Total Synthesis of (+)-Strychnine via a [4+2 ...ccc.chem.pitt.edu/wipf/Current...

Total Synthesis of (+)-Strychnine via a[4+2]-Cycloaddition/Rearrangement Cascade

Hongjun Zhang, Jutatip Boonsombat, and Albert Padwa*

Org. Lett., 2007, 9, 279-282.

William Paquette5-12-07 Literature Presentation

Wipf Group

Bill Paquette @ Wipf Group 5/12/2007

N

O

N

O

H

H

H

(-)-Strychnine

Strychnos nux vomica(found in southern Asia and Australia)

“For its molecular size it is the most complex substance known” (R.B. Woodward, ca. 1963)

Strychnine - A Highly Toxic Alkaloid

•Isolated in 1818 from an Indian poison nut•Its structure was determined in 1947 by Robert Robinson•Highly toxic to humans and animals•Commonly used as a pesticide

•From a synthetic perspective, its structure has fascinated organic chemists for decades•Consists of a heptacyclic core with 6 contiguous stereocenters

•Numerous synthetic efforts have been conducted


OMe

OMe

O

N

H

OMe

OMe

NMe2

N

H

OMe

OMe

NMe3

I-

1. NaCNN

H

OMe

OMe

NH2

2. formaldehyde,dimethylamine

1. PPA,phenylhydrazine

2. LiAlH4

H

OEt

O

O N

H

OMe

OMe

N

CO2Et

NOMe

OMe

NTs

CO2Et

HAc

O3

MeOH

N

CO2Me

CO2Me

NTs

CO2Et

HAc

1. TsCl, pyridine

2. NaBH4

3. Ac2O, pyr

N CO2Me

NTs

CO2Et

O

N CO2Me

NAc

CO2Me

O

N

CO2Me

NAc

O

OH

MeOH-HClreflux

1. HI,red phosphorus2. MeOH-HCl

3. acetylation

NaOMe/MeOH

A Historical Perspective:The First Total Synthesis of Strychnine

Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749.Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. Tetrahedron 1963, 19, 247.


N

CO2Me

NAc

O

OH

N

CO2H

NAc

O

H N

NAc

OOAc

1. tosylation2. sodium benzylmercaptide(thiobenzyl ether formation)

3. Raney Ni, EtOH4. H2, Pd/C5. KOH/MeOH

Ac2O, pyrreflux

1. HCl & AcOH (aq)2. SeO2, EtOH

N

O

N

O

O

H

HNa1.

2. Lindlar

3. LiAlH4

N

N

O

H

OHN

N

O

H1a. HBr/AcOH

OH

b. H2SO4 (aq)

EtOH/KOH N

O

N

O

H

H

H

(-)-Strychnine

The Woodward Synthesis:Final Approach


CN

NO2NH2

N CO2Me

CHOMeO2C

MeO2C

N

N CO2Me

CO2Me

5 steps79% overall

then ClCO2MePhNEt2, 85%

Diastereoselective Synthesis of StrychnineRapid Access to the Heptacyclic Natural Product

Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59, 2685.

HN

N

CO2Me

CO2MeO

HN

NH

Br

I

CH2OTBS

MeO2CK2CO3

O

N

NI

OTBS

H

benzene, 185 oC

99%

TMSI, CHCl3 acetone:DMF (5:1)

quant

75% (2 steps)

1. Pd(OAc)2, Bu4NCl DMF, K2CO3

2. 2N HCl

HO

HN

N

O

O

H

H

H

N

N

O

(-)-Strychnine

EtOH/KOH

71%


Strychnine Synthesis via an aza-Cope-Mannich Reaction

Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc. 1993, 115, 9293.

Me3Sn

Ot-Bu

OTIPS

N

NMeMeN

O

I

2.5% Pd2dba3,22% Ph3As

CO, LiCl,NMP, 80%

Ot-Bu

OTIPS

N

O

1. t-BuO2H, Triton B, 91%2. Ph3P=CH2, 92%3. TBAF, 100%

Ot-Bu

OH

N

O MsCl, iPr2NEt,LiCl, NH2COCF3

Ot-Bu

NHCOCF3

N

OMeN

MeN

MeN

MeN

MeN

MeN

O

OONaH, PhH

100 oC

N

HO

N NMe

MeN O

H

Ot-Bu

(CH2O)n,

Na2SO4

CH3CN. 80oC

98%

N

Ot-Bu

ON

MeNNMe

O

1. LDA, NCCO2Me2. HCl-MeOH

70%NH

N

OH

CO2Me

(-)-Strychnine

83% 62%


Padwa’s Approach Toward the Synthesis of Complex Alkaloids

N

O

O Me

H

H

EtH H

H

N

O

O

H HH

HOOH

NMeO

MeO

N

MeH

OO

ONH

OR

N

OMe

MeO

Me

N

O

O

ON2

CO2Me

CO2t-BuRh(II)

