TS Analogue Inhibitors of UDP-GlcNAc 2-Epimerase
was cooled to 0 °C and quenched with methanol (30 mL). After
5 min, the solution was concentrated under reduced pressure
and coevaporated with toluene. Purification by flash chroma-
tography (toluene/acetone 2:1) afforded 12 (3.0 g, 6.4 mmol,
86%) as a colorless solid: TLC (toluene/acetpme ) 2:1), Rf )
0.27; [R]D (c ) 1, acetone) +22.4; mp 152 °C; 1H NMR (250
MHz, CDCl3) δ ) 1.96, 2.01, 2.05, 2.09 (4 s, 12 H, Ac), 2.13 (d,
J H,P ) 18.5 Hz, 2 H, 1a,b-H), 3.70, 3.72 (2 d, J H,P ) 11.3 Hz, 6
H, OMe), 4.11 (dd, J 7a,b ) 12.4 Hz, J 7a,6 ) 2.4 Hz, 1 H, 7a-H),
4.20 (dd, J 7a,b ) 12.4 Hz, J 7b,6 ) 4.4 Hz, 1 H, 7b-H), 4.29 (ddd,
J 6,5 ) 10.1 Hz, J 6,7b ) 4.4 Hz, J 6,7a ) 2.4 Hz, 1 H, 6-H), 4.87
(dd, J 3,4 ) 10.0 Hz, J 3,OH ) 1 Hz, 1 H, 3-H), 5.06 (dd, J 5,6 ) J 5,4
) 10 Hz, 1 H, 5-H), 5.49 (dd, J 4,5 ) J 4,3 ) 10 Hz, 1 H, 4-H),
6.22 (bs, 1 H, OH); MALDI-MS (positive mode, DHB) m/z )
493.9 [M + Na]+. C17H27O13P (470.37), calcd: C, 43.41; H, 5.79.
Found: C, 43.72; H, 5.57.
(Z)-3,4,5,7-Tet r a -O-a cet yl-2,6-a n h yd r o-1-d eoxy-1-d i-
m eth oxyp h osp h or yl-D-m a n n o-h ep t-1-en itol (16). The pro-
cedure described for the synthesis of 15 was followed using
13 (218 mg, 0.46 mmol) to afford 16 (154 mg, 0.33 mmol, 72%)
as a colorless oil: TLC (toluene/acetone ) 4:3), Rf ) 0.19; [R]D
1
(c ) 1, acetone), +7.5; H NMR (250 MHz, CDCl3) δ ) 2.06,
2.07, 2.08, 2.10 (4 s, 12 H, Ac), 3.70 (2 d, J H,P ) 11.5 Hz, 6 H,
OMe), 4.18 (m, 1 H, 6-H), 4.30 (m, 2 H, 7a,b-H), 5.13 (d, J 1,P
)
10.3 Hz, 1 H, 1-H), 5.21 (m, 2 H, 4-H, 5-H), 5.67 (d, J 3,4 ) 3.0
Hz, 1 H, 3-H); 13C NMR (63 MHz, CDCl3) δ ) 18.2, 18.3, 18.6,
18.6 (4 C, 4 Ac), 50.4 (2d, J C,P ) 6 Hz, 2 C, OMe), 60.1 (1 C,
7-C), 64.7 (1 C, 5-C), 65.6 (d, J C,P ) 15.7 Hz, 1 C, 3-C), 67.5 (1
C, 4-C), 74.5 (1 C, 6-C), 95.5 (d, J C,P ) 191 Hz, 1 C, 1-C), 158.4
(1 C, 2-C), 167.2, 167.2, 167,5, 168.4 (4 C, 4 Ac); 31P NMR (162
MHz, CDCl3) δ ) 18.4 (1P); MALDI-MS (positive mode, DHB,
THF) m/z ) 453 [M + H]+, 475 [M + Na]+, 491 [M + K]+.
C
17H25O12P (452.36), calcd: C, 45.14; H, 5.57. Found: C, 44.79;
H, 5.18.
