1. 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

2. 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

3. 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

4. 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

5. 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

6. Model System synthesis

7. 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

8. 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

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

10. 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

11. 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

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

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

14. 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

15. 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)

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