Decarboxy- and Deoxysqualestatins as SQS Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 213
7.1-7.3 (m, 5H, C6H5); MS (DCI, NH3, +ve) m/ z 944 (M +
NH4)+. Anal. (C52H78O14) C, H.
CHdCHCO), 5.94 (s, 1H, H-6), 6.95 (dd, 1H, J ) 15, 8 Hz,
CHdCHCO), 7.20-7.38 (m, 5H, C6H5).
16 (0.4 g, 8%): NMR (CDCl3) δ 1.02 (d, 3H, J ) 7 Hz,
CHdCHCHCH3), 2.1 (s, 3H, CH3CO2), 2.7 (bdd, 1H, one proton
of PhCH2), 3.28 and 3.32 (d, 1H, J ) 3.5 Hz, H-4), 3.95 and
4.11 (d, 1H, J ) 1.5 Hz, H-7), 4.62 and 4.66 (d, 1H, J ) 3.5
Hz, H-3), 4.95 and 4.98 (bs, 2H, CdCH2), 5.51 and 5.71 (d,
1H, J ) 1.5 Hz, H-6), 5.80 and 5.81 (d, 1H, J ) 15 Hz,
CHdCHCO), 6.91 (dd, 1H, J ) 7, 15 Hz, CHdCHCO), 7.1-
7.3 (m, 5H, C6H5).
[1S-[1r(4R*,5S*),3r,4â,5r,6r,7â]]-1-[4-(Acetyloxy)-5-m eth -
y l-3-m e t h y le n e -6-p h e n y lh e x y l]-6,7-d i h y d r o x y -2,8-
d ioxa bicyclo[3.2.1]octa n e-3,4,5-tr ica r boxylic Acid (4). A
solution of 3 (70 mg, 0.105 mmol) in dry DMF (2 mL) was
treated with Et3N (63 µL, 0.47 mmol) and N-methylhydroxy-
lamine hydrochloride (26 mg, 0.311 mmol) at room tempera-
ture. After stirring for 16 h, the solvent was evaporated under
reduced pressure. The residue was purified by reverse-phase
HPLC (column A) eluting with 43% MeCN-H2O and acidified
with 0.15 mL/L concentrated H2SO4 to give 4 (30 mg, 55%):
NMR (CD3OD) δ 0.85 (d, 3H, J ) 7 Hz, CH3CH), 2.10 (s, 3H,
CH3CO2), 2.7 (dd, 1H, J ) 6, 14 Hz, one proton of PhCH2),
2.95 (d, 1H, J ) 12 Hz, H-4), 4.0 (d, 1H, J ) 1 Hz, H-7), 7.1-
7.3 (m, 5H, C6H5); MS (-ve FAB) m/ z 521 (M - H)-. Anal.
(C25H30O12‚2.5H2O) C, H.
[1S-[1r(4R*,5S*),3r,4â,5r,6r(2E,4R*,6R*),7â]]-1-(4-Hy-
d r oxy-5-m et h yl-3-m et h ylen e-6-p h en ylh exyl)-6,7-d ih y-
d r oxy-2,8-d ioxa b icyclo[3.2.1]oct a n e-3,4,5-t r ica r b oxylic
Acid , 6-(4,6-Dim eth yl-2-octen oa te) (7). A solution of 3 (25
mg, 0.037 mmol) in acetone:H2O (3:1, 1 mL) at room temper-
ature was treated with concentrated H2SO4 (0.05 mL, 0.92
mmol). After stirring for 14 days, the organic solvent was
evaporated and the residue was purified by reverse-phase
HPLC (column A) eluting with 60% MeCN-H2O acidified with
0.15 mL/L concentrated H2SO4 to give 7 (17 mg, 70%): NMR
(CD3OD) δ 1.0 (d, 3H, J ) 7 Hz, CHdCHCHCH3), 2.75 (dd,
1H, J ) 6, 12.5 Hz, one proton of PhCH2), 3.05 (d, 1H, J ) 11
Hz, H-4), 3.90 (d, 1H, J ) 5 Hz, CH(OH)CdCH2), 4.03 (d, 1H,
J ) 1.5 Hz, H-6), 5.80 (d, 1H, J ) 15.5 Hz, CHdCHCO), 6.85
(dd, 1H, J ) 8.5, 15.5 Hz, CHdCHCO), 7.1-7.3 (m, 5H, C6H5).
