Synthetic Handle Research Articles

ChemInform Abstract: Metal‐ and Catalyst‐Free, Formal [4 + 1] Annulation via Tandem C=O/C=S Functionalization: One‐Pot Access to 3,5‐Disubstituted/Annulated Isothiazoles.

An operationally simple and user-friendly new protocol for the synthesis of 3,5-disubstituted/annulated isothiazoles is devised utilizing β-ketodithioesters/β-ketothioamides and NH4OAc via C═O/C═S bond functionalization under metal- and catalyst-free conditions. The strategic [4 + 1] annulation initiated by NH4OAc is carbon-economic and relies on a sequential imine formation/cyclization/aerial oxidation cascade forming consecutive C–N and S–N bonds in one pot. A wide range of previously inaccessible and synthetically challenging isothiazoles are compatible with this transformation under nontoxic conditions with excellent functional group tolerance. The products bear useful synthetic handles for further functionalization.

Depositing SiO2 on Al2O3: a Route to Tunable Brønsted Acid Catalysts

Strongly Brønsted acidic silica–alumina materials are workhorse catalysts in petroleum processes, including cracking, isomerization, and hydrocarbon synthesis. Here thin, conformal overcoats of SiO2, 2–5 nm by TEM, were synthesized on pre-existing Al2O3 supports by stepwise addition of tetraethyl orthosilicate under basic conditions, and the surfaces were interrogated by N2 physisorption along with NH3 and pyridine chemisorption. SiO2 layers thicker than 5 nm give largely inert surfaces, but adding only 2 nm of SiO2 is shown to quench the underlying Lewis acidity and unexpectedly form Brønsted acid sites strong enough to protonate gas-phase pyridine. Alternately, the use of a molecular template grafted to the alumina surface before SiO2 deposition selectively preserves the most reactive AlOH. In the catalytic cracking of 1,3,5-triisopropylbenzene at 450 °C, Al2O3 overcoated by 2 nm of SiO2 proved to be a highly active catalyst with 10 times higher conversion in comparison to that of Al2O3. Finally, the silica overlayer was deliberately cracked to expose strong interfacial sites, likely between tetrahedral Al and SiO2. In comparison to a material with an intact overlayer, this catalyst had 1.5 times higher conversion and 3 times higher selectivity to deep dealkylation products, including cumene and benzene. This core–shell SiO2@Al2O3 catalyst gives total dealkylation yields, per surface area, similar to those of conventionally prepared SiO2–Al2O3 or zeolite Y catalysts while providing for new synthetic handles for catalyst optimization.

Porphyrins as Templates for Site-Selective Atomic Layer Deposition: Vapor Metalation and in Situ Monitoring of Island Growth.

Examinations of enzymatic catalysts suggest one key to efficient catalytic activity is discrete size metallo clusters. Mimicking enzymatic cluster systems is synthetically challenging because conventional solution methods are prone to aggregation or require capping of the cluster, thereby limiting its catalytic activity. We introduce site-selective atomic layer deposition (ALD) on porphyrins as an alternative approach to grow isolated metal oxide islands that are spatially separated. Surface-bound tetra-acid free base porphyrins (H2TCPP) may be metalated with Mn using conventional ALD precursor exposure to induce homogeneous hydroxide synthetic handles which acts as a nucleation point for subsequent ALD MnO island growth. Analytical fitting of in situ QCM mass uptake reveals island growth to be hemispherical with a convergence radius of 1.74 nm. This growth mode is confirmed with synchrotron grazing-incidence small-angle X-ray scattering (GISAXS) measurements. Finally, we extend this approach to other ALD chemistries to demonstrate the generality of this route to discrete metallo island materials.

