Trans-Concerted Addition to Alkynes: the case of Ynamide Silylzincation.

An original concerted antarafacial mechanism for the addition of diorganosilyl-zinc reagents across the C-C triple bond of ynamides is computationally investigated using DFT calculations. This concerted mechanism, leading to a trans-product in only one step, results in the formation of a Si-C and a Zn-C σ-bond on opposite sides of the π-system. We demonstrate that the mechanism going through a η2-vinyl intermediate and the proposal of a radical chain pathway are energetically unsustainable. The retained concerted antarafacial pathway is tested on experimental selectivities: the regioselectivity, in favor of the silyl ß-addition in ynamide, and stereoselectivity, which is cis- with (Me2PhSi)2Zn but trans- with [(Me3Si)3Si]2Zn, are well reproduced by DFT calculations. The regio- and stereoselectivity are discussed using the activation strain model and a chemical bonding analysis.

Enantioselective Sequential Catalytic Arylation-Fukuyama Cross-coupling of 1,1-Biszincioalkane Linchpins.

1,1-Bis(iodozincio)alkanes are used as dinucleophilic linchpins in an enantioselective double cross-coupling reaction sequence involving aryl iodides and then thioesters. The two catalytic C-C bond-forming reactions are achieved in the same pot through two distinct palladium-based catalytic systems: a first non-enantioselective one delivering configurationally labile secondary benzylzinc species from an achiral precursor, and a second enantioconvergent one that operates a highly efficient dynamic kinetic resolution of the racemic intermediates. This strategy, new in the area of asymmetric synthesis through two consecutive electrophilic substitution reactions of geminated C(sp3 )-organodimetallics, provides useful methodology to access in a modular fashion acyclic α-disubstituted ketone products with very high enantiomeric purity.

α-(Aminomethyl)acrylates as acceptors in radical-polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping.

We demonstrate that α-(aminomethyl)acrylates are suitable acceptors for 1,4-additions of dialkylzincs in aerobic conditions. The air-promoted radical-polar crossover process involves the 1,4-addition of an alkyl radical followed by homolytic substitution at the zinc atom of dialkylzinc. Coordination of the nitrogen atom to zinc enables this SH2 process which represents a rare example of alkylzinc-group transfer to a tertiary α-carbonyl radical. The zinc enolate thus formed readily undergoes ß-fragmentation unless it is trapped by electrophiles in situ. Enolates of substrates having free N-H bonds undergo protodemetalation to provide ultimately the 1,4-addition adduct. In the presence of carbonyl acceptors, aldol condensation occurs providing overall a tandem 1,4-addition-aldol process. When a tert-butanesulfinyl moiety is present on the nitrogen atom, these electrophilic substitution reactions occur with good levels of chiral induction, paving the way to enantioenriched ß2-amino acids and ß2,2-amino acids.

Synergy of the Tropical Earthworm Pontoscolex corethrurus and Oil Palm Bagasse in the Removal of Heavy Crude Oil.

The tropical endogeic earthworm Pontoscolex corethrurus, a non-standard species used in ecotoxicity, has been found in crude oil-contaminated habitats. We estimated the removal of total hydrocarbons from heavy crude "Maya" oil on an artificially contaminated soil with a median lethal concentration of P. corethrurus and an addition of oil palm bagasse. P. corethrurus had a high survival rate, and the addition of oil palm bagasse led to a greater growth and an increase in abundance of bacteria and fungi. The activity of P. corethrurus and the nutritional quality of oil palm bagasse had a significant impact on the removal of a larger amount of petroleum hydrocarbons from contaminated soil. We concluded that the endogeic earthworm P. corethrurus and oil palm bagasse acted synergistically to achieve a more effective removal of total petroleum hydrocarbons from soil. These results show the potential for using P. corethrurus to remove, either directly or indirectly, crude oil from soil.

Modular synthesis of 2-furyl carbinols from 3-benzyldimethylsilylfurfural platforms relying on oxygen-assisted C-Si bond functionalization.

