Vinylogous Amide Research Articles

Tumor targeted alpha particle therapy with an actinium-225 labelled antibody for carbonic anhydrase IX.

Selective antibody targeted delivery of α particle emitting actinium-225 to tumors has significant therapeutic potential. This work highlights the design and synthesis of a new bifunctional macrocyclic diazacrown ether chelator, H2MacropaSqOEt, that can be conjugated to antibodies and forms stable complexes with actinium-225. The macrocyclic diazacrown ether chelator incorporates a linker comprised of a short polyethylene glycol fragment and a squaramide ester that allows selective reaction with lysine residues on antibodies to form stable vinylogous amide linkages. This new H2MacropaSqOEt chelator was used to modify a monoclonal antibody, girentuximab (hG250), that binds to carbonic anhydrase IX, an enzyme that is overexpressed on the surface of cancers such as clear cell renal cell carcinoma. This new antibody conjugate (H2MacropaSq-hG250) had an average chelator to antibody ratio of 4 : 1 and retained high affinity for carbonic anhydrase IX. H2MacropaSq-hG250 was radiolabeled quantitatively with [225Ac]AcIII within one minute at room temperature with micromolar concentrations of antibody and the radioactive complex is stable in human serum for >7 days. Evaluation of [225Ac]Ac(MacropaSq-hG250) in a mouse xenograft model, that overexpresses carbonic anhydrase IX, demonstrated a highly significant therapeutic response. It is likely that H2MacropaSqOEt could be used to modify other antibodies providing a readily adaptable platform for other actinium-225 based therapeutics.

Development of Green Asymmetric Organocatalytic Synthesis

Organocatalysts, which are less toxic than metal catalysis, as well as inexpensive, environmentally benign, and stable against moisture and oxygen compared to metal-based catalysts, have received considerable attention for being efficient and clean catalysts. With respect to green chemistry, the development of organocatalysis is a significant research subject for a sustainable society. This article reviews studies on the development of novel organocatalysts and the reactions achieved from using them. Focusing on the push-pull ethylene moiety, in which two electron-withdrawing groups (EWGs) were introduced, we proposed that the vinylogous amide proton (N-H) will lead to the design of organocatalysts. We have developed the diaminomethylenemalononitrile (DMM) organocatalysts, which are push-pull ethylenes having two cyano groups as EWGs, and proved that they are effective for highly stereoselective hydrophosphonylation with aldehydes. The catalytic ability of the DMM organocatalyst was demonstrated in the development of the first asymmetric hydrophosphonylation of ketones using organocatalysts. The DMM organocatalyst can be applied to the selective 1,4-addition asymmetric hydrophosphonylation of enones. In addition, we designed and synthesized novel organocatalysts bearing squaramide-sulfonamide motif as multiple hydrogen bond donors. Squaramide-sulfonamide organocatalysts efficiently catalyzed the asymmetric direct vinylogous aldol reactions of furan-2(5H)-one with aldehydes. Successively, we achieved the synthesis of γ,γ-disubstituted-δ-hydroxy-γ-butenolide via asymmetric direct vinylogous aldol reaction of furanone derivatives using the squaramide-sulfonamide organocatalysts.

Preparation of the Key Dolutegravir Intermediate via MgBr2-Promoted Cyclization.

A novel approach for synthesizing the key dolutegravir intermediate is described via MgBr2-promoted intramolecular cyclization. Condensation of commercially available methyl oxalyl chloride and ethyl 3-(N,N-dimethylamino)acrylate afforded the vinylogous amide in an excellent yield. Subsequent substitution by aminoacetaldehyde dimethyl acetal and methyl bromoacetate gave rise to the expected precursor for cyclization, which was promoted by MgBr2 to highly selectively convert into pyridinone diester. The key dolutegravir intermediate was finally prepared by the selective hydrolysis of the corresponding diester via LiOH.

The Bonding Interactions in Fluorinated Vinylogous Amides: A CF3‐Substituted Carbonyl‐β‐Aminoenone as a Case Study

AbstractA new perfluoromethylated vinylogous amide, (Z)‐4,4,4‐trifluoro‐1‐(2‐hydroxyphenyl)‐3‐(2‐methoxyethylamino)‐2‐buten‐1‐one, is chosen as an example to investigate the bonding interactions in solid state. The Z, s‐cis form is the dominant conformation in both solution and solid state. Intramolecular hydrogen bonding determines this conformational preference in a nonpolar solvent (NMR spectra). Carbonyl and phenol groups are sensitive to the intra‐ and intermolecular contacts (vibrational spectra). The supramolecular assembly (X‐ray diffraction) is governed by NH⋯O and OH⋯O strong intermolecular hydrogen bonds giving rise to center‐symmetric and graph‐set motifs. The π‐stacking, F⋯H and F⋯F interactions are also discussed (Hirshfeld analysis).