(Z)-3,4,5,7-Tet r a -O-a cet yl-2,6-a n h yd r o-1-d eoxy-1-d i-
3,4,5,7-Tetr a-O-acetyl-1-deoxy-1-dim eth oxyph osph or yl-
r-D-m a n n o-2-h ep t u lop yr a n ose (13). The procedure de-
scribed for the synthesis of 12 was followed using 10 (600 mg,
0.91 mmol) to afford 13 (240 mg, 0.51 mmol, 56%) as a colorless
syrup: TLC (toluene/acetone ) 3:2), Rf ) 0.55; [R]D (c ) 1,
acetone) +1.8; 1H NMR (250 MHz, CDCl3) δ ) 1.93, 2.01, 2.03,
2.15 (4 s, 12 H, Ac), 1.95 (m, 1 H, 1a-H), 2.25 (dd, J H,P ) 19
Hz, J 1a,b ) 15.2 Hz, 1 H, 1b-H), 3.72, 3.78 (2 d, J H,P ) 11.2 Hz,
m eth oxyp h osp h or yl-D-ga la cto-h ep t-1-en itol (17). The pro-
cedure described for the synthesis of 15 was followed using
14 (200 mg, 0.43 mmol) to afford 17 (156 mg, 0.34 mmol, 80%)
as a colorless oil: TLC (toluene/acetone ) 1:1), Rf ) 0.25; [R]D
1
(c ) 1, acetone), +86.7; H NMR (250 MHz, CDCl3) δ ) 1.98,
2.06, 2.13, 2.16 (4 s, 12 H, 4 Ac), 3.72 (2 d, J H,P ) 11.5 Hz, 6
H, OMe), 4.14-4.29 (m, 3 H, 6-H, 7a,b-H), 5.05-5.13 (m, 2 H,
1-H, 4-H), 5.54 (d, J ) 3 Hz, 1 H, 5-H), 5.73 (ddd, J 3,4 ) 10.6
Hz, J 3,P ) 3.7 Hz, J 3,1 ) 1.8 Hz, 1 H, 3-H); 13C NMR (63 MHz,
6 H, OMe), 4.08-4.28 (m, 3 H, 6-H, 7a,b-H), 5.17 (dd, J 5,6
)
J 5,4 ) 9.9 Hz, 1 H, 5-H), 5.23 (d, J 3,4 ) 3.4 Hz, 1 H, 3-H), 5.46
(dd, J 4,5 ) 9.9 Hz, J 4,3 ) 3.4 Hz, 1 H, 4-H), 6.34 (s, 1 H, OH);
MALDI-MS (positive mode, DHB, dioxane) m/z ) 493.0 [M +
Na]+, 509.0 [M + K]+. C17H27O13P (470.37), calcd: C, 43.41;
H, 5.79; Found: C, 43.13; H, 5.84.
CDCl3) δ ) 20.5, 20.6, 20.7, 20.7 (4 C, 4 Ac), 52.0 (2 d, J C,P
6 Hz, 2 C, OMe), 61.0(1 C, 7-C), 66.6 (d, J C,P ) 13.1 Hz, 1 C,
3-C), 67.0 (1 C, 5-C), 70.7, 76.3 (2 C, 4-C, 6-C), 97.5 (d, J C,P
)
)
3,4,5,7-Tetr a-O-acetyl-1-deoxy-1-dim eth oxyph osph or yl-
r-D-ga la cto-2-h ep tu lop yr a n ose (14). The procedure de-
scribed for the synthesis of 12 was followed using 11 (1.8 g,
2.7 mmol) to afford 14 (280 mg, 0.6 mmol, 22%) as a colorless
syrup: TLC (toluene/acetone ) 3:2), Rf ) 0.35; [R]D (c ) 0.5,
190 Hz, 1 C, 1-C), 163.2 (1 C, 2-C), 169.7-170.5 (4 C, 4 Ac);
MALDI-MS (positive mode, DHB, THF) m/z ) 475.4 [M +
Na]+, 491.5 [M + K]+. C17H25O12P (452.36), calcd: C, 45.14;
H, 5.57. Found: C, 44.94; H, 5.48.
