Synthesis of an Advanced Intermediate of the Macrotricyclic Core of Roseophilin

Abstract

A facile approach for the preparation of a cyclopenta[b]pyrrole derivative, the key precursor in Frontier’s synthesis of the macrotricyclic core of roseophilin, was developed. The key steps involved two successive pyrrole acylations and a Sc(OTf)₃-catalyzed Nazarov cyclization reaction.

Key words

pyrrole acylation - Knoevenagel reaction - Nazarov ­cyclization - olefin cross-metathesis - scandium triflate

References

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8

Mp 75-77 ˚C. IR (KBr): 1743, 1678, 1643, 1594, 1488, 1358, 1258, 1172, 1110 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.92 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 6.94 (d, J = 3.6 Hz, 1 H), 6.08 (d, J = 3.6 Hz, 1 H), 5.81 (ddt, J = 17.2, 10.4, 6.8 Hz, 1 H), 5.01 (d, J = 17.2 Hz, 1 H), 4.96 (d, J = 10.4 Hz, 1 H), 3.82 (s, 2 H), 3.72 (s, 3 H), 2.92 (t, J = 7.8 Hz, 2 H), 2.43 (s, 3 H), 2.05 (m, 2 H), 1.65 (m, 2 H), 1.41 (m, 4 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 181.8, 167.8, 147.2, 144.9, 138.8, 136.5, 135.1, 129.6, 127.6, 123.5, 114.5, 111.5, 52.4, 47.3, 33.6, 28.9, 28.8, 28.6, 21.7. MS (ESI): m/z (%) = 440 (100) [M + Na]⁺, 424 (5), 418 (6) [M + H]⁺. HRMS-ESI: m/z [M + Na]⁺ calcd for C₂₂H₂₇NNaO₅S: 440.1508; found: 440.1521.

10

IR (neat): 1724, 1662, 1597, 1557, 1480, 1435, 1371, 1330, 1294, 1247, 1191, 1175, 1103. ^¹H NMR (400 MHz, CDCl₃): δ = 8.04 (m, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 6.84 (d, J = 11.2 Hz, 0.63 H), 6.78 (d, J = 3.6 Hz, 0.63 H), 6.62 (d, J = 3.6 Hz, 0.37 H), 6.60 (d, J = 10.4 Hz, 0.37 H), 6.08 (d, J = 3.6 Hz, 0.63 H), 6.02 (d, J = 3.6 Hz, 0.37 H), 5.80 (ddt, J = 16.8, 10.4, 6.4 Hz, 1 H), 5.01 (d, J = 16.8 Hz, 1 H), 4.95 (d, J = 10.4 Hz, 1 H), 3.80 (s, 1.11 H), 3.68 (s, 1.89 H), 3.01 (t, J = 7.6 Hz, 1.26 H), 2.84 (t, J = 7.6 Hz, 0.74 H), 2.51 (m, 1 H), 2.43 (s, 3 H), 2.05 (m, 2 H), 1.68 (m, 1.26 H), 1.59 (m, 0.74 H), 1.36-1.44 (m, 4 H), 1.10 (d, J = 6.4 Hz, 2.22 H), 0.96 (d, J = 6.4 Hz, 3.78 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 182.5, 180.5, 166.3, 165.5, 157.5, 154.7, 148.3, 145.0, 144.9, 144.8, 138.8, 136.8, 136.3, 135.8, 134.8, 133.9, 131.3, 129.7, 129.5, 125.7, 122.3, 114.5, 114.4, 111.1, 110.9, 52.2, 52.1, 33.6, 29.5, 29.2, 28.9, 28.9, 28.7, 28.6, 28.3, 22.0, 21.8, 21.7. MS (ESI): m/z (%) = 494 (100) [M + Na]⁺, 472 (10) [M + H]⁺. HRMS-ESI: m/z [M + Na]⁺ calcd for C₂₆H₃₃NNaO₅S: 494.1977; found: 494.1986.

11

IR (neat): 1743, 1704, 1639, 1597, 1483, 1440, 1380, 1366, 1229, 1192, 1182, 1133, 1087, 1027, 970 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 8.4 Hz, 2 H), 7.31 (d,
J = 8.4 Hz, 2 H), 6.08 (s, 1 H), 5.82 (ddt, J = 17.2, 10.4, 6.8 Hz, 1 H), 5.03 (dd, J = 17.2, 1.6 Hz, 1 H), 4.97 (d, J = 10.4 Hz, 1 H), 3.77 (s, 3 H), 3.57 (d, J = 3.2 Hz, 1 H), 3.26 (dd, J = 5.8, 3.2 Hz, 1 H), 2.99 (m, 2 H), 2.42 (s, 3 H), 2.08 (m, 2 H), 1.92 (m, 1 H), 1.69-1.72 (m, 2 H), 1.44-1.46 (m, 4 H), 0.94 (d, J = 6.6 Hz, 3 H), 0.89 (d, J = 6.6 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 180.7, 170.3, 159.3, 152.2, 145.5, 138.8, 135.8, 132.5, 130.0, 127.8, 114.5, 109.0, 61.8, 52.6, 44.4, 33.6, 31.2, 28.8, 28.7, 28.6, 28.5, 21.7, 19.8, 19.7. MS (ESI): m/z (%) = 494 (100) [M + Na]⁺, 472 (75) [M + H]⁺. HRMS-ESI: m/z [M + Na]⁺ calcd for C₂₆H₃₃NNaO₅S: 494.1977; found: 494.1980.

13

IR (neat): 1736, 1702, 1597, 1483, 1438, 1380, 1321, 1229, 1181, 1134, 1089, 1026 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 8.4 Hz, 2 H), 6.08 (s, 1 H), 5.57-5.83 (m, 2 H), 4.65 (d, J = 6.6 Hz, 0.28 H), 4.54 (d, J = 6.6 Hz, 1.72 H), 3.78 (s, 3 H), 3.58 (d, J = 3.0 Hz, 1 H), 3.26 (dd, J = 6.0, 3.0 Hz, 1 H), 2.99 (m, 2 H), 2.43 (s, 3 H), 2.09 (m, 5 H), 1.92 (m, 1 H), 1.72 (m, 2 H), 1.46 (m, 4 H), 0.94 (d, J = 6.8 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 180.7, 170.9, 170.3, 159.4, 152.1, 145.5, 136.1, 135.7, 132.5, 129.9, 127.7, 124.0, 109.1, 65.2, 61.7, 52.6, 44.4, 32.0, 31.2, 28.8, 28.8, 28.6, 28.5, 21.7, 21.0, 19.8, 19.6. MS (ESI): m/z (%) = 566 (100) [M + Na]⁺, 552 (12), 544 (10) [M + H]⁺. HRMS-ESI: m/z
[M + Na]⁺ calcd for C₂₉H₃₇NNaO₇S: 566.2188; found: 566.2201.