Evidence for an enolate mechanism in the asymmetric Michael reaction of α,β-unsaturated aldehydes and ketones <i>via</i> a hybrid system of two secondary amine catalysts

Umekubo, Nariyoshi; Terunuma, Takahiro; Kwon, Eunsang; Hayashi, Yujiro

doi:10.1039/d0sc03359f

Cited by 21 publications

(14 citation statements)

References 43 publications

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“…This ammonium enolate mechanism has also been recently proposed by Hayashi et al . for the 2°‐amine catalyzed Michael reaction of α,β‐unsaturated aldehydes [12] …”

Section: Resultsmentioning

confidence: 99%

“…[11] This ammonium enolate mechanism has also been recently proposed by Hayashi et al for the 2°-amine catalyzed Michael reaction of α,βunsaturated aldehydes. [12] We next moved on to assess the biocompatibility of phenethylamine catalysts to E. coli. N-Methyl tyramine 17 and hordenine 18 inhibited growth (OD 600 ) and cell viability (cfu/mL) at 25 mM.…”

Section: Resultsmentioning

confidence: 99%

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Tyramine Derivatives Catalyze the Aldol Dimerization of Butyraldehyde in the Presence of Escherichia coli

2022

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Biogenic amine organocatalysts have transformed the field of synthetic organic chemistry. Yet despite their use in synthesis and to label biomolecules in vitro, amine organocatalysis in vivo has received comparatively little attention -despite the potential of such reactions to be interfaced with living cells and to modify cellular metabolites. Herein we report that biogenic amines derived from L-tyrosine catalyze the self-aldol condensation of butanal to 2-ethylhexenal -a key intermediate in the production of the bulk chemical 2-ethylhexanol -in the presence of living Escherichia coli and outperform many amine organocatalysts currently used in synthetic organic chemistry. Furthermore, we demonstrate that cell lysate from E. coli and the prolific amine overproducer Corynebacterium glutamicum ATCC 13032 catalyze this reaction in vitro, demonstrating the potential for microbial metabolism to be used as a source of organocatalysts for biocompatible reactions in cells.

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“…This ammonium enolate mechanism has also been recently proposed by Hayashi et al . for the 2°‐amine catalyzed Michael reaction of α,β‐unsaturated aldehydes [12] …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Tyramine Derivatives Catalyze the Aldol Dimerization of Butyraldehyde in the Presence of Escherichia coli

2022

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“…Dehydration afforded 45, and oxidative Nef reaction using molecular oxygen, which was a procedure that was developed by our group, 37 followed by isomerization afforded PGA 1 methyl ester (46). Diastereoselective epoxidation followed by reductive opening of the epoxide provided PGE 1 methyl ester (48). The last four reaction steps (44 → 48) proceeded in the same reaction vessel.…”

Section: Prostaglandin E 1 Methyl Estermentioning

confidence: 99%

“…In 2018, we developed a Michael reaction of α,β-unsaturated aldehydes and nonactivated ketones such as cyclohexanone, in which the enolate of the ketone is a key nucleophile (eq ). On the basis of this reaction, we designed another [3 + 2] cycloaddition reaction, a domino Michael/Michael reaction, for the construction of substituted cyclopentanones (eq ). That is, 3-silylpropenal 78 , a synthetic equivalent of 3-hydroxyprop-2-enal, was treated with ethyl 4-oxo-2-pentenoate ( 79 ), whereupon the first Michael reaction afforded enamine 81 , from which an intramolecular Michael reaction proceeded to provide 82 as a single isomer containing all of the carbons necessary for Corey lactone synthesis, with the correct stereochemistry, and in nearly optically pure form …”

Section: Corey Lactonementioning

confidence: 99%

Time and Pot Economy in Total Synthesis

Hayashi

2021

Acc. Chem. Res.

