59th Annual Report on Research 2014

Compared to the facile conversion of the aldehydes, conjugate addition of pyranone-ketones 6b,c derived from acetoxypyranone-enones 5b,c was non-spontaneous. Interestingly, upon addition of water (5%), trace lactol 7b was observed (entry 1). Increasing the concentration of water proved to be sufficient to afford the desired lactol 7b (entry 2). Similarly, acetoxypyranone-enone 5c afforded the analogous lactol 7c albeit with slightly decreased conversion (entry 3).

Whereas cross-metathesis provided α,β-unsaturated carbonyls (i.e. 5a-c) with excellent E-selectivity, cross-metathesis afforded moderate E-selectivity (7.4:1) of the desired anti-5d. This mixture was heated with N-methylpyrrolidine to provide good yield of bis-ether 7d. Unable to undergo conjugate addition from the convex face, pyranone-alcohol exo-8 arising from [5 + 2] cycloaddition of the minor Z-allylic alcohol 5d was also observed.

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

Rate-determining deprotonation of enal 5a or enone 5b followed by expulsion of the acetate affords oxidopyrylium-alkenes 10a,b toward endo-selective [5+2] cycloaddition. Conjugate addition may be advanced via hydrates 11a,b or oxocarbeniums 12a,b. Whereas formation of hydrate 11a from aldehyde 6a followed by spontaneous conjugate addition would afford lactol 7a, the corresponding ketone 6b would be far less prone to initial hydrate 11b formation. Initial formation of hydrate 11 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 6a as compared to ketone 6b. A third scenario, however, is an asynchronous concerted pathway in which neither hydrates 11a,b nor oxocarbeniums 12a,b are discrete intermediates. Based upon conformational analysis and ground state energy calculations, formation of a single diastereomer of lactol 7a seems unlikely assuming free rotation of hydrate 11a. Analogous computational studies on methyl ketone 6b and the corresponding hydrate 11b suggest that a highly-ordered, asynchronous concerted pathway is plausible. Ground state calculations on ketone 6b 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 6b or aldehyde 6a), 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. We pursue challenges with potential for enduring impact, yet with manageable goals suitable for undergraduates. 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, the obvious benefit of funding is that it is a lifeline for research, whether to purchase chemicals or pay students. Indeed, 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 months. Finally, the flexibility to pursue serendipitous discoveries that differ from initial proposals is greatly appreciated and has changed the course of our research program for the better.