60th Annual Report on Research 2015

Compared to the facile conversion of the aldehydes, conjugate addition of pyranone-ketones 8b,c derived from acetoxypyranone-enones 7b,c was non-spontaneous. Interestingly, upon addition of water (5%), trace lactol 9b was observed (entry 1). Increasing the concentration of water proved to be sufficient to afford the desired lactol 9b (entry 2). Similarly, acetoxypyranone-enone 7c afforded the analogous lactol 9c albeit with slightly decreased conversion (entry 3).

Whereas cross-metathesis provided α,β-unsaturated carbonyls (i.e. 7a-c) with excellent E-selectivity, cross-metathesis afforded moderate E-selectivity (7.4:1) of the desired anti-7d. This mixture was heated with N-methylpyrrolidine to provide good yield of bis-ether 9d. Unable to undergo conjugate addition from the convex face, pyranone-alcohol exo-9 arising from [5+2] cycloaddition of the minor Z-allylic alcohol 7d was also observed.

In an effort to extend the scope, we treated acetoxypyranone-enal 7a with a variety of alcohols to afford caged acetal-ethers 9e-l. Utilization of excess methanol (CH₃CN:MeOH 95:5) with 3Å molecular sieves to ensure the exclusion of water provided acetal 9e as a single diastereomer in 63% yield (entry 1). Additional functionalized primary alcohols afforded similar results (entries 2-4). More hindered alcohols gave mixed results; isopropanol delivered acetal 9i in moderate yield (entry 5), but tert-amyl alcohol afforded a complex mixture with no acetal 9j detected (entry 6). Although p-cresol gave poor yield, acetal 9k represents an interesting result arising from a different hydroxyl functionality (i.e. phenol) attacking the presumed pyranone-aldehyde 8a (entry 7). Finally, Boc-L-serine methyl ester provided acetal 9l in good yield as an expected mixture of inseparable diastereomers (entry 8).

Rate-determining deprotonation of enal 7a or enone 7b followed by expulsion of the acetate affords oxidopyrylium-alkenes 11a,b toward endo-selective [5+2] cycloaddition. Conjugate addition may be advanced via hydrates 13a,b or oxocarbeniums 12a,b. Whereas formation of hydrate 13a from aldehyde 8a followed by spontaneous conjugate addition would afford lactol 9a, the corresponding ketone 8b would be far less prone to initial hydrate 13b formation. Initial formation of hydrate 13 seems plausible, but it does little to explain the high diastereoselectivity. Although oxocarbenium 12 would provide a rational for selectivity via attack of the nucleophile from the convex face, it does not explain the more facile reaction of aldehyde 8a as compared to ketone 8b. A third scenario, however, is an asynchronous concerted pathway in which neither hydrates 13a,b nor oxocarbeniums 12a,b are discrete intermediates. Based upon conformational analysis and ground state energy calculations, formation of a single diastereomer of lactol 9a seems unlikely assuming free rotation of hydrate 13a. Analogous computational studies on methyl ketone 8b and the corresponding hydrate 13b suggest that a highly-ordered, asynchronous concerted pathway is plausible. Ground state calculations on ketone 8b revealed a low energy conformer wherein the lone pair was projected toward the π* orbital of the α,β-unsaturated carbonyl. This proposed n-π* stabilizing effect clearly leaves one face of the ketone more accessible to nucleophilic attack. Thus, as the nucleophile approaches the carbonyl (ketone 8b or aldehyde 8a), spontaneous O-C bond formation would occur via the n-π* coordination in an asynchronous concerted pathway.

    New discoveries are fascinating, but we are equally passionate about training next generation scientists. Upon completion of sophomore organic chemistry, students are well-prepared for research due to the abundance of operationally simple reactions developed over the past several decades. This award has significantly impacted our research in several ways. First, several students (B.S. and M.S.) have benefited from this funding and were given the opportunity to conduct full-time research during the summer. Also, flexibility to pursue serendipitous discoveries that differ from initial proposals is appreciated and has affected our research program for the better.