Chemo-enzymatic synthesis of all four diastereoisomers of 1-fluoro-2-amino-indane

Iacazio, Gilles; Réglier, Marius

doi:10.1016/j.tetasy.2005.09.015

Cited by 8 publications

(11 citation statements)

References 15 publications

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“…In many cases, fluorination of much less active precursors yielded potent drugs, with enhanced bioavailability, reduced toxicity, or improved affinity for the target receptor 3. A number of methods have been developed for synthesis of fluorinated compounds,4,5 including asymmetric fluorination strategies6,7 and chemo-enzymatic approaches8,9. Despite this progress, selective incorporation of fluorine at non-activated or weakly-reactive sites of a target scaffold remains difficult and may require several synthetic steps.…”

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confidence: 99%

Chemo-enzymatic fluorination of unactivated organic compounds

2008

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Fluorination has gained an increasingly important role in drug discovery and development. Here we describe a versatile strategy that combines cytochrome P450-catalyzed oxygenation with deoxofluorination to achieve mono-and polyfluorination of non-reactive sites in a variety of organic scaffolds. This procedure was applied for the rapid identification of fluorinated drug derivatives with enhanced membrane permeability.Fluorination has become an increasingly important tool for fine-tuning the pharmacokinetic and pharmacological properties of drugs and lead compounds, leading to a growing number of fluorine-containing pharmaceuticals on the market. 1 Benefits of hydrogen-to-fluorine substitutions arise principally from their effects on membrane permeability, metabolic stability, and/or receptor-binding properties of bioactive molecules. 1-3 In many cases, fluorination of much less active precursors yielded potent drugs, with enhanced bioavailability, reduced toxicity, or improved affinity for the target receptor. 3 A number of methods have been developed for synthesis of fluorinated compounds, 4,5 including asymmetric fluorination strategies 6,7 and chemo-enzymatic approaches 8,9 . Despite this progress, selective incorporation of fluorine at non-activated or weakly-reactive sites of a target scaffold remains difficult and may require several synthetic steps.Here we describe a facile, two-step procedure for the selective fluorination of one or more nonactivated sites in an organic molecule. This approach couples the exceptional ability of cytochrome P450 monooxygenases to selectively insert oxygen into non-reactive C-H bonds with a deoxofluorination (DF) reaction in which the newly generated hydroxyl group is substituted by fluorine by means of a nucleophilic fluorinating reagent (Fig. 1). To test the validity of this approach, we targeted various classes of small molecules, including marketed pharmaceuticals (Supplementary Figure 1 online). For the enzymatic step, we used variants of the bacterial long-chain fatty acid hydroxylase P450 BM3 from Bacillus megaterium. Catalytic self-sufficiency, high monooxygenase activity, and high expression level in E. coli render P450 BM3 an attractive catalyst for in vitro and in vivo applications. 10 For this work, we assembled a panel of 96 P450s derived from a catalytically-promiscuous P450 BM3 variant identified in the early stages of the directed evolution of a proficient alkane monoxygenase. 11 These variants were found to exhibit good activity and various degrees of selectivity on alkanes and non-alkane substrates. 11The first group of test molecules (1, 2 and 3; Fig. 2a,b) contains a cyclopentenone moiety found in several natural products (e.g. jasmonoids, cyclopentanoid antibiotic, and prostaglandins). The synthesis and functionalization of these scaffolds is not trivial. 12 The activities of the enzymes towards these substrates were probed in multi-well format using GC and GC-MS (Fig. 2a). Depending on the substrate, approximately 30 to 50% of the 96 enzyme var...

