Unprotected Carboxylic Acids Research Articles

One-Step Automatic Radiosynthesis and Evaluation of [18F]TM-30089 as GPR44 Radiotracer.

Recently, a G-protein coupled receptor 44 (GPR44) was discovered to play a significant role in the process of inflammation-related diseases, including cancer and diabetes. However, the precise role of GPR44 has yet to be fully elucidated. Currently, there is a strong and urgent need for the development of GPR44 radiotracers as a non-invasive methodology to explore the exact mechanism of GPR44 on inflammation-related diseases and monitor the progress of therapy. TM-30089 is a potent GPR44 antagonist that exhibits a high specificity and selectivity for GPR44. Its structure contains a fluorine nuclide, which could potentially be replaced with 18F. In the present study, we successfully took a highly effective synthesis strategy that pretreated the unprotected carboxylic acid group of the precursor and developed a feasible one-step automatic radiosynthesis strategy for [18F]TM-30089 with a high radiochemical purity and a good radiochemical yield. We further evaluated this radiotracer using mice models implanted with 1.1 B4 cell lines (GPR44-enriched cell lines) and human islets (high GPR44 expression), respectively. The results revealed the persistent and specific uptake of [18F]TM-30089 in GPR44 region, indicating that [18F]TM-30089 is a promising candidate for targeting GPR44. Further evaluation is ongoing.

Biomimetic Total Synthesis of (+)-Nocardioazine B and Analogs.

Nocardioazines A and B are prenylated, bioactive pyrroloindoline natural products, isolated from Nocardiopsis, with a desymmetrized cyclo-d-Trp-d-Trp DKP core. Based on our deeper biosynthetic understanding, a biomimetic total synthesis of (+)-nocardioazine B is accomplished in merely seven steps and 23.2% overall yield. This pathway accesses regio- and stereoselectively C3-isoprenylated analogs of (+)-nocardioazine B, using the same number of steps and in similar efficiency. The successful strategy mandated that the biomimetic C3-prenylation step be executed early. The use of an unprotected carboxylic acid of Trp led to high diastereoselectivity toward formation of key intermediates exo-12a, exo-12b, and exo-12c (>19:1). Evidence shows that N1-methylation causes the prenylation reaction to bifurcate away to result in a C2-normal-prenylated isomer. Nocardioazine A, possessing an isoprenoidal-epoxide bridge, inhibits P-glycoprotein (P-gp)-mediated membrane efflux, in multidrug-resistant mammalian colon cancer cells. As several P-gp inhibitors have failed due to their toxicity effects, endogenous amino-acid-derived noncytotoxic inhibitors (from the nocardioazine core) are worthy leads toward a rejuvenated strategy against resistant carcinomas. This total synthesis provides direct access to Trp-derived isoprenylated DKP natural products and their derivatives.

Atomically Precise Crystalline Materials Based on Kinetically Inert Metal Ions via Reticular Mechanopolymerization.

Atomistic control of the coordination environment of lattice ions and the distribution of metal sites within crystalline mixed-metal coordination polymers remain significant synthetic challenges. Herein is reported the mechanochemical synthesis of a reticular family of crystalline heterobimetallic metal-organic frameworks (MOFs) is now achieved by polymerization of molecular Ru2 [II,III] complexes, featuring unprotected carboxylic acid substituents, with Cu(OAc)2 . The resulting crystalline heterobimetallic MOFs are solid solutions of Ru2 and Cu2 sites housed within [M3 L2 ] phases. The developed mechanochemical strategy is modular and allows for systematic control of the primary coordination sphere of the Ru2 sites within an isoreticular family of materials. This strategy is anticipated to provide a rational approach to atomically precise mixed-metal materials.

Atomically Precise Crystalline Materials Based on Kinetically Inert Metal Ions via Reticular Mechanopolymerization

AbstractAtomistic control of the coordination environment of lattice ions and the distribution of metal sites within crystalline mixed‐metal coordination polymers remain significant synthetic challenges. Herein is reported the mechanochemical synthesis of a reticular family of crystalline heterobimetallic metal–organic frameworks (MOFs) is now achieved by polymerization of molecular Ru2[II,III] complexes, featuring unprotected carboxylic acid substituents, with Cu(OAc)2. The resulting crystalline heterobimetallic MOFs are solid solutions of Ru2 and Cu2 sites housed within [M3L2] phases. The developed mechanochemical strategy is modular and allows for systematic control of the primary coordination sphere of the Ru2 sites within an isoreticular family of materials. This strategy is anticipated to provide a rational approach to atomically precise mixed‐metal materials.

Chemoselective Catalytic α-Oxidation of Carboxylic Acids: Iron/Alkali Metal Cooperative Redox Active Catalysis.

