Biomimetic transannular oxa-conjugate addition approach to the 2,6-disubstituted dihydropyran of laulimalide yields an unprecedented transannular oxetane

J Org Chem. 2009 Feb 20;74(4):1454-63. doi: 10.1021/jo8023494.


2,6-Disubstituted dihydropyrans are a common feature in many bioactive polyketides, including the anticancer marine polyketide laulimalide. While much of the uncharacterized biosynthetic pathway for laulimalide can be confidently postulated, the biosynthetic origins of the trans 2,6-disubstituted dihydropyran cannot. We hypothesize that a transannular oxa-conjugate addition in a macrocyclic laulimalide precursor could be the origin of the 2,6-dihydropyran. To test this hypothesis, we constructed a model containing the key functional groups for oxa-conjugate addition-mediated dihydropyran formation. Under acid-mediated conditions, the model under went regiospecific oxa-conjugate addition producing a stable trans oxetane as the only regioisomer. The desired, more stable dihydropyran was not detected. This unprecedented regiospecificity is unexpected due to the ring strain of the oxetane and the anticipated facile ring opening retro-oxa-conjugate addition. The oxetane is stable to acid and basic conditions, as are a number of literature acyclic oxetanes that could undergo similar retro-oxa-conjugate addition. While the source of the oxetane kinetic stability is yet to be characterized, it may enable general oxetane construction via oxa-conjugate addition. The more stable dihydropyran regioisomer could not be generated due to poor geometrical orbital alignment and hard-soft incompatibility between the hard oxygen nucleophile and the soft activated polyenoate electrophile. These factors disfavor the breaking of conjugation by oxa-conjugate addition. Based on these results we propose that dihydropyran formation does not occur on completed polyketide macrocycles as we had proposed but rather during polyketide biosynthesis on the growing polyketide chain.

MeSH terms

  • Acids / chemistry
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Biomimetics*
  • Catalysis
  • Ethers, Cyclic / chemistry*
  • Kinetics
  • Macrolides / chemistry*
  • Macrolides / metabolism
  • Pyrans / chemical synthesis*
  • Pyrans / chemistry
  • Pyrans / metabolism
  • Quantum Theory
  • Stereoisomerism
  • Substrate Specificity
  • Thermodynamics


  • Acids
  • Antineoplastic Agents
  • Ethers, Cyclic
  • Macrolides
  • Pyrans
  • laulimalide
  • oxetane