Evolution of Biocatalysis at Novartis over the last 40 Years.

The fortieth anniversary of biocatalysis started at Ciba-Geigy and later at Novartis is a great time to pause and reflect on development of science and technology in this field. Enzyme-based synthesis became a highly valued enabling tool for pharmaceutical research and development over the last decades. In this perspective we aim to discuss how the scientific approaches and trends evolved over the time and present future challenges and opportunities.

Fostering Research Synergies between Chemists in Swiss Academia and at Novartis.

We present a short overview of the way Novartis chemists interact and collaborate with the academic chemistry community in Switzerland. This article exemplifies a number of collaborations, and illustrates opportunities to foster research synergies between academic and industrial researchers. It also describes established programs available to academic groups, providing them access to Novartis resources and expertise.

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.

Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis.

Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, and fibrosis. While there are currently no approved therapies for NASH, the bile acid-derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in clinical studies. Previously, we described the discovery of tropifexor (LJN452), the most potent non-bile acid FXR agonist currently in clinical investigation. Here, we report the discovery of a novel chemical series of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole core from which emerged nidufexor (LMB763), a compound with partial FXR agonistic activity in vitro and FXR-dependent gene modulation in vivo. Nidufexor has advanced to Phase 2 human clinical trials in patients with NASH and diabetic nephropathy.

Synthetic studies on (-)-lemonomycin: an efficient asymmetric synthesis of lemonomycinone amide.

Asymmetric synthesis of lemonomycinone amide (2) was accomplished from readily accessible starting materials. Enantioselective alkylation of N-(diphenylmethylene)glycine tert-butyl ester (11) by 5-tert-butyldimethylsilyloxy-2,4-dimethoxy-3-methylbenzyl bromide (10) in the presence of Corey-Lygo's phase transfer catalyst [O-(9)-ally-N-(9'-anthracenylmethyl) cinchonidium bromide, 0.1 equiv] afforded, after chemoselective hydrolysis of the imine function (THF/H(2)O/AcOH), the substituted l-tert-butyl phenylalanate 13 in 85% yield. A Pictet-Spengler reaction of 14 with benzyloxyacetaldehyde (15) provided the 1,3-cis-disubstituted tetrahydroisoquinoline 16 in 85% yield as a single diastereomer. Coupling of hindered secondary amine 16 with amino acid 9 was accomplished under carefully controlled conditions to furnish the amide 22, which was in turn converted to hemiaminal 24. A hafnium triflate catalyzed conversion of hemiaminal to alpha-amino thioether followed by a silver tetrafluoroborate promoted intramolecular Mannich reaction of 26 afforded the tetracycle 27 in excellent overall yields. Debenzylation of 27 [Pd(OH)(2), H(2), MeOH, 0 degrees C], removal of N-Boc function (aqueous 3 N HCl, MeOH/H(2)O), and oxidation of hydroquinone to quinone [(NH(4))(2)Ce(NO(3))(6), H(2)O, rt] afforded the lemonomycinone amide 2 in 76% yield over three steps.

Aziridinium from N,N-dibenzyl serine methyl ester: synthesis of enantiomerically pure beta-amino and alpha,beta-diamino esters.

[reaction: see text] Reaction of N,N-dibenzyl-O-methylsulfonyl serine methyl ester with a variety of heteronucleophiles (sodium azide, sodium phthalimide, amines, thiols) and carbanions (sodium malonate) gave, via an aziridinium intermediate, the corresponding beta-amino or alpha,beta-diamino ester in good to excellent yield. A short synthesis of orthogonally protected and enantiomerically pure 2,3-diamino propionate (Dap) is described.

Total Synthesis of (±)-Halomon by a Johnson-Claisen Rearrangement.

The total synthesis of the polyhalogenated antitumour agent halomon (1) was accomplished with two novel transformations as key steps: a Johnson-Claisen rearrangement of a dichlorinated alkene for the preparation of the tertiary chlorinated C3 and a new rearrangement of bromohydrins for the regiospecific introduction of the bromine and chlorine atoms on C6 and C7, respectively.