Sequential C–H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11β-HSD-1 Inhibitor

Wei, Xudong; Qu, Bo; Zeng, Xiaoming; Savoie, Jolaine; Fandrick, Keith R.; Desrosiers, Jean‐Nicolas; Tcyrulnikov, Sergei; Marsini, Maurice A.; Buono, Frédéric G.; Li, Zhibin; Yang, Bing‐Shiou; Tang, Wenjun; Haddad, Nizar; Gutiérrez, Osvaldo; Wang, Jun; Lee, Heewon; Ma, Shengli; Campbell, Scot; Lorenz, Jon C.; Eckhardt, Matthias; Himmelsbach, Frank; Peters, Stefan; Patel, Nitinchandra D.; Tan, Zhulin; Yee, Nathan K.; Song, Jinhua J.; Roschangar, Frank; Kozlowski, Marisa C.; Senanayake, Chris H.

doi:10.1021/jacs.6b09764

Cited by 51 publications

(33 citation statements)

References 63 publications

(61 reference statements)

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“…Cyclodehydration of this compound was performed in the presence of triethyl orthoformate in refluxing toluene to give the desired 5‐benzimidazole carboxylic acid [ 13 C 6 ]‐(20) in 92% yield . Finally amide bond formation using propylphosphonic anhydride solution (T 3 P, 50% solution in THF) and triethylamine in acetonitrile between this acid and (4a R ,9a S )‐2,3,4,4a,9,9a‐hexahydro‐1 H ‐indeno[2,1‐b]pyridine‐6‐carbonitrile (21) gave [ 13 C 6 ]‐(2) in 36% yield after silica gel chromatography.…”

Section: Resultsmentioning

confidence: 99%

Potent and selective inhibitors of 11β‐hydroxysteroid dehydrogenase type 1 labeled with carbon‐13 and carbon‐14

Latli

Hrapchak

Savoie

et al. 2017

Labelled Comp Radiopharmac

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(S)-6-(2-Hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (1) and (4aR,9aS)-1-(1H-benzo[d]midazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1-H-indeno[2,1-b]pyridine-6-carbonitrile hydrochloride (2) are potent and selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 enzyme. These 2 drug candidates developed for the treatment of type-2 diabetes were prepared labeled with carbon-13 and carbon-14 to enable drug metabolism, pharmacokinetics, bioanalytical, and other studies. In the carbon-13 synthesis, benzoic- C acid was converted in 7 steps and in 16% overall yield to [ C ]-(1). Aniline- C was converted in 7 steps to 1H-benzimidazole-1-2,3,4,5,6- C -5-carboxylic acid and then coupled to a tricyclic chiral indenopiperidine to afford [ C ]-(2) in 19% overall yield. The carbon-14 labeled (1) was prepared efficiently in 2 radioactive steps in 41% overall yield from an advanced intermediate using carbon-14 labeled methyl magnesium iodide and Suzuki-Miyaura cross coupling via in situ boronate formation. As for the synthesis of [ C]-(2), 1H-benzimidazole-5-carboxylic- C acid was first prepared in 4 steps using potassium cyanide- C, then coupled to the chiral indenopiperidine using amide bond formation conditions in 26% overall yield.

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Section: Resultsmentioning

confidence: 99%

Potent and selective inhibitors of 11β‐hydroxysteroid dehydrogenase type 1 labeled with carbon‐13 and carbon‐14

Latli

Hrapchak

Savoie

et al. 2017

Labelled Comp Radiopharmac

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“…HPLC-grade solvents [acetonitrile, methanol, water, and dimethylsulfoxide (DMSO)] were purchased from Sigma-Aldrich. BI 187004 (Wei et al, 2016), 13 C 6 -BI 187004 (Latli et al, 2017), M1, and N-methylbenzimidazole regioisomer 2 (M14) were synthesized internally at Boehringer Ingelheim Pharmaceuticals, Inc. (Ridgefield, CT).…”