3-Silylated furfurals, readily prepared in three steps from biomass-derived furfural and 5-methylfurfural, are converted into 3-silylated 2-furyl carbinols upon condensation with organomagnesium or organolithium reagents. The hydroxy unit of the carbinol adducts can be exploited to promote C3(sp2)-Si bond functionalization through intramolecular activation. Two approaches were contemplated for this purpose. Activation by alkoxides of the C3-SiEt3 or C3-SiMe2 t-Bu bonds was ineffective. Conversely, treatment of the C3-benzyldimethylsilyl-appended derivatives with tetrabutylammonium fluoride led to cyclic siloxanes, which revealed to be competent donors for copper-catalyzed cross-coupling reactions, such as arylation reactions catalyzed by Pd2(dba)3/CuI, as well as allylation and methylation reactions catalyzed by CuI⋅PPh3. C3-Benzyldimethylsilyl-appended furfurals are thus introduced as versatile platforms, providing a modular access to 3-substituted 2-furyl carbinols from renewable feedstock.

Transfusion support in COVID-19 patients: Impact on hospital blood component supply during the outbreak.

BACKGROUND: During the COVID-19 outbreak, most hospitals deferred elective surgical procedures to allow space for the overwhelming number of COVID-19 patient admissions, expecting a decrease in routine blood component requirements. However, because transfusion support needs of COVID-19 patients are not well known, its impact on hospital blood supply is uncertain. The objective of this study was to assess the effect of the COVID-19 pandemic on transfusion demand. STUDY DESIGN AND METHODS: Transfusion records during the peak of the COVID-19 pandemic (March 1-April 30, 2020) were reviewed in our center to assess changes in blood requirements. RESULTS: During this period 636 patients received a total of 2934 blood components, which reflects a 17.6% reduction in transfusion requirements with regard to the same period of 2019, and blood donations in Madrid dropped by 45%. The surgical blood demand decreased significantly during the outbreak (50.2%). Blood usage in the hematology and oncology departments remained unchanged, while the day ward demand halved, and intensive care unit transfusion needs increased by 116%. A total of 6.2% of all COVID inpatients required transfusion support. COVID-19 inpatients consumed 19% of all blood components, which counterbalanced the savings owed to the reduction in elective procedures. CONCLUSION: Although only a minority of COVID-19 inpatients required transfusion, the expected reduction in transfusion needs caused by the lack of elective surgical procedures is partially offset by the large number of admitted patients during the peak of the pandemic. This fact must be taken into account when planning hospital blood supply.

Radical Germylzincation of α-Heteroatom-Substituted Alkynes.

The regio- and stereoselective addition of germanium and zinc across the C-C triple bond of nitrogen-, sulfur-, oxygen-, and phosphorus-substituted terminal and internal alkynes is achieved by reaction with a combination of R3GeH and Et2Zn. Diagnostic experiments support a radical-chain mechanism and the ß-zincated vinylgermanes that show exceptional stability are characterized by NMR spectroscopy and X-ray crystallography. The unique feature of this new radical germylzincation reaction is that the C(sp2)-Zn bond formed remains available for subsequent in situ Cu(I)- or Pd(0)-mediated C-C or C-heteroatom bond formation with retention of the double bond geometry. These protocols offer modular access to elaborated tri- and tetrasubstituted vinylgermanes decorated with heteroatom substituents ß to germanium that are useful for the preparation of stereodefined alkenes.

Harnessing the Lewis Acidity of HFIP through its Cooperation with a Calcium(II) Salt: Application to the Aza-Piancatelli Reaction.

A method to extend the scope of the aza-Piancatelli reaction between 2-furylcarbinols and anilines is depicted. We found that 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) is the solvent of choice for this transformation, as it outcompetes the usual solvents in terms of rate and yield. Side reactions and other issues raised by the title reaction are prevented, thereby providing an avenue to complex molecules that were previously inaccessible. Lewis acidity studies and computations were carried out to unveil the role of HFIP. Based on these results, we propose that HFIP is, in fact, acting as a Lewis acid and that its acidity can be enhanced when combined with a calcium(II) salt.

tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon-Nitrogen Bond Forming Reactions.

The use of tert-butanesulfinamides as nitrogen nucleophiles in carbon-nitrogen bond forming reactions is reviewed. This field has grown in the shadow of the general interest in N-tert-butanesulfinyl imines for asymmetric synthesis and occupies now an important place in its own right in the chemistry of the chiral amine reagent tert-butanesulfinamide. This article provides an overview of the area and emphasizes recent contributions wherein the tert-butanesulfinamides act as chiral auxiliaries or perform as nitrogen donors in metal-catalyzed amination reactions.

