Secondary Nucleophiles Research Articles

A novel synthesis of 2-((2-oxopropyl)selanyl) benzamide derivatives by cascade selenenylation-acylation reaction and in vitro cytotoxicity evaluation

Based on the Se-N bond modify strategy emerging from ebselen, a facile, solvent-free cascade selenenylation-acylation reaction for synthesis of novel 2-((2-oxopropyl)selanyl) benzamide organoselenium compounds was developed, by using 2-chloroselenobenzoyl chloride as biselectrophile reagent, where acetone as primary nucleophile for the selenenylation reaction, and amine as secondary nucleophile for the acylation. In vitro cytotoxicity was evaluated by using CCK8 assay, and some of the newly synthesized compounds exhibited equally or superior activities to cisplatin against five cancer cell lines, including A549, EC109, HCT116, HepG2, and MCF-7.

Catalytic Enantioselective Cross-Couplings of Secondary Alkyl Electrophiles with Secondary Alkylmetal Nucleophiles: Negishi Reactions of Racemic Benzylic Bromides with Achiral Alkylzinc Reagents

We have developed a nickel-catalyzed method for the asymmetric cross-coupling of secondary electrophiles with secondary nucleophiles, specifically, stereoconvergent Negishi reactions of racemic benzylic bromides with achiral cycloalkylzinc reagents. In contrast to most previous studies of enantioselective Negishi cross-couplings, tridentate pybox ligands are ineffective in this process; however, a new, readily available bidentate isoquinoline-oxazoline ligand furnishes excellent ee's and good yields. The use of acyclic alkylzinc reagents as coupling partners led to the discovery of a highly unusual isomerization that generates a significant quantity of a branched cross-coupling product from an unbranched nucleophile.

Nickel-Catalyzed Negishi Cross-Coupling Reactions of Secondary Alkylzinc Halides and Aryl Iodides

A general Ni-catalyzed process for the cross-coupling of secondary alkylzinc halides and aryl/heteroaryl iodides has been developed. This is the first process to overcome the isomerization and β-hydride elimination problems that are associated with the use of secondary nucleophiles, and that have limited the analogous Pd-catalyzed systems. The impact of salt additives was also investigated. It was found that the presence of LiBF(4) dramatically improves both isomeric retention and yield for challenging substrates.

Engineering Platelet‐Activating Factor Acetylhydrolase as a Catalytic Bioscavenger for Organophosphorus Compounds

Platelet‐activating factor acetylhydrolase (PAFAH) offers a unique platform on which to engineer a catalytic bioscavenger for organophosphorus compounds (OP). Liposome‐associated enzymes, like PAFAH and PON1, circulate within the plasma and interact with OPs before cholinergic disruption. Wild type PAFAH and butyrylcholinesterase (BuChE) were tested for their ability to interact with the OPs tabun (GA), sarin (GB), and soman (GD). BuChE could be completely inhibited with 10 uM of each OP while PAFAH was resistant, and maintained at least 55% of original activity. We investigated W298, F322 and L153 within human PAFAH as sites for a secondary nucleophile to improve reactivation of the OP‐inhibited enzyme. Mutants screened were less reactive than wild type to the soluble substrates p‐nitrophenyl butyrate (PNPB) and 2‐thio PAF. We tested mutants against VX, VR, V2 (an analog of VX), and echothiophate, but found no appreciable catalytic power against these OPs. We mutated residue Q352 to G, N, and W to determine its contribution to binding soluble substrates. For the smaller substrate PNPB, all mutants had higher KMs, but catalytic efficiencies were similar to wild type. For 2‐thio PAF, Q352N had low activity, whereas Q352W increased the catalytic efficiency by 20‐fold over Q352G and 80‐fold over wild type by reducing KM. Spontaneous reactivation rates with a variety of OPs will be discussed.

ChemInform Abstract: Nickel‐Catalyzed Negishi Cross‐Couplings of Secondary Nucleophiles with Secondary Propargylic Electrophiles at Room Temperature.

