Dithiocarbamates: new organic catalysts for the photochemical generation of radicals

En la meva tesis doctoral hem pres els anions dithiocarbamat i xantat com a organocatalitzadors per generar radicals sota condicions fotocatalítiques. Aquesta nova classe de catalitzadors ens ha sorprès en utilitzar mecanismes distinctius i complementaris als anteriorment descrits per activar diferents substractes de forma radicalaria. Particularment, l'alta nucleofilitat del nostre catalitzador ditiocarbamat ens ha permès generar radicals intermedis des de (pseudo)halurs d'alquil comercials a través d'un mecanisme tipus SN2. Posteriorment, aquests radicals han sigut acoplats amb enolats de silil èter aconseguint la formació de cetones á-alquilades. La nostra nova metodologia, que funciona en condicions suaus i tolera una gran varietat de grups funcionals, ens ha permès instal·lar substituents que no són possibles d'obtindre amb metodologies aniòniques més clàssiques. A més a més, sota aquestes noves condicions, el procediment permet l'ús d'un nou catalitzador d'amina que posteriorment ha estat utilitzat de forma efectiva per fer de forma enantioselectiva l'alquilació de cetones cícliques.activar una varietat de precursors radicalaris i generar aquests radicals de forma fotocatalítica amb energia fotònica de baixa intensitat. Aquestes noves estratègies catalítiques aporten noves tècniques molt útils al camp de la química orgànica sintètica. En mis estudios de doctorado hemos usado los aniones ditiocarbamato y xantato como organocatalizadores para la generación de radicales en condiciones fotoquímicas. Curiosamente, esta nueva clase de catalizadores podría utilizar mecanismos distintos y complementarios para activar diferentes sustratos hacia la formación de radicales. En particular, la alta nucleofilidad de nuestro catalizador de ditiocarbamato nos permitió generar intermediarios de capa abierta a partir de (pseudo) haluros de alquilo fácilmente disponibles vía SN2. Los radicales resultantes han sido atrapados por silil enol éteres para liberar cetonas á-alquiladas. Las condiciones de reacción suaves del método y la tolerancia del grupo funcional nos permitieron instalar, en la posición á de las cetonas, restos no compatibles con los procesos aniónicos clásicos. Además, las condiciones redox neutrales de este proceso lo hicieron tolerante a un catalizador de amina a base de cinchona, que se utilizó para desarrollar un protocolo efectivo para la alquilación asimétrica de cetonas cíclicas. Por otro lado, la alta donicidad de electrones de los donantes de ditiocarbamato y xantogenato se ha explotado para activar el precursor de radicales activos redox a través de un colector complejo aceptor de donantes de electrones (EDA) catalítico.En conclusión, se ha demostrado que los aniones ditiocarbamato y xantato son una clase versátil de organocatalizadores útiles para activar una variedad de precursores de radicales y generar intermediarios de capa abierta bajo fotoirradiación con fotones de baja energía. Las estrategias catalíticas desarrolladas pueden enriquecer las herramientas disponibles en química orgánica sintética. In my doctoral studies, I have exploited dithiocarbamate and xanthate anions as organocatalysts for the generation of radicals under photochemical conditions. Interestingly, this new class of catalysts could use distinct and complementary mechanisms to activate different substrates towards radical formation. In particular, the high nucleophilicity of our dithiocarbamate catalyst allowed us to generate open-shell intermediates from readily available alkyl (pseudo)halides through an SN2 pathway. The ensuing radicals have been trapped by silyl enol ethers to deliver á-alkylated ketones. The method's mild reaction conditions and functional group tolerance allowed us to install, at the ketones' á-position, moieties not compatible with classical anionic processes. In addition, the redox neutral conditions of this process made it tolerant of a cinchona-based amine catalyst, which was used to develop an effective protocol for the asymmetric alkylation of cyclic ketones. On the other hand, the high electron-donicity of dithiocarbamate and xanthogenate donors have been exploited to activate redox active radical precursor through a catalytic electron donor acceptor (EDA) complex manifold. The radicals generated via the catalytic EDA approach have been exploited in redox-neutral and net-reductive transformations

A Protocol for Continual Explanation of SHAP

Continual Learning trains models on a stream of data, with the aim of learning new information without forgetting previous knowledge. Given the dynamic nature of such environments, explaining the predictions of these models can be challenging. We study the behavior of SHAP values explanations in Continual Learning and propose an evaluation protocol to robustly assess the change of explanations in Class-Incremental scenarios. We observed that, while Replay strategies enforce the stability of SHAP values in feedforward/convolutional models, they are not able to do the same with fully-trained recurrent models. We show that alternative recurrent approaches, like randomized recurrent models, are more effective in keeping the explanations stable over time.Comment: ESANN 2023, 6 pages, added link to cod

A Protocol for Continual Explanation of SHAP

Continual Learning trains models on a stream of data, with the aim of learning new information without forgetting previous knowledge. Given the dynamic nature of such environments, explaining the predictions of these models can be challenging. We study the behavior of SHAP values explanations in Continual Learning and propose an evaluation protocol to robustly assess the change of explanations in Class-Incremental scenarios. We observed that, while Replay strategies enforce the stability of SHAP values in feedforward/convolutional models, they are not able to do the same with fully-trained recurrent models. We show that alternative recurrent approaches, like randomized recurrent models, are more effective in keeping the explanations stable over time

