Turning Spiroketals Inside Out: A Rearrangement Triggered by an Enol Ether Epoxidation

Abstract

Spiroketals organize small molecule structures into well-defined, three-dimensional configurations that make them good ligands of proteins. We recently discovered a tandem cycloisomerization–dimerization reaction of alkynyl hemiketals that delivered polycyclic, enol-ether-containing spiroketals. Here we describe rearrangements of those compounds, triggered by epoxidation of their enol ethers that completely remodel their structures, essentially turning them “inside out”. Due to the high level of substitution on the carbon skeletons of the substrates and products, characterization resorted to X-ray crystallography and advanced computation and NMR techniques to solve the structures of representative compounds. In particular, a new proton-detected ADEQUATE NMR experiment (1,1-HD-ADEQUATE) enabled the unequivocal assignment of the carbon skeleton of one of the new compounds. Solution of the structures of the representative compounds allowed for the assignment of product structures for the other compounds in two separate series. Both the rearrangement and the methods used for structural determination of the products are valuable tools for the preparation of characterization of new small molecule compounds.

Observation of untoward 3Jcc correlations in 1,1‐ADEQUATE spectra of pyrimidine analogs: Avoiding potential interpretation pitfalls

“…Over the past few years, our group has been involved in several internal projects and external collaborations that necessitated the acquisition of 1,1‐ADEQUATE spectra on different classes of small molecules ranging from natural products to synthetic molecular structures . The present study is a follow‐up to previous studies in which we have observed multiple‐bond correlations “leaking” into 1,1‐ADEQUATE spectra due to unusually large 2 J CC and 3 J CC couplings for particular structural motifs that can be nearly as large as some 1 J CC couplings .…”

“…As mentioned above, the 1,1‐HD‐ADEQUATE experiment can enhance resolution and afford a sensitivity improvement for correlations involving quaternary carbons through HD. This was clearly noted in the structural characterization of synthetic spiroketal ( 3 ), whereby a 40‐Hz 1,1‐HD‐ADEQUATE spectrum was acquired. A rather intense 2 J CC correlation was observed across the carbonyl to the spirocarbon.…”

“…In the former case, a 2 J CC correlation was observed across the carbonyl as shown for the natural product cryptospirolepine (structure 1 ) . Even though the small quantity of the alkaloid available precluded the measurement of the coupling constant, the density functional theory (DFT)‐calculated 2 J CC coupling constant was 15.6 Hz.…”

“…1 mg of small to midsized molecules to acquire reasonable quality ADEQUATE spectra over a weekend. A modified version of the original pulse sequence incorporating homodecoupling (HD) has recently been described that leads to a further boost in sensitivity and resolution for spin systems involving adjacent quaternary carbons . Data acquisition times can also be improved via nonuniform sampling …”

Observation of potentially troublesome2JCCcorrelations in 1,1-ADEQUATE spectra

“…[20] An analog of one type of product afforded suitable crystals for X-ray analysis. Members of the other group did not afford suitable crystals for X-ray and routinely employed NMR methods (COSY, HSQC, and HMBC) were unable to assemble the fragments whose structures could be gleaned from the data into a final structure.…”