Abstract 4331: Discovery of potent 2-Indole-acylsulfonamide Mcl-1 inhibitors using structure guided fragment-based methods

Abstract Mcl-1 (Myeloid cell leukemia 1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and is one of the major acquired resistance mechanisms for many anticancer therapies. Targeting Mcl-1 with small molecules is very challenging because Mcl-1 exerts its effects through protein-protein interactions. Here we describe our continuing efforts in the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. We previously described the discovery of small-molecule Mcl-1 inhibitors containing a 2-indole-carboxylic core that primarily bind to the P2 pocket. In order to enhance potency, we extend our molecules to occupy the entire BH3 binding interface. A number of P4 site hits were identified using a fragment-based screening while the P2 pocket of Mcl-1 was saturated with our previously reported lead. P4 site ligands were then linked to our initial lead guided by the ternary Mcl-1 structure containing both P2 and P4 units using an acylsulfonamide as a synthetic handle that retained the critical charged-charged interaction with R263. X-ray co-crystal structures of new inhibitors occupying both P2 and P4 sites bound Mcl-1 provided detailed information on how these small-molecules bind to the target and guided subsequent potency optimization. From the efforts, we discovered a novel series of 2-indole-acylsulfonamide containing Mcl-1 inhibitors that exhibit low nanomolar binding affinities to the target and greater than 500-fold selectivity over Bcl-xL. These compounds represent useful starting points for the discovery of clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers. Citation Format: Subrata Shaw, James Chris Tarr, Nicholas Pelz, Zhiguo Bian, Johannes Belmar, Bin Zhao, Craig Goodwin, Allison Arnold, John Sensintaffar, Olivia Rossanese, Taekyu Lee, Edward Olejniczak, Stephen Fesik. Discovery of potent 2-Indole-acylsulfonamide Mcl-1 inhibitors using structure guided fragment-based methods. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4331.

Asymmetric Syntheses of (+)-Preussin B, the C(2)-Epimer of (-)-Preussin B, and 3-Deoxy-(+)-preussin B.

Efficient de novo asymmetric syntheses of (+)-preussin B, the C(2)-epimer of (-)-preussin B, and 3-deoxy-(+)-preussin B have been developed, using the diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 4-phenylbut-2-enoate and diastereoselective reductive cyclizations of γ-amino ketones as the key steps to set the stereochemistry. Conjugate addition followed by enolate protonation generated the corresponding β-amino ester. Homologation using the ester functionality as a synthetic handle gave the corresponding γ-amino ketone. Hydrogenolytic N-debenzylation was accompanied by diastereoselective reductive cyclization in situ; reductive N-methylation then gave 3-deoxy-(+)-preussin B as the major diastereoisomeric product. Meanwhile, the same conjugate addition but followed by enolate oxidation with (+)-camphorsulfonyloxaziridine gave the corresponding anti-α-hydroxy-β-amino ester. α-Epimerization by oxidation and diastereoselective reduction then gave access to the corresponding syn-α-hydroxy-β-amino ester. Homologation of both of these diastereoisomeric α-hydroxy-β-amino esters gave the corresponding β-hydroxy-γ-amino ketones. N-Debenzylation and concomitant diastereoselective reductive cyclization, followed by reductive N-methylation, provided the C(2)-epimer of (-)-preussin B and (+)-preussin B as the major diastereoisomeric products, respectively. The overall yields (from phenylacetaldehyde) were 19% for 3-deoxy-(+)-preussin B over seven steps, 8% for the C(2)-epimer of (-)-preussin B over nine steps, and 7% for (+)-preussin B over eleven steps.

Metal- and Catalyst-Free, Formal [4 + 1] Annulation via Tandem C═O/C═S Functionalization: One-Pot Access to 3,5-Disubstituted/Annulated Isothiazoles.

An operationally simple and user-friendly new protocol for the synthesis of 3,5-disubstituted/annulated isothiazoles is devised utilizing β-ketodithioesters/β-ketothioamides and NH4OAc via C═O/C═S bond functionalization under metal- and catalyst-free conditions. The strategic [4 + 1] annulation initiated by NH4OAc is carbon-economic and relies on a sequential imine formation/cyclization/aerial oxidation cascade forming consecutive C-N and S-N bonds in one pot. A wide range of previously inaccessible and synthetically challenging isothiazoles are compatible with this transformation under nontoxic conditions with excellent functional group tolerance. The products bear useful synthetic handles for further functionalization.

Brønsted Acid-Mediated Hydrative Arylation of Unactivated Alkynes.

