Synthetic Studies on Azaspiracid: Synthesis of Key Intermediate for the Construction of the FGHI Ring System

J. S. Yadav; C. Venugopal

doi:10.1055/s-2007-985585

LETTER

Synthetic Studies on Azaspiracid: Synthesis of Key Intermediate for the Construction of the FGHI Ring System

J. S. Yadav*, C. Venugopal
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax: +91(40)27160512; e-Mail: yadavpub@iict.res.in;

Abstract

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Abstract

A highly stereoselective and convergent approach for the key intermediate of the FGHI ring system of azaspiracid is described. The synthesis features the desymmetrization strategy for the construction of the C27-C33 fragment, Masamune-Roush coupling conditions for the C33-C34 bond formation, and Sharpless asymmetric dihydroxylation as the key steps. One more important feature of this synthetic route is that we can synthesize other enantiomers of the FGHI ring system by changing asymmetric hydroboration conditions and valerolactone.

Key words

desymmetrization - Masamune-Roush coupling conditions - Sharpless asymmetric dihydroxylation - asymmetric hydroboration

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References

References and Notes

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13

Analytical Data for Compound 18: Liquid; [α]_D ²⁵ -20.18 (c = 2.0, CHCl₃). IR (Neat): 2958, 2172, 1671, 1613, 1513, 1462, 1427, 1249, 1172, 1110, 1036, 843 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 0.13 (s, 9 H), 0.85 (d, J = 6.7 Hz, 3 H), 0.89 (m, 1 H), 0.94 (d, J = 6.6 Hz, 3 H), 0.98 (d, J = 6.2 Hz, 3 H), 1.04 (s, 9 H), 1.49-1.61 (m, 1 H), 1.64-1.78 (m, 2 H), 2.14-2.45 (m, 6 H), 2.55-2.65 (m, 1 H), 3.25-3.32 (m, 1 H), 3.37 (dd, J = 6.4, 9.8 Hz, 1 H), 3.45-3.52 (m, 1 H), 3.76 (s, 3 H), 4.33 (q, J = 11.3, 16.6 Hz, 2 H), 6.06 (d, J = 15.8 Hz, 1 H), 6.66-6.78 (m, 1 H), 6.75 (d, J = 8.6 Hz, 2 H), 7.09 (d, J = 8.6 Hz, 2 H), 7.29-7.42 (m, 6 H), 7.59-7.65 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 0.1, 15.6, 18.1, 19.2, 19.5, 26.8, 26.9, 28.8, 33.3, 33.5, 34.5, 36.4, 45.6, 55.1, 68.7, 71.6, 81.2, 86.2, 105.2, 113.6, 127.5, 129.2, 129.5, 130.5, 132.1, 133.8, 135.5, 144.7, 159.0, 199.4. HRMS (ESI): m/z [M + NH₄]⁺ calcd for C₄₄H₆₂O₄Si₂: 728.4530; found: 728.4501.

14

Analytical Data for Compound 19: Liquid; [α]_D ²⁵ -2.584 (c = 0.6, CHCl₃). IR (Neat): 2958, 2931, 2172, 1714, 1610, 1513, 1462, 1374, 1301, 1249, 1169, 1082, 1034, 844, 758, 703, cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 0.12 (s, 9 H), 0.85 (d, J = 6.7 Hz, 3 H), 0.97 (d, J = 4.5 Hz, 6 H), 1.05 (s, 9 H), 1.30-1.39 (m, 1 H), 1.36 (s, 3 H), 1.40 (s, 3 H), 1.48-1.62 (m, 2 H), 1.68-1.90 (m, 3 H), 2.12-2.27 (m, 3 H), 2.35 (dd, J = 6.0, 18.1 Hz, 1 H), 2.74 (dd, J = 6.0, 18.1 Hz, 1 H), 3.29-3.47 (m, 2 H), 3.48-3.58 (m, 1 H), 3.76 (s, 3 H), 3.85 (d, J = 7.5 Hz, 1 H), 3.96-4.10 (m, 1 H), 4.24 (d, J = 11.3 Hz, 1 H), 4.37 (d, J = 11.3 Hz, 1 H), 6.74 (d, J = 9.0 Hz, 2 H), 7.08 (d, J = 8.3 Hz, 2 H), 7.64 (m, 6 H), 7.60-7.68 (d, J = 6.7 Hz, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 0.1, 15.8, 18.4, 19.2, 19.4, 26.2, 26.6, 26.8, 27.3, 33.2, 33.4, 35.3, 35.8, 44.0, 55.2, 68.7, 71.7, 75.3, 79.6, 85.5, 86.2, 105.1, 109.9, 113.6, 127.5, 129.1, 129.4, 131.0, 133.9, 135.6, 158.9, 208.9. HRMS (ESI): m/z [M + Na]⁺ calcd for C₄₇H₆₈O₆Si₂: 807.4452; found: 807.4474.

