The Pennsylvania State University The Graduate School Eberly College of Science STEREOSELECTIVE SYNTHESIS OF (Z)-2-ACYL-2-ENALS VIA RETROCYCLOADDITIONS OF 5-ACYL-4-ALKYL-4H-1,3-DIOXINS: APPLICATIONS IN NATURAL PRODUCT SYNTHESIS A Thesis in Chemistry By Ronald A. Aungst, Jr. © 2007 Ronald A. Aungst, Jr. Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy August 2007 The thesis of Ronald A. Aungst, Jr., was reviewed and approved* by the following: Raymond L. Funk Professor of Chemistry Thesis Advisor Chair of Committee Steven M. Weinreb Russell and Mildred Marker Professor Of Natural Products Chemistry Kenneth S. Feldman Professor of Chemistry J. Martin Bollinger, Jr. Associate Professor of Biochemistry and Molecular Biology Associate Professor of Chemistry Ayusman Sen Professor of Chemistry Head of Chemistry *Signatures are on file in the Graduate School ABSTRACT Reported herein are several approaches for the synthesis of substituted acrolein derivatives via the retrocycloaddition of substituted 4H-1,3-dioxins. Upon thermal or Lewis acid mediated retro hetero Diels-Alder reactions of these substrates, an appropriately substituted acrolein derivative is generated (stereoselectively in most cases) which can be utilized as a substrate for a variety of cycloaddition reactions. These cycloadditions, including Diels-Alder, hetero Diels-Alder, and [4 + 3], have provided access to several ring systems with excellent control over regio- and stereoselectivity. A strategy for the stereocontrolled synthesis of (Z)-2-acylenals has been developed through utilization of a retrocycloaddition reaction of 5-acyl-4-alkyl-4H- 1,3-dioxins. This approach has provided concise synthetic routes to several natural products containing the 5-acyl-2H-3,4-dihydropyran substructure. Application of this methodology has been showcased in the natural product syntheses of both the immunosuppressant loganetin and the cytotoxin euplotin A. This methodology has also been investigated in a synthetic approach towards the synthesis of the xenicin core. Similarly, retrocycloadditions of 4H-4-alkyl-5-(trialkylsilyloxy)-1,3-dioxins proceed smoothly in refluxing toluene to afford (Z)-2-(trialkylsilyloxy)-2-alkenals with complete stereoselectivity. These enals undergo Sasaki-type [4 + 3] cyclization with dienes in the presence of Lewis acids, in many instances with excellent regio- and/or stereoselectivity. iii Also, throughout our investigations of forming 1,3-dioxins it was found that these retrocyloaddition precursors could be formed by a variety of reaction sequences. An example of a deconjugation approach for the formation of dioxins is exemplified in the development of a thermally labile solid-phase linker. A similar approach was also utilized in the synthesis of the 1,3-dioxin precursors for the preparation of the labdane/clerodane ring system. Subsequent thermolysis of this substrate provided clean conversion, via a one- pot retro- hetero Diels-Alder reaction and successive intramolecular Diels-Alder reaction, to provide the requisite trans-decalin ring system with an axial bridgehead aldehyde. Finally, in our studies toward the synthesis of 1,3-dioxins, a Diels-Alder approach to the sesquiterpene illudin C ring system was investigated. Unfortunately, this approach proved unproductive; however, it did lead to an alternative approach to illudin C. A convergent total synthesis of illudin C is described. The tricyclic ring system of the natural product was quickly assembled from cyclopropane and cyclopentene precursors via a novel oxime dianion coupling reaction and a subsequent intramolecular nitrile oxide-olefin cycloaddition. iv TABLE OF CONTENTS LIST OF SCHEMES ix LIST OF FIGURES xii LIST OF TABLES xiii ACKNOWLEDGEMENTS xiv CHAPTER 1. Stereoselective Synthesis of (Z)-2-Acyl-2-enals 1 1.1 Previous synthesis and utility of 2-acyl-2-enals 1 1.2 Novel preparation of substituted acroleins via 3 retro Diels-Alder reactions of 1,3-dioxins 1.2.1 Stereoselective generation of 3-alkylacroliens 4 1.2.2 Synthesis of 2-acyloxy and 2-amido acroleins 5 1.2.3 Synthesis of 2-alkyl and 2-acylacroleins 8 1.3 Development of methodology for the stereoselective 10 generation of (Z)-2-acyl-2-enals 1.3.1 Synthesis of 4-alkyl-1,3-dioxan-5-ones 11 1.3.2 Regioselective generation of the vinyl triflates 13 1.3.3 Palladium catalyzed coupling reactions to yield 14 4,5-disubstituted-4H-1,3-dioxins 1.3.4 Investigation of the stereoselectivity of the 16 retrocycloaddition reactions of 5-acyl-4-alkyl-4H-1,3-dioxins 1.3.5 Investigation of the stereoselectivity of the 19 v hetero Diels-Alder reaction of (Z)-2-acyl-2-enals CHAPTER 2. Application of (Z)-2-Acyl-2-enals in 22 Natural Product Synthesis 2.1 Background on the iridoid natural products 22 2.2 An approach to the iridoid natural products 26 2.2.1 An approach to the synthesis of the 26 immunosuppressant (±)-loganetin 2.2.2 Completion