Synthesis of a Prenylated and Immunosuppressive Marine Galactosphingolipid
FULL PAPER
(500 MHz, CDCl3): δ ϭ Ϫ0.34 (dt, J ϭ 9.5, 4.9 Hz, 2 H, 23-, 23Ј- 5ЈЈЈ-docosenoylamido)docosane (32): A solution of ceramide 30
Ha), 0.04 (s, 3 H, SiMe), 0.05 (s, 6 H, SiMe2), 0.06 (s, 3 H, SiMe), (12 mg, 12.7 µmol) in dry benzene (2 mL) and dry nitromethane
0.09 (s, 3 H, SiMe), 0.11 (s, 3 H, SiMe), 0.53Ϫ0.58 (m, 2 H, 23-, (2 mL) was heated at 110 °C to remove moisture by azeotropic co-
23Ј-Hb), 0.64 (br. s, 4 H, 11-, 12-, 11Ј-, 12Ј-H), 0.87 (t, J ϭ 7.0 Hz, distillation with benzene. The mixture was concentrated to a vol-
6 H, 22-, 22Ј-H3), 0.88 (s, 18 H, CMe3), 0.94 (s, 9 H, CMe3), ume of 1 mL and cooled under argon. It was then treated dropwise
1.09Ϫ1.60 (m, 54 H, 5-, 6-, 7-, 8-, 9-, 10-, 13-, 14-, 15-, with a solution of bromo sugar 31 (11.4 mg, 25.4 µmol) in dry
16-, 17-, 18-, 19-, 20-, 21-, 8Ј-, 9Ј-, 10Ј-, 13Ј-, 14Ј-, 15Ј-, 16Ј-, 17Ј-, nitromethane (0.3 mL) and portionwise with Hg(CN)2 (6.4 mg,
18Ј-, 19Ј-, 20Ј-, 21Ј-H2), 1.70Ϫ1.93 (m, 4 H, 4-, 3Ј-H2), 2.01Ϫ2.17
(m, 4 H, 4Ј-, 7Ј-H2), 3.68 (dd, J ϭ 10.4, 6.5 Hz, 1 H, 1-Ha), 3.71
25.4 µmol). The resulting mixture was stirred for 2 h at 90 °C. After
cooling, it was diluted with ethyl acetate, washed with water, satur-
(dd, J ϭ 10.4, 6.1 Hz, 1 H, 1-Hb), 3.84Ϫ3.88 (m, 1 H, 3-H), ated aqueous NaHCO3 solution, and brine, dried with MgSO4, and
4.01Ϫ4.57 (m, 1 H, 2-H), 4.16 (t, J ϭ 5.5 Hz, 1 H, 2Ј-H), 5.32Ϫ5.39
concentrated in vacuo. The residue was chromatographed on silica
(m, 2 H, 5Ј-, 6Ј-H), 6.76 (d, J ϭ 8.3 Hz, 1 H, NH). Ϫ gel to give 13 mg (78%) of 32; n2D3 ϭ 1.4729. Ϫ [α]2D2 ϭ ϩ4.83 (c ϭ
C64H129NO4Si3 (1061): calcd. C 72.45, H 12.25, N 1.32; found C 0.07, CHCl3). Ϫ IR (film): ν˜max ϭ 3425 cmϪ1 (w, NH), 3060 (w,
72.50, H 12.26, N 1.57.
