A Simple Preparation of Chloromethyl Esters of the Blocked Amino Acids

Harada, Naoyuki; Hongu, Mitsuya; Tanaka, Takashi; Kawaguchi, Takayuki; Hashiyama, Tomiki; Tsujihara, Kenji

doi:10.1080/00397919408011298

Cited by 19 publications

(13 citation statements)

References 4 publications

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“…The alkylation of Boc‐ d ‐Leu‐OH 14 with dihalomethane was also unsuccessful − it gave a complicated mixture, from which it was difficult to separate the desired product. Compound 15 was finally synthesized by alkylating Boc‐ d ‐Leu‐OH 14 with chloromethyl chlorosulfate 13 (37–39) in a two‐phase system of methylene chloride and aqueous sodium bicarbonate in the presence of a phase transfer agent ( n ‐Bu 4 NHSO 4 ) (Fig. 4).…”

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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“…18 On the basis of Scheme 2, assuming that all the Lewis acid/ base equilibria are rapidly established, we can express the total concentration of SO 3 weighed into the reaction mixture by Eqn. (2), where, for simplicity, charges have been omitted from the representations of the species:…”

Section: Kinetics and Mechanism Of The Trimethyl Borate-catalysed Rea...mentioning

confidence: 99%

“…Analogous polysulfates have been implicated as transient intermediates in aromatic sulfonation by SO 3 , reactions which show kinetic orders in SO 3 of two or more 18. On the basis of Scheme 2, assuming that all the Lewis acid/ base equilibria are rapidly established, we can express the total concentration of SO 3 weighed into the reaction mixture by Eqn (2),. where, for simplicity, charges have been omitted from the representations of the species:…”

mentioning

confidence: 99%

Chloromethyl chlorosulfate: a new, catalytic method of preparation and reactions with some nucleophiles

Power

Bethell

Proctor³

et al. 2004

Org. Biomol. Chem.

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The reaction of liquid (gamma-) SO3 with CH2Cl2 at room temperature leads to SO3 insertion into the C-Cl bonds, giving the useful chloromethylating agent chloromethyl chlorosulfate (CMCS). The process is very slow but becomes rapid on addition of catalytic quantities of trimethyl borate. The product mixture consists almost entirely of CMCS and the product of further sulfation, methylene bis(chlorosulfate)(MBCS), in a ratio of ca. 2 : 1, but typical yields of CMCS, isolated by distillation, are only 30-35%. The catalysed reaction in the homogeneous liquid phase at -45 degrees C has been followed as a function of time and of reactant concentration by 1H nmr spectroscopy. It is observed that, besides CMCS and MBCS, three additional, transient products (designated A, B and C) are formed. Products A, B and C decompose slowly at -45 degrees C but much more rapidly if the reaction mixture is raised to room temperature, giving additional CMCS and MBCS. From an analysis of the SO3 balance, it is inferred that products A, B and C arise from the reaction of one molecule of CH2Cl2 with respectively two, three and four molecules of SO3; they are suggested to be chloromethyl chloropolysulfates. By measuring initial rates of CMCS formation or total CH2Cl2 consumption, it is shown that the reaction is first order in the catalyst and roughly third order in SO3. A mechanistic scheme is proposed in which SO3 forms equilibrating zwitterionic molecular complexes with CH2Cl2. of 1 : 1, 2 : 1 and higher stoichiometries. The boron-containing catalyst can activate these complexes towards nucleophilic attack at carbon by the negatively charged oxygen of another zwitterion. An analogous mechanism can be written for the conversion of CMCS into MBCS by SO3 in the presence of trimethyl borate. CMCS reacts rapidly with anionic nucleophiles, such as halide or acetate ions (X-), in homogeneous solution of their tetrabutylammonium salts in CD3CN, or in a two-phase system (CDCl3/H2O) using alkali-metal salts in conjunction with a phase-transfer catalyst. In both situations the products (ClCH2X) arise by rapid nucleophilic displacement of the chlorosulfate moiety; this then more slowly liberates chloride ion, which converts further CMCS into CH2Cl2. The reactivity of CMCS has been compared with that of MBCS and methyl chlorosulfate (MCS) in competitive experiments; the reactivity order is MCS > MBCS > CMCS >> CH2Cl2. Evidence is also presented suggesting that, in contrast to the halide nucleophiles, reaction of CMCS with sodium phenoxide in tetrahydrofuran solution leads to nucleophilic displacement of the sulfur-bound chloride.

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“…A soln. of NRB (0.5 g, 1.0 mmol), chloromethyl dodecanoate (0.5 g, 2.0 mmol), Cs 2 CO 3 (0.39 g, 1.2 mmol), and Et 4 NI (25 mg, 0.1 mmol) in DMF (15 ml) was stirred at r.t. overnight. The mixture was then diluted with Et 2 O and washed with brine.…”

Section: Experimental Partmentioning

confidence: 99%

Fatty Acid‐Derived Pro‐Toxicants of the Rat Selective Toxicant Norbormide

Choi

Conole

Atkinson

et al. 2016

Chemistry & Biodiversity

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Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, as an acute vasoactive, NRB has a rapid onset of action which makes it relatively unpalatable to rats, often leading to sublethal uptake and accompanying bait shyness. A series of NRB-derived pro-toxicants (3a - i, 4a - i, and 5a - i) were prepared in an effort to 'mask' this acute response and improve both palatability and efficacy. Their synthesis, in vitro biological evaluation (vasocontractile response in rat vasculature, stability in selected rat media) and palatability/efficacy in Sprague-Dawley, wild Norway, and wild ship rats is described. Most notably, pro-toxicant 3d was revealed to be free of all pre-cleavage vasoconstrictory activity in rat caudal artery and was subsequently demonstrated to release NRB in the presence of rat blood, liver, and pancreatic enzymes. Moreover, it consistently displayed a high level of acceptance by rats in a two-choice bait-palatability and efficacy trial, with accompanying high mortality. On this evidence, fatty acid ester prodrugs would appear to offer a promising platform for the further development of NRB-derived toxicants with enhanced palatability and efficacy profiles.

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A Simple Preparation of Chloromethyl Esters of the Blocked Amino Acids

Cited by 19 publications

References 4 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

Chloromethyl chlorosulfate: a new, catalytic method of preparation and reactions with some nucleophiles

Fatty Acid‐Derived Pro‐Toxicants of the Rat Selective Toxicant Norbormide

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