The Brønsted acid-mediated reaction of unactivated alkynes with aryl sulfoxides leads to simultaneous hydration and intermolecular C-C bond formation. This solvent- and metal-free transformation directly delivers α-arylated carbonyl compounds as the products of a formal hydrative arylation in an atom-economical manner. The products bear useful synthetic handles for further functionalization.

Catalytic Enantioselective Synthesis of Amino Skipped Diynes.

The Cu-catalyzed synthesis of nonracemic 3-amino skipped diynes via an enantiodetermining C-C bond formation is described using StackPhos as ligand. Despite challenging issues of reactivity and stereoselectivity inherent to these chiral skipped diynes, the reaction tolerates an extremely broad substrate scope with respect to all components and provides the title compounds in excellent enantiomeric excess. The alkyne moieties are demonstrated here to be useful synthetic handles, and 3-amino skipped diynes are convenient building blocks for enantioselective synthesis.

Preparation of Tri‐ and Hexasubstituted Triptycene Synthons by Transition Metal Catalyzed Cross‐Coupling Reactions for Post‐Modifications

AbstractRational building strategies and appropriate synthons have been developed for the use of triptycene as a rigid presenting scaffold. Palladium‐catalyzed cross‐coupling reactions, such as Sonogashira and Suzuki couplings, were used to install a variety of different synthetic handles around the triptycene periphery in a high‐yielding and controlled manner. These triptycene molecular handles were investigated for their potential in the construction of molecular arrays with defined spatial orientation e.g., for host‐guest interactions or drug delivery systems. Such molecular synthons afforded expansion from the triptycene core by employing arm extension to increase the internal free volume characteristic of triptycene scaffolds for such applications. In addition, a range of mesogenic and glycosyl triptycene derivatives were achieved as a synthetic proof of concept for future work on potential drug delivery systems.

Synthesis of 1,3,6-Trisubstituted Azulenes.

We have developed a short, general synthetic route to 1,3,6-trisubstituted azulenes. The key intermediate, 6-methylazulene, was synthesized from readily available and inexpensive starting materials in 63% yield over two steps. The methyl group of 6-methylazulene was then used as a synthetic handle to introduce different substituents at the 6-position via two different methods. Subsequently, the 1- and 3-positions were substituted with additional functional handles, such as formyl, chloromethylketone, and iodide. The efficiency of the synthetic route was demonstrated by preparing a collection of three different products with the best demonstrated yield 33% over seven steps.

An expedient strategy for the diversity-oriented synthesis of macrocyclic compounds with natural product-like characteristics

Naturally-derived macrocyclic compounds are associated with a diverse range of biological activities, including antibacterial effects, and there are over 100 marketed macrocycle drugs derived from natural products. However, synthetic macrocycles are widely considered to be poorly explored in antibiotic development (indeed, within drug discovery in general). This has been attributed to challenges associated with the generation of such compounds. Whilst there are synthetic methods that can produce large collections of structurally similar macrocycles (i.e., compounds with varying appendages based around similar core macrocyclic ring architectures) there is a relative dearth of strategies for the efficient generation of more structurally diverse macrocycle collections in which there is greater variation in the nature of macrocyclic scaffolds present. Such macrocycle collections should contain compounds with a broad range of biological activities (including antibacterial activities) and the requisite robust synthetic methodology useful for analogue synthesis and lead optimization once an active compound has been identified in a biological screen. Herein, we describe a new and expedient diversity-oriented synthesis (DOS) strategy for the generation of a library of novel structurally diverse macrocyclic compounds with a high level of scaffold diversity. The strategy is concise, proceeds from readily-available starting materials, is modular in nature and features a variety of macrocyclisation techniques. In this proof-of-concept study, the synthesis of several previously unreported macrocyclic compounds was achieved. Each of these macrocycles was based around a distinct molecular scaffold and contained natural product-like structural features (e.g., three-dimensionality and multiple hydrogen bond donors and acceptors) as well as synthetic handles for potential further elaboration. The successful generation of these macrocycles demonstrates the feasibility of the new DOS strategy as a synthetic platform for library generation.

