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ChemInform Abstract: Synthesis of Mono-Fluorinated Functionalized Cyclopropanes and Aziridines Using the ??-Fluorovinyl Diphenyl Sulfonium Salt.
Abstract
The α-fluorovinyl diphenyl sulfonium salt is attractive due to its high potential for the synthesis of mono-fluorinated cyclopropanes and aziridines as useful three-membered rings. The synthetically useful salt is readily prepared from α-fluorovinyl phenyl sulfide and diphenyl iodonium salt in one step.
... Similarly, cyclopropanation was also demonstrated using the α-fluorinated vinylsulfonium salt 557 (Scheme 94). 330 ...
Organosulfur compounds have long played a vital role in organic chemistry and in the development of novel chemical structures and architectures. Prominent among these organosulfur compounds are those involving a sulfur(IV) center, which have been the subject of countless investigations over more than a hundred years. In addition to a long list of textbook sulfur-based reactions, there has been a sustained interest in the chemistry of organosulfur(IV) compounds in recent years. Of particular interest within organosulfur chemistry is the ease with which the synthetic chemist can effect a wide range of transformations through either bond formation or bond cleavage at sulfur. This review aims to cover the developments of the past decade in the chemistry of organic sulfur(IV) molecules and provide insight into both the wide range of reactions which critically rely on this versatile element and the diverse scaffolds that can thereby be synthesized.
The fluorinated building block strategy and the direct fluorination strategy are of great importance for the synthesis of new fluorinated molecules. These strategies complement each other and can be combined to develop a new methodology for the construction of a wide variety of fascinating organofluorine compounds. In our opinion, the versatile building blocks used in this method should satisfy the following conditions: 1) readily prepared from commercially available reagents; 2) easy to handle; 3) storage under ordinary conditions without noticeable decomposition; 4) wide applicability. Based on the aforementioned requirements, we focused on the use of vinyl sulfonium salts. This brief review describes the synthesis of five types of fluorinated vinyl sulfonium salts and their reactions. Especially, we featured typical fluorinated groups containing trifluoromethyl (CF3 ), difluoromethyl (CF2 H), monofluoromethyl (CFH2 ), monofluoro (F) or β-bromotetrafluoroethyl (BrCF2 CF2 ) moieties in combination with vinyl sulfonium salts.
This manuscript reports the synthesis and structure of an unprecedented sulfonium salt, 5‐(trifluorovinyl)dibenzothiophenium triflate, and its use as a versatile reagent for the introduction of the bioisosteric 1,1,2‐trifluoroethylene linker in drug‐like structures. The protocol developed consists of the reaction of this compound with alcohols and phenols to deliver a complete set of 1,2,2‐trifluoro‐2‐(alkoxy‐/aryloxy)ethyl sulfonium salts, which have been purified by column chromatography and fully characterized. Subsequent single electron reduction under mild photochemical conditions efficiently affords the corresponding fluoroalkyl radicals that are trapped either intra‐ or intermolecularly through their reaction with (hetero)arenes. Theoretical calculations are used to evaluate the conformational consequences derived from the presence of the CF2‐CHF tether.
A facile synthesis of cyclopropenes and fluorinated cyclopropanes from readily available alkyl triflones was developed. The reaction, regardless of electronic effect, gave products in good to excellent yields and moderate diastereoselectivity. The mechanism may involve tandem Michael addition of triflones/intramolecular nucleophilic cyclization (elimination of ‐SO2CF3)/elimination of fluoride. Various cyclopropenes and fluorinated cyclopropanes were prepared from readily available alkyl triflones and electron‐deficient alkenes via a Michael addition initiated ring closure (MIRC) process. This protocol not only has a broad substrates scope but also achieves good chemical yields and moderate diastereoselectivity. The mechanism may involve tandem Michael addition of triflones/intramolecular nucleophilic cyclization (elimination of ‐SO2CF3)/elimination of fluoride.
We have synthesized (E)-b-(bromotetrafluoroethyl)vinyl sulfonium salt as a novel vinyl sulfonium salt. The excellent performance of the salt was demonstrated in the efficient synthesis of the corresponding 2-(bromotetrafluoroethyl)-N-substituted aziridines and (bromotetrafluoroethyl)cyclopropane derivatives in high yields.
