Synthesis of the (±)-trans-Whiskey and Cognac Lactones via a Donor–Acceptor Cyclopropane Hemimalonate

Abstract

Aging alcohol is a timeless process that has seen little variation since the time of its invention. Molecules stored within the wood can be extracted by the alcohol to produce unique flavors. Among these molecules exist the whiskey and cognac lactones. Herein we report a short synthesis of the trans-whiskey and cognac lactones using a rearrangement of cyclopropane hemimalonates.

Key words

whiskey lactone - cognac lactone - cyclopropane - total synthesis - heterocycles - natural products

Publication History

Received: 11 June 2024

Accepted after revision: 05 August 2024

Article published online:
22 August 2024

• References

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• 20 Cyclopropanation Diethyl bromomalonate (12) (1.0 equiv.) and crotonaldehyde (1.1 equiv.) were dissolved in ethanol (9 mL) and the reaction flask was sealed and subjected to an inert atmosphere. Subsequently, 9 mL of a 2.5 M solution of EtONa in ethanol was added dropwise at 0 °C. The mixture was warmed to room temperature and left to react for 16 h. The reaction mixture was then concentrated and extracted three times with EtOAc. The combined organic layer was washed three times with water, dried with MgSO₄ and concentrated. The obtained yellow oil was purified by flash chromatography (hexanes/EtOAc, 8:2) to afford cyclopropane 13 in 44% yield. The ¹H NMR spectrum was in accordance with the literature.19
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• 22 Wittig Olefination; Typical Procedure Propyltriphenylphosphonium bromide (1.0 equiv.) was dissolved in THF. The mixture was cooled to 0 °C under an inert atmosphere in the absence of light, and t-BuOK (1.0 M in THF, 1 equiv.) was added dropwise. The mixture was left to stir for one hour and then trans-aldehyde cyclopropane 13 (0.9 equiv.) was added dropwise at 0 °C under an inert atmosphere in the absence of light. The mixture was left to react at 40 °C for 4 h. The resulting mixture was concentrated and a solution of NH₄Cl (aq) was added to a separating funnel along with the crude product which was extracted three times with EtOAc. The organic layer was washed three times with water. The organic layer was dried with MgSO₄ and concentrated before being purified by flash chromatography (hexanes/EtOAc, 7:1). This reaction afforded cyclopropane 14 in 78% yield.
• 23 Monosaponification; Typical Procedure In a 50 mL flask, alkene cyclopropane 14 (0.7 g, 1.0 equiv) was dissolved in ethanol (4.5 mL). Next, a 1.7 M solution of NaOH in water was added and the mixture was left to react for 24 h. The mixture was diluted with water and acidified to pH 2 using a 10% HCl solution. The organic layer was extracted three times with EtOAc. The combined organic layer was washed three times with water and then dried with MgSO₄ and concentrated. The resulting oil was purified via flash chromatography (hexanes/EtOAc, 8:2). This reaction yielded cyclopropane 16 (0.4797 g, 77%), the structure of which was confirmed via ¹H NMR, ¹³C NMR, and mass spectrometry. Additional sets of signals were observed in the NMR spectra due to the E-isomer as a result of the Wittig olefination and cis substituents on the cyclopropane ring.
• 24 Ring Expansion Assisted by Microwave Irradiation; Typical Procedure To a microwave vial were added cyclopropane 16 (1 equiv.) and DMF (8 mL). To the resulting mixture were added LiCl (2 equiv.) and Et₃N·HCl (1.4 equiv.). A stream of argon was gently blown over the open vial to displace the atmosphere. The vial was quickly sealed and then placed into the microwave reactor under the specified conditions. The resulting clear brown solution was placed in a separating funnel with EtOAc and water. The organic layer was washed several times to remove most of the DMF. Ice was used occasionally during washing to aid the solubility of DMF in water. The organic layer was dried with MgSO₄ and concentrated. The resulting oil was purified via flash chromatography (hexanes/EtOAc, 8:2) to afford lactone 18 in 86% yield.
• 25 Olefin Reduction; Typical Procedure Lactone 18 (1 equiv.) was added to a mixture of THF and water (1:1, 9 mL). Next, tosyl hydrazine (10 equiv.) and sodium acetate (13 equiv.) were added to the mixture, which was heated at reflux for 24 h. After cooling, the resulting mixture was placed in a separating funnel and then extracted three times with EtOAc. The combined organic layer was washed three times with water, dried with MgSO₄ and concentrated. The resulting oil was purified via flash chromatography (hexanes/EtOAc, 8:2) to afford lactone 1 (113.9 mg, 93%). The structure was confirmed via ¹H NMR and ¹³C NMR. Additional sets of signals were observed in the NMR spectra due to the cis substituents on the lactone ring.