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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.


Synthesis of macrocycle 4 via tandem cycloisomerization–dimerization followed by ozonolysis.
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fig01: Synthesis of macrocycle 4 via tandem cycloisomerization–dimerization followed by ozonolysis.

Mentions: We recently reported the discovery of a phosphine-mediated cycloisomerization of alkynyl hemiketals (e.g., 1 to 2 in Figure 1). For terminal alkynes, enone intermediate 2 rapidly dimerized to give a spiroketal product, 3.13 The reaction led to relatively complex spiroketals from starting materials that were readily accessible. With DOS in mind,14 we took the opportunity to further diversify these small molecules through subsequent reactions. One obvious choice was to cleave the carbon–carbon double bond through oxidation to produce new macrocycles.15 Conversion of spiroketal 3 to macrocycle 4 under various oxidation conditions (O3, NaIO4) proceeded in modest (23–44 %) yields.16 With an eye toward a step-wise oxidative cleavage of the bond, epoxidation of 2 with m-chloro peroxybenzoic acid (mCPBA) was conducted. To our surprise, the physical data for the isolated material (76 %, Table 1) was inconsistent with a product of simple epoxidation or even epoxidation–hydrolysis to give 4.


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)

Synthesis of macrocycle 4 via tandem cycloisomerization–dimerization followed by ozonolysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: Synthesis of macrocycle 4 via tandem cycloisomerization–dimerization followed by ozonolysis.
Mentions: We recently reported the discovery of a phosphine-mediated cycloisomerization of alkynyl hemiketals (e.g., 1 to 2 in Figure 1). For terminal alkynes, enone intermediate 2 rapidly dimerized to give a spiroketal product, 3.13 The reaction led to relatively complex spiroketals from starting materials that were readily accessible. With DOS in mind,14 we took the opportunity to further diversify these small molecules through subsequent reactions. One obvious choice was to cleave the carbon–carbon double bond through oxidation to produce new macrocycles.15 Conversion of spiroketal 3 to macrocycle 4 under various oxidation conditions (O3, NaIO4) proceeded in modest (23–44 %) yields.16 With an eye toward a step-wise oxidative cleavage of the bond, epoxidation of 2 with m-chloro peroxybenzoic acid (mCPBA) was conducted. To our surprise, the physical data for the isolated material (76 %, Table 1) was inconsistent with a product of simple epoxidation or even epoxidation–hydrolysis to give 4.

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.