188885-85-0Relevant articles and documents
Asymmetric synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740)
Dominguez, Carmen,Ezquerra, Jesus,Prieto, Lourdes,Espada, Modesta,Pedregal, Carmen
, p. 511 - 514 (1997)
The assymetric synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) 1, a potent and selective group 2 mGluR agonist, has been accomplished starting from the readily available enantiomerically pure cyclopentenone 4. Thus, cyclopropanation with ethyl(dimethylsulfuranylidene)acetate generated in situ with DBU, followed by deketalization gave rise to the dihydroxy bicyclic ketone 9. After protecting the ketone as 1,3-dioxolane and its transformation to the orthoformate 11, this was pyrolytically deoxygenated in a sealed tube to the bicyclic enone 13. The synthesis was completed after hydrogenation, stereoselective Bucherer-Bergs reaction and hydantoin hydrolysis, yielding LY354740 (+)-1 with an e.e. ≤98%. reserved.
PRODRUG OF AMINO ACID DERIVATIVE
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Paragraph 0181, (2017/11/14)
Provided is an amino acid derivative prodrug represented by general formula (I-A) that is a prodrug form of an amino acid derivative which is a group 2 metabotropic glutamate receptor antagonist, or a pharmaceutically acceptable salt thereof. More specifically, provided is an amino acid derivative prodrug represented by general formula (I-A) that is a preventive or therapeutic drug for mood disorders (including depression and bipolar disorder), anxiety disorder, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, movement disorders associated with muscular rigidity, sleep disorders, Huntington's chorea, eating disorders, drug dependence, epilepsy, brain infarction, cerebral ischemia, cerebral insufficiency, cerebral edema, spinal cord disorders, head trauma, inflammation and immune- related diseases, and so on.
Constrained cycloalkyl analogues of glutamic acid: Stereocontrolled synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) and its 6-phosphonic acid analogue
Krysiak, Jerzy,Midura, Wanda H.,Wieczorek, Wanda,Sieron, Leslaw,Mikolajczyk, Marian
experimental part, p. 1486 - 1493 (2010/11/04)
A new stereocontrolled synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2.6- dicarboxylic acid (LY354740) 1, a potent and selective 2mGluR agonist, has been accomplished in four steps with an overall yield of 27% starting from the enantiopure (+)-(R)-2-(p-tolylsulfinyl)cyclopent-2-enone 3. The key steps include asymmetric cyclopropanation of 3 with (dimethylsulfuranylidene)acetate (EDSA) and removal of the chiral p-tolylsulfinyl auxiliary from the cycloadduct ent-4c upon treatment with iso-propylmagnesium chloride. The stereoselective hydantoin formation from the bicyclic ketone 6 formed (Bucherer-Bergs reaction) and subsequent hydrolysis completed the synthesis of 1. The same reaction sequence has been applied in the first synthesis of enantiopure (+)-2-amino-6-phosphonobicyclo[3.0.1]hexane-2-carboxylic acid 2, a structural 6-phosphono analogue of 1. The starting bicyclic ketophosphonates 9-11 have been obtained by asymmetric cyclopropanation of (-)-(S)-3 with phosphoryl sulfonium ylides, producing only two endo-isomers. The major endo-isomer (+)-11a containing the 6-diisopropoxyphosphoryl group has been converted in three steps into (+)-endo-2 in 46% overall yield.
Synthesis of the potent anticancer agents ottelione A and ottelione B in both racemic and natural optically pure forms
Clive, Derrick L. J.,Liu, Dazhan
, p. 3078 - 3087 (2008/09/19)
(Chemical Equation Presented) The powerful antitumor agents ottelione A and B were synthesized in racemic form by a method that relies on selective ring closing metathesis. Optically pure natural (+)-ottelione A was then made from D-ribose, via an α-keto cyclopropane. A key feature of the route is that the cyclopropyl group controls the stereochemistry in the attachment of the ArCH2 unit and is then converted by the action of SmI2 into a vinyl group, so that the substituents on the resulting five-membered ring have the required trans relationship. Epimerization of an intermediate gave access by the same method to the trans ring fused isomer (-)-ottelione B.