Diverse sp(3) C-H functionalization through alcohol β-sulfonyloxylation.

Site-selective C-H functionalization has emerged as an attractive tool for derivatizing complex synthetic intermediates, but its use for late-stage diversification is limited by the functional groups that can be introduced, especially at unactivated sp(3)-hybridized positions. To overcome this, we introduce a strategy that directly installs a sulfonyloxy group at a β-C-H bond of a masked alcohol and subsequently employs nucleophilic substitution reactions to prepare various derivatives. Hydroxyl groups are widely found in bioactive molecules and are thus readily available as synthetic handles. A directing group is easily added (and subsequently removed) from the alcohols such that a formal site-selective β-C-H sulfonyloxylation of these alcohols is achieved. Substitution reactions with carbon, nitrogen, oxygen and other nucleophiles then lead to diverse functionalizations that may help to streamline the synthesis of complex analogues for drug discovery.

Late-stage C-H functionalization of complex alkaloids and drug molecules via intermolecular rhodium-carbenoid insertion.

Alkaloids constitute a large family of natural products possessing diverse biological properties. Their unique and complex structures have inspired numerous innovations in synthetic chemistry. In the realm of late-stage C-H functionalization, alkaloids remain a significant challenge due to the presence of the basic amine and a variety of other functional groups. Herein we report the first examples of dirhodium(II)-catalysed intermolecular C-H insertion into complex natural products containing nucleophilic tertiary amines to generate a C-C bond. The application to a diverse range of alkaloids and drug molecules demonstrates remarkable chemoselectivity and predictable regioselectivity. The capacity for late-stage diversification is highlighted in the catalyst-controlled selective functionalizations of the alkaloid brucine. The remarkable selectivity observed, particularly for site-specific C-H insertion at N-methyl functionalities, offers utility in a range of applications where efficient installation of synthetic handles on complex alkaloids is desired.

KAHA ligations that form aspartyl aldehyde residues as synthetic handles for protein modification and purification.

Aldehydes are widely recognized as valuable synthetic handles for the chemoselective manipulation of peptides and proteins. In this report, we show that peptides and small proteins containing the aspartic acid semialdehyde (Asa) side chain can be easily prepared by a chemoselective amide-forming ligation that results in the formation of the Asa residue at the ligation site. This strategy employs the α-ketoacid-hydroxylamine (KAHA) ligation in combination with a new isoxazolidine monomer that forms a side-chain aldehyde upon ligation. This monomer is easily prepared on a preparative scale by a catalytic, enantioselective approach and is readily introduced onto the N-terminus of a peptide segment by solid phase peptide synthesis. The ligated product can be further functionalized by bioorthogonal reactions between the aldehyde residue and alkoxyamines or hydrazides. We demonstrated that glucagon aldehyde, an unprotected 29-mer peptide prepared by KAHA ligation, can be site specifically and chemoselectively modified with biotin, dyes, aliphatic oximes, and hydroxylamines. We further describe a simple and high recovery one-step purification process based on the capture of a 29-mer glucagon aldehyde and a 76-mer ubiquitin aldehyde by an alkoxyamine-functionalized polyethylene glycol resin. The peptide or protein was released from the resin by addition of a hydroxylamine to provide the corresponding oximes.

2′-Deoxy-2′,2′-difluorothymidine analogues for radiolabeling with fluorine-18 and other biomedical applications

Novel 2′-deoxy-2′,2′-difluorothymidine analogues with potential applications as antiviral, cytotoxic and cancer imaging agents have been synthesized. Introduction of the hydroxymethyl functionality at the 5-position of 2′-deoxy-2′,2′-difluoruridine provided a key intermediate with a suitable synthetic handle for the generation of these nucleoside derivatives.

A novel Fischer pseudo-benzylic decarboxylation approach to the 1,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl system

A novel Fischer pseudo-benzylic decarboxylation approach to the 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl system was developed starting from geminally substituted cyclopentanone derivatives and appropriately substituted phenyl hydrazines. In addition, we demonstrate that substituents at the 3- and 7-positions can, for example, be useful synthetic handles for further functionalization.

