24 research outputs found
One-Pot Ketone Synthesis with Alkylzinc Halides Prepared from Alkyl Halides via a Single Electron Transfer (SET) Process: New Extension of Fukuyama Ketone Synthesis
One-pot
ketone synthesis has been developed with in situ activation
of alkyl halides to alkylzinc halides in the presence of thioesters
and Pd-catalyst. The new method provides us with a reliable option
for a coupling at a late stage in a convergent synthesis of complex
molecules, with use of a near 1:1 molar ratio of coupling partners.
First, two facile, orthogonal methods have been developed for preparation
of alkylzinc halides: (1) direct insertion of zinc dust to 1°-
and 2°-alkyl halides in the presence of LiI in DMI and (2) early
transition-metal assisted activation of alkyl halides via a single
electron transfer (SET) process. CrCl<sub>2</sub> has been found as
an unprecedented, inevitable mediator for preparation of alkylzinc
halides from alkyl halides, where CrCl<sub>2</sub> likely functions
to trap R·, generated via a SET process, and transfer it to ZnÂ(II)
to form RZnX. In addition to a commonly used CoPc, a new radical initiator
NbCpCl<sub>4</sub> has been discovered through the study. Second,
with use of the two orthogonal methods, three sets of coupling conditions
have been developed to complete one-pot ketone synthesis, with Condition <b>A</b> (Pd<sub>2</sub>dba<sub>3</sub>, PR<sub>3</sub>, Zn, LiI,
TESCl, DMI), Condition <b>B</b> (<b>A</b> + CrCl<sub>2</sub>), and Condition <b>C</b> (<b>B</b> + NbCpCl<sub>4</sub> or CoPc) being useful for simple linear and α-substituted
substrates, simple linear and β-substituted substrates, and
complex substrates, respectively. Condition <b>C</b> is applicable
to the broadest range of substrates. Overall, one-pot ketone synthesis
gives excellent yields, with good functional group tolerance. Controlled
formation of alkylzinc halides by a combination of CrCl<sub>2</sub> and NbCpCl<sub>4</sub> or CoPc is crucial for its application to
complex substrates. Interestingly, one-pot ketone synthesis does not
suffer from the chemical instability due to the inevitable radical
pathway(s), for example a 1,5-H shift. Notably, even with the increase
in molecular size, no significant decrease in coupling efficiency
has been noticed. To illustrate the synthetic value at a late stage
in a complex molecule synthesis, ketone <b>4sc</b>, containing
all the carbons of Eribulin, has been synthesized from <b>1s</b> and <b>3c</b>
Asymmetric Approach toward Chiral Cyclohex-2-enones from Anisoles via an Enantioselective Isomerization by a New Chiral Diamine Catalyst
A 3-step asymmetric approach toward the optically active
chiral
cyclohex-2-enones from anisoles has been developed. The crucial asymmetric
induction step is an unprecedented catalytic enantioselective isomerization
of β,γ-unsaturated cyclohex-3-en-1-ones to the corresponding
α,β-unsaturated chiral enones. This new asymmetric transformation
was realized by cooperative iminium-base catalysis with an electronically
tunable new organic catalyst. The synthetic utility of this methodology
is highlighted by the enantioselective total synthesis of (−)-isoacanthodoral
Extension of Pd-Mediated One-Pot Ketone Synthesis to Macrocyclization: Application to a New Convergent Synthesis of Eribulin
Recently reported Pd-mediated one-pot
ketone synthesis from an
unactivated alkyl bromide and a thioester has been extended to a macrocyclic
ketone synthesis. In situ generation of alkylzinc halide via single
electron transfer (SET), using NbCpCl<sub>4</sub> and CrCl<sub>3</sub>, was the key for the success of macrocyclization. A new convergent
synthesis of eribulin has been achieved, using (1) catalytic asymmetric
Ni/Cr-mediated coupling to form the C19–C20 bond, (2) base-induced
cyclization to form the methylenetetrahydrofuran ring, and (3) Pd-mediated
one-pot ketone synthesis to form the macrocyclic ketone
Transcription Factor σ<sup>B</sup> Plays an Important Role in the Production of Extracellular Membrane-Derived Vesicles in <i>Listeria monocytogenes</i>
