Disconnection Approach Research Articles

Cost‐Effective Carbon Quaternization with Redox‐Active Esters and Olefins

AbstractQuaternary carbons are embedded in various natural products, pharmaceuticals, and organic materials. However, constructing this valuable motif is far from trivial. Conventional approaches mainly rely on classical polar disconnections and encounter bottlenecks concerning harsh conditions, functional group tolerance, regioselectivity, and step economy. In this context, Kawamata, Baran, Shenvi, and co‐workers recently demonstrated that two feedstock chemicals, alkyl carboxylic acids and olefins, could be utilized to construct tetrasubstituted carbons in the presence of an inexpensive iron porphyrin catalyst and a suitable reductant combination through quaternization of the radical intermediates. The method enables access to various sterically encumbered quaternary carbons under mild and robust conditions. Taking a complete detour from conventional approaches, the present heteroselective radical–radical coupling simplifies the synthesis of quaternary carbon‐containing molecules through an innovative and distinctive disconnection approach.

Cost-Effective Carbon Quaternization with Redox-Active Esters and Olefins.

Quaternary carbons are embedded in various natural products, pharmaceuticals, and organic materials. However, constructing this valuable motif is far from trivial. Conventional approaches mainly rely on classical polar disconnections and encounter bottlenecks concerning harsh conditions, functional group tolerance, regioselectivity, and step economy. In this context, Kawamata, Baran, Shenvi, and co-workers recently demonstrated that two feedstock chemicals, alkyl carboxylic acids and olefins, could be utilized to construct tetrasubstituted carbons in the presence of an inexpensive iron porphyrin catalyst and a suitable reductant combination through quaternization of the radical intermediates. The method enables access to various sterically encumbered quaternary carbons under mild and robust conditions. Taking a complete detour from conventional approaches, the present heteroselective radical-radical coupling simplifies the synthesis of quaternary carbon-containing molecules through an innovative and distinctive disconnection approach.

Tert‐Butyl as a Functional Group: Non‐Directed Catalytic Hydroxylation of Sterically Congested Primary C−H Bonds

AbstractThe tert‐butyl group is a common aliphatic motif extensively employed to implement steric congestion and conformational rigidity in organic and organometallic molecules. Because of the combination of a high bond dissociation energy (~100 kcal mol−1) and limited accessibility, in the absence of directing groups, neither radical nor organometallic approaches are effective for the chemical modification of tert‐butyl C−H bonds. Herein we overcome these limits by employing a highly electrophilic manganese catalyst, [Mn(CF3bpeb)(OTf)2], that operates in the strong hydrogen bond donor solvent nonafluoro‐tert‐butyl alcohol (NFTBA) and catalytically activates hydrogen peroxide to generate a powerful manganese‐oxo species that effectively oxidizes tert‐butyl C−H bonds. Leveraging on the interplay of steric, electronic, medium and torsional effects, site‐selective and product chemoselective hydroxylation of the tert‐butyl group is accomplished with broad reaction scope, delivering primary alcohols as largely dominant products in preparative yields. Late‐stage hydroxylation at tert‐butyl sites is demonstrated on 6 densely functionalized molecules of pharmaceutical interest. This work uncovers a novel disconnection approach, harnessing tert‐butyl as a potential functional group in strategic synthetic planning for complex molecular architectures.

Tert-Butyl as a Functional Group: Non-Directed Catalytic Hydroxylation of Sterically Congested Primary C-H Bonds.

The tert-butyl group is a common aliphatic motif extensively employed to implement steric congestion and conformational rigidity in organic and organometallic molecules. Because of the combination of a high bond dissociation energy (~ 100 kcal mol-1) and limited accessibility, in the absence of directing groups, neither radical nor organometallic approaches are effective for the chemical modification of tert-butyl C-H bonds. Herein we overcome these limits by employing a highly electrophilic manganese catalyst, [Mn(CF3bpeb)(OTf)2], that operates in the strong hydrogen bond donor solvent nonafluoro-tert-butyl alcohol (NFTBA) and catalytically activates hydrogen peroxide to generate a powerful manganese-oxo species that effectively oxidizes tert-butyl C-H bonds. Leveraging on the interplay of steric, electronic, medium and torsional effects, site-selective and product chemoselective hydroxylation of the tert-butyl group is accomplished with broad reaction scope, delivering primary alcohols as largely dominant products in preparative yields. Late-stage hydroxylation at tert-butyl sites is demonstrated on 6 densely functionalized molecules of pharmaceutical interest. This work uncovers a novel disconnection approach, harnessing tert-butyl as a potential functional group in strategic synthetic planning for complex molecular architectures.

