Title: Dihydropyran and oxetane formation via a transannular oxaconjugate addition
1Dihydropyran and oxetane formation via a
transannular oxa-conjugate addition
- Steve Houghton
- Christopher Boddy
- Syracuse University
- Department of Chemistry
- June 15, 2007
2Laulimalide
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
Microtubules (green) during cell division
3Producing 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
4Proposal for biosynthetic origin of dihydropyran
scytophycin C
laulimalide
Pyran and cis olefin may form via a non-enzymatic
method
5Hypothesis 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
6Model System synthesis
71,3-Diols are separable
dr 11
anti
syn
- Deprotection revealed 2 spots on TLC
- Characterized by Rychnovshky method by preparing
acetonides
8Oxa-conjugate addition unexpected product
Single diastereomer Confirmed by COSY, HSQC,
HMBC, NOESY
syn diastereomer
14.2 kcal/mol higher energy than dihydropyran
- Highly strained trans oxetane is formed
- Under basic conditions diols are not reactive
Energy calculations DFT B3LYP/6-G31 d p level
9Two possible mechanisms for oxetane formation
- SN2 displacement
- Elimination/addition
- If SN2, anti diastereomer must produce cis
oxetane
10Anti diastereomer also produces trans oxetane
anti diastereomer
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
11E1cB-like mechanism
- Elimination is likely rate determining
- Not reversible mechanism
- Intermediate is not observed
12Cis triene may access dihydropyrans
- Olefin geometry may play role in oxetane formation
Energy calculations DFT B3LYP/6-G31 d p level
13Cyclic carbonate produces cis triene
- Cis triene is generated under basic conditions
from both syn and anti diastereomers
14Cis triene produces new compound
trans oxetane
- Amberlyst conditions yields a new compound as
shown by LC-MS
cis triene
4 hrs
uncharacterized new compound
15Conclusions
- 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)
16Acknowledgements
- Dr. Christopher Boddy
- The Boddy lab members
- Deborah Kerwood
- Department of Chemistry
- Syracuse University