Chelation controlled reduction of N-protected β-amino ketones toward the synthesis of HPA-12 and analogues

Chacko, Shibin; Kalita, Mrinal; Ramapanicker, Ramesh

doi:10.1016/j.tetasy.2015.04.016

Cited by 10 publications

(15 citation statements)

References 47 publications

(13 reference statements)

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“…The group of Delgado [17] described at hree-step sequences tarting from keto amino acid 43 easily obtained from d-aspartic acid (Scheme 13). [12a] Af ew months later,R amapanicker and co-workers [26] (Scheme 14) also proposed as ynthesis of (1R,3S)-HPA-12 and analogues.T or each g-aryl-g-oxo-b-amino alcohol 45 as an advancedi ntermediate, they substituted the l-serine iodide derivative 44 with lithiated phenyl dithiane, hydrolyzed the N,Oacetalu nder acidic conditions, and the dithiane by diiodide treatment. [12a] Af ew months later,R amapanicker and co-workers [26] (Scheme 14) also proposed as ynthesis of (1R,3S)-HPA-12 and analogues.T or each g-aryl-g-oxo-b-amino alcohol 45 as an advancedi ntermediate, they substituted the l-serine iodide derivative 44 with lithiated phenyl dithiane, hydrolyzed the N,Oacetalu nder acidic conditions, and the dithiane by diiodide treatment.…”

Section: Syntheses Of Hpa-12mentioning

confidence: 99%

“…Synthesis of (1R,3S)-HPA-12 by Ramapanicker: [26] a) nBuLi, THF, À20 8C, 85 %; b) TFA( 7%), MeOH, 93 %; c) I 2 ,NaHCO 3, CH 3 CN-H 2 O, 84 %; d) NaBH 4 ,CeCl 3, MeOH, 0 8C, 98 %(d.r.85:15);e)i )HCl (10 %), EtOAc,08C; ii)C 11 H 23 COCl, NaHCO 3 ,THF,08C, 70 %. Synthesis of (1R,3S)-HPA-12 by Ramapanicker: [26] a) nBuLi, THF, À20 8C, 85 %; b) TFA( 7%), MeOH, 93 %; c) I 2 ,NaHCO 3, CH 3 CN-H 2 O, 84 %; d) NaBH 4 ,CeCl 3, MeOH, 0 8C, 98 %(d.r.85:15);e)i )HCl (10 %), EtOAc,08C; ii)C 11 H 23 COCl, NaHCO 3 ,THF,08C, 70 %.…”

Section: Syntheses Of Hpa-12mentioning

confidence: 99%

“…N-Acylation of 43 followed by esterification afforded the ester 10.A sd escribed by Kobayashi and co-workers, [18a] combinationo fK -Selectride and LiBEt 3 H directly reduced the keto ester derivative 10 into am ajor HPA-12 diastereoisomer,previously shown to be 1R,3S. [12a] Af ew months later,R amapanicker and co-workers [26] (Scheme 14) also proposed as ynthesis of (1R,3S)-HPA-12 and analogues.T or each g-aryl-g-oxo-b-amino alcohol 45 as an advancedi ntermediate, they substituted the l-serine iodide derivative 44 with lithiated phenyl dithiane, hydrolyzed the N,Oacetalu nder acidic conditions, and the dithiane by diiodide treatment. The obtained b-keto amino ketone 45 then had to be diastereoselectively reduced.…”

Section: Syntheses Of Hpa-12mentioning

confidence: 99%

“…Scheme14. Synthesis of (1R,3S)-HPA-12 by Ramapanicker: [26] a) nBuLi, THF, À20 8C, 85 %; b) TFA( 7%), MeOH, 93 %; c) I 2 ,NaHCO 3, CH 3 CN-H 2 O, 84 %; d) NaBH 4 ,CeCl 3, MeOH, 0 8C, 98 %(d.r.85:15);e)i )HCl (10 %), EtOAc,08C; ii)C 11 H 23 COCl, NaHCO 3 ,THF,08C, 70 %.…”

