128
A. M. Downey, C. W. Cairo / Carbohydrate Research 381 (2013) 123–132
1.78 (dddd, 1H, J = 15.3, 8.4, 7.4, 2.2 Hz, H-6b); 13C NMR (125 MHz,
CDCl3): d 136.2, 135.6(2), 135.6(1), 126.0, 125.9(9), 125.9(7),
125.9(6), 125.9(3), 125.9(1), 125.6, 125.5(4), 125.5(2), 125.4(6),
125.4(3), 125.3(7), 125.2(5), 125.2(2), 125.1(7), 95.4 (C-1), 79.4
(C-3), 79.0 (C-4), 77.6 (C-2), 73.3 (CH2Ph), 72.6 (CH2Ph), 70.9 (CH2-
Ph), 63.4 (d, JC–P = 14.2 Hz, C-5), 61.8 (d, JC–P = 164.2 Hz, C-7), 52.8
(CH3O), 50.9 (d, JC–P = 7.0 Hz, CH3OP), 50.7 (d, JC–P = 7.0 Hz, CH3OP),
30.7 (d, JC–P = 2.1 Hz, C-6); 31P NMR (202 MHz, CDCl3) d 24.37.
Spectroscopic data for the minor R isomer: 1H NMR (500 MHz,
CDCl3): d 7.37–7.25 (m, 15H, PhCH2), 4.98 (d, 1H, J = 10.8 Hz, CH2-
Ph), 4.90 (d, 1H, J = 11.0 Hz, CH2Ph), 4.80 (d, 1H, J = 10.8 Hz, CH2Ph),
4.79 (d, 1H, J = 12.2 Hz, CH2Ph), 4.64 (d, 1H, J = 11.8 Hz, CH2Ph),
4.60 (d, 1H, J = 11.0 Hz, CH2Ph), 4.53 (d, 1H, J = 3.6 Hz, H-1), 4.14
(ddd, 1H, J = 10.9, 7.1, 2.6 Hz, H-7), 3.95 (d, 1H, J = 9.2 Hz, H-3),
3.90–3.82 (m, 1H, H-5), 3.80-3.75 (m, 6H, 2 ꢁ CH3OP), 3.50 (dd,
1H, J = 9.5, 3.6 Hz, H-2), 3.38 (s, 3H, CH3O), 3.27 (app t, 1H,
J = 9.2 Hz, H-4), 2.34 (dddd, 1H, J = 14.8, 7.1, 2.8, 2.8 Hz, H-6a),
1.84 (m, 1H, H-6b); 13C NMR (125 MHz, CDCl3): d 136.2, 135.6(2),
135.6(1), 126.0, 125.9(9), 125.9(7), 125.9(6), 125.9(3), 125.9(1),
125.6, 125.5(4), 125.5(2), 125.4(6), 125.4(3), 125.3(7), 125.2(5),
125.2(2), 125.1(7), 95.7 (C-1), 79.2 (C-3), 79.1 (C-4), 77.3 (C-2),
73.3 (CH2Ph), 72.8 (CH2Ph), 71.0 (CH2Ph), 68.9 (d, JC–P = 17.3 Hz,
C-5), 65.4 (d, JC–P = 170.0 Hz, C-7), 53.0 (CH3O), 51.0 (d, JC–
P = 7.0 Hz, CH3OP), 50.7 (d, JC–P = 7.5 Hz, CH3OP), 30.7 (C-6); 31P
NMR (202 MHz, CDCl3) d 22.69.
OP), 3.71 (app dt, 1H, J = 9.6, 1.1, H-4), 3.51 (dd, 1H, J = 9.6,
3.5 Hz, H-2), 3.49 (s, 3H, CH3O); 13C NMR (125 MHz, CDCl3): d
134.7, 134.3, 134.1, 124.5(6), 124.5(2), 124.4(7), 124.1, 124.0(3),
124.0(2), 123.9, 123.7, 94.6 (C-1), 77.9 (C-3), 75.7 (C-2), 72.3
(d, J = 10.3C-P Hz, C-4), 71.8 (CH2Ph), 71.1 (CH2Ph), 69.5 (CH2Ph),
65.7 (C-5), 62.0 (d, JC–P = 162.4 Hz, C-6), 51.8 (CH3O), 49.6 (d,
JC–P = 6.4, Hz, CH3OP), 48.6 (d, JC–P = 7.2 Hz, CH3OP); 31P NMR
(160 MHz, CDCl3): d 24.78.