Sensitivity, Specificity, and Predictive Values of Tru-Cut® Biopsy in Grading Primary Localized Myxoid Liposarcomas of the Extremities

Biopsy is an essential step in the diagnosis of myxoid liposarcoma (MLs) since the histological grade is a strong determinant of the appropriate treatment in the management of this pathology. The aim of our retrospective study was to investigate the diagnostic accuracy of Tru-cut((R)) biopsy (TCB) and the potential impact on a patient's survival in the case of misdiagnosis. We established that in MLs, diagnosis with TCB might differ from that of surgical specimens, with a histological grade concordance rate of 64% (Kappa 0.30). Neoadjuvant treatments were associated with pathological downgrading with a lower effect of chemotherapy alone compared to neoadjuvant-combined treatments, although such discordance did not modify the prognosis. In the group of patients not treated in neoadjuvant settings, the sensitivity and specificity of TCB were 57% and 100%, respectively. TCB results are useful in leading the clinician in the diagnostic pathway thought; the diagnosis of MLs should be supported by other diagnostic techniques.(1) Background: Histological diagnosis and tumor grading are major prognostic and predictive factors in soft tissue sarcomas (STS), as they dictate the treatment strategies with a direct impact on patient survival. This study aims to investigate the grading accuracy, sensitivity, and specificity of Tru-Cut((R)) biopsy (TCB) in primary localized myxoid liposarcomas (MLs) of the extremities and its impact on patient prognosis. (2) Methods: Patients with ML undergoing TCB and a subsequent tumor resection between 2007 and 2021 were evaluated. Concordance between the preoperative assessment and definitive histology was calculated with a weighted Cohen's kappa coefficient. Sensitivity, specificity, and diagnostic accuracy were calculated. (3) Results: Of 144 biopsies, the histological grade concordance rate was 63% (Kappa 0.2819). Neoadjuvant chemotherapy and/or radiotherapy impacted concordance with a downgrading effect in high-grade tumors. Among forty patients not treated in neoadjuvant settings, the sensitivity of TCB was 57%, the specificity was 100%, and the overall predictive values of positive and negative TCB were 100% and 50%, respectively. Misdiagnosis did not impact overall survival. (4) Conclusions: TCB may underestimate ML grading due to tumor heterogeneity. Neoadjuvant ChT and/or radiotherapy are associated with pathological downgrading; however, discordance in diagnosis does not modify patient prognosis because systemic treatment decision-making also includes other variables

Switchable photocatalysis for the chemodivergent benzylation of 4-cyanopyridines

We report a photocatalytic strategy for the chemodivergent radical benzylation of 4-cyanopyridines. The chemistry uses a single photoredox catalyst to generate benzyl radicals upon N–F bond activation of 2-alkyl N-fluorobenzamides. The judicious choice of different photocatalyst quenchers allowed us to select at will between mechanistically divergent processes. The two reaction manifolds, an ipso-substitution path proceeding via radical coupling and a Minisci-type addition, enabled selective access to regioisomeric C4 or C2 benzylated pyridines, respectively. Mechanistic investigations shed light on the origin of the chemoselectivity switc

A Photochemical Organocatalytic Strategy for the a-Alkylation of Ketones by using Radicals

Reported herein is a visible-light-mediated radical approach to the a-alkylation of ketones. This method exploits the ability of a nucleophilic organocatalyst to generate radicals upon SN2-based activation of alkyl halides and blue light irradiation. The resulting open-shell intermediates are then intercepted by weakly nucleophilic silyl enol ethers, which would be unable to directly attack the alkyl halides through a traditional two-electron path. The mild reaction conditions allowed functionalization of the a position of ketones with functional groups that are not compatible with classical anionic strategies. In addition, the redox-neutral nature of this process makes it compatible with a cinchona-based primary amine catalyst, which was used to develop a rare example of enantioselective organocatalytic radical a-alkylation of ke- tones

Bismuth radical catalysis in the activation and coupling of redox-active electrophiles

Radical cross-coupling reactions represent a revolutionary tool to forge C(sp3)–C and C(sp3)–heteroatom bonds, by means of transition metals, photoredox or electrochemical approaches. This study demonstrates how a low-valent bismuth complex is able to undergo one-electron oxidative addition with redox-active alkyl radical precursors in an autonomous manner, mimicking the behavior of first-row transition metals. This reactivity paradigm for bismuth gives rise to unique radical-equilibrium complexes, which could be fully characterized in solution and solid state. The resulting Bi(III)–C(sp3) intermediates display divergent reactivity patterns depending on the α-substituents of the alkyl fragment. Mechanistic investigations on this reactivity led to the development of a bismuth-catalyzed C(sp3)–N cross-coupling reaction that operates under mild conditions and accommodates synthetically relevant N-heterocycles as coupling partners