Department of Chemistry Dihydropyran and oxetane formation via a transannular oxa-conjugate addition Steve Houghton Christopher Boddy Syracuse University Department of Chemistry June 15, 2007

Laulimalide Cytotoxic marine polyketide Pacific marine sponge Cacospongia mycofijiensis Cytotoxic marine polyketide Potential anticancer agent, similar to Taxol Stabilizes microtubules Isolated from sponge in trace amounts Insufficient material for clinical development Phil Crews (UC Santa Cruz and Chatgilialoglu) Supply problem Same location, symbiotic bacteria Microtubules (green) during cell division

Producing laulimalide Engineering of a recombinant biosynthetic pathway Produce macrocyclic precursors by fermentation Several synthetic transformations will have to be validated install the transannular dihydropyran 2,3-Z olefin. Provides new rapid and efficient strategy for total synthesis The 2-3 Z dihydropyran is of particular interest as it is a unique dihyropyran

Proposal for biosynthetic origin of dihydropyran laulimalide scytophycin C Rizzacassa and co-workers have demonstrated successful oxa-conjugate additions under acidic conditions in the synthesis of Apicularen Pyran and cis olefin may form via a non-enzymatic method

Hypothesis tested using model system 8.2 kcal/mol more stable Can we form dihydropyrans via transannular oxa-conjugate addition in 20-membered rings? Is oxa-conjugate addition a stereoselective reaction? Kinetic or thermodynamically controlled? Energy calculations: DFT B3LYP/6-G31 d p level

Model System synthesis

1,3-Diols are separable Deprotection revealed 2 spots on TLC dr 1:1 anti syn Deprotection revealed 2 spots on TLC Characterized by Rychnovshky method by preparing acetonides

Oxa-conjugate addition unexpected product syn diastereomer Single diastereomer Confirmed by COSY, HSQC, HMBC, NOESY 14.2 kcal/mol higher energy than dihydropyran SYN diastereomer only Highly strained trans oxetane is formed Under basic conditions diols are not reactive Energy calculations: DFT B3LYP/6-G31 d p level

Two possible mechanisms for oxetane formation SN2 displacement Elimination/addition If SN2, anti diastereomer must produce cis oxetane

Anti diastereomer also produces trans oxetane 14.2 kcal/mol 13.3 kcal/mol higher energy than dihydropyran Since inversion of stereochemisty is not observed cannot be SN2 displacement Mechanism must be elimination, oxa-conjugate addition Energy calculations: DFT B3LYP/6-G31 d p level

E1cB-like mechanism Elimination is likely rate determining Product re exposed to reaction conditions does not generate starting material Elimination is likely rate determining Not reversible mechanism Intermediate is not observed

Cis triene may access dihydropyrans Olefin geometry may play role in oxetane formation Energy calculations: DFT B3LYP/6-G31 d p level

Cyclic carbonate produces cis triene Cis triene is generated under basic conditions from both syn and anti diastereomers

Cis triene produces new compound trans oxetane Amberlyst conditions yields a new compound as shown by LC-MS cis triene 4 hrs uncharacterized new compound

Conclusions Transannular oxa-conjugate addition can occur High energy oxetane favored over low energy dihydropyran Unusual regioselectivity of acid catalyzed oxa-conjugate addition Regioselectivity could be attributed to olefin geometry of elimination (triene intermediate)

Acknowledgements Dr. Christopher Boddy The Boddy lab members Deborah Kerwood Department of Chemistry Syracuse University