Silver-Catalyzed Asymmetric Double Desymmetrization via Vinylogous Michael Addition of Prochiral α,α-Dicyanoalkenes to Cyclopentendiones.

An asymmetric double desymmetrization methodology has been developed for synthesizing densely functionalized chiral cyclopentylcyclohexane scaffolds. We have constructed four chiral centers, including an all-carbon quaternary stereocenter in a single C-C bond formation event. The methodology has high functional-group tolerance and delivers a broad range of enantioenriched products. This vinylogous Michael addition reaction of prochiral α,α-dicyanocyclohexane to 2,2-disubstituted cyclopentene-1,3-dione is catalyzed by a chiral Ag-(R)-DTBM-SEGPHOS catalyst.

Intramolecular Silanoxy-Michael Reactions with Pendant Nitroalkenes: Racemic and Enantioselective.

We present the first racemic and scalemic examples of di-tert-butyl silanoxy-Michael additions. Our operationally simple protocol is selective for nitro-olefins and simply involves stirring the substrate with an appropriate hydrogen-bond donor catalyst without any special precautions to exclude air or moisture. For each substrate examined, we have developed complementary protocols that optimize yield and enantioselectivity. Our reactions scale well, and the products are valuable intermediates for further transformations, including for the preparation of enantioenriched vicinal amino alcohols.

The Development of a Sulfamate-Tethered Aza-Michael Cyclization Allows for the Preparation of (-)-Negamycin tert-Butyl Ester.

We present the first examples of intramolecular aza-Michael cyclizations of sulfamates and sulfamides onto pendant α,ß-unsaturated esters, thioesters, amides, and nitriles. Stirring the substrate with catalytic quantities of the appropriate base delivers the product in good yield and excellent diastereoselectivity. The reactions are operationally simple, can be performed open to air, and are tolerant of a variety of important functional groups. We highlight the utility of this technology by using it in the preparation of a (-)-negamycin derivative.

Oxidations of Alcohols, Aldehydes, and Diols Using NaBr and Selectfluor.

We present protocols for the oxidation of alcohols and aldehydes and for the oxidative cyclization of diols which use a combination of Selectfluor and NaBr. For most substrates, the optimal solvent system is a 1:1 mixture of CH3CN/H2O, but, in select cases, biphasic 1:1 mixtures of EtOAc/H2O or CH2Cl2/H2O are superior. This procedure is operationally simple, uses inexpensive and readily available reagents, and tolerates a variety of functional groups. Mechanistic studies suggest that the active oxidant is hypobromous acid, generated by the almost instantaneous oxidation of Br- by Selectfluor in an aqueous milieu.

Organocatalytic Asymmetric Direct Vinylogous Michael Initiated Ring Closure Reaction of 4-Nitroisoxazole Derivatives to 3-Isopropylidene Oxindoles.

Herein, we present the first ever use of 3-isopropylidene oxindoles as electrophiles in vinylogous Michael initiated ring closure reaction (MIRC). Among the various alkylidene oxindoles used in enantioselective spirocyclization reactions, isopropylidene oxindoles are the least explored to date. The competing reactivity of isopropylidene oxindoles (electrophilicity vs nucleophilicity) in the presence of a chiral organocatalyst is controlled by the logical selection of a more reactive nucleophile. The methodology produces a library of densely substituted highly enantioenriched spirocyclopropyl oxindoles with excellent yield and stereoselectivities. Moreover, the first enantioselective synthesis of HIV-1 NNRT inhibitor indicates the importance of our synthesized spiro-cyclopropyl oxindole core.

Hydroxyselenylation and Tethered Silanoxyselenylation of Allylic Silanols.

