Development and Synthesis Applications of Olefin Isomerization-Claisen Rearrangement Reactions by Kan Wang B. S.,University of Science and Technology of China, 1997 M. S., Shanghai Institute of Organic Chemistry, Chinese Academy of Science 2000 Submitted to the Graduate Faculty of the Department of Chemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2007 UNIVERSITY OF PITTSBURGH FACULTY OF ARTS AND SCIENCES This dissertation was presented by Kan Wang It was defended on 11 29, 2007 and approved by Craig S. Wilcox, Professor, Department of Chemistry Theodore Cohen, Professor, Department of Chemistry Billy W. Day, Professor, Department of Pharmaceutical Sciences Dissertation Advisor: Scott G. Nelson, Professor, Department of Chemistry ii Copyright © by Kan Wang 2007 iii Development and Synthesis Applications of Olefin Isomerization-Claisen Rearrangement Reactions Kan Wang, PhD University of Pittsburgh, 2007 Iridium(I)-catalyzed olefin isomerization in bis(allyl) ethers was integrated into a generally applicable strategy for affecting highly stereoselective Claisen rearrangements. Catalyzed alkene isomerization afforded allyl vinyl ethers from easily prepared di(allyl) ethers; direct thermolysis of these reaction mixtures led to highly diastereoselective [3,3] sigmatropic rearrangements affording syn-2,3-dialkyl-4-pentenal derivatives. O 1 O R cat. Ir(PCy3)3 O R1 2 H R 3 2 R R then PPh3 R3 R2 [3,3] H O R1 O R1 3 R R2 R3 R2 H Merging the catalytic asymmetric synthesis of di(allyl) ethers with ensuing olefin isomerization-Claisen rearrangement (ICR) reactions provided a convenient, two-step route to asymmetric aliphatic Claisen rearrangements from easily obtained starting materials. These reactions delivered the 2,3-disubstituted 4-pentenal derivatives characteristic of aliphatic Claisen rearrangements with excellent relative and absolute stereocontrol. A catalytic enantioselective synthesis of the (+)-calopin dimethyl ether demonstrated the utility of this reaction technology in asymmetric synthesis enterprises. iv H R3-M O R1 O chiral catalyst ICR O R1 2 R3 R2 H R then R3 R2 X R1 (step 1) (step 2) Me O OMe OMe O OH Me (+)-calopin dimethyl ether Stereoselective quaternary all-carbon stereocenter construction was often not easily achieved from methodologies developed primarily for accessing less substituted stereogenic carbons. Olefin isomerization-Claisen rearrangement (ICR) reactions offered a strategy for recruiting the Claisen rearrangement for asymmetric quaternary carbon construction. Several complementary strategies for enantioselective quaternary carbon synthesis derived directly from the ICR reaction design. 1 R R1 O O 4 cat. Ir(PCy3)3 O R R4 2 H R 3 2 R R then PPh3 R3 R2 [3,3] H R1 R4 O R1 O R4 3 R R2 R3 R2 H v TABLE OF CONTENTS 1.0 CLAISEN REARRANGEMENT-INTRODUCTION.............................................. 1 1.1 CLAISEN VARIANTS........................................................................................ 2 1.1.1 Preparation of allyl vinyl ether.................................................................... 2 1.1.2 Activated Claisen variants ........................................................................... 6 1.2 TRANSITION METAL-CATALYZED ALLYL ETHER ISOMERIZATION REACTION ........................................................................................ 8 1.3 OLEFIN ISOMERIZATION-CLAISEN REARRANGEMENT.................. 14 1.3.1 Precedents of ICR reaction ........................................................................ 14 1.3.2 Requirements for good ICR reaction........................................................ 17 2.0 IRIDIUM-CATALYZED OLEFIN ISOMERIZATION LEADING TO HIGHLY STEREOSELECTIVE CLAISEN REARRANGEMENTS OF ALIPHATIC ALLYL VINYL ETHERS ........................................................................................................................ 20 2.1 REACTION DEVELOPMENT ....................................................................... 20 2.1.1 Selection of precatalyst............................................................................... 21 2.1.2 Results and discussions............................................................................... 22 2.1.3 Halide abstractor ........................................................................................ 24 2.1.4 Optimization of ICR reaction .................................................................... 26 2.2 ICR REACTIONS OF SUBSTITUTED DI(ALLYL) ETHERS................... 28 vi 2.2.1 Preparation of substrates and the summary of ICR result..................... 28 2.2.2 Isomerization reaction................................................................................ 31 2.2.3 Thermal Claisen rearrangement of different substrates......................... 