SAR of Capsaicin and Resiniferatoxin Analogues
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15 2949
6.80 (3H, m, vanillyl ArH), 7.51 (1H, m, H-1). FAB-MS (M +
1)+ 533 (40). Accurate mass (FAB MH+): calcd for C31H37O9,
553.2438; found, 553.2434.
H3-18), 1.72 (1H, d, H-12R), 1.84 (3H, s, CH3 H3-17), 1.86 (3H,
br m, CH3 H3-19), 2.20-2.38 (2H, m, H-5R, H-12â), 2.59 (1H,
AB, H-5â), 2.76 (1H, m, H-11), 3.26 (2H, br m, H-8, H-10), 4.08
(2H, s, H2-20), 4.49 (1H, d, H-14), 4.91 (1H, m, H-16), 5.06 (1H,
s, H-16), 5.92 (1H, br m, H-7), 7.40 (3H, m, orthobenzoyl
ArH3,4,5), 7.62 (1H, m, H-1), 7.75 (2H, m, orthobenzoyl ArH2,6).
9,13,14-Or t h ob en zoylr esin ifer on yl 20-(4-Acet oxy-3-
m eth oxyp h en yla ceta te). 9,13,14-Orthobenzoylresiniferonol
(14 mg, 0.031 mmol) was dissolved in dry CH2Cl2 (3 mL) and
Resin ifer on ol. Resiniferonol 9,13,14-orthophenylacetate
(105 mg, 0.23 mmol) was dissolved in MeOH (70 mL), and 1
N HCl (24 mL, 24 mmol) was added. The reaction mixture
was stirred for 4 h at room temperature before the addition of
1 M NaOMe solution in MeOH (30 mL, final pH ) 10) and
stirring for a further 30 min. After this time the reaction
mixture contained only starting material and resiniferonol by
HPLC. The solvent was evaporated, and the crude product
was purified by preparative HPLC (MeOH/H2O gradient, 10-
70%). The pure fractions were evaporated to give a colorless
glass, yield 53.7 mg (60%), as well as 37 mg (35%) of recovered
starting material: TLC (silica gel, CH2Cl2/MeOH, 10:1) Rf )
0.16; analytical reversed-phase HPLC (gradient 10-70%
MeOH/H2O) tR ) 11.2 min, >99% pure; 1H NMR (CD3OD, 200
MHz) δ 0.94 (3H, d, CH3 H3-18), 1.74 (3H, br d, CH3 H3-19),
1.77 (3H, s, CH3 H3-17), 1.90-2.02, (2H, m, H2-12), 2.33-2.35
(2H, m, AB, H-5R, H-11), 2.50 (1H, AB, H-5â), 3.16 (1H, br
m, H-10), 3.42 (1H, br m, H-8), 3.96 (2H, m, H2-20), 4.01 (1H,
d, H-14), 5.05 (2H, m, H2-16), 5.90 (1H, m, H-7), 7.52 (1H, m,
H-1); FAB-MS (M + 1)+ 391 (100).
Resin ifer on ol 14,20-Diben zoa te. Resiniferonol (54 mg,
0.14 mmol) was dissolved in dry EtOAc (6 mL), DMAP (38 mg,
0.31 mmol) was added, and the mixture was stirred at room
temperature under a N2 atmosphere. A solution of benzoic
anhydride (70 mg, 0.31 mmol) in EtOAc (3 mL) was slowly
added, and the reaction mixture was stirred for 18 h. TLC
indicated the absence of resiniferonol but the presence of
significant monobenzoylated material. Further benzoic an-
hydride (14 mg, 0.062 mmol) and DMAP (7.6 mg, 0.062 mmol)
were added, and the solution was stirred for a further 18 h.
After this time TLC indicated that the reaction mixture was
mainly dibenzoylated material. The solution was washed with
water and NaCl (saturated) and dried over MgSO4. The crude
product was purified by flash column chromatography (silica
gel, EtOAc/cyclohexane, 1:4) to give a colorless glass, yield 40.7
mg (51.5%): TLC (silica gel, EtOAc/cyclohexane, 1:1) Rf ) 0.35;
1H NMR (CD3OD, 200 MHz) δ 1.05 (3H, d, CH3 H3-18), 1.70
(1H, d, H-12R), 1.75 (3H, s, CH3 H3-17), 1.86 (3H, br d, CH3
H3-19), 2.25-2.46 (3H, m, H-5R, H-11, H-12â), 2.64 (1H, AB,
H-5â), 3.11 (1H, br m, H-8), 4.02 (1H, br m, H-10), 4.68 (2H,
m, H2-20), 5.12 (1H, s, H-16), 5.18 (1H, 2, H-16), 5.77 (1H, br
stirred at room temperature under a N2 atmosphere.
