6.5 Hz, 5.5 Hz and 4.5 Hz, 1H, H-4), 3.48 (dd, J = 11.5 Hz and

4.5 Hz, 1H, H-5), 3.42 (dd, J = 11.5 Hz and 6.5 Hz, 1H, H-5), 1.92 (s, 3H, H-Ac); 13C-

APT NMR (75 MHz, CD3OD) 172.7, 135.5, 117.4, 74.7, 64.5, 55.3, 22.7; ESI-MS (m/z):

182.0 [M+Na]+.

OH

OH

OH

OH

NHAc

OH 1H NMR (500 MHz, CD3OD) 5.97 (ddd, J = 17.5 Hz, 10.5 Hz and 6.0 Hz, 1 H, H-2),

5.18 (dt, J = 17.5 Hz and 1.5 Hz, 1 H, H-1), 5.13 (dt, J = 10.5 Hz and 1.5 Hz, 1H, H-1),

4.47 (m, 1H, H-3), 3.85 (td, J = 6.0 Hz and 0.5 Hz, 1H, H-4), 3.68 (dd, J = 8.5 Hz and 0.5

Hz, 1H), 3.57 (m, 4H), 1.94 (s, 3H, H-Ac); 13C-APT NMR (75 MHz, CD3OD) 173.4,

137.3, 116.5, 72.3, 71.7, 71.0, 70.5, 65.0, 55.4, 22.7; ESI-MS (m/z): 272.0 [M+Na]+.

General procedure for 1,3-dipolar cycloaddition with nitrone 19: Polyhydroxy olefin

(1.0 mmol) and nitrone 19 (346 mg, 2.0 mmol) in dioxane (20.0 ml) were stirred at 30 oC

for 14 days. After the complete conversion of the starting material as monitored by TLC,

the solvent was removed through evaporation and the residue was purified with normal

4

silica gel chromatography by eluting with MeOH and CH2Cl2 (the ratio is 2 % to 10 % of

MeOH in CH2Cl2 depended on different products. The yield of the desired product is 80-

90 %.

OH

OH

OH

OH

NHAc

O N

CO2Et

1H NMR (500 MHz, CD3OD) 4.68 (ddd, J = 8.5 Hz , 7.0 Hz and 1,5 Hz, 1H , H-4), 4.14

(m, 2H, H-CH2), 3.93 (t, J = 8.5 Hz, 1H, H-2), 3.87 (dd, J = 10.0 Hz and 1.5 Hz, 1H, H-

5), 3.80 (dd, J = 10.0 Hz and 0.5 Hz 1H, H-6), 3.73 (dd, J = 11.0 Hz and 3.0 Hz, 1H, H-

9), 3.63 (ddd, J = 8.5 Hz, 5.5 Hz and 3.5 Hz, 1H, H-8), 3.55 (dd, J = 11.5 Hz and 6.0 Hz,

1H, H-9), 3.34 (dd, J = 8.5 Hz and 0.5 Hz, 1H, H-7), 2.54 (ddd, J = 12.5 Hz, 8.5 Hz and

7.0 Hz, 1H, H-3), 2.15 (dt, J = 12.5 Hz and 8.5 Hz, 1H, H-3), 2.01 (s, 3H, H-Ac), 1.21 (t,

J = 7.0 Hz, 3H, H-CH3), 1.08 (s, 9H, H-CH3); 13C-APT NMR (75 MHz, CD3OD): 175.1,

174.3, 77.5, 72.2, 71.4, 70.6, 65.2, 62.5, 62.2, 61.3, 53.8, 39.0, 25.9(3C), 22.8, 14.4; ESI-

MS (m/z): 393.1 [M+H]+, 337.1 [M+H-C4H8]+.