This Minireview describes recent advances toward the synthesis of fluoro‐, monofluoromethyl‐, difluoromethyl‐, and trifluoromethyl‐substituted three‐membered rings such as cyclopropanes, aziridines, epoxides, episulfides, cyclopropenes, and 2 H‐azirines. The main synthetic methodologies since 2016 for cyclopropanes and since 2010 for the other three‐membered rings are reported. Better with three: Fluorinated three‐membered rings are valuable compounds with many applications. In this Minireview, the synthesis of fluoro‐, monofluoromethyl‐, difluoromethyl‐, and trifluoromethyl‐substituted cyclopropanes, cyclopropenes, aziridines, azirines, epoxides, and thiiranes over the past decade are described.
Johnson-Corey-Chaykovsky fluorocyclopropanation of double activated alkenes utilizing S‐monofluoromethyl‐S‐phenyl‐2,3,4,5‐tetramethylphenylsulfonium tetrafluoroborate is an efficient approach to obtain a range of monofluorocyclopropane derivatives. So far, fluoromethylsulfonium salts display the broadest scope for direct fluoromethylene transfer. In contrast to more commonly used fluorohalomethanes or freon derivatives, diarylfluoromethylsulfonium salts are bench stable, easy-to use reagents useful for the direct transfer of a fluoromethylene group to alkenes giving access to the challanging products - fluorocyclopropane derivatives. An interplay between reactivity of starting materials and stability of formed fluorocyclopropanes determines the outcome of the process.
Diarylfluoromethylsulfonium salts, alternatives to freons or advanced fluorinated building blocks, are bench stable and easy-to-use sources of direct fluoromethylene (:CHF) transfer to alkenes. These salts enabled development of a trans-selective monofluorinated Johnson-Corey-Chaykovsky reaction with vinyl sulfones or vinyl sulfonamides to access synthetically challenging monofluorocyclopropane scaffolds. The described method offers rapid access to monofluorinated cyclopropane building blocks with further functionalization opportunities to deliver more complex synthetic targets diastereoselectively.
An unprecedented direct fluorocyclopropanation of allylic alcohols is successfully achieved. This simple method involves the not so elusive fluoroiodomethyllithium, a carbenoidic intermediates, that under the developed conditions discloses its electrophilic...
Cyclopropanes, one of the most important strained rings, have drawn much attention for more than a century on account of the charming and unique reactivity. They not only exist in many natural products, but also have been widely used in the fields of organic synthesis, medicinal chemistry and materials science as versatile building blocks. Based on sustainable development in this area, this review mainly focus on the recent advances in the synthesis of cyclopropanes classified by the types of catalytic systems, and the related applications of cyclopropanes are also mentioned.
A new synthetic approach to dihydrofuran derivatives via the annulation reaction of β-naphthols and 4-hydroxycoumarins with vinylsulfonium salts had been developed. A variety of dihydrofuran derivatives were prepared in moderate...
Cycloaddition reactions between methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate and various 2-tosylacetamides are described. Various 2-tosylacetamides react with methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate in the presence of NaH at room temperature in one step to form trifluoromethylated pyroglutamates as single diastereomers. However, employing the same reactants using t-BuOK as base at −78 °C results in the formation of trifluoromethylated 2-pyridones. A ring-closure mechanism is proposed for the reaction.
Arylsulfonium salts are versatile arylation reagents for the synthesis of functional molecules. This digest focuses on the recent advances on the transition metal-mediated or -free arylation using the stable arylsulfonium salts or the metastable arylsulfonium intermediates as arylation agents.
A series of diaryl(fluoroalkyl)sulfonium salts were synthesized from electron-rich diaryl sulfides and fluoroalkyl trifluoromethanesulfonates under solvent-free conditions. Unlike diaryl sulfides, dialkyl and alkyl(aryl) sulfides reacted with fluoroalkyl trifluoromethanesulfonates (e.g. CF3SO3CH2CF3, CF3SO3CH2CF2H) to provide trialkyl- and aryl(dialkyl)sulfonium trifluoromethanesulfonates in good yields, wherein dialkyl- and alkyl(aryl)(fluoroalkyl)sulfonium salts were formed, respectively, and nucleophilically attacked by a second sulfide to yield the non-fluorinated sulfoniums. The SN2-type reaction could stop at the first step and exclusively afford dialkyl- and alkyl(aryl)(fluoroalkyl)sulfonium salts, which was dramatically dependent upon the structure of sulfides, the nature of fluoroalkyl trifluoromethanesulfonates, the reactant ratio, and/or the reaction temperature. This protocol allows for an efficient and convenient access to a variety of alkyl and fluoroalkyl sulfonium salts.