4.2.5. Methyl 2,3,4-tri-O-benzyl-6-deoxy-6-E/Z-(diethoxypho
sphoryl-10-bromomethylene)-
a-D
-glucopyranoside (3)
Tetraethyl
methylenediphosphonate (TEMDP)
(640 lL,
2.58 mmol, 2.05 equiv.) was added dropwise to a stirring solution
of 60% NaH in mineral oil (103 mg, 2.58 mmol, 2.05 equiv) in
nhydrous THF (12.5 mL) under N2 at 0 °C. After 30 min N-bromo-
succinimide (471 mg, 2.65 mmol, 2.1 equiv) was added in one
portion. After stirring at rt for 13 h, the reaction was concentrated
in vacuo to remove the THF and re-dissolved in CH2Cl2. The organic
layer was subsequently washed with a saturated NH4Cl solution
and brine, dried over Na2SO4, and concentrated in vacuo to yield
a faint yellow oil (10; crude wt: 1.0 g). NMR indicated a 67% con-
version to the monobromo product and the 31P NMR chemical
shifts matched those reported in the literature.39 The product
was dried on a high vacuum without further purification.
Compound 10 was removed from the high vacuum and dis-
solved in anhydrous THF (10 mL). The solution was subsequently
cooled to 0 °C under N2 and to it was added 60% NaH in mineral
oil (100 mg, 2.52 mmol, 2.0 equiv) with rigorous stirring. After
30 min crude aldehyde 8, as prepared in the synthesis of 9
(0.583 g, 1.26 mmol, 1.0 equiv), in anhydrous THF (7.5 mL), was
added to the solution by cannula. The solution was allowed to
warm to rt and stirring was continued under N2 for 1 h. TLC in
1:2 EtOAc:hexane indicated two spots with Rf values of 0.78 and
0.44 that were later determined to be the E and Z alkenes, respec-
tively. Column chromatography (1:2 EtOAc–hexane to 1:1 EtOAc–
hexane) furnished two products (E isomer, 195 mg, 0.290 mmol,
23%; Z isomer, 289 mg, 0.429 mmol, 37%) as colorless oils. Data
4.2.4. Methyl 2,3,4-tri-O-benzyl-6-dimethoxyphosphoryl-
L-
glycero- -gluco-pyranoside (9)
a-D
A solution of oxalyl chloride (0.14 mL, 1.592 mmol, 4.0 equiv) in
anhydrous CH2Cl2 (3 mL) under an N2 atmosphere was cooled to –
78 °C and anhydrous DMSO (0.23 mL, 31.8 mmol, 8.0 equiv) was
added dropwise with rigorous stirring. After stirring at –78 °C for
20 min,
a pre-dissolved solution of 5 (0.185 g, 0.398 mmol,
1.0 equiv) in anhydrous CH2Cl2 (3 mL) was added dropwise via syr-
inge. Stirring was continued for 1 h before the reaction was
quenched with NEt3 (0.89 mL, 6.37 mmol, 16.0 equiv). Stirring
was continued at –78 °C for 15 min before the reaction was
warmed to room temperature. The reaction was diluted with
20 mL of CH2Cl2 and the organic layer was washed with concen-
trated NH4Cl (10 mL). The aqueous layer was rinsed with CH2Cl2
(5 mL) and the combined organic layers were washed with brine
(2 ꢁ 10 mL), dried over Na2SO4, and concentrated. The crude alde-
hyde, 8, was isolated as a dark orange oil that was freshly prepared
each time, dried on a high vacuum, and subsequently used without
purification.
for the E isomer: Rf = 0.78 (1:1 EtOAc–hexane); [
a
]
D
+41.90 (c
0.21, CH2Cl2); 1H NMR (500 MHz, CDCl3) d 1H NMR (500 MHz,
CDCl3): d 7.37–7.26 (m, 15H, PhCH2), 6.63 (dd, 1H, J = 38.0,
