cas 63106-93-4, (1S,5R)-1-PHENYL-3-OXA-BICYCLO[3.1.0]HEXAN-2-ONE

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Microbiological transformations 34: Enantioselective hydrolysis of a key-lactone involved in the synthesis of the antidepressant milnacipran
The enantioselective hydrolysis of a key-lactone allowing for the synthesis of the antidepressant milnacipran is described. Several biocatalysts were screened in order to achieve this biotransformation, the best results being obtained using whole-cells cultures of the fungi Beauveria sulfurescens and Cunninghamella blakesleeana.
Viazzo, Pascale,Alphand, Veronique,Furstoss, Roland
p. 4519 - 4522
(1996)
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Tandem Insertion/[3,3]-Sigmatropic Rearrangement Involving the Formation of Silyl Ketene Acetals by Insertion of Rhodium Carbenes into S-Si Bonds
Allyl 2-diazo-2-phenylacetates are shown to react with trimethylsilyl thioethers in the presence of rhodium(II) catalysts to generate α-allyl-α-thio silyl esters. The transformation involves a tandem process involving formal rhodium-catalyzed insertion of the carbene group into the S-Si bond to generate a silyl ketene acetal, followed by a spontaneous Ireland-Claisen rearrangement. The silyl ester products were isolated as the corresponding carboxylic acids after aqueous workup. Intramolecular cyclopropanation of the allyl fragment generally competes with addition of the heteroatom to the carbene center. The reaction occurs under mild conditions and in high yield, allowing for rapid entry into rearrangement tetrasubstituted products. Propargyl esters were shown to generate the corresponding α-allenyl products.
Combs, Jason R.,Lai, Yin-Chu,Van Vranken, David L.
p. 2841 - 2845
(2021/05/05)

Direct Synthesis of Cyclopropanes from gem-Dialkyl Groups through Double C-H Activation
Cyclopropanes are important structural motifs found in numerous bioactive molecules, and a number of methods are available for their synthesis. However, one of the simplest cyclopropanation reactions involving the intramolecular coupling of two C-H bonds on gem-dialkyl groups has remained an elusive transformation. We demonstrate herein that this reaction is accessible using aryl bromide or triflate precursors and the 1,4-Pd shift mechanism. The use of pivalate as the base was found to be crucial to divert the mechanistic pathway toward the cyclopropane instead of the previously obtained benzocyclobutene product. Stoichiometric mechanistic studies allowed the identification of aryl- and alkylpalladium pivalates, which are in equilibrium via a five-membered palladacycle. With pivalate, a second C(sp3)-H activation leading to the four-membered palladacycle intermediate and the cyclopropane product is favored. A catalytic reaction was developed and showed a broad scope for the generation of diverse arylcyclopropanes, including valuable bicyclo[3.1.0] systems. This method was applied to a concise synthesis of lemborexant, a recently approved anti-insomnia drug.
Clemenceau, Antonin,Thesmar, Pierre,Gicquel, Maxime,Le Flohic, Alexandre,Baudoin, Olivier
p. 15355 - 15361
(2020/10/20)

IMPROVED PROCESS FOR THE PREPARATION OF LEVOMILNACIPRAN
The present invention discloses cost-effective, industrially efficient and safe process synthesis of levomilnacipran that is devoid of 1-phenyl-1- diethylaminocarbonyl-2- chloromethylcyclopropane.
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Page/Page column 7-8

(2019/06/09)