CH), 1755 (vs, CϭO), 1675 (s, CϭO), 1515 (m), 1465 (m, CH),
1250 (s), 1080 (m), 911 (s), 780 (s), 735 (m). Ϫ 1H NMR (500 MHz,
CDCl3): δ ϭ Ϫ0.30 to Ϫ0.33 (m, 2 H, 23-, 23ЈЈЈ-H), 0.05 (s, 3 H,
SiMe), 0.07 (s, 3 H, SiMe), 0.13 (s, 3 H, SiMe), 0.14 (s, 3 H, SiMe),
0.53Ϫ0.58 (m, 2 H, 23-, 23ЈЈЈ-H), 0.64 (m, 4 H, 11-, 12-, 11ЈЈЈ-,
12ЈЈЈ-H), 0.88 (t, J ϭ 7.4 Hz, 6 H, 22-, 22ЈЈЈ-Me), 0.88 (s, 9 H,
CMe3), 0.95 (s, 9 H, CMe3), 1.11Ϫ1.60 (m, 54 H, 5-, 6-, 7-, 8-, 9-,
10-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 21-, 8ЈЈЈ-, 9ЈЈЈ-, 10ЈЈЈ-,
13ЈЈЈ-, 14ЈЈЈ-, 15ЈЈЈ-, 16ЈЈЈ-, 17ЈЈЈ-, 18ЈЈЈ-, 19ЈЈЈ-, 20ЈЈЈ-, 21ЈЈЈ-H),
1.62Ϫ1.81 (m, 4 H, 4-, 3ЈЈЈ-H2), 1.97Ϫ2.07 (m, 4 H, 4ЈЈЈ-, 7ЈЈЈ-H),
1.98 (s, 3 H, acetyl), 2.05 (s, 3 H, acetyl), 2.14 (s, 3 H, acetyl),
3.65Ϫ3.75 (m, 2 H, 2-, 3-H), 3.85 (dd, J ϭ 9.0, 9.0 Hz, 1 H, 1-H),
3.91 (t, J ϭ 6.1 Hz, 1 H, 5Ј-H), 4.09Ϫ4.22 (m, 4 H, 1-, 2ЈЈЈ-H, 6Ј-
H2), 4.14 (s, 2 H, ClCH2CO), 4.51 (d, J ϭ 7.7 Hz, 1 H, 1Ј-H), 5.04
(dd, J ϭ 10.7, 3.4 Hz, 1 H, 3Ј-H), 5.17 (dd, J ϭ 10.7, 7.6 Hz, 1 H,
2Ј-H), 5.30Ϫ5.37 (m, 2 H, 5ЈЈЈ-, 6ЈЈЈ-H), 5.39 (d, J ϭ 3.1 Hz, 1 H,
4Ј-H), 6.73 (d, J ϭ 8.9 Hz, 1 H, NH). Ϫ HR-FABMS (positive-ion
mode) [C72H133ClNO13Si2]: calcd. 1310.9004; found 1310.8995.
(2S,3R,11S,12R,2ЈR,5ЈZ,11ЈS,12ЈR)-3,2Ј-Bis(tert-butyldimethyl-
silyloxy)-11,12-methylene-2-(11Ј,12Ј-methylene-5Ј-docosenoyl-
amido)-1-docosanol (30): To a stirred solution of 29 (84 mg, 79.2
µmol) in THF (2 mL), 10% aq. TFA (0.2 mL) was added dropwise
and the resulting mixture was stirred for 3 h at room temperature. It
was then diluted with diethyl ether, washed with saturated aqueous
NaHCO3 solution and brine, dried with MgSO4, and concentrated
in vacuo. The residue was chromatographed on silica gel to give
37 mg (49%) of 30 and 31 mg (37%) of recovered 29; n2D3 ϭ 1.4719.
Ϫ [α]2D2 ϭ ϩ11.8 (c ϭ 0.06, CHCl3). Ϫ IR (film): νmax ϭ 3420 cmϪ1
(w, OH, NH), 3060 (w, CH), 1665 (s, CϭO), 1520 (m), 1465 (m,
CH), 1255 (m), 1110 (m), 835 (s), 775 (m). Ϫ H NMR (500 MHz,
˜
1
CDCl3): δ ϭ Ϫ0.33 (dt, J ϭ 9.4, 5.2 Hz, 2 H, 23-, 23Ј-H), 0.08 (s,
3 H, SiMe), 0.10 (s, 6 H, SiMe), 0.11 (s, 3 H, SiMe), 0.12 (s, 3 H,
SiMe), 0.53Ϫ0.58 (m, 2 H, 23-, 23Ј-Hb), 0.64 (br. s, 4 H, 11-, 12-,
11Ј-, 12Ј-H), 0.88 (t, J ϭ 7.3 Hz, 6 H, 22-, 22Ј-H3), 0.90 (s, 9 H,
CMe3), 0.95 (s, 9 H, CMe3), 1.12Ϫ1.52 (m, 54 H, 5-, 6-, 7-, 8-, 9-,
10-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 21-, 8Ј-, 9Ј-, 10Ј-, 13Ј-,
14Ј-, 15Ј-, 16Ј-, 17Ј-, 18Ј-, 19Ј-, 20Ј-, 21Ј-H2), 1.74Ϫ1.80 (m, 4 H,
4-, 3Ј-H2), 1.95Ϫ2.17 (m, 4 H, 4Ј-, 7Ј-H2), 3.53 (dd, J ϭ 11.7,
2.7 Hz, 1 H, 1-Ha), 3.85Ϫ3.92 (m, 2 H, 2-, 3-H), 3.98 (dd, J ϭ
11.7, 3.4 Hz, 1 H, 1-Hb), 4.20 (t, J ϭ 4.6 Hz, 1 H, 2Ј-H), 5.34Ϫ5.40
(m, 2 H, 5Ј-, 6Ј-H), 7.50 (d, J ϭ 6.7 Hz, 1 H, NH). Ϫ
C58H115NO4Si2 (946.7): calcd. C 73.58, H 12.24, N 1.48; found C
73.27, H 12.31, N 1.63.
