| 1. |
- Akaberi, Dario, et al.
(författare)
-
Identification of a C2-symmetric diol based human immunodeficiency virus protease inhibitor targeting Zika virus NS2B-NS3 protease
- 2020
-
Ingår i: Journal of Biomolecular Structure and Dynamics. - : Informa UK Limited. - 0739-1102 .- 1538-0254. ; 38:18, s. 5526-5536
-
Tidskriftsartikel (refereegranskat)abstract
- Zika virus (ZIKV) is an emerging mosquito-borne flavivirus and infection by ZIKV Asian lineage is known to cause fetal brain anomalies and Guillain-Barrés syndrome. The WHO declared ZIKV a global public health emergency in 2016. However, currently neither vaccines nor antiviral prophylaxis/treatments are available. In this study, we report the identification of a C2-symmetric diol-based Human immunodeficiency virus type-1 (HIV) protease inhibitor active against ZIKV NS2B-NS3 protease. The compound, referred to as 9b, was identified by in silico screening of a library of 6265 protease inhibitors. Molecular dynamics (MD) simulation studies revealed that compound 9b formed a stable complex with ZIKV protease. Interaction analysis of compound 9b's binding pose from the cluster analysis of MD simulations trajectories predicted that 9b mostly interacted with ZIKV NS3. Although designed as an aspartyl protease inhibitor, compound 9b was found to inhibit ZIKV serine protease in vitro with IC50 = 143.25 ± 5.45 µM, in line with the in silico results. Additionally, linear interaction energy method (LIE) was used to estimate binding affinities of compounds 9b and 86 (a known panflavivirus peptide hybrid with IC50 = 1.64 ± 0.015 µM against ZIKV protease). The LIE method correctly predicted the binding affinity of compound 86 to be lower than that of 9b, proving to be superior to the molecular docking methods in scoring and ranking compounds. Since most of the reported ZIKV protease inhibitors are positively charged peptide-hybrids, with our without electrophilic warheads, compound 9b represents a less polar and more drug-like non-peptide hit compound useful for further optimization.Communicated by Ramaswamy Sarma.
|
|
| 2. |
|
|
| 3. |
- Akaberi, Dario, et al.
(författare)
-
Targeting the NS2B-NS3 protease of tick-borne encephalitis virus with pan-flaviviral protease inhibitors
- 2021
-
Ingår i: Antiviral Research. - : Elsevier. - 0166-3542 .- 1872-9096. ; 190
-
Tidskriftsartikel (refereegranskat)abstract
- Tick-borne encephalitis (TBE) is a severe neurological disorder caused by tick-borne encephalitis virus (TBEV), a member of the Flavivirus genus. Currently, two vaccines are available in Europe against TBEV. However, TBE cases have been rising in Sweden for the past twenty years, and thousands of cases are reported in Europe, emphasizing the need for antiviral treatments against this virus. The NS2B-NS3 protease is essential for flaviviral life cycle and has been studied as a target for the design of inhibitors against several well-known flaviviruses, but not TBEV. In the present study, Compound 86, a known tripeptidic inhibitor of dengue (DENV), West Nile (WNV) and Zika (ZIKV) proteases, was predicted to be active against TBEV protease using a combination of in silico techniques. Further, Compound 86 was found to inhibit recombinant TBEV protease with an IC50 = 0.92 mu M in the in vitro enzymatic assay. Additionally, two more peptidic analogues were synthetized and they displayed inhibitory activities against both TBEV and ZIKV proteases. In particular, Compound 104 inhibited ZIKV protease with an IC50 = 0.25 mu M. These compounds represent the first reported inhibitors of TBEV protease to date and provides valuable information for the further development of TBEV as well as pan-flavivirus protease inhibitors.
|
|
| 4. |
- Barlow, Nicholas, et al.