We present protocols for the highly regioselective hydroxyselenylation and silanoxyselenylation of allylic silanols. N-(Phenylseleno)phthalimide acts as the selenylating agent for both transformations. Under basic conditions, hydroxyselenylation proceeds with >20:1 regioselectivity, and the products are valuable synthons for further transformations. We show that the silanol plays a critical role in maintaining the yield and regioselectivity of this reaction. Surprisingly, under acidic conditions, the hydroxyselenylation pathway is blocked, and products of a tethered silanoxyselenylation are exclusive.

Asymmetric Synthesis of Spiro-3,3'-cyclopropyl Oxindoles via Vinylogous Michael Initiated Ring Closure Reaction.

A novel organocatalytic cascade approach for the synthesis of spiro-cyclopropyl oxindole derivatives has been developed. The methodology is based on asymmetric vinylogous Michael addition of 4-nitroisoxazole derivatives to N-Boc isatylidene malonates followed by intramolecular alkylation. Its remarkable stereocontrol, wide substrate scope, and scalability highlight this new developed strategy. Moreover, this work represents the first example of vinylogous Michael initiated ring closure (MIRC) reaction for the synthesis of chiral 3,3'-cyclopropyl oxindole.

Organocatalytic Asymmetric Hetero-Diels-Alder Reaction of in Situ Generated Dienes: Access to α,ß-Unsaturated δ-Lactones Featuring CF3-Substituted Quaternary Stereocenter.

Chiral bifunctional urea-catalyzed asymmetric direct hetero-Diels-Alder reaction between alkylidene azlactone-derived dienes and trifluoromethyl aryl ketones is reported for the first time. The direct hetero-Diels-Alder reaction followed by ring opening results in densely functionalized α,ß-unsaturated δ-lactones featuring a CF3-substituted quaternary stereocenter in high yields with excellent enantioselectivities. The method is compatible over a range of substrates. Moreover, the reaction is scaled up and the α,ß-unsaturated δ-lactones were converted to amino acid derivatives decorated with trifluoromethylated carbinol functionality.

Enantioselective Tandem Oxidation/Michael-Aldol Approaches to Tetrasubstituted Cyclohexanes.

Enantioselective tandem Michael-aldol and oxidative Michael-aldol approaches have been achieved for the formation of diversely substituted cyclohexanes in total regio-, diastereo- and enantioselective fashion. The presence of nitro, hydroxy and keto groups in the product provides a wide scope for further structural transformations. Furthermore, the utility of the catalytic process is demonstrated in the context of enantioselective formal synthesis of ABT-341, a DPP4 inhibitor.

Dancing Silanols: Stereospecific Rearrangements of Silanol Epoxides into Silanoxy-Tetrahydrofurans and Silanoxy-Tetrahydropyrans.

We have developed highly stereospecific rearrangements of silanol epoxides into 1'-silanoxy-tetrahydrofurans and 1'-silanoxy-tetrahydropyrans. Upon treatment with Ph3CBF4 and NaHCO3 in CH2Cl2, di-substituted trans-epoxide silanols rearrange into products with an erythro configuration; di-substituted cis-epoxide silanols give products with a threo configuration. We have used these reactions as key steps in the syntheses of (±)-solerone and (±)-muricatacin.

Asymmetric α-Functionalization of 2-Alkyl Azaarenes: Synthesis of Tertiary Fluorides Having Vicinal Stereogenic Centers.

An enantioselective approach for synthesizing fluorinated azaarenes containing vicinal quaternary-tertiary stereocenters is summarized. The chiral copper(I)-phosphine complex binds with the azaarenes followed by Michael addition to unsaturated acyl imidazoles, resulting in α-functionalized products with an excellent level of enantioselectivities (up to 99%), diastereoselectivities (>20:1), and yields (up to 97%). Furthermore, post-functionalization of the acyl imidazole part has also been demonstrated.

Tweet Classification to Assist Human Moderation for Suicide Prevention.