Enrichment of Semiconducting Single-Walled Carbon Nanotubes with Indigo-Fluorene-Based Copolymers and Their Use in Printed Thin-Film Transistors and Carbon Dioxide Gas Sensors.

High-purity semiconducting single-walled carbon nanotubes (sc-SWCNTs) are promising for portable and high-sensitivity gas sensors because of their excellent physical and electrical properties. Here, we describe the synthesis of a novel indigo-fluorene-based copolymer (PFIDBoc) that has been designed to selectively enrich sc-SWCNTs with excellent purity (>99.9%) yet contain a latent function in the form of a tert-butoxy (t-BOC)-protected amine that can be later revealed and exploited for carbon dioxide (CO2) gas sensing. SWCNTs wrapped with the PFIDBoc polymer can be easily converted via an on-chip thermal process to reveal a vinylogous amide moiety with a secondary amine nitrogen within the indigo building block of the copolymer which is perfectly suited for CO2 recognition. Thin-film transistors and sensors were inkjet-printed onto rigid and flexible substrates, demonstrating the versatility of enriched PFIDBoc-derived sc-SWCNT dispersions. The printed transistors exhibited a mobility up to 9 cm2 V-1 s-1 and on/off current ratios >105. We further demonstrate herein a CO2 sensor for indoor air quality monitoring even in low humidity environments, possessing a linear response with up to ∼5.4% sensitivity and a dynamic range between 400 and 2000 ppm in air with a relative humidity of ∼ 40%.

The roles of Ser-36, Asp-132 and Asp-201 in the reaction of Pseudomonas fluorescens Kynureninase

Kynureninase from Pseudomonas fluorescens (Pfkynase) catalyzes the pyridoxal-5′-phosphate (PLP) dependent hydrolytic cleavage of L-kynurenine to give anthranilate and L-alanine. Asp-132 and Asp-201 are located in the structure near the pyridine NH of the PLP, with Asp-201 forming a hydrogen bond. Mutation of Asp-132 to alanine and glutamate and Asp-201 to glutamate results in reduced catalytic activity with L-kynurenine and β-benzoyl-L-alanine, but not O-benzoyl-l-serine. D132A, D132E D201E and S36A mutant Pfkynases all can form quinonoid and vinylogous amide intermediates with β-benzoyl-L-alanine, similar to wild-type enzyme. D132A, D132E, and D201E Pfkynase react more slowly with β-benzoyl-L-alanine and benzaldehyde to form an aldol product absorbing at 490 nm than wild-type, with D132E reacting the slowest. The 1H NMR spectra of wild-type and D201E Pfkynase are very similar in the low field region from 10 to 18 ppm, but that of D132A Pfkynase is missing a resonance at 13.1 ppm. These results show that these residues modulate the reactivity of the PLP at different stages during the reaction cycle. Ser-36 is located near the expected location of the carbonyl oxygen of the substrate. Mutation of Ser-36 to alanine results in a 230-fold reduction of kcat and 30-fold reduction in kcat/Km with L-kynurenine, but very little effect on the reaction of O-benzoyl-l-serine. Thus, the rate-determining step in the reaction of S36A Pfkynase is the Cβ-Cγ bond cleavage. These results support the hypothesis that Ser-36 together with Tyr-226 is part of an oxyanion hole that polarizes the carbonyl of the substrate in the catalytic mechanism of Pfkynase.

Oxazaborinines from Vinylogous N-Allylic Amides: Reactivities of Underexplored Heterocyclic Building Blocks.

Access to a new class of oxazaborinines using an efficient transition-metal-catalyzed rearrangement is demonstrated. The method overcomes the synthetic challenge of achieving an aza-Claisen rearrangement of vinylogous N-allylic amide substrates, giving rise to a variety of highly modifiable oxazaborinine products. An investigation of the unique reactivity of these boron-based heterocycles has unveiled their underexplored potential as valuable building blocks and intermediates for organic synthesis.

Two different products from the reaction of 1-aryl-5-chloro-3-methyl-1H-pyrazole-4-carbaldehyde with cyclohexylamine when the aryl substituent is phenyl or pyridin-2-yl: hydrogen-bonded sheets versus dimers.