Section: Methodsmentioning

confidence: 99%

N-Methylation of BI 187004 by Thiol S-Methyltransferase

et al. 2018

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BI 187004, an 11-hydroxysteroid dehydrogenase 1 inhibitor, was administered once daily for 14 days to eight patients with type 2 diabetes mellitus. -methylation was identified as a major biotransformation pathway. In four patients treated with BI 187004, the plasma exposure of an-methylbenzimidazole metabolite [-methylbenzimidazole regioisomer 1 (M1)] was 7-fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzymes responsible for -methylation, BI 187004 was incubated with human liver microsomes (HLM), human kidney microsomes (HKM), and their respective cytosolic preparations in the presence and absence of isoform-selective chemical inhibitors. Additionally, BI 187004 was incubated with several human recombinant methyltransferases: catechol-methyltransferase (rhCOMT), histamine -methyltransferase (rhHNMT), nicotinamide-methyltransferase (rhNNMT), glycine -methyltransferase (rhGNMT), and thiopurine-methyltransferase (rhTPMT). M1 was principally observed in HLM and HKM incubations, minimally formed in liver and kidney cytosol, and not formed during incubations with recombinant methyltransferase enzymes. In all microsomal and cytosolic incubations, the formation of M1 was inhibited only by 2,3-dichloro--methylbenzylamine (DCMB), an inhibitor of thiol -methyltransferase (TMT), providing evidence that TMT catalyzed the formation of M1. Interestingly, the-methylbenzimidazole regioisomer (M14) was only observed in vitro, predominantly during incubations with human kidney cytosol and rhHNMT. The formation of M14 was inhibited by amodiaquine (an HNMT inhibitor) and DCMB, providing additional evidence that both HNMT and TMT catalyzed M14 formation. Overall, using BI 187004 as a substrate, this study demonstrates a novel TMT-mediated -methylation biotransformation and an HNMT-mediated regioselective-methylation.

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“…The pyridinum ring was reduced to the piperidine derivative on a 1.5 kg scale to afford the intermediate toward the total synthesis of an 11β-hydroxysteroid dehydrogenase type 1 inhibitor (Table ). This transformation involves a series of hydride transfer, protonation, and tautomerization steps …”

Section: Iminesmentioning

confidence: 99%

“…Similarly, a large screening campaign of 8 ruthenium catalysts, 20 rhodium catalysts, and 35 iridium catalysts was required to find the optimum iridium-based catalyst for the OS ADH of an N-benzylindenopyridinium bromide (CN-14) needed for the synthesis of a candidate drug to treat diabetes. 132 The other catalysts were reported to have less than satisfactory activity and enantioselectivity toward the transformation. The best result was afforded using an [Ir(COD)Cl 2 ]-MeO-BoQPhos catalyst system under 450 psi H 2 with ∼98% yield on HPLC assay and 70% ee.…”

Section: ■ Iminesmentioning

confidence: 99%

Catalytic Homogeneous Asymmetric Hydrogenation: Successes and Opportunities

2018

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This is an overview of successes in the realm of catalytic homogeneous asymmetric hydrogenation of substrates primarily of interest in the synthesis of pharmaceuticals in order to identify important problems still unsolved. First, tables are provided that list the successful reductions to over 90% enantiomeric excess of prochiral ketones to alcohols, imines to amines, and olefins to saturated carbon centers. Noted in the tables are the metal (including "green" metals Mn, Fe, and Co) or enzyme, the class of ligand, the conditions of the medium, and the scale of reduction, if over 1 kg of product, as well as the nature of the process, whether direct hydrogenation using H 2 gas (DH), transfer hydrogenation (TH), or hydrogenation with dynamic kinetic resolution (DKR). Tables of representative pharmaceutical or fine chemicals products are provided for each class of substrate. With this overview, the opportunities for further research and development become clearer.

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Sequential C–H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11β-HSD-1 Inhibitor

Cited by 51 publications

References 63 publications

Potent and selective inhibitors of 11β‐hydroxysteroid dehydrogenase type 1 labeled with carbon‐13 and carbon‐14

Potent and selective inhibitors of 11β‐hydroxysteroid dehydrogenase type 1 labeled with carbon‐13 and carbon‐14

N-Methylation of BI 187004 by Thiol S-Methyltransferase

Catalytic Homogeneous Asymmetric Hydrogenation: Successes and Opportunities

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