A
solution of DCCI (7.2 mg, 0.034 mmol) and DMAP (0.42 mg,
0.0034 mmol) in CH2Cl2 (0.5 mL) was added followed by a
solution of acetylhomovanillic acid (7.8 mg, 0.034 mmol) in
CH2Cl2 (0.5 mL). The reaction mixture was stirred for 1 h at
room temperature, after which time no starting material
remained by TLC. The solvent was evaporated in vacuo, and
the residue was suspended in diethyl ether, the solid removed
by filtration, and the filtrate evaporated in vacuo to leave the
crude product which was purified by preparative HPLC
(isocratic 73% MeOH/H2
O); the pure fractions were evaporated
in vacuo to give a colorless glass, yield 14 mg (66%): TLC (silica
1
gel, EtOAc/cyclohexane, 1:1) Rf ) 0.42; H NMR (CDCl3, 200
MHz) δ 1.23 (3H, d, CH3 H3-18), 1.70 (1H, d, H-12a), 1.82 (6H,
br s, CH3 H3-17, H3-19), 2.05 (1H, d, H-5R), 2.20-2.38 (2H, s,
m, ArOCOCH3, H-5â, H-12â), 2.76 (1H, m, H-11), 3.15 (1H,
br m, H-8), 3.22 (1H, br m, H-10), 3.58 (2H, s, ArCH2CO), 3.81
(3H, s, ArOCH3), 4.44 (1H, d, H-14), 4.54 (2H, s, H2-20), 4.89
(1H, m, H-16), 5.05 (1H, s, H-16), 5.94 (1H, br m, H-7), 6.83-
7.02 (3H, m, vanillyl ArH), 7.40 (3H, m, orthobenzoyl ArH3,4,5),
7.55 (1H, m, H-1), 7.75 (2H, m, orthobenzoyl ArH2,6).
9,13,14-Or t h ob en zoylr esin ifer on yl 20-(4-H yd r oxy-3-
m eth oxyp h en yla ceta te) (10b). 9,13,14-Orthobenzoylresin-
iferonyl 20-(4-acetoxy-3-methoxyphenylacetate) (8 mg, 0.012
mmol) was dissolved in dry CH2Cl2 (1 mL) and stirred at room
temperature under N2. A solution of pyrrolidine (50 µL, 0.60
mmol) in CH2Cl2 (0.5 mL) was added and the reaction mixture
was stirred for 90 min, after which time no starting material
remained by TLC. The solvent was removed in vacuo, the
crude product was purified by preparative HPLC (isocratic 70%
MeOH/H2O), and the pure fractions were evaporated in vacuo
to give a colorless glass, yield 7 mg (93%): TLC (silica gel,
EtOAc/cyclohexane, 1:1) Rf ) 0.32; HPLC (isocratic 70%
1
MeOH/H2O) tR ) 10.5 min, 100% pure; H NMR (CDCl3, 200
MHz) δ 1.25 (3H, d, CH3 H3-18), 1.70 (1H, d, H-12R), 1.82 (6H,
br s, CH3 H3-17, H3-19), 2.05 (1H, d, H-5R), 2.30 (1H, m,
H-12â), 2.44 (1H, AB, H-5â), 2.72 (1H, m, H-11), 3.15 (1H, br
m, H-8), 3.24 (1H, br m, H-10), 3.52 (2H, s, ArCH2CO), 3.81
(3H, s, ArOCH3), 4.43 (1H, d, H-14), 4.53 (2H, AB, H2-20), 4.91
(1H, m, H-16), 5.06 (1H, s, H-16), 5.92 (1H, br m, H-7), 6.70-
6.85 (3H, m, vanillyl ArH), 7.35-7.44 (3H, m, orthobenzoyl
d, H-7), 5.87 (1H, s, H-14), 7.34-7.66 (7H, m, benzoyl ArH3,4,5
,
H-1), 7.92-8.08 (4H, m, benzoyl ArH2,6); FAB-MS (M + 1)+
573 (30).
