Total Synthesis of...

Total Synthesis of (-)-Mersicarpine

Guillaume Lapointe, January 21th 2010

Nakajima, R.; Ogino, T.; Yokoshima, S.; Fukuyama, T.. J. Am. Chem. Soc. 2010, ASAP.

Indole Alkaloids

- Indole alkaloids isolated from the flowering Kopsia species (Malaysia)

- Features of mersicarpine: - Atypical tetracyclic structure - Nitrogen atom at 3-position of indoline - Seven membered cyclic amine - Adjacent to the imine: quaternary carbon / hemiacetal

- Three synthesis reported so far, in which two involves a radical approach

Kerr’s Approach to (±)-Mersicarpine

- Key strategy: Mn(OAc)3-Mediated malonic radical cyclization onto the indole

(1) Magolan, J.; Kerr, M. A. Org. Lett. 2006, 8, 4561-4564. (2) Magolan, J.; Carson, J. A.; Kerr, M. A. Org. Lett. 2008, 10, 1437-1440.

Kerr’s Total Synthesis of (±)-Mersicarpine

Kerr’s Total Synthesis of (±)-Mersicarpine

- First total synthesis

- Involved Mn(OAc)3-mediated radical cyclization of a diketone into a indole

Zard’s Formal Synthesis of (±)-Mersicarpine

- Key strategy: Intermolecular radical addition-radical cyclization cascade

Biechy, A.; Zard, S. Z. Org. Lett. 2009, 11, 2800-2803.

Zard’s Formal Synthesis of (±)-Mersicarpine

Fukuyama’s Total Synthesis of (-)-Mersicarpine

Retrosynthetic analysis

- Construction of the indole skeleton via a Sonogashira coupling and a gold(III) catalyzed cyclization

-Eschenmoser-Tanabe-type fragmentation

Fukuyama’s Total Synthesis of (-)-Mersicarpine

O1) Ph NH2 , toluene, reflux

2) CO2Me , 65 oC, 3 days

83%, 99% ee after recryst.

OCO2Me

Eschenmoser-Tanabe Fragmentation

α,β-Epoxyketone fragment to alkyne and a ketone, passing throught the corresponding hydrazone

In the present paper, formation of hydrazones failed from 10 – Warkentin’s procedure worked

NCO2Me

O

HNH2N

OPb(OAc)4 CO2Me

O

NN

O

HN

CO2Me

O

NN

CO2MeO

NN

CO2Me

O

Fukuyama’s Total Synthesis of (-)-Mersicarpine

Fukuyama’s Total Synthesis of (-)-Mersicarpine

+ side product

- Yield of 1 not reproductible, always side product present

- Treatment with 18O2 after hydrogenation: 18O incorporated

- Potential side product arising from autooxidation of product 2 to19

Autooxidation of the Enamine 2

Addition of a reductant after oxidation may solve the problem!

Fukuyama’s Total Synthesis of (-)-Mersicarpine

- First enantioselective synthesis

- Done in 10 steps from ketoester 9, 13% overall yield

- Interesing indole ring construction, and Eschenmoser-Tanabe like rearrangement