Proline-Catalyzed Asymmetric Addition Reaction of 9-Tosyl-3,4-dihydro-β-carboline with Ketones

Itoh, Takashi; Yokoya, Masashi; Miyauchi, Keiko; Nagata, Kazuhiro; Ohsawa, Akio

doi:10.1021/ol030103x

Cited by 162 publications

(59 citation statements)

References 44 publications

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“…This transformation was developed by Itoh and coworkers, and has been successfully employed in the total synthesis of several structurally similar indole alkaloids. 54–56 The resulting tetracyclic ketone would serve as a versatile intermediate for the synthesis of a variety of analogs, including mitragynine itself (Figure 5). …”

Section: Resultsmentioning

confidence: 99%

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

et al. 2016

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Mu-opioid receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is associated with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of the Southeast Asian plant Mitragyna speciosa, represented by the prototypical member mitragynine, are an unusual class of opioid receptor modulators with distinct pharmacological properties. Here we describe the first receptor-level functional characterization of mitragynine and related natural alkaloids at the mu-, kappa-, and delta-opioid receptors. These results show that mitragynine and the oxidized analog 7-hydroxymitragynine, are partial agonists of the human mu-opioid receptor and competitive antagonists at the kappa- and delta-opioid receptors. We also show that mitragynine and 7-hydroxymitragynine are G-protein-biased agonists of the mu-opioid receptor, which do not recruit β-arrestin following receptor activation. Therefore, the Mitragyna alkaloid scaffold represents a novel framework for the development of functionally biased opioid modulators, which may exhibit improved therapeutic profiles. Also presented is an enantioselective total synthesis of both (-)-mitragynine and its unnatural enantiomer, (+)-mitragynine, employing a proline-catalyzed Mannich-Michael reaction sequence as the key transformation. Pharmacological evaluation of (+)-mitragynine revealed its much weaker opioid activity. Likewise, the intermediates and chemical transformations developed in the total synthesis allowed the elucidation of previously unexplored structure-activity relationships (SAR) within the Mitragyna scaffold. Molecular docking studies, in combination with the observed chemical SAR, suggest that Mitragyna alkaloids adopt a binding pose at the mu-opioid receptor that is distinct from that of classical opioids.

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Section: Resultsmentioning

confidence: 99%

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

et al. 2016

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“…[37] This process, catalyzed by (S)-proline (119), provided an efficient and direct approach to construct a chiral indole alkaloid core 120 in a highly stereoselective manner. This cascade reaction is initiated by an enaminemediated Mannich reaction, which in turn leads to the release of the nitrogen nucleophile, followed by an intramolecular aza-Michael addition on the iminium activated enone 122.…”

Section: Domino Reactions Initiated By An Aza-michael Additionmentioning

confidence: 99%

Organocatalytic Asymmetric Aza‐Michael Additions

Enders

Wang

Liebich

2009

Chemistry A European J

449

147

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The catalytic aza-Michael addition is an important reaction within synthetic organic chemistry, given the significance of the biologically and synthetically interesting products, such as beta-amino acids and beta-lactams. In the last decade organocatalysis emerged as a powerful tool in asymmetric synthesis and had a large impact on the development of asymmetric and catalytic conjugate additions of nitrogen nucleophiles to Michael acceptors. In this review a first summary of the recent rapid progress of asymmetric organocatalyzed aza-Michael reactions is presented.

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“…Particularly, organocatalytic domino/cascade reactions have come into focus and become a powerful synthetic approach that allows the construction of structurally diverse and complex molecules, minimizes the number of manual operations, and saves time, effort, and production costs [45–47]. Thus, many nitrogen-containing heterocyclic compounds have been efficiently generated by means of organocatalytic domino reactions [48–69]. …”

Section: Introductionmentioning

confidence: 99%

Organocatalytic cascade aza-Michael/hemiacetal reaction between disubstituted hydrazines and α,β-unsaturated aldehydes: Highly diastereo- and enantioselective synthesis of pyrazolidine derivatives

Geng¹,

Chen²,

et al. 2012

Beilstein J. Org. Chem.

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SummaryThe catalytic synthesis of nitrogen-containing heterocycles is of great importance to medicinal and synthetic chemists, and also a challenge for modern chemical methodology. In this paper, we report the synthesis of pyrazolidine derivatives through a domino aza-Michael/hemiacetal sequence with chiral or achiral secondary amines as organocatalysts. Thus, a series of achiral pyrazolidine derivatives were obtained with good yields (up to 90%) and high diastereoselectivities (>20:1) with pyrrolidine as an organocatalyst, and enantioenriched pyrazolidines are also achieved with good results (up to 86% yield, >10/1 regioselectivity, >20:1 dr, 99% ee) in the presence of (S)-diphenylprolinol trimethylsilyl ether catalyst.

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Proline-Catalyzed Asymmetric Addition Reaction of 9-Tosyl-3,4-dihydro-β-carboline with Ketones

Cited by 162 publications

References 44 publications

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

Organocatalytic Asymmetric Aza‐Michael Additions

Organocatalytic cascade aza-Michael/hemiacetal reaction between disubstituted hydrazines and α,β-unsaturated aldehydes: Highly diastereo- and enantioselective synthesis of pyrazolidine derivatives

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