Towards the development of synthetic routes using theoretical calculations: an application of in silico screening to 2,6-dimethylchroman-4-one

This study describes an attempt to develop a synthetic route using theoretical calculations, i.e., in silico synthesis route development. The KOSP program created four potential synthetic routes for generating 2,6-dimethylchroman-4-one. In silico screening of these four synthetic routes was then performed. In silico screening involves theoretical analysis of synthetic routes prior to actual experimental work. A synthetic route using the Mitsunobu reaction had already been reported by Hoddgets et al. Theoretical investigations were also conducted on two S(N)Ar reactions as well as a Michael reaction before they were examined experimentally. In silico screening using DFT calculations indicated that only the Michael reaction was likely to produce the target. Experimental work confirmed that the target was obtained in a yield of 76.4% using the Michael reaction. The other two routes, except for the Mitsunobu reaction, failed to generate the target. Our results demonstrate that theoretical calculations can be used to narrow down the number of experiments that need to be conducted when developing novel synthetic routes.     

Microwave-assisted expeditious and efficient synthesis of cyclopentene ring-fused tetrahydroquinoline derivatives using three-component Povarov reaction

We report here an efficient and expeditious microwave-assisted synthesis of cyclopentadiene ring-fused tetrahydroquinolines using the three-component Povarov reaction catalyzed by indium (III) chloride. This method has an advantage of shorter reaction time (10–15 min) with high and reproducible yields (up to 90%) and is suitable for parallel library synthesis. The optimization process is reported and the results from the microwave route are compared with those of the conventional synthetic route. In almost all cases, the microwave acceleration consistently provided improved yields favoring the cis-diastereomer.     

Biomimetic total synthesis of tricycloillicinone and mechanistic studies toward the rearrangement of prenyl phenyl ethers

The Letter describes a short and biomimetic synthesis of tricycloillicinone, which was found to enhance the action of choline acetyltransferase (ChAT). The synthetic route has two critical reactions: bulky, oxygenophilic methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide) (MABR) promoted rearrangement of prenyl phenyl ether and photochemical cyclization. Furthermore, experiments were designed to explore the process of MABR-promoted rearrangement. It was found that the stereochemistry of deuterium labeled prenyl group was only partially scrambled, which suggests that there may be two possible reaction pathways involved in this process. It also suggests that the direct migration of prenyl group to para-position under these conditions is slightly favored over the Claisen-Cope process. The highly efficient synthetic route also provides important new opportunities to explore the biological behavior of tricycloillicinone.     

Comparative triad of routes to an alkyne-BF2 azadipyrromethene near-infrared fluorochrome

A series of three inter-related synthetic routes to a water soluble alkyne substituted BF₂-azadipyrromethene fluorochrome is described. Each route allows for the introduction of the required reactive alkynyl group and water solubilizing propane-sulfonic acid through either more advanced pyrrole intermediates or through their earlier synthetic precursors. The advantages and disadvantages of each route lie in the number of synthetic steps required versus the formation of undesired azadipyrromethene by-products. Upon its synthesis, the alkyne-bearing fluorochrome was shown to efficiently participate in CuACC reactions with a series of azido substrates in water at room temperature and 37?°C. NIR-photophysical properties of the fluorochrome and its conjugates were similar, showing strong potential for in vitro and in vivo imaging applications.     

Visible light irradiation promoted catalyst-free and solvent-free synthesis of pyrano[2,3-d]pyrimidine scaffolds at room temperature

A catalyst-free and solvent-free synthetic route for convenient one-pot synthesizing pyrano[2,3-d] pyrimidine scaffolds through Knoevenagel-Michael cyclocondensation is reported using visible light irradiation as a green promoter at room temperature based on green chemistry principles. Completing the reactions takes thoroughly less time while obtaining the products in outstanding yields. This green method includes the application of non-hazardous reaction circumstances, direct work-up without column chromatographic separation, catalyst-free, solvent-free, cost effective, simple synthesis, one-pot procedure, and high atom-economy.     

