Dioxanone Approach to MEP and ME-2,4-cycloPP
hexane) afforded 470 mg (80%) of diol 15 as a white solid: mp
99-100 °C; TLC Rf 0.42 (100% EtOAc); H NMR (500 MHz,
Removal of the solvent under reduced pressure gave 110 mg (75%)
of the ammonium phosphate (2) as a white solid: [R]25 +11.3°
1
D
pyridine-d5) δ 1.67 (s, 3H), 4.02 (d, 1H, J ) 10.5 Hz), 4.14 (d,
1H, J ) 10.5 Hz), 4.23 (dd, 1H, J ) 11.8, 7.9 Hz), 4.40 (dd, 1H,
J ) 7.8, 2.5 Hz), 4.56 (dd, 1H, J ) 11.8, 1.9 Hz), 5.83 (s, 1H),
6.74 (br s, 2H, OH, exch. D2O), 7.38 (m, 3H), 7.73 (app dd, 2H,
Japp ) 7.9, 1.7 Hz); 13C NMR (125 MHz, pyridine-d5) δ 20.4, 61.2,
65.3, 78.6, 87.1, 102.3, 127.2, 128.4, 129.0, 139.5; 1H NMR (500
MHz, benzene-d6) δ 1.26 (s, 3H, CH3), 1.59 (bs, 1H, OH, D2O
exchange), 1.92 (bs, 1H, OH, exch. D2O), 3.41 and 3.70 (ABdd,
2H, JAB ) 10.5 Hz), 3.53-3.61 (m, 2H), 3.67 (m, 1H), 5.29 (s,
1H), 7.10-7.19 (m, 3H), 7.54 (d, 2H, J ) 7.5 Hz); 13C NMR (125
MHz, benzene-d6) δ 19.8, 61.7, 65.9, 77.2, 82.7, 101.8, 126.6, 127.4,
128.9, 138.5; IR (neat film) ν 3356, 2940, 2870, 1456, 1400, 1382,
1264, 1215 cm-1; HRMS (FAB) m/z calcd for C12H16O4 (M + 1)+,
225.1127; found, 227.1126.
(c ) 1.6, H2O); published data for the acid form, lit.61 for enzymatic
product, [R]21 +6.4 ° (c ) 0.1, H2O); lit.15a for 78% ee, [R]25
D
D
+6.8° (c ) 0.05, H2O), lit.15b for 72% ee, [R]20D +13.4° (c ) 0.8,
1
H2O); lit.15c for 50% ee, [R]20 + 6.1° (c ) 0.02); H NMR (500
D
MHz, D2O) δ 1.12 (s, 3H), 3.32 and 3.37 (ABdd, 2H, JAB ) 11.8
Hz), 3.74 (dd, 1H, J ) 7.5, 2.1 Hz), 3.8 (m, 1H), 3.98 (m, 1H);
13C NMR (125 MHz, D2O) δ 20.9, 67.6, 76.3, 76.7 (d, J ) 6.8
Hz), 74.0; 31P NMR (161.9 MHz, acetone-d6) δ 4.95 (s); negative
ion FAB MS (3:1 DTT-DTE), m/z 215.1 (39%, C5H12O7
P - H). The NMR data agree with the published data for the sodium
salt.16a
1,3-Benzylidene-2-C-methyl-D-erythritol 2,4-Bis(dibenzylphos-
phate) (18). This phosphorylation procedure was based on that
described by Yu and Fraser-Reid.38 A solution of dibenzyl N,N-
diisopropylphosphoramidite62 (460 mg, 1.3 mmol) and tetrazole
(140 mg, 2.0 mmol) in CH3CN (4 mL) was allowed to stir for 30
min at rt. A solution of diol 15 (100 mg, 0.44 mmol) in CH3CN (2
mL) was added dropwise over 1 min. After 4 h, the reaction mixture
was cooled to 0 °C and m-chloroperoxybenzoic acid (solid, 340
mg, 2.0 mmol) was added. The cooling bath was removed, and the
reaction mixture was allowed to stir at rt. After 30 min, the mixture
was diluted with Et2O (40 mL). The ethereal layer was washed
with 10% Na2S2O5 (2 × 15 mL), satd NaHCO3 (15 mL), and brine
(15 mL); dried (MgSO4); and evaporated to give 0.51 g of the crude
phosphate as a white solid. Purification by flash chromatography
(35:65, EtOAc:hexane) gave 300 mg (91%) of diphosphate 18 as
a colorless oil: TLC Rf 0.55 (50:50 EtOAc:hexane); [R]25D +16.9°
2-C-Methyl-D-erythritol (16). Deprotection of benzylidene acetal
15 (30 mg, 0.13 mmol) was accomplished by hydrogenation (200
psi of H2 for 12 h) using 20% Pd(OH)2/C (15 mg) suspended in
EtOH (0.4 mL) containing HCO2H (2 drops). The heterogeneous
reaction mixture was diluted with MeOH (6 mL) and filtered.
