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Progress:

              During this granting period, we expanded our study to include the reaction of a series of furans 1 with maleic anhydride at rt in the absence of solvent (eq 1).  The size of the silyl R¹ group was found to have a significant impact on the reaction; 1a reacts nearly instantaneously, 1b and 1c reacted over a few minutes, and 1d showed very little sign of cycloaddition, even after several days at rt.  Interestingly, analysis of H1 NMR spectra of reaction mixtures involving 1a-c revealed near exclusive formation of the exo-adduct 3a-c.

            We next turned our attention to various maleate esters to determine the effect of the dienophile structure on the course of the reaction.  In this series, the reaction of 1a with 4a,b produced oxabicycles 5 resulting from endo approach of the dienophile (eq 2).  While the reaction of 1a with 2 produced 3a almost immediately, use of 4a required three days to go to completion, giving 5a (R1 = TMS, R2 = Me) as observed by NMR.  In all cases we examined, the reaction rates corrolate with the size of the silyl group in the furan; larger silyl groups reacted at slower rates (Table 1).  Based upon coupling constants in the NMR spectra of the crude reaction mixtures, the endo-cycloadducts 5 were formed nearly exclusively.  Spectra taken at various time points throughout the reactions show no equilibration between endo- and exo- adducts, though a fast equilibrium favoring the endo-adduct cannot be ruled out by these experiments, and continuing progess of the reaction, not a rapidly established equilibrium between reactants and products.

         Experiments involving 1a and dimethyl fumarate show a strong preference for placing the carbonyl proximal to the silyl group in an endo orientation, providing cycloadducts 7 as determined by the analysis of coupling constants in the H1 NMR spectrum of the crude reaction mixture (eq 3).

            The nearly exclusive formation of the exo-adduct 3 was particularly surprising.  This and the particularly large difference in reaction rates as R1 increased in size led us to examine the reactions that form 3a and 5a using density functional methods (B3LYP/6-31G(d)).  The lowest energy transition states leading to both 3a and the corresponding endo-stereoisomer predicted that the endo-transition state I is 2.4 kcal/mol higher in energy than exo-transition state II (Figure 1).  Similarly, the lowest energy transition states leading to both 5a and the corresponding exo-stereoisomer predict that exo-transition state III is 4.6 kcal/mol higher in energy than the endo-transition state IV.  In both cases, the observed product distribution is consistent with that predicted by the calculated energy differences.  All of the transition states modeled show a high level of stretch-mode asynchronicity, where one of the forming bonds is significantly shorter than the other.  It is this asynchronicity that gives rise to the reversal of diastereoselectivity.  It is also clear how the size of the silicon group influence the stereics of the transition states leading to cycloadducts.

            Studies are currently underway to reduce each of the oxabicycles 3, 5, and 7 to demonstrate the synthetic potential this interesting diastereoselectivity has with respect controlling the four contiguous stereocenters formed in the reaction.

Impact:

             This grant has opened up a new avenue of research at Gustavus Adolphus College, and has attracted much student interest.  It has also provided the PI several examples with which to enrich his teaching.  The work accomplished under this grant has provided the foundation for an NSF grant submission.  During this grant period, the PI and a student presented this work as a poster at the fall 2010 ACS meeting in Boston.  Once we have the results of the oxabicycle reduction experiments, a paper will be submitted.

            On an institutional level, this grant has been part of a successful effort to increase undergraduate research opportunities in the summers.  In combination with two institutional grants (Merck Institute for Science Education and Howard Hughes Medical Institute), the PRF grant has helped altered the research atmosphere at Gustavus profoundly.

            Three different students have been trained under this grant period.  One student is applying to graduate schools in chemistry, one is applying to medical schools, and one has become interested in a research career.  Two of the three students currently trained under this grant period are women.