10.0 Hz, H-6), 5.36 (app t, 1H, J = 10.0 Hz, H-5), 4.97 (d, 1H, J =
10.7 Hz, CH2Ph), 4.84 (d, 1H, 11.1 Hz, CH2Ph), 4.79 (d, 2H,
J = 11.6 Hz, CH2Ph), 4.66 (d, 1H, J = 12.2 Hz, CH2Ph), 4.60 (d, 1H, J =
11.4 Hz, CH2Ph), 4.53 (d, 1H, J = 3.5 Hz, H-1), 4.17–4.00 (m, 4H,
CH3CH2OP + H-3), 3.88–3.82 (m, 1H, CH3CH2OP), 3.49 (dd, 1H,
J = 9.5, 3.5 Hz, H-2), 3.46 (s, 3H, CH3O), 3.27 (app t, 1H, J = 9.5 Hz,
H-4), 1.33 (t, 3H, J = 7.1 Hz, CH3CH2OP), 1.16 (t, 3H, J = 7.1 Hz, CH3
CH2OP); 13C NMR (125 MHz, CDCl3): d 149.2 (d, JC–P = 5.0 Hz, C-6),
138.7, 138.2, 138.1, 128.5(5), 128.5(3), 128.4(8), 128.4(5),
128.4(2), 128.3, 128.2, 128.1(6), 128.1(2), 128.0, 127.9, 127.7,
127.6(6), 116.8 (d, JC–P = 194.6 Hz, C-7), 98.4 (C-1), 81.5 (C-3),
81.2 (C-4), 80.0 (C-2), 75.8 (CH2Ph), 74.8 (CH2Ph), 73.4 (CH2Ph),
67.5 (d, JC–P = 2.8 Hz, C-5), 63.3 (d, J = 5.2 Hz, CH3CH2OP), 63.1 (d,
J = 5.2 Hz, CH3CH2OP), 55.6 (CH3O), 16.1(4) (d, JC–P = 4.6 Hz, CH3-
CH2OP), 16.1(8) (d, JC–P = 4.9 Hz, CH3CH2OP), 31P NMR (202 MHz,
CDCl3) d 6.52. HR ESIMS: m/z [M+Na+] calcd for: C33H40O8PBrNa:
697.1536. Found: 697.1524. Data for the Z isomer: Rf = 0.44 (1:1
To
a solution of dimethyl phosphite (73 lL, 0.796 mmol,
2.0 equiv) in anhydrous THF (2 mL) under an N2 atmosphere was
added NaH (60% in mineral oil, 24 mg, 0.597 mmol, 1.5 equiv) with
vigorous stirring for 30 min. After 30 min a pre-dissolved solution
of crude aldehyde 7 was added to the reaction by cannula. Stirring
was continued for 12 h, after which time the THF was removed in
vacuo. The crude residue was diluted with EtOAc (25 mL) and the
organic layer was rinsed with 1 M HCl (20 mL) and brine (20 mL),
dried over Na2SO4, and concentrated in vacuo to afford a pale
brown oil. The residue was purified using flash chromatography
(4:1 EtOAc–hexane to EtOAc) to furnish 9 (102 mg, 0.178 mmol,
dr: 93:7 S:R, 45%) as a colorless oil. Rf = 0.18 (4:1 EtOAc–hexane);
HR ESIMS: m/z [M+Na+] calcd for C30H37O9PNa: 595.2067. Found:
EtOAc–hexane); [a]
+11.29 (c 0.54, CH2Cl2); 1H NMR (500 MHz,
D
595.2060. Spectroscopic data provided are for the
[a]
L
-glycero isomer:
CDCl3) d 7.37–7.24 (m, 15H, PhCH2), 7.06 (dd, 1H, J = 14.5, 8.6 Hz,
H-6), 4.94 (d, 1H, J = 10.8 Hz, CH2Ph), 4.81 (d, 1H, J = 10.8 Hz, CH2
Ph), 4.80 (d, 1H, 12.1 Hz, CH2Ph), 4.77 (d, 2H, J = 10.8 Hz, CH2Ph),
4.72 (app td, 1H, J = 9.5, 1.8 Hz, H-5), 4.66 (d, 1H, J = 12.1 Hz, CH2
Ph), 4.58 (d, 1H, J = 11.2 Hz, CH2Ph), 4.56 (d, 1H, J = 3.5 Hz, H-1),
4.19–3.94 (m, 5H, CH3CH2OP + H-3), 3.53 (dd, 1H, J = 9.5, 3.5 Hz,
H-2), 3.44–3.43 (m, 4H, CH3O + H-4), 1.34 (td, 3H, J = 7.1, 0.4 Hz,
CH3CH2OP), 1.25 (td, 3H, J = 7.1, 0.5 Hz, CH3CH2OP); 13C NMR
D +10.60 (c 1.20, CHCl3); 1H NMR (500 MHz, CDCl3): d 7.40–7.29
(m, 15H, PhCH2), 5.02 (d, 1H, J = 11.8 Hz, CH2Ph), 4.95 (d, 1H,
J = 11.2 Hz, CH2Ph), 4.86 (d, 1H, J = 10.9 Hz, CH2Ph), 4.83 (d,
1H, J = 12.3 Hz, CH2Ph), 4.68 (d, 1H, J = 12.0 Hz, CH2Ph), 4.65
(d, 1H, J = 3.5 Hz, H-1), 4.20 (dd, 1H, J = 17.3, 1.1 Hz, H-6), 4.06
(app t, 1H, J = 9.6 Hz, H-3), 4.02 (ddd, 1H, J = 9.6, 3.3, 1.1 Hz, H-5),
3.82 (d, 3H, JH–P = 10.5 Hz, CH3OP), 3.77 (d, 3H, JH–P = 10.6 Hz, CH3