Synthesis of Ingenol

Structure of Ingenol

C20H28O5

Principal investigatorIsao Kuwajima
Publication year2003
Synthesis typeTotal
Number of steps 46 (linear)
References
Part 1 of 1
intermediate structure
NaH, AllylBr
PhH
70 °C, 3.5 h
intermediate structure
Cl2CHCO2H
DMF
125 °C to Reflux, 90 min, 79% (2 steps)
intermediate structure
NBS
DMSO, H2O
10 °C, 2 h, 32%
See the Prins Reaction
"Also isolated was the C2-epimer which was reverted to the starting material with zinc/ammonium chloride (52 % yield)."
intermediate structure
TESCl, Imidazole
DMF
0 °C, 60 min, 99%
intermediate structure
  1. TMS2NLi
  2. ZnBr2
  3. MeCHO
THF, Et2O
-78 to 0 °C, 2 h, 71%
See the Aldol Addition
intermediate structure
(CF3CO)2O, DBU
PhH, Pyr
-23 to 0 °C, 35 min, 95%
intermediate structure
MeCO2t-Bu, i-Pr2NLi, LiBr
Et2O
-78 °C, 90 min, 91%
See the Aldol Addition
intermediate structure
  1. AlMe3
  2. i-Pr2NLi
  3. HCl
  4. H2O
THF
-78 °C to RT, 30 h, 66%
intermediate structure
TIPSCl, DMAP
DMF
RT, 16 h, 100%
intermediate structure
LiAlH4
THF
0 to 50 °C, 4 h, 84%
"The yield was 92 % brsm."
intermediate structure
Pyr.SO3, Et3N
DMSO
RT, 10 min, 97%
intermediate structure + intermediate structure
n-BuLi
THF, Et2O
-98 °C to RT, 3 h, 85%
intermediate structure
  1. n-BuLi
  2. (CH2O)n
THF
-78 °C to RT, 2 h, 91%
intermediate structure
Ac2O, Et3N, DMAP
CH2Cl2
0 °C to RT, 30 min, 99%
intermediate structure
Co2(CO)8
CH2Cl2
RT, 60 min, 95%
intermediate structure
CH2Cl2
-23 to 0 °C, 2.5 h
See the Prins Reaction
intermediate structure
Li
NH3
-78 °C, 60 min, 67% (2 steps)
intermediate structure
CHBr3, NaOH, Et3NBn+ Cl-
CH2Cl2, EtOH, H2O
0 °C, 5 h, 32%
"The yield was 71% brsm."
intermediate structure
  1. MeLi
  2. CuI
  3. MeI
Et2O
-45 °C to RT, 13 h, 95%
intermediate structure
t-BuOOH, Ti(Oi-Pr)4
CH2Cl2
-20 to 0 °C, 60 min
intermediate structure
AlMe3
CH2Cl2
-78 °C, 60 min, 75% (2 steps)
intermediate structure
(COCl)2, DMSO, Et3N
CH2Cl2
-78 °C to RT, 2.5 h, 93%
See the Swern Oxidation
intermediate structure + intermediate structure
DMF
100 °C
intermediate structure
  1. i-Bu2AlH
  2. MeI
  3. THF
CH2Cl2
-78 °C to RT, 30 min, 98% (2 steps)
intermediate structure
NaBH4
EtOAc
-78 to 0 °C, 30 min, 95%
intermediate structure
i-Bu2AlH
CH2Cl2
-78 °C, 2 h
intermediate structure
  1. Tf2O
  2. 2,6-Lutidine
  3. DBU
CH2Cl2
-78 °C to RT, 90 min, 83% (2 steps)
intermediate structure
n-Bu4N+ F-
THF
RT, 30 min
intermediate structure
H2Cr2O7.2Pyr
CH2Cl2
RT, 2 h, 97% (2 steps)
intermediate structure
DMF
120 °C, 3 h, 78%
"The yield was 86% brsm."
intermediate structure
NaBH4, CeCl3
MeOH, H2O
-78 to -50 °C, 3 h
See the Luche Reduction
intermediate structure
TESCl, Imidazole
DMF
0 °C, 30 min, 99% (2 steps)
intermediate structure
OsO4
Pyr, Et2O
RT, 48 h, 59%
intermediate structure
CDI
PhH
RT, 60 min, 76%
"Also isolated was the desired regioisomer (18 % yield, see next step)."
intermediate structure
DMAP
PhMe
100 °C, 2 h, 27%
"The yield was 99 % brsm."
intermediate structure + intermediate structure
Camphorsulfonic acid
RT, 3 h, 92%
intermediate structure
SOCl2
Pyr
RT, 30 min
intermediate structure
Ac2O
H2O
60 °C, 3 h, 96% (2 steps)
intermediate structure
Me2S, NCS, Et3N
PhMe
-23 °C to RT, 50 min, 75%
intermediate structure
TESOTf, 2,6-Lutidine
CH2Cl2
0 °C, 60 min
intermediate structure
  1. i-Pr2NLi
  2. TMSCl
  3. Et3N
THF
-78 °C, 2 h
intermediate structure
NBS
CH2Cl2
0 °C, 30 min
intermediate structure
HF
MeCN, H2O
RT, 30 min
intermediate structure + intermediate structure
CH2I2, MeLi
THF
-78 °C, 60 min, 39% (5 steps)
intermediate structure
Zn, NH4Cl
THF, H2O
RT, 30 min, 91%
intermediate structure
KOH
MeOH
RT, 30 min, 89%
intermediate structure