Kinetics and mechanism of the addition of nucleophiles to alpha,beta-unsaturated thiol esters

Compounds containing the UV-absorbing chromophores p-methoxycinnamate, p-methoxycinnamide, or anthranilate and an alpha,beta- or alpha,beta,gamma,delta-unsaturated thiol ester (crotonyl or sorboyl) have been prepared. These compounds are subject to nucleophilic attack at the C=C conjugated to the thiol ester carbonyl group. The kinetics of the reactions of these thiol esters with N-acetyl-l-cysteine (NAC), N-acetylcysteamine, and N(2)-acetyl-L-lysine (NAL) have been studied, and the thiol addition products have been identified. The reaction rates increased at higher pH, and the reaction of NAC thiolate with a crotonyl thiol ester in 1:1 (v/v) acetonitrile/aqueous HEPES exhibited buffer catalysis as a result of protonation of the enolate intermediate. At the same concentration, NAC underwent approximately 300-fold more reaction than NAL with a crotonyl thiol ester at pH 9.8. Additionally, a crotonyl thiol ester was found to be 7.9 times more reactive than a sorboyl thiol ester toward NAC addition. These unsaturated thiol esters may serve as a means of covalently binding UVA and UVB sunscreens to the outer layer of skin to provide long-lasting protection.     

An easy stereoselective access to beta,gamma-aziridino alpha-amino ester derivatives via mannich reaction of benzophenone imines of glycine esters with N-sulfonyl alpha-chloroaldimines

Mannich-type addition of benzophenone imine glycinates across newly synthesized N-(p-toluenesulfonyl) alpha-chloroaldimines afforded gamma-chloro-alpha,beta-diamino ester derivatives with moderate diastereoselectivity as separable mixtures of anti and syn diastereomers. The gamma-chloro-alpha,beta-diamino esters were efficiently cyclized under basic conditions to the corresponding beta,gamma-aziridino alpha-amino ester derivatives, representing a new class of conformationally constrained heterocyclic alpha,beta-diamino acid derivatives. The relative configuration of the aziridines was determined via X-ray diffraction analysis. Mechanisms and intermediate transition states to explain the stereochemical outcome of the Mannich reaction with different substrates or under different conditions are proposed. The synthetic importance of the beta,gamma-aziridino alpha-amino ester derivatives is demonstrated by their conversion into the corresponding Boc-protected derivatives and ring opening reactions to alpha,beta-diamino esters and a gamma-amino alpha,beta-unsaturated amino ester.     

Asymmetric three- and [2 + 1]-component conjugate addition reactions for the stereoselective synthesis of polysubstituted piperidinones

The efficiency and stereoselectivity of the conjugate addition of lithium (Z)- or (E)-beta-amino ester enolates, generated by lithium amide conjugate addition to an alpha,beta-unsaturated ester or deprotonation of a beta-amino ester, respectively, to a range of alpha,beta-unsaturated acceptors has been investigated. Deprotonation of a beta-amino ester with LDA, followed by conjugate addition to a chiral alpha,beta-unsaturated oxazolidinone gives high 2,3-anti selectivity ( approximately 90% d.e.), with hydrogenolysis and purification to homogeneity generating stereodefined trisubstituted piperidinones as single stereoisomers. Asymmetric three-component couplings of alpha,beta-unsaturated esters and alkylidene malonates initiated by lithium amide conjugate addition proceeds with high levels of 2,3-anti stereoselectivity, with hydrogenolysis giving tetrasubstituted piperidinones.     