Anal. (C33H44O12‚1.5H2O) C, H.
[1S-[1r(4R*,5S*),3r,4r,5r,6r(2E,4R*,6R*),7â]]-1-[4-(Acety-
loxy)-5-m et h yl-3-m et h ylen e-6-p h en ylh exyl]-6-h yd r oxy-
2,8-d ioxa b icyclo[3.2.1]oct a n e-3,4,5-t r ica r b oxylic Acid ,
6-(4,6-Dim eth yl-2-octen oa te), 3,4,5-Tr is(1,1-d im eth yleth -
yl) Ester (18). A mixture of 16 (450 mg, 0.486 mmol) and
Amberlyst-15 (1 g) in MeOH (20 mL) was stirred at room
temperature for 3 days. The methanolic solution was evapo-
rated to give a residue which was purified by flash column
chromatography to afford 18 (200 mg, 49%): NMR (CDCl3) δ
1.02 (d, 3H, J ) 6.5 Hz, CHdCHCHCH3), 1.42-1.55 (3s, 27H,
3 t-BuO2C), 2.1 (s, 3H, CH3CO2), 2.7 (dd, 1H, J ) 13, 5 Hz,
one proton of PhCH2), 2.93 (d, 1H, J ) 2.5 Hz, CHOH), 3.3 (d,
1H, J ) 4 Hz, H-4), 3.95 (t, 1H, J ) 2.5 Hz, H-7), 4.67 (d, 1H,
J ) 4 Hz, H-3), 4.95 (s, 2H, CdCH2), 5.02 (d, 1H, J ) 2.5 Hz,
H-6), 5.1 (d, 1H, J ) 5 Hz, CHOAc), 5.8 (d, 1H, J ) 15 Hz,
CHdCHCO), 6.9 (dd, 1H, J ) 15, 8 Hz, CHdCHCO), 7.1-7.3
(m, 5H, C6H5); MS (DCI, NH3, +ve) m/ z 860 (M + NH4)+ for
C47H70O13; analytical HPLC (90% MeCN-H2O) showed 85%
purity (tR ) 5.9 min).
[1S-[1r(4R*,5S*),3r,4â,5r,6r(2E,4R*,6R*),7â]]-1-[4-(Acety-
loxy)-5-m et h yl-3-m et h ylen e-6-p h en ylh exyl]-6-h yd r oxy-
2,8-d ioxa b icyclo[3.2.1]oct a n e-3,4,5-t r ica r b oxylic Acid ,
6-(4,6-Dim eth yl-2-octen oa te), 3,4,5-Tr is(1,1-d im eth yleth -
yl) Ester (17). A solution of 15 (1.34 g, 1.44 mmol) in MeOH
(100 mL) at 60 °C was treated with pyridinium p-toluene-
sulfonate (0.1 g, 0.4 mmol). After 16 h of stirring at 60 °C,
the solvent was evaporated and EtOAc (150 mL) was added.
The organic phase was washed with a saturated aqueous
solution of NaHCO3 (30 mL) and a saturated aqueous solution
of NH4Cl (30 mL). The organic phase was dried and evapo-
rated to give 17 (1.15 g, 94%): NMR (CDCl3) δ 1.02 (d, 3H, J
) 7 Hz, CHdCHCHCH3), 1.44, 1.45, and 1.47 (s, 27H, 3
t-BuO2C), 2.10 (s, 3H, CH3CO2), 2.70 (dd, 1H, J ) 5, 13 Hz,
one proton of PhCH2), 2.95 (d, 1H, J ) 11 Hz, H-4), 3.07 (bd,
1H, OH), 3.98 (bs, 1H, H-7), 4.90 (d, 1H, J ) 11 Hz, H-3), 4.93
and 4.95 (bs, 2H, CdCH2), 5.10 (d, 1H, J ) 5 Hz, CHOAc),
5.72 (d, 1H, J ) 2 Hz, H-6), 5.75 (d, 1H, J ) 15 Hz,
CHdCHCO), 6.9 (dd, 1H, J ) 7, 15 Hz, CHdCHCO), 7.10-
7.30 (m, 5H, C6H5); MS (DCI, NH3, +ve) m/ z 860 (M + NH4)+.
