Tandem Cyclization in Ruthenium Vinylidene Complexes with Two Ester Groups

The reaction of [Ru]-Cl ([Ru] = Cp(PPh3)2Ru) with o-ethynyl-substituted methyl benzoate, followed by a sequential deprotonation and electrophilic alkylation reactions by further reacting with base and various alkyl haloacetates, respectively, generated several disubstituted ruthenium vinylidene complexes. In the deprotonation reactions of these disubstituted vinylidene complexes containing two ester groups, tandem cyclizations of the ligand is accompanied with a methanol elimination to generate a new organometallic product containing a three-ring indenofuranone ligand, which structure has been confirmed by a single-crystal X-ray diffraction analysis. Facile protonation and methylation are observed in these indenofuranone complexes. Additionally, for the simple furyl complex containing an O-benzyl group, a 1,3-migration of the benzyl group is observed to yield a lactone product and a Claisen rearrangement is also observed in analogous complexes with O-allyl or O-propargyl groups

A Ferric-Superoxide Intermediate Initiates P450-Catalyzed Cyclic Dipeptide Dimerization

The cytochrome P450 (CYP) AspB is involved in the biosynthesis of the diketopiperazine (DKP) aspergilazine A. Tryptophan-linked dimeric DKP alkaloids are a large family of natural products that are found in numerous species and exhibit broad and often potent bioactivity. The proposed mechanisms for C-N bond formation by AspB, and similar C-C bond formations by related CYPs, have invoked the use of a ferryl-intermediate as an oxidant to promote substrate dimerization. Here, the parallel application of steady-state and transient kinetic approaches reveals a very different mechanism that involves a ferric-superoxide species as a primary oxidant to initiate DKP-assembly. Single turnover kinetic isotope effects and a substrate analog suggest the probable nature and site for abstraction. The direct observation of CYP-superoxide reactivity rationalizes the atypical outcome of AspB and reveals a new reaction manifold in heme enzymes

Ruthenium Allenylidene and Allylcarbene Complexes from 1,6-Diyne

Reactions of the four 1,6-diynes 1−3 and 7, each with one terminal propargylic alcohol and one internal triple bond containing Me3Si groups, with [Ru]−Cl ([Ru] = Cp(PPh3)2Ru) led to two types of products. In the first type, only the propargylic group is involved in the reaction leading to vinylidene, allenylidene, or acetylide complexes. A C−C bond formation of two triple bonds in 1,6-diynes gave allylcarbene products of the second type. The reaction of 1 with [Ru]−Cl yielded only the first type, giving a mixture of two cationic complexes; the allenylidene complex 8 and the phosphonium acetylide complex 9, the latter resulting from further addition of a phosphine molecule to Cγ of 8. The same reaction in the presence of excess phosphine gave 9 only. However, with an additional methyl group, the 1,6-diyne 2 reacted with [Ru]−Cl to give the allylcarbene complex 11 also with a phosphonium group on the ligand. The reaction proceeds by a cyclization reaction involving two triple bonds on the metal accompanied by a migration of a phosphine ligand to Cα. In both reactions strong affinity between alkyne and phosphine was observed, resulting in formations of P−C bonds with different regioselectivity. Addition of HCl to 11 transforms the five-electron-donor allylcarbene ligand to the four-electron-donor diene ligand along with formation of a Ru−Cl bond, giving complex 12 in high yield. From the reaction of [Ru]−Cl with diyne 3 containing a tert-butyl group at the propargylic carbon, both the allenylidene complex 13 and the allylcarbene complex 14 were obtained. The reaction of diyne 7 with [Ru]−Cl also gave both types of complexes, namely the vinylidene complex 16 and the allylcarbene complex 17. Crystal structures of complexes 9, 11, 12, and 16 have been determined by single-crystal X-ray diffraction analysis