(författare)
-
Macrocyclic Peptidomimetics as Inhibitors of Insulin-Regulated Aminopeptidase (IRAP)
- 2020
-
Ingår i: RSC Medicinal chemistry. - : Royal Society of Chemistry (RSC). - 2632-8682. ; 11:2, s. 234-244
-
Tidskriftsartikel (refereegranskat)abstract
- Macrocyclic analogues of the linear hexapeptide, angiotensin IV (AngIV) have proved to be potent inhibitors of insulin-regulated aminopeptidase (IRAP, oxytocinase, EC 3.4.11.3). Along with higher affinity, macrocycles may also offer better metabolic stability, membrane permeability and selectivity, however predicting the outcome of particular cycle modifications is challenging. Here we describe the development of a series of macrocyclic IRAP inhibitors with either disulphide, olefin metathesis or lactam bridges and variations of ring size and other functionality. The binding mode of these compounds is proposed based on molecular dynamics analysis. Estimation of binding affinities (∆G) and relative binding free energies (∆∆G) with the linear interaction energy (LIE) method and free energy perturbation (FEP) method showed good general agreement with the observed inhibitory potency. Experimental and calculated data highlight the cumulative importance of an intact N-terminal peptide, the specific nature of the macrocycle, the phenolic oxygen and the C-terminal functionality.
|
|
| 5. |
- Benediktsdottir, Andrea, 1990-, et al.
(författare)
-
Antibacterial sulfonimidamide-based oligopeptides as type I signal peptidase inhibitors : Synthesis and biological evaluation
- 2021
-
Ingår i: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 224
-
Tidskriftsartikel (refereegranskat)abstract
- Oligopeptide boronates with a lipophilic tail are known to inhibit the type I signal peptidase in E. coli, which is a promising drug target for developing novel antibiotics. Antibacterial activity depends on these oligopeptides having a cationic modification to increase their permeation. Unfortunately, this modification is associated with cytotoxicity, motivating the need for novel approaches. The sulfonimidamide functionality has recently gained much interest in drug design and discovery, as a means of introducing chirality and an imine-handle, thus allowing for the incorporation of additional substituents. This in turn can tune the chemical and biological properties, which are here explored. We show that introducing the sulfonimidamide between the lipophilic tail and the peptide in a series of signal peptidase inhibitors resulted in antibacterial activity, while the sulfonamide isostere and previously known non-cationic analogs were inactive. Additionally, we show that replacing the sulfonamide with a sulfonimidamide resulted in decreased cytotoxicity, and similar results were seen by adding a cationic sidechain to the sulfonimidamide motif. This is the first report of incorporation of the sulfonimidamide functional group into bioactive peptides, more specifically into antibacterial oligopeptides, and evaluation of its biological effects.
|
|
| 6. |
- Benediktsdóttir, Andrea, 1990-
(författare)
-
Design and synthesis of enzyme inhibitors against Gram-negative bacteria : Targeting protein secretion and lipid A biosynthesis
- 2024
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The discovery and implementation of antibiotics for clinical use was unquestionably the greatest medical breakthrough of the 20th century. However, the widespread misuse and overuse of these antibiotics, has led to the rapid emergence and spread of antibiotic resistance. The 'ESKAPE' pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) represent a critical threat in multidrug-resistant infections. The Gram-negative species (such as E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii) are especially difficult to combat due to their dual-membrane and efficient efflux pumps, which limit the efficacy of many antibiotics. Despite significant efforts, no new antibiotic class with a new mechanism of action has been approved for Gram-negative pathogens in over five decades. New chemical classes of antibacterial compounds targeting distinct mechanisms within Gram-negative bacteria are therefore urgently called for. The studies outlined in this thesis addresses these challenges by designing and synthesising new antibacterial compounds of three distinct chemical classes, which interact with two unrealized targets, LepB and LpxH, in Gram-negative bacteria, including E. coli and K. pneumoniae. This thesis investigates the effect of macrocyclization of type I signal peptidase (LepB) inhibitors by optimizing previously studied linear lipopeptide boronic acids and esters to address their cytotoxic and hemolytic liabilities while retaining activity. This resulted in the synthesis of first-in-class P2-P1' boronic ester-linked macrocycles with modest improvement of cytotoxicity but at the cost of reduced antibacterial activity (paper I). In another optimization attempt, isosteric modification of LepB inhibitors was explored by introducing the sulfonimidamide motif into oligopeptide boronic esters, displaying potent LepB inhibitors. Prior to the synthesis of these pseudopeptides novel methods were developed to introduce sulfonimidamides into peptides on solid-phase (paper II and paper III). These studies demonstrated the potential of sulfonimidamides to alter the drug properties and which was herein compared to a corresponding sulfonamide. Additionally, the thesis describes how a new series of LpxH inhibitors, meta-sulfonamidobenzamide-based sulfonyl piperazine derivatives, were identified and prepared. This resulted in inhibitors with wild-type activity without causing hemolysis, cell toxicity or inhibition of hERG ion channel (paper IV). In summary, strategies suitable for the synthesis and optimization of new antibacterial compounds targeting two distinct Gram-negative bacterial targets, LepB and LpxH, are described in this thesis. While there was no success in separating toxicity from antibacterial activity of the LepB inhibitors, these results highlight the challenge in this task and contribute to a better understanding of the structure-activity and toxicity relationships of such inhibitors and provide strategies that could be of use in antibacterial drug discovery. The identification of the meta-sulfonamidobenzamide derivatives offer promising LpxH-targeting hits with the potential for further development in future hit-to-lead antibacterial programs.