Computational and experimental characterization of a fluorescent dye for detection of potassium ion concentration.

The fluorescence of the SKC-513 ((E)-N-(9-(4-(1,4,7,10,13-pentaoxa-16-azacyclooctadecan-16-yl)phenyl)-6-(butyl(3-sulfopropyl)amino)-3H-xanthen-3-ylidene)-N-(3-sulfopropyl)butan-1-aminium) dye is shown experimentally to have high sensitivity to binding of the K+ ion. Computations are used to explore the potential origins of this sensitivity and to make some suggestions regarding structural improvements. In the absence of K+, excitation is to two nearly degenerate states, a neutral (N) excited state with a high oscillator strength, and a charge-transfer (CT) state with a lower oscillator strength. Binding of K+ destabilizes the CT state, raising its energy far above the N state. The increase in fluorescence quantum yield upon binding of K+ is attributed to the increased energy of the CT state suppressing a nonradiative pathway mediated by the CT state. The near degeneracy of the N and CT excited states can be understood by considering SKC-513 as a reduced symmetry version of a parent molecule with 3-fold symmetry. Computations show that acceptor–donor substituents can be used to alter the relative energies of the N and CT state, whereas a methylene spacer between the heterocycle and phenylene groups can be used to increase the coupling between these states. These modifications provide synthetic handles with which to optimize the dye for K+ detection.

Synthesis, Characterization, and Unusual Behavior of a Perfluoroarylated Fullerene

Fullerenes and fullerene derivatives have attracted much attention due to their interesting optical and electronic properties. For example, further chemical elaborations of fullerenes possessing cyclo‐adducts (ie., phenyl‐C61‐butyric acid methyl ester, PCBM,1 and mono‐indene-C60, ICMA2) have shown promising use in photovoltaic energy conversion. Mono‐hydrofullerenes, C60RH, were shown as effective synthons for novel molecules3 with interesting physicochemical properties for various applications. The C‒H bond activation utilizing the acidic fullerenyl C60‒H proton can be realized by the use of strong bases. For instance, the dimerization of two RC60· radicals using NaOH in the presence of C60RH was used to form RC60‒C60R.4 In this work, we use the labile hydrogen atom on C60RH as a synthetic handle for further chemical elaborations, resulting in a novel perfluoroarylfullerene. One such product, a "fullerene-with-a-mohawk," was realized by the use of a base or by an one‐electron reductant. Products were characterized by 19F and 1H NMR spectroscopy, mass spectrometry, cyclic voltammetry, X‐ray crystallography, and DFT calculations. References (1) Reyes-Reyes, M.; Kim, K.; Carroll, D. L. Appl. Phys. Lett. 2005, 87, 083506.(2) Coffey, D. C.; Larson, B. W.; Hains, A. W.; Whitaker, J. B.; Kopidakis, N.; Boltalina, O. V.; Strauss, S. H.; Rumbles, G. J. Phys. Chem. C 2012, 116, 8916.(3) Allard, E.; Cheng, F.; Chopin, S.; Delaunay, J.; Rondeau, D.; Cousseau, J. New J. Chem. 2003, 27, 188.(4) Lu, S.; Jin, T.; Bao, M.; Yamamoto, Y. Org. Lett. 2012, 14, 3466.

ChemInform Abstract: Color‐Tunable Fluorescent Dyes Based on Benzo[c]coumarin.

AbstractSeveral fluorophores are synthesized via the Hurtley‐condensation.

Syntheses of 4-, 5-, 6-, and 7-substituted tryptamine derivatives and the use of a bromine atom as a protecting group

Orthogonal syntheses of 4-, 5-, 6-, and 7-chloro substituted tryptamine derivatives were performed under the Grandberg–Zuyanova-modified Fisher indole-synthesis conditions. In the 4- and 6-substituted tryptamine cases, a bromine atom was utilized as an easily cleavable protecting group, which allowed complete regiocontrol. In addition, a chlorine substituent was preserved in the debromination step and could be utilized as a synthetic handle for late-stage diversification under modern Pd(0) catalysis conditions.