The Pd-catalyzed Suzuki–Miyaura cross-coupling of alkyl- and fluoroalkyl(diphenyl)sulfonium triflates with arylboronic acids was compared. The fluorine substitution on the alkyl groups of [Ph2SR][OTf] had a big influence on the reaction. Perfluoroalkyl(diphenyl)sulfonium triflates (2b–d) were unsuccessful participants in the Pd-catalyzed phenylation of arylboronic acid under the standard conditions because of the strong electronegativity of the long-chain perfluoroalkyl groups, which underwent SRfn bond cleavage instead. Polyfluoroalkyl(diphenyl)sulfonium triflates (2f–h) reacted with arylboronic acid to afford the phenylation product in very low yields due to the tendency of deprotonation and β-F elimination of the sulfonium salts. Eventually, (2,2,2-trifluoroethyl)diphenylsulfonium triflate (2e), methyl- or ethyl(diphenyl)sulfonium triflate (2i or 2j), and triphenylsulfonium triflate (2m) were found to be more effective reagents than other tested phenylsulfounium salts for Pd-catalyzed phenylation, which provided much higher yields of the desired products under mild conditions.
An efficient synthesis of cyclohexane- and cyclopentane-1,3-dione-2-spirocyclopropanes from 1,3-cycloalkanediones using sulfonium salts was achieved. The reaction of 1,3-cycloalkanediones with (1-aryl-2-bromoethyl)-dimethylsulfonium bromides and powdered K2CO3 in EtOAc provided the corresponding spirocyclopropanes in high yields. Furthermore, a one-pot synthesis of tetrahydroindol-4(5H)-one from 1,3-cyclohexanedione was achieved using the present protocol and a sequential ring-opening cyclization of spirocyclopropane with a primary amine.
We demonstrate the first preparation of difluoromethyl (CF2H) vinyl sulfonium salt as a new difluoromethylated building block, followed by its application to the synthesis of CF2H-containing cyclopropanes in one step. The salt itself is readily prepared from 3-bromo-3,3-difluoropropene in three steps, in high overall yields, and is stable. A wide range of active methylene compounds participated in the cyclopropanation reaction using this salt, providing the corresponding products in high-to-excellent yields.
The discovery of new methods for the synthesis of classes of potentially bioactive molecules remains an important goal for synthetic chemists. Vinylsulfonium salts have been used for the synthesis of a wide variety of small heterocyclic motifs; however, further developments to this important class of reagents has been focused on reaction with new substrates rather than development of new vinylsulfonium salts. We herein report the synthesis of a range of α-substituted vinylsulfonium tetraphenylborates (10 examples) in a 3 step procedure from commercially available styrenes. The important role of the tetraphenylborate counterion on the stability and accessibility of the vinylsulfonium salts is also detailed. The α-substituted vinylsulfonium tetraphenylborates gave good to excellent yields in the epoxyannulation of β-amino ketones (15 examples) and the cyclopropanation of allylic amines (4 examples). Hydrogenation of an epoxyannulation product proceeded with good diastereoselectivity.
A rhodium-catalyzed cyclopropanation of 1-fluoro-1-(phenylsulfonyl)ethylene and diazo esters is described as an effective method for the stereoselective synthesis of cis-2-fluorocyclopropanecarboxylic acid. This process provides an example of the cyclopropanation of electron-deficient olefin and diazoacetates.
The synthesis of highly functionalized monofluorinated cyclopropanes based on a Michael Initiated Ring Closure (MIRC) reaction has been developed. The addition of quaternary ammonium salts derived from ethyl bromofluoroacetate on a panel of electron deficient alkenes followed by cyclization gave rise to an efficient access to monofluorinated cyclopropanes with good yields and remarkable diastereoselectivity.
