ew Methods of Indole Formations and Applications in Total Synthesis Palladium-Catalyzed Synthesis of 2-(Aminomethyl)indoles from Ethyl 3-(o-Trifluoroacetamidophenyl)-1-Propargyl Carbonate Ilaria Ambrogio, Sandro Cacchi and Giancario Fabrizi Org. Lett., 2006, ASAP and A ew Modular Indole Synthesis. Construction of the Highly Strained CDEF Parent Tetracycle of odulisporic Acids A and B Amos B. Smith, III, László Kürti and Akin H. Davulcu Org. Lett., 2006, ASAP Erick B. Iezzi, PhD Current Literature May 6, 2006 Erick Iezzi @ Wipf Group 1 5/10/2006
Why are these articles significant? ew 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 crosscoupling/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 O Br + Bischler-Möhlau synthesis H 2 heat H Palladium-catalyzed syntheses (over last 40 years): - industrial synthesis of acetaldehyde from ethylene (PdCl 2 and CuCl 2 ) launched a new area of research - fewer steps, less waste, etc. 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 Example Cacchi and Fabriz. Chem. Rev. 2005, 105, 2873 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 OEt I OMe OMe TsOH (10%), EtOH/H 2 O (8:2), 2 h, rt, 87% OMe OTHP OEt Pd(OAc) 2 (5 mol%), DMF, KOOCH, 40 o C, 4 h, 66% OEt OEt OTHP CHO OTHP TsOH (10%), Me 2 CO/H 2 O (8:2), 24 h, rt, 86% O OH H OMe CrO 3, Me 2 CO/HCl 2 (8:2), 2.5 h, rt, 79% O O OMe 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 -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 Two C- bonds formed in a single operation Stepwise pathways (2 & 3 positions) H Ph Ph Cl H Ar H aq. CH 2 O, CH 2 Cl 2 / AcOH (4:1), rt, 30 min. 50% H H R 2 H, DMF, 60 o C H Ar Gmeiner, et al. J. Med. Chem. 2000, 43, 4563 Erick Iezzi @ Wipf Group 8 5/10/2006
Synthesis of Starting Materials and Evaluation of Conditions for 2-(Piperazin-1-ylmethyl)indole Formation I O O TFAA, THF, Et 3, 0 o C, 2 h O O p-tsoh, 40 o C, Acetone/H 2 O (1:1), 6 h H 2 PdCl 2 (PPh 3 ) 2, CuI, Et 2 H, DMF, 60 o C 12 h HCOCF 3 Ethyl chloroformate, CH 2 Cl 2, Et 3, 0 o C, 2 h 80% (4 steps) HCOCF 3 OCO 2 Et 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 HCOCF 3 OCO 2 Et Amine, Pd cat. H or H R 2 X = C,O X Proposed mechanism ot acidic enough Erick Iezzi @ Wipf Group 11 5/10/2006
A ew Modular Indole Synthesis. Construction of the Highly Strained CDEF Parent Tetracycle of odulisporic Acids A & B (Smith et al., ASAP) odulisporanes: - 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 - odulisporic 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) 38 39 o reaction with 2.5 mol% cat. 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 ew 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