Alkyne-Assisted Approach to the Formal Synthesis of Antibiotic Macrolide (-)-A26771B

Abstract

A stereoselective formal synthesis of a 16-membered antibiotic macrolide (-)-A26771B is described starting from (R)-propylene oxide and (+)-diethyl tartrate. Key steps involved in this alkyne-assisted convergent approach are alkyne zipper reaction, Cadiot-Chodkiewicz coupling, and Yamaguchi macrolactonization.

Key words

alkyne - macrolide - zipper reaction - Cadiot-Chod­kiewicz reaction - Yamaguchi macrolactonization

References and Notes

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12

Spectral Data of Representative New Compounds
Compound 9: [α]_D ^²0 -24.8 (c 1.0, CHCl₃). IR (KBr): ν_max = 2989, 2933, 2864, 2121, 1726, 1635, 1454, 1376, 1241, 1214, 1086, 852, 740, 398 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.30-7.27 (m, 5 H), 4.59 (s, 2 H), 4.49 (dd, J = 2.2, 6.8 Hz, 1 H), 4.25-4.18 (m, 1 H), 3.60 (d, J = 4.5 Hz, 2 H), 2.44 (d, J = 2.2 Hz, 1 H), 1.48 (s, 3 H), 1.41 (s, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 137.5, 128.3, 127.7, 127.6, 110.8, 80.8, 80.6, 74.6, 73.5, 68.9, 67.1, 26.8, 26.0. ESI-HRMS: m/z calcd for C₁₅H₁₈O₃Na [M + Na]⁺: 269.1153; found: 269.1146.
Compound 5: [α]_D ^²0 -43.0 (c 1.0, CHCl₃). IR (KBr): ν_max = 2988, 2926, 2214, 1722, 1626, 1376, 1217, 1081, 1022, 851, 742, 700 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.34-7.27 (m, 5 H), 4.59 (s, 2 H), 4.53 (d, J = 7.5 Hz, 1 H), 4.35-4.18 (m, 1 H), 3.59 (d, J = 4.5 Hz, 2 H), 1.48 (s, 3 H), 1.41 (s, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 137.6, 128.3, 127.6, 127.5, 110.8, 80.4, 76.9, 73.4, 68.9, 68.0, 47.1, 26.8, 26.0. ESI-MS: m/z = 347 [M + Na]⁺.
Compound 10: [α]_D ^²0 -59.9 (c 1.0, CHCl₃). IR (KBr): ν_max = 3426, 2932, 2861, 2254, 1718, 1633, 1454, 1375, 1219, 1087, 1035, 851, 741, 699 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.35-7.26 (m, 5 H), 4.57 (s, 2 H), 4.55 (d, J = 6.8 Hz, 1 H), 4.25-4.18 (m, 1 H), 3.80-3.71 (m, 1 H), 3.58 (d, J = 4.5 Hz, 2 H), 2.29 (t, J = 6.8 Hz, 2 H), 1.60-1.36 (m, 8 H), 1.47 (s, 3 H), 1.40 (s, 3 H), 1.17 (d, J = 6.0 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 137.6, 128.2, 127.5, 127.4, 110.7, 81.9, 80.5, 73.3, 72.0, 71.3, 68.9, 67.6, 67.6, 64.3, 38.8, 28.5, 27.8, 26.7, 25.9, 24.9, 23.2, 18.9. ESI-MS: m/z = 407 [M + Na]⁺.
Compound 3: [α]_D ^²0 -20.7 (c 1.0, CHCl₃). IR (KBr): ν_max = 3413, 2926, 2856, 1631, 1455, 1374, 1220, 1049, 851, 763 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 3.85-3.80 (m, 1 H), 3.74 (dd, J = 3.0, 12.0 Hz, 2 H), 3.68-3.63 (m, 1 H), 3.54 (dd, J = 4.0, 12.0 Hz, 1 H),1.56-1.25 (m, 18 H), 1.38 (s, 3 H), 1.37 (s, 3 H), 1.17 (d, J = 6.0 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 108.4, 81.5, 76.9, 68.0, 62.0, 39.2, 33.0, 29.55, 29.51, 29.4, 29.3, 27.2, 26.9, 25.8, 25.6, 23.3. ESI-HRMS: m/z calcd for C₁₇H₃₄O₄Na [M + Na]⁺: 325.2354; found: 325.2363.
Compound 11: [α]_D ^²0 -10.3 (c 1.6, CHCl₃). IR (KBr): ν_max = 3452, 2938, 2855, 1722, 1655, 1373, 1300, 1260, 1169, 1042, 771, 555 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 6.83 (dd, J = 5.0, 15.0 Hz, 1 H), 6.08 (d, J = 15.0 Hz, 1 H), 4.21 (q, J = 7.0 Hz, 2 H), 4.11 (t, J = 7.0 Hz, 1 H), 3.80-3.73 (m, 1 H), 3.69 (q, J = 7.0 Hz, 1 H), 1.61-1.54 (m, 2 H), 1.51-1.22 (m, 16 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.31 (t, J = 7.0 Hz, 3 H), 1.18 (d, J = 6.0 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 166.0, 144.1, 122.5, 109.2, 80.5, 80.1, 68.0, 60.5, 39.2, 32.0, 29.5, 29.4, 29.3, 27.2, 26.5, 25.8, 25.6, 23.4, 14.1. ESI-HRMS: m/z calcd for C₂₁H₃₈O₅Na [M + Na]⁺: 393.2616; found: 393.2627.
Compound 2: [α]_D ^²0 +5.6 (c 0.78, CHCl₃). IR (KBr): ν_max = 2928, 2856, 1715, 1458, 1374, 1257, 1177, 1055, 987, 862 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 6.88 (dd, J = 7.0, 16.0 Hz, 1 H), 6.12 (d, J = 16.0 Hz, 1 H), 5.07-4.99 (m, 1 H), 4.13 (t, J = 7.0 Hz, 1 H), 3.78-3.72 (m, 1 H), 1.86-1.77 (m, 1 H), 1.69-1.58 (m, 2 H), 1.53-1.41 (m, 2 H), 1.43 (s, 3 H), 1.42 (s, 3 H), 1.35-1.18 (m, 13 H), 1.26 (d, J = 6.0 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 165.5, 144.3, 123.6, 109.2, 80.7, 80.0, 71.1, 35.2, 31.0, 27.8, 27.2, 27.1, 26.9, 26.5, 26.4, 24.7, 23.3, 20.5. ESI-HRMS: m/z calcd for C₁₉H₃₂O₄Na
[M + Na]⁺: 347.2198; found: 347.2206.