15

Analytical Data for Compound 20: Viscous liquid; [α]_D ²⁵ -21.804 (c = 0.6, CHCl₃). IR (KBr): 794, 1071, 1248, 1513, 2172, 2958 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 0.12 (s, 9 H), 0.78-0.86 (d, J = 6.7 Hz, 3 H), 0.87-0.93 (d, J = 6.7 Hz, 3 H), 0.94-1.00 (d, J = 6.0 Hz, 3 H), 1.04 (s, 10 H), 1.21-1.39 (m, 1 H), 1.33 (s, 3 H), 1.35 (s, 3 H), 1.40-1.88 (m, 7 H), 1.99-2.10 (dd, J = 6.7, 16.6 Hz, 1 H), 2.12-2.22 (dd, J = 5.2, 16.6 Hz, 1 H), 3.31-3.40 (dd, J = 6.7, 9.8 Hz, 1 H), 3.42-3.56 (m, 3 H), 3.58-3.65 (dd, J = 3.7, 8.3 Hz, 1 H), 3.73 (s, 3 H), 4.01-4.14 (m, 1 H), 4.24-4.32 (d, J = 10.5 Hz, 1 H), 4.34-4.42 (d, J = 11.3 Hz, 1 H), 4.48-4.56 (d, J = 12.0 Hz, 1 H), 4.58-4.65 (d, J = 11.3 Hz, 1 H), 6.64-6.71 (d, J = 8.3 Hz, 2 H), 7.03-7.10 (d, J = 8.3 Hz, 2 H), 7.17-7.27 (m, 5 H), 7.29-7.41 (m, 6 H), 7.59-7.68 (d, J = 7.5 Hz, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 0.1, 15.7, 18.5, 18.8, 19.2, 26.8, 27.0, 27.5, 27.7, 28.8, 33.4, 33.7, 35.8, 36.1, 37.1, 55.1, 68.7, 72.2, 72.4, 74.0, 75.9, 79.9, 80.0, 82.9, 85.7, 99.9, 105.8, 108.2, 113.5, 127.3, 127.5, 127.7, 128.2, 129.0, 129.4, 131.2, 133.9, 135.5, 138.5, 158.8. HRMS (ESI): m/z [M + Na]⁺ calcd for C₅₄H₇₆O₆Si₂: 899.5078; found: 899.5051.