35 2.2.4 ICR of other di(allyl) ethers....................................................................... 37 2.3 ICR REACTION OF ALLYL HOMOALLYL ETHERS............................. 40 2.3.1 ICR reactions of allyl homoallyl ethers..................................................... 40 2.3.2 Preparation of dienals with ICR protocol ................................................ 41 2.4 EXPERIMENTAL SECTION.......................................................................... 44 2.4.1 Experiment of section 2.2 ........................................................................... 45 2.4.2 Experiment of section 2.3. .......................................................................... 75 2.4.2.1 ICR reaction of allyl homoallyl ether................................................ 75 2.4.2.2 Preparation of dienal from ICR protocol......................................... 79 3.0 ENANTIOSELECTIVE CLAISEN REARRANGEMENTS ENABLED BY CATALYTIC ASYMMETRIC DI(ALLYL) ETHER SYNTHESES.................................... 84 3.1 ICR REACTION WITH ENANTIOENRICHED SUBSTRATES............... 84 3.2 ONE-POT REACTION FROM ALDEHYDE TO ENANTIOENRICHED DI(ALLYL) ETHER .......................................................................................................... 85 3.2.1 Reaction development................................................................................. 85 3.2.2 One-pot addition/allylation followed by ICR for the preparation of enantioenriched Claisen rearrangement products.................................................. 90 3.2.3 One-step reaction from alkenyl zinc addition .......................................... 93 3.3 SYNTHESIS OF (+)-DI-O-METHYL CALOPIN.......................................... 95 3.4 EXPERIMENTAL SECTION........................................................................ 101 vii 3.4.1 Experiment of section 3.2 ......................................................................... 101 3.4.1.1 One-pot reaction following ICR for preparation of enantioenriched Claisen adducts ................................................................................................ 101 3.4.1.2 One pot reaction from alkenyl zinc addition.................................. 112 3.4.2 Experiment of section 3.3 ......................................................................... 116 4.0 STEREOSELECTIVE QUATERNARY CARBON CONSTRUCTION ENABLED BY OLEFIN ISOMERIZATION-CLAISEN REARRANGEMENT REACTIONS............................................................................................................................. 125 4.1 CONSTRUCTION OF QUATERNARY CARBON CENTERS USING THE ICR REACTION .............................................................................................................. 127 4.1.1 ICR of 1,1-disubstituted allyl ethers for preparing aldehydes with quaternary carbon center........................................................................................ 128 4.1.2 ICR of 2,3-disubstituted allyl ether ......................................................... 134 4.1.3 ICR reaction for enantioenriched aldehyde with quaternary center... 137 4.2 ICR OF DI(ALLYL) ETHER BEARING AN ENOL ETHER- QUATERNARY CENTER WITH OXYGEN............................................................... 140 4.3 EXPERIMENTAL SECTION........................................................................ 144 4.3.1 Experiment of section 4.1 ......................................................................... 144 4.3.1.1 ICR for 2-substituted allyl ethers.................................................... 144 4.3.1.2 ICR for 2,3-disubstituted allyl ethers.............................................. 160 4.3.1.3 Asymmetric quaternary ICR reaction............................................ 166 4.3.2 Experiment of section 4.2 ......................................................................... 170 viii 5.0 LEWIS ACID-PROMOTED CLAISEN REARRANGEMENT AND CASCADE REACTIONS BASED ON ICR ............................................................................................... 178 5.1 ORGANOALUMINUM-PROMOTED CLAISEN REARRANGEMENT 180 5.2 CASCADE REACTION BASED ON ICR REACTION ............................. 186 5.2.1 Cascade Claisen/ene reaction................................................................... 186 5.2.2 Cascade isomerization/Claisen/Wittig/Cope reaction ........................... 190 5.2.3 Cascade tetrahydropyran rings formation............................................. 192 5.3 EXPERIMENTAL SECTION........................................................................ 194 5.3.1 Experiment of section 5.1 ......................................................................... 194 5.3.2