Alkoxy Diazomethylation of Alkenes by Photoredox-Catalyzed Oxidative Radical-Polar Crossover.

Herein, we present the discovery and development of the first photoredox-catalyzed alkoxy diazomethylation of alkenes with hypervalent iodine reagents and alcohols. This multicomponent process represents a new disconnection approach to diazo compounds and is featured by a broad scope, mild reaction conditions, and excellent selectivity. Key to the process was the generation of diazomethyl radicals, which engaged alkenes and alcohols in an inter- and intramolecular fashion by a photoredox-catalyzed oxidative radical-polar crossover leading to unexplored β-alkoxydiazo compounds. The synthetic utility of such diazo compounds was demonstrated with a series of transformations involving C-H, N-H, and O-H insertions as well as in the construction of complex sp3-rich heterocycles.

Catalytic Asymmetric Synthesis of α-Mono and α,α-Disubstituted 5- and 6-Membered α-Aza-lactams

AbstractFive- and six-membered cyclic amide structures with an embedded endocyclic α-aza group (α-aza-lactams) not only represent masked or protected forms of α-amino acids, but also form the core of other medicinally relevant compound families such as (thio)hydantoins and di(tri)ketopiperazines. In recent years, catalytic methods have been discovered to synthesize these molecular scaffolds, particularly those bearing an α-stereogenic tri- or tetrasubstituted carbon center, enantioselectively. The wide variety of methods and catalytic activation strategies that have been successfully applied to this end in a short period of years is notable. This short review covers the most significant, highlighting their differences and complementarities. The methods are organized according to the disconnection approach to the target α-aza-lactam structure, which in most cases is deeply bound to the type of catalysis applied.1 Introduction2 Catalyst-Controlled Cα–H Functionalization (Approach a)3 Decarboxylative α-AAA Reactions (Approach b)4 Cα–X Substitution Reactions (Approach c)5 De Novo Synthesis from Acyclic Precursors (Approach d)6 Hydrogenation of (Addition to) α-Alkyliden-α-aza-lactams (Approach e)7 Kinetic Resolution and Deracemization (Approach f)8 Conclusions

Rapid Access to cis-1,3-Dialkylindanes: Asymmetric Formal Syntheses of epi-Mutisianthol and epi-Jungianol

AbstractConcise and strategically unique asymmetric formal syntheses of epi-mutisianthol and epi-jungianol are presented. A novel disconnection approach is introduced to complement previous intramolecular cyclopentannulation strategies. Noteworthy features include: (a) control of the stereogenic benzylic carbon center through 1,3-chirality transfer from chiral indenols via the Johnson–Claisen rearrangement, which yields advanced indene-containing γ,δ-unsaturated esters, and (b) the diastereoselective construction of the cis-1,3-dialkylindane backbone via catalytic hydrogenation of the resulting indene. This approach presents a remarkable method for synthesizing structurally intriguing indane motifs.

Cooperative Photoredox and N-Heterocyclic Carbene Catalyzed Fluoroaroylation for the Synthesis of α-Trifluoromethyl-Substituted Ketones.

