Development of a Crystallization-Induced Diastereomer Transformation of Oxime Isomers for the Asymmetric Synthesis of (1S,6R)-3,9-Diazabicyclo[4.2.1]nonane.

Herein we report a practical crystallization-induced diastereomer transformation (CIDT) of oxime isomers for the scalable asymmetric synthesis of the bicyclic diamine (1S,6R)-3,9-diazabicyclo[4.2.1]nonane derivative that serves as a valuable building block in medicinal chemistry. The developed approach utilizes (S)-phenylethylamine as a chiral auxiliary handle for CIDT, and the starting nortropinone derivative is prepared in one step from commercially available materials. The resulting E-oxime is subjected to a stereospecific Beckmann rearrangement, followed by reduction of the resulting lactam with LiAlH4 to afford the monoprotected (1S,6R)-3,9-diazabicyclo[4.2.1]nonane derivative. The development of the CIDT and understanding of the mechanistic implications leading to the high selectivity are reported.

Coupling-Condensation Strategy for the Convergent Synthesis of an Imidazole-Fused 2-Aminoquinoline NLRP3 Agonist.

The development of a convergent route to the NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing protein 3) agonist BMS-986299 is reported. The synthesis relies on a key Miyaura borylation and a tandem Suzuki-Miyaura coupling between an iodoimidazole and an o-aminochloroarene, followed by acid-mediated cyclization to afford the aminoquinoline core. The subsequent Boc cleavage and regioselective acylation afford the target compound. Two routes to the iodoimidazole intermediate are presented, along with the synthesis of the o-aminochloroarene via Negishi coupling. The convergent six-step route leads to an 80% reduction in process mass intensity compared to the linear enabling synthesis.

Utilizing Native Directing Groups: Mechanistic Understanding of a Direct Arylation Leads to Formation of Tetracyclic Heterocycles via Tandem Intermolecular, Intramolecular C-H Activation.

A mechanistic study on a direct arylation using a native picolylamine directing group is reported. Kinetic studies determined the concentration dependence of substrates and catalysts, as well as catalyst degradation, which led to the development of a new set of reaction conditions capable of affording a robust kinetic profile. During reaction optimization, a small impurity was observed, which was determined to be a dual C-H activation product. A second set of conditions were found to flip the selectivity of the C-H activation to form this tetracycle in high yield. A catalytic cycle is proposed for the intermolecular/intramolecular C-H activation pathway.

Tunable Copper-Catalyzed Reaction of C60 with 2-Ethoxycarbonylacetamides and Subsequent BF3·Et2O-Mediated Isomerization of the Generated Dihydrofuran-Fused Fullerenes to Fulleropyrrolidinones.

A tunable copper-catalyzed reaction of C60 with 2-ethoxycarbonylacetamides using air as the oxidant has been explored, which selectively affords methanofullerenes (2) and dihydrofuran-fused fullerenes (3) under the CuI/DMAP and CuCl/NMI catalytic systems, respectively. Furthermore, the generated dihydrofuran-fused fullerenes could be transformed to fulleropyrrolidinones (4 and 5) upon treatment with BF3·Et2O.

Synthesis of HIV-Maturation Inhibitor BMS-955176 from Betulin by an Enabling Oxidation Strategy.

A concise and scalable second generation synthesis of HIV maturation inhibitor BMS-955176 is described. The synthesis is framed by an oxidation strategy highlighted by a CuI mediated aerobic oxidation of betulin, a highly selective PIFA mediated dehydrogenation of an oxime, and a subsequent Lossen rearrangement which occurs through a unique reaction mechanism for the installation of the C17 amino functionality. The synthetic route proceeds in 7 steps with 47% overall yield and begins from the abundant and inexpensive natural product betulin.

Cu(OAc)2-Mediated Reaction of C60 with Ureas for the Preparation of Fulleroimidazolidinones.

