Using singlet oxygen to synthesise a [6,6,5]-bis-spiroketal in one-pot from a simple 2,5-disubstituted furan

Abstract

Singlet oxygen (1O2) proves to be a powerful tool in mediating the one-pot synthesis of a salinomycin-type [6,6,5]-bis-spiroketal unit starting from a suitably substituted furan nucleus.

Green oxidations of furans—initiated by molecular oxygen—that give key natural product motifs

“…What remained ambiguous was if the nucleophilic opening of the ozonide by the appended dhydroxyl was going to be faster than the fragmentation pathway initiated by the hydroxyl at the a position of the furan's alkyl side chain. Indeed, when furan 38 was subjected to the 1 O 2 reaction conditions 32 followed by in situ treatment of the intermediate spirohydroperoxide 40 with Me 2 S and subsequently p-TsOH, we were gratified to see that the major product was the [6,6]-spiroketal 41 (5 : 1 mixture of anomers). Such spiroketal units are present in many biologically active natural products; such as, the terrestrially derived ionophore antibiotics salinomycin 33 and narasin, 34 as well as, the marine derived cytotoxic compounds PTX2c, PTX8-10, and PTX11c.…”

“…It is of note that when singlet oxygen was reacted with the oxidised analogue of furanol 38, furanone 42, d-spiroketal glactone 45 was isolated. 32 The reaction mechanism for this spiroketalisation/fragmentation is described in Scheme 8. Similar results have been previously observed for a furfural derivative of compound 42 by Feringa and Butselaar.…”

“…In situ reduction of this intermediate hydroperoxide followed by in situ transketalisation of the resulting bis-lactol (not shown), results in the formation of the final product a [6,6,5]-bis-spiroketal 53 (formed as a separable 2 : 1 mixture of diastereoisomers with the cis-isomer being the major one). 32 This discovery is exciting not only because yet another different motif has been produced by singlet oxygen oxidation of a furan, but because it may also prove useful as a method to access the [6,6,5]-bis-spiroketals that are present in the terrestrially derived ionophore antibiotics, salinomycin 33 and narasin. 34…”

“…With so much information gathered on exactly how hydroxysubstituted furans react, and with the proliferation of target molecules bearing more than one of our product motifs, we wondered whether it would be possible to take the cascade reaction sequence idea even further and design ambitious double sequences to be undertaken concurrently. In our first attempt, we sought to combine the methodology for the synthesis of [6,6]-spiroketals, 32 with that for the preparation of 3-keto-tetrahydrofurans 16 of PTXs 2c, 8, 9 and 11c and its substrate being relatively simple difuran 58.…”

The Achmatowicz Rearrangement – Oxidative Ring Expansion of Furfuryl Alcohols

“…A similar approach was pursued by Vassilikogiannakis and co-workers in their construction of polycyclic synthetic building blocks. 129,130…”