α-Trifluoromethylated ketones have attracted significant attention as valuable building blocks in organic synthesis. Such compounds are generally accessed through trifluoromethylation of ketones. Here we report an alternative disconnection approach for the construction of α-CF3 carbonyl compounds by using aroyl fluorides as bifunctional reagents for fluoroaroylation of gem-difluoroalkenes through cooperative photoredox and N-heterocyclic carbene (NHC) catalysis. This strategy bypasses the use of expensive or sensitive trifluoromethylation reagents and/or the requirement for ketone pre-functionalization, thus enabling an efficient and general synthetic method to access α-CF3 -substituted ketones. A wide variety of gem-difluoroalkenes and aroyl fluorides bearing a diverse set of functional groups are eligible substrates. Notably, the developed methodology also provides rapid access to mono- or difluoroalkyl ketones. Mechanistic studies reveal that merging photoredox catalysis with NHC catalysis is essential for the reaction.

Cooperative Photoredox and N‐Heterocyclic Carbene Catalyzed Fluoroaroylation for the Synthesis of α‐Trifluoromethyl‐Substituted Ketones

Abstractα‐Trifluoromethylated ketones have attracted significant attention as valuable building blocks in organic synthesis. Such compounds are generally accessed through trifluoromethylation of ketones. Here we report an alternative disconnection approach for the construction of α‐CF3 carbonyl compounds by using aroyl fluorides as bifunctional reagents for fluoroaroylation of gem‐difluoroalkenes through cooperative photoredox and N‐heterocyclic carbene (NHC) catalysis. This strategy bypasses the use of expensive or sensitive trifluoromethylation reagents and/or the requirement for ketone pre‐functionalization, thus enabling an efficient and general synthetic method to access α‐CF3‐substituted ketones. A wide variety of gem‐difluoroalkenes and aroyl fluorides bearing a diverse set of functional groups are eligible substrates. Notably, the developed methodology also provides rapid access to mono‐ or difluoroalkyl ketones. Mechanistic studies reveal that merging photoredox catalysis with NHC catalysis is essential for the reaction.

Modular, automated synthesis of spirocyclic tetrahydronaphthyridines from primary alkylamines

Spirocyclic tetrahydronaphthyridines (THNs) are valuable scaffolds for drug discovery campaigns, but access to this 3D chemical space is hampered by a lack of modular and scalable synthetic methods. We hereby report an automated, continuous flow synthesis of α-alkylated and spirocyclic 1,2,3,4-tetrahydro-1,8-naphthyridines (“1,8-THNs”), in addition to their regioisomeric 1,6-THN analogues, from abundant primary amine feedstocks. An annulative disconnection approach based on photoredox-catalysed hydroaminoalkylation (HAA) of halogenated vinylpyridines is sequenced in combination with intramolecular SNAr N-arylation. To access the remaining 1,7- and 1,5-THN isomers, a photoredox-catalysed HAA step is telescoped with a palladium-catalysed C–N bond formation. Altogether, this provides a highly modular access to four isomeric THN cores from a common set of unprotected primary amine starting materials, using the same bond disconnections. The simplifying power of the methodology is illustrated by a concise synthesis of the spirocyclic THN core of Pfizer’s MC4R antagonist PF-07258669.

The introduction of the disconnection approach into polymer synthesis

AbstractThe disconnection approach, a widely utilized method of design synthesis route, has played crucial roles in contemporary organic chemistry for decades. Here, we provide an introduction to the construction of polymer main chains. The implementation of the strategy hinges on determining where to disconnect based on the successful polymerization reaction in order to infer a suitable monomer. By investigating specific covalent bonds and structures in polymers, several specific linkers are highlighted to demonstrate how to design and synthesize polymer main chains using reverse thinking, thus inspiring those in polymer synthesis.

Photoinduced Electron Donor-Acceptor Complex-Mediated Radical Cascade Involving N-(Acyloxy)phthalimides: Synthesis of Tetrahydroquinolines.

We conceptualized a novel disconnection approach for the synthesis of fused tetrahydroquinolines that exploits a visible light-mediated radical (4 + 2) annulation between alkyl N-(acyloxy)phthalimides and N-substituted maleimides in the presence of DIPEA as an additive. The reaction proceeds through the formation of a photoactivated electron donor-acceptor complex between alkyl NHPI esters and DIPEA, and the final tetrahydroquinolines were obtained in a complete regioselective fashion. The methodology features a broad scope and good functional group tolerance and operates under metal- and catalyst-free reaction conditions. Detailed mechanistic investigations including density functional theory studies provide insight into the reaction pathway.

