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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

Influence of temperature on the conversion of diketone 3a at varying DMF concentrations: (♦) 40 vol.-% DMF, (R)-Arthrobacter sp., (▪) 20 vol.-% DMF, (R)-Arthrobacter sp., (•) 20 vol.-% DMF, A. citreus, (▴) 40 vol.-% DMF, A. citreus. Reagents and conditions: diketone 3a (25 mm), lyophilised E. coli cells containing the overexpressed ω-TA (20 mg), PLP (1 mm), NAD+ (1 mm), ammonium formate (150 mm), D- or L-alanine (500 mm), AlaDH (12 U), FDH (11 U), 20–40 vol.-% DMF, KPi buffer (100 mm, pH 7.0), 20–50 °C, 24 h, 700 rpm.
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fig06: Influence of temperature on the conversion of diketone 3a at varying DMF concentrations: (♦) 40 vol.-% DMF, (R)-Arthrobacter sp., (▪) 20 vol.-% DMF, (R)-Arthrobacter sp., (•) 20 vol.-% DMF, A. citreus, (▴) 40 vol.-% DMF, A. citreus. Reagents and conditions: diketone 3a (25 mm), lyophilised E. coli cells containing the overexpressed ω-TA (20 mg), PLP (1 mm), NAD+ (1 mm), ammonium formate (150 mm), D- or L-alanine (500 mm), AlaDH (12 U), FDH (11 U), 20–40 vol.-% DMF, KPi buffer (100 mm, pH 7.0), 20–50 °C, 24 h, 700 rpm.

Mentions: Having identified two suitable enzymes with opposite stereopreference [Arthrobacter citreus for the (S)- and Arthrobacter sp. for the (R)-enantiomer] and cosolvents, further optimisation of temperature and pH was conducted. The biocatalytic monoamination of 3a was tested at different pH values (ranging from 6.5 to 9.9) at varied DMF concentrations (20 and 40 vol.-%) (Figure 3). Subsequently, the conversion was studied as a function of temperature at varied DMF concentrations (20 and 40 vol.-%; Figure 4). Thereby, the highest conversion was obtained for the asymmetric reductive amination of diketone 3a at 20 vol.-% DMF, pH 6.5, and 30 °C with the ω-TA originating from (R)-Arthrobacter sp., whereas 20 vol.-% DMF (pH 7.0) and elevated temperatures of 40 °C were best suited for the (S)-selective ω-TA of Arthrobacter citreus.


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)

Influence of temperature on the conversion of diketone 3a at varying DMF concentrations: (♦) 40 vol.-% DMF, (R)-Arthrobacter sp., (▪) 20 vol.-% DMF, (R)-Arthrobacter sp., (•) 20 vol.-% DMF, A. citreus, (▴) 40 vol.-% DMF, A. citreus. Reagents and conditions: diketone 3a (25 mm), lyophilised E. coli cells containing the overexpressed ω-TA (20 mg), PLP (1 mm), NAD+ (1 mm), ammonium formate (150 mm), D- or L-alanine (500 mm), AlaDH (12 U), FDH (11 U), 20–40 vol.-% DMF, KPi buffer (100 mm, pH 7.0), 20–50 °C, 24 h, 700 rpm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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fig06: Influence of temperature on the conversion of diketone 3a at varying DMF concentrations: (♦) 40 vol.-% DMF, (R)-Arthrobacter sp., (▪) 20 vol.-% DMF, (R)-Arthrobacter sp., (•) 20 vol.-% DMF, A. citreus, (▴) 40 vol.-% DMF, A. citreus. Reagents and conditions: diketone 3a (25 mm), lyophilised E. coli cells containing the overexpressed ω-TA (20 mg), PLP (1 mm), NAD+ (1 mm), ammonium formate (150 mm), D- or L-alanine (500 mm), AlaDH (12 U), FDH (11 U), 20–40 vol.-% DMF, KPi buffer (100 mm, pH 7.0), 20–50 °C, 24 h, 700 rpm.
Mentions: Having identified two suitable enzymes with opposite stereopreference [Arthrobacter citreus for the (S)- and Arthrobacter sp. for the (R)-enantiomer] and cosolvents, further optimisation of temperature and pH was conducted. The biocatalytic monoamination of 3a was tested at different pH values (ranging from 6.5 to 9.9) at varied DMF concentrations (20 and 40 vol.-%) (Figure 3). Subsequently, the conversion was studied as a function of temperature at varied DMF concentrations (20 and 40 vol.-%; Figure 4). Thereby, the highest conversion was obtained for the asymmetric reductive amination of diketone 3a at 20 vol.-% DMF, pH 6.5, and 30 °C with the ω-TA originating from (R)-Arthrobacter sp., whereas 20 vol.-% DMF (pH 7.0) and elevated temperatures of 40 °C were best suited for the (S)-selective ω-TA of Arthrobacter citreus.

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