Section: Syntheses Of Hpa-12mentioning

confidence: 99%

“…Ramapanicker and co-workers [26] Long alkyl chain in meta-o rpara-position on aromatic ring Aza-Michael-based crystallization-induced asymmetric transformation followed by Sonogashira coupling and triple bond reduction EC 50 determination by TR-FRET binding assay by competition versus biotinylated-ceramide bound to the STARTd omain of CERT [32] Daïch, GØnisson, Berkeš and coworkers [33] Replacement of the phenyl ring by long alkyl chains Aza-Michael-based crystallization-induced asymmetric transformation followed by hydrodesulfurization of thiophene ring EC 50 determination by TR-FRET binding assay by competition versus biotinylated-ceramide bound to STARTd omain of CERT [32] Daïch, GØnisson, Berkeš and coworkers [33] Not evaluated…”

Section: Not Evaluatedmentioning

confidence: 99%

See 4 more Smart Citations

Chemistry and Biology of HPAs: A Family of Ceramide Trafficking Inhibitors

Berkeš¹,

Daı̈ch

Santos

et al. 2016

Chemistry A European J

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In 2001, two years before the disclosure of the CERT-associated Cer transfer machinery, N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)alkanamides (HPAs) were described as the first, and to date unique, family of intracellular Cer trafficking inhibitors. The dodecanamide derivative, HPA-12, turned out to be a benchmark as a cellular inhibitor of CERT-mediated de novo sphingomyelin biosynthesis. In only 15 years after its first disclosure, this compound has prompted a growing number of biological and chemical studies. Its initial chemical development closely paralleled the study of the CERT protein. It was only after its structural revision in 2011 that HPA-12 received broad attention from the synthetic chemistry community, leading to novel analogues with enhanced protein binding. This Minireview aims at presenting an exhaustive report of the syntheses of HPA-12 and analogues. Biological activities of this CERT inhibitor and structure-activity relationships are also presented to afford a comprehensive overview of the chemistry and biology of the HPA series.

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Section: Syntheses Of Hpa-12mentioning

confidence: 99%

Section: Syntheses Of Hpa-12mentioning

confidence: 99%

Section: Syntheses Of Hpa-12mentioning

confidence: 99%

Section: Syntheses Of Hpa-12mentioning

confidence: 99%

Section: Not Evaluatedmentioning

confidence: 99%

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Chemistry and Biology of HPAs: A Family of Ceramide Trafficking Inhibitors

Berkeš¹,

Daı̈ch

Santos

et al. 2016

Chemistry A European J

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Asymmetric Synthesis and Binding Study of New Long‐Chain HPA‐12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT

Ďuriš

Daı̈ch

Santos

et al. 2016

Chemistry A European J

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A series of 12 analogues of the Cer transfer protein (CERT) antagonist HPA-12 with long aliphatic chains were prepared as their (1R,3S)-syn and (1R,3R)-anti stereoisomers from pivotal chiral oxoamino acids. The enantioselective access to these intermediates as well as their ensuing transformation relied on a practical crystallization-induced asymmetric transformation (CIAT) process. Sonogashira coupling followed by triple bond reduction and thiophene ring hydrodesulfurization (HDS) into the corresponding alkane moieties was then implemented to complete the synthetic routes delivering the targeted HPA-12 analogues in concise 4- to 6-step reaction sequences. Ten compounds were evaluated regarding their ability to bind to the CERT START domain by using the recently developed time-resolved FRET-based homogeneous (HTR-FRET) binding assay. The introduction of a lipophilic appendage on the phenyl moiety led to an overall 10- to 1000-fold enhancement of the protein binding, with the highest effect being observed for a n-hexyl residue in the meta position. The importance of the phenyl ring for the activity was indicated by the reduced potency of the 3-deoxyphytoceramide aliphatic analogues. The 1,3-syn stereoisomers were systematically more potent than their 1,3-anti analogues. In silico studies were used to rationalized these trends, leading to a model of protein recognition coherent with the stronger binding of (1R,3S)-syn HPAs.

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