C-H activation/functionalization catalyzed by simple, well-defined low-valent cobalt complexes.

A facile C-H activation and functionalization of aromatic imines is presented using low-valent cobalt catalysts. Using Co(PMe3)4 as catalyst we have developed an efficient and simple protocol for the C-H/hydroarylation of alkynes with an anti selectivity. Deuterium-labeling experiments, DFT calculations coupled with the use of a well-defined catalyst have for the first time shed light on the elusive black box of cobalt catalyzed C-H functionalization.

Trans-selective radical silylzincation of ynamides.

The silylzincation of terminal ynamides is achieved through a radical-chain process involving (Me3Si)3SiH and R2Zn. A potentially competing polar mechanism is excluded on the basis of diagnostic control experiments. The unique feature of this addition across the C≡C bond is its trans selectivity. One-pot electrophilic substitution of the C(sp2)-Zn bond by Cu(I)-mediated C-C bond formation and subsequent manipulation of the C(sp2)-Si bond provides a modular access to Z-α,ß-disubstituted enamides.

Use of Eltrombopag to Improve Thrombocytopenia and Tranfusion Requirement in Anti-CD19 CAR-T Cell-Treated Patients.

Background/Objectives: Immune effector cell-associated hematotoxicity (ICAHT) is a frequent adverse event after chimeric antigen receptor (CAR)-T cell therapy. Grade ≥ 3 thrombocytopenia occurs in around one-third of patients, and many of them become platelet transfusion-dependent. Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) able to accelerate megakaryopoiesis, which has been used successfully in patients with bone marrow failure and immune thrombocytopenia (ITP). Its role in managing thrombocytopenia and other cytopenias in CAR-T cell-treated patients has been scarcely addressed. Our aim was to report the safety and efficacy of this approach in patients included in the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC) registry. Methods: This is a retrospective, multicenter, observational study. Patients who developed platelet transfusion dependence subsequently to CAR-T cells and received eltrombopag to improve platelet counts were recruited in 10 Spanish hospitals. Results: Thirty-eight patients were enrolled and followed up for a median (interquartile range [IQR]) of 175 (99, 489) days since CAR-T cell infusion. At the moment eltrombopag was indicated, 18 patients had thrombocytopenia and another severe cytopenia, while 8 patients had severe pancytopenia. After 32 (14, 38) days on eltrombopag, 29 (76.3%) patients recovered platelet transfusion independence. The number of platelet units transfused correlated with the time needed to restore platelet counts higher than 20 × 109/L (Rho = 0.639, p < 0.001). Non-responders to eltrombopag required more platelet units (58 [29, 69] vs. 12 [6, 26] in responders, p = 0.002). Nineteen out of twenty-three (82.6%) patients recovered from severe neutropenia after 22 (11, 31) days on eltrombopag. Twenty-nine out of thirty-five (82.9%) patients recovered red blood cell (RBC) transfusion independence after 29 (17, 44) days. Seven patients recovered all cell lineages while on treatment. No thromboembolic events were reported. Only two transient toxicities (cholestasis, hyperbilirubinemia) were reported during eltrombopag treatment, none of which compelled permanent drug withdrawal. Conclusions: Eltrombopag could be safely used to manage thrombocytopenia and accelerate transfusion independence in CAR-T cell-treated patients.

Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease after Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide: A Study on Behalf of the Spanish Hematopoietic Stem Cell Transplantation and Cellular Therapy Group (GETH).

