Dihydropyran and oxetane formation via a transannular oxaconjugate addition

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Dihydropyran and oxetane formation via a
transannular oxa-conjugate addition

• Steve Houghton
• Christopher Boddy
• Syracuse University
• Department of Chemistry
• June 15, 2007

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Laulimalide
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
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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

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Proposal for biosynthetic origin of dihydropyran
scytophycin C
laulimalide
Pyran and cis olefin may form via a non-enzymatic
method
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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
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Model System synthesis
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1,3-Diols are separable
dr 11
anti
syn

• Deprotection revealed 2 spots on TLC
• Characterized by Rychnovshky method by preparing
  acetonides

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Oxa-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
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Two possible mechanisms for oxetane formation

• SN2 displacement
• Elimination/addition
• If SN2, anti diastereomer must produce cis
  oxetane

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Anti 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
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E1cB-like mechanism

• Elimination is likely rate determining
• Not reversible mechanism
• Intermediate is not observed

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Cis triene may access dihydropyrans

• Olefin geometry may play role in oxetane formation

Energy calculations DFT B3LYP/6-G31 d p level
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Cyclic carbonate produces cis triene

• Cis triene is generated under basic conditions
  from both syn and anti diastereomers

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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
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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)

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Acknowledgements

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