GENERALIZATION OF HIGHLY γ-REGIOSELECTIVE SUBSTITUTIONS IN ALLYL HALIDES BY ALKYLZINCS AND APPLICATIONS TO ZINC-ENE CYCLIZATIONS AND THE SYNTHESIS OF (R)-(+)-DIHYDRO-α-IONONE. by Roman A. Ivanov MS, Moscow State University, 1999 Submitted to the Graduate Faculty of University of Pittsburgh in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2008 UNIVERSITY OF PITTSBURGH CHEMISTRY DEPARTMENT This thesis was presented by Roman A. Ivanov It was defended on February 25, 2008 and approved by Peter Wipf, University Professor, Department of Chemistry Craig Wilcox, Professor, Department of Chemistry Michael Mokotoff, Professor Emeritus, Department of Pharmaceutical Science Dissertation Advisor: Theodore Cohen, Professor Emeritus, Department of Chemistry ii Copyright © by Roman A. Ivanov 2008 iii GENERALIZATION OF HIGHLY γ-REGIOSELECTIVE SUBSTITUTIONS IN ALLYL HALIDES BY ALKYLZINCS AND APPLICATIONS TO ZINC-ENE CYCLIZATIONS AND THE SYNTHESIS OF (R)-(+)-DIHYDRO-α-IONONE. Roman A. Ivanov, Ph. D. University of Pittsburgh, 2008 Allyl phenyl sulfides have proven to be extremely versatile and widely used reagents in organic chemistry. There are thousands of publications that relate their uses in synthesis. However, the conventional method of preparing γ-substituted allyl phenyl sulfides by alkylation of deprotonated commercially available allyl phenyl sulfides, only allows electrophilic groups to be introduced. This method fails if the alkylating agent is tertiary, secondary, vinylic, or arylic. In this work a new method, in which a nucleophilic group can be introduced at the carbon atom bearing the phenylthio group, referred to as γ-allylic substitution, is thoroughly studied and used in several examples to demonstrate its significance for synthesis. This procedure should vastly increase access to a wide variety of allyl phenyl sulfides. In this work, copper mediated γ-allylic substitution reactions of organozinc reagents with allyl chlorides bearing a γ-phenylthio group are reported and the best reaction conditions for mono- and dialkylzincs are revealed. The scope and limitations of γ-allylic substitutions of organozincs with a variety of different allyl chlorides were thoroughly investigated and an important temperature effect was observed and used to expand the scope of these reactions. iv Furthermore, this work deals with an important aspect of the preparation of the organometallic nucleophiles required for these γ-substitutions. Many of these can be prepared by reductive lithiation of readily available alkyl phenyl thioethers by aromatic radical-anions. However, large-scale preparations suffer from the requirement of separation of the desired product from the aromatic byproduct using either slow column chromatography or vacuum sublimation. An improved procedure for reductive lithiation of phenyl thioethers with 1-(N,N- dimethylamino)naphthalenide was developed to overcome this drawback. Reductive lithiation was then used not only as a preliminary step in the preparation of organozincs for copper mediated γ-regioselective substitution reactions but also as a key step in the enantioselective synthesis of (R)-(+)-dihydro-α-ionone. It was demonstrated that the combination of reductive lithiations, zinc-ene reactions and copper mediated organozinc γ-regioselective substitutions can be used for efficient syntheses of ring-fused intermediates in an iterative and stereoselective fashion from inexpensive commercially available starting compounds. v TABLE OF CONTENTS PREFACE ............................................................................................................................... XVII 1.0 ALKYLZINC REAGENTS IN γ-ALLYLIC SUBSTITUTION REACTIONS MEDIATED BY COPPER (I) CATALYSTS ............................................................................ 1 1.1 INTRODUCTION ............................................................................................... 1 1.1.1 Organozinc Reagents ....................................................................................... 1 1.1.2 Copper-mediated Nucleophilic Substitution in Allylic Halides and Phosphate Esters at the γ-Allylic Carbon Atom (γ-SAL) by Organometallics. ........ 5 1.2 RESULTS AND DISCUSSION ........................................................................ 17 1.2.1 General considerations .................................................................................. 17 1.2.2 Preparation of Allyl Phenyl Sulfides and 1-Phenylthio-3-chloropropenes ………………………………………………………………………………..18 1.2.3 Preparation of Other Substituted Allyl Chlorides and Phosphoric Esters ……………………………………………………………………………… 20 1.2.4 Dialkylzincs (R2Zn) in Model Copper Catalyzed γ-Substitution Reactions with 1-Phenylthio-3-chloropropene .......................................................................... 