First Enantioselective Synthesis of (-)-(2S,6S)-(6-Ethyltetrahydropyran-
2-yl)formic Acid

Abstract

We describe in this letter the first enantioselective synthesis of (-)-(2S,6S)-(6-ethyltetrahydropyran-2-yl)formic acid (2) in five steps (30% overall yield, 87% ee), from the commercial chiral template (R)-2,3-isopropylideneglyceraldehyde (4). The two stereogenic centers in 2 were controlled by diastereoselective ­Barbier allylation of 4 in aqueous media and an efficient Prins ­cyclization reaction between 5 with propanal.

enantioselective synthesis - antinociceptive activity - tetrahydropyran - Prins cyclization - Barbier reaction - (R)-2,3-O-isopropylideneglyceraldehyde

References

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11b

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12a The diastereoisomeric purity of 5 was determined through ¹³C NMR spectroscopy (ref.⁹), and its enantiomeric purity through comparison of its optical rotation with literature reference data: [α]_D 15.0 (92% de and 87% ee). See: Roush WH. Walts AE. Hoong LK. J. Am. Chem. Soc.  1985,  107:  8186 

12b

Spectroscopical data of anti-5: ¹H NMR (200 MHz, CDCl₃): δ = 5.92-5.75 (m, 1 H), 5.20 (m, 1 H), 5.10 (m, 1 H), 4.05-3.87 (m, 3 H), 3.77 (dq, J = 8.8, 4.4 Hz, 1 H), 2.43-2.10 (m, 2 H), 2.00 (d, J = 3.4 Hz, 1 H), 1.43 (s, 3 H), 1.37 (s, 3 H). ¹³C NMR (50 MHz, CDCl₃): δ = 133.8, 118.1, 108.9, 77.9, 70.2, 65.0, 37.4, 26.3, 25.0. MS (70 eV): m/z (%) = 59 (100), 73 (35), 101 (72), 114 (2.5), 131 (7), 157 (45). IR (KBr, neat): 3444, 3078, 2987, 2936, 2899, 1642, 1456, 1435, 1381, 1254, 1215, 1066, 917, 854 cm^-1.

13

Experimental Procedure for Diastereoisomeric Enrichment of anti -5.
To a stirred solution of the diastereoisomeric mixture of 5 (3.0 g, 17.4 mmol) in 45 mL of dry acetone, under Ar atmosphere, is added in one portion 0.2 g of p-TSA (1.04 mmol). The reaction is left stirring at -15 °C for 48 h, then the solvent is evaporated under reduced pressure and the residue submitted to flash column chromatography yielding 1.6 g (71%) of diastereoisomeric enriched 5 (92% de).

14

To a stirred solution of 5 (0.5 g, 2.9 mmol) in dry CH₂Cl₂ (5 mL), under an Ar atmosphere, is added propanal (0.5 mL, 6 mmol). The reaction mixture is cooled in an ice bath and then a solution of SnBr₄ (1.25 g in 3 mL of dry CH₂Cl₂) is slowly added. The reaction is monitored through TLC and then quenched with 4 mL of a sat. solution of NaHCO₃ followed by 5 mL of EtOAc. The mixture is left stirring for more 40 min. The aqueous phase is then extracted with EtOAc (3 × 5 mL). The combined organic phases are dried with anhyd NaSO₄ and then concentrated. The crude product is filtered through silica (eluted with 20% EtOAc-hexanes) furnishing 0.55 g of 8 as a mixture of four diastereomers.

15

Spectroscopical data of 9: [α]_D -5.5 (c 2.9, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 3.8 (m, 2 H), 3.6 (m, 1 H), 3.4 (dq, 1 H, J = 11.09, 5.12, 1.83 Hz), 3.20 (m, 2 H), 2.40 (br s, 1 H), 1.90 (m, 1 H), 1.20-1.70 (m, 7 H), 0.90 (t, 3 H, J = 7.33 Hz). ¹³C NMR (50 MHz, CDCl₃): δ = 79.9, 79.5, 73.5, 63.7, 30.9, 29.1, 27.2, 23.0, 9.7. MS (70 eV): m/z (%) = 143 (9), 131 (4), 113 (57), 95 (98), 69 (61), 55 (100). IR (KBr, neat): 3390, 2934, 2856, 1460, 1441, 1085, 1045 cm^-1.

16

Spectroscopical data of 2 [α]_D -45.2 (c 0.53, CHCl₃, 87% ee). ¹H NMR (200 MHz, CDCl₃): δ = 4.0 (dd, 1 H, J = 9.1, 2.7 Hz), 3.4 (m, 1 H), 2.40 (m, 1 H), 2.00 (m, 2 H), 1.00-1.80 (m, 6 H), 0.99 (t, 3 H, J = 7.2 Hz). ¹³C NMR (50 MHz, CDCl₃): δ = 147.3, 79.5 75.8, 29.9, 28.7, 28.3, 23.0, 9.6. MS (70 eV): m/z (%) = 129 (10), 113 (77), 101 (33), 95 (100). IR (KBr, neat): 3412, 2961, 2938, 2877, 2861, 1732, 1651, 1441, 1383, 1203, 1105, 918 cm^-1.