|
|
| 7. |
- Benediktsdottir, Andrea, et al.
(författare)
-
Design, synthesis, and in vitro biological evaluation of meta-sulfonamidobenzamide-based antibacterial LpxH inhibitors
- 2024
-
Ingår i: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 278
-
Tidskriftsartikel (refereegranskat)abstract
- New antibacterial compounds are urgently needed, especially for infections caused by the top-priority Gram-negative bacteria that are increasingly difficult to treat. Lipid A is a key component of the Gram-negative outer membrane and the LpxH enzyme plays an important role in its biosynthesis, making it a promising antibacterial target. Inspired by previously reported ortho-N-methyl-sulfonamidobenzamide-based LpxH inhibitors, novel benzamide substitutions were explored in this work to assess their in vitro activity. Our findings reveal that maintaining wild-type antibacterial activity necessitates removal of the N-methyl group when shifting the ortho-N-methyl-sulfonamide to the meta-position. This discovery led to the synthesis of meta-sulfonamidobenzamide analogs with potent antibacterial activity and enzyme inhibition. Moreover, we demonstrate that modifying the benzamide scaffold can alter blocking of the cardiac voltage-gated potassium ion channel hERG. Furthermore, two LpxH-bound X-ray structures show how the enzyme-ligand interactions of the meta-sulfonamidobenzamide analogs differ from those of the previously reported ortho analogs. Overall, our study has identified meta-sulfonamidobenzamide derivatives as promising LpxH inhibitors with the potential for optimization in future antibacterial hit-to-lead programs.
|
|
| 8. |
- Chinthakindi, Praveen K., et al.
(författare)
-
Solid Phase Synthesis of Sulfonimidamide Pseudopeptides and Library Generation
- 2020
-
Ingår i: European Journal of Organic Chemistry. - : Wiley-VCH Verlagsgesellschaft. - 1434-193X .- 1099-0690. ; 2020:25, s. 3796-3807
-
Tidskriftsartikel (refereegranskat)abstract
- Many synthetic routes have been explored to make small molecule sulfonimidamides (SIAs), however, its introduction into larger molecules such as oligopeptides has not been studied before. We herein demonstrate three alternative and complementary methods for synthesis of SIA based pseudopeptides, on solid phase, using both on and off‐resin SIA‐synthesis, via sulfonimidoyl chlorides from sulfonamides, in high conversion. Beside evaluation of various resins such as 2‐CTC, Wang, and Rink amide‐ChemMatrix, the possibilities to further N‐functionalize and cyclize the SIA functionality on solid support are shown. The diastereomers of SIA containing pseudopeptides could in most cases be separated using normal reverse phase preparative HPLC. The solid phase SIA methodology has many advantages when it comes to handling and purification as compared to in solution, and will therefore enable exploration of the SIA group as isosteric substitutions and peptidomimetic building blocks in the development of drug‐like pseudopeptides in many ways. Of particular note these approaches facilitate combinatorial library synthesis as demonstrated herein.
|
|
| 9. |
- Chinthakindi, Praveen K., et al.