9,13,14-Or th oben zoylr esin ifer on ol 20-Ben zoa te. A so-
lution of resiniferonol 14,20-dibenzoate (20.6 mg, 0.036 mmol)
in dry dichloroethane (20 mL) was added by syringe to a dry
flask containing anhydrous CaCl2 (206 mg, 1.86 mmol) and
anhydrous toluenesulfonic acid (6 mg, 0.036 mmol). The
reaction mixture was heated to 80 °C for 1 h after which no
starting material remained. The precipitate was removed by
filtration, the solvent was evaporated, and the crude product
was purified by preparative HPLC (isocratic 75% MeOH/H2O).
The pure fractions were evaporated in vacuo to give a colorless
glass, yield 19.6 mg (98%): TLC (silica gel, EtOAc/cyclohexane,
1:1) Rf ) 0.62; 1H NMR (CDCl3, 200 MHz) δ 1.28 (3H, d, CH3
H3-18), 1.75 (1H, d, H-12R), 1.83 (3H, s, CH3 H3-17), 1.86 (3H,
br m, CH3 H3-19), 2.20-2.38 (2H, m, H-5R, H-12â), 2.68 (1H,
AB, H-5â), 2.77 (1H, m, H-11), 3.31 (2H, br m, H-8, H-10), 4.53
(1H, d, H-14), 4.78 (2H, AB, H2-20), 4.92 (1H, s, H-16), 5.07
(1H, s, H-16), 6.10 (1H, br m, H-7), 7.38-8.04 (11H, m, benzoyl,
orthobenzoyl ArH, H-1).
9,13,14-Or th oben zoylr esin ifer on ol. 9,13,14-Orthoben-
zoylresiniferonol 20-benzoate (19.6 mg, 0.035 mmol) was
dissolved in dry MeOH (10 mL) and stirred at room temper-
ature under a N2 atmosphere. A solution of NaOMe (390 µL
of 1 M solution, 0.39 mmol) in dry methanol was added, and
the reaction mixture was stirred for 1 h, after which time no
starting material remained by TLC. The crude product was
purified by preparative HPLC (isocratic 65% MeOH/H2O), and
the pure fractions were evaporated in vacuo to give a colorless
glass, yield 14.5 mg (91%): TLC (silica gel, EtOAc/cyclohexane,
1:1) Rf ) 0.19; 1H NMR (CDCl3, 200 MHz) δ 1.25 (3H, d, CH3
ArH3,4,5
FAB-MS (M + 1)
for C37H39O9, 615.2594; found, 615.2590.
), 7.60 (1H, m, H-1), 7.75 (2H, m, orthobenzoyl ArH2,6);
+ 615 (20). Accurate mass (FAB MH+): calcd
9,13,14-Or th oph en ylacetyl-3â-h ydr oxyr esin ifer on yl 20-
(4-Hyd r oxy-3-m eth oxyp h en yla ceta te) (11b). Resinifera-
toxin (11.3 mg, 0.018 mmol) was dissolved in absolute ethanol
(1 mL) and stirred at room temperature. NaBH4 (3.4 mg, 0.089
mmol) was added and the reaction mixture stirred for 2 h.
After this time no starting material remained by TLC, and so
AcOH (15 µM) was added and the solvent removed in vacuo.
The residue was redissolved in CH2Cl2, washed with water
and saturated NaCl, and dried over Na2SO4. The solvent was
removed in vacuo to leave a glass which was purified by
preparative HPLC (isocratic 75% MeOH/H2O). The pure
fractions were evaporated to give a colorless glass, yield 6.8
mg (60%): TLC (silica gel, EtOAc/cyclohexane, 1:1) Rf ) 0.24;
analytical reversed-phase HPLC (gradient 10-100% MeCN/
0.1% aqueous TFA) tR ) 17.2 min, 100% pure; 1H NMR (CD3-
OD, 200 MHz) δ 0.98 (3H, d, CH3 H3-18), 1.42 (1H, d, H-12R),
1.51 (3H, s, CH3 H3-17), 1.72 (3H, br d, CH3 H3-19), 2.10 (1H,
AB, H-5R), 2.16 (1H, m, H-12â), 2.40 (1H, AB, H-5â), 2.65 (1H,
m, H-11), 2.69 (1H, br m, H-10), 3.02 (1H, br m, H-8), 3.12
(2H, s, ortho ester CH2Ph), 3.54 (2H, AB, ArCH2CO), 3.80 (3H,
s, ArOCH3), 3.89 (1H, br, H-3), 4.15 (1H, d, H-14), 4.55 (2H,
AB, H2-20), 4.66 (1H, s, H-16), 4.71 (1H, s, H-16), 5.48 (1H, br
m, H-1), 5.83 (1H, m, H-7), 6.70-6.83 (3H, m, vanillyl ArH),