Enantioselective Synthesis of γ,δ-Disubstituted β-Hydroxy δ-Lactones from Furans: Synthesis of (+)-Prelactone B and its C-4 Epimer

Abstract

A new method for the enantioselective synthesis of γ,δ-disubstituted β-hydroxy δ-lactones (5,6-dialkyl-5,6-dihydropyran-2-ones) is reported and exemplified for (+)-prelactone B and its C-4 epimer. Our approach is based on the ring-enlargement of suitably functionalized optically pure 4-hydroxycyclopentanones, which are readily obtained from chiral 4-hydroxycyclopent-2-enones derived from furans. The procedure is amenable to the large-scale synthesis of the title compounds.

Key words

furans - cyclopentenones - lactones - natural products - stereoselective synthesis

References

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• 12 Selected data of (-)-7: mp = 76-78 °C. [α]_D = -4.5 (c 0.8, CHCl₃).

7

The optical purity of compound (-)- 2 {[α]_D = -15.9 (c 2.0, CHCl₃)} was determined by formation of the Mosher’s ester [(S)-(+)-α-methoxy-α-trifluoromethylphenylacetic acid chloride] and comparison of the ¹⁹F and ¹H NMR spectra with those of a racemic sample obtained from rac-2. Both diastereomers showed the same δ-value for the CF₃ signal in the ¹⁹F NMR (δ = 71.95 ppm, CDCl₃, 235.3 MHz). However, integration of the α-CH₂ or the CH₃ signals in the ¹H NMR spectra (CDCl₃, 200 MHz) allowed for the determination of the ee values.

8

The optical purity (+)-5 {[α]_D = +50.1 (c 2.5, CHCl₃)} was determined by transformation into (+)- 2 followed by Mosher’s ester analysis. See text and ref. [7]

13

(+)-Prelactone B: [α]_D = +40 (c 0.7, MeOH). The spectroscopical data are in agreement with those previously reported. See ref. [3b]

14

Selected data of (+)-9. [α]_D = +30 (c 0.2, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 6.58 (dd, ³ J = 9.7 Hz, ⁴ J = 2.6 Hz, 1 H), 5.91 (dd, ³ J = 9.7 Hz, ³ J = 2.6 Hz, 1 H), 3.87 (dd, ³ J = 3.2 Hz, ³ J = 10.0 Hz, 1 H), 2.56 (m, 1 H), 1.91 (m, 1 H), 1.40 (d, ³ J = 7.2 Hz, 3 H), 1.38 (d, ³ J = 7.2 Hz, 3H), 0.91 (d, ³ J = 7.2 Hz, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 164.9, 151.8, 120.1, 87.7, 30.9, 29.1, 19.6, 16.3, 15.4 ppm.

15

The optical rotation of 1b was not determined. Extensive decomposition was observed upon attempted purification by chromatography on silica gel.

16

Selected data of (+)-8: mp = 132-134 °C. [α]_D = +18 (c 0.4, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 4.34 (dd, ³ J = 10.1 Hz, ³ = 2.5 Hz, 1 H), 4.11 (m, 1 H), 3.67 (d, J = 3.6 Hz, 2 H), 2.81 (m, 2 H), 1.13 (d, ³ J = 7.1 Hz, 3 H), 1.04 (d, ³ J = 7.1 Hz, 3 H), 0.90-1.13 (d, ³ J = 7.1 Hz, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 175.3, 83.9, 68.0, 39.2, 34.6, 28.8, 19.7, 13.9, 13.3 ppm.

17

These transformations have been carried out at 50 mmol scale.