TMSI-Mediated Prins Cyclization: Diastereoselective Synthesis of 4-Iodo-2,6-Disubstituted Tetrahydropyrans and Synthesis of (±)-Centrolobine [1]

Abstract

The reaction of aldehydes with homoallyl alcohols in the presence of TMSI generated in situ from TMSCl and NaI produced 4-iodo-tetrahydropyrans in good yields as a mixture of diastereo­isomers, which are separated and characterized. These iodo pyrans are reported for the first time. This methodology was extended to the synthesis of (±)-centrolobine.

Prins reaction - iodotetrahydropyrans - homoallyl alcohols - TMSI - (±)-centrolobine

References

1

IICT communication number: 050506.

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11

Experimental.
To a stirred solution of homoallyl alcohol 1c (1 g, 5.7 mmol), anisaldehyde (2c, 773 mg, 5.7 mmol), and NaI (852 mg, 5.7 mmol) in dry MeCN (10mL) was added TMSCl (0.72 mL, 5.7 mmol) dropwise at r.t. After the reaction was complete as indicated by TLC (see Table [1] ), the reaction mixture was taken up into Et₂O, washed with Na₂S₂O₃ solution, brine and dried over anhyd Na₂SO₄. Evaporation of the solvent afforded a crude product, which was further purified by column chromatography (hexane-EtOAc, 98: 2). The diastereomers 3c and 4c were obtained in 7.5:2.5 ratio, respectively, and in a total yield of 92%.
Representative Spectral Data:
Compound 3c: ¹H NMR (400 MHz, CDCl₃): δ = 7.28 (dd, J _H9-H10 = 8.6 Hz, J _H9-H9 = 2.2 Hz, 2 H, H-9), 6.89 (dd,
J _H9-H10 = 8.6 Hz, J _H9-H9 = 2.2 Hz, 2 H, H-10), 7.26-7.17 (m, 5 H, CH₂-Ph), 4.37 (tt, J _H4-H5-Pro-R = 4.2 Hz, J _H4-H3-Pro-S = 4.2 Hz, J _H4-H5-Pro-S = 12.3 Hz, J _H4-H3-Pro-R = 12.3 Hz,1 H, H-4), 4.29 (dd, J _H2-H3vPro-S = 2.1 Hz, J _H2-H3-Pro-R = 11.2 Hz, 1 H, H-2), 3.81 (s, 3 H, OMe), 3.44 (dddd, J _H6-H5-Pro-R = 2.1 Hz, J _H6-H5-Pro-S = 10.8 Hz, J _H6-H7 = 8.3 Hz, J _{H6-H7 ′} = 4.2 Hz, 1 H, H-6), 2.79 (m, 1 H, H-8), 2.68 (m,1 H, H-7′), 2.54 (ddd, J _H3-Pro-S-H2 = 2.1 Hz, J _H3-Pro-S-H4 = 4.2 Hz, J _{H3-Pro-S-H3-Pro-R} = 13.1 Hz, 1 H, H₃-Pro-S), 2.37 (ddd, J _H4-H5-Pro-R = 4.2 Hz, J _H6-H5-Pro-R = 2.1 Hz, J _{H5-Pro-S-H5-Pro-R} = 12.9 Hz, J _{H3-Pro-S-H5-Pro-R} = 2.1 Hz, 1 H, H₅-Pro-R), 2.19 (ddd,
J _H3-Pro-R-H4 = 12.3 Hz, J _{H3-Pro-S-H3-Pro-R} = 13.1 Hz,
J _H2-H3-Pro-R = 11.2 Hz, 1 H, H₃-Pro-R), 2.04 (ddd, J _{H5-Pro-S-H5-Pro-R} = 12.9 Hz, J _H5-Pro-S-H4 = 12.3 Hz, J _H5-Pro-S-H6 = 10.8 Hz, 1 H, H₅-Pro-S), 1.94 (m, 1 H, H-7), 1.77 (m,1 H, H-7′). ¹³C NMR (300 MHz, CDCl₃): δ = 22.39, 31.28, 37.14, 44.89, 47.01, 55.26, 77.83, 79.99, 113.78, 125.78, 126.96, 128.31, 128.43. MS: m/z = 421 [M + H], 295 [M - I].
Compound 4c: ¹H NMR (400 MHz, CDCl₃): δ = 7.28 (dd, J _H9-H10 = 8.7 Hz, J _H9-H9 = 2.2 Hz, 2 H, H-9), 7.26-7.18 (m, 5 H, -CH₂-Ph), 6.87 (dd, J _H9-H10 = 8.7 Hz, J _H9-H9 = 2.2 Hz, 2 H, H-10), 4.93 (dddd, J _H4-H5-Pro-R = 4.6 Hz, J _H4-H5-Pro-S = 3.7 Hz, J _H4-H3-Pro-S = 4.8 Hz, J _H4-H3-Pro-R = 3.4 Hz, 1 H, H-4), 4.82 (dd, J _H2-H3-Pro-R = 10.8 Hz, J _H2-H3-Pro-S = 2.3 Hz, 1 H, H-2), 4.01 (m, 1 H, H-6), 3.80 (s, 3 H, OMe), 2.84 (m, 1 H, H-8), 2.71 (m, 1 H, H-8′), 2.21 (ddd, J _H3-Pro-S-H2 = 2.3 Hz,
J _H3-Pro-S-H4 = 4.8 Hz, J _{H3& ndash;Pro-S-H3-Pro-R} = 14.8 Hz, 1 H, H₃-Pro-S, 1 H, H₃-Pro-S), 2.05 (ddd, J _H4-H5-Pro-R = 4.6 Hz, J _H6-H5-Pro-R = 2.3 Hz, J _{H5-Pro-S-H5-Pro-R} = 14.6 Hz, 1 H, H₅-Pro-R), 1.96 (m, 1 H, H-7), 1.82 (m, 1 H, H-7′), 1.76 (ddd, J _H2-H3-Pro-R = 10.8 Hz, J _{H3-ProS-H3-Pro-R} = 14.8 Hz,
J _H4-H3-Pro-R = 3.4 Hz, 1 H, H₃-Pro-R), 1.63 (ddd,
J _{H5-Pro-R-H5-Pro-S} = 14.6 Hz, J _H4-H5-Pro-S = 3.7 Hz,
J _H6-H5-Pro-S = 10.5 Hz, 1 H, H₅-Pro-S). ¹³C NMR (300 MHz, CDCl₃): δ = 30.44, 31.87, 37.38, 40.49, 42.59, 55.25, 73.33, 75.05, 96.23, 113.82, 125.82, 127.18, 128.39, 128.47. MS: m/z = 421 [M + H], 295 [M - I].

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13

(±)-Centrolobine.
White solid, mp 87-88 °C (lit. [12] 85-87 °C). ¹H NMR (300 MHz, CDCl₃): δ = 7.28 (d, J = 8.18 Hz, 2 H), 6.95 (d, J = 8.18 Hz, 2 H), 6.83 (d, J = 8.92 Hz, 2 H), 6.62 (d, J = 8.18 Hz, 2 H), 5.40 (br s, OH), 4.28 (dd, J = 2.20, 11.15 Hz, 1 H), 3.78 (s, 3 H), 3.32-3.50 (m, 1 H), 2.55-2.75 (m, 2 H), 1.55-1.95 (m, 6 H), 1.22-1.48 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 159.0, 153.5, 135.7, 134.2, 129.6, 126.9, 114.5, 113.4, 79.5, 77.8, 55.2, 38.4, 33.2, 31.5, 30.7, 24.8. MS: m/z = 312 [M⁺].