Development of the biocatalytic resolution of 2-azabicyclo[2.2.1]hept-5-en-3-one as an entry to single-enantiomer carbocyclic nucleosides

Taylor, Stephen J.; McCague, Raymond; Wisdom, Richard; Lee, Carol; Dickson, K.; Ruecroft, Graham; O'Brien, Fergal; Littlechild, Jennifer A.; Bevan, J. W.; Roberts, Stanley M.; Evans, Claire

doi:10.1016/s0957-4166(00)80218-9

Cited by 99 publications

(56 citation statements)

References 10 publications

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“…The (+) and (-) enantiomers of 2-azabicyclo[2.2.1]hept-5-en-3-one and the (-) and (+) enantiomers of cis-4-aminocyclopent-2-ene-1-carboxylic acid were obtained through opening of the lactam ring. Taylor et al [13] reported that the use of the more selective and stable ENZA-25 and ENZA-22 strains with lactamase activity was more suitable for the resolution of 2-azabicyclo[2.2.1]-hept-5-en-3-one.…”

Section: Introductionmentioning

confidence: 98%

Enzymatic Method for the Synthesis of Blockbuster Drug Intermediates – Synthesis of Five‐Membered Cyclic γ‐Amino Acid and γ‐Lactam Enantiomers

Forró

Fülöp

2008

Eur J Org Chem

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Section: Introductionmentioning

confidence: 98%

Enzymatic Method for the Synthesis of Blockbuster Drug Intermediates – Synthesis of Five‐Membered Cyclic γ‐Amino Acid and γ‐Lactam Enantiomers

Forró

Fülöp

2008

Eur J Org Chem

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“…The pure (À)-lactam produced by the scheme above has been used as a building block for important drugs such as Carbovir, an anti-HIV agent (Taylor et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Crystallization and preliminary X-ray analysis of a γ-lactamase

Gonsalvez

Isupov

Littlechild

2001

Acta Crystallogr D Biol Cryst

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An enzyme from Comomonas acidovorans has been isolated that is speci®c for the stereospeci®c hydrolysis of (+)-lactam. This so-called (+)-lactamase has important applications in biotransformation reactions. The enzyme has been crystallized by vapour-phase diffusion using polyethylene glycol 4000 as a precipitant. Addition of a detergent, -octylglucoside, was found to be essential for obtaining diffraction-quality crystals. The crystals grow in the space group P1, with unit-cell parameters a = 63.0, b = 93.2, c = 152.4 A Ê , = 104.3, = 92.6, = 108.5 , and diffract to 2 A Ê resolution using synchrotron radiation. Native data from these crystals have been collected to 2.4 A Ê .

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“…This chiral building block was used because of its versatility in the synthesis of other carbocyclic nucleosides [20]. Synthesis of the key intermediate, (5) from 4 involved the following transformations: hydroxylation of 4 through treatment with osmium tetroxide in the presence of N-methylmorpholine-N-oxide (NMO), which resulted in hydroxylation from the α-face, as previously reported [16,[21][22][23]; protection of the diol and the lactam NH groups; reductive cleavage of the lactam and protection of the resulting alcohol; and selective aqueous hydrolysis of the NH protecting group [16]. It is relevant to note that the use of tert-butyldimethylsilyl ether (TBDMS) for protection of the 5'-hydroxyl group proved less successful, as the eventual deprotection step became problematic because of the poor water solubility of the TBDMS-protected compound.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of a Novel Carbocyclic Analog of Bredinin

Nair

Zhang

2013

Molecules

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Abstract:The natural nucleoside antibiotic, bredinin, exhibits antiviral and other biological activities. While various nucleosides related to bredinin have been synthesized, its carbocyclic analog has remained unknown. Synthesis of this heretofore unknown analog of bredinin is described. The key precursor, (3aS,4R,6R,6aR)-6-((methoxymethoxy)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine (5), was prepared from the commercially available compound, (1R,4S)-2-azabicyclo[2.2.1] hept-5-en-3-one (4). Our initial approach used intermediate 6, derived in three transformations from 5, for the key photolytic step to produce the desired ring-opened precursor to the target compound. This photochemical transformation was unsuccessful. However, an appropriately protected and related precursor was synthesized from 5 through the following side-chain functional group transformations: elaboration of the amino group through malonyl ester formation, oximation at the central carbon, conversion of ester to amide and catalytic reduction of the oxime group. This precursor, on treatment with triethylorthoformate and catalytic acetic acid in ethanol, underwent cyclization to produce the desired 4-carbamoyl-imidazolium-5-olate ring. Deprotection of the latter product proceeded smoothly to give the carbocyclic analog of bredinin. This target molecule exhibits antiviral activity, albeit low, against a number of RNA viruses. Further biological evaluations are in progress.

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Development of the biocatalytic resolution of 2-azabicyclo[2.2.1]hept-5-en-3-one as an entry to single-enantiomer carbocyclic nucleosides

Cited by 99 publications

References 10 publications

Enzymatic Method for the Synthesis of Blockbuster Drug Intermediates – Synthesis of Five‐Membered Cyclic γ‐Amino Acid and γ‐Lactam Enantiomers

Enzymatic Method for the Synthesis of Blockbuster Drug Intermediates – Synthesis of Five‐Membered Cyclic γ‐Amino Acid and γ‐Lactam Enantiomers

Crystallization and preliminary X-ray analysis of a γ-lactamase

Synthesis of a Novel Carbocyclic Analog of Bredinin

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