Relative Reactivity of Benzothiophene-Fused Enediynes in the Bergman Cyclization

Abstract

To find promising analogues of naturally occurring enediyne antibiotics with a sufficient reactivity in the Bergman cyclization and moderately stable under isolation and storage, a scale of relative enediynes reactivity was created on the basis of calculated free activation energies for the Bergman cyclization within 12 known and new benozothiophene, benzene, and cinnoline annulated 9- and 10-membered enediynes. To verify the predicted reactivity/stability balance, three new carbocyclic enediynes fused to a benzothiophene core bearing 3,4,5-trimethoxybenzene, fluoroisopropyl, and isopropenyl substituents were synthesized using the Nicholas-type macrocyclization. It was confirmed that annulation of a 3,4,5-trimethoxybenzene moiety to a 10-membered enediyne macrocycle imparts high reactivity to an enediyne while also conferring instability under ambient temperature. Fluoroisopropyl-substituted 10-membered enediyne from the opposite end of the scale was found to be stable while moderately reactive in the Bergman cyclization. Along with the experimentally confirmed moderate reactivity (DSC kinetic studies), (fluoroisopropyl)enediyne showed a significant DNA damaging activity in plasmid cleavage assays comparable with the known anticancer drug Zeocin.

10-Membered Azaenediyne Fused to a Benzothiophene through the Nicholas Macrocyclization: Synthesis and DNA Cleavage Ability

“…Solvents, reagents, and chemicals (o-iodothioanisole, but-3-yn-1-ol, p-toluenesulfonamide and 1,4-bis(trimethylsilyl)buta-1,3-diyne) used for reactions were purchased from commercial suppliers. Catalyst Pd(PPh 3 ) 4 and Co 2 (CO) 8 were purchased from Sigma-Aldrich. 1- (5-Methoxypenta-1,3-diyn-1-yl)-2-methylsulfanylbenzene 6, 1 3-Iodo-2-(3-methoxyprop-1-yn-1yl)benzo[b]thiophene 7, 1 N-tosylbut-3-yn-1-amine 8, 2 methylpropargyl ether 3 were synthesized by known procedures without any modification.…”

“…nulation of an enediyne system with benzothiophene is beneficial because the arising strain increased reactivity of benzothiophene-fused enediynes in the Bergman cyclization compared to corresponding benzo analogues. 43 In order to expand the scope of the Nicholas-type macrocyclization as a synthetic tool for the construction of enediynes, here we report the first successful example of the aza-Nicholas reaction for the synthesis of 10-membered azaenediyne fused to a benzothiophene (Scheme 1, D) and an investigation of its ability to cleave DNA.…”

“…10,[18][19][20] Moreover, known active N-tosylazaenediynes 32 allowed to consider the target azacycle as a promising object for biological trials with a good balance of stability/reactivity. 43 The synthesis of enediyne 1 is based on the synthetic route towards unsymmetrically substituted heterocyclefused acyclic enediynes developed earlier -a stepwise formation of o-functionalized (buta-1,3-diynyl)arenes, their iodocyclization with the formation of iodoethynylheterocycles and the second Sonogashira coupling of C-I atom with an appropriate alkyne. [49][50][51] Following this way and using starting materials with essential functional groups, i.e., oiodothioanisol (4), MeOCH 2 -substitited TMS-butadiyne 5, and N-tosylbut-3-yn-1-amine (8), acyclic enediyne 9 was obtained in good overall yield (Scheme 3).…”

“…Recently we have discovered that the Nicholas-type macrocyclization is a good synthetic tool for the construction of 10-membered oxa-and carbocyclic enediynes fused to a benzothiophene (Scheme 1, C), 43,44 whereas another macrocyclization technique based on the Nozaki reaction 45 and ring-closing metathesis (RCM) 46,47 can be used only for larger cycles because of increased strain that came from the benzothiophene fusion. We have also confirmed, that an-N. A. Danilkina et al…”

Ring Expansion of Alkylidenecarbenes Derived from Lactams, Lactones, and Thiolactones into Strained Heterocyclic Alkynes: A Theoretical Study

“…Medium-sized, moderately strained carbocyclic and heterocyclic alkynes have proven to be of particular importance in the field of bioorthogonal chemistry [27,28,29,30,31,32,33,34,35,36,37,38,39]. Larger carbocyclic and oxygen incorporated enediynes have also been prepared, and their Bergman cyclization activity investigated for potential therapeutic use [40,41]. Herein, we describe our computational investigations into the chemistry of cyclic alkylidenecarbenes ( 10 ) derived by formally replacing the carbonyl oxygen of lactams, lactones, and thiolactones ( 9 ) with a divalent carbon (Scheme 3).…”