1
Bis-2,6-lu tid in iu m (Z)-3,4,5,7-Tetr a -O-a cetyl-2,6-a n h y-
d r o-1-d eoxy-D-glu co-h ep t-1-en itol-1-yl P h osp h on a te (18).
To a solution of 15 (70 mg, 0.15 mmol) in abs acetonitrile (4
mL) and 2,6-lutidine (99 µL, 0.85 mmol) was added dropwise
TMSBr (84 µL, 0.77 mmol) at 0 °C and under argon. After
stirring at 0 °C to room temperature for 3 h, the reaction
mixture was concentrated under reduced pressure. After
coevaporation with abs acetonitrile (twice) and then with dry
methanol, the residue was again dissolved in methanol and
Et3N (0.1 mL) was added. Concentration under reduced
pressure gave the 2,6-lutidinium salt 18 in quantitative yield.
dioxane) + 58.8; H NMR (250 MHz, CDCl3) δ ) 1.93, 2.00,
2.09, 2.12 (4 s, 12 H, 4Ac), 1.91-2-22 (m, 2 H, 1a,b-H), 3.70,
3.77 (2 d, J H,P ) 11.2 Hz, 6 H, OMe), 4.09 (m, 2 H, 7a,b-H),
4.50 (ddd, J 6,7a ) J 6,7b ) 6.7 Hz, J 6,5 ) 1 Hz, 1 H, 6-H), 5.11
(dd, J 3,4 ) 10.5 Hz, J 3,OH ) 1.6 Hz, 1 H, 3-H), 5.36 (d, J 4,3
)
10.5 Hz, J 4,5 ) 3.3 Hz, 1 H, 4-H), 5.46 (dd, J 5,4 ) 3.3 Hz, J 5,6
) 1.3 Hz, 1 H, 5-H), 6.19 (bs, 1 H, OH); MALDI-MS (positive
mode, DHB, dioxane) m/z ) 493.1 [M + Na]+, 509.1 [M + K]+;
C
17H27O13P (470.37), calcd: C, 43.41; H, 5.79. Found: C, 43.41;
H, 5.51.
(Z)-3,4,5,7-Tet r a -O-a cet yl-2,6-a n h yd r o-1-d eoxy-1-d i-
Compound 18 was used for the next step without purifica-
tion: 1H NMR (250 MHz, MeOH-d4) δ ) 2.02, 2.03, 2.05, 2.12
(4 s, 12 H, Ac), 2.78 (s, 12 H, lutidine), 4.08 (ddd, J 6,5 ) 9.5
m eth oxyp h osp h or yl-D-glu co-h ep t-1-en itol (15). To a solu-
tion of 12 (1.3 g, 2.7 mmol) in abs dichloromethane (50 mL)
were added pyridine (5 mL) and trifluoroacetic anhydride (3.5
mL, 24 mmol) at 0 °C. The solution was stirred at room
temperature for 16 h. The reaction was stopped by adding a
solution of NaHCO3, and the water phase was extracted with
EtOAc. The organic layer was dried over MgSO4 and concen-
trated under reduced pressure. Purification by flash chroma-
tography (toluene/acetone 2:1) afforded 15 (940 mg, 2.1 mmol,
77%) as a colorless oil: TLC (toluene/acetone ) 4:3), Rf ) 0.18;
Hz, J 6,7b ) 4.6 Hz, J 6,7a ) 2.4 Hz, 1 H, 6-H), 4.26 (dd, J 7a,b
)
13.4 Hz, J 7a,6 ) 2.4 Hz, 1 H, 7a-H), 4.39 (dd, J 7b,a ) 13.4 Hz,
J 7b,6 ) 4.6 Hz, 1 H, 7b-H), 5.17 (dd, J 4,5 ) J 5,6 ) 9.5 Hz, 1 H,
4-H), 5.22 (dd, J 5,4 ) J 5,6 ) 9.5 Hz, 1 H, 5-H), 5.32 (dd, J 1,P
)
10.8 Hz, J 1,3 ) 1.8 Hz, 1 H, 1-H), 5.42 (ddd, J 3,4 ) 9.5 Hz, J 3,P
) 3.0 Hz, J 3,1 ) 1.8 Hz, 1 H, 3-H), 7.57 (d, 4 H, lutidine), 8.18
(dd, 2 H, lutidine); MALDI-MS (negative mode, ATT) m/z )
423.8 [M - 2 Lut+ + H+]-; C15H19O12P × 2 C7H10N (638.6).