A Comparative Study of Conventional and Microwave‐Assisted Synthesis of Quinoxaline 1,4‐di‐N‐oxide N‐acylhydrazones Derivatives Designed as Antitubercular Drug Candidates

Quinoxaline 1,4‐di‐N‐oxide (QdNO) and N‐acylhydrazone subunit are considered privileged scaffolds in medicinal chemistry because of its wide spectrum of biological activities, such as antibacterial, antitubercular, antiviral, anticancer, and antifungal. Beirut's reaction is the mostly commonly employed synthetic method to obtain QdNO; however, extended time, low yields, and byproduct formation are common features observed during the synthesis. Microwave‐assisted organic synthesis (MW) has gained popularity as an effective way to speed up chemical reactions, increasing yields and selectivity of a variety of reactions. Therefore, in an effort to synthesize compounds with potential to tuberculosis treatment, we reported herein the use of MW as a tool to obtain new QdNO derivatives containing the N‐acylhydrazone subunit. Four different synthetic routes were evaluated by using different benzofuroxan derivatives in the Beirut's reaction. The synthetic route D, which employed a dioxolan‐benzofuroxan derivative, has shown to be the best condition to obtain the desired hybrid quinoxaline. MW drastically reduces the reaction time to obtain all compounds compared to conventional heating. For compound 13 , for example, the use of MW instead of conventional heating was able to reduce the reaction time in 192‐fold. In conclusion, the use of a benzofuroxan derivative without additional electrophilic sites besides N‐oxide nitrogen and the employment of the microwave‐assisted synthesis have proved to be the optimum condition to obtain quinoxaline 1,4‐di‐N‐oxide N‐acylhydrazone derivatives.     

Total Synthesis of (+)‐Asteriscanolide: Further Exploration of the Rhodium(I)‐Catalyzed [(5+2)+1] Reaction of Ene‐Vinylcyclopropanes and CO

The total synthesis of (+)‐asteriscanolide is reported. The synthetic route features two key reactions: 1) the rhodium(I)‐catalyzed [(5+2)+1] cycloaddition of a chiral ene‐vinylcyclopropane (ene‐VCP) substrate to construct the [6.3.0] carbocyclic core with excellent asymmetric induction, and 2) an alkoxycarbonyl‐radical cyclization that builds the bridging butyrolactone ring with high efficiency. Other features of this synthetic route include the catalytic asymmetric alkynylation of an aldehyde to synthesize the chiral ene‐VCP substrate, a highly regioselective conversion of the [(5+2)+1] cycloadduct into its enol triflate, and the inversion of the inside–outside tricycle to the outside–outside structure by an ester‐reduction/elimination to enol‐ether/hydrogenation procedure. In addition, density functional theory (DFT) rationalization of the chiral induction of the [(5+2)+1] reaction and the diastereoselectivity of the radical annulation has been presented. Equally important is that we have also developed other routes to synthesize asteriscanolide using the rhodium(I)‐catalyzed [(5+2)+1] cycloaddition as the key step. Even though these routes failed to achieve the total synthesis, these experiments gave further useful information about the scope of the [(5+2)+1] reaction and paved the way for its future application in synthesis.     

Amino acids as selective acylating agents: regioselective N-acylation of imidazolidin-4-one derivatives of the antimalarial drug primaquine

The acylation of bioactive primaquine-based imidazolidin-4-ones was studied using N^α-Boc-protected glycine as acylating agent. Two synthesis routes, eight different coupling methods and seven distinct solvents were compared. Mild carbodiimide-based couplings on high dielectric constant solvents such as DMF or MeCN increased acylation yields, whereas alcohols inhibited carbodiimide-mediated acylations to take place. Achievement of the synthetic goals was limited by the size of the imidazolidin-4-one ring substituents R¹, R² and R³, but resort to MW-assisted synthesis allowed overcoming such obstacle, though with very modest reaction yields. All reactions involving a Boc-protected amino acid were regioselective, independent of reaction conditions employed. In contrast, regioselective acetylation of the imidazolidin-4-ones could only be achieved by resort to very mild coupling procedures.     

Diastereoselective, large-scale synthesis of β-amino acids via asymmetric aza-Michael addition as α2δ ligands for the treatment of generalized anxiety disorder and insomnia

Scalable synthetic routes to β-amino acids 1 and 2 are presented. These two compounds, which bind to the α2δ subunit of calcium channels and have important medical applications, have been prepared on kilogram scale in our pilot plant through an improved synthesis that avoids the use of highly toxic reagents and hazardous chemistry present in the original Medicinal Chemistry route. The two chiral centers are introduced through asymmetric Michael and aza-Michael reactions with excellent diastereoselectivity.     

