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Synlett 2010(3): 457-461  
DOI: 10.1055/s-0029-1219191
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Stereoselective Total Synthesis of (-)-Ovalicin

J. S. Yadav*, P. Narayana Reddy, B. V. Subba Reddy
Division of Organic Chemistry I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax: +91(40)27160512; e-Mail: yadavpub@iict.res.in;
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Publication History

Received 28 August 2009
Publication Date:
11 January 2010 (online)

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Abstract

A new synthetic route for epoxyketone 3 is described, which is a key intermediate in Barton’s synthesis of ovalicin (1), a powerful anti-angiogenetic inhibitor, from commercially available d-ribose. The key reactions involved in this synthesis are ring-closing metathesis, Rubottom oxidation and Corey-Chaykovsky epoxidation. The subsequent transformations are carried out according to Barton’s strategy to complete the total synthesis of (-)-ovalicin.

Keywords

ribose - Rubottom oxidation - ring-closing metathesis - Corey-Chaykovsky epoxidation

    References and Notes

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19

Spectroscopic Data for Selected Products:
(3a S ,7a R )-2,2-Dimethyl-3a,4,5,7a-tetrahydro-1,3-benzodioxol-4-ol (8): major isomer, brown solid; mp 88-
90 ˚C; [α]D -18.1 (c = 1, CHCl3). IR (neat): 3440, 2923, 1648, 1373, 1075 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.37 (s, 3 H), 1.40 (s, 3 H), 1.96 (d, J = 8.7 Hz, 1 H), 2.25 (m, 2 H), 3.83 (m, 1 H), 4.34 (m, 1 H), 4.56 (s, 1 H), 5.69 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 126.6, 126.0, 109.4, 76.1, 73.4, 67.1, 28.7, 27.3, 26.3. MS (ESI): m/z = 193 [M + Na]+.
(3a S ,7a R )-2,2-Dimethylperhydro-1,3-benzodioxol-4-ol (9): mixture of isomers, yellow oil; [α]D -26.6 (c = 1, CHCl3). IR (neat): 3446, 2937, 1376, 1032, 876 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.35 (s, 3 H), 1.50 (s, 3 H), 1.54-1.80 (m, 6 H), 2.07 (s, 1 H), 3.68-3.76 (m, 1 H), 4.14-4.22 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 108.5, 81.5, 75.7, 74.4, 72.6, 68.2, 30.4, 28.3, 27.6, 27.5, 27.0, 26.7, 26.2, 25.6, 18.6, 17.4. MS (ESI): m/z = 195 [M + Na]+.
(3a R,7a R )-2,2-Dimethylperhydro-1,3-benzodioxol-4-one (10): white solid; mp 112-114 ˚C; [α]D -63.2 (c = 1, CHCl3). IR (neat): 3447, 2937, 1726, 1376, 1220 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 1.36 (s, 3 H), 1.41 (s, 3 H), 1.82-2.06 (m, 3 H), 2.14-2.38 (m, 2 H), 2.43-2.56 (m, 1 H), 4.22 (d, J = 5.4 Hz, 1 H), 4.53-4.61 (m, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 208.4, 109.4, 79.1, 39.9, 26.9, 26.7, 25.8, 20.2, 17.4. MS (ESI): m/z = 171 [M + H]+.
