AmericanChemicalSociety.com
Reports: UNI1 50081-UNI1: Stereocontrolled Organocatalytic Synthesis of Oxacycles
My original proposal to PRF outlined a number of project goals related to the asymmetric organocatalytic synthesis of oxacycles via the intramolecular oxa-Michael cyclization of hydroxy enals. Over the past year, my research group has made significant progress toward several of our objectives.
In the area of substrate synthesis, we have discovered that the use of the Hoveyda-Grubbs 2nd Generation metathesis catalyst provides a more convenient preparation of several hydroxy enal substrates. Previous work with the 2nd Generation Grubbs catalysts gave satisfactory results; however, the extended reaction time (usually 24-48 hrs) and slightly elevated reaction temperature (45 °C) resulted in some thermal (uncatalyzed) cyclization to form racemic oxacycles. Cross metathesis with the more reactive 2nd generation Hoveyda-Grubbs variant occurs in a shorter period (typically 12-16 hrs) at ambient temperature. Under these conditions little, if any, thermal cyclization of the substrate is observed.
At the time of proposal submission (February 2009), my group had established the viability of the organocatalyzed oxa-Michael cyclization by demonstrating that prolinol-derived organocatalysts promote the cyclization of 7-hydroxyhept-2-enal to give (after in situ reduction) tetrahyro-2H-pyran-2-ylethanol in 72% yield and 92% enantiomeric excess. Our recent work has been focused on expanding the scope of this oxacyclization.
Over the past year, we have established that replacing the C5 methylene group of the original substrate with sulfur or oxygen allows for the synthesis of the 4-thiaoxacycle and 1,4-dioxanes derivatives. These heterocycles are obtained in moderate yield (50% and 60% respectively) and good enantiomeric excess (86% for both).
If we delete the C5 methylene, organocatalyzed cyclization affords the tetrahydrofuranyl analogue as a racemate. We are still investigating the reason for the complete loss of stereocontrol in the synthesis of the five-membered ring; some precedent suggests that the slight thermodynamic destabilization of the five-membered oxacycle (as compared to the six-membered derivative) may facilitate a retro-Michael cyclization which would, over time, racemize the new stereogenic center.
We have also made progress toward the synthesis of nitrogen-containing analogues, with the intention of establishing a convenient asymmetric synthesis of 2-substituted chiral morpholines. We have explored a number of potential routes into the required substrates, and have settled on the sequential allylation and reduction of N-protected amino acid esters, followed by cross metathesis with acrolein. We anticipate subjecting these compounds to organocatalytic conditions in the coming months.
Ongoing work in my group remains focused on extending the scope of the oxacyclization. We are also expanding into the synthesis of simple pharmaceutically-relevant oxacyclic targets, including (+)-SCH 50911, a compound with anti-depressant and anti-anxiolytic biological activity.
Support of PRF through this award has been a significant asset to my research group. The data that my students and I have collected over the past year will form the backbone of a manuscript that I plan to submit during summer 2011, in time for my tenure review in the fall. Fund provided by PRF have allowed me to offer full time summer research experiences to two undergraduates whom I would not otherwise been able to hire. Notably, both of these students are now chemistry majors, and plan to pursue graduate study upon leaving Willamette.