Anal. (C47H70O13‚1.5H2O) C, H.
[1S-[1r(4R*,5S*),3r,4â,5r,6r(2E,4R*,6R*),7â]]-1-[4-(Acety-
loxy)-5-m eth yl-3-m eth ylen e-6-ph en ylh exyl]-6,7-dih ydr oxy-
2,8-d ioxa b icyclo[3.2.1]oct a n e-3,4,5-t r ica r b oxylic Acid ,
6-(4,6-Dim et h yl-2-oct en oa t e) (3) a n d [1S-[1r(4R*,5S*),-
3r,4â,5r,6r(2E,4R*,6R*),7â]]-1-[4-(Acetyloxy)-5-m eth yl-3-
m eth ylen e-6-ph en ylh exyl]-6,7-dih ydr oxy-2,8-dioxabicyclo-
[3.2.1]octa n e-3,4,5-tr ica r boxylic Acid , 6-(4,6-Dim eth yl-2-
octen oa te), 7-Meth a n oa te (19). A solution of 17 (1.1 g, 1.32
mmol) in formic acid (10 mL) was stirred at room temperature.
After 16 h, the formic acid was evaporated; the residue was
purified by reverse-phase HPLC (column B) eluting with 68%
MeCN-H2O and acidified with 0.15 mL/L concentrated H2-
SO4 to give 3 (0.385 g, 43%): NMR (CD3OD) δ 0.83-0.91 (m,
9H, 3 CH3), 1.03 (d, 3H, J ) 6.5 Hz, CHdCHCHCH3), 2.09 (s,
3H, CH3CO2), 2.67 (dd, 1H, J ) 13.5, 6.5 Hz, one proton of
PhCH2), 3.08 (d, 1H, J ) 10.5 Hz, H-4), 4.01 (d, 1H, J ) 2 Hz,
H-7), 4.98 and 5.01 (2s, 2H, CdCH2), 5.06 (d, 1H, J ) 5 Hz,
CHOAc), 5.82 (d, 1H, J ) 16 Hz, CHdCHCO), 5.86 (d, 1H, J
) 2 Hz, H-6), 6.87 (dd, 1H, J ) 16, 8 Hz, CHdCHCO), 7.09-
7.30 (m, 5H, C6H5); MS (-ve FAB) m/ z 673 (M - H)-. Anal.
(C35H46O13‚H2O) C, H.
19 (0.121 g, 13%): NMR (CD3OD) δ 2.1 (s, 3H, CH3CO2),
2.66 (dd, 1H, J ) 6, 14 Hz, one proton of PhCH2), 3.02 (d, 1H,
J ) 11 Hz, H-4), 4.93 (d, 1H, J ) 11 Hz, H-3), 5.05 (d, 1H, J
) 5 Hz, CHOAc), 5.27 (d, 1H, J ) 2 Hz, H-7), 5.80 (d, 1H, J )
15 Hz, CHdCHCO), 6.20 (d, 1H, J ) 2 Hz, H-6), 6.85 (dd, 1H,
J ) 9, 15 Hz, CHdCHCO), 7.10-7.30 (m, 5H, C6H5), 8.25 (s,
1H, OCHO); MS (-ve FAB) m/ z 701 (M - H)-. Anal.
(C36H46O14‚1.3H2O) C, H.