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100

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Conspectus We would all like to make or obtain the materials or products we want as soon as possible. This is human nature. This is true also for chemists in the synthesis of organic molecules. All chemists would like to make their target molecules as soon as possible, particularly when their interest is in the physical or biological properties of those molecules. As demonstrated by today’s COVID-19 (SARS-CoV-2) pandemic, rapid synthesis is also crucial to enable chemists to deliver effective therapeutic agents to the community. Several concepts are currently well-accepted as important for achieving this: atom economy, step economy, and redox economy. Considering the importance of synthesizing organic molecules rapidly, I recently proposed adding the concept of time economy. In a multisep synthesis, each step has to be completed within a short period of time to make the desired molecule rapidly. The development of rapid reactions is important but also insufficient. After each step, frequent and repetitive workup operations such as quenching the reaction, extraction, separation of water and organic phases, drying the organic phase, filtration, evaporation, and purification may be required, and the time necessary for these processing operations must be taken into account. Indeed, some of the most time-consuming operations in most syntheses are the purification stages. On the other hand, one-pot reactions are processes in which several sequential reactions are conducted in a single reaction vessel, which avoids the need to purify intermediates. One-pot reactions are a useful way to shorten the total synthesis time, and the approach generally leads to an increase in the yield and a reduction in the amount of chemical waste formed. Thus, I also propose the importance of pot economy. On the basis of these concepts of time and pot economy, we have accomplished efficient syntheses of several natural products and medicines. The key to the success of these syntheses is the use of diphenylprolinol silyl ether as an effective catalyst in a one-pot reaction, in which it does not disturb the subsequent reactions. Our strategy is (1) to construct the chiral key skeletons and/or key components of natural products and medicines directly using organocatalyst-mediated one-pot reactions and (2) to conduct the subsequent transformations to the final molecules in a small number of pots utilizing the internal quench method. By means of this strategy, PGE1 methyl ester, estradiol methyl ether, and clinprost were synthesized in three, five, and seven pots, respectively. Furthermore, (−)-oseltamivir, ABT-341, baclofen, and Corey lactone were synthesized in a single reaction vessel. Further optimization of the reactions in terms of time economy allowed (−)-oseltamivir and Corey lactone to be synthesized within 60 and 152 min, respectively. These syntheses will be highlighted as case studies. Although the organocatalyst is a key compound in this Account, pot- and time-economical syntheses can be expanded to organometallic chemistry and, ind...

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“…Although aldol condensation product 11 was obtained, we did not observe any aldol product. We speculated catalyst A and 6b reacted to generate iminium ion, which reacted with enolate of methyl ketone via the Mannich (1,2-addition) reaction to afford β-amino ketone, followed by deamination to provide 11 . As the triphenylsilyl substituent of 6b is bulkier than dimethylphenylsilyl group, the Michael reaction toward 6b was suppressed, and the 1,2-addition reaction proceeded as a side reaction (Figure B).…”

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confidence: 99%

Pot-Economical Total Synthesis of Clinprost

Umekubo

Hayashi

2020

Org. Lett.

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The pot-economical synthesis of clinprost is reported, in which the core bicyclo[3.3.0]octenone structure was synthesized by two key steps: an asymmetric domino Michael/Michael reaction catalyzed by diphenylprolinol silyl ether and an intramolecular Horner−Wadsworth−Emmons reaction. The trisubstituted endocyclic alkene was selectively introduced by 1,4reduction followed by trapping of the generated enolate with Tf 2 NPh and subsequent utilization of the Suzuki−Miyaura coupling reaction. Chiral, nonracemic clinprost was synthesized in seven pots with a 17% total yield and excellent enantioselectivity.

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Evidence for an enolate mechanism in the asymmetric Michael reaction of α,β-unsaturated aldehydes and ketones via a hybrid system of two secondary amine catalysts

Abstract: The key nucleophile was found to be neither an enamine nor an enol, but an enolate in the direct Michael reaction of α,β-unsaturated aldehyde and non-activated ketone catalyzed by two...

Cited by 21 publications

References 43 publications

Tyramine Derivatives Catalyze the Aldol Dimerization of Butyraldehyde in the Presence of Escherichia coli

Tyramine Derivatives Catalyze the Aldol Dimerization of Butyraldehyde in the Presence of Escherichia coli

Time and Pot Economy in Total Synthesis

Pot-Economical Total Synthesis of Clinprost

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