Preparation method of levomilnacipran hydrochloride
The invention relates to the field of chemical medicines and organic synthesis and in particular relates to a preparation method of levomilnacipran hydrochloride. Aiming at solving the problems of anexisting method for preparing the levomilnacipran hydrochloride that the cost is relatively high or a generation process is relatively dangerous so that large-scale industrial production is limited, the preparation method is characterized by comprising the following steps: [1] enabling phenylacetonitrile and (R)-2-chloromethyl ethylene oxide to react under the action of sodium amide to obtain a compound 1; then carrying out hydrolysis cyclization on the compound 1 to obtain a compound 2; [2] enabling the compound 2 and thionyl chloride to react in alcohol, so as to obtain a compound 3; [3] enabling the compound 3 to be subjected to exchange reaction through introducing nitryl and amino, so as to obtain a compound 6; [4] reducing nitryl in the compound 6 and forming salt in situ to obtain the levomilnacipran hydrochloride. The preparation method provided by the invention is applicable to industrial production of the levomilnacipran hydrochloride.
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Paragraph 0057-0058

(2018/09/28)

(+)-Methyl (1 R, 2S)-2-{[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]methyl}-1-phenylcyclopropanecarboxylate [(+)-MR200] derivatives as potent and selective sigma receptor ligands: Stereochemistry and pharmacological properties
Methoxycarbonyl-1-phenyl-2-cyclopropylmethyl based derivatives cis-(+)-1a [cis-(+)-MR200], cis-(-)-1a [cis-(-)-MR201], and trans-(±)-1a [trans-(±)-MR204], have been identified as new potent sigma (σ) receptor ligands. In the present paper, novel enantiomerically pure analogues were synthesized and optimized for their σ receptor affinity and selectivity. Docking studies rationalized the results obtained in the radioligand binding assay. Absolute stereochemistry was unequivocally established by X-ray analysis of precursor trans-(+)-5a as camphorsulfonyl derivative 9. The most promising compound, trans-(+)-1d, showed remarkable selectivity over a panel of more than 15 receptors as well as good chemical and enzymatic stability in human plasma. An in vivo evaluation evidenced that trans-(+)-1d, in contrast to trans-(-)-1d, cis-(+)-1d, or cis-(-)-1d, which behave as σ1 antagonists, exhibited a σ1 agonist profile. These data clearly demonstrated that compound trans-(+)-1d, due to its σ1 agonist activity and favorable receptor selectivity and stability, provided an useful tool for the study of σ1 receptors.
Amata, Emanuele,Rescifina, Antonio,Prezzavento, Orazio,Arena, Emanuela,Dichiara, Maria,Pittalà, Valeria,Montilla-García, ángeles,Punzo, Francesco,Merino, Pedro,Cobos, Enrique J.,Marrazzo, Agostino
supporting information
p. 372 - 384
(2018/01/17)

PROCESS FOR THE PREPARATION OF (1S,2R)-MILNACIPRAN
The invention relates to a process for the preparation of Levomilnacipran, a compound useful in the treatment of depression, comprising the following steps: a) directly converting the enantiomerically enriched form of alcohol (D) into the enantiomerically enriched form of the phthalimido derivative (C) by treatment with phthalimide in the presence of a trialkyl or triarylphosphine and of a dialkyl azodicarboxylate, formula (I) wherein the amount of phthalimide is comprised between 1 and 1.3 equivalents with respect to the molar amount of alcohol (D) used, and the amounts of both the phosphine and the azodicarboxylate are comprised, independently from each other, between 1 and 1.5 equivalents with respect to the molar amount of alcohol (D) used; b) deblocking the enantiomerically enriched form of the phthalimido derivative (C) to obtain Levomilnacipran, formula (II).
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Page/Page column 10; 11

(2016/06/01)

Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist
The orexin/hypocretin receptors are a family of G protein-coupled receptors and consist of orexin-1 (OX1) and orexin-2 (OX2) receptor subtypes. Orexin receptors are expressed throughout the central nervous system and are involved in the regulation of the sleep/wake cycle. Because modulation of these receptors constitutes a promising target for novel treatments of disorders associated with the control of sleep and wakefulness, such as insomnia, the development of orexin receptor antagonists has emerged as an important focus in drug discovery research. Here, we report the design, synthesis, characterization, and structure-activity relationships (SARs) of novel orexin receptor antagonists. Various modifications made to the core structure of a previously developed compound (-)-5, the lead molecule, resulted in compounds with improved chemical and pharmacological profiles. The investigation afforded a potential therapeutic agent, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006), an orally active, potent orexin antagonist. The efficacy was demonstrated in mice in an in vivo study by using sleep parameter measurements. (Chemical Equation Presented).
Yoshida, Yu,Naoe, Yoshimitsu,Terauchi, Taro,Ozaki, Fumihiro,Doko, Takashi,Takemura, Ayumi,Tanaka, Toshiaki,Sorimachi, Keiichi,Beuckmann, Carsten T.,Suzuki, Michiyuki,Ueno, Takashi,Ozaki, Shunsuke,Yonaga, Masahiro
supporting information
p. 4648 - 4664
(2015/06/30)

COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of neurological conditions may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of fibromyalgia, depression, neuropathic pain, severe pain, chronic pain, generalized pain, injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, post herpetic neuralgia, diabetic neuropathy, cancer pain, fibromyalgia and lower back pain.
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Paragraph 0122; 0123

(2015/05/05)

Enantioselective iron-catalyzed intramolecular cyclopropanation reactions
An iron-catalyzed asymmetric intramolecular cyclopropanation was realized in high yields and excellent enantioselectivity (up to 97% ee) by using the iron complexes of chiral spiro-bisoxazoline ligands as catalysts. The superiority of iron catalysts exhibited in this reaction demonstrated the potential abilities of this sustainable metal in asymmetric carbenoid transformation reactions.
Shen, Jun-Jie,Zhu, Shou-Fei,Cai, Yan,Xu, Huan,Xie, Xiu-Lan,Zhou, Qi-Lin
p. 13188 - 13191
(2015/01/09)

AN IMPROVED PROCESS FOR THE PREPARATION OF 1-ARYL 2-AMINOMETHYL CYCLOPROPANE CARBOXYAMIDE (Z) DERIVATIVES, THEIR ISOMERS AND SALTS
The present invention relates to an improved and one-pot process for the preparation of 1-Aryl 2-aminomethyl cyclopropane carboxyamide (z) derivatives, their isomers of formula (I) or its pharmaceutically acceptable salt thereof wherein R1 and R2 are represents independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, which aryl or alkylaryl group is optionally substituted by a halogen atom.
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Page/Page column 30; 31

(2014/02/15)

PROCESS FOR PREPARING LEVOMILNACIPRAN HCL
The invention relates to one-pot process for preparing (1S,2R)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-aminomethylcyclopropane of formula (I) comprising the step of reacting (1S,2R)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropanecarboxamide successively with the following reactants 1) triethyl orthoformate and methanesulfonic acid or triethylamine and methanesulfonyl chloride, 2) a phthalimidating agent, 3) aqueous EtNH2, wherein the reaction is carried out in toluene. In another aspect the invention concerns a process for preparing (1S,2R)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropanecarboxamide trough a step of crystallization of (1S,5R)-1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one.
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Paragraph 0093-0097

(2014/12/09)

Synthesis and evaluation of novel radioligands for positron emission tomography imaging of the orexin-2 receptor
Orexin receptors (OXRs) in the brain have been implicated in diverse physiological and neuropsychiatric conditions. Here we describe the design, synthesis, and evaluation of OXR ligands related to (1R,2S)-2-(((2-methyl-4- methoxymethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyridin-2-yl) -2-(3-fluorophenyl)cyclopropanecarboxamide (9a) applicable to positron emission tomography (PET) imaging. Structural features were incorporated to increase binding affinity for OXRs, to enable carbon-11 radiolabeling, and to adjust lipophilicity considered optimal for brain penetration and low nonspecific binding. 9a displayed nanomolar affinity for OXRs, and autoradiography using rat brain sections showed that specific binding of [11C]9a was distributed primarily to neocortical layer VI and hypothalamus, consistent with reported localizations of orexin-2 receptors (OX2Rs). In vivo PET study of [11C]9a demonstrated moderate uptake of radioactivity into rat and monkey brains under deficiency or blockade of P-glycoprotein, and distribution of PET signals in the brain was in agreement with autoradiographic data. Our approach and findings have provided significant information for development of OX2R PET tracers.
Oi, Norihito,Suzuki, Michiyuki,Terauchi, Taro,Tokunaga, Masaki,Nakatani, Yosuke,Yamamoto, Noboru,Fukumura, Toshimitsu,Zhang, Ming-Rong,Suhara, Tetsuya,Higuchi, Makoto
p. 6371 - 6385
(2013/09/23)

COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
The invention relates to the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for the treatment of neurological conditions may he formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may he used to treatment: of fibromyalgia, depression, neuropathic pain, severe pain, chronic pain, generalized pain, injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multipie sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, post herpetic neuralgia, diabetic neuropathy, cancer pain, fibromyalgia and lower back pain.
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Paragraph 0098; 0099

(2013/12/03)

CYCLOPROPANE DERIVATIVES
A cyclopropane derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof has orexin receptor inhibitory action, and thus, is extremely useful as an agent for preventing or treating sleep disorder or dyssomnia caused by orexin, including insomnia as a typical example: wherein A1, A2 and A3 each independently represent an aryl group, a heterocyclyl group or the like, R1, R2 and R3 each independently represent a hydrogen atom, a C1-6 alkyl group or the like, X represents an oxygen atom or the like, and L represents a bond or the like.
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Page/Page column 22-23

(2012/07/13)

Enantioselective synthesis of levomilnacipran
A novel approach for the asymmetric synthesis of the active (1S,2R)-enantiomer of the antidepressant milnacipran is reported. The two stereogenic centers borne by the cyclopropane ring were sequentially installed starting from phenylacetic acid.
Alliot, Julien,Gravel, Edmond,Pillon, Florence,Buisson, David-Alexandre,Nicolas, Marc,Doris, Eric
supporting information; experimental part
p. 8111 - 8113
(2012/09/21)

Conformational restriction approach to β-Secretase (BACE1) inhibitors: Effect of a cyclopropane ring to induce an alternative binding mode
Improvement of a drugs binding activity using the conformational restriction approach with sp3 hybridized carbon is becoming a key strategy in drug discovery. We applied this approach to BACE1 inhibitors and designed four stereoisomeric cyclopropane compounds in which the ethylene linker of a known amidine-type inhibitor 2 was replaced with chiral cyclopropane rings. The synthesis and biologic evaluation of these compounds revealed that the cis-(1S,2R) isomer 6 exhibited the most potent BACE1 inhibitory activity among them. X-ray structure analysis of the complex of 6 and BACE1 revealed that its unique binding mode is due to the apparent CH-π interaction between the rigid cyclopropane ring and the Tyr71 side chain. A derivatization study using 6 as a lead molecule led to the development of highly potent inhibitors in which the structure-activity relationship as well as the binding mode of the compounds clearly differ from those of known amidine-type inhibitors.
Yonezawa, Shuji,Higashino, Kenichi,Tanaka, Yoshikazu,Nakano, Toru,Yamamoto, Takahiko,Yamakawa, Hidekuni,Muto, Chie,Hosono, Motoko,Hattori, Kazunari,Yutsudo, Takashi,Sakagami, Masahiro,Takemoto, Hiroshi,Iwamoto, Hideo,Kondo, Yutaka,Togame, Hiroko,Arisawa, Mitsuhiro,Shuto, Satoshi
p. 8838 - 8858,21
(2020/09/16)

A nonmetal approach to α-heterofunctionalized carbonyl derivatives by formal reductive X-H insertion
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Miller, Eric J.,Zhao, Wei,Herr, Jonathan D.,Radosevich, Alexander T.
supporting information
p. 10605 - 10609,5
(2020/09/02)

