Synthesis of Ingenol

Structure of Ingenol

C20H28O5

Principal investigator	Isao Kuwajima
Publication year	2003
Synthesis type	Total
Number of steps	46 (linear)
References	J. Am. Chem. Soc. 2003, 125, 1498.

Part 1 of 1

intermediate structure

AllylBr, NaH

PhH

70 °C, 3.5 h

See the Williamson Ether Synthesis

intermediate structure

Cl2CHCO2H

DMF

125 °C to Reflux, 90 min, 79% (2 steps)

See the Claisen Rearrangement

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

Imidazole, TESCl

DMF

0 °C, 60 min, 99%

intermediate structure

TMS2NLi
ZnBr2
MeCHO

Et2O, THF

-78 to 0 °C, 2 h, 71%

See the Aldol Addition

intermediate structure

DBU, (CF3CO)2O

PhH, Pyr

-23 to 0 °C, 35 min, 95%

intermediate structure

i-Pr2NLi, LiBr, MeCO2t-Bu

Et2O

-78 °C, 90 min, 91%

See the Aldol Addition

intermediate structure

AlMe3
i-Pr2NLi
HCl , 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%

See the Parikh-Doering Oxidation

intermediate structure

+

intermediate structure

n-BuLi

Et2O, THF

-98 °C to RT, 3 h, 85%

See the Horner-Wadsworth-Emmons Reaction

intermediate structure

n-BuLi
(CH2O)n

THF

-78 °C to RT, 2 h, 91%

See the Fritsch-Buttenberg-Wiechell Rearrangement

intermediate structure

Et3N, DMAP, Ac2O

CH2Cl2

0 °C to RT, 30 min, 99%

intermediate structure

Co2(CO)8

CH2Cl2

RT, 60 min, 95%

intermediate structure

Special reagent

CH2Cl2

-23 to 0 °C, 2.5 h

See the Prins Reaction

See the Nicholas Reaction

intermediate structure

Li

NH3

-78 °C, 60 min, 67% (2 steps)

intermediate structure

CHBr3, Et3NBn+ Cl-, NaOH

CH2Cl2, EtOH, H2O

0 °C, 5 h, 32%

"The yield was 71% brsm."

intermediate structure

CuI , MeLi
MeI

Et2O

-45 °C to RT, 13 h, 95%

See the Corey-Posner, Whitesides-House Reaction

intermediate structure

Ti(Oi-Pr)4, t-BuOOH

4 Å MS

CH2Cl2

-20 to 0 °C, 60 min

intermediate structure

AlMe3

CH2Cl2

-78 °C, 60 min, 75% (2 steps)

See the Semi-Pinacol Rearrangement

intermediate structure

Et3N, DMSO, (COCl)2

CH2Cl2

-78 °C to RT, 2.5 h, 93%

See the Swern Oxidation

intermediate structure

+

intermediate structure

DMF

100 °C

See the Mannich Reaction

intermediate structure

i-Bu2AlH
MeI , 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

Tf2O , 2,6-Lutidine
DBU

CH2Cl2

-78 °C to RT, 90 min, 83% (2 steps)

intermediate structure

n-Bu4N+ F-

THF

RT, 30 min

intermediate structure

H2Cr2O7.2Pyr

4 Å MS

CH2Cl2

RT, 2 h, 97% (2 steps)

intermediate structure

Special reagent

DMF

120 °C, 3 h, 78%

"The yield was 86% brsm."

intermediate structure

CeCl3, NaBH4

H2O, MeOH

-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

Et2O, Pyr

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

NCS, Et3N, Me2S

PhMe

-23 °C to RT, 50 min, 75%

See the Corey-Kim Oxidation

intermediate structure

TESOTf, 2,6-Lutidine

CH2Cl2

0 °C, 60 min

intermediate structure

TMSCl , i-Pr2NLi
Et3N

THF

-78 °C, 2 h

intermediate structure

NBS

CH2Cl2

0 °C, 30 min

intermediate structure

HF

H2O, MeCN

RT, 30 min

intermediate structure

+

intermediate structure

CH2I2, MeLi

THF

-78 °C, 60 min, 39% (5 steps)

intermediate structure

Zn, NH4Cl

H2O, THF

RT, 30 min, 91%

intermediate structure

KOH

MeOH

RT, 30 min, 89%

intermediate structure

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