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Review
. 2008;13(10):2570-600.
doi: 10.3390/molecules13102570.

Recent synthetic approaches toward non-anomeric spiroketals in natural products

Sylvain Favre  1 , Pierre Vogel, Sandrine Gerber-Lemaire
Affiliations
Review

Recent synthetic approaches toward non-anomeric spiroketals in natural products

Sylvain Favre et al. Molecules. 2008.

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.

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Figures

Figure 1
Figure 1
Members of the spongistatins/altohyrtins family.
Figure 2
Figure 2
Possible conformations of hemiacetals and acetals.
Figure 3
Figure 3
Epimerization of spiroacetals through acid-catalyzed heterolysis.
Figure 4
Figure 4
Possible conformers for diastereoisomeric [n,m]-spiroketals (n,m > 3).
Scheme 1
Scheme 1
Synthesis of the AB spiroketal subunit of spongistatin1 by Paterson et al.
Scheme 2
Scheme 2
Kinetically-controlled synthesis of the CD spiroketal of spongistatin 1 according to Paterson et al.
Scheme 3
Scheme 3
Synthesis of the CD spiroketals of spongistatin 1 under thermodynamic control according to Paterson et al.
Scheme 4
Scheme 4
Synthesis of AB and CD spiroketals of spongistatin 1 according to Ley et al.
Scheme 5
Scheme 5
Synthesis of an advanced precursor of the AB spiroketal of spongistatins according to Vogel et al.
Scheme 6
Scheme 6
Synthesis of tricyclic spiroketals according to Vogel et al.
Scheme 7
Scheme 7
Access to thermodynamically non stabilized [6,6]-spiroketals according to Koutek et al.
Scheme 8
Scheme 8
Access to “non-anomeric” spiroketals from carbohydrate derived precursors according to Goekjian et al.
Scheme 9
Scheme 9
Carbohydrate-based synthesis of spiroketals according to Quayle et al.
Scheme 10
Scheme 10
Spirocyclizations from glycal epoxides according to Tan et al.
Scheme 11
Scheme 11
Synthesis of spiroketals from endocyclic enol ethers according to Fuwa and Sasaki.
Scheme 12
Scheme 12
Synthesis of the spiroketals of Spirofungins A and B according to Shimizu et al.
Scheme 13
Scheme 13
Synthesis of the spiroketals of Spirofungins A and B according to Paterson et al.
Scheme 14
Scheme 14
Synthesis of the spiroketals of pteridic acids A and B according to Kuwahara et al.
Scheme 15
Scheme 15
Mechanism of cyclization according to Rychnovsky et al.
Scheme 16
Scheme 16
Synthesis of the spiroketal core of Attenol A according to Rychnovsky et al.
Scheme 17
Scheme 17
Synthesis of the spiroketal core of pectenotoxins according to Rychnovsky et al.
Scheme 18
Scheme 18
Synthesis of nonanomeric [5,6]-spiroketals according to Pihko et al.
Scheme 19
Scheme 19
Synthesis of spiroketals according to Mootoo et al.
Scheme 19
Scheme 19
Synthesis of spiroketals according to Mootoo et al.
Scheme 20
Scheme 20
Synthesis of the LM spiroketal of ciguatoxin CTX3C according to Domon et al.
Scheme 21
Scheme 21
Isolation and epimerization of okaspirodiol according to Beder et al.
Scheme 22
Scheme 22
Diverse members of the aculeatins family.
Scheme 23
Scheme 23
Synthetic approaches to Aculeatins A and B.
Scheme 24
Scheme 24
Mechanism of oxidative spirocyclization according to Wong et al.
Scheme 25
Scheme 25
Synthesis of aculeatin D and 6-epi-aculeatin D according to Baldwin et al.
Scheme 26
Scheme 26
Mechanistic proposal for the oxidative spirocyclization according to Baldwin et al.
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