Chiral transfer: the fluorinated sulfoximine (see scheme; Ts=p-toluenesulfonyl) was synthesized and used as the first chiral fluoromethylenation reagent for the synthesis of cyclopropanes that contain fluorinated tertiary stereogenic carbon centers in good yields, good diastereoselectivity, and excellent enantioselectivity.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
(1-Fluorovinyl) phenyl sulfoxide 2 was prepared in two steps from (1-fluorovinyl)methyldiphenylsilane. Although the sulfoxide 2 underwent Diels-Alder reaction with very reactive diene, 1,3-diphenylisobenzofuran, to give the corresponding fluorinated-naphthalene derivative in one step, it did not afford cycloadducts with other dienes employed.
Highly enantio- and diastereoenriched monofluorocyclopropanes were accessed via the Simmons-Smith fluorocyclopropanation of allylic alcohols using difluoroiodomethane and ethylzinc iodide as the substituted carbenoid precursors. The scrambling of halogens at the zinc carbenoid led to the formation of the fluorocyclopropanating agent (fluoroiodomethyl)zinc(II) fluoride. This strategy circumvented the ongoing limitation in Simmons-Smith fluorocyclopropanations relying on the use of the relatively inaccessible and expensive carbenoid precursor fluorodiiodomethane.
Triethylborane mediated iodine atom-transfer radical addition of fluoroiodoacetate to 1-alkene or cyclic alkene proceeded in a good yield to give the α-fluoro-γ-iodo esters in non-diastereoselective manner, while the subsequent cyclopropane formation via enolate of the α-fluoro ester provided the corresponding fluorocyclopropanecarboxylate in a highly cis- or F-endo-selective manner.
From a unique fluorinated cyclopropane scaffold, a straight-forward, easy and practical access to various amino-acid analogues (methionine, leucine, lysine and arginine) was described. Moreover, the synthesis, for the first time, of one tripeptide incorporating a fluorinated cyclopropane amino-acid (FCAA) analogue was reported.
The combination of a fluorine atom and a cyclopropane ring, which both possess unique structural and chemical features, can generate new relevant building blocks for the discovery of efficient fluorinated biologically active agents. In this review, we report the different strategies to access monofluorocyclopropanes and highlight some of their attractive biological applications.
Monofluorinated cyclopropanecarboxylates are available in racemic or optically active form by transition metal-catalyzed reactions of vinylfluorides with diazoacetates. From α-fluorostyrene and tert-butyl diazoacetate in the presence of 2mol% of an enantiopure bis(oxazoline) copper complex, a 81:19 mixture of tert-butyl trans- and cis-2-fluoro-2-phenylcyclopropanecarboxylates was obtained with high enantiomeric excess (ee) of 93 or 89%, respectively. The corresponding racemic ethylesters were used as starting materials for the synthesis of carboxamides, of the cis- and trans-isomers of analogues of tranylcypromine, an anti-depressive drug and several of its homologous fluorinated cyclopropylmethyl and cyclopropylethyl amines. Corresponding enantiopure cyclopropylmethanols and several of their derivatives were synthesized also. Solid state structures of a selection of these compounds were examined by X-ray crystallography. Particularly, the cis-configurated fluorinated phenylcyclopropane derivatives showed extremely close intermolecular CH⋯FC contacts. The shortest of such distances (2.17Å) was found in the N-(4-bromophenyl)carbamate of (1S,2R)-(2-fluoro-2-phenylcyclopropyl)methanol.
Herein we describe the diastereoselective synthesis of glutamic acid analogs and the evaluation of their agonist activity towards metabotropic glutamate receptor subtype 4 (mGluR4). These analogs are based on a monofluorinated cyclopropane core substituted with an α-aminoacid function. The potential of this new building block as a tool for the development of a novel class of drugs is demonstrated with racemic analog 11a that displayed the best agonist activity with an EC50 of 340 nM.
The unique combination of Zn/LiCl allowed generation of reactive zinc enolate from ethyl dibromofluoroacetate. This fluorinated enolate reacts efficiently with a wide range of functionalized electron-deficient alkenes to afford the corresponding monofluorinated cyclopropylcarboxylates in good yields.