C-O-bond cleavage of esters with a naphthyl group in the higher triplet excited state during two-color two-laser flash photolysis

A C-O-bond cleavage of esters having a naphthyl group, NpCO-OR and RCO-ONp (Np=alpha- and beta-naphthyl ((alpha)Np and (beta)Np, respectively), R=Ph and Me), was found during the two-color two-laser flash photolysis in acetonitrile. The C-O-bond cleavage occurred when NpCO-OR and RCO-ONp were excited to the singlet excited states (S1). On the other hand, no reaction occurred from the lowest triplet excited states (T1). When NpCO-OR(T1) and RCO-ONp(T1) were excited to the higher triplet excited states (Tn) using the second laser during the two-color two-laser flash photolysis, the C-O-bond cleavage occurred. The C-O-bond cleavage quantum yield (Phi) was estimated from the plots of the T1-state esters disappeared within a laser flash versus the second laser intensities. The C-O-bond cleavage in (beta)NpCO-OPh(Tn) occurred more efficiently than in (alpha)NpCO-OPh(Tn) and that in PhCO-O(beta)Np(Tn) occurred more efficiently than in PhCO-O(alpha)Np(Tn). The Phi value for ester with Ph and beta-Np groups was larger than that for ester with Ph and alpha-Np groups. The Phi value for MeCO-O(alpha)Np(Tn) was similar to those for PhCO-ONp(Tn), while that for MeCO-O(beta)Np(Tn) was much smaller than those for PhCO-ONp(Tn) and MeCO-O(alpha)Np(Tn). On the other hand, no C-O-bond cleavage was observed in NpCO-OMe(Tn). The Phi value depended on the characters of the groups (Np, Ph, and Me) on the ester. Whether R is Ph or Me with or without pi electron, respectively, is important for the C-O-bond cleavage. In other words, electronic delocalization of the T(n) state including Np and ester groups is necessary for the occurrence of the C-O-bond cleavage in NpCO-OR(Tn) and RCO-ONp(Tn).     

Enantioselective conjugate addition of a lithium ester enolate catalyzed by chiral lithium amides

Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on alpha,beta-unsaturated esters. Michael adducts were obtained in ee's up to 76% combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction was found to be determined by both the relative configuration of the stereogenic centers borne by the amide and the solvent in which the reaction was conducted. [reaction: see text]     

Michael addition of stannyl ketone enolate to alpha,beta-unsaturated esters catalyzed by tetrabutylammonium bromide and an ab initio theoretical study of the reaction course

Michael addition of stannyl ketone enolates to alpha,beta-unsaturated esters was accomplished in the presence of a catalytic amount of tetrabutylammonium bromide (Bu(4)NBr). Other typical systems using lithium enolate or silyl enolate with catalysts (TiCl(4) or Bu(4)NF) failed to give the desired products. The bromide anion from Bu(4)NBr coordinates to the tin center in enolate to accelerate the conjugate addition where a five-coordinated tin species was generated. The coordination of the bromide anion significantly raises the HOMO level of tin enolate and enhances its nucleophilicity. The conjugate addition provides the intermediate Michael adduct, which has an ester enolate moiety, and the adduct immediately transforms to alpha-stannyl gamma-ketoester by keto-enol tautomerization. This step contributes to the stabilization of the product system and leads to a thermodynamically favorable reaction course. An ab initio calculation reveals that the activation energy in the reaction using the bromide anion is lower than that of the reaction without using it. The transition state in either reaction course has a linear structure, not a cyclic one. This system can be applied to a variety of tin enolates and alpha,beta-unsaturated carbonyls involving enoates, enones, and unsaturated amides.     

Synthesis of a hydroxyethylene isostere of the tripeptide Arg-Gly-Leu via a convergent acyl-like radical addition strategy

