A novel and versatile method for the enantioselective syntheses of tropane alkaloids

Mao, Zhong‐Yi; Huang, Shih-Chien; Gao, Longhui; Wang, Ai‐E; Huang, Pei‐Qiang

doi:10.1007/s11426-013-4998-2

Cited by 15 publications

(3 citation statements)

References 68 publications

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“…This alkaloid is manufactured as a racemic mixture of diastereomers from (±)-6β-hydroxytropinone [61][62][63] and (±)-tropic acid for the treatment of septic shock and circulatory disorders. 64 To our knowledge, no synthesis of single anisodamine stereoisomers has been reported although relevant enantioenriched intermediates have been prepared in multistep routes by asymmetric synthesis, [65][66][67][68] from (R)or (S)-malic acid, 69 and by resolution. [70][71][72] In this context, screening of N-Boc-nortropinone, 7…”

Section: A Stereoselective Synthesis Of Anisodaminementioning

confidence: 99%

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Enantioselective oxidation of unactivated C–H bonds in cyclic amines by iterative docking-guided mutagenesis of P450BM3 (CYP102A1)

Zhang

Xiong²,

et al. 2022

Nat. Synth

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Selective oxidation of ring C-H bonds is an attractive route to functionalised cyclic amines which are versatile intermediates in drug synthesis and important fragment molecules in drug discovery. Here we report a combined substrate and enzyme engineering approach to achieve enantioselective functionalisation of all unactivated C-H bonds of azepane, azocane, 7azabicyclo[2.2.1]heptane, and 8-azaspiro[4.5]decane by cytochrome P450BM3 (CYP102A1).Different N-modifying groups provide product diversity at high enantioselectivity (up to 99% e.e.) from a panel of just 48 variants of P450BM3. Substrate docking into molecular dynamics simulation structures of enzyme variants is shown to be useful for designing mutations to increase enantioselectivity by disfavouring binding poses leading to the unwanted enantiomer, and to increase enzymatic activity by disfavouring non-productive poses from 10 or so variants per generation. The synthetic application of remote C-H activation within cyclic amines is exemplified by the synthesis of anisodamine via enantioselective hydroxylation of N-Bocnortropinone.

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Section: A Stereoselective Synthesis Of Anisodaminementioning

confidence: 99%

“…The single-step enzymatic conversion of substrate 7 into (6R)-7a (76%) represents a substantial improvement on the analogous asymmetric chemical synthesis of (6R)-acetoxytropinone from tropinone that requires five steps (44%). 69…”

Section: A Stereoselective Synthesis Of Anisodaminementioning

confidence: 99%

Enantioselective oxidation of unactivated C–H bonds in cyclic amines by iterative docking-guided mutagenesis of P450BM3 (CYP102A1)

Zhang

Xiong²,

et al. 2022

Nat. Synth

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“…Historically, the most notorious member of the tropane alkaloid family is cocaine 1 , a banned substance because of its highly addictive properties (Figure ). Intriguingly, the 8-azabicyclo[3.2.1]octane core structure found in cocaine 1 is found in dihydroxytropane natural products, isolated in the form of mono- and diesters such as vaccinine B 2 , valeroidine 6 , , merredissine 7 , , or pervilleine B/C/F 3 – 5 , ,, which display promising multidrug resistant inhibitory activities. − Other natural products from the nor tropane family characterized by a secondary nitrogen atom are also known, such as ipvelutine 10 or (−)-Bao Gong Teng A 8 and (−)-erycibelline 9 , for which diverse biological activities have been reported (Figure ). , Of considerable interest was the prospect of using of Bao Gong Teng A as an antiglaucoma compound .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Aza-Bridged Perhydroazulene Chimeras of Tropanes and Hederacine A

et al. 2023

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We report the synthesis of two novel azaperhydroazulene tropane-hederacine chimeras A and B, which contain an 8-azabicyclo[3.2.1]octane ring and a 7-azabicyclo[4.1.1]octane ring, respectively. The synthesis of both chimeras was achieved by epoxide ring opening and was governed by the stereochemistry of the hydroxy-epoxide unit. Finally, a density functional theory study was conducted to explain the regioselectivity of the cyclization and the importance of the stereochemistry of the hydroxyl group.

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Further Studies on the Direct Synthesis of α,β‐Unsaturated Ketimines and α,β‐Enones by Chemoselective Dehydrative Addition of Functionalized Alkenes to Secondary Amides

Huang

2017

Chin. J. Chem.

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Described in this paper are the results of an investigation on the extension of the C‐H alkyliminylation and acylation of alkenes with secondary amides. The nucleophilic partner has been extended to cover a series of functionalized alkenes bearing functional groups including ester, α,β‐unsaturated ester, uncongested ketone groups, as well as enol derivatives of acetaldehyde such as enol ether and enamides. The electrophilic partner has been extended from N‐(2,6‐dimethylphenyl) and N‐methyl amides to N‐n‐butyl, and N‐cyclohexyl amides. The results demonstrated that the method can be used to synthesize a number of functionalized α,β‐unsaturated ketimines and α,β‐enones in an efficient, high yielding, and one‐pot manner. The method was applied to a concise synthesis of (E)‐6‐styryltetrahydro‐2H‐pyran‐2‐one (5), an immediate intermediate in the syntheses of a series of styryllactone natural products including (±)‐goniothalamine (6), (±)‐goniothalamine oxide (7), (±)‐goniodiol (8), (±)‐leiocarpin A (9), (±)‐9‐deoxygoniopypyrone (10), and (±)‐7‐epi‐goniodiol (11).

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A novel and versatile method for the enantioselective syntheses of tropane alkaloids

Cited by 15 publications

References 68 publications

Enantioselective oxidation of unactivated C–H bonds in cyclic amines by iterative docking-guided mutagenesis of P450BM3 (CYP102A1)

Enantioselective oxidation of unactivated C–H bonds in cyclic amines by iterative docking-guided mutagenesis of P450BM3 (CYP102A1)

Synthesis of Aza-Bridged Perhydroazulene Chimeras of Tropanes and Hederacine A

Further Studies on the Direct Synthesis of α,β‐Unsaturated Ketimines and α,β‐Enones by Chemoselective Dehydrative Addition of Functionalized Alkenes to Secondary Amides

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