Synthesis of Ingenol

Structure of Ingenol

C20H28O5

Principal investigator	John L. Wood
Publication year	2004
Synthesis type	Total
Number of steps	33 (linear)
References	J. Am. Chem. Soc. 2004, 126, 16300. Org. Lett. 2001, 3, 1563.

Part 1 of 1

intermediate structure

MeLi, CuCN

Et2O

-78 °C, 2 h

See the Michael Addition

intermediate structure

TsOH, (CH2OH)2

Dean-Stark

PhH

Reflux, 12 h, 35% (2 steps)

"The product was separated from the resulting four diastereoisomers."

intermediate structure

LiAlH4

Et2O

RT, 2 h

intermediate structure

HCl

Acetone

RT, 30 min, 95% (2 steps)

intermediate structure

DMAP, Ac2O

Pyr

RT, 30 min, 96%

intermediate structure

DBU

PhH

Reflux, 10 h, 88%

intermediate structure

+

intermediate structure

BF3.OEt2

																	PhMe															

								-78 °C, 								85 min, 								59%
							
								See the Diels-Alder Reaction
							
								"The product was separated from the resulting three diastereoisomers."

intermediate structure

Grubbs catalyst (2nd gen.), C2H4

CH2Cl2

RT, 12 h, 98%

See the Olefin Metathesis

intermediate structure

NMO, OsO4

H2O, THF

RT, 8 h

See the Upjohn Dihydroxylation

intermediate structure

NaIO4

H2O, MeOH, THF

RT, 60 min

intermediate structure

Pyr.TsOH, (CH2OH)2

Dean-Stark

PhH

Reflux, 4 h, 73% (3 steps)

intermediate structure

+

intermediate structure

KH

THF

Reflux, ON, 98%

intermediate structure

Grubbs-Hoveyda catalyst (2nd gen.)

PhMe

RT, 30 h, 76%

See the Olefin Metathesis

intermediate structure

HCl

H2O, THF

Reflux, 3 h

intermediate structure

NaBH4

EtOH, THF

0 °C, 15 min, 77% (2 steps)

intermediate structure

Ph3P, Imidazole, I2

THF

0 °C, 3 h

See the Appel Reaction

intermediate structure

KOt-Bu

DMSO

RT, ON, 94% (2 steps)

intermediate structure

t-BuOOH, SeO2

AcOH, CH2Cl2

0 °C to RT, 2 h, 49%

"The yield was 70 % brsm."

intermediate structure

Dess-Martin Periodinane

CH2Cl2

-40 to 10 °C, 90 min, 74%

See the Dess-Martin Oxidation

intermediate structure

RhCl3

Sealed tube

EtOH, H2O

115 °C, 35 min, 74%

intermediate structure

P(OMe)3, O2, KOt-Bu

t-BuOH, THF

-40 °C, 45 min, 94%

intermediate structure

VO(acac)2, t-BuOOH

PhH

10 °C to RT, 10 h, 73%

intermediate structure

TMSOTf, Et3N

CH2Cl2

-10 to -5 °C, 60 min, 72%

intermediate structure

NaBH4

MeOH

RT, 5 h

intermediate structure

Pyr.TsOH, 2,2-Dimethoxypropane

CH2Cl2

Reflux, 30 min, 86% (2 steps)

intermediate structure

DDQ

CH2Cl2

RT, 18 h, 90%

intermediate structure

MsCl, Et3N

CH2Cl2

-78 °C, 45 min, 96%

intermediate structure

Li2CO3, PhSH

DMF

55 °C, 5 h, 76%

intermediate structure

(NH4)6Mo7O24.4H2O, H2O2

EtOH, H2O

RT, 6 h, 97%

intermediate structure

DBU

PhH

Reflux, 5 h, 47%

"Also isolated was a mixture of E/Z exocyclic sulfones (47 % yield) which could be equilibrated to afford the desired allylic sulfone."

intermediate structure

Na2HPO4, Na(Hg)

MeOH

-20 to -10 °C, 25 min, 76%

intermediate structure

HCl

H2O, THF

RT, 5 h, 92%

intermediate structure

SiO2, SeO2

THF

80 °C, 2 h, 40%

"The yield was 89 % brsm."

intermediate structure

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