Here we present the ambiphilic reactivity of alkyl sulfonyl fluorides in the stereoselective synthesis of diverse cyclopropanes from olefins, under palladium(II) catalysis. The sulfonyl fluoride functionality serves as both an acidifying group and an internal oxidant within the ambiphile, enabling successive carbopalladation and oxidative addition steps in the catalytic cycle, respectively. The transformation grants access to cis-substituted cyclopropanes and exhibits broad compatibility with various alkyl sulfonyl fluorides, including those bearing –CN, –CO2R, isoxazolyl, pyrazolyl and aryl groups. With internal alkene substrates, 1,2,3-trisubstituted cyclopropanes that are otherwise challenging to synthesize are formed in good-to-moderate yields and predictable diastereoselectivity. Detailed mechanistic insights from reaction progress kinetic analysis and density functional theory calculations reveal that the SN2-type C–SO2F oxidative addition is the turnover-limiting and diastereoselectivity-determining step. The ambiphilic reactivity of alkyl sulfonyl fluorides in stereoselective cyclopropanation under Pd(II) catalysis is reported. The method provides convenient access to cis-disubstituted cyclopropanes that are otherwise challenging to access. A representative carboxylic acid cyclopropane building block is scaled up to 100 mmol, demonstrating the practicality of this transformation.

A simple and practical method for the synthesis of 1-alkyl-5-methyl ester-1H-1,2,3-triazole-5-carboxylate from low boiling point azides is demonstrated. The triazoles were constructed by 1,3-dipolar cycloaddition of methyl 3-(trimethylsilyl) propiolate with alkyl azides containing one to four carbons. To better handle the volatility of the alkyl azides, a flow chemistry method was developed to ensure a safer reaction.

By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis. The resulting advanced lead compounds enabled a tumor growth inhibition study which was pivotal in assessing the potential value of MASTL as an oncology therapeutic target.

A facile approach to densely functionalized cyclopropanes is described. The reaction proceeds under mild conditions via the directed nucleopalladation of non-conjugated alkenes with readily available pronucleophiles and gives excellent yields and good anti-selectivity using I2 and TBHP as oxidants. Pronucleophiles bearing a diverse collection electron-withdrawing groups, including–CN, –CO2R, –COR, –SO2Ph, -CONHR and –NO2, are well tolerated. Internal alkenes, which are generally challenging substrates in other cyclopropanation methods, provide excellent yields and good diastereoselectivity in this methodology, allowing for controlled access to cyclopropanes substituted at all three C-atoms.

2- or 4-Pyridyl benzylic amines represent a privileged motif in drug discovery. However, the formation of heterocyclic benzylic amines with fully substituted α-carbons can require the execution of lengthy synthetic routes, which limit their application. Addition of various nucleophilic agents to Ellman's imines has been well established; however, there is no precedented literature reported for pyridyl-type nucleophiles, which are very important for medicinal chemistry. In this letter, we disclose the development of a one-step synthesis of heterocyclic benzylic amines with fully substituted α-carbons from heteroaryl halides and sulfinyl imines. Starting from 2,4-dibromopyridine, regioselective synthesis of 2- or 4-pyridyl benzylic amines could be achieved by choosing toluene or MTBE as a solvent.

We describe a catalytic cascade sequence involving directed C(sp3)–H activation followed by β-heteroatom elimination to generate a PdII(π-alkene) intermediate that then undergoes redox-neutral annulation with an ambiphilic aryl halide to access 5- and 6-membered (hetero)cycles. Various alkyl C(sp3)–oxygen, nitrogen, and sulfur bonds can be selectively activated, and the annulation proceeds with high diastereoselectivity. The method enables modification of amino acids with good retention of enantiomeric excess, as well as σ-bond ring-opening/ring-closing transfiguration with low-strain heterocycles. Despite its mechanistic complexity, the method employs simple conditions and is operationally straightforward to perform.

In this study, we systematically evaluate different ambiphilic organohalides for their ability to participate in anti-selective carbo- or heteroannulation with non-conjugated alkenyl amides under Pd catalysis. Detailed optimization of reaction conditions has led to protocols for synthesizing tetrahydropyridines, tetralins, pyrrolidines, and other carbo/heterocyclic cores via [n+2] (n = 3–5) (hetero)annulation. Expansion of scope to otherwise unreactive ambiphilic haloketones through Pd(II)/amine co-catalysis is also demonstrated. Compared to other annulation processes, this method proceeds via a distinct Pd(II)/Pd(IV) mechanism involving Wacker-type directed nucleopalladation. This distinction results in unique reactivity and selectivity patterns, as revealed through assessment of reaction scope and competition experiments.

Indazoles represent a privileged motif in drug discovery. However, the formation of highly substituted indazoles can require the execution of lengthy synthetic routes with minimal opportunities to introduce diversity. In this report, we disclose the development of a late-stage diversification strategy for the 4- and 5-positions of 4,5,6-trisubstituted indazoles. A regioselective C-H functionalization and subsequent nucleophilic aromatic substitution provide two sequential points of diversification. The synthetic sequence delivers rapid access to an array of 4,5,6-trisubstituted indazoles in only four steps from readily available starting materials.