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT). However, its characterization after haploidentical HSCT (haplo-HSCT) with post-transplantation cyclophosphamide (PT-Cy) is scarce. This study aimed to describe characteristics and outcomes of patients with SOS/VOD after haplo-HSCT with PT-Cy. We conducted a retrospective study of 797 patients undergoing a haplo-HSCT with PT-Cy between 2007 and 2019 in 9 centers in Spain. SOS/VOD was defined according to modified Seattle, Baltimore, or revised European Society for Blood and Marrow Transplantation (EBMT) criteria. Severity was graded retrospectively according to revised EBMT severity criteria into 4 categories: mild, moderate, severe, and very severe. From a total of 797 haplo-HSCTs performed, 46 patients (5.77%) were diagnosed with SOS/VOD at a median of 19 days (range, 4 to 84 days) after transplantation. Based on revised EBMT severity criteria, the SOS/VOD cases were classified as mild (n = 4; 8.7%), moderate (n = 10; 21.7%), severe (n = 12; 26.1%), and very severe (n = 20; 43.5%). Overall, 30 patients (65%) achieved SOS/VOD complete response, 25 (83%) of whom were treated with defibrotide. Twenty patients (43%) died before day +100 post-HSCT. Death was attributed to SOS/VOD in 11 patients, and 5 patients died of other causes without resolution of SOS/VOD. The incidence of SOS/VOD after haplo-HSCT with PT-Cy was comparable to those reported after HLA-identical HSCT series. Most of the patients developed very severe SOS/VOD according to revised EBMT severity criteria. Despite a promising SOS/VOD complete response (CR) rate (65%), 100-day mortality remained high (43%), indicating that further improvement in the management of this potentially fatal complication is needed.

Three-carbon homologation of diorganozincs with lithiated acetylenic epoxides.

Reaction of dialkylzincs with lithiated acetylenic epoxides is described to give zincates that undergo a 1,2-metallate rearrangement by an anti-S(N)2' pathway. This rearrangement occurs with the transfer of an alkyl or a silyl group affording allenylzinc intermediates. Allenic and/or homopropargylic alcohols are obtained upon hydrolysis. Quenching the reaction mixture with aldehydes or ketones is shown to give access to 2-alkynyl-1,3-diols in a stereoselective manner.

Radical zinc-atom-transfer-based carbozincation of haloalkynes with dialkylzincs.

The formation of alkylidenezinc carbenoids by 1,4-addition/carbozincation of dialkylzincs or alkyl iodides based on zinc atom radical transfer, in the presence of dimethylzinc with ß-(propargyloxy)enoates having pendant iodo- and bromoalkynes, is disclosed. Formation of the carbenoid intermediate is fully stereoselective at -30 °C and arises from a formal anti-selective carbozincation reaction. Upon warming, the zinc carbenoid is stereochemically labile and isomerizes to its more stable form.

Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors.

(1) Background: Despite the prognostic improvements achieved with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), a minority of patients still fail TKIs. The recent introduction of asciminib may be a promising option in intolerant patients, as it is a first-in-class inhibitor with a more selective mechanism of action different from the ATP-competitive inhibition that occurs with TKIs. Therefore, our goal was to analyze toxicities shown with asciminib as well as to study cross-toxicity with previous TKIs. (2) Methods: An observational, multicenter, retrospective study was performed with data from 77 patients with CML with therapeutic failure to second-generation TKIs who received asciminib through a managed-access program (MAP) (3) Results: With a median follow-up of 13.7 months, 22 patients (28.5%) discontinued treatment: 32% (7/22) due to intolerance and 45% (10/22) due to resistance. Fifty-five percent of the patients reported adverse effects (AEs) with asciminib and eighteen percent grade 3-4. Most frequent AEs were: fatigue (18%), thrombocytopenia (17%), anemia (12%), and arthralgias (12%). None of the patients experienced cardiovascular events or occlusive arterial disease. Further, 26%, 25%, and 9% of patients required dose adjustment, temporary suspension, or definitive discontinuation of treatment, respectively. Toxicities under asciminib seemed lower than with prior TKIs for anemia, cardiovascular events, pleural/pericardial effusion, diarrhea, and edema. Cross-toxicity risk was statistically significant for thrombocytopenia, anemia, neutropenia, fatigue, vomiting, and pancreatitis. (4) Conclusion: Asciminib is a molecule with a good safety profile and with a low rate of AEs. However, despite its new mechanism of action, asciminib presents a risk of cross-toxicity with classical TKIs for some AEs.

Intima media thickness in children undergoing dialysis.

