Tandem Michael addition alkylation of vinylphosphonates

The formation of vasoconstrictors (e.g., angiotensin II and endothelin) and the inactivation of vasodilators (e.g., bradykinin and atrial natriuretic) by membrane-bound zinc metallopeptidases are key mechanisms in the control of blood pressure and fluid homeostasis. The way in which these peptides modulate physiological functions has been intensively studied. With the aim to develop compounds that can jointly block the three metallopeptidases-neutral endopeptidase (NEP, neprilysin), angiotensin-converting enzyme (ACE), and endothelin-converting enzyme (ECE-1)-we studied the common structural specificity of the S1' subsites of these peptidases. Various mercaptoacyl amino acids of the general formula HS-CH2-CH(R1')CO-Trp-OH, possessing more or less constrained R1' side chains, were designed. The mercapto-acyl synthons contain one or two asymmetrical centers. The K(i) values of the separated stereoisomers of the most efficient inhibitors were used to determine the stereochemical preference of each enzyme. A guideline for the joint inhibition of the three peptidases was obtained with the (2R,3R) isomer of compound 13b. Its K(i) values on NEP, ACE, and ECE were 0.7, 43, and 26 nM, respectively.

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“…2-(Diethoxyphosphoryl)-3-diphenyl-propionic acid ethyl ester (2d): 7.8 g (87%). TLC (cyclohexane:ethyl acetate, 70:30): R f = 0.17.…”

Section: Methodsmentioning

confidence: 99%

“…2-(Diethoxyphosphoryl)-3-diphenyl-propionic acid ethyl ester (2d): 31 2-(Diethoxyphosphoryl)-3-methyl-3-phenyl-propionic acid ethyl ester (2e): 15 11.9 g (91%). TLC (cyclohexane: ethyl acetate:acetic acid, 5:5:0.5): Rf ) 0.54.…”

Section: Diethoxyphosphoryl-2-(biphen-4-yl)-acetic Acid Methyl Ester ...mentioning

confidence: 99%

Toward an Optimal Joint Recognition of the S₁‘ Subsites of Endothelin Converting Enzyme-1 (ECE-1), Angiotensin Converting Enzyme (ACE), and Neutral Endopeptidase (NEP)

et al. 2002

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“…Homologation of a carbon chain can also be performed using a tandem Michael addition and alkylation. Described by Vieth and co-workers, 65 the addition of lithiumdimethylcuprate to isopropyl 2-diethoxyphosphorylcinnamate (293) resulted in the formation of adduct 294, which in the presence of halo compounds 295 or a proton donor was transformed into the mixture of diastereoisomeric phosphonates 296 (Scheme 58).…”

Section: Scheme 57mentioning

confidence: 99%

Michael Additions to Activated Vinylphosphonates

Janecki¹,

Kędzia²,

Wąsek³

2009

Synthesis

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Activated vinylphosphonates constitute a very important group of organic reagents which have found broad application in organic synthesis. The most important feature of activated vinylphosphonates is certainly their ability to undergo Michael additions in which a wide variety of carbo-and heteronucleophiles can be used. This review presents the potential of activated vinylphosphonates as Michael acceptors and shows possible applications of the thusformed adducts, in particular as Horner-Wadsworth-Emmons olefinating reagents, in the synthesis of important carbo-and heterocycles as well as acyclic compounds. Selected preparations of activated vinylphosphonates are also described.

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Acid‐Free Nickel Catalyst for Stereo‐ and Regioselective Hydrophosphorylation of Alkynes: Synthetic Procedure and Combined Experimental and Theoretical Mechanistic Study

et al. 2010

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Abstract:The nickel catalyst prepared in situ from nickel bis(acetylacetonate) [NiA C H T U N G T R E N N U N G (acac) 2 ] precursor and bis(diphenylphosphino)ethane (DPPE) ligand has shown excellent performance in the hydrophosphorylation of alkynes. Markovnikov-type regioselective addition to terminal alkynes and stereoselective addition to internal alkynes were carried out with high selectivity without an acidic co-catalyst (in contrast to the palladium/acid catalytic system). Various Hphosphonates and alkynes reacted smoothly in the developed catalytic system with up to 99% yield. The mechanisms of catalyst activation and C À P bond formation were revealed by experimental (NMR, ESI-MS, X-ray) and theoretical (density functional calculations) studies. Two different pathways of the alkyne insertion in the coordination sphere of the metal are reported for the first time.

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Tandem Michael addition alkylation of vinylphosphonates

Cited by 10 publications

References 13 publications

Toward an Optimal Joint Recognition of the S₁‘ Subsites of Endothelin Converting Enzyme-1 (ECE-1), Angiotensin Converting Enzyme (ACE), and Neutral Endopeptidase (NEP)

Toward an Optimal Joint Recognition of the S₁‘ Subsites of Endothelin Converting Enzyme-1 (ECE-1), Angiotensin Converting Enzyme (ACE), and Neutral Endopeptidase (NEP)

Michael Additions to Activated Vinylphosphonates

Acid‐Free Nickel Catalyst for Stereo‐ and Regioselective Hydrophosphorylation of Alkynes: Synthetic Procedure and Combined Experimental and Theoretical Mechanistic Study

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Tandem Michael addition alkylation of vinylphosphonates

Cited by 10 publications

References 13 publications

Toward an Optimal Joint Recognition of the S1‘ Subsites of Endothelin Converting Enzyme-1 (ECE-1), Angiotensin Converting Enzyme (ACE), and Neutral Endopeptidase (NEP)

Toward an Optimal Joint Recognition of the S1‘ Subsites of Endothelin Converting Enzyme-1 (ECE-1), Angiotensin Converting Enzyme (ACE), and Neutral Endopeptidase (NEP)

Michael Additions to Activated Vinylphosphonates

Acid‐Free Nickel Catalyst for Stereo‐ and Regioselective Hydrophosphorylation of Alkynes: Synthetic Procedure and Combined Experimental and Theoretical Mechanistic Study

Contact Info

Product

Resources

About

Toward an Optimal Joint Recognition of the S₁‘ Subsites of Endothelin Converting Enzyme-1 (ECE-1), Angiotensin Converting Enzyme (ACE), and Neutral Endopeptidase (NEP)

Toward an Optimal Joint Recognition of the S₁‘ Subsites of Endothelin Converting Enzyme-1 (ECE-1), Angiotensin Converting Enzyme (ACE), and Neutral Endopeptidase (NEP)