Two trifluoromethyl-substituted building blocks β-(trifluoromethyl)vinyl sulfonium salts 1 and 2 were developed. Reactions of β-(trifluoromethyl)vinyl sulfonium salt 1 with active methylene compounds containing electron-withdrawing groups using DBU as the base in DMSO occurred to give trifluoromethyl-substituted cyclopropane derivatives 7 as the major products. In contrast, reactions of β-(trifluoromethyl)vinyl sulfonium salt 2 with active methylene compounds occurred with the migration of one of the electron-withdrawing groups to give the products 8 as the major products when NaH was used as the base in DMSO. Moreover, when NaH was used as base in THF/CH(2)Cl(2) at -78 °C, reaction of β-(trifluoromethyl)vinyl sulfonium salt 1 gave trifluoromethyl-substituted 2,3-dihydrofuran derivatives 9 as the major products. A working mechanism was proposed to explain the different behaviors of the β-(trifluoromethyl)vinyl sulfonium salts 1 or 2 with active methylene compounds under these different conditions.
A series of racemic, diastereoisomeric aryl cyclopropylamines substituted with fluorine in the 2-position and electron-donating and electron-withdrawing groups on the aromatic ring have been prepared. These represent analogues of the classic MAO inhibitor tranylcypromine (trans-2-phenylcyclopropylamine, 1). Their activities as inhibitors of recombinant human liver monoamine oxidases A (MAO A) and B (MAO B) were determined. The trans-compounds were low micromolar inhibitors of both MAO A and MAO B with moderate MAO A selectivity while the less active cis-analogues were MAO B selective. In the trans-series, electron-withdrawing para-substituents increased the potency of MAO A inhibition while electron-donating groups such as methyl or methoxy had no influence on this activity. In contrast, aromatic ring substitution in the trans-series had essentially no effect on the inhibition of MAO B. The corresponding cis-compounds were shown to be 10-100 times less active against MAO A, while trans- and cis-compounds were quite similar in terms of inhibition of MAO B. The best MAO A/MAO B selectivity (7:1) in the trans-series was found for trans-2-fluoro-2-(para-trifluoromethylphenyl)cyclopropylamine (7d), while a 1:27 selectivity was found for cis-2-fluoro-2-(para-fluorophenyl)cyclopropylamine (10c). These results are discussed in connection with the pK(a) and logD values, the mechanism of action of tranylcypromines, and the geometry of the active site of the enzymes.
A series of para-substituted diastereopure cis- and trans-2-fluoro-2-arylcyclopropylamines were synthesized and these were investigated as inhibitors of microbial tyramine oxidase from Arthrobacter sp. All compounds were shown to be competitive inhibitors of this enzyme. The nature of the para-substituents in the more potent trans-isomer (cis-relationship between fluorine and the amino group) of 2-fluoro-2-arylcyclopropylamine influenced the inhibitory potency in a consistent fashion. Thus, electron-withdrawing groups (F, Cl) slightly decreased the activity, while the methyl group (+ I substituent) increased the activity by a factor of ca. 7 compared to trans-2-fluoro-2-phenylcyclopropylamine and by a factor of 90 compared to tranylcypromine. Activity also was strongly dependent on the absolute configuration. The (1S,2S)-enantiomer of 2-fluoro-2-phenylcyclopropylamine was an excellent inhibitor of tyramine oxidase whereas the (1R,2R)-enantiomer was essentially devoid of activity.
(Beta-trifluoromethyl)vinyl sulfonium salt as a novel three-carbon fluorinated building block was conveniently prepared from easily available (beta-trifluoromethyl)vinyl sulfide and diphenyl iodonium salt in excellent yield. This easily handled crystalline reagent displayed two types of useful transformation involving aziridination and vinylation to afford the corresponding trifluoromethylated compounds in excellent yields.