The Cu(OAc)2-mediated intermolecular diamination reaction of C60 with ureas allows the concise and efficient preparation of fulleroimidazolidinones involving the cleavage of two N-H bonds and formation of two C-N bonds. Both dialkylated and diarylated fulleroimidazolidinones can be synthesized using this method.

Reaction of C60 with Inactive Secondary Amines and Aldehydes and the Cu(OAc)2-Promoted Regioselective Intramolecular C-H Functionalization of the Generated Fulleropyrrolidines.

The thermal reaction of C60 with aromatic aldehydes and inactive secondary amines for the stereoselective synthesis of trans-1,2,5-trisubstituted fulleropyrrolidines has been developed. Moreover, when an o-hydroxyl group was located at the phenyl ring of the generated fulleropyrrolidines, the Cu(OAc)2-promoted regioselective intramolecular C-O coupling reaction occurred to generate unique tricycle-fused fullerene derivatives.

Autoxidation Products of Betulonaldehyde.

Three major degradation products resulted from the exposure of betulonaldehyde (1) to air in solution at room temperature. From HRMS and NMR data, the products, which were isolated by preparative supercritical fluid chromatography (SFC), were identified as betulonic acid (2) and C-17 hydroperoxide epimers 3 (ß-OOH) and 4 (α-OOH). For 3 and 4, the H-18 multiplet pattern of the isolated products established the configuration at C-17.

Cooperative tandem catalysis by an organometallic complex and a metalloenzyme.

Although chemical and enzymatic catalysts have been combined, reactions in which an organometallic catalyst and a metalloenzyme work cooperatively to create products, which cannot be generated with either catalyst alone or in comparable yields by sequential reactions of the two catalysts, have not been reported. Such reactions are challenging to achieve, in part because the milieu in which these catalysts operate are typically different. Herein, two classes of catalysts are demonstrated to react cooperatively in the same system. Combination of a metathesis catalyst and a P450 enzyme lead to a dynamic equilibration of alkenes and a selective epoxidation of the cross-metathesis products. These results show the potential of combining the two classes of catalysts for synthetic transformations.

Sterically controlled, palladium-catalyzed intermolecular amination of arenes.

We report the Pd-catalyzed amination of arenes to form N-aryl phthalimides with regioselectivity controlled predominantly by steric effects. Mono-, di-, and trisubstituted arenes lacking a directing group undergo amination reactions with moderate to high yields and high regioselectivities from sequential addition of PhI(OAc)2 as an oxidant in the presence of Pd(OAc)2 as catalyst. This sterically derived selectivity contrasts that for analogous arene acetoxylation.

A new family of nucleophiles for photoinduced, copper-catalyzed cross-couplings via single-electron transfer: reactions of thiols with aryl halides under mild conditions (O °C).

Building on the known photophysical properties of well-defined copper-carbazolide complexes, we have recently described photoinduced, copper-catalyzed N-arylations and N-alkylations of carbazoles. Until now, there have been no examples of the use of other families of heteroatom nucleophiles in such photoinduced processes. Herein, we report a versatile photoinduced, copper-catalyzed method for coupling aryl thiols with aryl halides, wherein a single set of reaction conditions, using inexpensive CuI as a precatalyst without the need for an added ligand, is effective for a wide range of coupling partners. As far as we are aware, copper-catalyzed C-S cross-couplings at 0 °C have not previously been achieved, which renders our observation of efficient reaction of an unactivated aryl iodide at -40 °C especially striking. Mechanistic investigations are consistent with these photoinduced C-S cross-couplings following a SET/radical pathway for C-X bond cleavage (via a Cu(I)-thiolate), which contrasts with nonphotoinduced, copper-catalyzed processes wherein a concerted mechanism is believed to occur.

Mechanistic studies on direct arylation of pyridine N-oxide: evidence for cooperative catalysis between two distinct palladium centers.

