Cascade condensation, cyclization, intermolecular dipolar cycloaddition by multi-component coupling and application to a synthesis of (±)-crispine A

Coldham, Iain; Jana, Samaresh; Watson, L. S.; Martin, Nathaniel G.

doi:10.1039/b822743h

Cited by 52 publications

(22 citation statements)

References 45 publications

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“…The residue was partitioned between aqueous ammonia(18 M, 10 mL) and CH 2 Cl 2 (20 mL) and was separated. The aqueous layer was extracted with CH 2 Cl 2(3…”

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confidence: 99%

Synthesis of Spirocyclic Amines by Using Dipolar Cycloadditions of Nitrones

2017

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Aliphatic ketones containing a chloride and alkene were heated with hydroxylamine to promote cascade, tandem condensation to oximes, cyclization to nitrones, and 1,3-dipolar cycloaddition to tricyclic isoxazolidines as single stereoisomers. Single regioisomers were obtained when three atoms linked the ketone and dipolarophile to give five-membered rings but mixtures resulted with four atoms in the tether unless a terminal ester was located on the alkene. The N-O bond in the products could be reduced to give spirocyclic amines and diamines.

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“…The residue was partitioned between aqueous ammonia(18 M, 10 mL) and CH 2 Cl 2 (20 mL) and was separated. The aqueous layer was extracted with CH 2 Cl 2(3…”

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confidence: 99%

Synthesis of Spirocyclic Amines by Using Dipolar Cycloadditions of Nitrones

2017

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“…In addition, we sought to improve the efficiency of the overall synthesis of enantiomer (R)-1 by utilising the microwave synthesis of the racemic amine coupled with the enhanced deracemisation that is brought about by changes to the MAO-N enzyme.To identify MAO-N variants that have improved activity towards compound (AE)-1, we modelled (S)-crispine A into the active site of the MAO-N-5 enzyme (PDB code 2VVM). [6] Four residues (Phe210, Leu213, Met242 and Met246), which are located at the entrance to the active site channel, were identified as providing possible steric interactions with the methoxy groups of crispine A (1). To optimise these residues, two randomised libraries were created: The first library targeted amino acids Phe210 and Leu213 (library A) and the second library targeted Met242 and Met246 (library B).…”

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Directed Evolution of the Enzyme Monoamine Oxidase (MAO‐N): Highly Efficient Chemo‐enzymatic Deracemisation of the Alkaloid (±)‐Crispine A

et al. 2012

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We have previously reported a general method for the deracemisation of racemic chiral amines (primary, [1] secondary [2] and tertiary [3] ) by using variants of the enzyme monoamine oxidase N (MAO-N) from Aspergillus niger. This deracemisation process employs a combination of an enantioselective enzymatic oxidation of the amine to afford the corresponding imine or iminium ion, together with a non-selective chemical reduction of the imine or iminium ion back to the racemic starting material (Scheme 1). The use of an (S)-selective MAO-N enzyme leads to accumulation of the (R)-amine in high enantiomeric excess and yield through several rounds of oxidation and reduction.Previously, we have applied this chemo-enzymatic approach to the deracemisation of the alkaloid (AE)-crispine A. [4] Crispine A (1) was first isolated from extracts of the plant Carduus crispus (welted thistle), along with the cytotoxic crispine B (2, Figure 1) and three other bicyclic isoquinoline alkaloids. [5] Although the deracemisation of (AE)-crispine A resulted in the generation of the R enantiomer in > 97 % ee, the reaction required 40 h to proceed to completion with a MAO-N-5 variant in an overall yield of 48 %. This previous study also highlighted that less-functionalised analogue 3 was more reactive with the same variant, taking only 6 h to reach completion (> 97 % ee), thus indicating that the two methoxy groups of racemate (AE)-1 resulted in lower activity. We reasoned that this drop in activity was due to steric interference between these two groups and residues within the active site of the enzyme. As a result, we employed a combination of molecular modelling and a rational re-design of the MAO-N-5 variant to identify and develop potential new MAO-N variants that could have enhanced activity towards enantiomer (S)-1. In addition, we sought to improve the efficiency of the overall synthesis of enantiomer (R)-1 by utilising the microwave synthesis of the racemic amine coupled with the enhanced deracemisation that is brought about by changes to the MAO-N enzyme.To identify MAO-N variants that have improved activity towards compound (AE)-1, we modelled (S)-crispine A into the active site of the MAO-N-5 enzyme (PDB code 2VVM). [6] Four residues (Phe210, Leu213, Met242 and Met246), which are located at the entrance to the active site channel, were identified as providing possible steric interactions with the methoxy groups of crispine A (1). To optimise these residues, two randomised libraries were created: The first library targeted amino acids Phe210 and Leu213 (library A) and the second library targeted Met242 and Met246 (library B). Both libraries were screened against compound (AE)-1 by using our previously reported solid-phase assay [7] (Figure 2); sixteen active "hits" were collected from each of the two libraries (A and B), which were then subjected to a second round of screening to eliminate any false positives. After the second round of screening, the two MAO-N variants from each library that had the highest activity, as judged by t...

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“…Another example is the synthesis of spiro indolizidines 104 from nitro chromans 22 [25]. In the reaction of tetraethyl vinylidenebis(phosphonate) (38) [25] the Coldham and co-workers have used 111, the homologous aldehyde of 95 (Scheme 17), in the three-component decarboxylative 1,3-DC with α-amino acids and dipolarophiles, affording 1:1 mixtures of endo:exo indolizidines 112 under refluxing toluene, by intermediacy of the azomethine ylide XVII (Scheme 21) [63,66].…”

Section: Multicomponent Synthesis Of Indolizidines By Decarboxylativementioning

confidence: 99%

Synthesis of pyrrolizidines and indolizidines by multicomponent 1,3-dipolar cycloaddition of azomethine ylides

Nájera

Sansano

2018

Pure and Applied Chemistry

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Different multicomponent 1,3-dipolar cycloadditions (1,3-DC) of cyclic α-amino acid derivatives with aldehydes and dipolarophiles have been described as efficient and simple methodologies for the synthesis of the pyrrolidine unit of pyrrolizidines and indolizidines. When free cyclic α-amino acids are used, a thermal promoted decarboxylative process generates in situ the corresponding non-stabilized azomethine ylides, which afforded the corresponding pyrrolizidines and indolizidines with a hydrogen in the bicyclic units. This methodology has been employed to the synthesis of complex systems including spiro derivatives when ketones are used as carbonyl component. In addition, working with cyclic α-amino acid derived esters, the three-component 1,3-DC takes place under milder reaction conditions giving the corresponding pyrrolizidines and indolizidines with an alkoxycarbonyl group in the bridge adjacent carbon to the nitrogen. This methodology can be carried out by a double consecutive or stepwise 1,3-DC to provide pyrrolizidines via the precursor prolinates. The conformation of the azomethine ylide controls the endo/exo diastereoselectivity of the 1,3-DC.

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Cascade condensation, cyclization, intermolecular dipolar cycloaddition by multi-component coupling and application to a synthesis of (±)-crispine A

Cited by 52 publications

References 45 publications

Synthesis of Spirocyclic Amines by Using Dipolar Cycloadditions of Nitrones

Synthesis of Spirocyclic Amines by Using Dipolar Cycloadditions of Nitrones

Directed Evolution of the Enzyme Monoamine Oxidase (MAO‐N): Highly Efficient Chemo‐enzymatic Deracemisation of the Alkaloid (±)‐Crispine A

Synthesis of pyrrolizidines and indolizidines by multicomponent 1,3-dipolar cycloaddition of azomethine ylides

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