New Methods of Indole Formations andApplications in Total Synthesis

Palladium-Catalyzed Synthesis of 2-(Aminomethyl)indolesfrom Ethyl 3-(o-Trifluoroacetamidophenyl)-1-Propargyl Carbonate

Ilaria Ambrogio, Sandro Cacchi and Giancario FabriziOrg. Lett., 2006, ASAP

and

A New Modular Indole Synthesis. Construction of the HighlyStrained CDEF Parent Tetracycle of Nodulisporic Acids A and B

Amos B. Smith, III, László Kürti and Akin H. DavulcuOrg. Lett., 2006, ASAP

Erick B. Iezzi, PhDCurrent Literature

May 6, 2006

Erick Iezzi @ Wipf Group 1 5/10/2006

Why are these articles significant?

• New routes to functionalized indoles: - significant for natural product and pharmaceutical drug synthesis

• Cacchi’s group developed a simple approach to 2-(aminomethyl)indoles and the important class of 2-(piperazin-1-ylmethyl)indoles

• Smith’s group developed a new synthesis of tetracyclic indoles via a Stille cross- coupling/Buckwald-Hartwig union/cyclization

Erick Iezzi @ Wipf Group 2 5/10/2006

Synthesis and Functionalization of Indoles

• Classical methods (over last 100 years):

- Fisher synthesis - Gassman synthesis - Madelung cyclization - Bischler synthesis

• Palladium-catalyzed syntheses (over last 40 years):

- industrial synthesis of acetaldehyde from ethylene (PdCl2 and CuCl2) launched a new area of research - fewer steps, less waste, etc.

O

BrH2N

+

HNheat

Bischler-Möhlau synthesis

Erick Iezzi @ Wipf Group 3 5/10/2006

Alkyne-Based Palladium-Catalyzed Assembly of Indoles

Mechanism

Example

Cacchi and Fabriz. Chem. Rev. 2005, 105, 2873

Erick Iezzi @ Wipf Group 4 5/10/2006

Alkene-Based Palladium-Catalyzed Assembly of Indoles

Mechanism

Cacchi and Fabriz. Chem. Rev. 2005, 105, 2873

Example

Erick Iezzi @ Wipf Group 5 5/10/2006

Palladium-catalyzed hydroarylation/cyclization of alkynes(Cacchi’s methodology)

• Used to construct heterocyclic rings: - butenolides - quinolines - chromenes - coumarins - chromanols

OTHP

OEt

OEt

Pd(OAc)2 (5 mol%),

DMF, KOOCH,

40 oC, 4 h, 66%

I OMe

OMe

OTHP

OEt

OEt CHO

OMe

OTHP

TsOH (10%),EtOH/H2O (8:2),2 h, rt, 87%

OOH

H

OMeTsOH (10%),Me2CO/H2O (8:2),24 h, rt, 86%

O

OMe

O

CrO3, Me2CO/HCl2N (8:2), 2.5 h, rt,79%

Cacchi, et al. Synlett. 1997, 1367

Erick Iezzi @ Wipf Group 6 5/10/2006

Palladium-Catalyzed Synthesis of 2-(Aminomethyl)indoles(Cacchi et al., ASAP)

desired product

* A new palladium-catalyzed cyclization of an acyclic alkyne to a free N-H functionalized indole!

interesting result

Erick Iezzi @ Wipf Group 7 5/10/2006

Synthesis of 2-(piperazin-1-ylmethyl)indoles (Cacchi et al., ASAP)

• 2 privileged structures (indole and piperazine nuclei) - significant components in pharmaceutical chemistry (i.e., Clozapine) - formed in a single step

HN

NPh

aq. CH2O, CH2Cl2/AcOH (4:1), rt, 30 min.

NH

NN

N Ph

NH

N

50%

• Stepwise pathways (2 & 3 positions)

Gmeiner, et al. J. Med. Chem. 2000, 43, 4563

NH

ClHN

NAr

R2NH, DMF, 60 oCNH

N

N

Ar

Two C-N bonds formedin a single operation

Erick Iezzi @ Wipf Group 8 5/10/2006

Synthesis of Starting Materials and Evaluation of Conditions for 2-(Piperazin-1-ylmethyl)indole Formation

I

NH2

O

O

PdCl2(PPh3)2, CuI,

Et2NH, DMF, 60 oC

12 h

TFAA, THF, Et3N,

0 oC, 2 h

NHCOCF3

OO

p-TsOH, 40 oC,

Acetone/H2O (1:1),

6 h

Ethyl chloroformate,

CH2Cl2, Et3N,

0 oC, 2 h

NHCOCF3

OCO2Et

80% (4 steps)

Erick Iezzi @ Wipf Group 9 5/10/2006

Evaluation of Functional Groups in 2-(Piperazin-1-ylmethyl)indole Formations

Erick Iezzi @ Wipf Group 10 5/10/2006

Evaluation of Secondary Amines and Proposed Reaction Mechanism

NHCOCF3

OCO2Et

Amine, Pd cat.

NH

N

X

X = C,O

NH

NR2

or

Proposed mechanism

Not acidic enough

Erick Iezzi @ Wipf Group 11 5/10/2006

A New Modular Indole Synthesis. Construction of the HighlyStrained CDEF Parent Tetracycle of Nodulisporic Acids A & B

(Smith et al., ASAP)

Nodulisporanes: - a novel class of indole diterpene alkaloids - display potent insecticidal properties (i.e., fleas and ticks) - modulation of the invertebrate-specific glutamate-gated chloride ion channels

- Nodulisporic acid A – first reported by Merck in 1997 as a lead compound (potentcy, stability and pharmacokinetic profile was not optimal!)

Erick Iezzi @ Wipf Group 12 5/10/2006

Attempts to Synthesize the CDE Core via Known Indole Formations(Smith et al., ASAP)

Reported approaches to CDE tricycle

Application of the Fisher Indole Synthesis

High strain in five-membered system!

Erick Iezzi @ Wipf Group 13 5/10/2006

Stille Cross-Coupling/Buchwald-Hartwig Union/Cyclization Tactic(Smith et al., ASAP)

No reaction with 2.5 mol% cat.

38

39

Erick Iezzi @ Wipf Group 14 5/10/2006

Preparation of a Highly Substituted and Strained Indole Derived from (+)-Estrone and Construction of Diverse Indoles

Erick Iezzi @ Wipf Group 15 5/10/2006

Summary of New Indole Methodologies

• Cacchi’s group developed a simple approach to 2-(aminomethyl)indoles and 2-(piperazin-1-ylmethyl)indoles under mild conditions in a single operation - high product yields - application to functionalized indoles

• Smith’s group developed a new indole synthesis via a Stille/Hartwig-Buchwald coupling using mild conditions - application to structurally diverse indoles, especially novel tricyclic systems

Erick Iezzi @ Wipf Group 16 5/10/2006