(författare)
-
Synthesis of Sulfonimidamide-Based Amino Acid Building Blocks with Orthogonal Protecting Groups
- 2019
-
Ingår i: European Journal of Organic Chemistry. - : WILEY-V C H VERLAG GMBH. - 1434-193X .- 1099-0690. ; :5, s. 1045-1057
-
Tidskriftsartikel (refereegranskat)abstract
- Herein, we report the synthesis of novel sulfonimidamides (SIAs) based on amino acid building blocks using a one-pot method from tert-butyldiphenylsilyl-protected (TBDPS) sulfonamides, as well as exploration of orthogonal deprotection strategies. Among the several protecting groups investigated, TBDPS showed higher conversion, allowed UV detection and simple diastereomeric separation; in particular in combination with amino acid tert-butyl esters. Moreover, we applied the present method to synthesize cyclic five-membered acyl sulfonimidamides in two steps. The described synthesis of SIA-based amino acid building blocks in combination with the orthogonal protection groups provide access to unnatural amino acid building blocks useful for further incorporation into larger molecules, such as peptide-based transition-state analogues and peptidomimetics. The chirality of the SIA group, as well as its additional point of diversity provided by the extra NH group, creates opportunities for the development of unique compound libraries that explore new chemical space, which is of considerable importance for the pharmaceutical and agrochemical industry.
|
|
| 10. |
|
|
| 11. |
- Hallberg, Mathias, 1971-, et al.
(författare)
-
From the Anti-Nociceptive Substance P Metabolite Substance P (1-7) to Small Peptidomimetics
- 2018
-
Ingår i: Current protein and peptide science. - : Bentham Science Publishers Ltd.. - 1389-2037 .- 1875-5550. ; 19:11, s. 1038-1048
-
Forskningsöversikt (refereegranskat)abstract
- Substance P (SP) is associated with pain and inflammatory processes and is released from terminals of specific sensory nerves. This undecapeptide that mediates its effects through the neurokinin type 1 (NK1) receptor, is rapidly degraded in vivo to smaller fragments. The heptapeptide SP(1-7) with a hitherto unknown receptor, is a major bioactive fragment and displays often opposite actions to those induced by SP. Hence, SP(1-7) elicits anti-nociceptive and anti-hyperalgesic effects. These observations have attracted a substantial interest and in this mini-review the efforts to transform the heptapeptide SP(1-7) into more drug-like small-molecule SP(1-7) peptidomimetics as a potential new class of analgesics are summarized. Structure-activity relationship studies and subsequent amidation of the C-terminal and truncations from the N-terminal of the heptapeptide delivered the bioactive dipeptide amide Gln-Phe-NH2 showing a high affinity at the SP(1-7) binding site. Similarly, endomorphin-2, an endogenous opioid ligand containing a C-terminal carboxamide group, demonstrated a high affinity at the SP(1-7) binding site. Endomorphin-2 subjected to truncations yielded the potent dipeptide amide Phe-Phe-NH2. Structural optimization of the latter furnished more drug-like high affinity ligands and among those a constrained cis-3-phenylpyrrolidine derivative that after peripheral administration produced a significant anti-allodynic effect in a mouse SNI model of neuropathic pain. This SP(1-7) peptidomimetic was as effective as SP(1-7) in alleviating mechanical allodynia in mice. Although, additional structural modifications are needed to achieve compounds exhibiting high/fair bioavailability after oral administration, the examples presented herein demonstrate that the bioactive peptides SP(1-7) and endomorphin-2 can be converted into low molecular weight compounds that are able to mimic the in vivo actions of the heptapeptide SP(1-7).
|
|
| 12. |
- Luttens, Andreas, et al.
(författare)
-
Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses
- 2022
-
Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 144:7, s. 2905-2920
-
Tidskriftsartikel (refereegranskat)abstract
- Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-based docking was used to screen a diverse library of 235 million virtual compounds against the active site. One hundred top-ranked compounds were tested in binding and enzymatic assays. Second, a fragment discovered by crystallographic screening was optimized guided by docking of millions of elaborated molecules and experimental testing of 93 compounds. Three inhibitors were identified in the first library screen, and five of the selected fragment elaborations showed inhibitory effects. Crystal structures of target-inhibitor complexes confirmed docking predictions and guided hit-to-lead optimization, resulting in a noncovalent main protease inhibitor with nanomolar affinity, a promising in vitro pharmacokinetic profile, and broad-spectrum antiviral effect in infected cells.
|
|
| 13. |
- Nyman, Julia, et al.
