Isopropenyl Chloroformate Research Articles

Detailed Analysis for the Solvolysis of Isopropenyl Chloroformate.

The specific rates of solvolysis (including those obtained from the literature) of isopropenyl chloroformate (1) are analyzed using the extended Grunwald-Winstein equation, involving the N(T) scale of solvent nucleophilicity (S-methyldibenzothiophenium ion) combined with a Y(Cl) scale based on 1-adamantyl chloride solvolysis. A similarity model approach, using phenyl chloroformate solvolyses for comparison, indicated a dominant bimolecular carbonyl-addition mechanism for the solvolyses of 1 in all solvents except 97% 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). An extensive evaluation of the outcomes acquired through the application of the extended Grunwald-Winstein equation resulted in the proposal of an addition-elimination mechanism dominating in most of the solvents, but in 97-70% HFIP, and 97% 2,2,2-trifluoroethanol (TFE), it is proposed that a superimposed unimolecular (S(N)1) type ionization is making a significant contribution.

Stoichiometric Effects. Correlation of the Rates of Solvolysis of Isopropenyl Chloroformate

Solvolysis rates of isopropenyl chloroformate (3) in water, D 2 O, CH 3 OD and in aqueous methanol, ethanol, 2,2,2-trifluoroethanol (TFE), acetone, 1,4-dioxane as well as TFE-ethanol at 10 °C are reported. Additional kinetic data for pure water, pure ethanol and 80%(w7w) 2,2,2-trifuoroethanol (T)-water (W) at various temperatures are also reported. These rates show the phenomena of maximum rates in specific solvents (30% (v/v) methanol-water and 20% (v/v) ethanol-water) and, variations in relative rates are small in aqueous alcohols. The kinetic data are analyzed in terms of GW correlations, steric effects, kinetic solvent isotope effects (KSIE), and a third order model based on general base catalysis (GBC). Solvolyses based on predominately stoichiometric solvation effect relative to medium solvation are proceeding in 3 and the results are remarkably similar to those forp-nitrobenzoyl chloride (4) in mechanism and reactivity.

Synthesis and release of 5-fluorouracil from poly( N-vinylpyrrolidinone) bearing 5-fluorouracil derivatives

1-β-Allyloxycarbonyloxymethyl-5-fluorouracil ( 4) and 1,3-bis(β-allyloxycarbonyloxymethyl)-5-fluorouracil ( 5) were synthesised by reacting 5-fluorouracil with formaldehyde followed by treating the product with isopropenyl chloroformate. The monomers 4 and 5 were copolymerized separately with N-vinylpyrrolidinone to form linear copolymers and cross-linked polymer networks, respectively. The monomer reactivity ratios in the copolymerization of 4 with NVP were evaluated by both linear and non-linear methods and the effect of monomer feed composition on copolymer molecular weight was examined. The degradation of the polymer networks in phosphate buffer (pH 7.4) was investigated. The hydrolytic scission of the carbonate groups resulted in release of 5-fluorouracil and a decrease in cross-linking density. The time-dependent fractional release of the 5-FU could be fitted by a power relationship with exponents between 0.10 and 0.25.

Facile synthesis of N-protected γ and δ-Amino-β-Keto-esters

The C-acylation of Meldrum's acid by protected amino acids, using isopropenyl chloroformate (IPCF) as the condensing agent, is described. The process is used to synthesize γ and δ-amino-β-keto-esters.

Synthesis and antiproliferative activity of a cyclic analog of dolastatin 10

A cyclic analog of the natural antiproliferative compound dolastatin 10 was synthesized by introducing an ester link between the N- and C-terminal residues which were modified accordingly. The final macrolactonization was performed by using isopropenyl chloroformate and DMAP as reagents. This analog exhibits submicromolar antiproliferative activity against the L1210 and HT29 cell lines and inhibits in vitro tubulin polymerization (IC 50, 39 μM).

The Dolastatins 20. A Convenient Synthetic Route to Dolastatin 15

A segment synthetic strategy was utilized for obtaining the Dolabella auricularia (Indian Ocean sea hare) depsipeptide dolastatin 15. Reaction of protected (S)-Hiva-(S)-Phe 2c with isopropenyl chloroformate followed by Meldrum's ester, cyclization (2c → 3a) of the product in toluene and finally methylation afforded the key (S)-dolapyrrolidine (Dpy) derivative 3b. Condensation of tripeptide 8 with the three unit Dpy segment 5b followed by deprotection and coupling (diethyl phosphorocyanidate) led to dolastatin 15 in 11% overall yield. The powerful and selective activity of dolastatin 15 against the U.S. National Cancer Institute's panel of human cell lines has been summarized.

