Synthesis of (1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexane, a Novel Achiral Diamine

Brighty, Katherine E.; Castaldi, Michael J.

doi:10.1055/s-1996-5684

Cited by 47 publications

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“…Asymmetric Synthesis of 2-Nitrocyclopropanecarboxylic Acids 2-Nitrocyclopropanecarboxylic acid derivatives are recognized as versatile precursors for biologically active compounds [126][127][128][129] as well as useful building blocks for the synthesis of highly functionalized molecular targets. [130][131][132][133] Therefore catalytic and enantioselective construction of these motifs is a valuable challenge for synthetic chemists.…”

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confidence: 99%

Development of Chiral Thiourea Catalysts and Its Application to Asymmetric Catalytic Reactions

2010

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We have developed several multifunctional thiourea catalysts bearing a tertiary amine or an 1,2-amino alcohol in expectation of their synchronous activation of a nucleophile and an electrophile through both acid-base and hydrogen-bonding interactions. From these studies, it was revealed that the weak acidity of thioureas compared with metallic Lewis acids could be overcome by this modification. The bifunctional aminothiourea could be used efficiently for a wide range of diastereoselective and enantioselective nucleophilic reactions such as Michael addition of 1,3-dicarbonyl compounds to nitroolefines, aza-Henry reaction of nitroalkanes to N-Boc imines, and hydrazination of cyclic b b-keto esters. We also discovered that multifunctional thiourea catalyst, bearing an 1,2-amino alcohol moiety, significantly accelerated the Petasis-type reaction of alkenylboronic acids to Nphenoxycarbonyl quinolinium salts, prepared from quinolines and phenyl chloroformate, to afford 1,2-addition products with high enantioselectivity (up to 97% ee). Furthermore, to expand the synthetic applicability of the thiourea-catalyzed asymmetric reactions, tandem organocatalyzed reactions were explored to establish the concise one-pot synthesis of chiral densely functionalized three-, five-, and six-membered compounds.

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confidence: 99%

Development of Chiral Thiourea Catalysts and Its Application to Asymmetric Catalytic Reactions

2010

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“…For example, ethyl diazoacetate reacts with 1-benzyloxycarbonyl-2,5-dihydropyrrole in the presence of rhodium acetate to form both the 6α-ethoxycarbonyl and 6β-ethoxycarbonyl substituted 3-azabicyclo[3.1.0]hexane derivatives. 5 In this case the 6β-or endo isomer is a significant minor product, and the observed endo : exo ratio is 1 : 2. Recently, other workers have described a synthesis of 6β-isomers of the 3-azabicyclo[3.1.0]hexanes starting from amino-chloroenamines, such as 1-benzyl-3-chloro-4-(dibenzylamino)-1,2,3,6-tetrahydropyridine.…”

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Synthesis of trovafloxacin using various (1α,5α,6α)-3-azabicyclo[3.1.0]hexane derivatives