METHOD FOR SYNTHESIS OF (1S, 2R)-MILNACIPRAN
The present invention relates to a method for synthesizing a pharmaceutically acceptable acid addition salt of (1S, 2R)-milnacipran comprising the following successive steps: (a) reaction of phenylacetonitrile and of (R)-epichlorhydrin in the presence of a base containing an alkaline metal, followed by a basic treatment, and then by an acid treatment in order to obtain a lactone; (b) reaction of said lactone with MNEt2, wherein M represents an alkaline metal, or with NHEt2 in the presence of a Lewis acid-amine complex, in order to obtain an amide-alcohol; (c) reaction of said amide-alcohol with thionyl chloride in order to obtain a chlorinated amide; (d) reaction of said chlorinated amide with a phthalimide salt in order to obtain a phthalimide derivative; (e) hydrolysis of the phthalimide group of said phthalimide derivative in order to obtain (1S, 2R)-milnacipran, and (f) salification of (1S, 2R)-milnacipran in a suitable solvent system in the presence of a pharmaceutically acceptable acid.
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Page/Page column 13-14

(2010/08/09)

METHOD FOR PRODUCING (Z)-1-PHENYL-1-DIETHYLAMINOCARBONYL-2-HYDROXYMETHYL CYCLOPROPANE
The present invention provides a process for producing (Z)-1-phenyl-1-diethylaminocarbonyl-2-hydroxymethylcyclopropane, which comprises reacting 2-oxo-1-phenyl-3-oxabicyclo[3.1.0]hexane with diethylamine in the presence of alkali metal alkoxide.
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Page/Page column 3

(2010/11/26)

Synthesis of enantiomerically pure milnacipran analogs and inhibition of dopamine, serotonin, and norepinephrine transporters
A series of Milnacipran analogs with variation in the aromatic moiety were prepared in high enantiomeric excess. Structure-activity relationships for two parallel enantiomeric series are described. The (-)-(1R,2S)-naphthyl analog (8h) showed the highest potency in the two series and is a triple reuptake inhibitor of the SERT, NET, and DAT.
Roggen, Heidi,Kehler, Jan,Stensbol, Tine Bryan,Hansen, Tore
p. 2834 - 2837
(2008/02/05)

METHOD FOR PRODUCING 2-OXO-1-PHENYL-3-OXABICYCLO[3.1.0]HEXANE
The present invention provides a process for producing 2-oxo-1-phenyl-3-oxabicyclo[3.1.0]hexane which comprises reacting phenylacetonitrile with epichlorohydrin in the presence of sodium hydride. According to the present invention, 2-oxo-1-phenyl-3-oxabicyclo[3.1.0]hexane can be produced safely, easily and industrially advantageously.
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(2008/06/13)

METHOD FOR PRODUCING (Z)-1-PHENYL-1-DIETHYLAMINOCARBONYL-2-AMINOMETHYL CYCLOPROPANE HYDROCHLORIDE
The present invention provides a process for producing (Z)-1-phenyl-1-diethylaminocarbonyl-2-aminomethylcyclopropane or hydrochloride thereof, which comprises a step of reacting (Z)-1-phenyl-1-diethylaminocarbonyl-2-phthalimidomethylcyclopropane by contacting said compound with an aqueous methylamine solution having a concentration of from 1 to 25% by weight to obtain (Z)-1-phenyl-1-diethylaminocarbonyl-2-aminomethylcyclopropane.
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Page/Page column 4

(2008/06/13)

Stereocontrolled synthesis of trisubstituted cyclopropanes: Expedient, atom-economical, asymmetric syntheses of (+)-bicifadine and DOV21947
An expedient, atom-economical, asymmetric synthesis of 1-aryl-3- azabicyclo[3.1.0]hexanes, including (+)-Bicifadine and DOV21947, in a single-stage through process without isolation of any intermediates has been developed. The key of this synthesis is the in-depth mechanistic understanding of the complicated epoxy nitrile coupling at each reaction stage. Therefore, the desired trisubstituted cyclopropane can be prepared in high ee and yield by controlling the reaction pathway through manipulating the nitrile anion aggregation state.
Xu, Feng,Murry, Jerry A.,Simmons, Bryon,Corley, Edward,Fitch, Kenneth,Karady, Sandor,Tschaen, David
p. 3885 - 3888
(2007/10/03)

