Stereospecific Synthesis of Cyclohexenone Acids by [3,3]-Sigmatropic Rearrangement Route

Abstract

Herein we report a modular synthetic method for the preparation of diaryl-substituted cyclohexenone acids starting from phenyl pyruvate and suitable enones. When the reaction is carried out in alkaline tert-butanol or toluene solutions in microwave-assisted conditions mainly anti configuration products are obtained with up to 86% isolated yield. However, when the reaction is carried out in alkaline water, a mixture of products with anti and syn conformations is obtained with up to 98% overall isolated yield. Mechanistically the product with anti conformation forms by a hemiketal-oxy-Cope type [3,3]-sigmatropic rearrangement-intramolecular aldol condensation route and syn product by an intermolecular aldol condensation-electrocyclization (disrotatory type) route.

Figure 1

Utilization of [3,3]-sigmatropic rearrangement of phenylpyruvic acid under microwave-assisted conditions with (a) cinnamaldehyde into sodium salt of dicarboxylic acid. (b) 4-Phenyl-3-buten-2-one into sodium salt of cyclohexanone acid (1a) (this work).

Figure 2

Molecular structure of the anion of the sodium salt of 1a (displacement parameters are drawn at the 50% probability level). Stereocenters are RR and its enantiomer SS due to centrosymmetry (CDCC 2193907).

Figure 3

Formation of cyclohexenone acids from aromatic pyruvates and presynthesized aromatic enone (4-phenyl-3-buten-2-one). Given isolated yields are calculated from pyruvic acid.

Figure 4

(a) In situ formation of aromatic enones from acetone and aromatic aldehydes. (b) Reaction conditions: α-ketoacid (2.0 mmol), aromatic aldehyde (2.0 mmol), acetone (2.0 mmol), NaOH (3 mmol, 10 M at H₂O solution), tert-butanol (3 mL); microwave vial was heated to 135 °C in 5 min and kept at 135 °C for 30 min. Products emerge as an enantiomeric pair of RR and SS. Yields are isolated yields calculated from phenylpyruvic acid.

Figure 5

Formation of cyclohexenone acid. Enolate tautomer of pheylpyruvic acid forms hemiketal i with an aromatic enone. Intermediate i undergoes oxy-Cope type [3,3]-sigmatropic rearrangement, and after H⁺ transfer, the intermediate ii is formed. Intermediate ii undergoes intramolecular aldol condensation (A) and after OH group elimination, the final cyclohexenone acid product is obtained as sodium salt.

Figure 6

Synthesis of Cyclohexenone Acids with extended ketone (R³). Reaction conditions: α-ketoacid (2.0 mmol), benzaldehyde (2.0 mmol), ketone (2.0 mmol), NaOH (3 mmol, 10 M at H₂O solution), and tert-butanol (3 mL); microwave vial was heated to 135 °C in 5 min and kept at 135 °C for 30 min. ^aEntry 4: 2 mmol of 4-(benzyloxy)benzaldehyde instead of benzaldehyde.

Figure 7

Molecular structures of 1st (a) and 2nd (b) crystallographic independent molecule of 14A (displacement parameters are drawn at 50% probability level) (CDCC 2193908, stereocenters: 1S, 2S, 5R, 6R and 1R, 2R, 5S, 6S) and molecular structure of 15a (solvent water omitted for clarity, displacement parameters are drawn at 50% probability level) (CDCC 2193909) with RRR and its enantiomer pair SSS.

Figure 8

Alternative pathway for the formation of cyclohexenone acid (an example is for 12b). Enol form of aromatic enone undergoes aldol condensation with phenylpyruvic acid. After elimination, the intermediate iii undergoes keto–enol tautomerization into intermediate iv, followed up by electrocyclisation. Final product is obtained after keto–enol tautomerisation. As intermediate iv undergoes electrocyclization by a disrotatory pathway, the final product is obtained as a syn conformation.