Correlation between the synthetic origin of methamphetamine samples and their 15N and 13C stable isotope ratios

The active ingredient of ecstasy, N-methyl-3,4-methyldioxyphenylisopropylamine (MDMA) can be manufactured by a number of easy routes from simple precursors. We have synthesised 45 samples of MDMA following the five most common routes using N-precursors from 12 different origins and three different precursors for the aromatic moiety. The ¹³C and ¹⁵N contents of both the precursors and the MDMA samples derived therefrom were measured by isotope ratio mass spectrometry coupled to an elemental analyser (EA-IRMS). We show that within-pathway correlation between the ¹⁵N content of the precursor and that of the derived MDMA can be strong but that no general pattern of correlation can be defined. Rather, it is evident that the δ¹⁵N values of MDMA are strongly influenced by a combination of the δ¹⁵N values of the source of nitrogen used, the route by which the MDMA is synthesised, and the experimental conditions employed. Multivariate analysis (PCA) based on the δ¹⁵N values of the synthetic MDMA and of the δ¹⁵N and δ¹³C values of the N-precursors leads to good discrimination between the majority of the reaction conditions tested.     

Catalytic asymmetric synthesis of stereoisomers of 1-C-n-butyl-LABs for the SAR study of α-glucosidase inhibition

We achieved synthesis of seven stereoisomers of 1-C-n-butyl-L-iminofuranose derivatives using catalytic asymmetric alkylation and Negishi coupling as key reactions. The synthetic strategy based on these key reactions was quite useful, since both α- and β-iminofuranoses could be obtained by switching the chirality of the ligand employed for the AAA reaction. The common intermediates for α- and β-isomers were subjected to further manipulations to install a diol unit at C2 and C3 to give the desired stereoisomers of L-iminofuranose derivatives. We achieved the preparation of all stereoisomers of 1-C-n-butyl-L-iminofuranose derivatives, with the exception of β-lyxo type iminofuranose. It is noteworthy that a synthetic route for many stereoisomers of iminofuranose derivatives was developed. Unfortunately, none of the L-iminofuranoses obtained showed inhibitory activity against the α-glycosidases examined—e.g., maltase, sucrase, and isomaltase.     

Phosphoramidite building blocks for efficient incorporation of 2′-O-aminoethoxy(and propoxy)methyl nucleosides into oligonucleotides

A simple and efficient method for the preparation of eight phosphoramidite building blocks for incorporation of 2′-O-(2-aminoethoxymethyl)ribonucleosides and 2′-O-(3-aminopropoxymethyl)ribonucleosides into synthetic oligonucleotides has been developed. The synthetic routes are maximally convergent and provide sufficient amounts of phosphoramidites for several solid-phase synthesis coupling reactions. Using acyclic derivatives 17a,b the overall yields of phosphoramidites 2 and 3 were increased up to 50% for pyrimidine nucleosides and up to 30% for purine derivatives with substantial decrease of total reaction steps. The 2′-O-substituent was found to be stable during oligonucleotide synthesis. The resulting oligonucleotides are of particular interest for post-synthetic functionalization and conjugation.     

Efficient approach for the diversity-oriented synthesis of macro-heterocycles on solid-support

The generation of macro-heterocycles starting from resin bound orthogonally protected lysine and using nucleophilic aromatic substitution is described. The method of cyclization required the coupling of o-fluoro-p-nitro benzoic acid followed by intramolecular displacement of the fluoro group. The described method allows a versatile synthetic route to the synthesis of libraries of macro-heterocycles in an attempt to establish lead drug candidates. The desired cyclic products were obtained in good yields and purities.     

Towards Asymmetrical Methylene Blue Analogues: Synthesis and Reactivity of 3-N′-Arylaminophenothiazines

The search for new ways to obtain analogues of the well-known Methylene Blue dye is an important synthetic task. Herein, we proposed and developed an approach to the synthesis of 3-N′-arylaminophenothiazines and asymmetrical 3,7-di(N′-arylamino)phenothiazines. This approach included the optimization of synthetic strategy by quantification analysis of the positive charge distribution in the cation of 3-N′-arylaminophenothiazine derivative. The obtained experimental data are confirmed by DFT studies. Two synthetic routes for asymmetrical phenothiazine diarylamino derivatives were suggested and verified. The developed convenient and versatile synthetic approach makes it easy to obtain aromatic Methylene Blue isostructural analogues with various substituents. As a result, a series of novel 3-N′-arylaminophenothiazines and asymmetrical 3,7-di(N′-arylamino)phenothiazines containing ester, tert-butoxycarbonyl, sulfonic acid, hydroxyl and amine groups were obtained in high yields.     

