Application of Transition-Metal Catalysis, Biocatalysis, and Flow Chemistry as State-of-the-Art Technologies in the Synthesis of LCZ696.

LCZ696 is a novel treatment for patients suffering from heart failure that combines the two active pharmaceutical ingredients sacubitril and valsartan in a single chemical compound. While valsartan is an established drug substance, a new manufacturing process suitable for large-scale commercial production had to be developed for sacubitril. The use of chemocatalysis, biocatalysis, and flow chemistry as state-of-the-art technologies allowed to efficiently build up the structure of sacubitril and achieve the defined performance targets.

Synthesis and Characterization of Electron-Deficient Asymmetrically Substituted Diarylindenotetracenes.

Electron-deficient asymmetrically substituted diarylindenotetracenes were prepared via a series of Friedel-Crafts acylations, aryl-aryl cross-couplings, and an intramolecular oxidative cyclization to form the indene ring. Single-crystal X-ray experiments showed good π-π overlap with π-π distances ranging from 3.26 to 3.76 Å. Both thermogravimetric analysis and differential scanning calorimetry indicated that asymmetrically substituted indenotetracenes (ASIs) are stable at elevated temperatures. From cyclic voltammetry experiments, HOMO/LUMO energy levels of ASI derivatives were determined to be near -5.4/-4.0 eV. UV/visible absorption spectra showed strong absorption of light between 400 and 650 nm with molar attenuation coefficients from 104 to 105 M-1 cm-1. ASIs were also found to have very low fluorescence quantum yields, less than 4%. Using the solid-state packing determined from the single-crystal X-ray experiments, computational modeling indicated that ASI molecules should favor electron transport.

Regioselective C5-alkylation and C5-methylcarbamate formation of 2,3-dihydro-4-pyridones and C3-alkylation and C3-methylcarbamate formation of 4-(pyrrolidin-1-yl)furan-2(5H)-one.

Reactions of N-alkyl-2,3-dihydro-4-pyridones and 4-(pyrrolidin-1-yl)furan-2(5H)-one with aldehydes and triethylsilane in a one-flask procedure provided C5 and C3 alkylated derivatives, respectively. Mannich-type reactions with formaldehyde and carbamates in the presence of lithium perchlorate furnished C5/C3 methylcarbamates.

Lithium Perchlorate-, Acetic Anhydride-, and Triphenylphosphine-assisted Multicomponent Syntheses of 4-Unsubstituted 2,5-Dioxooctahydroquinoline-3-carboxylates and 3-carbonitriles.

Lithium perchlorate and acetic anhydride were the key additives for the multi-component reaction between 3-aminocyclohex-2-enones, formaldehyde, and malonates yielding adducts that were annulated under acidic conditions to afford bicyclic 2,5-dioxooctahydroquinoline-3-carboxylates. When methyl cyanoacetate was subjected to the same reaction conditions in the presence of a catalytic amount of triphenylphosphine, the bicyclic 2,5-dioxooctahydroquinoline-3-carbonitriles were obtained in a one-flask reaction.

Structure-Activity Studies of N-Butyl-1-deoxynojirimycin (NB-DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2.

Analogues of N-butyl-1-deoxynojirimycin (NB-DNJ) were prepared and assayed for inhibition of ceramide-specific glucosyltransferase (CGT), non-lysosomal ß-glucosidase 2 (GBA2) and the lysosomal ß-glucosidase 1 (GBA1). Compounds 5 a-6 f, which carry sterically demanding nitrogen substituents, and compound 13, devoid of the C3 and C5 hydroxy groups present in DNJ/NB-DGJ (N-butyldeoxygalactojirimycin) showed no inhibitory activity for CGT or GBA2. Inversion of stereochemistry at C4 of N-(n-butyl)- and N-(n-nonyl)-DGJ (compounds 24) also led to a loss of activity in these assays. The aminocyclopentitols N-(n-butyl)- (35 a), N-(n-nonyl)-4-amino-5-(hydroxymethyl)cyclopentane- (35 b), and N-(1-(pentyloxy)methyl)adamantan-1-yl)-1,2,3-triol (35 f), were found to be selective inhibitors of GBA1 and GBA2 that did not inhibit CGT (>1 mm), with the exception of 35 f, which inhibited CGT with an IC50 value of 1 mm. The N-butyl analogue 35 a was 100-fold selective for inhibiting GBA1 over GBA2 (Ki values of 32 nm and 3.3 µm for GBA1 and GBA2, respectively). The N-nonyl analogue 35 b displayed a Ki value of ≪14 nm for GBA1 inhibition and a Ki of 43 nm for GBA2. The N-(1-(pentyloxy)methyl)adamantan-1-yl) derivative 35 f had Ki values of ≈16 and 14 nm for GBA1 and GBA2, respectively. The related N-bis-substituted aminocyclopentitols were found to be significantly less potent inhibitors than their mono-substituted analogues. The aminocyclopentitol scaffold should hold promise for further inhibitor development.

Diarylindenotetracenes via a selective cross-coupling/C-H functionalization: electron donors for organic photovoltaic cells.

A direct synthesis of new donor materials for organic photovoltaic cells is reported. Diaryindenotetracenes were synthesized utilizing a Kumada-Tamao-Corriu cross-coupling of peri-substituted tetrachlorotetracene with spontaneous indene annulation via C-H activation. Vacuum deposited planar heterojunction organic photovoltaic cells incorporating these molecules as electron donors exhibit power conversion efficiencies exceeding 1.5% with open-circuit voltages ranging from 0.7 to 1.1 V when coupled with C(60) as an electron acceptor.