(2S,3R,11R,12S,2ЈЈЈR,5ЈЈЈZ,11ЈЈЈR,12ЈЈЈS)-1-O-[3Ј,4Ј,6Ј-Tri-O-
acetyl-2Ј-O-(2ЈЈ-chloroacetyl)-β-D-galactopyranosyl]-3,2ЈЈЈ-bis(tert-
butyldimethylsilyloxy)-11,12-methylene-2-(11ЈЈЈ,12ЈЈЈ-methylene-
5ЈЈЈ-docosenoylamido)docosane (32Ј): In the same manner as de-
scribed above, 30Ј (58 mg, 61.3 µmol) was converted into 80 mg
(75%) of 32Ј; n2D3 ϭ 1.4781. Ϫ [α]2D2 ϭ Ϫ0.02 (c ϭ 0.20, CHCl3). Ϫ
IR (film): νmax ϭ 3420 cmϪ1 (w, NH), 3060 (w, CH), 1755 (vs, Cϭ
˜
O), 1680 (s, CϭO), 1515 (m), 1465 (m, CH), 1250 (s), 1080 (m),
910 (s), 840 (m), 780 (s). Ϫ 1H NMR (400 MHz, CDCl3): δ ϭ
Ϫ0.34 (dd, J ϭ 9.5, 5.2 Hz, 2 H, 23-, 23ЈЈЈ-H), 0.05 (s, 3 H, SiMe),
0.07 (s, 3 H, SiMe), 0.13 (s, 3 H, SiMe), 0.14 (s, 3 H, SiMe),
0.53Ϫ0.58 (m, 2 H, 23-, 23ЈЈЈ-H), 0.64 (br. s, 4 H, 11-, 12-, 11ЈЈЈ-,
12ЈЈЈ-H), 0.88 (t, J ϭ 6.7 Hz, 6 H, 22-, 22ЈЈЈ-Me), 0.88 (s, 9 H,
CMe3), 0.94 (s, 9 H, CMe3), 1.11Ϫ1.60 (m, 54 H, 5-, 6-, 7-, 8-, 9-,
10-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 21-, 8ЈЈЈ-, 9ЈЈЈ-, 10ЈЈЈ-,
13ЈЈЈ-, 14ЈЈЈ-, 15ЈЈЈ-, 16ЈЈЈ-, 17ЈЈЈ-, 18ЈЈЈ-, 19ЈЈЈ-, 20ЈЈЈ-, 21ЈЈЈ-H2),
1.64Ϫ1.82 (m, 4 H, 3ЈЈЈ-H2), 1.97Ϫ2.07 (m, 4 H, 4ЈЈЈ-, 7ЈЈЈ-H2),
1.98 (s, 3 H, acetyl), 2.05 (s, 3 H, acetyl), 2.14 (s, 3 H, acetyl),
3.65Ϫ3.75 (m, 2 H, 2-, 3-H), 3.85 (dd, J ϭ 9.0, 9.0 Hz, 1 H, 1-H),
3.91 (t, J ϭ 6.1 Hz, 1 H, 5Ј-H), 4.09Ϫ4.22 (m, 4 H, 1-, 2ЈЈЈ-H, 6Ј-
H2), 4.14 (s, 2 H, ClCH2CO), 4.51 (d, J ϭ 7.8 Hz, 1 H, 1Ј-H), 5.04
(dd, J ϭ 10.5, 3.4 Hz, 1 H, 3Ј-H), 5.17 (dd, J ϭ 10.5, 7.6 Hz, 1 H,
2Ј-H), 5.30Ϫ5.37 (m, 2 H, 5ЈЈЈ-, 6ЈЈЈ-H), 5.39 (d, J ϭ 3.1 Hz, 1 H,
4Ј-H), 6.75 (d, J ϭ 9.1 Hz, 1 H, NH). Ϫ HR-FABMS (positive-ion
mode) [C72H133ClNO13Si2]: calcd. 1310.9004; found 1310.9027.
