176027-90-0

Basic information

• Product Name: Bicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 2-amino-, (1R,2R,5S,6R)-rel- (9CI)
• Synonyms: Bicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 2-amino-, (1R,2R,5S,6R)-rel- (9CI);VTAARTQTOOYTES-RGDLXGNYSA-N
• CAS NO: 176027-90-0
• Molecular Formula: C8H11NO4
• Molecular Weight: 185.17724
• Product Categories: CYCLOPENTANE
• Mol File: 176027-90-0.mol

Chemical Properties

• Appearance: /
• CAS DataBase Reference: Bicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 2-amino-, (1R,2R,5S,6R)-rel- (9CI)(CAS DataBase Reference)
• NIST Chemistry Reference: Bicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 2-amino-, (1R,2R,5S,6R)-rel- (9CI)(176027-90-0)
• EPA Substance Registry System: Bicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 2-amino-, (1R,2R,5S,6R)-rel- (9CI)(176027-90-0)

Safety Data

• Hazardous Substances Data: 176027-90-0(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Bicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 2-amino-, (1R,2R,5S,6R)-rel(9CI) is used as a key intermediate in the synthesis of various pharmaceutical compounds. Its unique structure and functional groups make it a valuable building block for the development of new drugs with specific therapeutic properties.
Used in Neuropharmacology:
In the field of neuropharmacology, Bicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 2-amino-, (1R,2R,5S,6R)-rel(9CI) is used as a precursor for the development of analogs of glutamate, such as LY 354740. These analogs act as potent and selective group II (mGlu2/3) receptor agonists, which may be useful for treating anxiety-related disorders by modulating the activity of mGlu receptors in the brain.
Used in Drug Delivery Systems:
Similar to gallotannin, Bicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 2-amino-, (1R,2R,5S,6R)-rel(9CI) can be employed in the development of novel drug delivery systems. Its unique structure and functional groups can be utilized to enhance the delivery, bioavailability, and therapeutic outcomes of various pharmaceutical compounds, particularly those targeting the central nervous system.

Upstream product

• 188885-79-2 C₁₁H₁₄O₄ 
• 188885-85-0 (1S,5R,6S)-2-oxo-bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester 
• 188885-82-7 ethyl (1SR,5RS,6SR)-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylate 
• 219762-23-9 C₁₈H₂₅NO₇ 
• 219762-17-1 C₁₆H₂₁Cl₃O₅ 
• 219762-19-3 C₁₆H₂₁N₃O₆ 
• 219762-21-7 C₁₆H₂₃NO₆ 
• 219762-26-2 (1R,1aR,1bR,4aS,5R,5aS)-5-Acetylamino-3-ethoxy-hexahydro-2,4-dioxa-cyclopropa[a]pentalene-1,5-dicarboxylic acid dimethyl ester 
• 219762-25-1 (1S,2R,3S,4R,5R,6R)-2-Acetylamino-3,4-dihydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid dimethyl ester 
• 219762-27-3 (1S,2S,5R,6S)-2-Acetylamino-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid dimethyl ester 
• 188885-69-0 C₁₅H₂₀O₅ 
• 597540-60-8 (2aR,2bR,4aS,4bS)-1-(4-Methoxy-benzyl)-2-oxo-hexahydro-1-aza-cyclopropa[cd]pentalene-4a-carboxylic acid methyl ester 
• 488859-10-5 (1S,2S,5R,6S)-2-tert-butoxycarbonylaminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-methyl ester 
• 597540-63-1 (1S,2S,5R,6R)-2-tert-Butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid dimethyl ester 

Relevant articles and documents

Enantiospecific synthesis of (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane- 2,6-dicarboxylic acid by a modified Corey-Link reaction

(1S,2S,5R,6S)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) was synthesised enantiospecifically from a sugar derived enantiomerically pure cyclopentenone. The α-amino acid stereogenic centre was formed by reacting the ketone with chloroform anion and then the alcohol so formed was reacted with sodium azide/DBU in methanol to give an azido ester. Critically, this modified Corey-Link reaction gives the opposite stereochemical outcome to the traditional Bucherer-Bergs and Strecker reactions. The azide was reduced and acylated, the 1,2 diol deoxygenated and the protecting groups removed to give LY354740 with an e.e.>98%.

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

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.

Stereocontrolled synthesis of a potent agonist of group II metabotropic glutamate receptors, (+)-LY354740, and its related derivatives

Efficient synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740: 1) and its structurally related analogs (-)-2 and (-)-3 has been accomplished starting with (1S,2R)-1-amino-2-hydroxycyclopentane- or cyclohexanecarboxylic acid (4 or 17 ) via an intramolecular cyclopropanation of α-diazo acetamide.

Preparation of bicyclohexane derivative

A process for the preparation of (+)-2-amino-bicyclo[3.1.0]-hexane-2-6-dicarboxylic acid, or a pharmaceutically acceptable salt thereof, which comprises hydrolysing (-)-2-spiro-5''-hydantoinbicyclo[3.1.0]hexane-6-carboxylic acid or a salt thereof, and optionally forming a pharmaceutically acceptable salt. Also disclosed are intermediates useful in the process.

Asymmetric synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740)

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.

Preparation of bicyclohexane derivative

A process for the preparation of (+)-2-amino-bicyclo[3.1.0]-hexane-2-6-dicarboxylic acid, or a pharmaceutically acceptable salt thereof, which comprises hydrolysing (-)-2-spiro-5'-hydantoinbicyclo[3.1.0]hexane-6-carboxylic acid or a salt thereof, and optionally forming a pharmaceutically acceptable salt. Also disclosed are novel intermediates useful in the process.

Design, synthesis, and pharmacological characterization of (+)-2- aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): A potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties

2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (9) was designed as a conformationally constrained analog of glutamic acid. For 9, the key torsion angles (τ1 and τ2) which determine the relative positions of the α- amino acid and distal carboxyl functionalities are constrained where τ1 = 166.9°or 202°and τ2 = 156°, respectively. We hypothesized that 9 would closely approximate the proposed bioactive conformation of glutamate when acting at group 2 metabotropic glutamate receptors (mGluRs). The racemic target molecule (±)-9, its C2-diastereomer (±)-16, and its enantiomers (+)- 9 (LY354740) and (-)-9 (LY366563) were prepared by an efficient, stereocontrolled, and high-yielding synthesis from 2-cyclopentenone. Our hypothesis that 9 could interact with high affinity and specificity at group 2 mGluRs has been supported by the observation that (±)-9 (EC50 = 0.086 ± 0.025 μM) and its enantiomer (+)-9 (EC50 = 0.055 ± 0.017μM) are highly potent agonists for group 2 mGluRs in the rat cerebral cortical slice preparation (suppression of forskolin-stimulated cAMP formation) possessing no activity at other glutamate receptor sites (iGluR or group 1 mGluR) at concentrations up to 100 μM. Importantly, the mGluR agonist effects of (+)- 9 are evident following oral administration in mice in both the elevated plus maze model of anxiety (ED50 = 0.5 mg/kg) and in the ACPD-induced limbic seizure model (ED50 = 45.6 mg/kg). Thus, (+)-9 is the first orally active group 2 mGluR agonist described thus far and is an important tool for studying the effects of compounds of this class in humans.