Synthesis of Ingenol

Structure of Ingenol

C20H28O5

Principal investigator	Jeffrey D. Winkler
Publication year	2002
Synthesis type	Total
Number of steps	45 (linear)
References	J. Am. Chem. Soc. 2002, 124, 9726.

Part 1 of 1

intermediate structure

+

intermediate structure

NH3, Li

t-BuOH, THF

-78 to -5 °C, 75 min

See the Michael Addition

intermediate structure

TBSOTf, Et3N

CH2Cl2

RT, ON, 69% (2 steps)

intermediate structure

LiAlH4

Et2O

0 °C to RT, 20 min, 100%

intermediate structure

TsCl, Et3N, DMAP

CH2Cl2

0 °C to RT, ON, 88%

intermediate structure

AllylMgBr, CuI

Et2O

-20 to 0 °C, 90 min, 87%

intermediate structure

HF

THF

RT, ON, 83%

intermediate structure

i-Pr2NLi
MeO2CCN

HMPA, THF

-78 °C, 90 min, 89%

See the Claisen Condensation

intermediate structure

(4-MeOPh)CH2OH

Dean-Stark

PhMe

Reflux, 11 h, 97%

intermediate structure

(CF3CO)2O, CF3CO2H

Acetone

-78 °C to RT, ON, 93%

intermediate structure

t-BuOOH, SeO2, Salicylic acid

CH2Cl2

Reflux, ON, 71%

intermediate structure

Ph3P, C2Cl6

CH2Cl2, Et2O

0 °C, 60 min, 93%

See the Appel Reaction

intermediate structure

hν

Acetone, MeCN

0 °C, 16 h, 60%

See the De Mayo Reaction

intermediate structure

+

intermediate structure

K2CO3

MeOH

RT, 36 h

See the De Mayo Reaction

intermediate structure

+

intermediate structure

LiAlH4

THF

RT, 40 min

intermediate structure

+

intermediate structure

DBU

200 °C, 24 h

intermediate structure

TBSCl, Imidazole, DMAP

CH2Cl2

RT, 14 h, 35% (4 steps)

"Also isolated was the C6-epimer (10% yield)."

intermediate structure

CHBr3, Et3NBn+ Cl-, NaOH

H2O

RT, 15 min, 100%

intermediate structure

CuSCN , MeLi
MeI

Et2O

-78 to -15 °C, 3.5 h, 72%

See the Corey-Posner, Whitesides-House Reaction

intermediate structure

n-Bu4N+ F-

THF

RT, 3 h, 99%

intermediate structure

NaHCO3, Dess-Martin Periodinane

CH2Cl2

0 °C to RT, 6 h, 89%

See the Dess-Martin Oxidation

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

Pyr, NBS, NaOAc

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

OsO4, NMO

H2O, t-BuOH, THF

RT, 2 h, 69%

See the Upjohn Dihydroxylation

intermediate structure

TBDPSCl, Imidazole, DMAP

CH2Cl2

RT, 12 h, 85%

intermediate structure

TESOTf, 2,6-Lutidine

CH2Cl2

RT, 30 min, 83%

intermediate structure

OsO4

Pyr

0 °C to RT, 12 h, 93%

intermediate structure

DMAP, BzCl, Et3N

CH2Cl2

0 °C to RT, 30 min, 82%

intermediate structure

Pyr, SOCl2

CH2Cl2

RT, 10 min

intermediate structure

RuCl3, NaIO4

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

NaHCO3, Dess-Martin Periodinane

CH2Cl2

0 to 25 °C, 4 h, 96%

See the Dess-Martin Oxidation

intermediate structure

+

intermediate structure

i-Pr2NLi

Et2O

-78 °C, 2 h

See the Claisen Condensation

intermediate structure

MeI, K2CO3

Acetone

RT, 2 h

intermediate structure

Pd(OAc)2

MeCN

80 °C, 2 h, 20% (3 steps)

"The yield was 23 % brsm."

intermediate structure

CeCl3, NaBH4

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

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