Oxetanes

By: Mark Redlich, Chemfiles Volume 10 Article 4

Ph.D.
Product Manager
mark.redlich@sial.com

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Materials

Oxetanes are the closest homologs to epoxides, but historically have received far less attention than their three-membered ringed brethren. However, oxetanes have received increasing exposure as attractive modules for drug discovery, largely due to a recent series of reports from Rogers-Evans, Carreira, and coworkers. They have demonstrated the improved physico- and biochemical properties of a molecular scaff old when an oxetane unit replaces a gem-dimethyl unit1 and also reported an oxetane ring can function as a surrogate for a carbonyl group.1b,2 More recently, they have demonstrated the use of 1,6-substituted azaspiro[3.3]heptanes containing an oxetane ring as alternatives to unstable 1,3-heteroatom substituted cyclohexanes.3 In most cases, 3-oxetanone, 731536, was the principal building block employed by the authors to install the oxetane unit (Scheme 1).

Scheme 1: Oxetane Derivatives Synthesized from 3-Oxetanone

The presence of the oxetane moiety in drug-like and biologically active molecules is nothing new to synthetic and medicinal chemists. Perhaps the best-known examples of oxetane-containing drugs are the natural product paclitaxel (Taxol®) and its synthetic analog docetaxel (Figure 1). Joëlle Dubois and coworkers studied the eff ect of the deletion of the oxetane ring in analogs of docetaxel and found the analogs to be less active than docetaxel in biological assays.4 Merrilactone A (Figure 2) shows promise as a nonpeptidal neurotropic agent, 5 and the β-amino acid oxetin (Figure 3) has demonstrated both herbicidal and antibiotic activity.6

Figure 1: Paclitaxel (Taxol®) and Docetaxel

Figure 2: Merrilactone A

Figure 3: β-Amino Acid Oxetin

We are pleased to now offer a wide selection of new oxetane building blocks for a variety of applications in synthetic and medicinal chemistry.

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References

  1. (a) Wuitschik, G. et al. Angew. Chem., Int. Ed. 2006, 45, 7736. (b) Wuitschik, G. et al. J. Med. Chem. 2010, 53, 3227.
  2. Wuitschik, G. et al. Angew. Chem., Int. Ed. 2008, 47, 4512.
  3. Burkhard, J. A. et al. Org. Lett. 2010, 12, 1944.
  4. Deka, V. et al. Org. Lett. 2003, 5, 5031.
  5. (a) Birman, V. B.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 2080. (b) Huang, J.-M. et al. Tetrahderon Lett. 2000, 41, 6111. (c) Huang, J.-M. et al. Tetrahderon 2001, 57, 4691.
  6. Omura, S. et al. J. Antibiot. 1984, 37, 1324.

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