oxidative enolate coupling in total synthesiskanai/seminar/pdf/lit_shi_d2.pdf · oxidative enolate...
TRANSCRIPT
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
1
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.
11
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