Syntheses of (+)- and (−)-Dihydropinidine and (+)- and (−)-Epidihydropinidine by Using Yeast Reduction of Methyl (2-oxocyclohexyl)acetate

Yamauchi, Satoshi; Mori, Shunji; Hirai, Yoshio; Kinoshita, Yoshiro

doi:10.1271/bbb.68.676

Cited by 16 publications

(4 citation statements)

References 13 publications

(17 reference statements)

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“…13 C NMR (75 MHz, CDCl 3 ): δ [ppm] = 13.5, 16.9, 21.7, 29.9, 40.5, 43.9, 52.4, 57.2, 170.0, 205.0, 207.6. GC−MS (EI, 70 eV): m/z = 214 (M + , <1), 183 (8), 144 (44), 139 (30), 112 (26), 87 (12), 84 (22), 71 (100), 55 (12) 34 To a stirred suspension of CeCl 3 •7H 2 O (7.45 g, 20 mmol, 0.20 equiv) and NaI (1.50 g, 10 mmol, 0.10 equiv) in methyl butyrylacetate (6; 14.42 g, 100 mmol) was added dropwise freshly distilled but-3-en-2-one (5; 7.36 g, 105 mmol, 1.05 equiv) over 15 min. The mixture was stirred at room temperature for 18 h, at which time TLC analysis (silica gel 60, hexane/EtOAc = 3:1, CAM staining) indicated complete consumption of 6.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Dihydropinidine has been the target of considerable chemical and chemo-enzymatic asymmetric synthesis efforts. − In 2012, our research group reported a three-step route toward both enantiomers of the alkaloid that uses a highly regio- and stereoselective biocatalytic monoamination of diketone 3 as the asymmetric key step (Scheme A). The product of this transaminase-catalyzed reaction, imine 4 , was diastereoselectively transformed into 1 by catalytic hydrogenation .…”

Section: Introductionmentioning

confidence: 99%

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Asymmetric Synthesis of Dihydropinidine Enabled by Concurrent Multienzyme Catalysis and a Biocatalytic Alternative to Krapcho Dealkoxycarbonylation

et al. 2019

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Dihydropinidine is a piperidine alkaloid found in spruce needles that has shown promising antifeedant activity against the large pine weevil, a widespread and economically relevant pest of coniferous tree plantations. Chemo-enzymatic approaches have previously been shown to enable a stepeconomic access to both enantiomers of this alkaloid, but the scalability of these syntheses is limited. Herein, we report a chemo-enzymatic route to dihydropinidine that is dominated by biocatalytic steps and affords the target alkaloid in excellent stereoisomeric purity (>99% ee and de) and high yield (57% overall) on multigram scale. Our synthesis makes use of a solvent-free, Lewis acid-catalyzed Michael addition and a biocatalytic alternative to Krapcho dealkoxycarbonylation, achieved by pig liver esterase (PLE)-catalyzed ester hydrolysis and acidification, and specifically developed for this purpose, to access a key intermediate, nonane-2,6-dione. This diketone is then converted into dihydropinidine by a concurrent one-pot (cascade) biotransformation catalyzed by a transaminase, an imine reductase, and an alcohol dehydrogenase. High yields and excellent regio-and stereoselectivities of the individual transformations render chromatographic purification of intermediates unnecessary and make it possible to carry out the entire sequence with a final hydrochloride precipitation of the target alkaloid as the sole purification step.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Asymmetric Synthesis of Dihydropinidine Enabled by Concurrent Multienzyme Catalysis and a Biocatalytic Alternative to Krapcho Dealkoxycarbonylation

et al. 2019

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“…The use of baker's yeast as a stereospecific reduction biocatalyst has been well documented in the literature. Enantioselective reductions of various compounds, including dicarbonyl compounds (especially α‐ and β‐diketones, keto esters and cycloalkanediones)35, 40, 58, 60, 108, oxocarboxylic acids47, alkyl acetates23, 115 and aromatic ketones18, 67 have been successfully carried out, obtaining products with high enantiomeric excess (ee) in acceptable yields. It is widely used for the asymmetric reduction of prochiral ketones because such reductions with these microorganisms are readily executed and inexpensive.…”

Section: S Cerevisiae As Stereospecific Bio‐reduction Toolmentioning

confidence: 99%

Saccharomyces cerevisiae: a potential stereospecific reduction tool for biotransformation of mono‐ and sesquiterpenoids

Khor

Uzir

2010

Yeast

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Terpenes and terpenoids are among the key impact substances in the food and fragrance industries. Equipped with pharmacological properties and applications as ideal precursors for the biotechnological production of natural aroma chemicals, interests in these compounds have been escalating. Hence, the syntheses of new derivatives that can show improved properties are often called for. Stereoselective biotransformation offers several benefits to increase the rate of production, in terms of both the percentage yield and its enantiomeric excesses. Baker's yeast (Saccharomyces cerevisiae) is broadly used as a whole cell stereospecific reduction biocatalyst, due to its capability in reducing carbonyls and carbon-carbon double bonds, which also extends its functionality as a versatile biocatalyst in terpenoid biotransformation. This review provides some insights on the development and prospects in the reductive biotransformation of monoterpenoids and sesquiterpenoids using S. cerevisiae, with an overview of strategies to overcome the common challenges in large-scale implementation.

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“…Piperidine (2 S ,6 R )‐ 6 a has already been the object of numerous synthetic efforts, which have resulted in a variety of asymmetric syntheses based on, for example, chiral auxiliaries and chiral precursors 15. Although some syntheses are highly sophisticated, long reaction sequences (up to 14 steps),15f,h the use of protecting groups or stoichiometric amount of auxiliaries15c,g hampered their overall efficiency. Thus, the chemoenzymatic16 synthesis of 2,6‐disubsituted chiral piperidines based on the regioselective amination of diketones presented herein represents the shortest route by far, with an excellent overall yield.…”

Section: Methodsmentioning

confidence: 99%

Regio‐ and Stereoselective Monoamination of Diketones without Protecting Groups

et al. 2012

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Syntheses of (+)- and (−)-Dihydropinidine and (+)- and (−)-Epidihydropinidine by Using Yeast Reduction of Methyl (2-oxocyclohexyl)acetate

Cited by 16 publications

References 13 publications

Asymmetric Synthesis of Dihydropinidine Enabled by Concurrent Multienzyme Catalysis and a Biocatalytic Alternative to Krapcho Dealkoxycarbonylation

Asymmetric Synthesis of Dihydropinidine Enabled by Concurrent Multienzyme Catalysis and a Biocatalytic Alternative to Krapcho Dealkoxycarbonylation

Saccharomyces cerevisiae: a potential stereospecific reduction tool for biotransformation of mono‐ and sesquiterpenoids

Regio‐ and Stereoselective Monoamination of Diketones without Protecting Groups

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