Total Synthesis of Isodaphlongamine H: A Possible Biogenetic Conundrum

Chattopadhyay, Amit Kumar; Ly, Vu Linh; Jakkepally, Shashidhar; Berger, Gilles; Hanessian, Stephen

doi:10.1002/anie.201510861

Cited by 71 publications

(69 citation statements)

References 65 publications

(15 reference statements)

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“…In a related isolated example, Baati, Himo, and coworkers have studied the intramolecular aldol reaction of an acyclic keto aldehyde catalyzed by TBD through DFT calculations and proposed a proton‐shuttling general base mechanism. We have recently used the presently described TBD‐catalyzed intramolecular aldol cyclization in a critical key step toward the total synthesis of isodaphlongamine H To the best of our knowledge, the intramolecular TBD‐catalyzed aldol reaction of a triketone such as 1 has not been previously reported and offers distinct advantages.…”

Section: Resultsmentioning

confidence: 99%

Metal Coordination Controlled and Bifunctional H‐Bonded Catalysis in Stereoselective Intramolecular Aldol Cyclizations toward Carbocyclic Tertiary β‐Ketols

2017

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The principle of bifunctional catalysis is shown in the highly regio‐ and stereoselective intramolecular aldolization of 2‐methyl‐1,3‐cyclopentanedione, C2‐substituted with a methyl ethyl ketone group, to provide [3.2.1]‐bicyclooctanol diones in the presence of catalytic amounts of either LiBr and 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU), or 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene (TBD). Mechanistic investigations corroborated by DFT calculations show that LiBr engages in a bifunctional coordination of two carbonyl moieties and leads to the preorganization of the reactive enolate intermediate for a base‐mediated intramolecular aldol cyclization. On the other hand, TBD catalysis of the triketone substrate proceeds through a bifunctional H‐bonded mechanism to give the same aldol product as the major diastereomer. The LiBr and TBD‐catalyzed highly stereocontrolled intramolecular aldol cyclizations can be extended to other di‐ and triketones to give carbocyclic and carbobicyclic products as single diastereomers.

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Section: Resultsmentioning

confidence: 99%

Metal Coordination Controlled and Bifunctional H‐Bonded Catalysis in Stereoselective Intramolecular Aldol Cyclizations toward Carbocyclic Tertiary β‐Ketols

2017

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“…(R)-Methyl 2-(3-methoxyphenylamino)propanoate [( R )- 6 ], prepared following the above described procedure for the synthesis of 6 , starting from ( S )- 5 [ 27 ] . Oil; 95% yield.…”

Section: Methodsmentioning

confidence: 99%

Chiral Recognition of Flexible Melatonin Receptor Ligands Induced by Conformational Equilibria

et al. 2020

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N-anilinoethylamides are a class of melatoninergic agents with the aniline portion mimicking the indole ring of the natural ligand and the ethylamide chain reproducing that of melatonin. The simplest compound in this class, N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide (UCM793), has nanomolar binding affinity for MT1 and MT2 membrane receptors. To explore the effect of chain conformation on receptor binding, a methyl group was inserted on the methylene alpha or beta to the amide nitrogen and conformational equilibria were investigated by NMR spectroscopy and molecular dynamics simulations. Receptor affinity was conserved only for the beta-methyl derivative, which also showed significant stereoselectivity, with the (S) enantiomer being the eutomer. Molecular dynamics simulations, validated by NMR spectroscopy, showed that the beta-methyl group affects the conformational preferences of the ethylamide chain. Docking into the receptor crystal structure provides a rationale for the observed chiral recognition, suggesting that the (S)-beta-methyl group favors the conformation that better fits the receptor binding site.

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“…The congested polycyclic ring systems of these alkaloids, along with their promising bioactivities, make them highly attractive synthetic targets ,,. Since the pioneering syntheses of several daphniphyllum alkaloids by the Heathcock group, impressive total syntheses of various daphniphyllum alkaloids have been reported by the Carreira, Smith, Li, Hanessian, Fukuyama, Zhai, Dixon, and Qiu groups …”

Section: Figurementioning

confidence: 99%

A Concise Total Synthesis of (−)‐Himalensine A

Chen

Guo

et al. 2019

Angewandte Chemie

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The daphniphyllum alkaloids are a structurally fascinating and remarkably diverse family of natural products. General strategies for the chemical synthesis of their challenging architectures are highly desirable for efficiently accessing these intriguing alkaloids and addressing their pharmaceutical potential. Herein, a concise strategy designed to provide general and diversifiable access to various daphniphyllum alkaloids is described and utilized in the asymmetric synthesis of (−)‐himalensine A, which was accomplished in 14 steps. Key features of this strategy include a Cu‐catalyzed nitrile hydration, a Heck reaction to construct the challenging 2‐azabicyclo[3.3.1]nonane motif, a Meinwald rearrangement reaction, six, pot‐economic reactions, and the minimal use of protecting groups, which significantly improved the overall synthetic efficiency.

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Total Synthesis of Isodaphlongamine H: A Possible Biogenetic Conundrum

Cited by 71 publications

References 65 publications

Metal Coordination Controlled and Bifunctional H‐Bonded Catalysis in Stereoselective Intramolecular Aldol Cyclizations toward Carbocyclic Tertiary β‐Ketols

Metal Coordination Controlled and Bifunctional H‐Bonded Catalysis in Stereoselective Intramolecular Aldol Cyclizations toward Carbocyclic Tertiary β‐Ketols

Chiral Recognition of Flexible Melatonin Receptor Ligands Induced by Conformational Equilibria

A Concise Total Synthesis of (−)‐Himalensine A

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