Andrew Duncan, PhD , Willamette University
My original proposal to PRF was based on an organocatalytic method for the asymmetric synthesis of oxacycles, via an intramolecular oxa-Michael cyclization of hydroxy unsaturated enals. My 2010 Progress Report detailed our efforts in substrate synthesis and expansion of the scope of our methodology. I am pleased to offer this Report of our continued progress over the past year.
One of our principal goals has been to extend the oxa-Michael cyclization methodology to nitrogen-containing substrates, allowing for an asymmetric synthesis of 2-substituted morpholines. At the time of my last report, we were focused on the synthesis of the required substrates via allylation and reduction of N-protected amino acid esters, followed by cross metathesis with acrolein. Initial efforts focused on reactions of N-Cbz, N-benzyl, and N-tosyl derivatives; however, we found that use of these protecting groups precluded successful completion of the substrate synthesis. We have now been able to successfully derivatize N-Boc-protected glycine ethyl ester to the desired hydroxyl enal, and have found that cyclization of the substrate under our previously-optimized organocatalytic conditions affords the corresponding morpholine in 76% enantiomeric excess.
Another significant and necessary goal for this project has been a definitive proof of absolute stereochemistry in our oxacyclic catalysis products. A search of the literature revealed that optical rotation data for the compounds in question were either lacking or equivocal; therefore, we decided to synthesize a crystalline derivative of tetrahydro-2H-pyran-2-ylethanol and determine absolute configuration of the new stereogenic center using single-crystal X-ray diffraction. We produced a short series of derivatives and found that the (R)-camphanoyl ester afforded crystals suitable for single-crystal X-ray diffraction. Anomalous dispersion in the X-ray data was sufficient to definitively assign the absolute configuration of the newly-formed stereogenic center as R. Notably, this finding is consistent with the stereochemical model invoked for similar reactions catalyzed by trimethylsilylprolinol derivatives and suggests that the bulky organocatalyst substituent is the primary stereocontrolling element in the cyclization.
At this point, we are nearly to the point of preparing a manuscript detailing our oxa-Michael results. Experimentally, it remains only to optimize the purification of several products and complete characterization on several previously-unreported compounds.
With work in the oxa-Michael system nearing conclusion, we have begun to explore several new avenues. In recent months we have made progress towards the design and synthesis of several asymmetric ligands and chiral organocatalysts based on carbohydrate motifs. This work will continue with PRF's support (through a no-cost extension to my award) over the next year.