(författare)
-
The amino-terminal heptapeptide of the algesic substance P provides analgesic effect in relieving chronic neuropathic pain
- 2021
-
Ingår i: European Journal of Pharmacology. - : Elsevier. - 0014-2999 .- 1879-0712. ; 892
-
Tidskriftsartikel (refereegranskat)abstract
- Of painful conditions, somatic pain of acute nociceptive origin can be effectively managed clinically, while neuropathic pain of chronic neuropathy origin is difficult to control. For molecules involved in pain sensation, substance P (SP) is algesic, exacerbating painful sensation, while its amino-terminal fragment, heptapeptide SP(1-7), confers biological activities different from its full-length parent neuropeptide precursor. We previously demonstrated SP(1-7) interaction with pain processing to alleviate chronic pain. Here we evaluated SP(1-7) and its C-terminal amidated analogue SP(1-7) amide, together with SP and opioid agonist DAMGO. We tested mouse behaviors of both acute somatic pain in tail-flick latency assay, and neuropathic pain in sciatic nerve injury model of chronic constriction injury (CCI). DAMGO produced dose-dependent analgesia for somatic pain as expected, so did both SP(1-7) and its analogue SP(1-7) amide, while SP yielded the opposite effect of algesia, in a phenomenon we termed `contrintus', meaning 'opposite from within' to denote that two peptides of the same origin (SP and its metabolic fragment SP(1-7)) produced opposite effects. In CCI model, DAMGO showed a general reduction in allodynia sensitivity for both nerve-injured and normal paws, without selective effect for neuropathic pain, consistent with clinical observation that opioids are less effective for chronic neuropathic pain. On the other hand, both SP(1-7) and SP(1-7) amide displayed dose-dependent anti-allodynia effect that is selective for neuropathic pain. These findings suggest that SP(1-7) and its analogue may be useful for developing pharmaceuticals to treat neuropathic pain.
|
|
| 14. |
- Skogh, Anna, et al.
(författare)
-
Impact of N-methylation of the substance P 1-7 amide on anti-allodynic effect in mice after peripheral administration
- 2017
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 109, s. 533-540
-
Tidskriftsartikel (refereegranskat)abstract
- Substance P 1-7 (SP1-7, Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7) is the major bioactive metabolite formed after proteolytic degradation of the tachykinin substance P (SP). This heptapeptide often opposes the effects of the mother peptide. Hence, SP1-7 is having anti-inflammatory, anti-nociceptive and anti-hyperalgesic effects in experimental models. Despite all encouraging properties of SP1-7 its exact mode of action has not yet been elucidated which has hampered further development of this heptapeptide in drug discovery. Contrary to SP that mediates its biological activity via the NK-1 receptor, the N-terminal fragment SP1-7 acts through an unknown target that is distinct from all known opioid and tachykinin receptors. The SP1-7 amide 1 (Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7-NH2) was previously shown to be superior to the endogenous SP1-7 in all experimental pain models where the two compounds were compared. Herein, we report that N-methylation scan of the backbone of the SP1-7 amide (1) results in peptides that are significantly less prone to undergo proteolysis in plasma from both mouse and human. However, with the two exceptions of the [MeLys3]SP1-7 amide (3) and the [MeGln5]SP1-7 amide (4), the peptides with a methyl group attached to the backbone are devoid of significant anti-allodynic effects after peripheral administration in the spared nerve injury (SNI) mouse model of neuropathic pain. It is suggested that the N-methylation does not allow these peptides to form the accurate bioactive conformations or interactions required for efficient binding to the macromolecular target. The importance of intact N-terminal Arg1 and C-terminal Phe7, anticipated to serve as address and message residues, respectively, for achieving the anti-allodynic effect is emphasized. Notably, the three heptapeptides: the SP1-7 amide (1), the [MeLys3]SP1-7 amide (3) amide and the [MeGln5]SP1-7 amide (4) are all considerably more effective in the SNI mouse model than gabapentin that is widely used in the clinic for treatment of neuropathic pain.
|
|
| 15. |
- Skogh, Anna, et al.