Social media platforms are already engaged in leveraging existing online socio-technical systems to employ just-in-time interventions for suicide prevention to the public. These efforts primarily rely on self-reports of potential self-harm content that is reviewed by moderators. Most recently, platforms have employed automated models to identify self-harm content, but acknowledge that these automated models still struggle to understand the nuance of human language (e.g., sarcasm). By explicitly focusing on Twitter posts that could easily be misidentified by a model as expressing suicidal intent (i.e., they contain similar phrases such as "wanting to die"), our work examines the temporal differences in historical expressions of general and emotional language prior to a clear expression of suicidal intent. Additionally, we analyze time-aware neural models that build on these language variants and factors in the historical, emotional spectrum of a user's tweeting activity. The strongest model achieves high (statistically significant) performance (macro F1=0.804, recall=0.813) to identify social media indicative of suicidal intent. Using three use cases of tweets with phrases common to suicidal intent, we qualitatively analyze and interpret how such models decided if suicidal intent was present and discuss how these analyses may be used to alleviate the burden on human moderators within the known constraints of how moderation is performed (e.g., no access to the user's timeline). Finally, we discuss the ethical implications of such data-driven models and inferences about suicidal intent from social media. Content warning: this article discusses self-harm and suicide.

Robust suicide risk assessment on social media via deep adversarial learning.

OBJECTIVE: The prevalence of social media for sharing personal thoughts makes it a viable platform for the assessment of suicide risk. However, deep learning models are not able to capture the diverse nature of linguistic choices and temporal patterns that can be exhibited by a suicidal user on social media and end up overfitting on specific cues that are not generally applicable. We propose Adversarial Suicide assessment Hierarchical Attention (ASHA), a hierarchical attention model that employs adversarial learning for improving the generalization ability of the model. MATERIAL AND METHODS: We assess the suicide risk of a social media user across 5 levels of increasing severity of risk. ASHA leverages a transformer-based architecture to learn the semantic nature of social media posts and a temporal attention-based long short-term memory architecture for the sequential modeling of a user's historical posts. We dynamically generate adversarial examples by adding perturbations to actual examples that can simulate the stochasticity in historical posts, thereby making the model robust. RESULTS: Through extensive experiments, we establish the face-value of ASHA and show that it significantly outperforms existing baselines, with the F1 score of 64%. This is a 2% and a 4% increase over the ContextBERT and ContextCNN baselines, respectively. Finally, we discuss the practical applicability and ethical aspects of our work pertaining to ASHA, as a human-in-the-loop framework. DISCUSSION AND CONCLUSIONS: Adversarial samples can be helpful in capturing the diverse nature of suicidal ideation. Through ASHA, we hope to form a component in a larger human-in-the-loop infrastructure for suicide risk assessment on social media.

Asymmetric Multifunctional Modular Organocatalysis: One-Pot Direct Strategy to Enantiopure α,ß-Disubstituted γ-Butyrolactones.

A simple and efficient approach to enantioenriched α,ß-disubstituted γ-butyrolactones has been developed through multifunctional modular organocatalysis in a highly enantioselective (>99% ee) and diastereoselective (>30:1) manner following a one-pot sequential Michael-hemiacetalization-oxidation reaction. The catalytic process has great substrate compatibility, and the products have been transformed to synthetically useful molecules. The methodology has also been applied to the formal synthesis of (+)-Pilocarpine.

Asymmetric Construction of Remote Vicinal Quaternary and Tertiary Stereocenters via Direct Doubly Vinylogous Michael Addition.

An asymmetric direct doubly vinylogous Michael addition has been developed for the generation of sterically congested vicinal quaternary and tertiary stereocenters. This doubly vinylogous Michael addition of ß,γ-unsaturated butenolides to 3-methyl-4-nitro-5-alkenyl isoxazoles, powered by a bifunctional squaramide, affords a broad range of densely functionalized enantioenriched γ,γ-disubstituted butenolides in high yields with excellent diastereo- and enantioselectivities in most cases. Moreover, the strategy highlights the first application of ß,γ-unsaturated butenolides in an asymmetric 1,6-conjugate addition.