Literature Seminar 2010.6.2

Shi-Liang, Shi

Oxidative Enolate Coupling in Total Synthesis
AppointmentApril, 2009 Member, Skaggs Institute for Chemical Biology
June, 2008 Professor of Chemistry
July, 2006 Associate Professor of Chemistry (with Tenure)June, 2003 Assistant Professor of Chemistry (The Scripps Research Institute)

Phil S. Baran

Education
2001-2003 Postdoctoral Associate
Advisor: Professor E.J. Corey
Harvard University, Cambridge, Massachusetts
1997-2001
Ph.D. Graduate Student in Chemistry
Advisor: Professor K.C. Nicolaou
The Scripps Research Institute, La Jolla, CaliforniaAwards• 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

Contents:
1. Intermolecular enolate heterocoupling --- Baran Angew, 2006, 7083
Baran JACS, 2008, 11546
A: Introduction
B: Background
C: Discovery and Optimization
D: Scope
E: Mechanism
F: Application
2. Intramolecular enolate coupling
Baran Angew, 2005, 606. Angew, 2005, 3892.
A: The first total synthesis of Stephacidin A-JACS, 2006, 8678
B: The first total synthesis of (+/-)- Actinophyllic Acid----Overman L.E. JACS, 2008, 7568
C: The first total synthesis of Metacycloprodigiosin----Thomson R.J. JACS, 2009, 14579
3. Direct oxidative coupling indoles and pyrroles with carbonyl compounds---- Baran JACS, 2004, 7450
A: Introduction
Baran Angew, 2005, 609
B: Indole coupling
Baran JACS, 2007, 12857
C: Pyrrole coupling
D: Scope
E: Mechanism
F: 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, 17387
5. Perspectives
11. Intermolecular enolate heterocoupling
A: 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 carbonyl
subunits 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 step
without requiring prefunctionalization of the corresponding monomers.

Possible side products:Base[O]2

C: Discovery and Optimization

B : Backgroundf irst reportf irst use of soluable
Cu(II) oxidant

f irst heterocoupling

electrolytic method

Fe(III) as oxidant

f irst use ofoxazolidinone

a general enolate heterocoupling( amides, imides
ketones, esters,oxindoles)

Procedure:rt, in 5 min
oxazolidinone
and ketone (1:1)
in THF (0.3 M)

rt, 30 min
Fe(III)o-78 C,30 min-78 oCLDA 2.1 eq.
dropwise(0.5 M)
Fe(acac)3 2 eq.
one portion
0oC, in 5 minrt, 30 min
Cu(II)(0.5 M)Cu(2-ethylhexanote)2 1.5 eq.
one portion3

D: ScopeCarvoneOxindole4-Chromanone
quaternary carbon center

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), where
electron-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.

comments:
1. both steric environments(31-35)and functional group (3639) are tolerated.

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

4

E: Mechanism

the electrophilic f erric enolate is attacked by the lithium enolate of the oxazolidinone
Cu(II)-Chelated Transition States

F: Application

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2. Intramolecular enolate coupling
A: The first total synthesisof Stephacidin AOO

N P NClOBaran P.S. Angew, 2005, 606
Baran P.S. Angew, 2005, 3892
Baran P.S. JACS, 2006, 8678

OO

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

aza-Cope-Mannich
rearrangement

an intramolecular oxidative couplingof ketone and malonate enolate

overall y. 8 %6

C: The first asymmetric total synthesis of Metacycloprodigiosin
Thomson R.J. JACS, 2009, 14579
a Merged Conjugate Addition/Oxidative Coupling Sequence.
0 oC

86% ee11 steps, 13 % overall yield.

3. Direct oxidative coupling indoles and pyrroles with carbonyl compounds
A: Introduction

B: Indole coupling

Cross-coupling paradigms:

suzukiHeckHeck"Chemoselectivity: The Mother of Invention
in Total Synthesis"---Baran P.S.

Baran P.S. JACS, 2004, 7450

C: Pyrrole coupling

Representative Members of the Hapalindole
Family of Natural Products

Baran P.S. Angew, 2005, 609
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Procedure:
indole (2eq) orpyrrole (3 eq)oand ketone (1eq) -78 C,
30 minSolidCu(2-ethylhexanote)21.5 eq. one portion-78 oC
LHMDS
dropwise-78 oC to rtIndoles-78 oC to-60 oC, 3h-60 oC to rt
PyrrolesBaran P.S. JACS, 2007, 12857

D: Scope

Pyrrolecouplingsteroidmenthone

Advantages:
1. The reactions allow tremendous complexity to be built into a target molecule using simple chemistry, which would
otherwise 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 occurs
exclusively 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.

E: Mechanism study(1) Dimerization of indole or pyrrole is never observed.
suggests that the ketone is oxidized first and then reacts with indole.
suggests that selective heterocouplings can be designed by tuning the oxidation potential of
the oxidant to react preferentially with one coupling partner over the other.
(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 with
the indole or pyrrole anion, providing a radical anion intermediate. This radical anion could then be further
oxidized by the remaining copper(I).
8Mechanism for indole coupling

more resonable

Mechanism for pyrrole coupling

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

F. Application:2) Enantioselective total synthesis of (+)-Hapalindole Q and(-)-Fisherindole U

1) Total synthesis of Ketorolac

Ph2S

f irstO(CF3)2Ph
O(CF3)2Ph

mostconcise
route93) Enantioselective total synthesis of (+)-Fisherindole I and (-)-Fisherindole G

Baran P.S. JACS, 2005, 15394

NO
OMeNClNNOMe

DMT-MM4) Protecting-group-free synthesis of (+)-ambiguine H and (-)-hapalindole U

Baran P.S. Nature, 2007, 404

OMeNClNNOMe105) Protecting-group-free synthesis of(-)-fisherindole I and (+)-welwitindolinone A

4. Direct oxidative coupling phenols
with -keto esters
Iron-Catalyzed Tandem Oxidative Coupling
and Annulation: An Efficient Approach toConstruct Polysubstituted Benzofurans
Li Z.P. JACS, 2009, 17387

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

100 oC, 1 hdi-tert-butyl-peroxide(2 eq) dropwise

Mechanism:

5. Perspectives
A: 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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