Removal of the solvent under reduced pressure gave 12 mg (67%)
of 16 as a colorless oil: [R]25D +13.3° (c ) 0.30, H2O, l 0.5 dm);
lit.15 [R]21 +6.0° (c ) 0.05, H2O), [R]22 +9.0° (c ) 1.0, H2O),
D
D
[R]22D +7.2° (c ) 0.4, MeOH), [R]22D +11.2° (c ) 0.57, MeOH);
1H NMR (500 MHz, D2O) δ 1.07 (s, 3H), 3.42 (νB of ABq, 1H, J
) 11.8 Hz), 3.53 (νA of ABq, 1H, J ) 11.8 Hz), 3.54 (d, 1H, J )
11.6 Hz), 3.61 (dd, 1H, J ) 8.7, 2.5 Hz), 3.78 (dd, 1H, J ) 11.5,
2.5 Hz); 13C NMR (125 MHz, D2O) δ 20.8, 64.5, 68.8, 76.7, 77.5;
MS CI (methane, 12.1 V ionizing voltage): 137.1 (M + 1, 3.5%),
102.1 (56%), 101.1 (100%, M - (H2O + OH)), 85.1 (45%), 83.1
(37%), 71.1 (74%), 69.1 (43%), 67.1 (28%). The spectral data
agreed with those reported by Kis et al.16b
1
(c ) 1.0 in MeOH); H NMR (500 MHz, acetone-d6) δ 1.63 (s,
3H), 4.00 (d, 1H, J ) 10.7 Hz), 4.10 (dt, 1H, J ) 11.1, 8.4 Hz),
4.16 (app dd, 1H, J ) 8.3, 1.6 Hz), 4.27 (d, 1H, J ) 10.5 Hz),
4.40 (ddd, 1H, J ) 11.1, 6.9, 1.7 Hz), 5.00-5.12 (m, 8H), 5.60 (s,
1H), 7.30-7.50 (m, 25H); 13C NMR (125 MHz, acetone-d6) δ 18.0,
66.3 (m), 69.62 (m), 69.9 (app d, J ) 4.6 Hz), 75.6 (m), 75.9 (app
d, J ) 6.4 Hz), 81.9 (m), 102.4 (app d, J ) 7.4 Hz), 127.2, 128.7,
128.7, 128.8, 128.9, 129.1,129.1, 129.2, 129.2, 129.3, 129.3, 129.3,
129.8, 137.1 (d, J ) 2.8 Hz), 137.2 (d, J ) 1.8 Hz), 137.2 (d, J )
1.8 Hz), 137.2 (br s), 138.4; 31P NMR (202 MHz, acetone-d6) δ
-3.31, 0.83; MS (FAB, 70 eV) m/z (rel intensity %): 745 (100),
655 (17), 467 (20), 361 (23), 279 (17), 181 (62), 133 (22); IR (CCl4)
ν 3037, 2959, 1456, 1284, 1016 cm-1. Anal. Calcd for C40H42O10P2
(744.68): C, 64.51; H, 5.69. Found: C, 64.47; H, 5.67.
1,3-Benzylidene-2-C-methyl-D-erythritol, 4-Dibenzylphos-
phate (17). This phosphorylation was based on the procedure
described by Inage et al.37 A solution of diol 15 (135 mg, 0.6 mmol)
in dry THF (5.0 mL) was stirred and cooled at -75 °C as a solution
of 1.6 M n-BuLi in hexane (0.56 mL, 0.9 mmol) was added
dropwise. After 10 min, dibenzyl phosphorochloridate [prepared
from dibenzyl phosphite (236 mg, 0.9 mmol) and N-chlorosucci-
namide (120 mg, 0.5 mmol) in benzene (1.5 mL)]60 was added via
syringe. The resultant suspension was stirred for 10 min at
-75 °C and 15 min at rt. Water (2 mL) and ether (15 mL) were
added, and the organic layer was dried over MgSO4. The solvent
was removed under reduced pressure, and the crude product was
purified by flash chromatography (50:50 EtOAc:hexane). The
monophosphate (17, 230 mg, 79%) was obtained as a white solid:
mp 86-87 °C; TLC Rf 0.55 (70:30 EtOAc:hexane); [R]25D +27.2°
(c ) 1.0, MeOH); 1H NMR (400 MHz, acetone-d6) δ 1.33 (s, 3H),
3.71 and 3.79 (ABdd, 2H, JAB ) 10.7 Hz), 4.0 (dd, J ) 8.6, 1.5
Hz), 4.13 (ddd, 1H, J ) 11.0, 8.2, 1.3 Hz), 4.37 (s, 1H, OH, exch.