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New reactions of 2-methylenetetrahydropyrans. A three component coupling protocol for the synthesis of tetrahydropyranyl ketides.

Three component coupling of a 2-methylenetetrahydropyran, an activated aldehyde or ketone and a secondary nucleophile provides an efficient preparation of tetrahydropyranyl ketides, a unit common to many complex natural products.

Nickel‐Catalyzed Negishi Cross‐Couplings of Secondary Nucleophiles with Secondary Propargylic Electrophiles at Room Temperature

In recent years, significant progress has been made in the development of metal-catalyzed cross-couplings of alkyl electrophiles.[1] A number of substantial challenges have not yet been met, including the coupling of sterically demanding partners. For example, we are not aware of reports of palladium- or nickel-catalyzed cross-couplings of secondary alkyl electrophiles with secondary organometallic nucleophiles.[2] Recognizing the importance of overcoming this limitation, we have recently turned our attention to addressing this deficiency. Due in part to the ease of synthesis and functional-group compatibility of alkylzinc reagents, we chose to focus our efforts on Negishi reactions.[3, 4, 5] In this communication, we describe the first nickel-based catalysts that achieve cross-couplings of secondary nucleophiles with secondary electrophiles [Eq. (1)]. (1) As part of our initial investigation, we explored the Negishi reaction illustrated in Table 1.[6] Unfortunately, none of the methods that have previously been reported for cross-couplings of secondary alkyl electrophiles with primary alkylzinc reagents furnishes the desired product in substantial yield (<20%).[7,8] By optimizing the various reaction parameters, we were able to develop a catalyst system that achieves this Negishi cross-coupling with good efficiency at room temperature (89% yield; Table 1, entry 1).[9] In the absence of NiCl2•glyme or terpyridine, essentially no carbon–carbon bond formation occurs (entries 2 or 3). If the bulky TIPS substituent is replaced with a smaller silyl or alkyl group, the yield of the cross-coupling decreases, due to the formation of a substantial amount of homocoupled electrophile (entries 4 and 5).[10] The other ligands, both bidentate and tridentate, that we have examined, are less useful than terpyridine (entries 6–8), as are solvents other than DMA (entries 9–11). Table 1 Negishi reactions of secondary nucleophiles with secondary propargylic electrophiles: Effect of reaction parameters. Our optimized method (NiCl2•glyme/terpyridine/DMA) can be applied to cross-couplings of a range of secondary propargylic bromides with secondary alkylzincs (Table 2). Esters, olefins (no E/Z isomerization), ethers, and carbamates are compatible with the reaction conditions.[11] Table 2 Room-temperature Negishi reactions of secondary nucleophiles with secondary propargylic electrophiles. Although our primary objective was to develop a method for secondary–secondary cross-couplings, we were also interested in exploring the versatility of this catalyst. We have determined that, without modification, NiCl2•glyme/terpyridine/DMA can also be applied to Negishi reactions of less-hindered coupling partners, e.g., primary alkylzinc reagents with secondary/primary propargylic bromides (Table 3). Cross-couplings proceed in very good yield in the presence of an unactivated primary alkyl chloride, an ether, and an ester.[12] Table 3 Negishi reactions of primary nucleophiles with secondary and primary propargylic electrophiles. If the alkyl group of the organozinc reagent is more hindered than cyclohexyl or isopropyl, the efficiency of NiCl2•glyme/terpyridine/DMA diminishes significantly (e.g., for entry 1 of Table 4: 20% yield). However, by replacing terpyridine with a related ligand, 2,6-bis(N-pyrazolyl)pyridine, and switching to THF as the solvent, the desired Negishi cross-coupling can be achieved in good yield (entry 1 of Table 4: 86% yield).[13,14] Functional groups such as alkynes, unactivated alkyl chlorides, and ethers are tolerated by this method (Table 4).[15] Table 4 Room-temperature Negishi reactions of secondary nucleophiles with secondary propargylic electrophiles. We have determined that our coupling conditions can be employed not only for propargylic bromides, but also for propargylic chlorides (also at room temperature; [Eq. (2) and Eq. (3)]. (2) (3) We have applied our method for secondary-secondary cross-couplings to the formal total synthesis of α-cembra-2,7,11-triene-4,6-diol (Scheme 1), a cembranoid diterpene with antitumor activity that has been synthesized by Marshall[16] and by Thomas.[17] We envisioned that the isopropyl substituent could be installed by a Negishi reaction of propargylic bromide 1, which can be generated from farnesyl acetate; indeed, using our Ni/terpyridine method, we were able to achieve the desired cross-coupling in 61% yield on a gram-scale. In preliminary studies, we have converted coupling product 2 into 14-membered macrocycle 3, which served as an intermediate in the Thomas synthesis of α-cembra-2,7,11-triene-4,6-diol.[17,18] Scheme 1 Application of a secondary-secondary Negishi cross-coupling in a formal total synthesis of α-2,7,11-cembranetriene-4,6-diol. In conclusion, we have developed the first method for secondary–secondary cross-couplings with a Group X catalyst, specifically a nickel-based system for coupling propargylic halides with alkylzinc reagents that proceeds under mild conditions (room temperature and no basic activators). Future efforts will focus on further expanding the scope of cross-coupling reactions of alkyl electrophiles.