NMeO

MeO

NO

O

MeCO2Me

CO2t-Bu

H

N

NH

MeO

R

H

Structural Motif

epi-zephyranthine

Ergot alkaloid (+)-stenine

(+)-aspidophytineOrg. Lett. 2006, 8, 3275

O


N

O

R

R'

N

O

R

R'

O O N

R

O

R'

O N

R

R'

Me2N

OTBS

OH

N

Boc

BrBr

NaH O N

Boc

Br

O N

Boc

MeO2C

Me2N

OTBS

Pd(PPh3)4, CO,iPr2EtN, MeOH

70% 70% CH3CN, !

O N

TBSO

Boc

MeO2C

NMe2

O N

CO2Me

O

Boc

N

O

CO2Me

Boc

HF-pyr toluene, 60%

Construction of the Ergot Alkaloid Skeleton

Padwa, A.; Bur, S. K.; Zhang, H. J. Org. Chem. 2005, 70, 6833.


N

O

O Me

H

H

EtH H

H

(+)-stenine

HO

NHCbz

CO2H

L-Tyrosine

PhI(OAc)2, NaHCO3,

MeOH, 21-40 oC

NO

OH

CO2Me

CbzH

N

H

CbzH

OTIPS

O

O

Diverse Approaches Toward the Synthesis of Stenine

Padwa, A.; Ginn, J. D. J. Org. Chem. 2005, 70, 5197.

Wipf, P; Kim, Y.; Goldstein, D. M. J. Am Chem. Soc. 1995, 117, 11106.

DMSTF - dimethyl(methylthio)sulfonium tetrafluoroborate

N

OMeS

MeS

O

CO2Me

NN O

CO2Me

O

MeS

87%

H

MeS

OOAc

DMSTF 25 oC

MeO2C

O


O

H

H

H

N

N

O

HN

OMe

N

OMOMDMB

HN

O

N

DMB

I

CH2OMOM

HN

O

N

Ac

O

Me

N

Ac

N

O

O

MeIMDAF

cycloaddition

enamide reduction

Intramolecularvinylation

acid hydrolysis/condensation

O

H

H

H

N

N

O

(-)-Strychnine

HO

HN

N

O

Isostrychnine

O

H

H

NH

HO

N

Wieland-Gumlichaldehyde

Total Synthesis of (+)-Strychnine via aCycloaddition/Rearrangement Pathway

Zhang, H.; Boonsombat, J.; Padwa, A. Org. Lett. 2007, 9, 279.


HN

O

N

DMB

I

CH2OMOM

1. ArCHO,NaBH(OAc)3, 86%2. TPAP, NMO, 80%

1. Pd(PPh3)4,PhOK, 56%

2. Ph2P(O)CH2OMe LDA, 72%

HN

OMe

N

OMOMDMB

1. NaBH4

2. NaOMe

3. LiAlH4

4. NaBH(OAc)365% H

NH OH

N

Me

H2, Pd(OH)2

70%

HNH OH

NH

K2CO3, DMF/H2O

I

HBr

OMOM

HNH OH

N I

CH2OMOM

80%

N

Ac

N

O

O

Me

!

trace MgI2

HN

N

Ac

O

Me

HN

O

N

Ac

O

Me

O

H+

HN

OH

N

Ac

O

Me

H

95%

Diastereoselective Construction of the Strychnine Core


O

H

H

NH

HO

N

Wieland-Gumlichaldehyde

54%CH2(CO2H)2

Ac2O

NaOAc,AcOH, 80%

O

H

H

H

N

N

O

(+)-Strychnine

HN

OMe

N

OMOMDMB

3N HCl

HN

OMe

N

OHDMB

HNH

OMe

N

OH

Completion of the Total Synthesis


Summary

N

O

N

O

H

H

H

(-)-Strychnine

MeO2C

N

N CO2Me

CO2Me

N CO2Me

NTs

CO2Et

O

N

Ot-Bu

ON

MeNNMe

O

N

Ac

N

O

O

Me

WoodwardThe First Total Synthesis

RawalA Concise Approach

OvermanUtilization of an aza-Cope-Mannich Reaction

PadwaCycloaddition/Rearrangement Strategy

•Strychnine’s complex structure provides a great opportunity toshowcase unique and powerful methodologies en route to its synthesis


Total Synthesis of (+)-Strychnine via a [4+2 ...ccc.chem.pitt.edu/wipf/Current...

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