Stereocontrolled Synthesis of Spiroketals: An Engine for Chemical and Biological Discovery

Abstract

Spiroketals are key structural motifs found in diverse natural products with compelling biological activities. However, stereocontrolled synthetic access to spiroketals, independent of their inherent thermodynamic preferences, is a classical challenge in organic synthesis that has limited in-depth biological exploration of this intriguing class. Herein, we review our laboratory's efforts to advance the glycal epoxide approach to the stereocontrolled synthesis of spiroketals via kinetically controlled spirocyclization reactions. This work has provided new synthetic methodologies with applications in both diversity- and target-oriented synthesis, fundamental insights into structure and reactivity, and efficient access to spiroketal libraries and natural products for biological evaluation.

Keywords: catalysis; diversity-oriented synthesis; glycal epoxide; kinetic spiroketalization; spiro compounds.

Figure 1

Spiroketals are found in a wide range of natural products as well as synthetic compounds with diverse biological activities, serving as both binding pharmacophores and rigid scaffolds.

Figure 2

Synthesis of spiroketals by spirocyclization of cyclic epoxides. (a) Wallace and Cremins’ synthesis of spiroketals from a chromenone epoxide. (b) Friesen and Sturino’s synthesis of the spiroketal core of the papulacandins via DMDO epoxidation of a glycal.

Figure 3

The glycal epoxide approach to stereocontrolled spiroketal synthesis using stereocomplementary kinetic spirocyclization reactions. * = site of potential stereochemical diversity.

Figure 4

Enantioselective synthesis of (a) threo-glycal (18) and (b) erythro-glycal (24) substrates.

Figure 5

C1-alkylation of glycals via B-alkyl Suzuki–Miyaura cross-coupling of glycal iodides with alkene-derived side chains.

Figure 6

Discovery of a methanol-induced kinetic spirocyclization with inversion of configuration. (a) Epoxidation of threo-glycal 30 (derived from the corresponding side chain acetate, not shown) and MeOH-induced spirocyclization provides contra-thermo-dynamic inversion spiroketal 32. (b) Examples of threo-series (left) and erythro-series (right) spiroketals in which TsOH equilibration does not favor the stereocomplementary retention product. ^a Remainder methylglycosides (cf. 34). ^b C3-desilylated product recovered.

Figure 7

Discovery of a Ti(Oi-Pr)₄-mediated kinetic spirocyclization with retention of configuration. (a) Mechanistic hypothesis for Lewis acid-tethered epoxide opening spirocyclization. (b) Epoxidation of erythro-glycal 42 and Ti(Oi‐Pr)₄-mediated spirocyclization provides contra-thermo-dynamic retention spiroketal 38. ^a C3-desilylated product recovered.

Figure 8

Stereocontrolled synthesis of benzannulated spiroketals. (a) Stille and B-alkyl Suzuki–Miyaura cross couplings were used to install various arene-containing C1 side chains, followed by epoxidation and kinetic spirocyclization. (b) Conformational analysis of diastereomeric benzannulated spiroketals. * = site of stereochemical diversity.

Figure 9

Possible S_N2 and S_N1 reaction mechanisms for the MeOH-induced kinetic spirocyclization of glycal epoxides leading to inversion of configuration at the anomeric carbon.

Figure 10

Mechanistic studies of (a) MeOH-induced kinetic spirocyclization reactions and (b) acid-catalyzed spiroketal equilibration. 55–59a–f: X = OMe (a), Me (b), H (c), Cl (d), CF₃ (e), NO₂ (f).

Figure 11

Proposed hydrogen-bonding mechanism for MeOH-induced kinetic spirocyclization reaction.

Figure 12

Synthesis of benzannulated spiroketals via solvent-dependent stereoselective spirocyclizations of exo-glycal epoxides.

Figure 13

The pyrrolomorpholine spiroketal family of natural products.

Figure 14

Retrosynthetic approach to acortatarins A and B.

Figure 15

Stereoselective synthesis and thermodynamic preferences of acortatarins A and B. (a) Synthesis of acortatarin B via reductive epoxide-opening spirocyclization and of acortatarin A via Hg-mediated spirocyclization. (b) Acid equilibration favors the α-anomer in both systems. (c) Acortatarins A and B exhibit distinct ring conformations to enable double anomeric stabilization.