[reaction: see text] A hydroxyethylene isostere of the tripeptide Arg-Gly-Leu, representing an important fragment of a novel cyclic-peptide-based uPA inhibitor, was synthesized in few steps employing as the key step a samarium diiodide promoted coupling of either the 4-thiopyridyl ester of N(alpha)-Fmoc- or N(alpha)-Cbz-protected L-ornithine with the N-acryloyl derivative of L-leucine methyl ester. Epimerization under the coupling conditions at the chiral center in the alpha-position to the ketone was demonstrated not to take place. A stereoselective reduction of the Cbz-protected aminoketone obtained from this radical reaction was promoted by the same single-electron reducing agent in the presence of methanol providing the syn-amino alcohol with a diastereoselectivity of 85:15. With the use of lithium tri-tert-butoxyaluminum hydride in methanol, the corresponding anti-isomer was obtained almost exclusively. Subsequent elaboration of the ornithine moiety in the anti-isomer by introduction of the guanidine group followed by hydrolysis of the C-terminal ester bond and protection of the alcohol as its tert-butyldimethylsilyl ether provided the desired tripeptide mimic. The long reaction times required for the radical addition reactions with N(delta)-Boc-L-ornithine (up to 5 days) led to a short study where a series of 4-thiopyridyl esters of Cbz-protected amino acids were reacted with two acrylates. Whereas N(delta)-Boc-L-ornithine, alanine, phenylalanine, proline, and leucine all provided the aminoketone in 43-79% yield, valine only afforded traces of the coupling product.     

Intermolecular cross-double-michael addition between nitro and carbonyl activated olefins as a new approach in C-C bond formation

A novel intermolecular cross-double-Michael addition between nitro and carbonyl activated olefins has been developed through Lewis base catalysis. The reaction took place with a large group of beta-alkyl nitroalkenes and alpha,beta-unsaturated ketone/esters, producing an allylic nitro compound in good to excellent yields.     

Investigation of the diastereoselective cyclization of bis-sulfonyl esters

[reaction: see text] The diastereoselective cyclization of bissulfonyl esters was investigated by varying both the size and the placement of the substituent on the tether adjoining the reacting centers. Substitution at either the alpha or beta position relative to the ester moiety gave diastereomeric ratios of (1-3):1, while gamma substitution dramatically increased the diastereomeric ratios to (6-20):1.     

Synthesis of Linear Amphipathic Porphyrin Dimers and Trimers: An Approach to Bilayer Lipid Membrane Spanning Porphyrin Arrays

A modular building-block approach has been developed for the construction of linear amphipathic porphyrin arrays. The reaction of meso-(trifluoromethyl)dipyrromethane and an aldehyde under the conditions of the two-step room temperature porphyrin synthesis affords the trans-substituted porphyrin (13-56% yields). A similar reaction with two different aldehydes provides access to porphyrins bearing two different functional groups. An ethyne porphyrin and an iodo porphyrin (either free base or zinc) are selectively joined via Pd(0)-catalyzed coupling reactions, affording a linear array with porphyrins in defined metalation states. Coupling of a zinc-porphyrin bearing iodo and ester groups with a free base porphyrin bearing ethyne and ester groups yielded the zinc-free base porphyrin dimer. Coupling of a bis-ethyne porphyrin with a porphyrin bearing iodo and ester groups afforded the porphyrin trimer. Cleavage of the esters yielded the amphipathic porphyrin dimer and trimer arrays. The arrays with adjacent zinc and free base porphyrins undergo efficient electronic energy transfer. Both amphipathic porphyrin arrays have been incorporated into L-alpha-phosphatidylcholine vesicles. This versatile synthetic strategy provides access to a family of porphyrin arrays for studies of photophysical processes in supramolecular assemblies.     

Copper-catalyzed addition of diboron reagents to alpha,beta-acetylenic esters: efficient synthesis of beta-boryl-alpha,beta-ethylenic esters

The efficient copper-catalyzed addition reaction of bis(pinacolato)diboron to alpha,beta-acetylenic esters has been developed, which produces the corresponding beta-borylated-alpha,beta-ethylenic esters in high yields under mild reaction conditions.     

