SYNTHESIS OF PYRAN AND RELATED NATURAL PRODUCTS Bun Yeung, BSc Thesis submitted for the degree of Master of Philosophy The University of York Department of Chemistry September 2012 Synthesis of pyran and related natural products Bun Yeung Abstract This study was aimed at preparing dihydropyrans (DHPs) for the synthesis of 2,6-disubstituted tetrahydropyrans (THPs) in a diastereoselective manner. In an attempt to develop a novel methodology for the synthesis of DHPs from δ- hydroxy-β-ketoester and thioamide in the presence of Lewis acid, unexpected dihydrothiopyran (DHT) formed as the sole product in the reaction instead of the expected DHP. A thorough investigation of the DHT forming-reaction showed that it is a promising method to synthesize 2,6-disubstituted DHT compounds. Various substituents at C2 and C6 positions were incorporated into the DHT by using different δ-hydroxy-β-ketoesters and thioamides. This methodology was applied to the first total synthesis of citreothiopyrane A in 4% yield over three steps. The synthesis of a number of citreothiopyrane A analogs with different substituents at C6 position was also achieved. N-heterocyclic carbene and quinuclidine were tested to promote the formation of δ-hydroxy-β-ketoesters form diketene, but the only product identified was the methyl acetoacetonate and stable quinuclidine-enolate respectively. In the investigation of (-)-apicularen A synthesis, it was proposed that the THP core could be accessed by the asymmetric Maitland-Japp reaction, using Chan’s diene and two synthesized aldehydes. However, it was found that the aldehyde with ketal protecting group is too unstable under Lewis acid condition. Further improvements are needed, such as using a more acid-stable protecting group, or by replacement of the aldehyde functionality. i Synthesis of pyran and related natural products Bun Yeung Table of content Abstract ................................................................................................................... i Table of content ..................................................................................................... ii List of Schemes ..................................................................................................... iv List of Figures ....................................................................................................... ix List of Tables ......................................................................................................... x Acknowledgement ................................................................................................ xi Declaration ........................................................................................................... xii 1. Introduction .................................................................................................... 1 1.1 Natural products with tetrahydropyran building blocks .............................. 1 1.2. Methodologies toward THP ring synthesis .................................................. 3 1.2.1 Prins cyclization ........................................................................................ 3 1.2.2 Hetero-Diels-Alder reaction .................................................................... 10 1.2.3 Petasis-Ferrier Rearrangement ................................................................ 19 1.2.4 Intramolecular oxy-Michael addition ...................................................... 26 1.2.5 Maitland-Japp reaction ............................................................................ 28 1.3 Aims and Objectives .................................................................................. 39 2. Results and discussion ............................................................................... 40 2.1. Synthesis of Dihydropyrans ....................................................................... 40 2.2. Synthesis of dihydrothiopyrans .................................................................. 46 2.3. Study of mechanism and formation of dihydrothiopyran .......................... 52 2.4. Synthesis of citreothiopyrane A ................................................................. 57 2.5. Synthesis of citreothiopyrane A analogs .................................................... 62 2.6. Investigation of using N-heterocyclic carbene as an organic catalyst for the diketene addition reaction .............................................................................. 64 2.7. Investigation of using tertiary amine to catalyze the diketene addition reaction ................................................................................................................. 70 2.8. Investigation toward the synthesis of THP fragment (C1 – C15) of (-)- apicularen A ......................................................................................................... 74 2.9. Conclusion and future work ....................................................................... 91 3. Experimental ................................................................................................ 96 3.1. General Information ................................................................................... 96 ii Synthesis of pyran and related natural products Bun Yeung 3.2. Materials .................................................................................................... 97 3.3. Synthesis of dihydropyran-4-one ............................................................... 97 3.4. Synthesis of single diastereomeric 2,6-trans-tetrahydropyran-4-one ...... 101 3.5. Synthesis of dihydrothiopyran ................................................................. 103 3.6. Synthesis of citreothiopyrane A and analogous ....................................... 109 3.7. Synthesis of apicularen A THP core ........................................................ 120 4. Appendix .................................................................................................... 128 5. Abbreviations ............................................................................................. 130 6. References .................................................................................................. 132 iii Synthesis of pyran and related natural products Bun Yeung List of Schemes Scheme 1: Prins cyclization...................................................................................3 Scheme 2: Side chain exchange and racemization via 2-oxonia Cope rearrangement in Prins cyclization.........................................................................4 Scheme 3: π-cyclizations of α-methoxycarbonyl oxycarbenium ions..................5 Scheme 4: Cyclization of electron-rich enantioenriched alcohol..........................6 Scheme 5: Cyclization of electron-deficient enantioenriched Alcohol..................7 Scheme 6: Racemization of Prins cyclization by allyl transfer and 2-oxonia Cope rearrangement.........................................................................................................9 Scheme 7: Improved Prins cyclization.................................................................10 Scheme 8: HDA reaction with Danishefsky’s diene and aldehyde......................11 Scheme 9: Diastereoselective hetero Diels-Alder reaction catalyzed by chromium(III) Schiff base complex.....................................................................12 Scheme 10: Reagents and conditions: a) Jacobsen’s catalyst 50b (17%), 4 Å mol. sieves, 52, Me2CO, 3 hr, then 53, 38 hr; b) AcOH (2 eq), TBAF (1.5 eq), THF, 20 oC, 1.5 hr..........................................................................................................13 Scheme 11: Synthesis of five-substituted THP by HDA reaction.......................14 Scheme 12: Asymmetric synthesis of DHP by inverse electron – HDA reaction.................................................................................................................15 Scheme 13: Reagents and conditions: a) Ph2Se2O3, SO3-Pyr, TEA, THF, 23 °C then hexanes, 50 °C, 63%.....................................................................................16 Scheme 14: Proposed catalytic cycle for bifunctional catalyzed inverse electron – demand HDA reaction..........................................................................................17 Scheme 15: Bifunctional-catalyzed inverse electron – demand HDA reaction...18 iv Synthesis of pyran and related natural products Bun Yeung Scheme 16: Ferrier I type rearrangement, LA = BF3.OEt2, SnCl4, Nu = OR, SR2, NR2.......................................................................................................................19 Scheme 17: Ferrier II type rearrangement...........................................................20 Scheme 18: Petasis rearrangement.......................................................................20 Scheme 19: Petasis-Ferrier rearrangement for cis-tetrahydropyranone synthesis................................................................................................................21 Scheme 20: Unproductive coordination of an aluminium Lewis acid leading to fail rearrangement.................................................................................................22 Scheme 21: Productive coordination of an aluminium Lewis acid giving to suceessful rearrangement......................................................................................23 Scheme 22: Construction of C20 – C28 THP motif by Petasis-Ferrier rearrangement.......................................................................................................24