16

Analytical Data for Compound 21: Viscous liquid; [α]_D ²⁵ -15.098 (c = 0.25, CHCl₃). IR (Neat): 3310, 2950, 2885, 2097, 1736, 1612, 1513, 1463, 1362, 1247, 1081, 837, 773, 632 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.01 (s, 3 H), 0.02 (s, 3 H), 0.06 (s, 3 H), 0.07 (s, 3 H), 0.74 (d, J = 6.5 Hz, 3 H), 0.88 (s, 9 H), 0.92 (s, 9 H), 0.94 (d, J = 6.5 Hz, 3 H), 0.97 (d, J = 6.5 Hz, 3 H), 0.85-1.08 (m, 3 H), 1.40-1.55 (m, 2 H), 1.66-1.91 (m, 4 H), 1.94-2.06 (m, 1 H), 2.07-2.17 (m, 2 H), 2.90 (dd, J = 7.3, 11.7 Hz, 1 H), 3.08-3.17 (m, 1 H), 3.33-3.41 (m, 1 H), 3.52-3.58 (m, 1 H), 3.67-3.75 (m, 1 H), 3.79 (s, 3 H), 3.93 (dd, J = 3.6, 10.2 Hz, 1 H), 4.25 (d, J = 10.2 Hz, 1 H), 4.51 (d, J = 10.9 Hz, 1 H), 4.62 (d, J = 11.7 Hz, 1 H), 4.69 (d, J = 12.4 Hz, 1 H), 6.79 (d, J = 8.7 Hz, 2 H), 7.17 (d, J = 8.7 Hz, 2 H), 7.23-7.31 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = -4.7, -4.5, -4.2, -3.1, 16.6, 17.9, 18.9, 19.2, 25.6, 25.9, 26.7, 28.7, 31.3, 31.4, 35.2, 38.6, 55.2, 57.4, 69.3, 70.4, 71.7, 71.9, 75.7, 77.8, 80.3, 83.0, 113.5, 120.4, 127.0, 127.3, 128.1, 128.7, 131.5, 139.5, 158.8. HRMS (ESI): m/z [M + Na]⁺ calcd for C₄₄H₇₃N₃O₅Si₂: 802.4986; found: 802.4968.

17

Analytical data for Compound 22: Liquid; [α]_D ²⁵ -47.136 (c = 1.1, CHCl₃). IR (Neat): 3417, 2119, 1618, 1389, 1204, 772 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.95 (d, J = 6.5 Hz, 3 H), 1.06 (d, J = 6.5 Hz, 3 H), 1.09 (d, J = 6.5 Hz, 3 H), 1.23-1.36 (m, 2 H), 1.45-1.71 (m, 3 H), 1.74-2.05 (m, 3 H), 2.18 (dd, J = 2.1, 5.8 Hz, 2 H), 2.61 (m, 1 H), 2.68 (d, J = 5.8 Hz, 2 H), 3.07-3.21 (m, 2 H), 3.40 (m, 1 H), 3.64-3.71 (m, 1 H), 3.74 (s, 0.5 H), 3.85 (s, 0.5 H), 4.07-4.15 (m, 1 H), 4.52 (d, J = 11.7 Hz, 1 H), 4.68 (d, J = 11.7 Hz, 1 H), 7.27-7.41 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 17.0, 17.8, 19.7, 25.9, 28.8, 31.4, 36.2, 37.0, 44.3, 44.5, 57.6, 68.3, 69.7, 71.9, 73.8, 78.6, 82.5, 127.9, 128.2, 128.5, 137.8, 213.9. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₃₅N₃O₄: 452.2525; found: 452.2512.

18

Analytical data for Compound 5 (Major Diastereomer): Liquid; [α]_D ²⁵ -18.801 (c = 0.6, CHCl₃). IR (Neat): 3418, 2925, 2097, 1665, 1622, 1553, 1527, 1383, 1111, 616 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.92 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 6.2 Hz, 3 H), 1.01 (d, J = 7.1 Hz, 3 H), 1.39 (s, 1 H), 1.54-1.73 (m, 3 H), 1.77-2.05 (m, 4 H), 2.07-2.23 (m, 4 H), 2.55 (d, J = 7.1 Hz, 1 H), 3.07 (dd, J = 6.2, 11.6 Hz, 1 H), 3.18 (s, 3 H), 3.24 (dd, J = 6.2, 11.6 Hz, 1 H), 3.85-3.91 (m, 1 H), 3.95 (dd, J = 3.5, 6.2 Hz, 1 H), 4.37-4.44 (m, 1 H), 4.65 (d, J = 11.6 Hz, 1 H), 4.77 (d, J = 11.6 Hz, 1 H), 7.27-7.40 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 16.3, 18.8, 19.2, 26.2, 28.7, 32.1, 32.4, 36.9, 37.0, 43.3, 47.7, 57.5, 69.6, 72.4, 72.5, 76.2, 82.8, 83.2, 111.2, 127.6, 127.9, 128.3, 138.5. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₅H₃₇N₃O₄: 466.2681; found: 466.2680.