Oxidative Enolate Coupling in Total Synthesis

Transcription

1 Literature Seminar Oxidative Enolate Coupling in Total Synthesis Shi-Liang, Shi Appointment April, 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 Postdoctoral Associate Advisor: Professor E.J. Corey Harvard University, Cambridge, Massachusetts Ph.D. Graduate Student in Chemistry Advisor: Professor K.C. icolaou The Scripps Research Institute, La Jolla, California Awards Thieme-IUPAC Prize in Synthetic Organic Chemistry, 2010 ACSAwardinPureChemistry,2010 Sackler Prize, 2009 ational Fresenius Award, ACS, 2007 ovartis Lecturer, Hirata Gold Medal, 2007 Pfizer Award for Creativity in Organic Synthesis, 2006 Beckman Foundation Fellow, Alfred P. Sloan Foundation Fellow, BMS Unrestricted Freedom to Discover Grant, SF CAREER Award, Eli Lilly Young Investigator Award, 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, Contents: 1. Intermolecular enolate heterocoupling --- Baran Angew, 2006, 7083 A: Introduction Baran JACS, 2008, B: Background C: Discovery and Optimization D: Scope E: Mechanism F: Application 2. Intramolecular enolate coupling Baran Angew, 2005, 606. Angew, 2005, 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, 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, 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, protecting-group-free synthesis of (+)-ambiguine H and (-)-hapalindole U---Baran ature, 2007, protecting-group-free synthesis of (-)-fisherindole I and (+)-welwitindolinone A--Baran ature, 2007, Direct oxidative coupling phenols with carbonyl compounds----li Z.P. JACS, 2009, Perspectives 1

2 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 in Figure 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

3 B : Background C: Discovery and Optimization first report f irst use of soluable Cu(II) oxidant f irst heterocoupling electrolytic method Fe(III) as oxidant first use of oxazolidinone a general enolate heterocoupling ( amides, imides ketones, esters, oxindoles) Procedure: rt, in 5 min rt, 30 min oxazolidinone and ketone (1:1) in THF (0.3 M) -78 o C, 30 min (0.5 M) Fe(acac) 3 2eq. one portion Fe(III) -78 o C LDA 2.1 eq. dropwise 0 o C, in 5 min rt, 30 min (0.5 M) Cu(2-ethylhexanote) eq. one portion Cu(II) 3

4 D: Scope Carvone Oxindole 4-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 (36-39) are tolerated. 2. Electron-rich (45-48), - neutral (41-44), and - deficient aromatic units (49,50) are tolerated. 4

5 E: Mechanism the electrophilic ferric enolate is attacked by the lithium enolate of the oxazolidinone Cu(II)-Chelated Transition States F: Application 5

6 2. Intramolecular enolate coupling A: The first total synthesis of Stephacidin A O O P Cl O O O Baran P.S. Angew, 2005, 606 Baran P.S. Angew, 2005, 3892 Baran P.S. JACS, 2006, 8678 B: The first total synthesis of (+/-)- Actinophyllic Acid Overman L.E. JACS, 2008, 7568 aza-cope-mannich rearrangement an intramolecular oxidative coupling of ketone and malonate enolate overall y. 8 % 6

7 C: The first asymmetric total synthesis of Metacycloprodigiosin Thomson R.J. JACS, 2009, a Merged Conjugate Addition/Oxidative Coupling Sequence. 0 o C 86% ee 11 steps, 13 % overall yield. 3. Direct oxidative coupling indoles and pyrroles with carbonyl compounds A: Introduction B: Indole coupling Cross-coupling paradigms: suzuki Heck Heck "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 atural Products Baran P.S. Angew, 2005, 609 7

8 Procedure: indole (2eq) or pyrrole (3 eq) and ketone (1eq) -78 o C, 30 min Solid Cu(2-ethylhexanote) eq. one portion -78 o Ctort Indoles -78 o C LHMDS dropwise -78 o Cto -60 o C, 3h -60 o Ctort Pyrroles D: Scope Baran P.S. JACS, 2007, Pyrrole coupling steroid menthone 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 to scaleup). 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) -Protected indoles or pyrroles are unreactive; the free -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 -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

9 Mechanism for indole coupling more resonable Mechanism for pyrrole coupling the characteristic red-brown color of copper(i) salts is often observed at the end of the reaction F. Application: 1) Total synthesis of Ketorolac 2) Enantioselective total synthesis of (+)-Hapalindole Q and (-)-Fisherindole U Ph 2 S O(CF 3) 2 Ph O(CF 3 ) 2 Ph first most concise route 9

10 3) Enantioselective total synthesis of (+)-Fisherindole I and (-)-Fisherindole G Baran P.S. JACS, 2005, O OMe Cl OMe DMT-MM 4) Protecting-group-free synthesis of (+)-ambiguine H and (-)-hapalindole U Baran P.S. ature, 2007, 404 OMe Cl OMe 10

11 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 to Construct Polysubstituted Benzofurans Li Z.P. JACS, 2009, Procedure: ethyl benzoylacetate (1 eq) phenol (3 eq) FeCl 3 6H 2 O (0.1eq) rt 100 o C, 1 h DCE di-tert-butyl-peroxide (2 eq) dropwise Mechanism: 5. Perspectives A: Catalytic asymmetric oxidative enolate coupling 1) The proposed metal-chelated transition state mechanisms make "metal-catalytzed" and "asymmetric induction" (ligand control) possible. 2) Using molecular O 2 as oxidant is the final goal. B: To find new application in total synthsis. 11