Synthesis of unsymmetrically 2,6-disubstituted 2,3-dihydrothiopyran-4-ones

Rosiak, Anna; Christoffers, Jens

doi:10.1016/j.tetlet.2006.05.080

Cited by 19 publications

(8 citation statements)

References 16 publications

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“…Thiols are also substantially more nucleophilic; consequently, the resulting ynone should favor the desired 6- endo-dig cyclization pathway over the undesired 5- endo-dig pathway observed with 7 . 30 We thus began the synthesis of 13 , the 2,3-dihydro-4-thiopyranone analogue of 2 and 3 (Scheme 3). …”

Section: Resultsmentioning

confidence: 99%

Synthesis of a 3-Amino-2,3-dihydropyrid-4-one and Related Heterocyclic Analogues as Mechanism-Based Inhibitors of BioA, a Pyridoxal Phosphate-Dependent Enzyme

Eiden

Aldrich

2017

J. Org. Chem.

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Amiclenomycin (ACM) is a chemically unstable antibiotic with selective activity against Mycobacterium tuberculosis (Mtb) due to mechanism-based inhibition of BioA, a pyridoxal 5′-phosphate (PLP) dependent aminotransferase. The first-generation ACM analogue dihydro-2-pyridone 1 is semi-stable and maintains a similar bioactivation mechanism concluding with covalent labeling of the PLP cofactor. To improve on 1, we report the synthesis of dihydro-4-pyranone 2, dihydro-4-pyridone 3 and dihydro-4-thiopyranone 13, which were rationally designed to boost the rate of enzyme inactivation by lowering the pKa of their α-protons. We employed a unified synthetic strategy for construction of the desired heterocycles featuring α-amino ynone generation followed by 6-endo-dig cyclization. However, competitive 5-exo-dig cyclization, β-elimination of the ynone, and dimerization of the resultant α-amino carbonyls all complicated the syntheses of the dihydro-4-pyranone and dihydro-4-pyridone scaffolds. These obstacles were overcome by Teoc protection of the β-amino group in the assembly of 3 and Boc-MOM protection of the α-amino group in the synthesis of 2, enabling the efficient construction of 2 and 3 in seven steps from commercially available starting materials. Dihydro-4-pyridone 3 possessed improved enzyme inhibition as measured by its kinact value against BioA, validating our pKa–based design strategy.

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Section: Resultsmentioning

confidence: 99%

Synthesis of a 3-Amino-2,3-dihydropyrid-4-one and Related Heterocyclic Analogues as Mechanism-Based Inhibitors of BioA, a Pyridoxal Phosphate-Dependent Enzyme

Eiden

Aldrich

2017

J. Org. Chem.

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“…In organic synthesis, cross‐conjugated enynones are precursors of different cyclization products through two types of reactions, that is, electrocyclization upon enolization, which leads to methylenecyclopentenones or phenols depending on the reaction conditions, and double Michael additions in the presence of soft nucleophiles such as sulfides or activated methylene compounds to give the corresponding unsaturated six‐membered dihydrothiopyran‐4‐one and cyclohex‐2‐enone rings (Scheme ). Analogously, the double addition of water (or an oxygenated equivalent), which would give the dihydropyran‐4‐one core has not yet been described, probably because the hardness of oxygen does not favor conjugate additions.…”

Section: Introductionmentioning

confidence: 99%

“…Plausible reaction mechanisms for the formation of dihydropyran-4-ones are discussed. ence of soft nucleophiles such as sulfides [5] or activated methylene compounds [6] to give the corresponding unsaturated sixmembered dihydrothiopyran-4-one and cyclohex-2-enone rings (Scheme 1). Analogously, the double addition of water (or an oxygenated equivalent), which would give the dihydropyran-4-one core has not yet been described, probably because the hardness of oxygen does not favor conjugate additions.…”

Section: Introductionmentioning

confidence: 99%

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Brønsted Acid Promoted Cyclization of Cross‐Conjugated Enynones into Dihydropyran‐4‐ones

et al. 2017

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In triflic acid or sulfuric acid, diaryl‐substituted cross‐conjugated enynones undergo addition of the acid to the carbon–carbon triple bond to afford the corresponding vinyl triflates or sulfates. The vinyl triflates are stable under aqueous workup, whereas the vinyl sulfates are hydrolyzed to α,β‐unsaturated 1,3‐diketones (existing as conjugated enol forms). Extended reaction times lead to cyclization into dihydropyran‐4‐ones with yields of up to 95 %. The protonated forms of the vinyl triflates or sulfates in triflic and sulfuric acid, respectively, are studied as reactive intermediates by NMR spectroscopy. Plausible reaction mechanisms for the formation of dihydropyran‐4‐ones are discussed.

