Lautens Chiral Building Blocks

By: Dr. Daniel Weibel, Chemfiles Volume 10 Article 1

        Dr. Daniel Weibel

Dr. Daniel Weibel
Product Manager
Email:daniel.weibel@sial.com

Professor Mark Lautens and his group at the University of Toronto have developed a powerful catalytic asymmetric ring opening reaction enabling the production of highly functionalized hydronaphthalene scaffolds in enantioenriched form. This method is providing access to a myriad of highly functionalized scaffolds from achiral, readily available low-cost starting materials.1 Josiphos type ligands2 complexed to Rh promote the ring opening of meso oxabicyclic and azabicyclic alkenes with heteroatom nucleophiles such as alcohols, phenols, aliphatic amines, carboxylates, malonates and sulfides with very high enantioselectivities (Scheme 1).

Scheme 1

Scheme 1 (227951 ) (683132)  (88719 )


The hydronaphthalene skeleton is found in a wide range of compounds possessing diverse biological activities, thus these chiral building blocks have proven to be extremely useful in the synthesis of biologically active molecules of pharmaceutical interest.3 A number of drug candidates in various clinical phases, as well as natural and launched products, is shown in Figure 1.

Figure 1

Figure 1


In a very recent study the Lautens and Tomaszewski groups have synthesized a small library of amides and amines of 1-aminotetralin scaffolds via this methodology.4 Screening of these libraries against human opioid receptors led to the identification of a highaffinity selective m ligand (IC50 m = 5 nM, k= 707 nM, d= 3,795 nM) displaying agonist/antagonist properties due to its partial agonism (EC50 = 2.6 mM Emax = 18%). Drugs with a similar profile have proved beneficial in the treatment of pain as well as for the treatment of drug addiction particularly due to their low dependence-inducing potential (buprenorphine, a partial m agonist is used in both analgesia and the treatment of heroin addiction) .

Scheme 2

Scheme 2


Sigma-Aldrich is pleased to offer our first selection of highly useful chiral building blocks, and we intend to continually expand our chiral building blocks product portfolio.

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Materials

     

References

  1. Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48.
  2. For a list of available chiral ligands from Solvias, see: sigma-aldrich.com/solvias
  3. (a) Lautens, M.; Rovis, T. Tetrahedron 1999, 55, 8967. (b) Lautens, M.; Fagnou, K.; Zunic, V. Org. Lett. 2002, 4, 3465. (c) Fan, E.; Shi, W.; Lowary, T. J. Org. Chem. 2007, 72, 2917. (d) Madan, S.; Cheng, C. J. Org. Chem. 2006, 71, 8312.
  4. Dockendorff, C.; Jin, S.; Olsen, M.; Lautens, M.; Coupal, M.; Hodzic, L.; Spear, N.; Payza, K.; Walpole, C.; Tomaszewski, M. J. Bioorg. Med. Chem. Lett. 2009, 19 1228.

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