Enantioselective Organocatalytic Synthesis of 2-Oxopiperazines from Aldehydes: Identification of the Elusive Epoxy Lactone Intermediate

Kaplaneris, Nikolaos; Spyropoulos, Constantinos; Kokotou, Maroula G.; Kokotos, Christoforos G.

doi:10.1021/acs.orglett.6b02699

Cited by 31 publications

(12 citation statements)

References 37 publications

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“…First, benzyl protecting group was selected and monobenzyl‐protected 1,10‐decanediol 1 was converted to aldehyde by oxidation with pyridinium chlorochromate (Scheme ). Among the different enantioselective enamine‐based chlorination methodologies in literature, a modified procedure employing (2 R ,5 S )‐2‐( tert ‐butyl)‐3,5‐dimethylimidazolidin‐4‐one trifluoroacetate as the organocatalyst and 2,3,4,5,6,6‐hexachlorocyclohexa‐2,4‐dien‐1‐one as the chlorination agent was selected for the chlorination of aldehyde 2 . Subsequently, reduction by NaBH 4 , followed by treatment with KOH, led to the formation of epoxide 3 in a one‐pot procedure.…”

Section: Resultsmentioning

confidence: 99%

Asymmetric Synthesis of Saturated Hydroxy Fatty Acids and Fatty Acid Esters of Hydroxy Fatty Acids

et al. 2019

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The recent discovery of a novel class of endogenous lipids, named Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs), that present antidiabetic and anti‐inflammatory activities, has attracted the interest on hydroxy fatty acids (HFAs) and their derivatives. We present herein the development of a convenient and general methodology for the asymmetric synthesis of HFAs and FAHFAs. The enantioselective organocatalytic synthesis of asymmetric terminal epoxides starting from monoprotected α,ω‐diols and their subsequent ring opening by a Grignard reagent are the key‐steps for our methodology, allowing the introduction of the hydroxy group at different positions of the long chain by proper selection of the starting diol and the Grignard reagent. MacMillan's third generation imidazolidinone organocatalyst has been employed for the epoxide formation, ensuring products in high enantiomeric purity. Furthermore, an approach for the synthesis of deuterated HFAs and FAHFAs was developed, leading to deuterated derivatives, which can be useful in biological studies and in mass spectrometry studies as internal standards.

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Section: Resultsmentioning

confidence: 99%

Asymmetric Synthesis of Saturated Hydroxy Fatty Acids and Fatty Acid Esters of Hydroxy Fatty Acids

et al. 2019

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“…A number of different enantioselective methodologies for the α-chlorination of aldehydes have been reported in literature, and the enantiomeric excess of the product depends on the catalyst, the chlorination agent and the reaction conditions [16,17,18,19,20]. For the chlorination of long chain aldehydes, we selected a modified procedure employing (2 R ,5 S )-2-( tert -butyl)-3,5-dimethylimidazolidin-4-one trifluoroacetate as the organo-catalyst and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one as the chlorination agent [21].…”

Section: Resultsmentioning

confidence: 99%

Enantioselective Organocatalysis-Based Synthesis of 3-Hydroxy Fatty Acids and Fatty γ-Lactones

et al. 2019

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3-Hydroxy fatty acids have attracted the interest of researchers, since some of them may interact with free fatty acid receptors more effectively than their non-hydroxylated counterparts and their determination in plasma provides diagnostic information regarding mitochondrial deficiency. We present here the development of a convenient and general methodology for the asymmetric synthesis of 3-hydroxy fatty acids. The enantioselective organocatalytic synthesis of terminal epoxides, starting from long chain aldehydes, is the key-step of our methodology, followed by ring opening with vinylmagnesium bromide. Ozonolysis and subsequent oxidation leads to the target products. MacMillan’s third generation imidazolidinone organocatalyst has been employed for the epoxide formation, ensuring products in high enantiomeric purity. Furthermore, a route for the incorporation of deuterium on the carbon atom carrying the hydroxy group was developed allowing the synthesis of deuterated derivatives, which may be useful in biological studies and in mass spectrometry studies. In addition, the synthesis of fatty γ-lactones, corresponding to 4-hydroxy fatty acids, was also explored.

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“…Enantiomerically enriched α‐chlorinated aldehydes constitute important chiral building blocks . In 2004, MacMillan and Jørgensen reported the first asymmetric organocatalytic α‐chlorination of aldehydes via enamine catalysis using imidazolidinones or diarylpyrrolidines as catalysts.…”

Section: Figurementioning

confidence: 99%

Mechanistic Studies on the Organocatalytic α‐Chlorination of Aldehydes: The Role and Nature of Off‐Cycle Intermediates

et al. 2018

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Herein we report the isolation and characterization of aminal intermediates in the organocatalytic α-chlorination of aldehydes. These species are stable covalent ternary adducts of the substrate, the catalyst and the chlorinating reagent. NMR-assisted kinetic studies and isotopic labeling experiments with the isolated intermediate did not support its involvement in downstream stereoselective processes as proposed by Blackmond. By tuning the reactivity of the chlorinating reagent, we were able to suppress the accumulation of rate-limiting off-cycle intermediates. As a result, an efficient and highly enantioselective catalytic system with a broad functional group tolerance was developed.

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Enantioselective Organocatalytic Synthesis of 2-Oxopiperazines from Aldehydes: Identification of the Elusive Epoxy Lactone Intermediate

Cited by 31 publications

References 37 publications

Asymmetric Synthesis of Saturated Hydroxy Fatty Acids and Fatty Acid Esters of Hydroxy Fatty Acids

Asymmetric Synthesis of Saturated Hydroxy Fatty Acids and Fatty Acid Esters of Hydroxy Fatty Acids

Enantioselective Organocatalysis-Based Synthesis of 3-Hydroxy Fatty Acids and Fatty γ-Lactones

Mechanistic Studies on the Organocatalytic α‐Chlorination of Aldehydes: The Role and Nature of Off‐Cycle Intermediates

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