Total Synthesis of Lysergic Acid

Penghao Chen

Dong Group Seminar

N 14th 2012Nov 14th 2012

Core Structure of Ergot AlkaloidsCo e St uctu e o got a o ds

Epimerisation of lysergic/isolysergic acidp e sat o o yse g c/ so yse g c ac d

E. C.  Kornfeld & R. B. WoodwardC o e d & ood a d

J. Am. Chem. Soc. 1956, 78, 3087–3114.

Direct Introduction of Nitrogen at C4ect t oduct o o t oge at C

Addition of a Carbon Chain at C5

O O

O OR

Cl

OO

Br

dd t o o a Ca bo C a at C5

N

O

Br

O

OR

ZnN

hydrolysisCl

Cl

O

toluene

N3

DCM

HBr(aq)

NBBz BzBz

OO

OOH

O

ONMe

HO

OH

NaBH4

NB

N

NH2

100oCN

Bz Bz Bz

Yield is too low, abandoned

Addition of a Carbon Chain at C5dd t o o a Ca bo C a at C5

Unsaturated AldehydeU satu ated de yde

Unsaturated AldehydeU satu ated de yde

Unsaturated AldehydeU satu ated de yde

Unsaturated AldehydeU satu ated de yde

NHOOC

H

NH

R. Ramageg

NHOOC

H

epimerisation

NHOOC

H

NH NHNH

NH

HOOC

NH

Tetrahedron Letter No. 47, pp 4311‐4314, 1976

R. Ramage

OCOOCH3

Ph P

H3COOCCOOH

g

N

O Ph3PCOOtBu

benzene/tBuOHreflux 4d

90% TFA

25oC, 2h

Bzreflux, 4d

NBz

H3COOCNH2

13

Curtius Degradation

NH2

methylationcyclization products

NBz

J. Rebek, Jr.,

T t h d L tt V l 24 N 9 859 860 1983Tetrahedron Letters, Vol. 24, No. 9, pp 859‐860, 1983J. Am . Chem. Soc. 1984, 106, 1813‐1819

J. Rebek, Jr.,

James B. Hendrickson

Org. Lett., Vol. 6, No. 1, 2004

Bondset b‐>a

X COOMe N

MeOOCN

MeOOC

O

NH

N

COCl

+OXEMgBr

ZnCl2

NH

O

COClNH

NH

N

MeOOCN

MeOOC

O

N

X -HX

O

N NH

Bondset a‐>b

Yanxing Jiag

(R)‐5

Org. Lett., Vol. 13, No. 18, 2011

Yanxing Jiag

Hiroaki Ohno & Nobutaka Fujiij

NHTs

NHOH

TsH

OH

NHTs

NTs N

HBr

NTs NTs

Org. Lett., Vol. 10, No. 22, 2008J Org Chem 2011 76 5506 5512J. Org. Chem. 2011, 76, 5506‐5512J. Org. Chem. 2011, 76, 2072‐2083

Hiroaki Ohno & Nobutaka Fujii

Ph Ph

j

NTs

Pd(PPh3)4, InI TsHN OHaldehyde

PhCH(OMe)2CSA

DCE

O NTsNIS, AgNO3

THF

O NTs

IBr Pd(PPh3)4, Et3B

allyl alcohol

Br TsCl, NaOHn-Bu4NHSO4

Br

NH

allyl alcohol

NH

NTs

TsN Ph18

1) OsO4, NMOTHF/H2O

BrO

O

NTsPhI

BrO

2) NaIO4THF/H2O

NTs

NHK reactionNTs

OH

Hiroaki Ohno & Nobutaka Fujii

BrO

TsN Ph

O

TsN Ph

j

NTs

Br

OH

Dess-Martinperiodinane

DCMN

Br

OTs N

Ts

BrO

TsN Ph

NsNHNH2DEAD Ph3P

BrH

NHTsPTSA

(R)-alpine-Borane

THFNTs

OH

THFNTs

HOHMeOH/DCM

H

1a

(S) l i B

BrO

TsN Ph

NsNHNH2DEAD Ph3P

Br

H

OH

NHTs

PTSA

H

(S)-alpine-Borane

THFNTs

OH

THFNTs

MeOH/DCM1b

Hiroaki Ohno & Nobutaka Fujiij

Hiroaki Ohno & Nobutaka Fujii

1) Dess-Martin periodinane, DCM2) NaClO2 NaH2PO4 2-methylbut-2-ene

j

NH

HOTs

2) NaClO2, NaH2PO4, 2 methylbut 2 enet-BuOH/THF/H2O

3) TMSCHN2, MeOH/toluene4) seperation

NH

MeOOC Ts

NTs NTs

1) sodium naphthalenide2) formalin, NaBH3CN

AcOH, MeOH

NH

MeOOCN

H

HOOC

hydrolysis,

NH NH

Hiroaki Ohno & Nobutaka Fujiij

Hiroaki Ohno & Nobutaka Fujii

ORPd-catalyzeddomino cyclization

Myers alleneformation

j

NH

Ts

Br

H

H

NHTs

OR

NTs NTs

H

BrH

OH

regioselectivereduction

O

NTs

BrOR

NHTNTs

BrOR

O

NHTs TsNHTs

BrOR

BrOH

Sonogashiracoupling

Br

NTs

NHTsNTs

NHTs

Tohru Fukuyamay

Tohru Fukuyamay

Tohru Fukuyamay

Tohru Fukuyamay

Tohru Fukuyamay

Albert Padwa’s Isomunchnone

N

OO

R1

N

OO

R1

N

R3

R2N

R3

R2

munchnone

OR1HOR1

NR3

R2

O NR3

R2

O

isomunchnone

Albert Padwa’s Isomunchnone

O

NN2

ORh++

N

O

OO O O O

O COM

N

O COMeO

Albert Padwa’s Isomunchnone

Albert Padwa’s Isomunchnone

O H

I

O

NHMe1) H

TMS

PdCl (Ph P)

O

NHMe

H

1) Cl

O O

OEt HO

PdCl2(Ph3P)2CuI, Ph3P, Et3N

2) K2CO3, MeOH

2) MsN3, Et3NNO

N2

CO2Et

OONHMe

ONHMe O

Rh++NO

OO

EtO

HEt3SiH

BF3 Et2O

O H

O

EtO2C OO

EtO2C OEtO

+ +

SummarySummary

1. Chirality of C2 is obtained by epimerisation

2. Chirality of C1 is obtained by resolution,2. Chirality of C1 is obtained by resolution, chiral starting substances or asymmetric cyclizationcyclization

3. Old methods always use indoline while recent methods can tolerate                                     indole ring during total synthesisindole ring during total synthesis                            process

AcknowledgementAcknowledgement

COOHCOOH

alcoholic hydrogen

COOH

N

chlorideplatinic oxideconc. HCl

NHN

HH