A Chemo-Enzymatic Route to Enantiomerically Pure Cyclic Tertiary Amines

Dunsmore, Colin J.; Carr, Reuben; Fleming, Toni; Turner, Nicholas J.

doi:10.1021/ja058536d

Cited by 207 publications

(140 citation statements)

References 16 publications

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“…As such, we adapted existing synthetic protocols (33) to prepare N-methyl-2-phenylpyrroline (MPP). Recrystallization of the dibenzoyl tartrate salt (at the phenylpyrrolidine stage) gave the S enantiomer.…”

Section: Resultsmentioning

confidence: 99%

“…Hydroxy or amino acids were appended to the dinucleotide dCA and enzymatically ligated to the truncated 74-nucleotide TQOpS' tRNA as previously described (30 Synthesis of N-Methyl-2-Phenylpyrrolidine Hydrochloride. Racemic 2-phenylpyrrolidine (5.0 g, 34 mmol), prepared according to a published protocol (33), was mixed with dibenzoyl-L-taratric acid (6.1 g, 17 mmol) in a 100-mL round-bottom flask equipped with a reflux condenser. To this was added 35% ethanol in ethylacetate (30 mL).…”

Section: Methodsmentioning

confidence: 99%

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Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH

Blum

Lester

Dougherty

2010

Proc. Natl. Acad. Sci. U.S.A.

120

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Pharmacophore models for nicotinic agonists have been proposed for four decades. Central to these models is the presence of a cationic nitrogen and a hydrogen bond acceptor. It is now wellestablished that the cationic center makes an important cation-π interaction to a conserved tryptophan, but the donor to the proposed hydrogen bond acceptor has been more challenging to identify. A structure of nicotine bound to the acetylcholine binding protein predicted that the binding partner of the pharmacophore's second component was a water molecule, which also hydrogen bonds to the backbone of the complementary subunit of the receptors. Here we use unnatural amino acid mutagenesis coupled with agonist analogs to examine whether such a hydrogen bond is functionally significant in the α4β2 neuronal nAChR, the receptor most associated with nicotine addiction. We find evidence for the hydrogen bond with the agonists nicotine, acetylcholine, carbamylcholine, and epibatidine. These data represent a completed nicotinic pharmacophore and offer insight into the design of new therapeutic agents that selectively target these receptors.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH

Blum

Lester

Dougherty

2010

Proc. Natl. Acad. Sci. U.S.A.

120

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“…This concept was very recently extended to the deracemization of tertiary amines, such as N-methyl-2-phenylpyrrolidine, using a new variant of this monoamine oxidase containing five mutations (Ile246Met/Asn336Ser/Met348Lys/ Thr384Asn/Asp385Ser, 'MAO-N-5') which was obtained after several rounds of directed evolution. [101] …”

Section: Combining An Oxidase With a Chemical Reducing Agentmentioning

confidence: 99%

From a Racemate to a Single Enantiomer: Deracemization by Stereoinversion

et al. 2006

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Abstract:The stereoinversion of one enantiomer into its mirror-image counterpart within a racemate furnishes a single stereoisomeric product in 100 % theoretical yield. This extremely efficient type of deracemization, whereby substrate and product possess an identical chemical structure, can be achieved by using bio-or chemo-catalysts or combinations thereof and is applicable to secondary alcohols, amines and a-substituted carboxylic acids. Special emphasis is devoted to the theoretical background of the onepot, single-step deracemization of sec-alcohols.

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“…The genes encoding MAO-N (EC 1.4.3.4) and its variants were subcloned from previously used pET-16b constructs (Carr et al, 2005;Dunsmore et al, 2006) into the vector pETYSBLIC-3C, which endows the expressed gene products with a 3C protease-cleavable N-terminal hexahistidine tag with sequence MGSSHHHHHHSSG-LEVLFQGPA. Genes were amplified from pET-16b constructs using the following PCR primers: forward, 5 0 -CCAGGGACCAGCAAT-GACCTCCCGAGACGGATACCAG-3 0 , and reverse, 5 0 -GAGGAG-AAGGCGCGTTETCACAAACGAGCCTTCACCTCC-3 0 .…”

Section: Cloningmentioning

confidence: 99%

Cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of variants of monoamine oxidase fromAspergillus niger

et al. 2008

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Monoamine oxidase from Aspergillus niger (MAO-N) is an FAD-dependent enzyme that catalyses the conversion of terminal amines to their corresponding aldehydes. Variants of MAO-N produced by directed evolution have been shown to possess altered substrate specificity. Crystals of two of these variants (MAO-N-3 and MAO-N-5) have been obtained; the former displays P2 1 symmetry with eight molecules per asymmetric unit and the latter has P4 1 2 1 2 or P4 3 2 1 2 symmetry and two molecules per asymmetric unit. Solution of these structures will help shed light on the molecular determinants of improved activity and high enantioselectivity towards a broad range of substrates.

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A Chemo-Enzymatic Route to Enantiomerically Pure Cyclic Tertiary Amines

Abstract: Deracemization of racemic chiral tertiary amines has been achieved by combination of an enantioselective amine oxidase, obtained through directed evolution, and ammonia borane in a one-pot process.

Cited by 207 publications

References 16 publications

Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH

Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH

From a Racemate to a Single Enantiomer: Deracemization by Stereoinversion

Cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of variants of monoamine oxidase fromAspergillus niger

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