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

Lorenc C, Saurí J, Moser A, Buevich AV, Williams AJ, Williamson RT, Martin GE, Peczuh MW - ChemistryOpen (2015)

Bottom Line: Here we describe rearrangements of those compounds, triggered by epoxidation of their enol ethers that completely remodel their structures, essentially turning them "inside out".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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Connecticut 55 N. Eagleville Road, U3060, Storrs, CT, 06269, USA.

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.

No MeSH data available.


Numbering scheme for compound  14. Bonds shown in bold red were determined from the 40 Hz optimized 1,1-HD-ADEQUATE data. The correlation from C13 to the C12 carbonyl was intentionally folded to afford better F1 digitization and to minimize data acquisition times. The red arrow denotes the 2JCC=11.3 Hz correlation observed in the 1,1-HD-ADEQUATE spectrum. The black arrows denote correlations in the 2 Hz optimized LR-HSQMBC spectrum that linked the two dimethyl sprioketals to rings B and D, in addition to providing some additional cross-ring correlations, for example H7ax–C1 and H17–C11.
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fig03: Numbering scheme for compound  14. Bonds shown in bold red were determined from the 40 Hz optimized 1,1-HD-ADEQUATE data. The correlation from C13 to the C12 carbonyl was intentionally folded to afford better F1 digitization and to minimize data acquisition times. The red arrow denotes the 2JCC=11.3 Hz correlation observed in the 1,1-HD-ADEQUATE spectrum. The black arrows denote correlations in the 2 Hz optimized LR-HSQMBC spectrum that linked the two dimethyl sprioketals to rings B and D, in addition to providing some additional cross-ring correlations, for example H7ax–C1 and H17–C11.

Mentions: The compact nature of the product structure and the indeterminate nature of correlations in the HMBC spectrum can be circumvented by utilizing 1,1-ADEQUATE spectra to unequivocally define the carbon skeleton of these molecules. To facilitate the acquisition of the ADEQUATE data, we utilized a newly developed, partially homodecoupled 1,1-ADEQUATE (1,1-HD-ADEQUATE) experiment optimized for 1JCC=40 Hz (comparison of conventional versus 1,1-HD-ADEQUATE data is presented in the Supporting Information).22 Utilizing these data and beginning from the hydroxyl-bearing methine (C1, see Figure 3), the constitution of rings B (C1–C2–C6–C7), C (C20–C21), and D (C13–C17–C18) suggested in the Structure Elucidator calculation were confirmed. Correlations from C1 and C21 to the C9 spiroketal carbon linked rings B and C. A correlation from C20 to the C11 spiroketal carbon and an unexpected 2JCC correlation from C13 to C11 established the link between rings C and D. Density functional theory (DFT) calculations revealed an unusually large 2JCC coupling (12.8 Hz calculated; 11.3 Hz measured using a J-modulated ADEQUATE spectrum) between C13 and C11 that was visualized in the 40 Hz optimized 1,1-HD-ADEQUATE spectrum (see Supporting Information). The ADEQUATE 1JCC correlations linked the 22- and 23-methyl groups to C4 and the 24- and 25-methyl groups to C15. Additionally, 4JCH correlations in a 2 Hz optimized LR-HSQMBC23 experiment linked the two dimethylspiroketal moieties to rings B and D, respectively completing the confirmation of the structure (see Supporting Information).


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

Lorenc C, Saurí J, Moser A, Buevich AV, Williams AJ, Williamson RT, Martin GE, Peczuh MW - ChemistryOpen (2015)

Numbering scheme for compound  14. Bonds shown in bold red were determined from the 40 Hz optimized 1,1-HD-ADEQUATE data. The correlation from C13 to the C12 carbonyl was intentionally folded to afford better F1 digitization and to minimize data acquisition times. The red arrow denotes the 2JCC=11.3 Hz correlation observed in the 1,1-HD-ADEQUATE spectrum. The black arrows denote correlations in the 2 Hz optimized LR-HSQMBC spectrum that linked the two dimethyl sprioketals to rings B and D, in addition to providing some additional cross-ring correlations, for example H7ax–C1 and H17–C11.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608522&req=5

fig03: Numbering scheme for compound  14. Bonds shown in bold red were determined from the 40 Hz optimized 1,1-HD-ADEQUATE data. The correlation from C13 to the C12 carbonyl was intentionally folded to afford better F1 digitization and to minimize data acquisition times. The red arrow denotes the 2JCC=11.3 Hz correlation observed in the 1,1-HD-ADEQUATE spectrum. The black arrows denote correlations in the 2 Hz optimized LR-HSQMBC spectrum that linked the two dimethyl sprioketals to rings B and D, in addition to providing some additional cross-ring correlations, for example H7ax–C1 and H17–C11.
Mentions: The compact nature of the product structure and the indeterminate nature of correlations in the HMBC spectrum can be circumvented by utilizing 1,1-ADEQUATE spectra to unequivocally define the carbon skeleton of these molecules. To facilitate the acquisition of the ADEQUATE data, we utilized a newly developed, partially homodecoupled 1,1-ADEQUATE (1,1-HD-ADEQUATE) experiment optimized for 1JCC=40 Hz (comparison of conventional versus 1,1-HD-ADEQUATE data is presented in the Supporting Information).22 Utilizing these data and beginning from the hydroxyl-bearing methine (C1, see Figure 3), the constitution of rings B (C1–C2–C6–C7), C (C20–C21), and D (C13–C17–C18) suggested in the Structure Elucidator calculation were confirmed. Correlations from C1 and C21 to the C9 spiroketal carbon linked rings B and C. A correlation from C20 to the C11 spiroketal carbon and an unexpected 2JCC correlation from C13 to C11 established the link between rings C and D. Density functional theory (DFT) calculations revealed an unusually large 2JCC coupling (12.8 Hz calculated; 11.3 Hz measured using a J-modulated ADEQUATE spectrum) between C13 and C11 that was visualized in the 40 Hz optimized 1,1-HD-ADEQUATE spectrum (see Supporting Information). The ADEQUATE 1JCC correlations linked the 22- and 23-methyl groups to C4 and the 24- and 25-methyl groups to C15. Additionally, 4JCH correlations in a 2 Hz optimized LR-HSQMBC23 experiment linked the two dimethylspiroketal moieties to rings B and D, respectively completing the confirmation of the structure (see Supporting Information).

Bottom Line: Here we describe rearrangements of those compounds, triggered by epoxidation of their enol ethers that completely remodel their structures, essentially turning them "inside out".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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Connecticut 55 N. Eagleville Road, U3060, Storrs, CT, 06269, USA.

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.

No MeSH data available.