Oxidative Enolate Coupling in Total SynthesisLiterature Seminar 2010.6.2 Shi-Liang, Shi

AppointmentApril, 2009 Member, Skaggs Institute for Chemical BiologyJune, 2008 Professor of ChemistryJuly, 2006 Associate Professor of Chemistry (with Tenure)June, 2003 Assistant Professor of Chemistry (The Scripps Research Institute)

Education2001-2003 Postdoctoral Associate

Advisor: Professor E.J. CoreyHarvard University, Cambridge, Massachusetts

1997-2001Ph.D. Graduate Student in ChemistryAdvisor: Professor K.C. NicolaouThe Scripps Research Institute, La Jolla, California

Awards• Thieme-IUPAC Prize in Synthetic Organic Chemistry, 2010• ACS Award in Pure Chemistry, 2010• Sackler Prize, 2009• National Fresenius Award, ACS, 2007• Novartis Lecturer, 2007 – 2008• Hirata Gold Medal, 2007• Pfizer Award for Creativity in Organic Synthesis, 2006• Beckman Foundation Fellow, 2006 – 2008• Alfred P. Sloan Foundation Fellow, 2006 – 2008• BMS Unrestricted “Freedom to Discover” Grant, 2006 – 2010• NSF CAREER Award, 2006 – 2010• Eli Lilly Young Investigator Award, 2005 – 2006• AstraZeneca Excellence in Chemistry Award, 2005• DuPont Young Professor Award, 2005• Roche Excellence in Chemistry Award, 2005• Amgen Young Investigator Award, 2005• Searle Scholar Award, 2005• GlaxoSmithKline Chemistry Scholar Award, 2005 – 2006

1. Intermolecular enolate heterocoupling ---A: IntroductionB: BackgroundC: Discovery and OptimizationD: ScopeE: MechanismF: Application

2. Intramolecular enolate couplingA: The first total synthesis of Stephacidin A--B: The first total synthesis of (+/-)- Actinophyllic Acid----Overman L.E. JACS, 2008, 7568C: The first total synthesis of Metacycloprodigiosin----Thomson R.J. JACS, 2009, 14579

3. Direct oxidative coupling indoles and pyrroles with carbonyl compounds----A: IntroductionB: Indole couplingC: Pyrrole couplingD: ScopeE: MechanismF: Application

--synthesis of Ketorolac--enantioselective toral synthesis of (+)-Hapalindole Q and (-)-Fisherindole U--enantioselective total synthesis of (+)-Fisherindole I and (-)-Fisherindole G----Baran JACS, 2005, 15394--protecting-group-free synthesis of (+)-ambiguine H and (-)-hapalindole U---Baran Nature, 2007, 404--protecting-group-free synthesis of (-)-fisherindole I and (+)-welwitindolinone A--Baran Nature, 2007, 404

4. Direct oxidative coupling phenols with carbonyl compounds----Li Z.P. JACS, 2009, 173875. Perspectives

Contents:

Phil S. Baran

Baran Angew, 2005, 606. Angew, 2005, 3892.JACS, 2006, 8678

Baran Angew, 2006, 7083Baran JACS, 2008, 11546

Baran JACS, 2004, 7450Baran Angew, 2005, 609Baran JACS, 2007, 12857

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1. Intermolecular enolate heterocouplingA: Introduction

The 2,3-disubstituted-1,4-dicarbonyl moiety is ubiquitous within natrural products and medicinal compounds.To achieve target-oriented syntheses concisely and efficiently is a longstanding dream of organic chemists.

The direct, convergent synthesis of unsymmetrical 2,3-disubstituted-1,4-dicarbonyl compounds from two carbonylsubunits has proven extremely difficult; Several methods for the synthesis of hypothetical succinate are depicted inFigure 2. Multistep sequences or prefunctionalization of one or both of the monomers were necessary in most cases.

The oxidative enolate heterocoupling could directly join two different sp3-hybridized carbon centers in a single stepwithout requiring prefunctionalization of the corresponding monomers.

Base[O]

Possible side products:

2

B : Background C: Discovery and Optimization

oxazolidinoneand ketone (1:1)in THF (0.3 M)

-78 oCLDA 2.1 eq.dropwise

-78 oC,30 min

rt, in 5 min

Fe(acac)3 2 eq.one portion

(0.5 M)

rt, 30 min

Fe(III)

0oC, in 5 min

Cu(2-ethylhexanote)2 1.5 eq.one portion

(0.5 M)

rt, 30 min

Cu(II)

Procedure:

f irst report

f irst use of soluableCu(II) oxidant

f irst heterocoupling

electrolytic method

Fe(III) as oxidant

f irst use ofoxazolidinone

a general enolate heterocoupling( amides, imidesketones, esters,oxindoles)

3

D: Scope

1. electron-neutral and electron-rich aromatic rings on both the oxazolidinone (5, 6, 4) and propiophenone (11, 12, 4)coupling partners lead to much more efficient Fe(III)-based couplings.2. Electron deficiency is much better tolerated on the propiophenones (13-15) than the oxazolidinone (7-9), whereelectron-withdrawing groups suppress coupling. Interestingly, the Cu(II)-based couplings showed the opposite trends.3. the bulkier auxiliary modestly improving the diastereoselectivity (17-21).4.The oxindoles were also cross-coupled with carvone (22,23) and cyclic aryl ketone 4-chromanone (24,25)affording complex compouds containing quaternary carbon center in good yield.