SYNTHETIC STUDY OF Pc-2, AN ACTIVE COMPOUND FROM INDONESIAN RED BETEL LEAF

PC-2 is one of the active compounds isolated from Indonesian red betel leaf. The structure of the compound is named 2-allyl-4-(1'-hydroxy-1'-(3",4",5"-trimethoxyphenyl)propan-2'-yl)-3,5-dimethoxycyclohexa-3,5-dienone and included in the neolignan’s structure category. This compound was reported to have very good biological activity in giving antiproliferative effects on human breast (T47D) cells. From 2.12 g of its leaf methanolic extract, only 12.1 mg of Pc-2 was collected. This amount is too small to do more studies about its biological activities. The synthetic work should be applied to get a sufficient amount. This paper is aimed to explain the synthetic study and design of the Pc2 compound. The first approach is by involving the aldol reaction in the synthetic pathway through the disconnection approach. The result showed that this attempt did not work very well. The second approach is to design the new synthetic pathway by using the synthia Organic Retrosynthesis Software by Merck. This software gave a reasonable result to be tried. The result proposed the use of the Suzuki coupling reaction for the new synthetic pathway of Pc-2.

Medial orbitofrontal cortex and nucleus accumbens mediation in risk assessment behaviors in adolescents and adults.

Risk assessment behaviors are necessary for gathering risk information and guiding decision-making. Risky decision-making heightens during adolescence, possibly as a result of low risk awareness and an increase in sensitivity to reward-associated cues and experiences. Higher adolescent engagement in high-risk behaviors may be, in part, due to developing circuits that contribute to risk assessment behaviors. Nucleus accumbens (NAc) activity is linked to risky decision-making and receives inputs carrying sensory and emotional information. Namely, the medial orbitofrontal cortex (MO) contributes to behavior guided by reward probability and sends direct projections to the NAc (MO→NAc), which may permit risk assessment in a mature circuit. Here, we evaluated risk assessment behaviors in adult and adolescent rats during elevated plus maze (EPM) exploration, including stretch and attend postures, head dips, and rears. We found that adolescents exhibited fewer EPM risk assessment behaviors than adults. We also quantified MO→NAc projections using a fluorescent anterograde tracer, Fluoro-Ruby, in both age groups. Labeled MO→NAc pathways exhibited greater total fluorescence in adults than in adolescents, indicating MO→NAc fibers increase over development. Using a disconnection approach to measure the contribution of the MO-NAc pathway in adults, we found that ipsilateral inactivation of the MO-NAc did not alter risk assessment behavior; however, MO-NAc disconnection reduced the number of stretch-and-attend postures. Together, this work suggests that the development of MO-NAc pathways can contribute to age-dependent differences in risk assessment.

Catalytic alkene skeletal modification for the construction of fluorinated tertiary stereocenters.

Herein we describe the first construction of fluorinated tertiary stereocenters based on an alkene C(sp2)–C(sp2) bond cleavage. The new process, that takes advantage of a Rh-catalyzed carbyne transfer, relies on a branched-selective fluorination of tertiary allyl cations and is distinguished by a wide scope including natural products and drug molecule derivatives as well as adaptability to radiofluorination.

Total Synthesis of a Chimeric Glycolipid Bearing the Partially Acetylated Backbone of Sponge-Derived Agminoside E.

We describe the total synthesis of a chimeric glycolipid bearing both the partially acetylated backbone of sponge-derived agminoside E and the (R)-3-hydroxydecanoic acid chain of bacterial rhamnolipids. The branched pentaglucolipid skeleton was achieved using a [3 + 2] disconnection approach. The β-(1 → 2) and β-(1 → 4)-glycosidic bonds were synthesized through a combination of NIS/Yb(OTf)3- and TMSOTf-mediated stereoselective glycosylations of thiotolyl, N-phenyltrifluoroacetimidate, and trichloroacetimidate donors. Late-stage pentaacetylation, Staudinger reduction of a (2-azidomethyl)benzoyl group, followed by continuous-flow microfluidic hydrogenolysis completed the total synthesis of the structurally simplified glycolipid, whose partial acetylation pattern on the glycan part was identical to agminoside E. Our study lays the foundation for the total synthesis of sponge-derived agminosides and the understanding of their biological functions in sponges.