(3a R ,5 R ,7a R )-5-[1-( tert -Butyl)-1,1-diphenylsilyl]oxy-2,2-dimethylperhydro-1,3-benzodioxol-4-one (13): colorless liquid; [α]D -62.4 (c = 1.7, CHCl3). ¹H NMR (300 MHz, CDCl3): δ = 1.08 (s, 9 H), 1.36 (s, 3 H), 1.37 (s, 3 H), 1.73-1.92 (m, 2 H), 1.95-2.05 (m, 1 H), 2.41-2.55 (m, 1 H), 4.18 (dd, J = 2.2, 3.7 Hz, 1 H), 4.61 (m, 1 H), 4.82 (d, J = 5.2 Hz, 1 H), 7.31-7.46 (m, 6 H), 7.50-7.54 (m, 2 H), 7.58-7.62 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 206.4, 135.5, 135.4, 134.7, 132.9, 130.1, 129.5, 127.8, 127.6, 109.6, 78.5, 77.8, 76.3, 29.2, 26.9, 26.8, 26.5, 26.1, 20.6. MS (ESI): m/z = 447 [M + Na]+.
(7 R ,8 R ,11 R )-11-[1-( tert -Butyl)-1,1-diphenylsilyl]oxy-1,5-dithiaspiro[5.5]undecane-7,8-diol (14): semi solid; [α]D +16.7 (c = 1.3, CHCl3). IR (neat): 3446, 2925, 2854, 1109, 702 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 1.09 (s, 9 H), 1.32-2.16 (m, 7 H), 2.56-2.70 (m, 1 H), 2.75-2.89 (m, 2 H), 2.92-3.11 (m, 2 H), 3.91 (dd, J = 3.8 Hz, 1 H), 4.08-4.22 (m, 2 H), 7.28-7.47 (m, 6 H), 7.65-7.81 (m, 4 H). ¹³C NMR (75 MHz, CDCl3): δ = 136.5, 135.5, 132.7, 132.2, 130.1, 129.6, 127.8, 127.4, 75.0, 74.4, 73.1, 29.6, 29.2, 27.2, 26.8, 23.3, 19.2. MS (ESI): m/z = 497 [M + Na]+.
(7 R ,8 R ,11 R )-7-(Acetyloxy)-11-[1-( tert -butyl)-1,1-diphenylsilyl]oxy-1,5-dithiaspiro[5.5]undec-8-yl Acetate (15): semi solid; [α]D +25.2 (c = 1, MeOH). IR (neat): 3451, 2929, 2856, 1743, 1245, 703 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.10 (s, 9 H), 1.24-1.61 (m, 5 H), 1.93 (s, 3 H), 1.96 (s, 3 H), 2.02-2.16 (m, 1 H), 2.50-2.60 (m, 1 H), 2.74-2.84 (m, 1 H), 2.98-3.10 (m, 1 H), 3.14-3.26 (m, 1 H), 3.88 (dd, J = 4.5, 12.0 Hz, 1 H), 5.53-5.62 (m, 1 H), 5.77 (d, J = 1.5 Hz, 1 H), 7.31-7.41 (m, 6 H), 7.68-7.73 (m, 2 H), 7.76-7.81 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 136.3, 136.0, 135.2, 134.7, 129.6, 129.4, 127.5, 127.3, 73.4, 69.1, 60.5, 26.9, 26.5, 25.6, 24.8, 23.5, 20.8, 20.6, 19.6, 18.9. MS (ESI): m/z = 581 [M + Na]+.
(7 R ,8 R )-7-(Acetyloxy)-11-oxo-1,5-dithiaspiro[5.5]undec-8-yl Acetate (17): white solid; mp 82-84 ˚C; [α]D +163.1
(c = 1, CHCl3). IR (neat): 2924, 2854, 1747, 1236, 721 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 1.95-2.07 (m, 6 H), 2.11 (s, 3 H), 2.13-2.31 (m, 1 H), 2.41-2.55 (m, 1 H), 2.66-2.84 (m, 2 H), 2.91-3.24 (m, 3 H), 5.72-5.83 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 200.9, 170.0, 169.5, 73.9, 67.5, 59.6, 33.8, 26.9, 26.4, 24.6, 24.0, 20.7, 20.4. MS (ESI): m/z = 319 [M + H]+.