<div><p>Gram-negative bacteria produce extracellular outer membrane vesicles (OMVs) that interact with host cells. Unlike Gram-negative bacteria, less is known about the production and role of extracellular membrane vesicles (MVs) in Gram-positive bacteria. The food-borne pathogen <i>Listeria monocytogenes</i> can survive under extreme environmental and energy stress conditions and the transcription factor σ<sup>B</sup> is involved in this survival ability. Here, we first determined the production of MVs from <i>L. monocytogenes</i> and evaluated whether general stress transcription factor σ<sup>B</sup> affected production of MVs in <i>L. monocytogenes. L. monocytogenes</i> secreted MVs during <i>in vitro</i> broth culture. The wild-type strain actively produced MVs approximately nine times more and also produced more intact shapes of MVs than those of the isogenic Δ<i>sigB</i> mutant. A proteomic analysis showed that 130 and 89 MV proteins were identified in the wild-type and Δ<i>sigB</i> mutant strains, respectively. Wild-type strain-derived MVs contained proteins regulated by σ<sup>B</sup> such as transporters (OpuCA and OpuCC), stress response (Kat), metabolism (LacD), translation (InfC), and cell division protein (FtsZ). Gene Ontology (GO) enrichment analysis showed that wild-type-derived MV proteins corresponded to several GO terms, including response to stress (heat, acid, and bile resistance) and extracellular polysaccharide biosynthetic process, but not the Δ<i>sigB</i> mutant. Internalin B (InlB) was almost three times more contained in MVs derived from the wild-type strain than in MVs derived from the Δ<i>sigB</i> mutant. Taken together, these results suggest that σ<sup>B</sup> plays a pivotal role in the production of MVs and protein profiles contained in MVs. <i>L. monocytogenes</i> MVs may contribute to host infection and survival ability under various stressful conditions. </p> </div
Western blot analysis of Internalin B (InlB) and Listeriolysin O (LLO) in the cell lysate and MVs.
<p>(A) Samples were separated on 10% SDS-PAGE and immunoblotted with anti-InlB and anti-LLO antibodies. CL, <i>L. monocytogenes</i> cell lysate; MVs, membrane-derived vesicles. (B) Band intensities were measured using image analysis software.</p
Extracellular membrane vesicles (MVs) produced by <i>L. monocytogenes</i>.
<p>Transmission electron micrograph of MVs prepared from wild-type (A) and the isogenic ∆<i>sigB</i> mutant of <i>L. monocytogenes</i> (B) cultured in BHI broth. (C) Arrow indicates bilayered structure.</p
Venn diagram of extracellular membrane vesicle (MV) proteins identified by LC-ESI-MS/MS.
<p>Of the 130 proteins, 46 (35%) were identified only in wild-type <i>L. monocytogenes</i> MVs and of the 89 proteins, five (6%) were identified only in the Δ<i>sigB</i> mutant MVs. Eighty-four MV proteins were identified commonly in the wild-type and Δ<i>sigB</i> mutant of <i>L. monocytogenes</i>.</p
Distribution of significant Gene Ontology (GO) terms from extracellular membrane vesicle (MV) proteins that were categorized only in wild-type <i>L. monocytogenes.</i>
<p>Distribution of significant Gene Ontology (GO) terms from extracellular membrane vesicle (MV) proteins that were categorized only in wild-type <i>L. monocytogenes.</i></p
Novel Plasminogen Activator Inhibitor-1 Inhibitors Prevent Diabetic Kidney Injury in a Mouse Model
<div><p>Diabetic nephropathy is the leading cause of end-stage renal disease worldwide, but no effective therapeutic strategy is available. Because plasminogen activator inhibitor-1 (PAI-1) is increasingly recognized as a key factor in extracellular matrix (ECM) accumulation in diabetic nephropathy, this study examined the renoprotective effects of TM5275 and TM5441, two novel orally active PAI-1 inhibitors that do not trigger bleeding episodes, in streptozotocin (STZ)-induced diabetic mice. TM5275 (50 mg/kg) and TM5441 (10 mg/kg) were administered orally for 16 weeks to STZ-induced diabetic and age-matched control mice. Relative to the control mice, the diabetic mice showed significantly increased (p < 0.05) plasma glucose and creatinine levels, urinary albumin excretion, kidney-to-bodyweight ratios, glomerular volume, and fractional mesangial area. Markers of fibrosis and inflammation along with PAI-1 were also upregulated in the kidney of diabetic mice, and treatment with TM5275 and TM5441 effectively inhibited albuminuria, mesangial expansion, ECM accumulation, and macrophage infiltration in diabetic kidneys. Furthermore, in mouse proximal tubular epithelial (mProx24) cells, both TM5275 and TM5441 effectively inhibited PAI-1-induced mRNA expression of fibrosis and inflammation markers and also reversed PAI-1-induced inhibition of plasmin activity, which confirmed the efficacy of the TM compounds as PAI-1 inhibitors. These data suggest that TM compounds could be used to prevent diabetic kidney injury.</p></div
Metabolic characteristics of STZ-induced diabetic mice after treatment with PAI-1 inhibitors.
<p>Metabolic characteristics of STZ-induced diabetic mice after treatment with PAI-1 inhibitors.</p