Synthesis of the otteliones A and B: Use of a cyclopropyl group as both a steric shield and a vinyl equivalent
Clive, Derrick L. J.,Liu, Dazhan
, p. 3738 - 3740 (2008/02/14)
(Chemical Equation Presented) To A and B: The extremely powerful antitumor agents ottelione A and B have been synthesized from D-ribose. Key steps in the synthesis involve the use of a cyclopropane unit fused onto a five-membered ring to control the stere
Asymmetric sulfonium ylide mediated cyclopropanation: Stereocontrolled synthesis of (+)-LY354740
Aggarwal, Varinder K.,Grange, Emma
, p. 568 - 575 (2008/09/21)
The reaction of ester-stabilized sulfonium ylides with cyclopentenone to give (+)-5 ((1S,5R,6S)-ethyl 2-oxobicyclo[3.1.0]hexane-6-carboxylate), an important precursor to the pharmacologically important compound (+)-LY354740, has been studied using chiral sulfides operating in both catalytic (sulfide, Cu(acac)2, ethyl diazoacetate. 60°C) and stoichiometric modes (sulfonium salt, base, room temperature). It was found that the reaction conditions employed had a major influence over both diastereo- and enantio-selectivity. Under catalytic conditions, good enantioselectivity with low diastereoselectivity was observed, but under stoichiometric conditions low enantioselectivity with high diastereoselectivity was observed. When the stoichiometric reactions were conducted at high dilution, diastereoselectivity was reduced. This indicated that base-mediated betaine equilibration was occurring (which is slow relative to ring closure at high dilution). Based on this model, conditions for achieving high enantioselectivity were established as follows: use of a preformed ylide, absence of base, hindered ester (to reduce ylide-mediated betaine equilibration), and low concentration. Under these conditions high enantioselectivity (95% ee) was achieved, albeit with low diastereocontrol. Our model for selectivity has been applied to other sulfonium ylide mediated cyclopropanation reactions and successfully accounts for the diastereoselectivity observed in all such reported reactions to date.
PRODRUGS OF EXCITATORY AMINO ACIDS
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Page 98-99, (2008/06/13)
This invention relates to synthetic excitatory amino acid prodrugs and processes for their preparation. The invention further relates to methods of using, and pharmaceutical compositions comprising, the compounds for the treatment of neurological disorder
Method of resolving 2-oxobicyclo [3.1.0] hexane-6-carboxylic acid derivatives
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Page column 30, (2008/06/13)
There is disclosed a method of resolving 2-oxobicyclo[3.1.0]hexane-6-carboxylates having the following relative configuration of formula (1): wherein X1, X2, R1, R2and R3have the same meanings as defined below, into one enantiomer ester thereof and the other enantiomer acid, which is characterized by contacting an enzyme having an ability to preferentially hydrolyze one enantiomer ester contained in 2-oxobicyclo[3.1.0]hexane-6-carboxylate of formula (1) as defined above, with 2-oxobicyclo[3.1.0]hexane-6-carboxylates of formula (1) as defined above to obtain one enantiomer as an acid and the other enantiomer as an ester.
Excitatory amino acid receptor modulators
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, (2008/06/13)
The present invention relates to compounds of the formula ???in which R1 is defined in the specification, and non-toxic metabolically labile esters and amides thereof are useful as modulators of metabotropic glutamate receptor function.
EXCITATORY AMINOACID RECEPTOR MODULATORS
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, (2008/06/13)
Compounds of the formula STR1 in which R 1 and R 2 are as defined in the specification, and non-toxic metabolically labile ester and amides thereof are useful as modulators of metabotropic glutamate receptor function.