OH

OH

OH

OH

HN

OOAc

O N

CO2Et

1H NMR (500 MHz, CD3OD) 4.69 (td, J = 8.0 Hz and 1.5 Hz, 1H, H-4), 4.59 (dd, J =

24.0 Hz and 15.0 Hz, 2H, H-Gc), 4.13 (m, 2H, H-CH2), 3.95 (dd, J = 10.0 Hz and 1.5 Hz,

1H, H-5), 3.91 (t, J = 8.0 Hz, 1H, H-2), 3.85 (dd, J = 10.0 Hz and 1.0 Hz, 1H, H-6), 3.74

(dd, J = 11.0 Hz and 3.5 Hz, 1H, H-9), 3.63 (ddd, J = 8.5 Hz, 5.5 Hz and 3.0 Hz, 1H, H-

8), 3.55 (dd, J = 11.5 Hz and 6.0 Hz, 1H, H-9), 3.37 (dd, J = 9.0 Hz and 1.0 Hz, 1H, H-7),

2.66 (ddd, J = 12.5 Hz, 8.5 Hz and 7.5 Hz, 1H, H-3), 2.16 (dt, J = 12.5 Hz and 8.0 Hz,

1H, H-), 1.21 (t, J = 7.0 Hz, 3H, H-CH3), 1.09 (s, 9H, H-CH3); 13C-APT NMR (75 MHz,

CD3OD) 174.3, 171.9, 171.6, 77.3, 72.3, 71.3, 70.5, 65.3, 63.7, 62.5, 62.1, 61.1, 53.9,

38.9, 26.0(3C), 20.6, 14.4; ESI-MS (m/z): 451.1 [M+H]+, 395.0 [M+H-C4H8]+.

5

OH

OH

NHAc

O N

CO2Et

1H NMR (500 MHz, CD3OD) 4.62 (ddd, J = 8.5 Hz, 7.0 Hz and 1.5 Hz, 1 H, H-4), 4.14

(m, 2H, H-CH2), 3.93 (t, J = 8.5 Hz, 1H, H-2), 3.81 (dd, J = 9.5 Hz and 2.0 Hz, 1H, H-5),

3.55 (ddd, J = 9.5 Hz, 5.5 Hz and 2.5 Hz, 1H, H-6), 3.53 (dd, J = 12.5 Hz and 2.5 Hz, 1H,

H-7), 3.42 (dd, J = 12.0 Hz and 6.0 Hz, 1H, H-7), 2.62 (ddd, J = 12.5 Hz, 8.5 Hz and 7.0

Hz, 1H, H-3), 2.12 (dt, J = 12.5 Hz and 8.5 Hz, 1H, H-3), 1.21 (t, J = 7.0 Hz, 3H, H-

CH3), 1.08 (s, 9H, H-CH3); 13C-APT NMR (75 MHz, CD3OD) 174.4, 174.3, 77.4, 73.1,

65.0, 62.5, 62.2, 61.3, 53.6, 38.8, 25.9 (3C), 22.8, 14.4; ; ESI-MS (m/z): 333.1 [M+H]+,

277.0 [M+H-C4H8]+.

OH

OH

OH

OH

NHAc

O N

CO2Et

OH

1H NMR (500 MHz, CD3OD) 4.69 (ddd, J = 8.5 Hz, 7.0 Hz and 1.5 Hz, 1H, H-4), 4.15

(m, 2H, H-CH2), 3.94 (t, J = 8.0 Hz, 1H, H-2), 3.87 (m, 2H, H-5 and H-6), 3.82 (dd, J =

10.5 Hz and 0.5 Hz, 1H, H-8), 3.59 (m, 3H, H-9 and 2H-10), 3.51 (dd, J = 9.5 Hz and 0.5

Hz, 1H, H-7), 2.65 (ddd, J = 12.5 Hz, 8.5 Hz and 7.0 Hz, 1 H, H-3), 2.15 (dt, J = 12.5 Hz

and 8.5 Hz, 1H, H-3), 1.21 (t, J = 7.0 Hz, 3H, H-CH3), 1.08 (s, 9H, H-CH3); 13C-APT

NMR (75 MHz, CD3OD) 175.1, 174.3, 77.5, 71.7, 70.7, 70.6, 70.3, 65.1, 62.5, 62.2, 61.3,

54.0, 39.0, 25.9 (3C), 22.8, 14.4; ESI-MS (m/z): 423.1 [M+H]+, 367.1 [M+H-C4H8]+.

General procedure for the ring opening of isoxazoline catalyzed by base: Isoxazoline

(0.25 mmol) and MeONa in anhydrous MeOH (0.05M, 10 ml) were stirred at room

temperature overnight. Then water (10 ml) was added and the solution was stirred for 24

hrs. The mixture was purified directly with ion-exchange chromatography (Dowex 1X8-

6

100 resin, formate form) with a 0-2 N gradient of formic acid, providing the desired

product in the pure form in 55-60% yield.