D2O), 4.45 (ddd, 1H, J ) 10.9, 6.7, 1.8), 5.03 (app t, 4H, J ) 8.0
Hz), 5.59 (s, 1H), 7.34 (m, 13H), 7.50 (m, 2H); 13C NMR (100
MHz, acetone-d6) δ 19.8, 65.1, 67.0, 69.5, 69.6, 78.0, 83.9, 102.1,
127.1, 128.5, 128.7, 129.0, 129.4, 136.9, 137.0, 139.0; 31P NMR
(161.9 MHz, acetone-d6) δ 0.39 (s); IR (CCl4) ν 3378, 2971, 1456,
1382, 1260, 1107, 1018. HRMS (FAB) calcd for M + H of
C26H29O7P, 485.1729; found, 485.1729.
1,3-Benzylidene-2-C-methyl-D-erythritol 2,4-Diphosphate,
Ammonium Salt. A suspension of 2,4-bis(dibenzyl) phosphate 18
(100 mg, 0.13 mmol) and 10% Pd/C (22 mg) in MeOH (8.5 mL)
was stirred at -10 °C under H2 (1 atm, 0.52 mmol) for 20 min.
The H2 uptake was monitored with a gas burette. The catalyst was
filtered off (celite), and the filtrate was neutralized with satd NH3/
MeOH solution (2 mL) at 0 °C. The resultant precipitate was
collected and dissolved in 0.2% NH4HCO3 (5 mL). Lyophilization
afforded the ammonium diphosphate intermediate (59 mg, 97%)
as a flocculent, amorphous solid: 1H NMR (500 MHz, D2O) δ
1.62 (s, 3H), 3.84 (m, 1H), 4.09 and 4.30 (ABdd, 2H, JAB ) 10.8
Hz), 4.17 (d, 1H, J ) 8.4 Hz), 4.24 (ddd, 1H, J ) 1.5, 5.8, 11.4
Hz), 5.75 (s, 1H), 7.46-7.48 (m, 3H), 7.55-7.57 (m, 2H); 13C
NMR (125 MHz, D2O) δ 19.8, 65.6 (d, J ) 4.6 Hz), 73.1 (d, J )
6.4 Hz), 78.3, 85.6 (dd, J ) 8.1, 10.5 Hz), 104.6, 129.1, 131.4,
132.6, 139.0; 31P NMR (202 MHz, D2O) δ -1.43, 3.33; MS (FAB)
m/z 385 (M + 1 - 4NH3).
2-C-Methyl-D-erythritol, 4-Phosphate, Diammonium Salt (2).
To a solution of dibenzyl phosphate 17 (210 mg, 0.4 mmol) in
ethanol (5.0 mL) was added 20% Pd(OH)2/C (50 mg) under N2.
The resulting heterogeneous mixture was stirred under an H2
atmosphere at rt. After 12 h, the mixture was diluted with MeOH
(12 mL) and filtered, and the filtrate was cooled to 0 °C. A slow
stream of NH3 gas was bubbled through the solution for ∼2 min.
1,3-Benzylidene-2-C-methyl-D-erythritol 2,4-Cyclodiphos-
phate, Ammonium Salt (19). The 2,4-bis(dibenzyl) phosphate 18
(61) Kuzuyama, T.; Takahashi, S.; Watanabe, H.; Seto, H. Tetrahedron
Lett. 1998, 39, 4509-4512.
(62) (a) Tanaka, T.; Tamatsukuri, S.; Ikehara, M. Tetrahedron Lett. 1986,
27, 199-202. (b) Dreef, C. E.; Tulnman, R. J.; Lefeber, A. W. M.; Elle, C.
J. J.; van der Marel, G. A.; van Boom, J. H. Tetrahedron 1991, 47, 4709-
4722.
(60) Buck, I. M.; Reese, C. B. J. Chem. Soc., Perkin Trans. 1 1990,
2937-2942.
J. Org. Chem, Vol. 72, No. 26, 2007 9893