N,N-dihalophosphoramides—X : The addition of diethyl N,N-dichlorophosphoroamidate (DCPA) to α-olefins and α,β-unsaturated esters

The addition of DCPA to several α-olefins and α,β-unsaturated esters has been studied. The reaction was found to proceed in boiling benzene and was evidently accelerated by UV irradiation. N-Chloro adducts, formed in reasonable yields, afforded the corresponding diethyl N-(β-chloroalkyl) phosphoroamidates upon reduction with sodium bisulphite solution. β-Chloroamine hydrochlorides or α-chloro-β-aminoacid ester hydrochlorides could be produced from the latter compounds by PN bond cleavage with hydrogen chloride in benzene. The full regioselectivity for anti-Markovnikov addition, as proven by NMR evidence, is in accord with the photolytically initiated radical-chain mechanism proposed for the reaction. This reaction offers an easy, two-step approach to aminochlorination of a double bond in α-olefins and α,β-unsaturated esters.     

Study of photopolymer. XIX. Novel syntheses of the polymers with pendant ester and chloromethyl groups by addition reactions of the copolymer of glycidyl methacrylate with acid chlorides

Polymer with pendant cinnamic ester and chloromethyl groups was synthesized by the addition reaction of poly(glycidyl methacrylate–co–methyl methacrylate) (PGMA) with cinnamoyl chloride. Also, polymers with pendant benzoic esters and chloromethyl groups were synthesized by reaction of PGMA with the corresponding benzoyl chlorides. Furthermore, polymers with cinnamic or benzoic esters and alkylazide groups were prepared by the substitution reaction of the obtained polymers with sodium azide.     

Chiral ligand-controlled asymmetric conjugate addition of lithium amides to enoates

The external chiral ligand-controlled asymmetric conjugate addition reaction of lithium amides with alpha,beta-unsaturated esters provided beta-amino esters in high yields and high enantioselectivities.     

Reaction of benzohydroximinoyl chlorides and β‐(trifluoromethyl)‐acetylenic esters: Synthesis of regioisomeric (trifluoromethyl)‐isoxazolecarboxylate esters and oxime addition products

The triethylamine induced reaction of benzohydroximinoyl chlorides, precursors of nitrile oxides, with β‐trifluoromethylacetylenic esters gives rise to three products: 5‐trifluoromethyl‐4‐isoxozolecarboxylate esters, regioisomeric 4‐trifluoromethyl‐5‐isoxazolecarboxylate esters and an unexpected oxime 1,4‐addition adduct. Product distribution is rationalized in terms of two competing reaction modes, either 1,4 addition of the oxime anion to the acetylenic ester or formation of the nitrile oxide followed by 1,3‐dipolar cycloaddi‐tion. Anionic 1,4‐addition of the oximinoyl chloride to the acetylenic ester is preferred at low temperatures, while nitrile oxide formation followed by cycloaddition is preferred at temperatures above 0 °C. Regioisomeric products from addition of nitrile oxides to various perfluoroalkylacetylenes are compared and assigned by ¹³C NMR.     

Asymmetric synthesis of beta-amino-gamma-substituted-gamma-butyrolactones: double diastereoselective conjugate addition of homochiral lithium amides to homochiral alpha,beta-unsaturated esters

Chiral alpha,beta-unsaturated esters, containing a single, gamma-stereogenic centre, show modest levels of substrate control upon conjugate addition of lithium dibenzylamide. Double diastereoselective conjugate additions of homochiral lithium N-benzyl-N-(alpha-methylbenzyl)amide to the homochiral alpha,beta-unsaturated esters display "matching" and "mismatching" effects. In each case, however, these additions proceed under the dominant stereocontrol of the lithium amide to give the corresponding beta-amino esters in high de. A remarkable reversal in stereoselectivity is noted by changing the ester functionality to an oxazolidinone. Subsequent O-deprotection and cyclisation of the resultant beta-amino adducts gives access to the corresponding beta-amino-gamma-substituted-gamma-butyrolactones in good yield and high de.     