2,2,3,3-Tetramethylcyclopropanecarboxylic acid (TMCA, 4) is a cyclic analogue of the antiepileptic drug (AED) valproic acid (VPA) (1). alpha-F, alpha-Cl, alpha-Br, and alpha-methyl derivatives of 4 and their amides were synthesized and tested in rodent models for anticonvulsant potency and AED-induced teratogenicity. In the anticonvulsant rat-maximal electroshock (MES) and subcutaneous metrazol (scMet) tests, alpha-Cl-TMCD (17) had ED(50) values of 97 and 27 mg/kg, respectively. alpha-F-TMCD (11) was 120 times more potent than VPA in the rat-scMet test (ED(50) = 6 mg/kg) and had a protective index (PI = TD(50)/ED(50)) of 20. In the 6 Hz psychomotor mouse model 11 had ED(50) values of 57 mg/kg (32 mA) and 59 mg/kg (44 mA). The ED(50) values of 11 in the hippocampal-kindled rat model and in the pilocarpine-induced-status rat model were 30 and 23 mg/kg, respectively. Unlike 1, 11 was nonteratogenic in mice. This novel compound has the potential to become a candidate for development as a new potent and safe antiepileptic and CNS drug.
Two series of diastereopure phenylcyclopropylamine analogues, 2-fluoro-2-phenylcyclopropylamines and 2-fluoro-2-phenylcyclopropylalkylamines, as well as 2-fluoro-1-phenylcyclopropylamines and 2-fluoro-1-phenylcyclopropylmethylamines, were synthesized in order to study the effects of fluorine substitution on monoamine oxidase inhibition. Inhibitory activity was assayed using commercially available microbial tyramine oxidase. Characterization of tyramine oxidase, carried out prior to the inhibition experiments, confirmed earlier suggestions that this enzyme is a semicarbazide-sensitive copper-containing monoamine oxidase. The most potent competitive inhibitor was trans-2-fluoro-2-phenylcyclopropylamine, which had an IC(50) value 10 times lower than that of the nonfluorinated compound, tranylcypromine. 2-Fluoro-1-phenylcyclopropylmethylamine was found to be a weak noncompetitive inhibitor of tyramine oxidase. The presence of a free amino group, directly bonded to the cyclopropane ring, and a fluorine atom in a relationship cis to the amino group were structural features that increased tyramine oxidase inhibition.
Novel group II metabotropic glutamate receptor (mGluR) antagonists, 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives 11 and 12, were discovered by the incorporation of a hydroxy or alkoxyl group onto the C-3 portion of selective and potent group II mGluR agonist 5, (1R,2S,5R,6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. Among these compounds, (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (-)-11be (MGS0039) was a highly selective and potent group II mGluR antagonist with the best pharmacokinetic profile. Compound (-)-11be exhibited high affinities for mGlu 2 (Ki = 2.38 +/- 0.40 nM) and mGlu 3 (4.46 +/- 0.31 nM) but low affinity for mGluR 7 (Ki = 664 +/- 106 nM), and potent antagonist activities for mGlu 2 (IC50 = 20.0 +/- 3.67 nM) and mGluR 3 (IC50 = 24.0 +/- 3.54 nM) but much less potent antagonist activities for mGlu 4 (IC50 = 1740 +/- 1080 nM), mGlu 6 (IC50 = 2060 +/- 1270 nM), mGlu 1 (IC50 = 93300 +/- 14600 nM), and mGluR 5 (IC(50) = 117000 +/- 38600 nM). No significant agonist activities of (-)-11be were found for mGluRs 2, 3, 4, 6, 1, and 5 (EC50 > 100,000 nM). Furthermore, (-)-11be exhibited dose-dependent oral absorption (plasma C(max): 214 +/- 56.7, 932 +/- 235, and 2960 +/- 1150 ng/mL for 3 mg/kg, 10 mg/kg, and 30 mg/kg, po, respectively) and acceptable blood-brain barrier penetration (brain C(max): 13.2 ng/mL for 10 mg/kg, p.o. 6 h). In this paper, we report the synthesis, in vitro pharmacological profile, and structure-activity relationships (SARs) of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives 11 and 12, and pharmacokinetic profiles of several typical compounds.