Ruthenium Allenylidene and Allylcarbene Complexes from 1,6-Diyne

Reactions of the four 1,6-diynes 1−3 and 7, each with one terminal propargylic alcohol and one internal triple bond containing Me3Si groups, with [Ru]−Cl ([Ru] = Cp(PPh3)2Ru) led to two types of products. In the first type, only the propargylic group is involved in the reaction leading to vinylidene, allenylidene, or acetylide complexes. A C−C bond formation of two triple bonds in 1,6-diynes gave allylcarbene products of the second type. The reaction of 1 with [Ru]−Cl yielded only the first type, giving a mixture of two cationic complexes; the allenylidene complex 8 and the phosphonium acetylide complex 9, the latter resulting from further addition of a phosphine molecule to Cγ of 8. The same reaction in the presence of excess phosphine gave 9 only. However, with an additional methyl group, the 1,6-diyne 2 reacted with [Ru]−Cl to give the allylcarbene complex 11 also with a phosphonium group on the ligand. The reaction proceeds by a cyclization reaction involving two triple bonds on the metal accompanied by a migration of a phosphine ligand to Cα. In both reactions strong affinity between alkyne and phosphine was observed, resulting in formations of P−C bonds with different regioselectivity. Addition of HCl to 11 transforms the five-electron-donor allylcarbene ligand to the four-electron-donor diene ligand along with formation of a Ru−Cl bond, giving complex 12 in high yield. From the reaction of [Ru]−Cl with diyne 3 containing a tert-butyl group at the propargylic carbon, both the allenylidene complex 13 and the allylcarbene complex 14 were obtained. The reaction of diyne 7 with [Ru]−Cl also gave both types of complexes, namely the vinylidene complex 16 and the allylcarbene complex 17. Crystal structures of complexes 9, 11, 12, and 16 have been determined by single-crystal X-ray diffraction analysis

Ruthenium Allenylidene and Allylcarbene Complexes from 1,6-Diyne

Reactions of the four 1,6-diynes 1−3 and 7, each with one terminal propargylic alcohol and one internal triple bond containing Me3Si groups, with [Ru]−Cl ([Ru] = Cp(PPh3)2Ru) led to two types of products. In the first type, only the propargylic group is involved in the reaction leading to vinylidene, allenylidene, or acetylide complexes. A C−C bond formation of two triple bonds in 1,6-diynes gave allylcarbene products of the second type. The reaction of 1 with [Ru]−Cl yielded only the first type, giving a mixture of two cationic complexes; the allenylidene complex 8 and the phosphonium acetylide complex 9, the latter resulting from further addition of a phosphine molecule to Cγ of 8. The same reaction in the presence of excess phosphine gave 9 only. However, with an additional methyl group, the 1,6-diyne 2 reacted with [Ru]−Cl to give the allylcarbene complex 11 also with a phosphonium group on the ligand. The reaction proceeds by a cyclization reaction involving two triple bonds on the metal accompanied by a migration of a phosphine ligand to Cα. In both reactions strong affinity between alkyne and phosphine was observed, resulting in formations of P−C bonds with different regioselectivity. Addition of HCl to 11 transforms the five-electron-donor allylcarbene ligand to the four-electron-donor diene ligand along with formation of a Ru−Cl bond, giving complex 12 in high yield. From the reaction of [Ru]−Cl with diyne 3 containing a tert-butyl group at the propargylic carbon, both the allenylidene complex 13 and the allylcarbene complex 14 were obtained. The reaction of diyne 7 with [Ru]−Cl also gave both types of complexes, namely the vinylidene complex 16 and the allylcarbene complex 17. Crystal structures of complexes 9, 11, 12, and 16 have been determined by single-crystal X-ray diffraction analysis