Norris

Braish

Butters

et al. 2000

J. Chem. Soc., Perkin Trans. 1

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Trovafloxacin, a novel broad spectrum antibacterial, contains the unusual (1α,5α,6α)-3-azabicyclo[3.1.0]hexane ring system. The prototype of the industrial synthesis of this ring system and possible mechanistic pathways to exclusive formation of the exo or 6α-nitro derivative 4 are described, which leads to the key 6α-nitro-3-azabicyclo[3.1.0]hexane intermediate 10. The synthesis of 6α-amino-3-azabicyclo[3.1.0]hexane 16 and useful protected exo 6-amino derivatives 15 and 17 follows from 10. These can be coupled with the 7-chloronaphthyridone 18 to yield protected trovafloxacin compounds 20-22 in good yield. The ethyl ester of trovafloxacin 21 can also be accessed from the product of coupling 19, derived from 18 and the exo 6-nitro-3-azabicyclo[3.1.0]hexane compound 12. Removal of protecting groups from 20-22 with methanesulfonic acid yields trovafloxacin mesylate from which trovafloxacin zwitterion 1 can be liberated with base treatment. Zwitterion 1 can also be prepared directly from 16 tosylate salt and naphthyridone-2-carboxylic acid 26.Trovafloxacin 1 is a new and powerful antibiotic that is active against a wide variety of microorganisms. 1 It contains the interesting 3-azabicyclo[3.1.0]hexane ring system. 2 This paper describes the synthesis and chemistry of a number of new (1α,5α,6α)-3-azabicyclo[3.1.0]hexanes and new naphthyridone coupled intermediates that can be used to make trovafloxacin. Possible mechanisms to interesting intermediates and the formation of some side products are also discussed.The reaction of N-benzylmaleimide 2 and bromonitromethane 3 in the presence of base 3 is used to assemble the bicyclic ring system of 4. Many bases can be used, but yields are often below 15%. Amidine bases are useful, particularly 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine 4 (DMTHP). This base improves the yield to the 30-35% range when the reaction is carried out at about Ϫ10 ЊC. The reaction can be carried out in many solvents but toluene is preferred because removal of the many tar like side products formed during the reaction is somewhat easier. It appears that the reaction produces almost exclusively the exo or 6α-nitro product 4. The endo or 6β-nitro product 5 is detected at very low level, in the range 0.5-1.5% relative to exo 4, in the presence of a base. The endo compound 5 can be formed by epimerization of 4 in the presence of potassium carbonate in acetonitrile. The equilibrium favours the exo form to a very significant extent and the endo-exo equilibrium is approximately 2 : 98 when measured by HPLC. The endo compound 5 has been isolated from the mother liquors of an equilibrium mixture by fractional crystallization and fully characterized by X-ray crystallography (see Fig. 1b). Steric hindrance is not a complete barrier to the synthesis of 6-substituted endo 3-azabicyclo[3.1.0]hexane products. For example, ethyl diazoacetate reacts with 1-benzyloxycarbonyl-2,5-dihydropyrrole in the presence of rhodium acetate to form both the 6α-ethoxycarbonyl and 6β-ethoxycarbonyl substituted 3-azabicyclo[3.1.0]hex...

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“…9). Cyclopropanation of a pyrroline compound 81 or 82 by a C 1 -unit (bromonitromethane, base and 81 [85,86], ethyl diazoacetate and 81 [87] or 82/ rhodium acetate [87,88], dibenzylformamide, titanium inside-attack outside-attack tetraisopropoxide, isopropylmagnesium bromide and 82 [89]) or aza-annulation of derivatives of type 83 [90,91] served as access to the azabicyclohexane skeleton.…”

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confidence: 99%

“…[87,88] 6α/ 6β ratio ≈ 1:2). Subsequent reduction of the nitro group or application of a Curtius rearrangement were used for generation of the amino function.…”

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confidence: 99%

Complementary Ways to Diastereomers of Bridged Aminopiperidine Derivatives - A Stereochemical Challenge

Vilsmaier¹

2000

J. prakt. Chem.

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Abstract. Routes to diastereomers of constrained 4-aminopiperidines -a common pharmaceutically used diaminic building block -are realized mainly on the basis of CN-double bond species or their radicalic or anionic analogues. Kinetically controlled reactions on the one hand and thermodynamic control of reactions, reversible introduction of a repulsive group, direction of a reactant by intramolecular complexation, or involvement of radicalic or anionic intermediates with strong isomerization tendency on the other hand are the tools for a complementary accessibility of both diastereomers.

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Synthesis of (1α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexane, a Novel Achiral Diamine

Cited by 47 publications

References 0 publications

Development of Chiral Thiourea Catalysts and Its Application to Asymmetric Catalytic Reactions

Development of Chiral Thiourea Catalysts and Its Application to Asymmetric Catalytic Reactions

Synthesis of trovafloxacin using various (1α,5α,6α)-3-azabicyclo[3.1.0]hexane derivatives

Complementary Ways to Diastereomers of Bridged Aminopiperidine Derivatives - A Stereochemical Challenge

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