Direct arylations of pyridine N-oxide (PyO), a convenient method to prepare 2-arylpyridines, catalyzed by Pd(OAc)(2) and PtBu(3) have been proposed to occur by the generation of a PtBu(3)-ligated arylpalladium acetate complex, (PtBu(3))Pd(Ar)(OAc) (1), and the reaction of this complex with PyO. We provide strong evidence that 1 does not react directly with PyO. Instead, our data imply that the cyclometalated complex [Pd(OAc)(tBu(2)PCMe(2)CH(2))](2), which is generated from the decomposition of 1, reacts with PyO and serves as a catalyst for the reaction of PyO with 1. The reaction of PyO with 1 occurs with an induction period, and the reaction of 1 with excess PyO in the presence of [Pd(OAc)(tBu(2)PCMe(2)CH(2))](2) is zeroth-order in 1. Moreover, the rates of reactions of PyO with bromobenzene catalyzed by [Pd(OAc)(tBu(2)PCMe(2)CH(2))](2) and [Pd(PtBu(3))(2)] depend on the concentration of [Pd(OAc)(tBu(2)PCMe(2)CH(2))](2) but not on the concentration of [Pd(PtBu(3))(2)]. Finally, the reaction of 1 with a model heteroarylpalladium complex containing a cyclometalated phosphine, [(PEt(3))Pd(2-benzothienyl)(tBu(2)PCMe(2)CH(2))], rapidly formed the arylated heterocycle. Together, these data imply that the rate-determining C-H bond cleavage occurs between PyO and the cyclometalated [Pd(OAc)(tBu(2)PCMe(2)CH(2))](2) rather than between PyO and 1. In this case, the resulting heteroarylpalladium complex transfers the heteroaryl group to 1, and C-C bond-formation occurs from (PtBu(3))Pd(Ar)(2-pyridyl oxide). This mechanism proposed for the direct arylation of PyO constitutes an example of C-H bond functionalization in which C-H activation occurs at one metal center and the activated moiety undergoes functionalization after transfer to a second metal center.

Assessment of the intermediacy of arylpalladium carboxylate complexes in the direct arylation of benzene: evidence for C-H bond cleavage by "ligandless" species.

Palladium-catalyzed direct arylations of benzene have been proposed to occur by the generation of a phosphine-ligated arylpalladium pivalate complex LPd(Ar)(OPiv) and reaction of this complex with benzene. We have isolated an example of the proposed intermediate and evaluated whether this complex does react with benzene to form the biaryl products of direct arylation. In contrast to the proposed mechanism, no biaryl product was formed from cleavage of the benzene C-H bond by LPd(Ar)(OPiv). However, reactions of LPd(Ar)(OPiv) with benzene and additives that displace or consume the phosphine ligand formed the arylated products in good yield, suggesting that a "ligandless" arylpalladium(II) carboxylate complex undergoes the C-H cleavage step. Consistent with this conclusion, we found that reactions catalyzed by Pd(OAc)(2) without a ligand occur faster than, and with comparable selectivities to, reactions catalyzed by Pd(OAc)(2) and a phosphine ligand.

DNA-Model-Based Design and Execution of Some Fused Benzodiazepine Hybrid Payloads for Antibody-Drug Conjugate Modality.

A new series with the tetrahydroisoquinoline-fused benzodiazepine (TBD) ring system combined with the surrogates of (1-methyl-1H-pyrrol-3-yl)benzene ("MPB") payloads were designed and executed for conjugation with a monoclonal antibody for anticancer therapeutics. DNA models helped in rationally identifying modifications of the "MPB" binding component and guided structure-activity relationship generation. This hybrid series of payloads exhibited excellent in vitro activity when tested against a panel of various cancer cell lines. One of the payloads was appended with a lysosome-cleavable peptide linker and conjugated with an anti-mesothelin antibody via a site-specific conjugation method mediated by the enzyme bacterial transglutaminase (BTGase). Antibody-drug conjugate (ADC) 50 demonstrated good plasma stability and lysosomal cleavage. A single intravenous dose of ADC 50 (5 or 10 nmol/kg) showed robust efficacy in an N87 gastric cancer xenograft model.

Palladium-catalyzed amination of aromatic C-H bonds with oxime esters.