METHOD FOR PRODUCING 2-OXO-1-PHENYL-3-OXABICYCLO[3.1.0]HEXANE
Disclosed is a method for producing 2-oxo-1-phenyl-3-oxabicyclo[3.1.0]hexane comprising a step for reacting phenyl acetonitrile with epichlorohydrin in the presence of sodium hydride. With this method, 2-oxo-1-phenyl-3-oxabicyclo[3.1.0]hexane can be produced safely, simply and commercially advantageously.
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Page/Page column 6-7

(2008/06/13)

CYCLOPROPYL DERIVATIVES AS NK3 RECEPTOR ANTAGONISTS
The present invention relates to cyclopropyl derivatives of formula (I) and salt thereof. These compounds are NK3 receptor antagonists and may therefore be useful for treatment of diseases where the NK3 receptor is implicated, e.g. psychotic disorders.
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Page/Page column 57

(2010/02/10)

A New Enantioselective Synthesis of Milnacipran and an Analogue by Catalytic Asymmetric Cyclopropanation
Milnacipran and analogues are conveniently prepared by a short sequence of steps from phenylacetic acid, the key step being highly enantio-selective catalytic asymmetric cyclopropanation.
Doyle, Michael P.,Hu, Wenhao
p. 299 - 302
(2007/10/03)

Synthesis and pharmacological evaluation of potent and enantioselective σ1 and σ2 ligands
In a previous study we found that substitutions of the (+)-cis-N-normetazocine nucleus of (+)-MPCB with 1-adamantanamine provide the compound (±)-10 with high affinity and selectivity for σ receptors. Starting with this result we have synthesized a new series of eight 1-phenyl-2-cyclopropylmethylamines structurally related to (±)-10, and binding affinities, with respect to σ1, σ2, opioid and dopaminergic D2 receptors, have been reported. All compounds showed a negligible opioid and dopaminergic affinity and high selectivity for σ receptors. Modifications on the amino moiety and methylcarboxyester group of 10 provide compounds with different σ1 and σ2 binding affinity and selectivity. Moreover, we have also synthesized the respective enantiomers of componds (±)-10 and (±)-18 in order to evaluate the enantioselectivity for σ1 and σ2 receptors. The binding data showed that carboxymethylester on the cyclopropane ring was more critical for enantioselectivity than the hydroxymethylenic group. In fact, the (-)-10 enantiomer showed a preference for σ1 whereas (+)-10 showed a preference for σ2.
Marrazzo, Agostino,Prezzavento, Orazio,Pasquinucci, Lorella,Vittorio, Franco,Ronsisvalle, Giuseppe
p. 181 - 189
(2007/10/03)