O

OH

CO2HHOAcHN

OHHO

OH

1H NMR (500 MHz, D2O) 4.07 (m, 1H), 4.04 (dd, J = 10.5 Hz and 1.0 Hz, 1H), 3.95 (t, J

= 10.0 Hz, 1H), 3.87 ( dd, J = 12.0 Hz and 3.0 Hz, 1H), 3.78 (m, 1H), 3.65 (dd, J = 10.5

Hz and 6.5 Hz, 1H), 3.56 (dd, J = 9.0 Hz and 1.0 Hz, 1H), 2.28 (dd, J = 13.0 Hz and 5.0

Hz, 1H), 2.08 (s, 3H), 1.88 (dd, J = 13.0 Hz and 11.5 Hz, 1H); 13C-APT NMR (75 MHz,

D2O) 175.0, 174.6, 95.8, 70.5, 70.4, 68.4, 67.0, 63.3, 52.2, 39.1, 22.2; HRMS (ESI-TOF)

calcd for C11H19NO9 (M-H)- 308.0982, found 308.0990.

O

HO

OH

CO2H

OH

OH

HO

OHO

HN

D-Neu5Gc 1H NMR (500 MHz, D2O) 4.18 (s, 2H), 4.15 (m, 2H), 4.06 (t, J = 10.0 Hz, 1H), 3.87 (dd,

J = 12.0 Hz and 2.5 Hz, 1H), 3.81 (m, 1H), 3.65 (dd, J = 12.0 Hz and 6.0 Hz, 1H), 3.57

(d, J = 9.0 Hz, 1H), 2.28 (dd, J = 13.0 Hz and 5.0 Hz, 1H), 1.88 (t, J = 12.5 Hz, 1H); 13C-

APT NMR (75 MHz, D2O) 176.8, 175.7, 96.6, 70.6, 70.2, 68.5, 67.1, 63.3, 61.1, 52.1,

39.6; HRMS (ESI-TOF) calcd for C11H19NO10 (M-H)- 324.0931, found 324.0956.

O

OH

CO2HHOAcHN

OH

1H NMR (500 MHz, D2O) 4.04 (ddd, J = 11.5 Hz, 10.0 Hz and 5.0 Hz, 1H), 3.83 (ddd, J

= 10.5 Hz, 5.0 Hz and 2.5 Hz, 1H), 3.75 (t, J = 10.0 Hz, 1H), 3.69 (m, 2H), 2.29 (dd, J =

13.0 Hz and 5.0 Hz, 1H), 2.08 (s, 3H), 1.86 (dd, J = 13.0 Hz and 12.0 Hz, 1H); 13C-APT

7

NMR (75 MHz, D2O) 175.8, 175.0, 96.0, 72.8, 67.0, 61.2, 52.5, 39.5, 22.2; HRMS (ESI-

TOF) calcd for C9H15NO7 (M-H)- 248.0770, found 248.0785.

O

OH

CO2HHOAcHN

OHHOHO

OH

1H NMR (500 MHz, D2O) 3.94-4.08 (m, 4H), 3.70-3.76 (m, 4H), 2.26 (dd, J = 13.0 Hz

and 4.5 Hz, 1H), 2.10 (s, 3H), 1.88 (t, J = 12.5 Hz, 1H); 13C-APT NMR (75 MHz, D2O)

176.9, 175.0, 96.7 70.5, 70.3, 69.1, 67.7, 67.4, 63.4, 52.5, 39.5, 22.2; HRMS (ESI-TOF)

calcd for C12H21NO10 (M-H)- 338.1087, found 338.1101.

8

Compound 6

9

Compound 6

10

Compound 9

11

Compound 9

12

Compound 16

13

Compound 16

14

Compound 16

15

Compound 18

16

Compound 18

17

Compound 19

18

Compound 19

19

Compound 19

20

Compound 20

21

Compound 20

22

Compound 21

23

Compound 21

24

Compound 22

25

Compound 22

26

Compound 22

27

Compound 23

28

Compound 23

29

Compound 24

30

Compound 24

31

Compound 25

32

Compound 25

33

Compound 25

34

Compound 26

35

Compound 26