We report a conceptually new approach to the direct amination of aromatic C-H bonds. In this process, an oxime ester function reacts with an aromatic C-H bond under redox-neutral conditions to form, in the case studied, an indole product. These reactions occur with relatively low catalyst loading (1 mol %) by a mechanism that appears to involve an unusual initial oxidative addition of an N-O bond to a Pd(0) species. The Pd(II) complex from oxidative addition of the N-X bond has been isolated for the first time, and evidence for the intermediacy of such oxidative addition products in the catalytic reaction has been gained.

Development of a Platform for Near-Infrared Photoredox Catalysis.

Over the past decade, chemists have embraced visible-light photoredox catalysis due to its remarkable ability to activate small molecules. Broadly, these methods employ metal complexes or organic dyes to convert visible light into chemical energy. Unfortunately, the excitation of widely utilized Ru and Ir chromophores is energetically wasteful as ∼25% of light energy is lost thermally before being quenched productively. Hence, photoredox methodologies require high-energy, intense light to accommodate said catalytic inefficiency. Herein, we report photocatalysts which cleanly convert near-infrared (NIR) and deep red (DR) light into chemical energy with minimal energetic waste. We leverage the strong spin-orbit coupling (SOC) of Os(II) photosensitizers to directly access the excited triplet state (T1) with NIR or DR irradiation from the ground state singlet (S0). Through strategic catalyst design, we access a wide range of photoredox, photopolymerization, and metallaphotoredox reactions which usually require 15-50% higher excitation energy. Finally, we demonstrate superior light penetration and scalability of NIR photoredox catalysis through a mole-scale arene trifluoromethylation in a batch reactor.

A Biochemiluminescent Sialidase Assay for Diagnosis of Bacterial Vaginosis.

Bacterial vaginosis (BV) is a common condition among women of reproductive age. A sensitive, quantitative and rapid assay is needed for the diagnosis of and, particularly, therapy monitoring for BV. Bacterial sialidase appears to play an important role in bacterial biofilms on vaginal epithelium, a condition closely associated with BV. Here, we report a biochemiluminescent sialidase assay that uses a substrate derivatized with firefly luciferin. In the presence of sialidase in the reaction, the substrate is cleaved to release luciferin, which is subsequently oxidized by firefly luciferase to generate a light signal. Thus, the light signal intensity can be used to detect and measure the relative concentration of sialidase in a vaginal sample as a means of BV diagnosis. All reagents are present in a reagent bead and sample buffer, enabling essentially a one-step assay. The assay is highly sensitive and quantitative, with a sensitivity and specificity of 95.40% and 94.94%, respectively, compared to the Amsel method. Interestingly, only 27.6% of those with BV had high levels of sialidase activity with a signal to cutoff ratio of 10 or more. The assay may be used for diagnosis of BV, risk assessment of BV patients in terms of sialidase activity levels, and monitoring antibiotic therapy.

A mechanistic investigation of the photoinduced, copper-mediated cross-coupling of an aryl thiol with an aryl halide.

Photoinduced, copper-catalyzed cross-coupling can offer a complementary approach to thermal (non-photoinduced) methods for generating C-X (X = C, N, O, S, etc.) bonds. In this report, we describe the first detailed mechanistic investigation of one of the processes that we have developed, specifically, the (stoichiometric) coupling of a copper-thiolate with an aryl iodide. In particular, we focus on the chemistry of a discrete [CuI(SAr)2]- complex (Ar = 2,6-dimethylphenyl), applying a range of techniques, including ESI-MS, cyclic voltammetry, transient luminescence spectroscopy, optical spectroscopy, DFT calculations, Stern-Volmer analysis, EPR spectroscopy, actinometry, and reactivity studies. The available data are consistent with the viability of a pathway in which photoexcited [CuI(SAr)2]-* serves as an electron donor to an aryl iodide to afford an aryl radical, which then reacts in cage with the newly generated copper(II)-thiolate to furnish the cross-coupling product in a non-chain process.