We developed a chemoselective catalytic activation of carboxylic acid for a 1e- radical process. α-Oxidation of a variety of carboxylic acids, which preferentially undergo undesired decarboxylation under radical conditions, proceeded efficiently under the optimized conditions. Chemoselective enolization of carboxylic acid was also achieved even in the presence of more acidic carbonyls. Extensive mechanistic studies revealed that the cooperative actions of iron species and alkali metal ions derived from 4 Å molecular sieves substantially facilitated the enolization. For the first time, catalytic enolization of unprotected carboxylic acid was achieved without external addition of stoichiometric amounts of Brønsted base. The formed redox-active heterobimetallic enediolate efficiently coupled with free radical TEMPO, providing synthetically useful α-hydroxy and keto acid derivatives.

Inside Cover: An Enzymatic N‐Acylation Step Enables the Biocatalytic Synthesis of Unnatural Sialosides (Angew. Chem. Int. Ed. 13/2020)

The selective N-acylation of glucosamine with unprotected carboxylic acids enables the biosynthesis of unnatural glycosides and their subsequent enzymatic modification. In their Communication on page 5308, L. Liu, S. L. Flitsch, J. Voglmeir et al. report that the enzyme chitobiose deacetylase from Cyclobacterium marinum has promiscuous N-acylation activity without the need for activation of the acid. This selective N-acylation step provides the last missing link for the fully enzymatic multistep synthesis of C5-modified sialosides from chitin.

Direct arylation of C60Cl6 and C70Cl8 with carboxylic acids: a synthetic avenue to water-soluble fullerene derivatives with promising antiviral activity.

We report unprecedented Friedel-Crafts arylation of chlorofullerenes C60Cl6 and C70Cl8 with unprotected carboxylic acids as an efficient single-step synthesis of the inherently stable water-soluble fullerene derivatives. Using this method, a series of previously unaccessible compounds was obtained without chromatographic purification in almost quantitative yields. Promising anti-HIV activity comparable to characteristics of commercial drugs was demonstrated for some of these compounds.

One-step radiosynthesis of the MCTs imaging agent [18F]FACH by aliphatic 18F-labelling of a methylsulfonate precursor containing an unprotected carboxylic acid group

Monocarboxylate transporters 1 and 4 (MCT1 and MCT4) are involved in tumour development and progression. Their level of expression is particularly upregulated in glycolytic cancer cells and accordingly MCTs are considered as promising drug targets for treatment of a variety of human cancers. The non-invasive imaging of these transporters in cancer patients via positron emission tomography (PET) is regarded to be valuable for the monitoring of therapeutic effects of MCT inhibitors. Recently, we developed the first 18F-radiolabelled MCT1/MCT4 inhibitor [18F]FACH and reported on a two-step one-pot radiosynthesis procedure. We herein describe now a unique one-step radiosynthesis of this radiotracer which is based on the approach of using a methylsulfonate (mesylate) precursor bearing an unprotected carboxylic acid function. With the new procedure unexpected high radiochemical yields of 43 ± 8% at the end of the radiosynthesis could be obtained in a strongly reduced total synthesis time. Moreover, the radiosynthesis was successfully transferred to a TRACERlab FX2 N synthesis module ready for future preclinical applications of [18F]FACH.

Catalytic enantioselective addition of organometallics to unprotected carboxylic acids

Conjugate addition of organometallics to carbonyl based Michael acceptors is a widely used method that allows the building of new carbon-carbon (C-C) bonds and the introduction of chirality in a single step. However, conjugate additions to the simplest Michael acceptors, namely unprotected, unsaturated carboxylic acids, are considered to be prohibited by the fact that acid-base reactions overpower any other type of reactivity, including nucleophilic addition. Here we describe a transient protecting group strategy that allows efficient catalytic asymmetric additions of organomagnesium reagents to unprotected α,β-unsaturated carboxylic acids. This unorthodox pathway is achieved by preventing the formation of unreactive carboxylate salts by means of a reactive intermediate, allowing modifications of the carbon chain to proceed unhindered, while the stereochemistry is controlled with a chiral copper catalyst. A wide variety of β-chiral carboxylic acids, obtained with excellent enantioselectivities and yields, can be further transformed into valuable molecules through for instance catalytic decarboxylative cross-coupling reactions.

Chiral Lewis Base Catalyzed Aldol Reaction of Unprotected Carboxylic Acids

Chiral Lewis Base Catalyzed Aldol Reaction of Unprotected Carboxylic Acids

Catalytic Enantioselective Aldol Reactions of Unprotected Carboxylic Acids under Phosphine Oxide Catalysis

AbstractThe first catalytic enantioselective aldol reaction of various unprotected carboxylic acids is described. In the presence of a chiral bis(phosphine oxide) as a Lewis base catalyst, carboxylic acids were activated with silicon tetrachloride to form the corresponding bis(trichlorosilyl)enediolates in situ, which subsequently underwent an aldol reaction with an aldehyde or a ketone to produce β‐hydroxycarboxylic acids in high enantioselectivities of up to 92 % ee.

Catalytic Enantioselective Aldol Reactions of Unprotected Carboxylic Acids under Phosphine Oxide Catalysis.

