Chemical Emulation of the Biosynthetic Route to Anthrasteroids: Synthesis of Asperfloketal A

The anthrasteroid rearrangement has been discussed for the formation of the eponymous substance class since its discovery. We here report its chemical emulation from a plausible biogenetic precursor and show how it accounts for the formation of asperflo­ketals A and B through a mechanistic bifurcation event. As a result, these natural products arise from double Wagner–Meerwein rearrangements and, thus, are 1(10→5),​1(5→6)​- and 1(10→5),​4(5→6)​diabeo-14,15-seco­steroids, respectively. To establish an efficient route to a bioinspired precursor, we devised a sequence of orchestrated oxidative activation and rearrangement from ergosterol

Optical microscopy images of trypan blue and trypan blue combined with lutein/zeaxanthin in aqueous solution with no and after 120 hours of blue-light irradiation at 460 nm.

<p>In the trypan blue—lutein/zeaxanthin solution, fine homogenous yellow granules of lutein/zeaxanthin were observed, which changed into heterogeneous brown clots during the process of irradiation, as shown in the viewframe below. Scale bars represent 20 μm.</p

MALDI-TOF mass spectrometry of selected fragment ion peaks for the blue light irradiation series.

<p>Distinct mass signatures of trypan blue decomposition intermediates were formed subsequent to dissociation of methoxyamine (m/z = 825.6 [M– 47]⁺) <b>(a)</b> that accumulates over time (r = 0.917, p < 0.001); and following dissociation of sulfonyl arin (m/z = 671.1 [M– 47–155]⁺) <b>(b)</b> that is consumed in the course of irradiation (r = -0.488, p = 0.040).</p

Schematic illustration of proposed major/preferred trypan blue photochemical degradation pathways (primary and secondary steps, respectively).

<p>It is suggested that the self-sensitized photodegradation of trypan blue occurs under dissociation of dimethyl sulfate (m/z = 745.6 [M– 127.2]⁺), presumably followed by elimination of phenol (m/z = 651.4 [M– 127.2–94.2]⁺). In the presence of lutein/zeaxanthin, photochemical degradation of trypan blue is triggered and performs under presumed generation of methoxyamine (m/z 825.6 [M– 47]⁺), followed by dissociation of sulfonyl arin (m/z = 671.1 [M– 47–155]⁺).</p

Nuclear magnetic resonance spectra of trypan blue—Lutein/zeaxanthin mixture with no (lower graph) and after 120 hours (top graph) of blue light irradiation at 460 nm.

<p>Trypan blue and Lutein/zeaxanthin signals: ¹H NMR (700 MHz, DMSO-<i>d</i>₆, RT, ppm) <i>δ</i> = 8.08 (d, <i>J</i> = 8.4 Hz, 2H), 7.69 (d, <i>J</i> = 8.4 Hz, 1H), 7.68 (s, 2H), 7.32 (s, 2H), 7.06 (d, <i>J</i> = 1.5 Hz, 2H), 6.89 (d, <i>J</i> = 1.5 Hz, 2H), <i>δ</i> = 6.71 (d, <i>J</i> = 8.8 Hz, 2H), 6.69–6.60 (m, 2H), 6.39 (d, <i>J</i> = 14.9 Hz, 2H), 6.33 (d, <i>J</i> = 8.8 Hz, 2H), 6.22 (d, <i>J</i> = 11.5 Hz, 2H), 6.19–6.09 (m, 5H) ppm.</p

Nuclear magnetic resonance spectra of trypan blue with no (lower graph) and after 120 hours (top graph) of blue light irradiation at 460 nm.

<p>Trypan blue signals: ¹H NMR (700 MHz, DMSO-<i>d</i>₆, RT, ppm) <i>δ</i> = 8.08 (d, <i>J</i> = 8.4 Hz, 2H), 7.69 (d, <i>J</i> = 8.4 Hz, 1H), 7.68 (s, 2H), 7.32 (s, 2H), 7.06 (d, <i>J</i> = 1.5 Hz, 2H), 6.89 (d, <i>J</i> = 1.5 Hz, 2H) ppm. Dimethyl sulfate signal: ¹H NMR (700 MHz, DMSO-<i>d</i>₆) <i>δ</i> = 4.00 ppm (top graph).</p

Photometric spectra of trypan blue (dotted line) and trypan blue combined with lutein/zeaxanthin (black line) in aqueous solution.

<p>Characteristic absorption maxima are highlighted with marking lines: 379 nm (lutein/zeaxanthin), 580 nm (trypan blue) and 460 nm/505 nm (lutein/zeaxanthin diacetate).</p

MALDI-TOF spectra of examined dye solutions, comprising of 0.4 mg/mL trypan blue and 10.0 mg/mL lutein/zeaxanthin, with no (a) and after 120 hours of blue light irradiation at 460 nm (b).

<p>MALDI-TOF spectra of examined dye solutions, comprising of 0.4 mg/mL trypan blue and 10.0 mg/mL lutein/zeaxanthin, with no (a) and after 120 hours of blue light irradiation at 460 nm (b).</p

General Synthetic Approach to Functionalized Dihydrooxepines

A three-step sequence to access functionalized 4,5-dihydrooxepines from cyclohexenones has been developed. This approach features a regioselective Baeyer–Villiger oxidation and subsequent functionalization via the corresponding enol phosphate intermediate

Synthesis and Biological Evaluation of Epidithio‑, Epitetrathio‑, and bis-(Methylthio)diketopiperazines: Synthetic Methodology, Enantioselective Total Synthesis of Epicoccin G, 8,8′-<i>epi</i>-<i>ent</i>-Rostratin B, Gliotoxin, Gliotoxin G, Emethallicin E, and Haematocin and Discovery of New Antiviral and Antimalarial Agents

An improved sulfenylation method for the preparation of epidithio-, epitetrathio-, and bis-(methylthio)­diketopiperazines from diketopiperazines has been developed. Employing NaHMDS and related bases and elemental sulfur or bis­[bis­(trimethylsilyl)­amino]­trisulfide (<b>23</b>) in THF, the developed method was applied to the synthesis of a series of natural and designed molecules, including epicoccin G (<b>1</b>), 8,8′-<i>epi</i>-<i>ent</i>-rostratin B (<b>2</b>), gliotoxin (<b>3</b>), gliotoxin G (<b>4</b>), emethallicin E (<b>5</b>), and haematocin (<b>6</b>). Biological screening of selected synthesized compounds led to the discovery of a number of nanomolar antipoliovirus agents (i.e., <b>46</b>, 2,2′-<i>epi</i>-<b>46</b>, and <b>61</b>) and several low-micromolar anti-Plasmodium falciparum lead compounds (i.e., <b>46</b>, 2,2′-<i>epi</i>-<b>46</b>, <b>58</b>, <b>61</b>, and <b>1</b>)