(författare)
-
Importance of N-and C-terminal residues of substance P 1-7 for alleviating allodynia in mice after peripheral administration
- 2017
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier. - 0928-0987 .- 1879-0720. ; 106, s. 345-351
-
Tidskriftsartikel (refereegranskat)abstract
- The heptapeptide SP1-7 (1, Arg(1)-Pro(2)-Lys(3)-Pro(4)-Gln(5)-Gln(6)-Phe(7)) is the major bioactive metabolite formed after proteolytic processing of the neuropeptide substance P (SP, Arg(1)-Pro(2)-Lys(3)-Pro(4)-GIn(5)-Gln(6)-Phe(7)-Phe(8)-Gly(9)-Leu(10)-Meti(11)-NH2). The heptapeptide 1 frequently exhibits opposite effects to those induced by SP, such as exerting antinociception, or attenuating thermal hyperalgesia and mechanical allodynia. The heptapeptide SP1-7 amide (2, Arg(1)-Pro(2)-Lys(3)-Pro(4)-Gln(5)-Gln(6)-Phe(7)-NH2 ) is often more efficacious than 1 in experimental pain models. We have now assessed the anti-allodynic outcome after systemic administration of 2 and a series of Ala substituted and truncated analogues of 2, in the spared nerve injury (SNI) mice model and the results obtained were correlated with in vitro plasma stability and permeability measurements. It is herein demonstrated that an intact Arg(1) in SP1-7 amide analogues is fundamental for retaining a potent in vivo effect, while Lys(3) of 2 is less important. A displacement with Ala(1) or truncation rendered the peptide analogues either inactive or with a significantly attenuated in vivo activity. Thus, the pentapeptide SP3-7 amide (7, t(1/2) = 11.1 min) proven to be the major metabolite of 2, demonstrated an in vivo effect itself although considerably less significant than 2 in the SNI model. Intraperitoneal administration of 2 in a low dose furnished the most powerful anti-allodynic effect in the SNI model of all the analogous evaluated, despite a fast proteolysis of 2 in plasma (t(1/2) = 6.4 min). It is concluded that not only the C-terminal residue, that we previously demonstrated, but also the N-terminal with its basic side chain, are important for achieving effective pain relief. This information is of value for the further design process aimed at identifying more drug-like SP1-7 amide related peptidomimetics with pronounced antiallodynic effects.
|
|
| 16. |
- Svennebring, Andreas, 1973-
(författare)
-
Fast Microwave-Enhanced Intra-, Pseudo-intra- and Intermolecular Heck Reactions
- 2006
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Heck reaction is one of the most appreciated methods for carbon-carbon bond formation. Due to its mildness and ability to be tuned by additives, it often leaves few alternative competitive reactions. It has also proven easy to develop the reaction conditions in an environmentally benign direction. Through the introduction of palladium chelating groups in olefinic precursors for the Heck reaction, it has been possible to direct the substitution in the following Heck arylation in favor of the terminal position with good regioselectivity. In this thesis, the concept has been utilized to produce a small array of drug-like compounds at useful yields under fast microwave-enhanced conditions utilizing the thermostable Herrmanns palladacycle. During the last decade, this, together with other palladacycles has become commonly employed as precatalyst for the Heck reaction. However, there have been conflicting opinions regarding the mechanisms governing its catalytic effect. A PdII-PdIV catalytic cycle has been suggested to be operative, in contrast to the classical Pd0-PdII cycle. In order to clarify the presence of such a mechanism, a set of Heck reactions was performed with the advent of different palladium precatalysts (classical and palladacycles), which revealed that the regiochemicαal substitution pattern is highly conserved, regardless of which precatalyst was employed, and thus, the same mechanism seems to be operative. This is also supported by data from ESI-MS investigations where all the reactions investigated gave rise to the same set of oxidative addition complexes. A crafted route to 3-aryl-1,2-cyclohexandiones has been developed in which 1,2-cyclohexandione is produced is situ from 2,3-epoxycyclohexanone, followed by Heck arylation. A diverse array of aryl bromides encompassing electron-rich, electron-poor, neutral and sterically hindered repressentatives has been successfully utilized to produce the corresponding products at useful yields.The intramolecular Heck reaction offers a route to quaternary carbonic centersand is being increasingly exploited in synthetic endeavors. However, the use of electron-rich olefinic precursors is only reported in a few cases. The implementation of one capto-dative and five electron-rich olefins has therefore been successfully subjected to Heck reaction conditions rendering the corresponding spiro compounds.
|
|