Substituted 1-phenyl-2-cyclopropylmethylamines with high affinity and selectivity for sigma sites
A series of 1-phenyl-2-cyclopropylmethylamines structurally related to (+)- and (-)-MPCB were synthesized and their binding affinities for σ1, σ2, opioid and dopamine (D2) receptors were evaluated. Substitution of the cis-N-normetazocine with different aminic moieties provided compounds with high affinity and selectivity for σ binding sites with respect to opioid and dopamine (D2) receptors. The observed increase in σ2 affinity as compared to the parent (+)-MPCB, supports the idea that the particular stereochemistry of (+)-cis-N-normetazocine affects σ1 selectivity but does not affect σ1 affinity. The (±)-cis isomers of methyl 2-[(1-adamantylamino)methyl]-1-phenylcyclopropane-1-carboxylate (18) displayed a higher affinity and selectivity for the σ1 and σ2 receptor subtypes compared to the (±)-trans 19. Interestingly, the enantiomer (-)-cis 18 displayed a preference for σ1 receptor subtype whereas the (+)-cis 18 did for σ2. These results prompt us to synthesize compounds with modification of nitrogen and carboxyl groups. The compounds obtained showed high affinities and selectivity for σ sites. Moreover, modifications of carboxyl groups provided compounds with the highest affinities in the series. In particular, compound 25 with reverse-type ester showed a K(i) of 0.6 and 4.05nM for σ1 and σ2 binding sites, respectively. Copyright (C) 2000 Elsevier Science Ltd.
Ronsisvalle, Giuseppe,Marrazzo, Agostino,Prezzavento, Orazio,Pasquinucci, Lorella,Falcucci, Barbara,Di Toro, Rosanna,Spampinato, Santi
p. 1503 - 1513
(2007/10/03)

Dirhodium(II) tetrakis[methyl 2-oxaazetidine-4-carboxylate]: A chiral dirhodium(II) carboxamidate of exceptional reactivity and selectivity
A new chiral azetidinone-carboxylate ligand for dirhodium(II) catalysts enhances reactivity toward diazo decomposition and selectivity toward cyclopropanation enabling diazomalonates, vinyldiazoacetates, and aryldiazoacetates to be effectively used with a dirhodium(II) carboxamidate catalyst.
Doyle, Michael P.,Davies, Simon B.,Hu, Wenhao
p. 1145 - 1147
(2007/10/03)

Synthesis of (+)-(1'R,2'S) and (1'S,2'R)-6,11-Dimethyl-1,2,3,4,5,6- hexahydro-3-[[2'-(alkoxycarbonyl)-2'-phenylcyclopropyl]methyl]-2,6-methano- 3-benzazocin-8-ol. Comparison of the affinities for σ1 and opioid receptors with in the diastereoisomeric MPCB and CCB
The synthesis and the in vitro receptor affinity for σ and opiod receptors of the two diastereoisomers, of (+)-cis-MPCB namely, (+)-cis- (1'S,2'R)-6,11-Dimethyl-1,2,3,4,5,6-hexahydro-3-[[2'-(methoxycarbonyl)-2'- phenylcyclopropyl]methyl]-2,6-methano-3-benzazocin-8-ol, (1'S,2'R)6a and (+)- cis,(1'R,2'S)-6,11-Dimethyl-1,2,3,5,6-hexahydro-3-[[2'-(methoxycabonyl)-2'- phenylcyclopropyl]methyl]-2,6-methano-3-benzazocin-8-ol, (1'R,2'S)6a are reported. Affinities of (1'S,2'R)6a and (1'R,2'S)6a were compared with those of the (-)-cis-diastereoisomers of MPCB(1), and of its p-Cl phenyl derivative CCB(2). The (+)-cis-N-normetazocine derivatives showed higher affinity for the σ1 sites, labeled with [3H]-(+)-pentazocine than the corresponding (- )-cis- analogs. In particular, compound (1'S,2'R)6a showed a Ki = 66.7 nM for σ1 receptor, associated with a good selectivity for σ1 with respect to κ, μ, δ opioid receptors subtypes (Ki = > 1,000 nM). Analysis of the data seem to support the hypothesis that the (+)-cis-N-normetazocine nucleus posses a specific enantioselectivity for σ1 sites, when supporting bulkier N-substituents functionalized with a carboxy ester group.
Ronsisvalle,Prezzavento,Pasquinucci,Pappalardo,Marrazzo,Vittorio,Carboni,Spampinato
p. 471 - 476
(2007/10/03)

