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43629-AC1
Green Chemical Manufacturing: New Reagents and Methods for Asymmetric Synthesis
Our PRF research has a focus in green chemistry and asymmetric synthesis of molecules that are important for the treatment of malaria and HIV/AIDS.
We have achieved the solventless synthesis of phenanthrenes by photochemical ring closure in which the regiochemistry is controlled by the crystalline form of the molecule (example in figure 1, TOC). Form 1 of stilbene A undergoes ring closure to give only the desired intermediate for synthesis of the malaria drug halofantrine. Form 2, however, undergoes an alternative ring closure to yield the undesired product. This chemistry yielded a convenient, 5-step synthesis of halofantrine using only 3 solvents (other than water) for the entire synthesis. This contrasts with the 11-step synthesis currently used to manufacture this drug, utilizing the very same starting materials. We have also eliminated over 90% of the total solvent usage for this synthesis versus the original synthesis.
Nucleophilic aromatic substitution and “vicarious” nucleophilic substitution on nitro-arenes are well-known reactions. Yields are typically in the range of 65 – 85%. We have determined that byproducts for these reactions are almost exclusively derived from the use of alkoxide bases. Simple substitution of DBU for these reactions generally gives yields of >95% for a wide range of representative reactions of this type. Telescoping this reaction with a subsequent aldol condensation provides a convenient synthesis of a range of stilbenes, including that pictured in Figure 1.
The asymmetric addition of low-molecular weight aldehydes to carbonyl partners is a difficult reaction to achieve in good yields and high enantioselectivity. We have utilized proline and 5-methylproline as catalysts to achieve good yields of cross-condensation products of acetaldehyde and low-molecular weight analogs (eg propionaldehyde, butyraldehyde) with carbonyl and imine acceptors under very mild conditions and with excellent (>95%) enantioselectivities. This has yielded an enantioselective synthesis of the active metabolite of halofantrine, which is more potent and less toxic than the parent drug itself. Combination of these Mannich reactions with an asymmetric Henry reaction has given a single-pot synthesis of molecules containing 3 chiral centers that are critical intermediates for the synthesis of protease inhibitors for the treatment of HIV/AIDS.
