CU-Catalyzed Enantioselective Conjugate Addition of Organometal Reagents to Unsaturated Carbonyls : an Enantioselective Total Synthesis of Clavirolide C
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CU-catalyzed enantioselective conjugate addition of organometal reagents to unsaturated carbonyls : an enantioselective total synthesis of clavirolide C Author: Michael Kevin Brown Persistent link: http://hdl.handle.net/2345/964 This work is posted on eScholarship@BC, Boston College University Libraries. Boston College Electronic Thesis or Dissertation, 2008 Copyright is held by the author, with all rights reserved, unless otherwise noted. Boston College The Graduate School of Arts and Sciences Department of Chemistry CU-CATALYZED ENANTIOSELECTIVE CONJUGATE ADDITIONS OF ORGANOMETAL REAGENTS TO UNSATURATED CARBONYLS: AN ENANTIOSELECTIVE TOTAL SYNTHESIS OF CLAVIROLIDE C A Dissertation By MICHAEL KEVIN BROWN submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy December 2008 copyright by MICHAEL KEVIN BROWN 2008 CU-CATALYZED ENANTIOSELECTIVE CONJUGATE ADDITIONS OF ORGANOMETAL REAGENTS TO UNSATURATED CARBONYLS: AN ENANTIOSELECTIVE TOTAL SYNTHESIS OF CLAVIROLIDE C Michael Kevin Brown Thesis Advisor: Professor Amir H. Hoveyda Abstract Chapter 1. Methods for highly enantioselective Cu-catalyzed asymmetric conjugate additions of dialkylzinc reagents to unsaturated furanones and pyranones are presented. Transformations are promoted by a chiral peptide-based ligand in the presence of an appropriate Cu-salt. In order to carry out additions to a broad range of substrates, a small family of chiral peptide based ligands was utilized. The synthesis, characterization and use of air-stable Cu-peptide complexes is also presented. O O O Peptide-Based O O O Chiral Cu-Catalyst O n O n O O O n alkyl2Zn n alkyl alkyl O alkyl i-Pr i-Pr O t-Bu O H H NHn-Bu N N N N NHn-Bu N NHn-Bu O O Bn O PPh2 PPh2 PPh2 Ot-Bu Chapter 2. New methods for the highly enantioselective formation of all-carbon quaternary stereogenic centers through catalytic asymmetric conjugate additions of dialkyl- as well as diarylzinc reagents are summarized. As introduction to Cu-catalyzed asymmetric conjugate addition to prepared all-carbon quaternary stereogenic centers is presented. For reactions involving unactivated cyclic -substituted unsaturated carbonyls, a phenoxy-based N-heterocyclic carbene (NHC) ligand was found to optimal. Additions of diorganozinc reagents to cyclic unsaturated -ketoesters, however, required the use of a sulfonate-based NHC to provide the desired products efficiently and in high enantiomeric purity. The practicality of the method is demonstrated though the in situ preparation and use of diorganozinc reagents. Representative functionalizations of the enantiomerically enriched enolate are also included. Ph Ph N NMes O 5 mol % Ag-II O 5 mol % (CuOTf)2•C6H6 O Ag Ph Me Ph Zn, Et O, -30 °C, 48 h Ag Mes 2 2 Me Ag-II ON 96% ee N Ph 88% yield Ph Ph Ph O 2.5 mol % Ag-III O S N NMes O O O 2.5 mol % (CuOTf)2•C6H6 Ag i-Pr Zn, t-BuOMe, Ag CO t-Bu 2 CO t-Bu Ag-III 2 -30 °C, 15 h i-Pr 2 92% ee O O NMes N 64% yield S Ph O Ph Chapter 3. An enantioselective total synthesis of diterpenoid natural product clavirolide C is presented. The total synthesis requires 17 steps (longest liner) and provides the target compound in 3.5% overall yield. These studies have led to the development of a new method for the synthesis of all-carbon quaternary stereogenic centers though Cu-catalyzed ACA of trialkylaluminum reagents to -substituted cyclopentenone derivatives. Additional features of the synthesis include: (i) Cu- catalyzed asymmetric conjugate addition of dimethylzinc to an unsaturated lactone (ii) stereoselective aldol addition between an aliphatic-based aldehyde and a cyclopentenone- derived enolate (iii) the synthesis of an 11-membered ring though catalytic ring-closing metathesis. O Catalytic Me O Me ACA Stereoselective H Aldol O Me Catalytic Catalytic Me Ring-Closing ACA Metathesis Conjugate Addition clavirolide C Chapter 4. Several route for the synthesis of sulfonate-based NHC complexes are presented. In the course of these studies, a new method for the preparation of imidazolinium salts was discovered. Mechanistic studies, carried out to understand the details of the imidazolinium salt formation, eventually led to an improved synthesis. Physical properties of the sulfonate-based NHC are also summarized. Chapter 1. Highly Enantioselective Cu-Catalyzed Conjugate Additions of Dialkylzinc Reagents to Unsaturated Furanones and Pyranones: Preparation of Air- Stable and Catalytically Active Cu-Peptide Complexes ................................................ 4 1.1 Introduction ................................................................................................ 4 1.2 Background ................................................................................................ 