1
[R]D (c ) 2, acetone) +55.3; H NMR (600 MHz, CDCl3) δ )
2.02, 2.04, 2.10, 2.12 (4 s, 12 H, Ac), 3.71 (2 d, J H,P ) 11.3 Hz,
6 H, OMe), 4.07 (ddd, J 6,5 ) 8.2 Hz, J 6,7a ) 4 Hz, J 6,7b ) 1 Hz
1 H, 6-H), 4.25 (dd, J 7a,b ) 12.6 Hz, J 7a,6 ) 1 Hz, 1 H, 7a-H),
4.35 (dd, J 7b,a ) 12.6 Hz, J 7b,6 ) 4.3 Hz, 1 H, 7b-H), 5.13 (d,
J 1,P ) 10.2 Hz, 1 H, 1-H), 5.17 (dd, J 4,3 ) J 4,5 ) 8.2 Hz, 1 H,
2,6-Lu tid in iu m /Tr ieth yla m m on iu m (Z)-3,4,5,7-Tetr a -
O-a cet yl-2,6-a n h yd r o-1-d eoxy-D-m a n n o-h ep t -1-en it ol-1-
yl P h osp h on a te (19). Following the procedure described for
the synthesis of 18, compound 16 (95 mg, 0.21 mmol) was
deprotected to afford 19 as a mixture of the triethylammonium
and the lutidinium salts in quantitative yield. Compound 19
was used for the next step without purification: TLC (CHCl3/
4-H), 5.24 (dd, J 5,4 ) J 5,6 ) 8.4 Hz, 1 H, 5-H), 5.47 (d, J 3,4
)
8.1 Hz, 1 H, 3-H); 13C NMR (151 MHz, CDCl3) δ ) 20.49, 20.52,
20.6, 20.7 (4 C, Ac), 52.2, 52,7 (2 d, J C,P ) 5.8 Hz, 2 C, OMe),
61.3 (1 C, 7-C), 67.3 (1 C, 5-C), 69.1 (d, J C,P ) 13.9 Hz, 1 C,
3-C), 72.5 (1 C, 4-C), 76.4 (1 C, 6-C), 97.5 (d, J C,P ) 192.5 Hz,
1 C, 1-C), 161.6 (1 C, 2-C), 168.8, 169.2, 169,7, 170.5 (4 C, Ac);
31P NMR (243 MHz, CDCl3) δ ) 20.4 (1 P); MALDI-MS
(positive mode, DHB, THF) m/z ) 453.1 [M + H]+, 475.2 [M
+ Na]+, 491.2 [M + K]+; C17H25O12P (452.36), calcd: C, 45.14;
H, 5.57. Found: C, 45.09; H, 5.45.
1
MeOH/H2O 6:4:1 + 1% Et3N), Rf ) 0.6; H NMR (250 MHz,
MeOH-d4) δ ) 1.29 (t, 7 H, Et3NH), 1.96, 2.01, 2.02, 2.06 (4s,
12 H, Ac), 2.71 (s, 7 H, lutidine) 3.17 (q, 4.8 H, Et3NH), 4.06
(m, 1 H, 6-H), 4.30 (dd, J 7a,b ) 12.6 Hz, J 7a,6 ) 2.8 Hz, 1 H,
7a-H), 4.32 (dd, J 7b,a ) 12.6 Hz, J 7b,6 ) 4.0 Hz, 1 H, 7b-H),
5.12 (dd, J 4,5 ) 9.1 Hz, J 4,3 ) 3.4 Hz, 1 H, 4-H), 5.40 (m, 2 H,
1-H, 5-H), 5.60 (d, J 3,4 ) 3.5 Hz, 1 H, 3-H), 7.57 (d, 2.4 H,
lutidine), 8.18 (dd, 1.2 H, lutidine); MALDI-MS (positive mode,
J . Org. Chem, Vol. 69, No. 3, 2004 673