Efficient and Convenient Pyridine Ring-E Formation of the Cytotoxic Marine Alkaloid Ascididemin and Related Analogues.

Abstract

Conversion of tetracyclic quinone 1 to the cytotoxic pentacyclic alkaloid ascididemin (2) in 80% yield is achieved by reaction with paraformaldehyde and ammonium chloride in refluxing acetic acid. High yielding annelations are aiso observed for the related analogues N-8 deaza ascididemin (3) and kuanoniamine A (4).

Notes

We have previously reported 3 to have an HCT116 IC₅₀ value of >350 μM.⁴ Repeated testing on freshly prepared material has shown the correct value to be 74 μM.

The ¹H NMR data observed for our synthetically derived sample of kuanoniamine A (4) agreed well with the data previously reported by Kitahara et al., for synthesised 4. ⁸ However, these data were consistently 0.4 ppm upfield from the ¹H NMR data reported by Carroll and Scheuer for the naturally occurring alkaloid, despite being recorded in the same (d₆-DMSO + TMS) solvent system.⁷ Interestingly, we found complete agreement between ¹³C NMR data acquired for our synthetic sample of 4 versus the data reported for the natural product, perhaps suggesting incorrect referencing of the natural product ¹H NMR data. mp 258–260°C (decomp.) (lit.⁷ 255–258°C (decomp.)). MS: m/z, (%) 289 (M^+•, 92). High resolution EIMS calcd. for C₁₆H₇N₃OS m/z, 289.0310, found 289.0311. ¹H-NMR: (DMSO-d ₆ with TMS, 400 MHz), δ 8.06 (1H, td, J, = 7.9, 1.4, H-5), 8.11 (1H, td, J, = 8.5, 1.4, H-6), 8.47 (1H, d, J, = 8.5, H-7), 8.92 (1H, d, J, = 5.8, H-3), 9.04 (1H, d, J, = 7.9, H-4), 9.15 (1H, d, J, = 5.7, H-2), 9.72 (1H, s, H-11). ¹³C-NMR: (¹H-coupled, DMSO-d ₆ with TMS, 100 MHz), δ 116.54 (obscured, C-12c), 117.23 (dd, J, = 167, 9, C-3), 123.01 (m, C-3b), 124.03 (ddd, J, = 163, 7, 2, C-4), 130.97 (dd, J, = 163, 8, C-5), 131.93 (dd, J, = 163, 6, C-6), 131.98 (dd, J, = 163, 8, C-7), 136.03 (d, J, = 2.4, C-9a), 137.16(m, C-3a), 144.83 (ddd, J, = 8, 8, 2, C-7a), 147.06 (d, J, = 11.2, C-12b), 147.20 (s, C-8a), 148.98 (dd, J, = 181, 4, C-2), 157.79 (d, J, = 14.4, C-12a), 162.69 (d, J, = 217, C-11), 176.12 (s, C-9).