(10 R,11 R )-10,11-Dihydroxy-1,5-dithiaspiro[5.5]undecan-7-one (18): white solid; mp 101-103 ˚C; [α]D +145.9 (c = 1, CHCl3). IR (neat): 3446, 2924, 1705, 1219, 771 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.25 (s, 1 H), 1.52-1.69 (m, 1 H), 1.76-1.93 (m, 1 H), 2.03-2.26 (m, 2 H), 2.34-2.44 (m, 1 H), 2.60-2.70 (m, 3 H), 2.87-3.03 (m, 1 H), 3.18-3.32 (m, 1 H), 3.52 (d, J = 9.0 Hz, 1 H), 3.70-3.81 (m, 1 H), 4.08-4.18 (m, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 202.7, 78.9, 68.4, 67.0, 33.3, 27.3, 26.9, 26.1, 24.2. MS (ESI): m/z = 257 [M + Na]+.
(10 R,11 R )-10-[1-( tert -Butyl)-1,1-dimethylsilyl]oxy-11-hydroxy-1,5-dithiaspiro[5.5]undecan-7-one (19): semi solid; [α]D +93 (c = 1.25, CHCl3). IR (neat): 3504, 2928, 2855, 1709, 1109, 837 cm-¹. ¹H NMR (300 MHz, CDCl3):
δ = 0.12 (s, 3 H), 0.15 (s, 3 H), 0.92 (s, 9 H), 1.42 (s, 1 H), 1.74-1.93 (m, 2 H), 2.01-2.21 (m, 2 H), 2.54-2.68 (m, 3 H), 2.87-3.00 (m, 2 H), 3.26-3.38 (m, 1 H), 3.97 (d, J = 2.2 Hz, 1 H), 4.35-4.42 (m, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 207.2, 78.2, 77.7, 75.6, 30.8, 29.4, 27.0, 26.1, 25.5, 20.4, 17.9, -5.12, -5.17. MS (ESI): m/z = 371 [M + Na]+.
tert -Butyl[(3 S ,10 R ,11 R )-10-methoxy-1-oxa-5,9-dithiadispiro[2.0.5.4]tridec-11-yl]oxydimethylsilane (21): yellow oil; [α]D -21.9 (c = 0.35, CHCl3). IR (neat): 3373, 2922, 2853, 2365, 1466, 756 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 0.09 (s, 3 H), 0.10 (s, 3 H), 0.90 (s, 9 H), 1.53-2.19 (m, 5 H), 2.37-2.74 (m, 4 H), 3.21-3.40 (m, 2 H), 3.42-3.54 (m, 2 H), 3.56 (s, 3 H), 4.17-4.29 (m, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 88.6, 83.0, 71.3, 69.8, 52.7, 32.0, 31.1, 30.6, 29.6, 29.3, 28.1, 27.4, 25.8, 24.5, -4.7.
MS (ESI): m/z = 399 [M + Na]+.
(3 S ,5 R ,6 R )-6-[1-( tert -Butyl)-1,1-dimethylsilyl]oxy-5-methoxy-1-oxaspiro [2.5]octan-4-one (3): yellow oil; [α]D -1.20 (c = 1, CH2Cl2). IR (neat): 2922, 2852, 1737, 1461, 762 cm-¹. ¹H NMR (200 MHz, CDCl3) : δ = 0.07 (s, 3 H), 0.08 (s, 3 H), 0.92 (s, 9 H), 1.40-1.60 (m, 1 H), 2.00-2.20 (m, 2 H), 2.40-2.60 (m, 1 H), 2.77 (d, J = 4.7 Hz, 1 H), 3.29 (d, J = 4.7 Hz, 1 H), 3.44 (s, 3 H), 3.98 (d, J = 2.5 Hz, 1 H), 4.44 (m, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 202.4, 87.5, 72.3, 60.7, 58.5, 51.4, 28.9, 27.1, 25.9, 18.3, -4.4, -5.0. MS (ESI): m/z = 309 [M + Na]+.
(-)-Ovalicin (1): white solid; mp 94-95 ˚C; [α]D -112 (c = 0.2, CHCl3). IR (neat): 3438, 2923, 2853, 1728, 1627, 1459, 1216, 761 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 1.37 (s, 3 H), 1.41-1.45 (m, 1 H), 1.66 (s, 3 H), 1.75 (s, 3 H), 2.12-2.18 (m, 1 H), 2.30-2.45 (m, 2 H), 2.61-2.71 (m, 2 H), 2.73 (d, J = 4.2 Hz, 1 H), 2.90 (t, J = 6.3 Hz, 1 H), 3.10 (d, J = 4.2 Hz, 1 H), 3.14 (s, 1 H), 3.57 (s, 3 H), 4.23 (s, 1 H), 5.18 (t, J = 6.6 Hz, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 206.8, 135.7, 118.2, 86.3, 78.8, 60.7, 60.5, 59.5, 57.0, 51.5, 36.9, 30.5, 27.2, 25.9, 18.2, 14.6. MS (ESI): m/z = 319 [M + Na]+.