BACKGROUND: Uremic vasculopathy, including vascular calcification, increases the risk for cardiovascular disease and mortality in chronic kidney disease (CKD) patients. We have investigated the prevalence and factors associated with vasculopathy in children undergoing peritoneal dialysis (PD) or hemodialysis (HD) in a single center. METHODS: Common carotid intima media thickness (cIMT) and its relation with demographics, biochemical parameters and medication was analyzed in 60 patients (mean age 12.9 ± 3.4 years; 27 girls) treated with PD (n = 31) or HD (n = 29) for 34 ± 34 months. Patients were divided into two groups: normal cIMT and increased cIMT. RESULTS: Mean levels of calcium, phosphate and calcium/phosphate product were in the normal range, the but parathyroid hormone level, 729 ± 670 pg/mL, was higher than the National Kidney Foundation Kidney Disease Outcome Quality Iniative (K/DOQI) recommendations. Twenty-nine patients had increased cIMT, which was associated with time on dialysis of >2 years, hypercalcemia, higher daily dose of calcitriol and HD (vs. PD). In the multivariate analysis, accounting for time on dialysis, HD persisted as a risk for increased cIMT. CONCLUSIONS: The prevalence of increased cIMT in children on dialysis is similar to that reported in adults with CKD and increased with time on dialysis. HD was associated with increased cIMT, independently of time on dialysis; however, the results should be interpreted with caution due to the possible impact of confounding factors. These results underline the need to monitor and, if possible, prevent and treat increased cIMT in children on dialysis.

Modular access to substituted germoles by intramolecular germylzincation.

Intramolecular alkyne germylzincation giving access to a wide range of germoles is achieved from triarylhydrogermanes in the presence of diethylzinc and AIBN as radical initiator. The reaction proceeds through activation of the Ge-H bond, leading to a heteroarylzinc intermediate after cyclisation, which can then be involved in a post-functionalisation reaction. Our results show that only 5-endo-dig cyclizations occur, with benzogermoles being exclusively obtained.

Humoral/Cellular Immune Discordance in Stem Cell Donors: Impact on Cytomegalovirus-Specific Immune Reconstitution after Related Hematopoietic Transplantation.

Cytomegalovirus (CMV) reactivation is an important cause of complications after hematopoietic stem cell transplantation (HSCT). Discrepancies between serologic and cellular CMV-specific immune response have been reported. This study evaluated the impact of lack of CMV-specific CD8+ T cell response in seropositive donors (ie, discordant donors) on the reconstitution of CMV-specific cell-mediated immunity (CMI) after related HSCT in seropositive recipients. CMV-CMI was assessed in donors and recipients using the QuantiFERON-CMV assay (QF). CMV-CMI was prospectively assessed for 1 year in 81 CMV-seropositive HSCT recipients with a haploidentical or matched related donor. A Cox proportional hazard regression analysis was performed. Of the 67 CMV-seropositive donors, 54 (80.6%) were D+QFpos. The remaining 13 CMV-seropositive donors (19.4%) had a QFneg result and thus were classified as discordant donors (D+QFneg). We found that patients with D+QFneg had a significantly higher risk of impaired CMV-CMI reconstitution compared with patients with D+QFpos (log-rank test, P = .001) or D- donors (log-rank test, P = .023). In addition, the D+QFneg group had a higher incidence of single-episode reactivation compared with D+QFpos or D- donors (69.2% versus 44.4% and 28.6%, respectively) but a lower incidence of CMV recurrence compared with the D- group (7.7% versus 57.1%; P = .003). After adjusting for other relevant variables, immune discordance in donors was independently associated with impaired CMV-CMI reconstitution compared with D+QFpos donors (adjusted hazard ratio [HR], 0.18; 95% confidence interval [CI], .06 to .52; P = .001) and D- donors (adjusted HR, .17; 95% CI, .05 to .59; P = .005). Discordant donors were associated with undetectable CMV-CMI during the 12-month follow-up period using the QF assay. The inability of these patients to become QFpos persisted even after CMV reactivation. This might be related to the low frequency of CMV recurrence in this group. CMV-CMI assessment, in conjunction with CMV serostatus, can be of utility to better classify stem cell donors as well as the risk of impaired CMV-CMI reconstitution after HSCT.

Radical Germylzincation of Aryl- and Alkyl-Substituted Internal Alkynes.

The stereoselective germylzincation of internal alkynes delivering trisubstituted vinylgermanes is achieved via a radical chain process involving Ph3GeH and Et2Zn with AIBN as the initiator. Excellent levels of regiocontrol are observed for nonsymmetric (aryl, alkyl)-substituted alkynes and for propargylic alcohols with aryl-, alkyl-, or silyl-substituted alkynes. The germylzincation reaction can be combined in one pot with the Cu(I)-mediated electrophilic substitution of the C(sp2)-Zn bond to obtain synthetically challenging tetrasubstituted vinylgermanes.