Mass spectra of porphyrin alkyl esters and their copper complexes. Studies on products from humans and animals with porphyria

Mass spectra of methyl and higher aliphatic esters of biologically important porphyrins—prepared from human and bovine excreta—were recorded. Variation in the number of esterified carboxyl groups (4 to 8) or in the size of the ester groups causes no change in the fragmentation modes; only the abundances of the fragment ions vary. The conversion of a porphyrin ester to its copper-complex (chelate) has been achieved in a simple way. The mass spectra of the copper chelates are compared with those of the free porphyrin esters and minor differences are observed.     

Use of odorless thiols: formal asymmetric Michael addition of hydrogen sulfide to alpha-substituted alpha,beta-unsaturated carbonyl compounds

[reaction: see text] The Michael addition to alpha-substituted alpha,beta-unsaturated esters and amides using complex A containing a chiral odorless thiol proceeded diastereoselectively. The Michael adducts were converted to beta-mercapto esters and amides via a Wagner-Meerwein rearrangement with boron trifluoride etherate and a thiol exchange reaction using odorless 1-dodecanethiol. This conversion constitutes a formal asymmetric Michael addition of hydrogen sulfide to alpha,beta-unsaturated carbonyl compounds using odorless thiols instead of the toxic hydrogen sulfide.     

Catalytic asymmetric Mannich reactions of glycine derivatives with imines. A new approach to optically active alpha,beta-diamino acid derivatives

Imines of glycine alkyl esters react with imines in a diastereo- and highly enantioselective Mannich reaction in the presence of chiral copper(I) complexes as the catalyst to give optically active alpha,beta-diamino acid derivatives. A series of imines of glycine esters derived from glycine and aromatic carbonyl compounds has been screened as substrates for the Mannich reaction with different imines in the presence of various combinations of metal salts and chiral ligands. The benzophenone imine of glycine esters was found to react with N-protected imines in a diastereoselective fashion giving functionalized alpha,beta-diamino acid esters with excellent enantioselectivities. The most effective chiral catalysts are chiral copper(I) complexes having phosphino-oxazoline (P,N)-ligands, and among these ligands, those derived from (1R,2S)-dihydroxy-1,2,3,4-tetrahydronaphthalene gave the best results. The scope of this new catalytic asymmetric reaction of the benzophenone imine glycine esters is demonstrated for the reaction with different N-protected-C-aryl and C-alkyl imines giving the Mannich adducts with excellent optical purity. Furthermore, the synthetic aspects of the reaction are presented by converting the Mannich adducts into alpha,beta-diamino acid derivatives. The relative and absolute configuration of the Mannich adduct have been determined and based on the stereochemical outcome of the reaction a tetrahedral chiral-copper(I)-imino glycine alkyl ester intermediate is proposed. In this intermediate the Re-face of the benzophenone imine glycine ester is shielded by the chiral ligand leaving the Si-face available for approach of the Si-face of the imine. A series of semiempirical calculations has been performed to support the structure of the tetrahedral chiral-copper(I) complex and to account for the influence of the substituents in the chiral phosphino-oxazoline ligands.     

Amphiphilic meso(sulfonate ester fluoroaryl)porphyrins: refining the substituents of porphyrin derivatives for phototherapy and diagnostics

A set of amphiphilic fluorinated porphyrins appended with sulfonate ester groups were synthesized and fully characterized. The reaction proceeds efficiently, with high yields, with an improved methodology. Their potential use as imaging and phototherapeutic agents was assessed measuring relevant photophysical properties. It is shown that these porphyrins have good photostability, long triplet lifetimes (between 47 μs and 102 μs), high singlet oxygen quantum yields (0.74≤FD≤1.00), low fluorescence quantum yields (<0.04) and sharp 19F NMR peaks. The data on the new meso(sulfonate ester fluoroaryl)porphyrins illustrate the potential of perfluorinated sulfonate esters to improve physical properties relevant for cancer imaging and photodynamic therapy.