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

Hongjun Zhang, Jutatip Boonsombat, and Albert Padwa*Org. Lett.  2007, 9, 279-282.

Jixin Liu2/21/2012      Chem 635  

Outline

• Brief introduction of Dr. Albert Padwa.• Strychnine• Retrosynthesis• Forwardsynthesis • Summary

               

                                                        Dr. Albert Padwa

   Education:B.A., Columbia University; Ph.D., Columbia University; Postdoctoral Research Fellow, University of Wisconsin. Academic :-William P. Timmie Professor of Chemistry, Emory University-Mentored around 200 Graduate Students and Postdocs-Approximately 820 publications including many reviews and book chapters-Editorial Boards of JACS, JOC, Org. Lett. among others-Served as an Alternate Councilor, Chairman of the Organic Division of the ACS, and has been the President of the International Society of Heterocyclic Chemistry.-Avid Mountain Climber and Runner

Biography: http://www.arkat-usa.org/get-file/18783/

Strychnine

highly toxic colorless crystalline alkaloid, isolated In 1818.Structure determined by Robert Robinson in 1947.

Fruit of Strychnine

6 stereo centers, 5 of which are included within one saturated 6-membered ring

Completed Total Synthesis first by Woodward (1954), then by many others. 

N

O

OH

N

H

H

                           Strychnine

N

O

OH

N

H

H

Padwa Synthesis

Hongjun Zhang; Jutatip Boonsombat; Albert Padwa; Org. Lett.  2007, 9, 279-282Hongjun Zhang; Jutatip Boonsombat; Albert Padwa; Org. Lett.  2007, 9, 279-282

Hongjun Zhang; Jutatip Boonsombat; Albert Padwa; Org. Lett.  2007, 9, 279-282

Retrosynthesis

Forward synthesis      Key step

N

N

O

Me

O

Ac 7

Upon MMFF94 Minimization, Iteration  500; Final Energy: 97.153

N

N

O

Me

O

Ac

Forward synthesis

O

NMe

O

N

OMe

O

HN

O

N

OMe

DMF, 0 oC

NaH

Me

I

7

toluene, microwave MgI2

N

NO

O

Me

O Me

LiAlH4 NaBH(OAc)3

NH

N

Me

H OH

HN

NO

OH

Me

O Me

H

NH

NO

OH

Me

H

20% Pd on Pd(OH)2/C

(Pearlman's catalyst) NH

NH

OHH

OO

I

Br

NH

N

OHH

O

O

I

K2CO3, DMF/H2O

NH

N

OH

Me

H

NaBH4

NaOMe

8

13

1415

OHO

O

I

N

O Cl

OOOO

I

SO

OHO

O

OHOO

I triphenyl phosphine

N-bromosuccinimide

OO N

Br OO

I

Br

NH

NH

OHH

OO

I

Br

NH

N

OHH

O

O

I

K2CO3, DMF/H2O

N

N

OH

O

O

I

O O

O

O O

NaBH(OAc)3

CH3COOH

N

N

O

O

O

I

O O

CH3CN

NMO (N-methyl morpholine-N-oxide)

TPAP (tetra-n-propyl-ammonium perruthenate)

9

N

N

O

O O

H

OMOM

PhOK

t-BuOK, t-BuOH phenol

16

Pd(PPh3)4 THF

14 15

N-methyl morpholine-N-oxide

N+

O

O-

tetra-n-propyl-ammonium perruthenate

N+ Ru

O

O

O

O-

diisopropyl amine

NH

N

N

O

O O

H

OMOM

n-BuLi

Ph2P(O)CH2OMe N

N

O O

H

OMOM

OMe

HCl

55 oC,10 h

Wieland-Gumlich aldehyde

NH

HOOH

N

CH3COOH

AC2O, NaOAcN O

H

N

(+)-strychnine (4)

O

HO

OH

O

HO

Summary

•  a concise synthesis of the Strychnos alkaloid (+)-strychnine• The central step in the synthesis consists of an intramolecular [4+2] 

cycloaddition/rearrangement.• Closure of the remaining D-ring was carried out from the aza-tetracyclic 

intermediate by an intramolecular palladium-catalyzed enolate-driven cross-coupling between the N-tethered vinyl iodide and the keto group.

Thank you!