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Synlett 2008(12): 1910-1912  
DOI: 10.1055/s-2008-1078590
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Efficient Enantioselective Synthesis of the 3C Protease Inhibitor (-)-Thysanone

Jonathan Sperry, Margaret A. Brimble*
Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland 1142, New Zealand
Fax: +64(9)3737422.; e-Mail: m.brimble@auckland.ac.nz;
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Publication History

Received 15 May 2008
Publication Date:
02 July 2008 (online)

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Abstract

The enantioselective synthesis of the 3C protease inhibitor (-)-thysanone is described. The key step is the o-toluate anion addition to an α,β-unsaturated δ-lactone. Spectroscopic analysis of the synthetic material confirms the 1R,3S stereochemistry of the natural product.

Key words

thysanone - pyranonaphthoquinone - 3C protease

    References and Notes

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16

Compound 7: yield: 89 mg, 0.26 mmol, 91%; orange solid; mp 127-128 ˚C; [α]D ²4 +102.2 (c = 0.09, CH2Cl2). IR (neat): 2976, 1654, 1590, 1555, 1431, 1305, 1275, 1164, 1104, 1038, 908, 843, 724 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.33-1.46 (m, 15 H, 2 × CHMe 2 + 3-Me), 2.19-2.27 (m, 1 H, Hax-4), 2.62-2.67 (dt, J = 2.6, 18.6 Hz, 1 H, Heq-4), 3.60-3.65 (m, 1 H, H-3), 4.43-4.50 (dt, J = 3.4, 19.0 Hz, 1 H, Hax-1), 4.57-4.63 (m, 1 H, CHMe2), 4.70-4.76 (m, 1 H, CHMe2), 4.80-4.86 (dd, J = 2.0, 18.9 Hz, 1 H, Heq-1), 6.65 (d, J = 2.3 Hz, 1 H, ArH), 7.20 (d, J = 2.3 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl3): δ = 21.2 (Me), 21.9 (2 × CHMe 2), 29.1 (CH2), 63.8 (CH2), 69.5 (CH), 70.7 (CH), 71.2 (CH), 104.9 (CH), 107.7 (CH), 114.4 (CH), 135.9 (C), 138.7 (C), 144.3 (C), 160.6 (C), 162.9 (C), 181.5 (C=O), 184.1 (C=O). MS (EI+): m/z = 344 (72) [M]+, 329 (12), 302 (30), 260 (90), 242 (20), 231 (25), 216 (100), 188 (15), 43 (49). HRMS (EI+): m/z [M]+ calcd for C20H24O5: 344.1624; found: 344.1624.

17

Compound 8: yield: 31 mg, 0.12 mmol, 95%; orange solid; mp 176-178 ˚C (Lit.5 mp 171-173 ˚C); [α]D ²4 +149.2 (c = 0.15, MeOH) {Lit5 [α]D +160.0 (c = 0.28, MeOH)}. IR (neat): 3416, 2925, 2852, 1643, 1615, 1401, 1320, 1241, 1153, 1125, 1039, 773 cm-¹. ¹H NMR (400 MHz, acetone-d 6): δ = 1.30 (d, J = 6.0 Hz, 3 H, 3-Me), 2.19-2.27 (m, 1 H, Hax-4), 2.59-2.69 (m, 1 H, Heq-4), 3.68 (m, 1 H, H-3), 4.42-4.47 (dd, J = 3.2, 18.9 Hz, 1 H, Hax-1), 4.69-4.74 (m, 1 H, Heq-1), 6.57 (d, J = 2.6 Hz, 1 H, ArH), 7.06 (m, J = 2.6 Hz, 1 H, ArH), 9.96 (br s, 1 H, OH), 12.09 (s, 1 H, OH). ¹³C NMR (100 MHz, acetone-d 6): δ = 20.7 (3-Me), 62.5 (CH2), 69.5 (CH2), 107.3 (CH), 108.8 (CH), 112.9 (CH), 134.1 (C), 142.3 (C), 142.6 (C), 164.3 (C), 164.6 (C), 182.5 (C=O), 187.1 (C=O); 1 CH2 obscured by acetone-d 6. MS (EI+): m/z =  60 (100) [M]+, 245 (10), 231 (22), 216 (60), 188 (30), 108 (22), 41 (45). HRMS (EI+): m/z [M]+ calcd for C14H12O5: 260.0685; found: 260.0685 (data consistent with literature).5

18

Compound 1 [(-)-thysanone]: yield: 7 mg, 0.027 mmol, 89%; orange solid; mp 201-202 ˚C (Lit. isolation4 mp 205-206 ˚C, Lit. synthesis5b mp 197-198 ˚C); [α]D ²4 -21.2 (c = 0.003, MeOH) {Lit. isolation4 [α]D +29 (c = 1.62, MeOH); Lit. synthesis5b [α]D -29.7 (c = 0.002, MeOH)}. IR (neat): 3368, 2925, 1648, 1615, 1412, 1327, 1279, 1174, 1011 cm-¹. ¹H NMR (300 MHz, acetone-d 6): δ = 1.30 (d, J = 6.5 Hz, 3 H, 3-Me), 2.11-2.17 (dd, J = 11.1, 18.8 Hz, 1 H, Hax-4), 2.73-2.66 (dd, J = 3.5, 19.4 Hz, 1 H, Heq-4), 4.30-4.36 (m, 1 H, H-3), 5.93 (s, 1 H, H-1), 6.62 (d, J = 2.3 Hz, 1 H, ArH), 7.07 (d, J = 2.3 Hz, 1 H, ArH), 9.73-10.31 (br s, 1 H, OH), 12.26 (s, 1 H, OH). ¹³C NMR (75 MHz, acetone-d 6): δ = 21.6 (Me), 62.2 (CH2), 86.8 (CH), 108.5 (CH), 108.8 (CH), 109.5 (C), 135.1 (C), 142.0 (C), 144.5 (C), 165.4 (C), 165.8 (C), 184.2 (C=O), 187.6 (C=O); 1 CH2 obscured by acetone-d 6. MS (EI+): m/z = 276 (4%) [M]+, 258 (50), 229 (10), 129 (10), 97 (40), 83 (50), 55 (100). HRMS (EI): m/z [M]+ calcd for C14H12O6: 276.0634; found: 276.0634 (data consistent with literature).4,5