Ruthenium Allenylidene and Allylcarbene Complexes from 1,6-Diyne

Reactions of the four 1,6-diynes 1−3 and 7, each with one terminal propargylic alcohol and one internal triple bond containing Me3Si groups, with [Ru]−Cl ([Ru] = Cp(PPh3)2Ru) led to two types of products. In the first type, only the propargylic group is involved in the reaction leading to vinylidene, allenylidene, or acetylide complexes. A C−C bond formation of two triple bonds in 1,6-diynes gave allylcarbene products of the second type. The reaction of 1 with [Ru]−Cl yielded only the first type, giving a mixture of two cationic complexes; the allenylidene complex 8 and the phosphonium acetylide complex 9, the latter resulting from further addition of a phosphine molecule to Cγ of 8. The same reaction in the presence of excess phosphine gave 9 only. However, with an additional methyl group, the 1,6-diyne 2 reacted with [Ru]−Cl to give the allylcarbene complex 11 also with a phosphonium group on the ligand. The reaction proceeds by a cyclization reaction involving two triple bonds on the metal accompanied by a migration of a phosphine ligand to Cα. In both reactions strong affinity between alkyne and phosphine was observed, resulting in formations of P−C bonds with different regioselectivity. Addition of HCl to 11 transforms the five-electron-donor allylcarbene ligand to the four-electron-donor diene ligand along with formation of a Ru−Cl bond, giving complex 12 in high yield. From the reaction of [Ru]−Cl with diyne 3 containing a tert-butyl group at the propargylic carbon, both the allenylidene complex 13 and the allylcarbene complex 14 were obtained. The reaction of diyne 7 with [Ru]−Cl also gave both types of complexes, namely the vinylidene complex 16 and the allylcarbene complex 17. Crystal structures of complexes 9, 11, 12, and 16 have been determined by single-crystal X-ray diffraction analysis

Mechanistic Consequences of Chiral Radical Clock Probes: Analysis of the Mononuclear Non-Heme Iron Enzyme HppE with 2‑Hydroxy-3-methylenecyclopropyl Radical Clock Substrates

(<i>S</i>)-2-Hydroxypropylphosphonic acid [(<i>S</i>)-HPP] epoxidase (HppE) is a mononuclear iron enzyme that catalyzes the last step in the biosynthesis of the antibiotic fosfomycin. HppE also processes the (<i>R</i>)-enantiomer of HPP but converts it to 2-oxo-propylphosphonic acid. In this study, all four stereoisomers of 3-methylenecyclopropyl-containing substrate analogues, (2<i>R</i>, 3<i>R</i>)-<b>8</b>, (2<i>R</i>, 3<i>S</i>)-<b>8</b>, (2<i>S</i>, 3<i>R</i>)-<b>8</b>, and (2<i>S</i>, 3<i>S</i>)-<b>8</b>, were synthesized and used as radical probes to investigate the mechanism of the HppE-catalyzed reaction. Upon treatment with HppE, (2<i>S</i>, 3<i>R</i>)-<b>8</b> and (2<i>S</i>, 3<i>S</i>)-<b>8</b> were converted via a C1 radical intermediate to the corresponding epoxide products, as anticipated. In contrast, incubation of HppE with (2<i>R</i>, 3<i>R</i>)-<b>8</b> led to enzyme inactivation, and incubation of HppE with (2<i>R</i>, 3<i>S</i>)-<b>8</b> yielded the 2-keto product. The former finding is consistent with the formation of a C2 radical intermediate, where the inactivation is likely triggered by radical-induced ring cleavage of the methylenecyclopropyl group. Reaction with (2<i>R</i>, 3<i>S</i>)-<b>8</b> is predicted to also proceed via a C2 radical intermediate, but no enzyme inactivation and no ring-opened product were detected. These results strongly suggest that an internal electron transfer to the iron center subsequent to C–H homolysis competes with ring-opening in the processing of the C2 radical intermediate. The different outcomes of the reactions with (2<i>R</i>, 3<i>R</i>)-<b>8</b> and (2<i>R</i>, 3<i>S</i>)-<b>8</b> demonstrate the need to carefully consider the chirality of substituted cyclopropyl groups as radical reporting groups in studies of enzymatic mechanisms