Synlett 2005(15): 2347-2351  
DOI: 10.1055/s-2005-872668
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Gowravaram Sabitha*, K. Bhaskar Reddy, G. S. Kiran Kumar Reddy, Narjis Fatima, J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax: +91(40)27160512; e-Mail: sabitha@iictnet.org;
Further Information

Publication History

Received 26 May 2005
Publication Date:
07 September 2005 (online)

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.

1

IICT communication number: 050506.

    References

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1

IICT communication number: 050506.

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].

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+].