of the synthesis of (±)-loganetin 31 2.3 Total synthesis of the cytotoxin (±)-euplotin A 35 2.3.1 Biological importance of euplotin A 35 2.3.2 Structural determination of the euplotins 37 2.2.3 Biosynthetic route to the euplotins 39 2.3.4 Retrosynthetic analysis for the synthesis of euplotin A 41 2.3.5 Synthesis and alkylation of the dioxin side chain 44 2.3.6 Key retrocycloaddition/cycloaddition reaction 48 2.3.7 Completion of the (±)-euplotin A synthesis 55 2.4 Studies toward the total synthesis of the 60 xenicin class of compounds 2.4.1 Biological importance of the xenicins 60 2.4.2 Structural elucidation of xenicin 61 2.4.3 Synthetic approach to the xeniolides 62 2.4.2 A concise retrosynthetic analysis into the xenicanes 65 vi 2.4.3 Studies towards synthesis of the xenicane 66 ring system via an intramolecular cycloaddition 2.4.4 A concise retrosynthetic analysis into the xenicins 73 utilizing an intermolecular hetero Diels-Alder reaction 2.4.5 Studies towards synthesis of the xenicane 75 ring system via an intermolecular cycloaddition CHAPTER 3. Alternative Approaches to 1,3-Dioxins 89 3.1 Stereoselective generation of (Z)-2-(trialkylsilyloxy)-2-enals 89 3.1.1 Application of (Z)-2-(trialkylsilyloxy)-2-enals 91 in [4 + 3] cycloaddition reactions 3.2 Deconjugation route to form 1,3-dioxins 101 3.2.1 Approaches to the first thermally labile solid-phase linker 101 3.2.2 An approach to the labdane and clerodane natural 110 product ring systems 3.3 Diels-Alder approach to synthesize 1,3-dioxins: 115 Application in the Illudin C synthesis 3.3.1 Biological importance of the illudin compounds 115 3.3.2 Retrosynthetic analysis for a Diels-Alder 118 approach to the illudin C ring system 3.3.3 Synthesis and application of the Diels-Alder 119 substrate for the illudin C model system 3.3.4 Retrosynthetic analysis for an intramolecular 121 vii nitrile-oxide cycloaddition approach to the illudin C ring system 3.3.5 Synthesis and application of the nitrile-oxide cycloaddition 122 substrate for the total synthesis of illudin C 3.4 Conclusions 127 EXPERIMENTAL SECTION 129 REFERENCES 202 viii LIST OF SCHEMES Scheme 1. Previous utilization of 2-acyl-2-enals in organic synthesis 2 Scheme 2. Previous approaches to 2-acyl-2-enals 3 Scheme 3. Initial discovery of 1,3-dioxin retrocycloadditions 4 Scheme 4. Proposed route to taxane-A ring synthons 5 Scheme 5. Preparation and Diels-Alder reactions of 2-acyloxyacroliens 6 Scheme 6. Preparation of 2-triflamidoacroleins 7 Scheme 7. Uses of 2-amidoacroleins in natural product synthesis 8 Scheme 8. Preparation and utility 2-alkyl and 2-arylacroliens 9 Scheme 9. Preparation and utility of 2-acylacroliens 10 Scheme 10. Hydrazone approach to 4-alkyl-1,3-dioxan-5-ones 11 Scheme 11. Cyclohexylimine approach to 4-alkyl-1,3-dioxan-5-ones 12 Scheme 12. Preparation of 4-alkylidiene-1,3-dioxan-5-ones 12 Scheme 13. Regioselective synthesis of the vinyl triflate 36d 13 Scheme 14. Conformational analysis of the retrocycloaddition reaction 16 Scheme 15. Thermal isomerization of methyl 2-formyl-2-pentenoate 18 Scheme 16. Investigation of the enolization pathway to 19 olefin isomerization Scheme 17. Conformation analysis of the hetero Diels-Alder 20 reaction of enal 50 Scheme 18. Partridge’s synthesis of loganin 23 Scheme 19. Büchi’s synthesis of loganin 24 Scheme 20. Trost’s synthesis of loganin 25 Scheme 21. Claisen condensation approach to loganin 25 Scheme 22. Hiroi’s approach to loganin 26 Scheme 23. Retrosynthetic analysis of (±)-loganetin 27 Scheme 24. Loganetin retrocycloaddition/cycloaddition substrate 28 Scheme 25. Conformational analysis of the loganetin 29 cycloaddition reaction Scheme 26. Lewis acid promoted formation of (E)-retrocycloadduct 32 Scheme 27. Completion of total synthesis of (±)-loganetin 33 Scheme 28. Isolation of hydrolysis product of euplotin C 37 Scheme 29. Biosynthetic pathway to euplotin C 40 Scheme 30. Proposed biosynthetic pathway to euplotins A and B 41 Scheme 31. Retrosynthetic analysis of (±)-euplotin A 42 Scheme 32. Rate of 2-acyl-2-enal isomerization vs. 44 cycloaddition reaction Scheme 33. Initial approach to euplotin A alkylation substrate 45 Scheme 34. Ring closure of a xanthate radical 46 Scheme 35. Synthesis of alkyl iodide 113 47 Scheme 36. Preparation of the retrocycloaddition/cycloaddition 48 substrate 99 Scheme 37. Key retrocycloaddition/cycloaddition reaction of dioxin 99 49 Scheme 38. Installation of the ketone sidechain of euplotin A 50 Scheme 39. Retro-ene reaction of the Weinreb amide 51 ix Scheme 40. Attempted conversion to the acetoxy acetal 51 Scheme 41. Oxetane ring opening with ethanethiol 52 Scheme 42. Synthesis of alkyl iodide 126 53 Scheme 43. Preparation of the retrocycloaddition/cycloaddition 54 substrate 129 Scheme 44. Retrocycloaddition/cycloaddition reaction of dioxin 129 54 Scheme 45. Completion of the total synthesis of (±)-euplotin A 55 Scheme 46.