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“…图 2 3r 的晶体结构 Figure 2 The crystal structure of 3r 1.3 反应机理分析根据炔溴和端炔化合物在铜和碱催化下容易发生偶联反应的特点 [16] 以及该反应得到的产物, 我们推测反应可能经历以下过程(图 3): 8, 119.5, 125.2, 126.8, 127.3, 127.8, 128.0, 128.20, 128.24, 128.6, 128.7, 132.5, 132.8, 133.0, 133.2, 133.3, 137 8, 122.2, 124.6, 127.5, 128.5, 128.7, 129.4, 132.3, 133.2, 133.8, 137.1, 188 13 C NMR (CDCl 3 , 125 MHz) δ: 57.5, 85.6, 92.9, 112.4, 114.1, 123.0, 123.7, 128.4, 128.6, 128.8, 133.4, 133.6, 134.3, 136.8, 153.9, 188.6 9, 84.5, 92.7, 123.8, 128.4, 128.5, 128.7, 129.2, 129.8, 133.3, 133.4, 134.3, 136.8, 165.7, 188.5 13.6, 19.6, 22.0, 30.4, 79.2, 102.1, 126.3, 128.5, 128.6, 132.5, 133.0, 137.3, 189.2 21.7, 88.7, 97.5, 120.8, 124.1, 128.7, 128.8, 129.4, 133.1, 133.4, 134.6, 135.4, 144.2, 188 (d,J＝15.5 Hz,1H),7.36 (d,J＝8.5 Hz,2H),7.42～7.47 (m,3H),7.66 (t,J＝8.0 Hz,1H),7.86 (d,J＝7.5 Hz,1H),8.17 (d,J＝8.0 Hz, 1H), 8.24 (s, 1H); 13 C NMR (CDCl 3 , 125 MHz) δ: 88. 4,99.0,120.5,122.5 (q,J＝272.0 Hz),125.3 (q,J＝3.5 Hz),126.0,128.9,129.4,129.6 (q,J＝3.5 Hz),131.2 (q,J＝3.5 Hz),131.6,132.3,133.3,135.8,…”

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confidence: 99%

Pentynenones Formation through Copper Catalyzed Coupling- Isomerization Reaction between Alkynyl Bromides and Propargylic Alcohols

杨宗莲¹,

廖沛球²,

李兴奇³

et al. 2015

Chin. J. Org. Chem.

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1,5-Disubstituted (E)-pent-2-en-4-yn-1-ones can be exclusively synthesized by copper-catalyzed tandem coupling-isomerization reaction of alkynyl bromides and secondary propargylic alcohols in piperidine. This method is operation-simple and allows the synthesis of a wide variety of stereodefined 1,5-disubstituted pentynenones in 40%～83% yields. The mechanistic investigations suggest that piperidine plays a duel role being both a solvent and a base in the reaction.

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Synthesis of unsymmetrically 2,6-disubstituted 2,3-dihydrothiopyran-4-ones

Cited by 19 publications

References 16 publications

Synthesis of a 3-Amino-2,3-dihydropyrid-4-one and Related Heterocyclic Analogues as Mechanism-Based Inhibitors of BioA, a Pyridoxal Phosphate-Dependent Enzyme

Synthesis of a 3-Amino-2,3-dihydropyrid-4-one and Related Heterocyclic Analogues as Mechanism-Based Inhibitors of BioA, a Pyridoxal Phosphate-Dependent Enzyme

Brønsted Acid Promoted Cyclization of Cross‐Conjugated Enynones into Dihydropyran‐4‐ones

Pentynenones Formation through Copper Catalyzed Coupling- Isomerization Reaction between Alkynyl Bromides and Propargylic Alcohols

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