22 1.2.5 Monoalkylzincs (RZnX) in Model Copper Catalyzed γ-Substitution Reactions with 1-Phenylthio-3-chloropropene ........................................................ 24 vi 1.2.6 Monoalkylzincs (RZnX) in Model Copper Catalyzed γ-Substitution Reactions with Various Allyl Chlorides. Scope and Limitations. ......................... 29 1.2.7 Conclusions .................................................................................................... 39 1.3 EXPERIMENTAL SECTION .......................................................................... 41 2.0 PREPARATION OF VARIOUS ALKYLLITHIUMS BY REDUCTIVE LITHIATION OF THE CORRESPONDING ALKYL PHENYL SULFIDES WITH LITHIUM 1-(N,N-DIMETHYLAMINO)NAPHTHALENIDE ............................................. 73 2.1 INTRODUCTION ............................................................................................. 73 2.1.1 Lithium Radical-Anion Reagents ................................................................. 73 2.1.2 Reductive Lithiation of Alkyl Phenyl Sulfides ............................................ 77 2.2 RESULTS AND DISCUSSION ........................................................................ 82 2.2.1 LDMAN Preparation Procedure .................................................................. 82 2.2.2 Conclusions .................................................................................................... 85 2.3 EXPERIMENTAL SECTION .......................................................................... 86 3.0 EFFECTIVE CONVERGENT ENANTIOSELECTIVE SYNTHESIS OF A (R)- DIHYDRO-α-IONONE. APPLICATION OF THE ORGANOZINC γ-ALLYLIC SUBSTITUTIONS FOR SYNTHESIS OF A POTENTIAL PRECURSOR OF THE PYRROLIZIDINE TYPE PRODUCTS ................................................................................... 94 3.1 INTRODUCTION ............................................................................................. 94 3.1.1 Optically Active Ionones and their Derivatives: Properties and Preparation. ................................................................................................................ 94 3.1.2 Pyrrolizidine Alkaloids. .............................................................................. 106 3.2 RESULTS AND DISCUSSION ...................................................................... 110 vii 3.2.1 Enantioselective Synthesis of (R)-dihydro-α-ionone ................................. 110 3.2.2 A Novel Synthetic Approach to a Potential Precursor of the Pyrrolizidine Framework. .............................................................................................................. 113 3.2.3 Conclusions .................................................................................................. 116 3.3 EXPERIMENTAL SECTION ........................................................................ 117 4.0 ZINC-ENE CYCLIZATIONS. A NOVEL ITERATIVE APPROACH TO DI- AND TRIQUINANE SYNTHESES ........................................................................................ 128 4.1 INTRODUCTION ........................................................................................... 128 4.1.1 “Ene”-reactions. ........................................................................................... 128 4.1.1.1 Intermolecular Metallo-ene Reactions ............................................ 129 4.1.1.1.1 Intermolecular Magnesium-ene Reactions........................................... 129 4.1.1.1.2 Intermolecular Zinc-ene Reactions. ............................................. 130 4.1.1.2 Intramolecular Metallo-ene Cyclizations. ....................................... 132 4.1.1.2.1 Intramolecular Magnesium-ene Cyclizations. ............................. 132 4.1.1.2.2 Intramolecular Zinc-ene Cyclizations. ................................................. 134 4.1.2 Polyquinanes ................................................................................................ 141 4.1.2.1 Diquinanes ......................................................................................... 142 4.1.2.2 Linear Triquinanes ........................................................................... 144 4.2 RESULTS AND DISCUSSION ...................................................................... 151 4.2.1 Conclusions .................................................................................................. 161 4.3 EXPERIMENTAL SECTION ........................................................................ 162 BIBLIOGRAPHY ..................................................................................................................... 175 viii LIST OF TABLES 47 Table 1.1. Copper Catalyzed Reaction