Synthesis of (+)- and (-)-milnaciprans and their conformationally restricted analogs
Reaction of (R)-epichlorohydrin [(R)-5] and phenylacetonitrile (6) in the presence of NaNH2 in benzene gave a cyclopropane derivative which was isolated as lactone 4 [(1S,2R)-2-oxo-1-phenyl-3-oxabicyclo[3,1,0]hexane] of 96% e.e. in 67% yield, after alkaline hydrolysis of the cyano group. Compound 4 was readily converted to (+)-milnacipran [(+)-1], by which the absolute stereochemistry of (+)-1 was confirmed. (1S,2R)-1-phenyl-2-[(S)-1-aminoethyl]-cyclopropane-N,N-diethylcarboxam ides (2), a conformationally restricted analog of 1, was also synthesized in high enantiomeric purity from 4. Starting from (S)-epichlorohydrin [(S)-5], their corresponding enantiomers, namely (-)-milnacipran [(-)-1] and ent-2, were also synthesized.
Shuto, Satoshi,Ono, Shizuka,Hase, Yukako,Kamiyama, Noriko,Matsuda, Akira
p. 641 - 644
(2007/10/02)

Conformational restriction by repulsion between adjacent substituents on a cyclopropane ring: Design and enantioselective synthesis of 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides as potent NMDA receptor antagonists
Adjacent substituents on a cyclopropane ring mutually exert steric repulsion quite significantly, because they are fixed in eclipsed conformation to each other. Based on this structural feature of the cyclopropane ring, conformationally restricted analogs of milnacipran (1), namely 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides (2, 3, ent-2, and ent-3) were designed as potent NMDA receptor antagonists and were synthesized highly enantioselectively. Reaction of (R)-epichlorohydrin [(R)-5] and phenylacetonitrile (6) in the presence of NaNH2 in benzene gave a chiral cyclopropane derivative that was isolated as lactone 4 with 96% ee in 67% yield, after alkaline hydrolysis of the cyano group. The nucleophilic addition reaction of Grignard reagents to aldehyde 10, which was readily prepared from 4, proceeded highly selectively from the si-face to afford addition products 11 in high yields. Although hydride reduction of the corresponding ketone 15b, prepared from 11b, with L-Selectride also proceeded highly diastereoselectively, the facial selectivity was reversed to give the re-face addition product lib. On the other hand, reduction of 15 with DIBAL-H afforded the si-face addition product 12 in high yields. These results suggested that these nucleophilic addition reactions proceeded via either the bisected s-trans or s-cis conformation of the cyclopropylcarbonyl derivatives. From 11 and 12, the target conformationally resticted analogs, 2 and 3, were synthesized, respectively. Starting from (S)-epichlorohydrin [(S)-5], their corresponding enantiomers, ent-2 and ent-3, were also synthesized. The structures of the conformationally restricted analogs detected by the X-ray crystallographic analysis suggested that their conformations can be restricted as we hypothesized. Thus, a new method for restricting the conformation of cyclopropane derivatives has been developed.
Shuto, Satoshi,Ono, Shizuka,Hase, Yukako,Kamiyama, Noriko,Takada, Hironao,Yamasihita, Kanako,Matsuda, Akira
p. 915 - 923
(2007/10/03)

Furan-2(3H)- and -2(5H)-ones. Part 6. Di-?-methane rearrangement of the α-substituted 4-benzylfuran-2(5H)-one system
The effect of the 'central methane' substitution on the di-?-methane rearrangement in 4-benzyl-2,5-dihydrofuran-2-ones 8a-d was investigated.Significant enhancement of efficiency in the rearrangement leading in high combined yields to two isomeric products, endo-12 and exo-12, is discussed in terms of both the substituent effects at the benzylic carbon and the restrained features of the ring-enrolled ?-system.The origin of the difference in chemoselectivity compared with that of the 3-benzyl counterpart 5 where a photoarylated product 6 resulted upon photoirradiation was also investigated, and was rationalized by postulating a higher reactivity at the β-position of the enone system.
Muraoka, Osamu,Tanabe, Genzoh,Higachiura, Mie,Minematsu, Toshie,Momose, Takefumi
p. 1437 - 1444
(2007/10/02)