Synlett 2007(14): 2262-2266  
DOI: 10.1055/s-2007-985585
LETTER
© Georg Thieme Verlag Stuttgart · New York

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;
Further Information

Publication History

Received 4 June 2007
Publication Date:
14 August 2007 (online)

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.

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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.

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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.

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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.

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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.

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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.

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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.