Recent Synthetic Approaches Toward Non-anomeric Spiroketals in Natural Products

Abstract

Many natural products of biological interest contain [6,5]- and [6,6]-spiroketal moieties that can adopt various configurations, benefiting or not from anomeric conformation stabilizing effects. The spiroketal fragments are often important for the biological activity of the compounds containing them. Most stable spiroketal stereoisomers, including those benefiting from conformational anomeric effects (gauche conformers can be more stable than anti conformers because of a contra-steric stabilizing effect), are obtained easily under acidic conditions that permit acetal heterolysis (formation of tertiary oxycarbenium ion intermediates). The synthesis of less stable stereoisomers requires stereoselective acetal forming reactions that do not permit their equilibration with their most stable stereoisomers or, in the case of suitably substituted derivatives, concomitant reactions generating tricyclic products that quench the less stable spiroketal conformers. Ingenuous approaches have been recently developed for the synthesis of naturally occurring [6,6]- and [5,6]-nonanomeric spiroketals and analogues. The identification of several parameters that can influence the stereochemical outcome of spirocyclization processes has led to seminal improvements in the selective preparation of the non-anomeric isomers that are discussed herein. This review also gives an up-dated view of conformational anomeric effect which represents a small fraction of the enthalpic anomeric effect that makes gem-dioxy substituted compounds much more stable that their 1,n-dioxy substituted isomers (n > 1). Although models assuming sp3-hybridized oxygen atoms have been very popular (rabbit ears for the two non-bonding electron pairs of oxygen atom), sp2-hybridized oxygen atoms are used to describe the conformational anomeric effect.

High‐Performance Polymers from Nature: Catalytic Routes and Processes for Industry

“…The polyketide chain undergoes all late‐stage enzymatic modifications while it is still tethered either to the last sal PKS extension module at the C terminus of SalAIX or to an auxiliary enzyme 6. Stereospecific spiroketal formation in certain actinomycete polyketides—the antibiotics avermectin19 and reveromycin, for example20—proceeds by dehydrative cyclization of a dihydroxyketone precursor catalysed by a spirocyclase. However, in polyether ionophores such as salinomycin the trigger for spiroacetal formation is the ring opening of epoxide intermediates, catalysed by new epoxide hydrolase/cyclase enzymes of the MonB16 family, and neither the sal gene cluster nor any other cluster for a polyether ionophore encodes an enzyme with sequence similarity to known spirocyclases 19.…”

“…Various factors might govern the observed ratio of 2 to 3 . In many spiroacetals the configuration at the spiroacetal centre is determined by contributions from anomeric effects, dipole–dipole interactions, opportunities for intramolecular hydrogen‐bonding and steric effects 20. In the salinomycin system there is also a potential contribution from metal binding to the nascent chain, and it cannot be discounted that the specificity and kinetics of subsequent chain release affect the observed product ratios.…”

Combination of multicomponent KA2 and Pauson–Khand reactions: short synthesis of spirocyclic pyrrolocyclopentenones

“…Accordingly, with increasing interest for sp 3 -rich molecules, spirocyclic compounds are being considered valuable as molecular platforms for the generation of high-quality small molecule collections, taking advantage of the stereochemical diversity, and of their three-dimensional shape and structural bias to develop lead compounds, specifically in the field of protein-protein interactions [3][4][5][6]. Spiranic rings such as spiroketals are present in numerous natural products [7][8][9], a wide array of spirocyclic compounds are being studied in drug discovery and their chemical space have been systematically charted and characterized recently by Bajorath and co-workers ( Figure 1) [10]. This study revealed that spirocycles are found only in few approved drugs [11] and that there is a significant potential to explore the chemical space of spirocyclic scaffolds, especially in the case of the condensed ones.…”

Bimetallic Catalytic Asymmetric Tandem Reaction of β‐Alkynyl Ketones to Synthesize 6,6‐Spiroketals

“…Chiral spiroketals are key structural motifs in am ass of natural and synthetic bioactive compounds. [5,6] Among the family of spiroketals,6 ,6-spiroketal behaves as ac rucial pharmacophore in many natural products, [7] and also as an important skeleton in chiral ligands applied in various transition-metal-catalyzed asymmetric reactions (Scheme 1b). [8] In previous works,t he common strategy was to deliver chiral 6,6-spiroketal through intramolecular nucleophilic addition of alcohol to oxocarbenium ion intermediate or carbonyl group catalyzed by chiral Brønsted acids [9] or chiral iridium complexes.…”