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Concise Chemoenzymatic Three Step Total Synthesis of Isosolenopsin Through Medium Engineering.

Simon RC, Fuchs CS, Lechner H, Zepeck F, Kroutil W - European J Org Chem (2013)

Bottom Line: A short and efficient total synthesis of the alkaloid isosolenopsin and its enantiomer has been achieved.Diastereostelective chemical reduction (H2/Pd/C) of the biocatalytic product gave the target compound.The linear three step synthesis provided the natural product isosolenopsin in diastereomerically pure form (ee > 99%, d.r. = 99:1) with an overall yield of 64%.

View Article: PubMed Central - PubMed

Affiliation: ACIB GmbH, Heinrichstraße 28, 8010-Graz, Austria.

ABSTRACT
A short and efficient total synthesis of the alkaloid isosolenopsin and its enantiomer has been achieved. In the key step, a ω-transaminase catalyzed the regioselective mono-amination of the diketone pentadecane-2,6-dione which was obtained in a single step via Grignard reaction. Initial low conversions in the biotransformation could be overcome by optimisation of the reaction conditions employing suitable cosolvents. In the presence of 20 vol% DMF or n-heptane best results were obtained employing two enantio-complementary ω-transaminases originating from Arthrobacter between 30-40 °C; under these conditions conversions of >99% and perfect stereocontrol (ee > 99%) were achieved. Diastereostelective chemical reduction (H2/Pd/C) of the biocatalytic product gave the target compound. The linear three step synthesis provided the natural product isosolenopsin in diastereomerically pure form (ee > 99%, d.r. = 99:1) with an overall yield of 64%.

No MeSH data available.


Related in: MedlinePlus

Monoamination of diketone 3a to yield Δ1-piperideine 6a. Reagents and conditions: lyophilised E. coli cells containing the overexpressed ω-TA (20 mg), diketone 3a (12 mg, 50 mm), PLP (1 mm), NAD+ (1 mm), ammonium formate (150 mm), D- or L-alanine (500 mm), AlaDH (12 U), FDH (11 U), organic cosolvent and KPi buffer (100 mm, pH 7.0), 30 °C, 24 h in an Eppendorf orbital shaker (700 rpm).
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fig03: Monoamination of diketone 3a to yield Δ1-piperideine 6a. Reagents and conditions: lyophilised E. coli cells containing the overexpressed ω-TA (20 mg), diketone 3a (12 mg, 50 mm), PLP (1 mm), NAD+ (1 mm), ammonium formate (150 mm), D- or L-alanine (500 mm), AlaDH (12 U), FDH (11 U), organic cosolvent and KPi buffer (100 mm, pH 7.0), 30 °C, 24 h in an Eppendorf orbital shaker (700 rpm).

Mentions: Various enantiocomplementary ω-TAs were tested for the transformation of diketone 3a into the corresponding Δ1-piperideines 6a and 7a under designated reaction conditions by employing alanine as amine donor (Scheme 2). The equilibrium was shifted towards the product side by removal/recycling of the formed pyruvate with an alanine-dehydrogenase (AlaDH).12 Unfortunately, only low conversions were achieved, probably due to the low solubility of diketone 3a in pure buffer solution. Subsequently, various water-miscible organic solvents [acetonitrile, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), 1,2-dimethoxyethane (DME), dimethyl sulfoxide (DMSO)] and immiscible solvents (EtOAc, toluene) were assayed at 10 vol.-%. Although most of the investigated ω-TAs gave insufficient conversions (less than 5 %), four showed conversions of around 25 %, rendering them targets for a more detailed study. Notably, regioisomer 7a was not detected for any enzyme investigated (see the Supporting Information).


Concise Chemoenzymatic Three Step Total Synthesis of Isosolenopsin Through Medium Engineering.

Simon RC, Fuchs CS, Lechner H, Zepeck F, Kroutil W - European J Org Chem (2013)

Monoamination of diketone 3a to yield Δ1-piperideine 6a. Reagents and conditions: lyophilised E. coli cells containing the overexpressed ω-TA (20 mg), diketone 3a (12 mg, 50 mm), PLP (1 mm), NAD+ (1 mm), ammonium formate (150 mm), D- or L-alanine (500 mm), AlaDH (12 U), FDH (11 U), organic cosolvent and KPi buffer (100 mm, pH 7.0), 30 °C, 24 h in an Eppendorf orbital shaker (700 rpm).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4151137&req=5

fig03: Monoamination of diketone 3a to yield Δ1-piperideine 6a. Reagents and conditions: lyophilised E. coli cells containing the overexpressed ω-TA (20 mg), diketone 3a (12 mg, 50 mm), PLP (1 mm), NAD+ (1 mm), ammonium formate (150 mm), D- or L-alanine (500 mm), AlaDH (12 U), FDH (11 U), organic cosolvent and KPi buffer (100 mm, pH 7.0), 30 °C, 24 h in an Eppendorf orbital shaker (700 rpm).
Mentions: Various enantiocomplementary ω-TAs were tested for the transformation of diketone 3a into the corresponding Δ1-piperideines 6a and 7a under designated reaction conditions by employing alanine as amine donor (Scheme 2). The equilibrium was shifted towards the product side by removal/recycling of the formed pyruvate with an alanine-dehydrogenase (AlaDH).12 Unfortunately, only low conversions were achieved, probably due to the low solubility of diketone 3a in pure buffer solution. Subsequently, various water-miscible organic solvents [acetonitrile, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), 1,2-dimethoxyethane (DME), dimethyl sulfoxide (DMSO)] and immiscible solvents (EtOAc, toluene) were assayed at 10 vol.-%. Although most of the investigated ω-TAs gave insufficient conversions (less than 5 %), four showed conversions of around 25 %, rendering them targets for a more detailed study. Notably, regioisomer 7a was not detected for any enzyme investigated (see the Supporting Information).

Bottom Line: A short and efficient total synthesis of the alkaloid isosolenopsin and its enantiomer has been achieved.Diastereostelective chemical reduction (H2/Pd/C) of the biocatalytic product gave the target compound.The linear three step synthesis provided the natural product isosolenopsin in diastereomerically pure form (ee > 99%, d.r. = 99:1) with an overall yield of 64%.

View Article: PubMed Central - PubMed

Affiliation: ACIB GmbH, Heinrichstraße 28, 8010-Graz, Austria.

ABSTRACT
A short and efficient total synthesis of the alkaloid isosolenopsin and its enantiomer has been achieved. In the key step, a ω-transaminase catalyzed the regioselective mono-amination of the diketone pentadecane-2,6-dione which was obtained in a single step via Grignard reaction. Initial low conversions in the biotransformation could be overcome by optimisation of the reaction conditions employing suitable cosolvents. In the presence of 20 vol% DMF or n-heptane best results were obtained employing two enantio-complementary ω-transaminases originating from Arthrobacter between 30-40 °C; under these conditions conversions of >99% and perfect stereocontrol (ee > 99%) were achieved. Diastereostelective chemical reduction (H2/Pd/C) of the biocatalytic product gave the target compound. The linear three step synthesis provided the natural product isosolenopsin in diastereomerically pure form (ee > 99%, d.r. = 99:1) with an overall yield of 64%.

No MeSH data available.


Related in: MedlinePlus