(2S,3R,11R,12S,2ЈR,5ЈZ,11ЈR,12ЈS)-3,2Ј-Bis(tert-butyldimethyl-
silyloxy)-11,12-methylene-2-(11Ј,12Ј-methylene-5Ј-docosenoyl-
amido)-1-docosanol (30Ј): In the same manner as described above,
29Ј (131 mg, 0.12 mmol) was converted into 41 mg (35%) of 30Ј
with 65 mg (50%) of 29Ј being recovered; n2D0 ϭ 1.4728. Ϫ [α]2D5
ϭ
ϩ13.4 (c ϭ 0.47, CHCl3). Ϫ IR (film): νmax ϭ 3420 cmϪ1 (w, OH,
NH), 3060 (w, CH), 1665 (s, CϭO), 1520 (m), 1465 (m, CH), 1255
(m), 1110 (m), 835 (s), 780 (m). Ϫ 1H NMR (500 MHz, CDCl3):
δ ϭ Ϫ0.33 (dt, J ϭ 9.4, 5.2 Hz, 2 H, 23-, 23Ј-H), 0.08 (s, 3 H,
SiMe), 0.09 (s, 6 H, SiMe), 0.11 (s, 6 H, SiMe), 0.52Ϫ0.58 (m, 2
H, 23-, 23Ј-Hb), 0.64 (br. s, 4 H, 11-, 12-, 11Ј-, 12Ј-H), 0.88 (t, J ϭ
7.3 Hz, 6 H, 22-, 22Ј-H3), 0.89 (s, 9 H, CMe3), 0.95 (s, 9 H, CMe3),
1.12Ϫ1.52 (m, 54 H, 5-, 6-, 7-, 8-, 9-, 10-, 13-, 14-, 15-, 16-, 17-,
18-, 19-, 20-, 21-, 8Ј-, 9Ј-, 10Ј-, 13Ј-, 14Ј-, 15Ј-, 16Ј-, 17Ј-, 18Ј-,
19Ј-, 20Ј-, 21Ј-H2), 1.74Ϫ1.80 (m, 4 H, 4-, 3Ј-H2), 1.95Ϫ2.17 (m, 4
H, 4Ј-, 7Ј-H2), 3.52 (dd, J ϭ 11.7, 2.7 Hz, 1 H, 1-Ha), 3.85Ϫ3.92
(m, 2 H, 2-, 3-H), 3.98 (dd, J ϭ 11.7, 3.4 Hz, 1 H, 1-Hb), 4.20 (t,
J ϭ 4.6 Hz, 1 H, 2Ј-H), 5.34Ϫ5.40 (m, 2 H, 5Ј-, 6Ј-H), 7.52 (d, J ϭ
7.3 Hz, 1 H, NH). Ϫ C58H115NO4Si2 (946.7): calcd. C 73.58, H
12.24, N 1.48; found C 73.23, H 12.60, N 1.63.
˜
(2S,3R,11S,12R,2ЈЈЈR,5ЈЈЈZ,11ЈЈЈS,12ЈЈЈR)-1-O-[3Ј,4Ј,6Ј-Tri-O-
acetyl-β-
11,12-methylene-2-(11ЈЈЈ,12ЈЈЈ-methylene-5ЈЈЈ-docosenoylamido)-
(2S,3R,11S,12R,2ЈЈЈR,5ЈЈЈZ,11ЈЈЈS,12ЈЈЈR)-1-O-[3Ј,4Ј,6Ј-Tri-O- docosane (33): To a solution of 32 (19 mg, 14.5 µmol) in ethyl acet-
acetyl-2Ј-O-(2ЈЈ-chloroacetyl)-β- -galactopyranosyl]-3,2ЈЈЈ-bis(tert- ate (0.3 mL) and MeOH (0.3 mL), H2NNH2·AcOH (4.0 mg, 43.5
D-galactopyranosyl]-3,2ЈЈЈ-bis(tert-butyldimethylsilyloxy)-
D
butyldimethylsilyloxy)-11,12-methylene-2-(11ЈЈЈ,12ЈЈЈ-methylene-
µmol) was added portionwise and the mixture was stirred for 6 h
Eur. J. Org. Chem. 2001, 3797Ϫ3809
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