Synthesis of Ingenol

Structure of Ingenol

C20H28O5

Principal investigatorJeffrey D. Winkler
Publication year2002
Synthesis typeTotal
Number of steps 45 (linear)
References
Part 1 of 1
intermediate structure + intermediate structure
Li, NH3
t-BuOH, THF
-78 to -5 °C, 75 min
intermediate structure
Et3N, TBSOTf
CH2Cl2
RT, ON, 69% (2 steps)
intermediate structure
LiAlH4
Et2O
0 °C to RT, 20 min, 100%
intermediate structure
DMAP, Et3N, TsCl
CH2Cl2
0 °C to RT, ON, 88%
intermediate structure
CuI, AllylMgBr
Et2O
-20 to 0 °C, 90 min, 87%
intermediate structure
HF
THF
RT, ON, 83%
intermediate structure
  1. i-Pr2NLi
  2. MeO2CCN
HMPA, THF
-78 °C, 90 min, 89%
intermediate structure
(4-MeOPh)CH2OH
PhMe
Reflux, 11 h, 97%
intermediate structure
CF3CO2H, (CF3CO)2O
Acetone
-78 °C to RT, ON, 93%
intermediate structure
SeO2, t-BuOOH, Salicylic acid
CH2Cl2
Reflux, ON, 71%
intermediate structure
Ph3P, C2Cl6
CH2Cl2, Et2O
0 °C, 60 min, 93%
See the Appel Reaction
intermediate structure
Acetone, MeCN
0 °C, 16 h, 60%
intermediate structure + intermediate structure
K2CO3
MeOH
RT, 36 h
intermediate structure + intermediate structure
LiAlH4
THF
RT, 40 min
intermediate structure + intermediate structure
DBU
200 °C, 24 h
intermediate structure
DMAP, Imidazole, TBSCl
CH2Cl2
RT, 14 h, 35% (4 steps)
"Also isolated was the C6-epimer (10% yield)."
intermediate structure
NaOH, Et3NBn+ Cl-, CHBr3
H2O
RT, 15 min, 100%
intermediate structure
  1. MeI
  2. MeLi
  3. CuSCN
Et2O
-78 to -15 °C, 3.5 h, 72%
intermediate structure
n-Bu4N+ F-
THF
RT, 3 h, 99%
intermediate structure
Dess-Martin Periodinane, NaHCO3
CH2Cl2
0 °C to RT, 6 h, 89%
intermediate structure
t-BuBr
DMSO
Reflux, 10 h
intermediate structure
LiCl
DMF
Reflux, 60 min, 73% (2 steps)
intermediate structure
AcCl
Ac2O, Pyr
Reflux, 12 h, 80%
intermediate structure
NaOAc, NBS, Pyr
Acetone
0 °C to RT, 12.5 h
intermediate structure
LiCl
DMF
Reflux, 60 min, 50% (3 steps)
intermediate structure
i-Bu2AlH
THF
-78 °C, 30 min, 80%
intermediate structure
NMO, OsO4
H2O, t-BuOH, THF
RT, 2 h, 69%
intermediate structure
DMAP, Imidazole, TBDPSCl
CH2Cl2
RT, 12 h, 85%
intermediate structure
2,6-Lutidine, TESOTf
CH2Cl2
RT, 30 min, 83%
intermediate structure
OsO4
Pyr
0 °C to RT, 12 h, 93%
intermediate structure
BzCl, DMAP, Et3N
CH2Cl2
0 °C to RT, 30 min, 82%
intermediate structure
Pyr, SOCl2
CH2Cl2
RT, 10 min
intermediate structure
NaIO4, RuCl3
CCl4, H2O, MeCN
RT, 10 min, 79% (2 steps)
intermediate structure
DBU
PhMe
Reflux, 12 h
intermediate structure
H2SO4
H2O, MeCN, THF
RT, 60 min, 34% (2 steps)
"Also isolated was the desired TES-deprotected alcohol (40 % yield, see next step)"
intermediate structure
n-Bu4N+ F-
THF
-78 °C, 4 h, 72%
intermediate structure + intermediate structure
Camphorsulfonic acid
CH2Cl2
RT, 30 min, 86%
intermediate structure
K2CO3
MeOH, THF
RT, 2 h, 81%
intermediate structure
Dess-Martin Periodinane, NaHCO3
CH2Cl2
0 to 25 °C, 4 h, 96%
intermediate structure + intermediate structure
i-Pr2NLi
Et2O
-78 °C, 2 h
intermediate structure
K2CO3, MeI
Acetone
RT, 2 h
intermediate structure
Pd(OAc)2
MeCN
80 °C, 2 h, 20% (3 steps)
"The yield was 23 % brsm."
intermediate structure
NaBH4, CeCl3
MeOH
0 °C, 60 min
See the Luche Reduction
intermediate structure
HCl
MeOH
RT, 5 h
intermediate structure
n-Bu4N+ F-
THF
RT, 15 min, 28% (3 steps)
intermediate structure