Oxindole

Carvone

quaternary carbon center

4-Chromanone

E M h i

1. both steric environments(31-35)and functional group (36-39) are tolerated.

2. Electron-rich (45-48), -neutral (41-44), and -deficient aromatic units(49,50) are tolerated.

comments:

4

E: Mechanism

the electrophilic ferr ic enolate is attacked by the lithium enolate of the oxazolidinone

Cu(II)-Chelated Transition States

F: Application

5

2. Intramolecular enolate coupling

Overman L.E. JACS, 2008, 7568B: The first total synthesis of (+/-)- Actinophyllic Acid

aza-Cope-Mannichrearrangement

Baran P.S. Angew, 2005, 606Baran P.S. Angew, 2005, 3892Baran P.S. JACS, 2006, 8678A: The first total synthesis of Stephacidin A

an intramolecular oxidative couplingof ketone and malonate enolate

overall y. 8 %6

PO

NNCl

OO

O O

3. Direct oxidative coupling indoles and pyrroles with carbonyl compounds

Baran P.S. JACS, 2004, 7450

Thomson R.J. JACS, 2009, 14579a Merged Conjugate Addition/Oxidative Coupling Sequence.

C: The first asymmetric total synthesis of Metacycloprodigiosin

Representative Members of the HapalindoleFamily of Natural Products

11 steps, 13 % overall yield.

suzuki Heck Heck

Cross-coupling paradigms:

"Chemoselectivity: The Mother of Inventionin Total Synthesis"---Baran P.S.

A: Introduction B: Indole coupling

C: Pyrrole coupling

Baran P.S. Angew, 2005, 6097

86% ee

0 oC

(1) Dimerization of indole or pyrrole is never observed.

suggests that selective heterocouplings can be designed by tuning the oxidation potential ofthe oxidant to react preferentially with one coupling partner over the other.

suggests that the ketone is oxidized first and then reacts with indole.

(2) N-Protected indoles or pyrroles are unreactive; the free N-H is required for the reaction to proceed.suggests that the reaction is not proceeding via oxidation to a discrete -radical on the carbonyl compound(which could react with the N-protected heterocycles) but instead supports a chelated transition state.

(3) Moderate to excellent diastereoselectivity was observed.supports a chelated transition state.

(4) Only 1 equiv of oxidant, relative to the ketone, is necessary for the reaction to proceed.suggests that the reaction is proceeding by preferential oxidation of the carbonyl compound, which react withthe indole or pyrrole anion, providing a radical anion intermediate. This radical anion could then be furtheroxidized by the remaining copper(I).

E: Mechanism study

1. The reactions allow tremendous complexity to be built into a target molecule using simple chemistry, which wouldotherwise require multiple steps to accomplish.2. The coupling of unfunctionalized indoles and pyrroles with various carbonyl compounds such as esters, imides,lactones, lactams, ketones, and amides.3. The reaction exhibits high levels of chemoselectivity (functional group tolerability), regioselectivity (coupling occursexclusively at C-3 of indole or C-2 of pyrrole), stereoselectivity (substrate control), and practicality (amenable toscaleup).4. As a meaningful demonstration of its utility, the method has been applied effectively in total synthesis.

Pyrrolecoupling

menthone

steroid

D: Scope

Advantages:

Baran P.S. JACS, 2007, 12857

indole (2eq) orpyrrole (3 eq)and ketone (1eq)

-78 oCLHMDSdropwise

-78 oC,30 min

SolidCu(2-ethylhexanote)21.5 eq. one portion

-78 oC to rtProcedure:

-78 oC to-60 oC, 3h -60 oC to rt

Pyrroles

Indoles

8

more resonable

the characteristic red-brown color ofcopper(I) salts is often observed at theend of the reaction

Mechanism for indole coupling

Mechanism for pyrrole coupling

F. Application:

Ph2S O(CF3)2PhO(CF3)2Ph

f irstmostconciseroute

1) Total synthesis of Ketorolac

2) Enantioselective total synthesis of (+)-Hapalindole Q and(-)-Fisherindole U

9

Baran P.S. JACS, 2005, 153943) Enantioselective total synthesis of (+)-Fisherindole I and (-)-Fisherindole G

Baran P.S. Nature, 2007, 4044) Protecting-group-free synthesis of (+)-ambiguine H and (-)-hapalindole U

N

N

N

Cl

OMe

OMe

O

N

DMT-MM

N

N

N

Cl

OMe

OMe

10

5) Protecting-group-free synthesis of(-)-fisherindole I and (+)-welwitindolinone A

Iron-Catalyzed Tandem Oxidative Couplingand Annulation: An Efficient Approach toConstruct Polysubstituted Benzofurans

4. Direct oxidative coupling phenolswith -keto esters

Procedure:

Li Z.P. JACS, 2009, 17387

5. PerspectivesA: Catalytic asymmetric oxidative enolate coupling1) The proposed metal-chelated transition statemechanisms make "metal-catalytzed" and "asymmetricinduction" (ligand control) possible.2) Using molecular O2 as oxidant is the final goal.B: To find new application in total synthsis.

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Mechanism:

ethyl benzoylacetate (1 eq)phenol (3 eq)FeCl3 6H2O (0.1eq)

DCE di-tert-butyl-peroxide(2 eq) dropwise

rt 100 oC, 1 h