2,3-Dihydrobenzofurans and indolines are common substructures in medicines and natural products. Herein, we describe a method that enables direct access to these core structures from non-conjugated alkenyl amides and ortho-iodoanilines/phenols. Under palladium(II) catalysis this [3+2] heteroannulation proceeds in an anti-selective fashion and tolerates a wide variety of functional groups. N-Acetyl, -tosyl, and -alkyl substituted ortho-iodoanilines, as well as free –NH2 variants, are all effective. Preliminary results with carbon-based coupling partners also demonstrate the viability of forming indane core structures using this approach. Experimental and computational data with phenols support a mechanism involving turnover-limiting, endergonic directed oxypalladation, followed by intramolecular oxidative addition and reductive elimination.

Historically accessed through two-electron, anionic chemistry, ketones, alcohols, and amines are of foundational importance to the practice of organic synthesis. After placing this work in proper historical context, this Article reports the development, full scope, and a mechanistic picture for a strikingly different way of forging such functional groups. Thus, carboxylic acids, once converted to redox-active esters (RAEs), can be utilized as formally nucleophilic coupling partners with other carboxylic derivatives (to produce ketones), imines (to produce benzylic amines), or aldehydes (to produce alcohols). The reactions are uniformly mild, operationally simple, and, in the case of ketone synthesis, broad in scope (including several applications to the simplification of synthetic problems and to parallel synthesis). Finally, an extensive mechanistic study of the ketone synthesis is performed to trace the elementary steps of the catalytic cycle and provide the end-user with a clear and understandable rationale for the selectivity, role of additives, and underlying driving forces involved.

Hindered ethers represent an underexplored area of chemical space due to the difficulty and inoperability associated with conventional reactions, despite the high-value of such structural motifs in a variety of societal applications. Demonstrated herein is an exceptionally simple solution to this problem that leverages the power of electrochemical oxidation to liberate high-energy carbocations from simple carboxylic acids. The controlled formation of these reactive intermediates takes place with low electrochemical potentials under non-acidic conditions to capture an alcohol donor thereby producing a range (>80) of ethers that would be extremely difficult to otherwise access. Simple nucleophiles can also intercept such cations, leading to hindered alcohols and even alkyl fluorides. This method has been field tested to solve the synthetic bottlenecks encountered on twelve real-world chemical scaffolds with documented societal impact, resulting in a dramatic reduction in step-count and labor required, accompanied with a higher yield (average step-count, time, and yield = 6.3, ca. 100 h, 19% vs. 1.5, 9.8 h, 43%). Finally, the use of molecular probes coupled to kinetic studies support the proposed mechanism and role of additives in the conditions employed.

The copper-catalyzed hydroboration of benzylidenecyclopropanes, conveniently accessed in one step from readily available benzaldehydes, is reported. Under otherwise identical reaction conditions, two distinct phosphine ligands grant access to different products by either suppressing or promoting cyclopropane opening via β-carbon elimination. Computational studies provide insight into how the rigidity and steric environment of these different bis-phosphine ligands influence the relative activation energies of β-carbon elimination versus protodecupration from the key benzylcopper intermediate. The method tolerates a wide variety of heterocycles prevalent in clinical and pre-clinical drug development, giving access to valuable synthetic intermediates. The versatility of the tertiary cyclopropylboronic ester products is demonstrated through several derivatization reactions.

Transition-metal catalyzed 1,4-addition of arylboronic acids to enones and related conjugated alkenes has emerged as a reliable and robust method to introduce an aryl group at the b position of a carbonyl compound or functional group equivalent. In 1997 Miyaura reported a seminal study describing Rh(I)-catalyzed b-selective hydroarylation of enones using arylboronic acids (Scheme 1A). In 1998, Miyaura and Hayashi reported an asymmetric version of this reaction. Since then,

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The direct union of primary, secondary, and tertiary carboxylic acids with a chiral glyoxylate-derived sulfinimine provides rapid access into a variety of enantiomerically pure α-amino acids (>85 examples). Characterized by operational simplicity, this radical-based reaction enables the modular assembly of exotic α-amino acids, including both unprecedented structures and those of established industrial value. The described method performs well in high-throughput library synthesis, and has already been implemented in three distinct medicinal chemistry campaigns.

A catalytic γ-selective syn-hydroarylation of alkenyl carbonyl compounds using arylboronic acids has been developed using a substrate directivity approach with a palladium(II) catalyst. This method tolerates a wide range of functionalized (hetero)arylboronic acids and a variety of substitution patterns on the alkene.

A mechanistic study using a cyclopropylmethyl radical clock as a probe to investigate the formation of a macrolactam ring via an SmI2-mediated intramolecular Reformatsky reaction is experimentally explored. The results of our study indicate that the key Sm-III-enolate intermediate is formed by cleavage of a C-Br bond in an anion-mediated -elimination, and then eventually undergoes an intramolecular aldol condensation to form the macrolactam ring.

A series of 180 vinblastine 20' amides were prepared in three steps from commercially available starting materials, systematically exploring a typically inaccessible site in the molecule enlisting a powerful functionalization strategy. Clear structure-activity relationships and a structural model were developed in the studies which provided many such 20' amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogues that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines. The improvements in potency directly correlated with target tubulin binding affinity, and the reduction in differential functional activity against the sensitive and Pgp overexpressing resistant cell lines was found to correlate directly with an impact on Pgp-derived efflux.