First Total Syntheses of (+)-Garvensintriol and (+)-5-epi-Garvensintriol

Abstract

A concise and efficient carbohydrate-based approach for the total syntheses of (+)-garvensintriol and (+)-5-epi-garvensintriol is described in nine and six steps with 20% and 37% overall yield, respectively, starting from a known intermediate. A sequence of Grignard-assisted lactol opening with terminal alkyne, stereoselective keto reduction and oxidative lactonization are the key reactions.

Keywords

garvensintriol - goniotriol - cytotoxic - oxidative lactonization - Grignard-assisted lactol opening

References and Notes

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12

Analytical and Spectral Data of 8: white solid; mp 67 ˚C; [α]_D ^²5 +48.0 (c = 1.0, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 7.15-7.62 (m, 15 H), 4.60 (d, J = 6.0 Hz, 1 H), 4.46 (d, J = 13.6 Hz, 3 H), 4.29 (d, J = 11.3 Hz, 1 H), 3.96 (dd, J = 7.6, 2.7 Hz, 1 H), 3.48-3.72 (m, 4 H), 3.23 (br s, 1 H), 2.96 (br s, 1 H), 1.89 (br s, 1 H), 1.50-1.81 (m, 4 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 137.9, 137.5, 137.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.7, 83.2, 80.3, 74.3, 71.7, 71.5, 70.7, 62.6, 28.2, 24.9. MS (ESI): m/z = 437 [M + H]⁺.

13

Analytical and Spectral Data of 17: white solid; mp 139 ˚C; [α]_D ^²5 = -22.2 (c = 1.5, CHCl₃). IR (neat): 3395, 3029, 2960, 2911, 2859, 1746, 1453, 1396, 1259, 1086, 1028, 761, 705 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.17-7.51 (m, 15 H), 4.31-4.59 (m, 5 H), 4.19 (d, J = 11.3 Hz, 1 H), 3.99-4.12 (m, 2 H), 2.56-2.79 (m, 1 H), 2.19-2.55 (m, 2 H), 1.93-2.16 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 171.2, 137.7, 137.2, 128.6, 128.5, 128.4, 128.3, 128.2, 127.8, 127.7, 127.7, 81.8, 81.0, 74.4, 70.7, 70.5, 69.7, 26.0, 22.7. MS (ESI): m/z = 455 [M + Na]⁺.

15

Analytical and Spectral Data of 2: white solid; mp 163 ˚C; [α]_D ^²5 -10.1 (c = 0.5, EtOH). IR (neat): 3533, 3346, 2923, 1773, 1200, 1083, 1026, 897, 850, 705, 673 cm^-¹. ^¹H NMR (300 MHz, CD₃OD): δ = 7.07-7.51 (m, 5 H), 4.77 (m, 2 H), 4.60 (br s, 3 H), 3.65-3.78 (m, 2 H), 2.09-2.62 (m, 4 H). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.12-7.53 (m, 5 H), 5.35 (dd, J = 13.8, 3.8 Hz, 2 H), 4.84 (d, J = 4.9 Hz, 1 H), 4.71 (s, 2 H), 3.44-3.66 (m, 2 H), 1.95-2.48 (m, 4 H). ^¹³C NMR (75 MHz, CD₃OD): δ = 180.8, 142.2, 129.9, 128.9, 128.6, 83.1, 76.4, 75.3, 73.4, 29.8, 21.8. MS (ESI): m/z = 275 [M + Na]⁺.

17

Crystallographic data for the structure in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 755246 for 17. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]].

18

Analytical and Spectral Data of 7: white solid; mp 93 ˚C; [α]_D ^²5 +26.4 (c = 1.5, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 7.17-7.50 (m, 15 H), 4.40-4.64 (m, 4 H), 4.24 (d, J = 11.5 Hz, 1 H), 3.99 (t, J = 5.7 Hz, 1 H), 3.75 (t, J = 5.5 Hz, 1 H), 3.48 (t, J = 6.0 Hz, 2 H), 3.38 (d, J = 7.6 Hz, 1 H), 2.90 (br s, 3 H), 1.61-1.74 (m, 2 H), 1.38-1.52 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 137.9, 137.6, 137.5, 128.4, 128.3, 128.2, 128.0, 127.8, 82.6, 78.3, 74.3, 72.3, 72.0, 70.6, 62.5, 28.5, 26.5. MS (ESI): m/z = 437 [M + H]⁺.

19

Analytical and Spectral Data of 19: white solid; mp 127 ˚C; [α]_D ^²5 = +3.2 (c = 0.5, CHCl₃). IR (neat): 3464, 3030, 2923, 1736, 1494, 1452, 1354, 1239, 1201, 1090, 1055, 741, 700, 579 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.20-7.54 (m, 15 H), 4.75 (d, J = 3.6 Hz, 1 H), 4.60 (d, J = 11.7 Hz, 1 H), 4.41-4.55 (m, 3 H), 4.31 (d, J = 11.3 Hz, 1 H), 3.95 (br s, 1 H), 3.74 (dd, J = 8.7, 1.5 Hz, 1 H), 2.58-2.76 (m, 1 H), 2.88 (br s, 1 H), 2.35-2.56 (m, 1 H), 2.78-2.15 (m, 1 H), 1.57-1.78 (m, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 169.9, 137.7, 137.5, 136.3, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 80.7, 80.5, 71.3, 71.1, 71.0, 68.2, 25.4, 23.0. MS (ESI): m/z = 455 [M + Na]⁺.

20

Analytical and Spectral Data of 1: [α]_D ^²5 +70.3 (c = 1.5, MeOH). IR (neat): 3396, 2921, 1756, 1453, 1371, 1270, 1195, 1079, 1043, 917, 815, 705, 578 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.28-7.51 (m, 5 H), 4.95 (t, J = 6.2 Hz, 1 H), 4.85 (d, J = 6.6 Hz, 1 H), 3.93 (t, J = 7.6 Hz, 1 H), 3.59 (dd, J = 7.9, 1.3 Hz, 1 H), 2.58-2.75 (m, 1 H), 2.39-2.56 (m, 1 H), 2.14-2.38 (m, 2 H), 1.71 (br s, 2 H). ^¹³C NMR (75 MHz, CD₃OD): δ = 180.9, 142.2, 128.6, 128.9, 129.1, 81.3, 76.6, 75.6, 74.4, 29.5, 24.4. MS (ESI): m/z = 253 [M + H]⁺.