Towards the Total Synthesis of Thuggacin A: Synthesis of the C13-C25 Fragment Bearing All-syn Stereocenters

Abstract

The diastereoselective synthesis of the key C13-C25 fragment of thuggacin A is described. Two Evans aldolization steps and a diastereoselective addition of an allenylstannane control the required all-syn configuration of the five contiguous stereocenters.

Key words

macrolide - thuggacin - antituberculosis - aldolization - allenylstannane

References and Notes

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15

Selected Data for Compound 12
[α]_D ^²³.5 50 (c 1.20, CHCl₃). IR (film): 3490, 2968, 2929, 2870, 1780, 1711, 1612, 1514, 1391, 1249, 1111, 1034, 702, 513 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.51 (m, 6 H, SiCH₂CH₃), 0.84 (t, J = 7.8 Hz, 9 H, SiCH₂CH₃), 0.98 (d, J = 6.7 Hz, 3 H, H-12), 1.61 (m, 10 H, H-10, H-13, H-14, H-4), 2.29 (d, J = 6.5 Hz, 1 H, OH), 2.51 (dd, J = 10.1, 13.1 Hz, 1 H, H-16), 3.12 (dd, J = 2.6, 13.1 Hz, 1 H, H-16), 3.70 (s, 3 H, OCH₃), 3.78 (m, 1 H, H-3), 3.84 (d, J = 9.0 Hz, 1 H, H-5), 4.07 (m, 2 H, H-5), 4.52 (m, 3 H, H-11, H-4), 5.20 (d, J = 4.6 Hz, 1 H, H-2), 5.28 (q, J = 6.1 Hz, 1 H, H-9), 5.70 (s, 1 H, H-7), 6.80 (d, J = 7.8 Hz, 5 H, HAr), 7.16 (d, J = 7.8 Hz, 5 H, HAr), 7.20 (m, 5 H HAr). ^¹³C NMR (100 MHz, CDCl₃): δ = 4.81 (SiCH₂CH₃), 6.88 (SiCH₂CH₃), 9.95 (C-12), 12.32 (C-10), 13.59 (C-14), 16.43 (C-13), 37.49 (C-6′), 40.26 (C-4), 55.20 (COCH₃), 55.59 (C-4′), 66.58 (C-5′), 72.03 (C-2), 72.97 (C-11), 79.27 (C-5), 81.78 (C-3), 113.80 (CAr), 124.16 (C-9), 127.34-133.06 (CAr), 131.93 (C-7), 135.02 (C-6), 135.20 (C-8), 153.03 (C-2′), 159.60 (CAr), 171.13 (C-1). HRMS (ESI^-): m/z calcd for C₃₇H₅₃NO₇SiH: 650.3513; found: 650.3500.

17

Selected Data for Compound 14
[α]_D ^²³.5 -99.3 (c 2.9, CHCl₃). IR (film): 347, 2966, 2933, 2878, 1756, 1613, 1515, 1456, 1382, 1303, 1249, 1130, 1035, 1001, 824, 515, 419 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.91 (d, J = 7.2 Hz, 3 H, H-11), 1.68 (d, J = 6.9 Hz, 3 H, H-10), 1.71 (s, 3 H, H-13), 1.73 (s, 3 H, H-12), 2.19 (qdd, J = 7.2, 2.8, 2.4 Hz, 1 H, H-4), 2.40 (d, J = 2.3 Hz, 1 H, HOH), 3.66 (dt, J = 7.8, 2.4 Hz, 1 H, H-3), 3.81 (s, 3 H, HOCH₃), 4.09 (d, J = 8.0 Hz, 1 H, H-2), 4.55 (d, J = 11.2 Hz, 1 H, H-11′), 4.86 (d, J = 2.8 Hz, 1 H, H-5), 5.02 (d, J = 11.2 Hz, 1 H, H-11′), 5.38 (q, J = 6.9 Hz, 1 H, H-9), 6.08 (s, 1 H, H-7), 6.91 (d, J = 8.7 Hz, 2 H, HAr), 7.34 (d, J = 8.7 Hz, 2 H, HAr). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.02 (C-11), 13.67 (C-12), 15.38 (C-10), 16.62 (C-13), 38.99 (C-4), 55.28 (COCH₃), 72.85 (C-11′), 75.73 (C-3), 78.52 (C-2), 79.43 (C-5), 11.08 (CAr), 124.87 (C-9), 127.34 (C-8), 128.95 (C-6), 130.16 (CAr), 130.56 (C-7), 132. 43 (CAr), 170.02 (C-1). HRMS (ESI⁺): m/z calcd for C₁₉H₃₇NO₃Si + H⁺: 361.2015; found: 361.2018.

19

Selected Data for Compound 4
[α]_D ^²³.5 61.26 (c 1.11, CHCl₃). IR (film): 3542, 3311, 2913, 2954, 2876, 1613, 1514, 1461, 1302, 1249, 1036, 820, 743 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.60 (m, 12 H, SiCH₂CH₃), 0.94 (m, 18 H, SiCH₂CH₃), 1.02 (d, J = 6.7 Hz, 3 H, H-15), 1.68 (m, 6 H, H-13, H-17), 1.74 (s, 3 H, H-16), 1.90 (qd, J = 6.7, 13.5 Hz, 1 H, H-7), 1.97 (t, J = 2.6 Hz, 1 H, H-1), 2.34 (m, 1 H, H-3), 2.44 (d, J = 8.6 Hz, 1 H, HOH), 3.41 (dd, J = 2.4, 6.9 Hz, 1 H, H-5), 3.80 (m, 5 H, H-4, H-8, HOCH₃), 3.89 (d, J = 6.9 Hz, 1 H, H-6), 4.43 (d, J = 11.2 Hz, 1 H, H-14), 4.73 (d, J = 11.2 Hz, 1 H, H-14), 5.39 (q, J = 6.7 Hz, 1 H, H-12), 5.83 (s, 1 H, H-10), 6.87-7.22 (m, 4 H, HAr). ^¹³C NMR (100 MHz, CDCl₃): δ = 4.91 (SiCH₂CH₃), 5.52 (SiCH₂CH₃), 6.91 (SiCH₂CH₃), 7.10 (SiCH₂CH₃), 10.66 (C-15), 12.42 (C-17), 13.70 (C-13), 16.52 (C-16), 25.24 (C-3), 37.99 (C-7), 55.24 (COCH₃), 68.67 (C-4), 70.20 (C-1), 70.42 (C-6), 73.85 (C-14), 80.85 (C-5), 81.10 (C-2), 82.05 (C-8), 113.79 (CAr), 124.40 (C-12), 129.22 (CAr), 130.14 (C-11), 132.75 (C-10), 136.29 (C-9), 159.22 (CqOMe). HRMS (ESI⁺): m/z calcd for C₃₆H₆₂O₅Si₂ + Na⁺: 653.4028; found: 653.4019.