Diversity Oriented Synthesis of Allocolchicinoids with Fluoro and/or Oxygen Substituent(s) on the C‐Ring from a Single Common Intermediate

Abstract

Allocolchicinoids, with a distinct polyoxygenated dibenzocycloheptane skeleton, attract much attention as potential candidate anticancer drugs. In this study, eight C‐ring fluorinated analogues of allocolchicinoids, seven C‐ring oxygen‐substituted analogues, and known compounds N‐acetylcolchinol and NSC 51046 were synthesized as racemates from a single common intermediate by using either the deoxyfluorination/migration domino reaction or acid‐promoted migration as the key step. Among the products obtained, some of the fluorinated derivatives strongly inhibited the growth of prostate DU145 and pancreas Panc 1 cancer cell lines with efficacy comparable to or better than those of N‐acetylcolchinol and NSC 51046. They were also less toxic against a non‐cancerous cell line than the known compounds were.

Asymmetric synthesis of the allocolchicinoid natural product N-acetylcolchinol methyl ether (suhailamine), solid state and solution phase conformational analysis

“…Takubo et al 23 for the major species of NCME provided significant support for our assertion that the natural product and NCME share the same structure. As the congruency of our sample of NCME (21) with those of Brecht et al 22 and Takubo et al 23 had been established, it was unsurprising that our sample of NCME 21produced a very close match to the data reported for suhailamine: 2 generally |ΔδH| ≤ 0.04 25 and |ΔδC| ≤ 0.2. 25 The exceptions to this generalisation are the 1 H NMR chemical shift of the NH, for which |ΔδH| = 0.09, 25 and the 13 C NMR chemical shift for C(5), for which |ΔδC| = 1.0 25 (Fig.…”

“…As the axial chirality of these compounds is known to be an important feature in the tubulin-binding inhibition mode of the anti-cancer activity of these compounds (as well as that of colchicine), several investigations have appeared in which the preferred solid state and solution phase conformational preferences of this class of molecule are interrogated. 28 With reference to NCME itself, our own observations coupled with those of Takubo et al 23 -that three species are present for NCME in CDCl3 solution-reveals an incomplete picture of the solution phase conformational preference of this allocolchicinoid, as the atropisomerism alone cannot account for the presence of three species. We thus sought to unambiguously identify all three species 21a, 21b and 21c, observed in CDCl3 solution in a 69:24:7 ratio, respectively, in this study (and a 65:25:10 ratio in the study of Takubo et al).…”

“…21 As expected, the 1 H and 13 C NMR spectroscopic data recorded for the sample of NCME (21) prepared in this study using DMSO-d6 as the solvent matched well with these other, previously reported data. A smaller number of synthetic samples of NCME have 1 H and 13 C NMR spectroscopic data using CDCl3 as the solvent: Brecht et al 22 reported a 71:29 ratio of species for NCME in CDCl3, whilst Takubo et al 23 reported a 65:25:10 ratio of species. When our sample of NCME (21) was recorded in CDCl3, a 69:24:7 ratio of three species, 21a:21b:21c was observed.…”

Total Synthesis of (±)-Allocolchicine and Its Analogues Using Co-Catalyzed Alkyne [2 + 2 + 2]-Cyclotrimerization

“…In this article, we document the successful total synthesis of (±)-allocolchicine ( 1 ) employing Co-catalyzed alkyne [2 + 2 + 2]-cyclotrimerization for the simultaneous construction of rings B and C and the synthesis of several ring-modified allocolchicinoids. 17…”

Microflow Fluorinations of Benzynes: Efficient Synthesis of Fluoroaromatic Compounds

“…Given these limitations, the development of efficient methods for the fluorination of functionalized aromatic compounds under mild conditions has received increased attention over the latest decade. [16][17][18][19][20][21][22][23][24][25][26][27] In fact, our research group recently developed a method for the direct preparation of fluorobenzenes 1 from 2-(trimethylsilyl) phenols 2 28) ; this method involves O-nonafluorobutanesufonylation followed by the generation of the benzyne 4, [29][30][31][32][33][34] and the immediate nucleophilic addition of a fluoride ion at 4, to yield 1. In this method, Bu 4 NF(t-BuOH) 4 serves a dual role that generates the benzyne and then fluorinates it 35) (Chart 1-A).…”