Nickel‐Catalyzed Negishi Cross‐Couplings of Secondary Nucleophiles with Secondary Propargylic Electrophiles at Room Temperature

Der feine Milde: Die ersten Nickelkatalysatoren für die Kreuzkupplung sekundärer metallorganischer Nucleophile mit sekundären Alkylelektrophilen wurden entwickelt. So verlaufen Negishi-Kupplungen unter milden Bedingungen (bei Raumtemperatur und ohne basische Aktivierung) in Gegenwart von NiCl2⋅Glyme und einem dreizähnigen Liganden (siehe Schema).

Structural insight into the DNA polymerase β deoxyribose phosphate lyase mechanism

A large number of biochemical and genetic studies have demonstrated the involvement of DNA polymerase β (Pol β) in mammalian base excision repair (BER). Pol β participates in BER sub-pathways by contributing gap filling DNA synthesis and lyase removal of the 5′-deoxyribose phosphate (dRP) group from the cleaved abasic site. To better understand the mechanism of the dRP lyase reaction at an atomic level, we determined a crystal structure of Pol β complexed with 5′-phosphorylated abasic sugar analogs in nicked DNA. This DNA ligand represents a potential BER intermediate. The crystal structure reveals that the dRP group is bound in a non-catalytic binding site. The catalytic nucleophile in the dRP lyase reaction, Lys72, and all other potential secondary nucleophiles, are too far away to participate in nucleophilic attack on the C1′ of the sugar. An approximate model of the dRP group in the expected catalytic binding site suggests that a rotation of 120° about the dRP 3′-phosphate is required to position the ɛ-amino Lys72 close to the dRP C1′. This model also suggests that several other side chains are in position to facilitate the β-elimination reaction. From results of mutational analysis of key residues in the dRP lyase active site, it appears that the substrate dRP can be stabilized in the observed non-catalytic binding conformation, hindering dRP lyase activity.

Preparation of alkyl-Fp [Fp = (C5H5)Fe(CO)2] complexes via organometallic reagents: reactions of RMgX and RLi with Fp-I and Fp-THF+BF4-

The preparation of alkyl substituted Fp Complexes [Fp = (C5H5)Fe(CO)2] by the reaction of Grignard or alkyl lithium reagents with Fp-I and Fp -THF+BF4- has been investigated. Small alkyl substituents (Me, Pr, Bu) provided moderate yields of Fp-R in the reaction of the corresponding lithium or magnesium reagent with Fp-I. Cyclohexyl and phenyl Grignard reagents showed coupling of the organic fragments and concomitant production of Fp2. Increased yields of Fp-R and decreased generation of Fp2 were observed when Fp-THF+ was used in place of Fp-I. Secondary nucleophiles gave substantially lower yields.