Cyclohexylamine reacts with 5-chloro-3-methyl-1-(pyridin-2-yl)-1H-pyrazole-4-carbaldehyde to give 5-cyclohexylamino-3-methyl-1-(pyridin-2-yl)-1H-pyrazole-4-carbaldehyde, C16H20N4O, (I), formed by nucleophilic substitution, but with 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde the product is (Z)-4-[(cyclohexylamino)methylidene]-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one, C17H21N3O, (II), formed by condensation followed by hydrolysis. Compound (II) crystallizes with Z' = 2, and in one of the two independent molecular types the cyclohexylamine unit is disordered over two sets of atomic sites having occupancies of 0.65 (3) and 0.35 (3). The vinylogous amide portion in each compound shows evidence of electronic polarization, such that in each the O atom carries a partial negative charge and the N atom of the cyclohexylamine portion carries a partial positive charge. The molecules of (I) contain an intramolecular N-H...N hydrogen bond, and they are linked by C-H...O hydrogen bonds to form sheets. Each of the two independent molecules of (II) contains an intramolecular N-H...O hydrogen bond and each molecular type forms a centrosymmetric dimer containing one R2(2)(4) ring and two inversion-related S(6) rings.

Total synthesis of alkaloid 205B.

Concise and highly stereocontrolled total syntheses of racemic and enantiopure frog alkaloid 205B (1) were accomplished in 11 steps from 4-methoxypyridines 6 and 7 in overall yields of 8 and 8%, respectively. The assembly of the core of the natural product relies on a stereoselective Tsuji–Trost allylic amination reaction and a ring-closing metathesis. The synthesis features the use of an N-acylpyridinium salt reaction to introduce the first stereocenter and an unprecedented trifluoroacetic anhydride-mediated addition of an allylstannane to a vinylogous amide with complete facial selectivity. Deoxygenation of the C4 ketone proved difficult but was accomplished via a modified Barton–McCombie reaction in the presence of a catalytic amount of diphenyl diselenide.

ChemInform Abstract: Synthesis of Vinylogous Amides by Gold(I)‐Catalyzed Cyclization of N‐Boc‐Protected 6‐Alkynyl‐3,4‐dihydro‐2H‐pyridines.

The gold(I)-catalyzed cyclization of N-Boc-protected 6-alkynyl-3,4-dihydro-2H-pyridines, prepared by the Sonogashira coupling of lactam-derived enol triflates or phosphates, provides vinylogous amides, which are useful intermediates in the synthesis of natural compounds. The Au(I)-catalyzed reaction is carried out with Ph3PAuOTf as a catalyst and proceeds via a 6-endo-dig cyclization to form a vinylgold species that after protodeauration generates a cyclic carbamate intermediate. This intermediate is in most cases not isolated, but the addition of a base to the reaction mixture rapidly and quantitatively delivers the target vinylogous amide. The first synthesis of a natural compound from Sonneratia hainanensis has been accomplished by this approach.

Synthesis of Enaminone‐Based Vinylogous Peptides

AbstractVinylogous peptides 3 with a vinyl fragment inserted into the peptide C–N bond were prepared from ynones 6 and enaminones 7 that are easily available from Boc‐protected α‐amino acids 4. Coupling at the C terminus was achieved by 1,4‐addition of amino esters 5 to the C≡C bond in 6 or by substitution of the NMe2 group in 7 to give N‐terminal vinylogues 3a–p. Coupling at the N terminus of 3 and 7, in contrast, required temporary protection of the acidolytically labile enamino moiety. Thus, cyclization of 6 or 7 with hydroxylamine, removal of the Boc group with HBr–AcOH, acylation of free amine 10 with BocGlyOH (4a), and hydrogenolytic deprotection of the enamino moiety in the presence of GlyOMe (5a) led to tripeptides 3q–s with vinylogous amide as the central building block.

Synthesis of Vinylogous Amides by Gold(I)-Catalyzed Cyclization of N-Boc-Protected 6-Alkynyl-3,4-dihydro-2H-pyridines

The gold(I)-catalyzed cyclization of N-Boc-protected 6-alkynyl-3,4-dihydro-2H-pyridines, prepared by the Sonogashira coupling of lactam-derived enol triflates or phosphates, provides vinylogous amides, which are useful intermediates in the synthesis of natural compounds. The Au(I)-catalyzed reaction is carried out with Ph3PAuOTf as a catalyst and proceeds via a 6-endo-dig cyclization to form a vinylgold species that after protodeauration generates a cyclic carbamate intermediate. This intermediate is in most cases not isolated, but the addition of a base to the reaction mixture rapidly and quantitatively delivers the target vinylogous amide. The first synthesis of a natural compound from Sonneratia hainanensis has been accomplished by this approach.

ChemInform Abstract: Catalytic, Asymmetric Indolizidinone Aza‐Quaternary Stereocenter Synthesis: Expedient Synthesis of the Cylindricine Alkaloid Core.

AbstractThe cylindricine core (IX) is synthesized in 7 steps and 11% overall yield.

Preparation of indole containing building blocks for the regiospecific construction of indole appended pyrazoles and pyrroles

The preparation of an indole appended vinamidinium salt, an indole appended vinylogous amide and an indole appended chloroenal are described. The subsequent regiospecific conversion of these indole containing building blocks to functionalized pyrazoles and pyrroles is detailed.