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confidence: 99%

Chemo-enzymatic fluorination of unactivated organic compounds

2008

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“…For this purpose, commercially available indene was treated with N -bromosuccinimide (NBS) to give (+/−) trans -bromohydrin 1 [ 21 , 22 ]. Thus, compound 1 was treated with ammonium hydroxide to yield a mixture of products that could not be identified; however, the treatment of compound 1 with sodium azide led to the isolation of the corresponding racemic azide 2 [ 23 ] with a very good yield ( Scheme 1 ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of New Indanyl Nucleoside Analogues and their Biological Evaluation on Hepatitis C Virus (HCV) Replicon

et al. 2019

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Here, we report a convenient synthetic procedure for the preparation of four novel indanyl carbanucleoside derivatives in the racemic form. The action of these compounds against hepatitis C virus was evaluated in vitro using the replicon cell line, Huh7.5 SG. Contrary to our expectations, all these compounds did not inhibit, but rather promoted HCV genotype 1b (HCVg1b) replication. Similar effects have been reported for morphine in the replicon cell lines, Huh7 and Huh8. Several biological experiments and computational studies were performed to elucidate the effect of these compounds on HCVg1b replication. Based on all the experiments performed, we propose that the increase in HCVg1b replication could be mediated, at least in part, by a similar mechanism to that of morphine on the enhancement of this replication. The presence of opioid receptors in Huh7.5 SG cells was indirectly determined for the first time in this work.

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“…In a recent example, 1,1‐difluoro‐6‐nitroaminoindanes 177 were easily synthesized from bromo‐1,1‐difluoro‐6‐nitroindanes 176 by treatment with an amine in the presence of K 2 CO 3 as a base in DMF at RT (Scheme ) . In another process, nonracemic ( S , R )‐ and ( R , S )‐2‐azidoindan‐1‐ol ( 180 and 181 , respectively) were synthesized with excellent ee values by conversion of racemic trans ‐2‐bromoindan‐1‐ol 178 to racemic cis ‐2‐azidoindan‐1‐ol 179 followed by kinetic resolution with lipase, as shown in Scheme . Fluorination of 180 and 181 , followed by reduction of the amido group, allowed the synthesis of all four stereoisomers of 1‐fluoro‐2‐aminoindane as their hydrochloride salts in high ee values …”

Section: Synthesis Of Indanesmentioning

confidence: 99%

“… Synthesis of nonracemic ( S , R )‐ and ( R , S )‐2‐azidoindan‐1‐ol ( 180 and 181 , respectively) from trans ‐2‐bromoindan‐1‐ol 178 …”

Section: Synthesis Of Indanesmentioning

confidence: 99%

“…[82b] Haloindanes, aminoindanes and indanols have also been used as startingm aterials for the preparation of differently functionalized indanes. [83] In arecent example, 1,1-difluoro-6-nitroaminoindanes 177 were easily synthesized from bromo-1,1difluoro-6-nitroindanes 176 by treatment with an amine in the presence of K 2 CO 3 as ab ase in DMF at RT (Scheme72). [83a] In Scheme67.…”

Section: Functionalization Of Cyclic Precursorsmentioning

confidence: 99%

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Recent Advances in the Synthesis of Indanes and Indenes

Gabriele

Mancuso

Veltri

2016

Chemistry A European J

177

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Indanes and indenes are among the most important carbocycles. Many indane and indene derivatives have shown important pharmacological activities, and the indane and indene nuclei are structural motifs present in several natural products of biological relevance. In spite of their importance, only a few reviews on their preparation methods have appeared so far in the literature, the most recent ones being published about ten years ago. The present Review is aimed at filling this gap, presenting some of the most important and innovative approaches to indanes and indenes that have been published in the course of the last ten years (coverage: from 2005 to May, 2015).

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Chemo-enzymatic synthesis of all four diastereoisomers of 1-fluoro-2-amino-indane

Cited by 8 publications

References 15 publications

Chemo-enzymatic fluorination of unactivated organic compounds

Chemo-enzymatic fluorination of unactivated organic compounds

Synthesis of New Indanyl Nucleoside Analogues and their Biological Evaluation on Hepatitis C Virus (HCV) Replicon

Recent Advances in the Synthesis of Indanes and Indenes

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