Synthesis of Functionalized Difluorocyclopropanes: Unique Building Blocks for Drug Discovery

Bychek, Roman; Levterov, Vadym V.; Sadkova, Iryna V.; Tolmachev, Andrey A.; Mykhailiuk, Pavel K.

doi:10.1002/chem.201705708

Cited by 48 publications

(49 citation statements)

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“…10 ). The synthesis of these amino acids was reported very recently [ 100 ]. The reference compound 7 was also analyzed.…”

Section: Resultsmentioning

confidence: 99%

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

Kubyshkin¹

2020

Beilstein J. Org. Chem.

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Fluorine-containing analogues of proline are valuable tools in engineering and NMR spectroscopic studies of peptides and proteins. Their use relies on the fundamental understanding of the interplay between the substituents and the main chain groups of the amino acid residue. This study aims to showcase the polarity-related effects that arise from the interaction between the functional groups in molecular models. Properties such as conformation, acid–base transition, and amide-bond isomerism were examined for diastereomeric 4-fluoroprolines, 4-(trifluoromethyl)prolines, and 1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylates. The preferred conformation on the proline ring originated from a preferential axial positioning for a single fluorine atom, and an equatorial positioning for a trifluoromethyl- or a difluoromethylene group. This orientation of the substituents explains the observed trends in the pK a values, lipophilicity, and the kinetics of the amide bond rotation. The study also provides a set of evidences that the transition state of the amide-bond rotation in peptidyl-prolyl favors C4-exo conformation of the pyrrolidine ring.

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“…10 ). The synthesis of these amino acids was reported very recently [ 100 ]. The reference compound 7 was also analyzed.…”

Section: Resultsmentioning

confidence: 99%

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

Kubyshkin¹

2020

Beilstein J. Org. Chem.

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“…Recently, we have extended the original protocol of Prakash, Olah, and co‐workers towards alkenes bearing N ‐Boc protected secondary amino function . Another recent publication demonstrated the compatibility of this procedure with ether, ketal, as well as non‐conjugated ester and nitrile functions …”

Section: Introductionmentioning

confidence: 94%

Transition Metal‐free gem‐difluorocyclopropanation of Alkenes with CF₃SiMe₃−NaI System: a Recipe for Electron‐deficient Substrates

2018

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Reaction of various electron-deficient alkenes, as well as functionalized styrene derivatives with CF 3 SiMe 3 ÀNaI system is studied. Relative reactivity of the substrates is established. It is shown that many a,b-unsaturated esters can be difluorocyclopropanated efficiently under "slow addition protocol" conditions, which provides access to mono-and spirocyclic gem-difluorocyclopropyl-substituted carboxylic acids with good yields (36-79% for two steps) on up to 100 g scale.

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“…Because application of these reaction conditions to functionalized substrates is limited by their thermal stability and their susceptibility to side reactions at elevated temperatures, a selection of a TMSCF 3 –NaI system as a difluorocarbene equivalent was envisaged. The usage of TMSCF 3 , which is also referred as Ruppert–Prakash reagent, for gem ‐difluoromethylation reaction was first developed by Hu, Prakash and co‐workers, and was further adapted for preparation of gem ‐difluorocyclopropanes bearing diverse functional groups . Nonetheless, the addition of difluorocarbene equivalent derived from TMSCF 3 to alkenylboronic derivatives was unknown until the present study.…”

Section: Introductionmentioning

confidence: 96%

gem‐Difluorocyclopropanation of Alkenyl Trifluoroborates with the CF₃SiMe₃–NaI System

et al. 2020

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Difluorocyclopropanation of alkenyl trifluoroborates using TMSCF 3 -NaI system was reported for the first time. The developed method allowed preparation of monocyclic, spiroand fused-bicyclic gem-difluorocyclopropanes bearing addi-groups. [20][21][22][23][24] Nonetheless, the addition of difluorocarbene equivalent derived from TMSCF 3 to alkenylboronic derivatives was unknown until the present study. Scheme 1. Difluorocyclopropanation of alkenylboronic derivatives.In this work, application of TMSCF 3 -NaI system in refluxing THF (66°C) for the synthesis of gem-difluorocyclopropyl boronic derivatives and its effectiveness for multigram scale synthesis is reported (Scheme 1). It is shown that alkenyl trifluoroborates are optimal substrates for the preparation of aliphatic derivatives which facilitate isolation of the target products. The studied reaction scope included substrates bearing secondary N-Boc protected amine, ester, ether, phenyl and cyclopropyl moieties and provided products with spiro-and fused-bicyclic molecular topologies. Results and DiscussionOur study commenced with testing TMSCF 3 -NaI system in reaction with substrate 5a (Scheme 2), for which the difluorocyclopropanation using XCF 2 CO 2 Na (X = Cl, Br) at 180°C and 150°C, Scheme 2. Attempted difluorocyclopropanation of alkenyl boronic derivatives using the TMSCF 3 -NaI system. 2218Scheme 3. Preparation of trifluoroborate salts 7 from pinacolboronates 9.Scheme 4. Synthesis of pinacolboronates 9e (A) and 9p (B).

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Synthesis of Functionalized Difluorocyclopropanes: Unique Building Blocks for Drug Discovery

Abstract: Difluorocyclopropane-containing building blocks for drug discovery were synthesized from the functionalized alkenes and TMSCF /NaI. Novel fluorinated acids, amines, amino acids, alcohols, ketones and sulfonyl chlorides were obtained.

Cited by 48 publications

References 53 publications

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

Transition Metal‐free gem‐difluorocyclopropanation of Alkenes with CF₃SiMe₃−NaI System: a Recipe for Electron‐deficient Substrates

gem‐Difluorocyclopropanation of Alkenyl Trifluoroborates with the CF₃SiMe₃–NaI System

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Synthesis of Functionalized Difluorocyclopropanes: Unique Building Blocks for Drug Discovery

Abstract: Difluorocyclopropane-containing building blocks for drug discovery were synthesized from the functionalized alkenes and TMSCF /NaI. Novel fluorinated acids, amines, amino acids, alcohols, ketones and sulfonyl chlorides were obtained.

Cited by 48 publications

References 53 publications

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

Transition Metal‐free gem‐difluorocyclopropanation of Alkenes with CF3SiMe3−NaI System: a Recipe for Electron‐deficient Substrates

gem‐Difluorocyclopropanation of Alkenyl Trifluoroborates with the CF3SiMe3–NaI System

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Transition Metal‐free gem‐difluorocyclopropanation of Alkenes with CF₃SiMe₃−NaI System: a Recipe for Electron‐deficient Substrates

gem‐Difluorocyclopropanation of Alkenyl Trifluoroborates with the CF₃SiMe₃–NaI System