5 1.2.a ACA to Unsaturated Lactones (Type 1.I) ............................................ 5 1.2.b ACA to 3-Oxycyclohexenones (Type 1.II) ........................................... 9 1.2.c ACA to Cyclic Vinylogous Esters (Type 1.III) .................................. 10 1.3 Cu-Catalyzed ACA Reactions with Dialkylzinc Reagents Promoted by Chiral Amino Acid-Derived Phosphine Ligands ............................................. 11 1.4 Cu-Catalyzed Enantioselective Conjugate Additions of Dialkylzinc Reagents to Unsaturated Furanones and Pyranones ......................................... 21 1.4.a Cu-Catalyzed ACA to Unsaturated Lactones ................................... 21 1.4.b Cu-Catalyzed ACA to 3-Oxacyclohexenones .................................... 29 1.4.c Cu-Catalyzed ACA to Cyclic Vinylogous Esters ............................... 31 1.5 Preparation of Air-Stable and Catalytically Active Cu-Peptide Complexes. ....................................................................................................... 33 1.6 Conclusions .............................................................................................. 38 1.7 Experimentals .......................................................................................... 39 Chapter 2. Formation of All-Carbon Quaternary Stereogenic Centers through Cu-Catalyzed Asymmetric Conjugate Addition of Diorganozinc Reagents to Unsaturated Carbonyls ................................................................................................ 102 2.1 Introduction ............................................................................................ 102 2.2 Background ............................................................................................ 104 2.3 ACA to Cyclic Unsaturated γ-Ketoesters Promoted by Peptide-Based Ligands ........................................................................................................... 115 2.4 Cu-Catalyzed ACA of Diorganozinc Reagents Promoted by N- Heterocyclic Carbene (NHC) Based Ligands ................................................ 121 2.4.a General Characteristic of NHCs .................................................... 121 - 1 - 2.4.b Enantioselective Alkylation Reactions with Chiral Cu-NHC Complexes ................................................................................................... 125 2.4.b.1 Background .............................................................................. 125 2.4.b.2 Cu-Catalyzed ACA to Unactivated Cyclic Enones: Synthesis of All-Carbon Quaternary Stereogenic Centers ......................................... 134 2.4.b.3 Cu-Catalyzed ACA of Diorganozinc Reagents with a New Sulfonate-Based Ag-NHC Complex ........................................................ 140 2.4.b.4 Cu-Catalyzed ACA to Cyclic Unsaturated γ-Keto Esters: Synthesis of All-Carbon Quaternary Stereogenic Centers ..................... 144 2.4.b.5 Functionalizations of the ACA Adducts and Issues of Practicality. ............................................................................................. 149 2.4.b.6 Working Mechanistic Models .................................................. 154 2.5 Conclusions ............................................................................................ 162 2.6 Experimentals ........................................................................................ 163 Chapter 3. Enantioselective Total Synthesis of Clavirolide C: A Platform for New Methods and Catalyst Development............................................................................ 257 3.1 Introduction ............................................................................................ 257 3.2 Background ............................................................................................ 257 3.3 Enantioselective Total Synthesis of Clavirolide C ................................ 262 3.3.a Retrosynthesis ................................................................................. 262 3.3.b Cu-Catalyzed Asymmetric Conjugate Additions (ACAs) to Unactivated β-Substituted Cyclopentenones ............................................... 263 3.3.b.1 Background .............................................................................. 263 3.3.b.2 Optimization of ACA of AlMe3 to β-Substituted Cyclopentenones.. ................................................................................... 266 3.3.c Synthesis of Chiral Aldehyde 3.43 .................................................. 272 3.3.d Aldol Addition ................................................................................. 273 3.3.e Ring-Closing Metathesis Studies..................................................... 282 3.3.f Completion of the Total Synthesis ..................................................