The Preparation of alpha-Haloalkyl Esters.

Euranto, Erkki K.; Noponen, Asko; Kujanpää, Tauno; Hofsten, Bengt von; Williams, D. H.; Bunnenberg, E.; Djerassi, Carl; Records, Ruth

doi:10.3891/acta.chem.scand.20-1273

Cited by 32 publications

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“…In the synthesis of Boc‐ d ‐Leu‐OCH 2 I 5 , the preparation of α‐haloalkyl ester 15 (Boc‐ d ‐Leu‐OCH 2 Cl) was the key step. Various methods have been reported for the preparation of α‐haloalkyl esters (31–34). Most of these methods involved the reaction of an acid halide with an aldehyde at high temperature with strong Lewis acids.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and conformational analysis of a coumarinic acid‐based cyclic prodrug of an opioid peptide with modified sensitivity to esterase‐catalyzed bioconversion

Ouyang

Borchardt

Siahaan

et al. 2002

The Journal of Peptide Research

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The coumarinic acid-based cyclic DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH) prodrug 1a exhibited more favorable physicochemical properties than did DADLE for permeation across the intestinal mucosa. However, prodrug 1a, whose bioconversion to DADLE was slow, was subject to extensive biliary clearance when administered to rats in vivo. To increase the rate of esterase-catalyzed bioconversion of prodrug 1a, thus decreasing its biliary clearance, the oxymethyl-modified prodrug 1, in which an aldehyde equivalent is inserted between the phenolic group of the promoiety and the carboxylic acid group of the peptide, was synthesized from benzofuran-2-carboxylic acid 16 via a nine-step procedure. Briefly, phenacyl-protected 3-(2-hydroxyphenyl)-propynoic acid 17 was coupled with Boc-d-Leu-OCH(2)I 5 to give the intermediate 18, which was further elaborated and conjugated with tetrapeptide 4 to give linear precursor 2. Precursor 2 was then deprotected and cyclized to obtain compound 1 using a high dilution technique. In an attempt to investigate the effect of the physicochemical properties and the conformation of prodrug 1 on its permeation characteristics, we calculated its physicochemical parameters and determined its solution conformation using spectroscopic techniques (CD and NMR) and molecular dynamics simulations. Prodrug 1 showed a cLogP value and a molecular size similar to that of prodrug 1a. The deconvoluted CD spectra indicated that prodrug 1 has more random component (71%) than prodrug 1a (42%). 2D-NMR studies of prodrug 1 showed no signals for amide-amide hydrogen interactions and few ROE cross-peaks in ROESY spectra. Using distance restraints constructed from ROESY spectra, molecular dynamics simulations of prodrug 1 generated five conformation families. One family satisfied most of the distance restraints and all of the dihedral angles measured by NMR coupling constants. In summary, prodrug 1 showed favorable physicochemical properties for permeation of the intestinal mucosa. Prodrug 1 adopted a more random conformation in solution than prodrug 1a. These differences in solution conformation could affect the permeation of the prodrugs across the intestinal mucosa by passive diffusion and/or their ability to interact with efflux transporter(s) that would limit their transcellular permeation.

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Section: Resultsmentioning

confidence: 99%

Synthesis and conformational analysis of a coumarinic acid‐based cyclic prodrug of an opioid peptide with modified sensitivity to esterase‐catalyzed bioconversion

Ouyang

Borchardt

Siahaan

et al. 2002

The Journal of Peptide Research

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“…DescudØ [2] [3] reported in 1901 that the reaction of paraformaldehyde with acetyl chloride producedacetic anhydride,bis(chloromethyl)e ther (6a)a nd methanediyl diacetate (7a)b esidest he main product chloromethyl acetate(3a). In 1938, Kirrmann [4]r eacted acrolein with acetyl chloridea nd foundbesideso ft he envisaged 1-chloroprop-2-en-1-yl acetate (3m)-the productso fa n allylic rearrangement (Scheme 1)w hich even dominated aftere quilibrationw as complete.A nd latero n, Euranto [6] [7] was pointing ats everal by-products asw ell.…”

Section: Position Of the Equilibriummentioning

confidence: 99%

“…Euranto varied the acyl groupi ns everal cases [6][7],b ut this was not needed for our synthetic applications,a sC la nd Br were the better leaving groups anyway.I n principle however, there would be the option to change the leaving tendency of the AcO group of 3 4 ).…”

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confidence: 99%

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The Forgotten Carbonyl Reaction: Chloroacetylation and Bromoacetylation of Carbonyl Compounds

Neuenschwander

2015

Helvetica Chimica Acta

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Halomethyl acetates (3)could be preparedfrom aliphatic, a,b-unsaturated and aromatic aldehydes, as well as from alicyclic ketones with high yields in simple one-pot reactions. Very often, the products didnt have to be purified and could directly be used for synthetic purposes after evaporation of the solvent. Obviously,t he bad reputation of the reaction in the literature stemed from the fact that the reactions didnt take place under the best conditions.Carbonyl compounds (1)and acyl halides (2)form equilibria which are completely on the side of the halomethyl acetates(3)atroom temperature (starting with aliphatic and most aromatic aldehydes)and which can be strongly influenced by the reaction parameters. It is crucial to workatlow temperature in apolar solvents and to remove (or deactivate)t he catalyst before workup.Reactions may be realized with or without solvents.Side reactions were observed with formaldehyde and acetaldehydebut, with exception of formaldehyde,could be reduced closetozero (see Fig. 5). Byproducts were essentiallyavoided if the reaction took place in apolar solvents and with alocal excess of acetyl chloride.I nm any cases clean products werea vailable which could directly be used for synthetic purposes.Halomethyla cetates (3)a re bifunctionalc arbonyl derivatives with two different leaving groups, whose preparative advantages have been useful for the synthesis of various pentafulvenes,b ut were especially important for preparingu nstable parent fulvenes and fulvalenes.

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“…The ester had bp 55.0-55.5"C at 10 torr; lit. bp 69-70°C at 40 torr [13]. The fraction of 99.3% purity as determined by gas-liquid chromatography (FFAP-7% Chromosorb G AW DMCS and SE 30-3% Varaport 30,100-120 mesh) was used.…”

Section: Methodsmentioning

confidence: 99%

Gas‐phase elimination kinetics of 1‐substituted ethyl acetates. Effect of polar substituents at the α carbon of secondary acetates

Hernández

Chuchani

1983

Int J of Chemical Kinetics

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The gas-phase elimination of several polar substituents a t the N carbon of ethyl acetates has been studied in a static system over the temperature range of 31O41O0C and the pressure range of 39-313 torr. These reactions are homogeneous in both clean and seasoned vessels, follow a first-order rate law, and are unimolecular. The temperature dependence of the rate coefficients is given by the following Arrhenius equations: 2-acetoxypropionitrile, log kl (s-l)

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The Preparation of alpha-Haloalkyl Esters.

Cited by 32 publications

References 0 publications

Synthesis and conformational analysis of a coumarinic acid‐based cyclic prodrug of an opioid peptide with modified sensitivity to esterase‐catalyzed bioconversion

Synthesis and conformational analysis of a coumarinic acid‐based cyclic prodrug of an opioid peptide with modified sensitivity to esterase‐catalyzed bioconversion

The Forgotten Carbonyl Reaction: Chloroacetylation and Bromoacetylation of Carbonyl Compounds

Gas‐phase elimination kinetics of 1‐substituted ethyl acetates. Effect of polar substituents at the α carbon of secondary acetates

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