Preparation of 2-alkoxy-4-alkyl-5(4H)-oxazolones from mixed anhydrides of N-alkoxycarbonylamino acids.

A general procedure for the preparation of 2-alkoxy-4-alkyl-5(4H)-oxazolones (AlkOx's) from N-tert-butoxy-, N-benzyloxy- and N-(9-fluorenylmethoxy)-carbonylamino acids has been devised. Purified mixed anhydrides are prepared from the parent acid and isopropenyl chloroformate and left in chloroform (Boc) for 24 h or dimethylformamide (Z, Fmoc) for 0.5-2 h. Symmetrical anhydride that may originate from disproportionation or reaction of AlkOx with hydrolyzed product is partially removed by extracting the AlkOx into petroleum ether. The products contain 0.5-30% of symmetrical anhydride.

Studies on the disproportionation of mixed anhydrides of N-alkoxycarbonylamino acids.

Mixed anhydrides from Z-valine and ethyl, isobutyl, isopropyl and isopropenyl chloroformate, and from N-tert-butoxycarbonyl- (Boc) and N-benzyloxycarbonyl- (Z) leucine and phenylalanine and Boc- and N-9-fluorenylmethoxycarbonyl-valine and ethyl chloroformate were purified and left in dichloromethane at 23 degrees C. The symmetrical anhydride (SyAn) generated after 24 h was determined by normal phase high-performance chromatography. No SyAn was produced from the anhydrides of Z- and Boc-valine; SyAn was produced from the other anhydrides. Anhydrides examined without isolation generally produced more SyAn than the pure compounds. More SyAn was generated in dimethylformamide and tetrahydrofuran than in dichloromethane, or in the presence of an excess of N-methylmorpholine or triethylamine. The anhydride from isobutyl chloroformate was much more stable than the anhydride from ethyl chloroformate. It is suggested that disproportionation of pure mixed carboxylic acid--carbonic acid anhydrides occurs by a bimolecular mechanism.

Synthesis of 1,3-diacylaminopropan-2-ols and corresponding 2-acyl derivatives as amide isosteres of natural lipids

N, N′-diacyl-1,3-diaminopropan-2-ols as amide isosteres of 1,3-diacylglycerols are obtained in 50–79% yields by treatment of 1,3-diaminopropan-2-ol with acid chlorides either in ether or THF in the presence of triethylamine and catalytic amounts of 4-dimethyl-aminopyridine. Subsequent acylation of the secondary alcohol function with a variety of carboxylic acids (e.g. fatty acids, N-protected amino acids, drug compounds) can be effected by various techniques (i.e. acid chlorides, symmetrical anhydrides, isopropenyl chloroformate) with yields ranging from 56% to 76%.

Mono-esterification of N-protected di-acids aspartic and glutamic by chloroformate activation.

Mono-esters of N-protected di-acids aspartic and glutamic are prepared by a one-pot activation with alkyl chloroformates or isopropenyl chloroformate and an additionnal alcohol. This process involves the intermediate internal anhydride formation.

Stereospecific synthesis of N-protected statine and its analogues via chiral tetramic acid

The condensation of a chiral N-protected amino acid with Meldrum's acid in the presence of isopropenyl chloroformate (IPCF) and of 4-N,N-dimethylaminopyridine (DMAP) has been examined. The cyclisation of the reaction product, by heating in an organic solvent, gave the N-protected tetramic acid derivatives (4a–i) which, after reduction, afforded the corresponding threo-4-hydroxypyrrolidin-2- ones (5a–i). The regioselective alkaline or acid hydrolysis of the N-protected pyrrolidin-2-ones led to enantiomeric pure N- Boc-statine (6a) and its analogues (6b–i) in 40–60% yield from the N-protected amino acids. The corresponding statine methyl esters (7a–i) could also be synthesized in high yield.

Convenient one-pot esterification of N-protected aminoacids via isopropenyl chloroformate activation.

Activation of N-protected aminoacids by isopropenyl chloroformate leads to esters of primary, secondary and tertiary alcohols with 4-dimethylamino-pyridine as catalyst.

Le chloroformiate d'isopropenyle (ipcf) en chimie des amino-acides et des peptides - iii synthese d'esters actifs d' amino acides n-proteges

Isopropenyl chloroformate (IPCF) was used for preparation of mixed carbonates (Aryl and isopropenyl) which are very suitable reagents for active ester synthesis of amino acid derivatives ( Boc derivatives In particular).