[1S-[1r(4R*,5S*),3r,4â,5r,6r(2E,4R*,6R*),7â]]-1-[4-(Acety-
loxy)-5-m eth yl-3-m eth ylen e-6-ph en ylh exyl]-6,7-dih ydr oxy-
2,8-d ioxa b icyclo[3.2.1]oct a n e-3,4,5-t r ica r b oxylic Acid ,
6-(4,6-Dim eth yl-2-octen oa te), Tr ip ota ssiu m Sa lt (Tr ip o-
ta ssiu m Sa lt of 3). KHCO3 (3 equiv, 170 mg, 1.7 mmol) in
H2O (5 mL) was added slowly to a stirring solution of 3 (380
mg, 0.56 mmol) in a mixture of dioxane (20 mL) and H2O (2
mL). Stirring was continued until the cloudy solution became
clear. The resultant solution was freeze-dried to give the
potassium salt of 3 as a white solid (quantitative): NMR (D2O)
δ 0.80 (t, 3H, J ) 9 Hz, CH2CH3), 0.81 (d, 3H, J ) 7 Hz,
CHCH3), 0.91 (d, 3H, J ) 7 Hz, CHCH3), 1.01 (d, 3H, J ) 6.5
Hz, CHdCHCHCH3), 2.18 (s, 3H, CH3CO2), 2.60 (d, 2H, J ) 7
Hz, PhCH2CH), 2.69 (d, 1H, J ) 11 Hz, H-4), 3.90 (s, 1H, H-7),
4.72 (d, 1H, J ) 11 Hz, H-3), 4.89 (d, 1H, J ) 5 Hz, CHOAc),
4.97 and 5.03 (2s, 2H, CdCH2), 5.93 (d, 1H, J ) 15 Hz,
[1S-[1r(4R*,5S*),3r,4r,5r,6r(2E,4R*,6R*),7â]]-1-[4-(Acety-
loxy)-5-m eth yl-3-m eth ylen e-6-ph en ylh exyl]-6,7-dih ydr oxy-
2,8-d ioxa b icyclo[3.2.1]oct a n e-3,4,5-t r ica r b oxylic Acid ,
6-(4,6-Dim et h yl-2-oct en oa t e) (5) a n d [1S-[1r(4R*,5S*),-
3r,4r,5r,6r(2E,4R*,6R*),7â]]-1-[4-(Acetyloxy)-5-m eth yl-3-
m eth ylen e-6-ph en ylh exyl]-6,7-dih ydr oxy-2,8-dioxabicyclo-
[3.2.1]octa n e-3,4,5-tr ica r boxylic Acid , 6-(4,6-Dim eth yl-2-
octen oa te), 7-Meth a n oa te (20). 18 (200 mg, 0.237 mmol)
was dissolved in formic acid (5 mL) and stirred at room
temperature overnight. Removal of solvent gave a foam which
was purified by preparative HPLC (column A) eluting with
60% MeCN-H2O and acidified with 0.15 mL/L concentrated
H2SO4 (tR ) 10.69 min) to give 5 (108 mg, 67%): NMR (CD3-
OD) δ 0.82-0.92 (m, 9H, 3 CH3), 1.06 (d, 3H, J ) 7.2 Hz,
CHdCHCHCH3), 2.09 (s, 3H, CH3CO2), 2.67 (dd, 1H, J ) 13.5,
6.5 Hz, one proton of PhCH2), 3.61 (d, 1H, J ) 3.5 Hz, H-4),
3.99 (d, 1H, J ) 2.5 Hz, H-7), 4.94 and 5.01 (2s, 2H, CdCH2),
5.06 (d, 1H, J ) 5 Hz, CHOAc), 5.43 (d, 1H, J ) 2.5 Hz, H-6),
5.85 (d, 1H, J ) 15.5 Hz, CHdCHCO), 6.90 (dd, 1H, J ) 15.5,
8 Hz, CHdCHCO), 7.09-7.30 (m, 5H, C6H5); MS (-ve FAB)
m/ z 673 (M - H)-, 629 (M - CO2H)-. Anal. (C35H46O13‚2H2O)
C, H.
20 (20 mg, 8%): NMR (CD3OD) δ 0.81-0.92 (m, 9H, 3 CH3),
1.05 (d, 3H, J ) 7 Hz, CHdCHCHCH3), 2.09 (s, 3H, CH3CO2),