Synthesis of (S)-3-amino-benzo[b][1,4]oxazepin-4-one via Mitsunobu and SNAr reaction for a first-in-class RIP1 kinase inhibitor GSK2982772 in clinical trials

Two new synthetic routes were developed to prepare the RIP1 kinase inhibitor clinical candidate GSK2982772 involving a key (S)-3-amino-benzo[b][1,4]oxazepin-4-one intermediate prepared via Mitsunobu and S_NAr cyclization reactions. Both routes are practical and cost effective compared to the initial medicinal chemistry route and are also applicable to kilogram scale-up to support on-going clinical studies.     

Development of a practical and scalable synthesis of anti-HBV drug Y101

The process research and development of a practical and scalable synthetic method towards Anti-HBV Drug N-[N-benzoyl-O-(2-dimethylaminoethyl)-l-tyrosyl]-l-phenylalaninol (Y101) was described. Initial synthetic routes of Y101 in milligram quantities were unsuitable for large-scale synthesis to provide bulk material. As part of the collaboration between Medicinal Chemistry and Research active pharmaceutical ingredient (API), a fit for purpose route for the kilo scale synthesis of Y101 was developed. In contrast, the improved route described here did not require purification by column chromatography for all steps, and the formation of impurities was effectively suppressed. This highly efficient and scalable process was successfully demonstrated in the large-scale synthesis of Y101.     

Novel approach towards 3,7-disubstituted 1,6-naphthyridin-4(1H)-ones exploiting cross-coupling and SNAr reactions of a dihalogenated compound

A new route towards the synthesis of a series of 3,7-disubstituted 1,6-naphthyridin-4(1H)-ones in moderate to good yields is reported. The strategy involves the preparation of a 3,7-dihalogenated compound that undergoes differential functionalization using palladium-catalyzed cross-coupling and S_NAr reactions.     

Influence of precursor solvent extraction on stable isotope signatures of methylamphetamine prepared from over-the-counter medicines using the Moscow and Hypophosphorous routes

A number of methods of clandestine manufacture of methylamphetamine involve the extraction and subsequent reaction of pseudoephedrine hydrochloride with other essential chemicals. The precursor can be easily extracted from over-the-counter medication widely available in the UK and elsewhere. Essential chemicals such as iodine and red phosphorous are also readily available and can be extracted from iodine tinctures and matchboxes, respectively. This work reports the repetitive preparation of methylamphetamine using two popular routes (the Moscow and Hypophosphorous synthesis). The focus was on the extraction solvent used for isolation of the precursor chemical and any consequential isotopic variation which may arise in the final product. Six batches of methylamphetamine were prepared under precisely controlled conditions for each synthetic route and for each of three different precursor extraction solvents. Synthesis of the final product from laboratory grade precursor using the synthetic methods described was used as a template for comparison. The resultant IRMS data from all 48 prepared samples suggests some underlying trends in the identification of the synthetic route which may aid in the interpretation of IRMS data derived from clandestine samples.     

New efficient access to fused (Het)Aryltetrahydroindolizinones via N-acyl iminium intermediates

In this paper, we described the preparation of fused (Het)Aryltetrahydroindolizinones via N-acyl iminium intermediates. Two different routes were also explored to achieve the synthesis. The first one consists in the intramolecular reaction of β-hydroxylactams whereas the second route one is an intermolecular condensation between a 2-formylester or a β-alkoxylactone and an appropriate primary amine. We also developed two heterocyclic strategies to obtain the adequate unavailable starting materials in pyridine, pyrazine, quinoline, and quinaxoline series and then perform all inter or intramolecular reactions. Scope and limitations are given.     

Rhodium(III) catalyzed synthesis of isoquinolone fused azabicycles through C–H activation of N-pivaloyloxy benzamides

Herein we describe an efficient one pot strategy toward highly functionalized isoquinolone fused azabicycles having great synthetic potential via C–H activation of N-pivaloyloxy benzamides under very mild conditions. The reaction is accomplished at room temperature within one hour in good to excellent yields and is found to be compatible with a range of diazabicyclic olefins and benzamides. The present strategy offers an easy route for the synthesis of biologically relevant compounds which possess multiple points for divergent synthesis. N–N bond cleavage of synthesized compounds may enable their significant role as effective precursors for the preparation of diaminocyclopentane fused isoquinolones.