3-(3,4-Dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 5 (MGS0039) is a highly selective and potent group II metabotropic glutamate receptor (mGluR) antagonist (antagonist activities for mGluR2; IC50=20.0 nM, mGluR3; IC50=24.0 nM) and is detected in both plasma (492 ng/mL) and brain (13.2 ng/g) at oral administration of 10 ng/mL [J. Med. Chem.2004, 47, 4750], but the oral bioavailability of 5 was 10.9%. In order to improve the oral bioavailability of 5, prodrugs of 5 were discovered by esterification of carboxyl group on C6-position of bicyclo[3.1.0]hexane ring. Among these compounds, 6-alkyl esters exhibited approximately 10-fold higher concentrations of 5 in the plasma and brain of rats after oral administration (e.g., ethyl ester of 5; plasma, Cmax=20.7+/-1.3 microM) compared to oral administration of 5 (plasma, Cmax=2.46+/-0.62 microM). 3-(3,4-Dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-heptyl ester (7ao), a prodrug of MGS0039, showed antidepressant-like effects in rat forced swimming test and mouse tail suspension test following oral administration. Moreover, following oral administration of 7ao in mice, high concentrations of MGS0039 were detected in both the brain and plasma, while 7ao was barely detected. In this paper, we report the synthesis, in vitro metabolic stabilities, and pharmacokinetic profiles of the prodrugs of 5, and the antidepressant-like effects of 7ao.
Unlike the synthetically exploited oxiranes and thiiranes, aziridines that lack electron-withdrawing substituents, such as acyl or sulfonyl functionalities at nitrogen, are rather unreactive. As expected, three-membered aziridine 6 was calculated to be significantly more reactive than azetidine 7 in nucleophilic cleavage by ammonia, a typical nucleophile. The reactivity of 7 was about the same as that of an acyclic model compound, 8, when release of ring strain in the transition state was taken into account. Fluorine due to its similar size but vastly different electronegativity has been substituted for hydrogen as a means of modifying chemical properties for varied applications. In the present investigation, the effect of fluorine substitution at aziridine positions other than nitrogen was studied. Computations at the MP2(Full)/6-311++G(d,p)//MP2(Full)/6-31+G(d) level found a vast preference for attack by ammonia at the 3-position of 2-fluoroaziridine in the gas phase at 298 K. When release of ring strain was taken into account, this compound reacted more than 10(11) times faster than 6. The reaction rate with trans-2,3-difluoroaziridine was about twice that of 2-fluoroaziridine, while its diastereomer reacted with ammonia considerably slower. Acyclic fluorinated amine model compounds were employed to assess the generality of the effects produced by fluorine substitution. The results were rationalized by the energy contributions of strain energy releases, stabilization of the leaving group, and the relative electrostatic energies of the heterocycles in the transition states. The more reactive fluoroaziridines underwent nucleophilic attack at rates comparable to those of N-acetylaziridine.
A new route for the synthesis of stable 3-alkyl- and 3-aryl-2(,2)-(di)fluoroaziridines was developed by hydride reduction of novel alpha-bromo- and alpha-chloro-alpha(,alpha)-(di)fluoroketimines and subsequent ring closure of beta-fluorinated beta-chloro- and beta-bromoamines. This is the first report on the synthesis of 2,2-difluoroaziridines sensu stricto.
A straightforward synthesis toward 2-fluorinated aziridines was developed via ring closure of beta-fluorinated beta-chloroamines, which were obtained via reduction of the corresponding alpha-fluorinated amides by borane. When 1-benzyl-2-fluoroaziridine was treated with methanol, reaction occurred at the 2-position, giving rise to N-benzyl-2,2-dimethoxyethylamine, while in the case of 1-benzyl-2,2-difluoroaziridine the 3-position was attacked, giving rise to N-benzyl-2-methoxyacetamide. These reactions point to the divergent reactive behavior of monofluoro- and difluoroaziridines.
In this paper, we describe the synthesis of (+)-(1R( *),2R( *))-2-[(1S( *))-1-amino-1-carboxy-2-(9H-xanthen-9-yl)-ethyl]-1-fluorocyclopropanecarboxylic acid (+)-16a, a compound, that is, fluorinated at the alpha position of the carboxylic acid in the cyclopropane ring of a group II mGluRs antagonist, 1 (LY341495), using a previously reported stereoselective cyclopropanation reaction. The fluorinated compound (+)-16a exhibited almost the same affinity (IC(50)=3.49 nM) for mGluR2 as 1 but had a superior pharmacokinetic profile. Furthermore, a marked elevation of the plasma levels of (+)-16a was observed following the administration of a prodrug, (+)-17.