The first catalytic enantioselective aldol reaction of various unprotected carboxylic acids is described. In the presence of a chiral bis(phosphine oxide) as a Lewis base catalyst, carboxylic acids were activated with silicon tetrachloride to form the corresponding bis(trichlorosilyl)enediolates in situ, which subsequently underwent an aldol reaction with an aldehyde or a ketone to produce β-hydroxycarboxylic acids in high enantioselectivities of up to 92 % ee.

Decarboxylative couplings as versatile tools for late‐stage peptide modifications

AbstractWhile strategies for the late‐stage modification of peptides are crucial to the design and synthesis of new peptide‐based materials and therapeutics, synthetic methods have historically focused on the modification of select, nucleophilic amino acids. This review highlights decarboxylative coupling strategies as emerging tools for the targeted functionalization of native peptidic acids—α‐carboxylic acids and aspartic/glutamic acid residues—through complexity building CC and Cheteroatom bond formations. Decarboxylation strategies employing both activated carboxylic acids (redox‐active esters) and the direct application of unprotected carboxylic acids are discussed. Emphasis is placed on the scope and limitations of the methodologies as well as their compatibility with complex peptide substrates.

Oligoamides of 2-amino-5-alkylthiazole 4-carboxylic acids: anti-trypanosomal compounds

A range of minor groove binders (MGBs) and the intermediates formed in their synthesis was screened against infectious agents including bacteria and parasites. Activity was found against Trypanosoma brucei. Of particular interest is a molecule which does not contain a typical basic flexible tail group found in MGBs, but instead has an unprotected carboxylic acid group at that position (compound 4), which has activity of 63 nM against T. brucei.

Efficient synthesis of anacardic acid analogues and their antibacterial activities

Anacardic acid derivatives exhibit a broad range of biological activities. In this report, an efficient method for the synthesis of anacardic acid derivatives was explored, and a small set of salicylic acid variants synthesised retaining a constant hydrophobic element (a naphthyl tail). The naphthyl side chain was introduced via Wittig reaction and the aldehyde installed using directed ortho-metalation reaction of the substituted o-anisic acids. The failure of ortho-metalation using unprotected carboxylic acid group compelled us to use directed ortho-metalation in which a tertiary amide was used as a strong ortho-directing group. In the initial route, tertiary amide cleavage during final step was challenging, but cleaving the tertiary amide before Wittig reaction was beneficial. The Wittig reaction with protected carboxylic group (methyl ester) resulted in side-products whereas using sodium salt resulted in higher yields. The novel compounds were screened for antibacterial activity and cytotoxicity. Although substitution on the salicylic head group enhanced antibacterial activities they also enhanced cytotoxicity.

Enabling ScFvs as multi-drug carriers: A dendritic approach

To enable scFvs as multi-drug carriers, we designed and synthesized dendritic linker molecules bearing up to nine chlorambucil residues at the branch ends. A maleimide group was used at the focal point of the dendron for easy linkage to the scFv. Originally designed molecules showed poor water solubility. To address this problem, a lysine residue with an unprotected carboxylic acid group was inserted into the dendron branches. The new molecules showed excellent water solubility and are now suitable for conjugation. Such dendritic molecules will allow studies to understand the relationship between the drug/antibody ratio and the potency of the immunoconjugates. The dendritic approach could also be applied to drugs other than chlorambucil and carriers other than scFvs to greatly increase the drug/carrier ratio.

Attachment of amino acid derivatives to tungsten carbonyl complexes via four component condensations

Mononuclear 4-aminoimidazolin-2-ylidene tungsten complexes [W(CO) 5{ CN(H)C(NHR 1)C(R 2)N R 3}] ( 1– 10) have been synthesized by four component condensation (4CC) of [W(CN)(CO) 5] − with isocyanides (CNR 1; R 1=Cy, tBu), aldehydes (R 2CHO; R 2= tBu, Ph), and amino acid ester hydrochlorides (R 3NH 3 + Cl −; amino acid=glycine, l-serine, l-phenylalanine, l-tyrosine, l-tryptophane, l-aspartic acid, l-glutamine). A dipeptide substituent in 1-position ( 8) resulted when GlyValOMe hydrochloride was employed as amine component, while two compounds with unprotected carboxylic acid groups ( 9, 10) were obtained from β-alanine- and valerian acid-hydrochloride, respectively. 1,4-Terephthaldicarboxaldehyde as aldehyde component gave dinuclear bisheterocycle-bridged complexes 11– 15. The claimed structure of the products is confirmed by an X-ray structure analysis of [W(CO) 5{ CN(H)C(NH tBu)C( tBu)N (CH 2COOMe)}] ( 1) which reveals a C-bound five-membered heterocycle with the amino acid substituent in 1-position.

Direct epoxidation of unprotected olefinic carboxylic acids using HOF-CH 3CN

The reaction of HOF·CH 3CN complex, made directly by passing fluorine through aqueous acetonitrile, with double bond containing unprotected carboxylic acids and alcohols results in fast and almost quantitative epoxidation.