Catalytic, asymmetric indolizidinone aza-quaternary stereocenter synthesis: expedient synthesis of the cylindricine alkaloid core.

The Rh(I)•CKphos catalyzed [2 + 2 + 2] cycloaddition of 1,1-disubstituted alkenyl isocyanates and alkyl alkynes selectively forms previously inaccessible vinylogous amide indolizidinone cycloadducts, establishing an aza-quaternery stereocenter with excellent enantioselectivities (up to 98% ee). This advance enables a seven step catalytic, asymmetric synthesis of the tricyclic core of the cylindricine alkaloids with excellent control of product selectivity as well as regio- and enantioselectivity.

A Catalytic Asymmetric Synthesis of Polysubstituted Piperidines Using a Rhodium(I)‐Catalyzed [2+2+2] Cycloaddition Employing a Cleavable Tether

An enantioselective rhodium (I) catalyzed [2+2+2] cycloaddition with a cleavable tether has been developed. The reaction proceeds with a variety of alkyne substrates in good yield and high enantioselectivity. Upon reduction of the vinylogous amide in high diastereoselectivity (>19:1) and cleavage of the tether, N-methylpiperidine products with functional group handles can be accessed.

Perfluorinated Taddol Phosphoramidite as an L,Z-Ligand on Rh(I) and Co(-I): Evidence for Bidentate Coordination via Metal-C6F5 Interaction.

Perfluorinated Taddol-based phosphoramidite, CKphos, is a highly selective ligand for formation of the vinylogous amide cycloadduct in the Rh(I) catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and alkynes. CKphos overrides substrate bias of product selectivity in the cycloaddition, providing indolizinones in excellent product and enantioselectivities. Excellent selectivities are attributed to a shortened Rh-P bond and coordination of one C6F5 to rhodium via a Z-type interaction, making the phosphoramidite a bidentate L,Z-ligand on rhodium. Evidence for the shortened Rh-P and C6F5 coordination is provided by X-ray, NMR and DFT computation analyses. Additionally, an anionic cobalt complex with CKphos was synthesized and two Co-C6F5 interactions are seen. Rh(C2H4)Cl•CKphos catalyst in the [2+2+2] cycloaddition of alkenyl isocyanates and alkynes represents a rare example of metal-C6F5 Z-type interaction affecting selectivity in transition metal catalysis.

(2E)-1-Phenyl-2-[1-(2-phenylprop-2-en-1-yl)pyrrolidin-2-ylidene]ethanone

The title compound, C21H21NO, is a vinyl­ogous amide (enaminone) produced by reaction of 1-(2-phenyl­prop-2-en-1-yl)pyrrolidine-2-thione with phenacyl bromide. In the mol­ecule, the phenyl rings are twisted from the mean plane of the pyrrolidine ring by 11.2 (1) and 67.3 (1)°. In the crystal, weak C—H⋯O hydrogen bonds link the mol­ecules related by translation along the b axis into chains.

An unexpected transformation by reduction of isoxazolines

Abstract Aromatic nitrile oxides undergo regio- and stereo-specific 1,3-dipolar cycloaddition reactions with racemic 5-hydroxy-4-methyl-1,5-dihydropyrrol-2-one derivatives 1 . In each case, a single product 3 results from an anti approach to the hydroxyl group, the oxygen of the 1,3-dipole being attached to C-5 of pyrrolidinones. A detailed study of a procedure for the selective reduction of Δ 2 -isoxazolines to the corresponding vinylogous amide derivatives is reported.

Synthesis of (±)-7-Hydroxylycopodine

A seven-step synthesis of (±)-7-hydroxylycopodine that proceeds in 5% overall yield has been achieved. The key step is a Prins reaction in 60% sulfuric acid that gave the key tricyclic intermediate with complete control of the ring fusion stereochemistry. A one-pot procedure orthogonally protected the primary alcohol as an acetate and the tertiary alcohol as a methylthiomethyl ether. The resulting product was converted to 7-hydroxydehydrolycopodine by heating with KO-t-Bu and benzophenone in benzene followed by acidic workup. During unsuccessful attempts to make optically pure starting material, we observed the selective Pt-catalyzed hydrogenation of the 5-phenyl group of a 4,5-diphenyloxazolidine under acidic conditions and the Pt-catalyzed isomerization of the oxazolidine to an amide under neutral conditions. In attempts to hydroxylate the starting material so that we could adapt this synthesis to the preparation of (±)-7,8-dihydroxylycopodine (sauroine) we observed the novel oxidation of a bicyclic vinylogous amide to a keto pyridine with Mn(OAc)(3) and to an amino phenol with KHMDS and oxygen.