Investigations into the Parallel Synthesis of Novel Pyrrole-Oxazole Analogues of the Insecticide Pirate

Abstract

Investigations into the parallel synthesis of selected analogues of a structurally unique pyrrole-oxazole analogue of the pyrrole insecticide pirate, are reported. Acylaminoketone salts were obtained from ketobromides in moderate to high yields and excellent purity. A number of N-tosyl pyrroles were obtained; however, formation of the target acyl tosyl pyrroles was thwarted by the stereoelectronic effects of the pyrrole substituents. During the pyrrole subunit chemistry, an interesting pyrrole derivative, vinyl pyrrole, was isolated. By restricting diversity to the aryl subunit, the parallel synthesis of selected pyrrole-oxazoles in moderate purity, was achieved when electron-donating or no groups were present on the aryl ring.The natural product antibiotic, dioxapyrrolomycin (1) isolated from Streptomyces MG796-AF7, 1 displays moderate insecticidal and acaricidal activity against arachnids, mites and ticks 2 and has been found to be a potent uncoupler of oxidative phosphorylation. 3 Using 1 as a lead compound, 2-arylpyrroles, have been developed through QSAR studies 4 and identified as a novel class of insecticides and acaricides. In particular, Pirate™ 2 has been commercially developed as a broad-spectrum insecticide/ miticide. 3 The N-dealkylated analogue 3, of pirate, is the metabolically active compound, 5 where the activity of the pyrrole insecticides is primarily a function of lipophilicity (Log P) and acidity (pK a ). 2,6 Figure 1 Structures of known insecticides 1-3 and potential lead compounds 4 and 5As part of a study aimed at identifying new potential insecticides, we sought to synthesize novel, structurally unique analogues of pirate 2, that might ultimately deliver improved dosage rates and selectivity in the field, while reducing negative ecological impact. Previously 7 we generated simple pyrrole-oxazoles 4 and 5, and established that they displayed moderate cytotoxicity.During these investigations, 7 we established a viable synthetic route to pyrrole-oxazole 5 via coupling of 6 and 7a and subsequent conversion to the target pyrrole-oxazole 5 (Scheme 1) without any purification steps, in 21% yield (cf. 10% with purification steps). 7 This suggested that the sequence was robust enough for the generation of analogues using solution-phase parallel synthesis. In the present work we wish to report the results of our investigations on the parallel synthesis of selected analogues of pyrrole-oxazole 5. Scheme 1We examined the parallel synthesis of acylaminoketone salts, choosing commercially available ketobromides 10a-k, which varied in the steric and electronic influences of the group a to the ketone. Acylaminoketone salts 7a-k were obtained, in moderate to high yields and excellent purity (with the exception of 7j which, though high yielding, was impure), via a Delépine reaction in which the ketobromides 10a-k were reacted with hexamethylenetetramine 9 followed by cleavage of the resulting salt 11a-k with hydrobromic acid (Scheme 2). 10

Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors

“…In the next step, the bromine atom had to be replaced by an amino group in a substitution reaction. Due to steric effects, it was not possible to substitute the bromine atom with nitrogen, neither with azide (Staudinger reaction), phthalimide (Gabriel synthesis) nor methenamine (Delépine reaction). With respect to the published palladium‐catalyzed indole synthesis of β‐amino alcohols reacting with 1,3‐diketones, we planned the alternative route as reduction and subsequent primary amine synthesis of the ester 5 to compound 7 .…”

“…In the next step, the bromine atom had to be replaced by an amino group in asubstitution reaction. Due to steric effects, it was not possible to substitute the bromine atom with nitrogen, neither with azide (Staudinger reaction [9] ), phthalimide (Gabriel synthesis [10] )n or methenamine (DelØpine reaction [11] ). With respectt ot he published palladium-catalyzed indole synthesis [12] of b-amino alcohols reactingw ith 1,3-diketones, we planned the alternative route as reduction and subsequentp rimary amine synthesis of the ester 5 to compound 7.A gain, we did not succeed in formingt he desired reduction product 6,a s neither sodium borohydride [13] nor palladium/hydrogen gas for catalytic reduction were effective in reducing the ketone substructure of 5.T herefore, we envisioned the formationo fi ntermediate 11 and subsequently furan derivative 12 via aF eist-Benary reaction.…”

“…The indole derivative selisistat (2a)e xhibits the most potent SIRT1 inhibition (IC 50 = 98 nm) [8] by far,b oth in vitro and in vivo. [9][10][11] Structure-activity relationship studies revealed that expansion of the partially hydrogenated six-membered ring system of 2a to the homologous derivative 2b is feasible. [8] In fact, selisistat has already passed phaseIIc linical trials for the treatment of Huntington'sdisease.…”

“…ChemMedChem 2019, 14,853 -864 www.chemmedchem.org11.32 ppm (s, 1H);13 CNMR ([D 6 ]DMSO): d = 10.9, 13.4, 27.9, 28.2, 31.9, 35.2, 35.8, 42.2, 51.9, 112.6, 115.8, 123.7, 127.8, 129.7, 133.5, 134.3, 141.1, 166.6, 191.1 ppm;i somer 2: 1 HNMR ([D 6 ]DMSO): d = 1.03 (s, 6H), 1.99 (s, 3H), 2.07 (s, 3H), 2.18 (s, 2H), 2.62 (s, 2H), 2.84 (s, 3H), 4.21 (AB, 1H, 2 J AB = 16.0 Hz), 4.65 (AB, 1H, 2 J AB = 15.6 Hz), 6.78 (d, 1H, 3 J = 4.8 Hz), 7.29 (d, 1H, 3 J = 4.8 Hz), 11.37 ppm (s, 1H); 13 CNMR ([D 6 ]DMSO): d = 11.1, 12.9, 27.9, 28.2, 34.6, 35.2, 35.8, 46.3, 51.9, 112.4, 115.7, 123.7, 127.6, 130.0, 133.8, 134.8, 140.9, 166.6, 191.3 ppm;H RMS (ESI, m/z)[ M + H] + :c alcd for C 19 H 25 N 2 O 2 S + : 345.1631, found:3 45.1626. J AB = 15.2 Hz), 4.83 (AB, 1H, 2 J AB = 15.6 Hz), 7.28-7.3H), 4.22 (AB, 1H, 2 J AB = 15.6 Hz), 4.50 (AB, 1H, 2 J AB = 16.0 Hz), 7.05 (d, 1H, 3 J = 7.2 Hz), 7.10 (s, 1H), 7.28-7.42 (m, 2H), 11.33 ppm (s, 1H); 13 CNMR ([D 6 ]DMSO): d = 10.9, 27.9, 28.2, 35.2, 35.3, 35.8, 51.9, 52.8, 112.5, 115.7, 125.7, 126.8, 127.1, 127.7, 130.3, 133.2, 140.4, 141.2, 167.2, 191.4 ppm;H RMS (ESI, m/z)[ M + H] + :calcd for C 20 H 24 N 2 O 2 + :3 59.1521, found:359.1511.…”

Improved preparation of 4(5)-aryl-2-(β-d-glucopyranosyl)-imidazoles, the most efficient glucose analogue inhibitors of glycogen phosphorylase

“…2-Amino-1-arylethanones were synthesized according to literature procedures. 6,24 General procedure I for the synthesis of 4(5…”