A novel stroke lesion network mapping approach: improved accuracy yet still low deficit prediction.

Lesion network mapping estimates functional network abnormalities caused by a focal brain lesion. The method requires embedding the volume of the lesion into a normative functional connectome and using the average functional magnetic resonance imaging signal from that volume to compute the temporal correlation with all other brain locations. Lesion network mapping yields a map of potentially functionally disconnected regions. Although promising, this approach does not predict behavioural deficits well. We modified lesion network mapping by using the first principal component of the functional magnetic resonance imaging signal computed from the voxels within the lesioned area for temporal correlation. We measured potential improvements in connectivity strength, anatomical specificity of the lesioned network and behavioural prediction in a large cohort of first-time stroke patients at 2-weeks post-injury (n = 123). This principal component functional disconnection approach localized mainly cortical voxels of high signal-to-noise; and it yielded networks with higher anatomical specificity, and stronger behavioural correlation than the standard method. However, when examined with a rigorous leave-one-out machine learning approach, principal component functional disconnection approach did not perform better than the standard lesion network mapping in predicting neurological deficits. In summary, even though our novel method improves the specificity of disconnected networks and correlates with behavioural deficits post-stroke, it does not improve clinical prediction. Further work is needed to capture the complex adjustment of functional networks produced by focal damage in relation to behaviour.

An access to highly enantioenriched cis-3,5-disubstituted γ-lactones from α-bromoacetate and silyl enol ether.

A novel synthetic strategy for highly enantioenriched cis-3,5-disubstituted γ-lactones has been developed by the AgOTf-promoted nucleophilic substitution of α-bromoacetates with silyl enol ethers and subsequent reductive lactonization. The utility of this synthetic method was further demonstrated through the concise stereodivergent synthesis of cis- and trans-2,4-disubstituted tetrahydrofurans.

Teaching of Polymer Synthesis Design: Application of the Disconnection Approach in Polymer Chemistry

Teaching of Polymer Synthesis Design: Application of the Disconnection Approach in Polymer Chemistry

Prelimbic cortical projections to rostromedial tegmental nucleus play a suppressive role in cue-induced reinstatement of cocaine seeking

The prelimbic (PL) region of prefrontal cortex has been implicated in both driving and suppressing cocaine seeking in animal models of addiction. We hypothesized that these opposing roles for PL may be supported by distinct efferent projections. While PL projections to nucleus accumbens core have been shown to be involved in driving reinstatement of cocaine seeking, PL projections to the rostromedial tegmental nucleus (RMTg) may instead suppress reinstatement of cocaine seeking, due to the role of RMTg in behavioral inhibition. Here, we used a functional disconnection approach to temporarily disrupt the PL-RMTg pathway during cue- or cocaine-induced reinstatement. Male Sprague Dawley rats self-administered cocaine during daily 2-h sessions for ≥10 days and then underwent extinction training. Reinstatement of extinguished cocaine seeking was elicited by cocaine-associated cues or cocaine prime. Prior to reinstatement, rats received microinjections of the GABA agonists baclofen/muscimol (1/0.1 mM) into unilateral PL and the AMPA receptor antagonist NBQX (1 mM) into contralateral or ipsilateral RMTg. Functional disconnection of PL-RMTg via contralateral inactivation markedly increased cue-induced reinstatement, but did not increase cocaine-induced reinstatement or drive reinstatement of extinguished cocaine seeking in the absence of cues or cocaine. Enhanced cue-induced reinstatement was also observed with ipsilateral inactivation of PL and RMTg, but not with unilateral inactivation of PL or RMTg alone, indicating that both ipsilateral and contralateral projections from PL to RMTg have an inhibitory influence on behavior. These data further support a suppressive role for PL in cocaine seeking by implicating PL efferent projections to RMTg in inhibiting cue-induced reinstatement.