Showing papers on "Alkylation published in 1991"

Enantioselective Addition of Organometallic Reagents to Carbonyl Compounds: Chirality Transfer, Multiplication, and Amplification†

Abstract: Nucleophilic addition of organometallic reagents to carbonyl substrates constitutes one of the most fundamental operations in organic synthesis. Modification of the organometallic compounds by chiral, nonracemic auxiliaries offers a general opportunity to create optically active alcohols, and the catalytic version in particular provides maximum synthetic efficiency. The use of organozinc chemistry, unlike conventional organolithium or -magnesium chemistry, has realized an ideal catalytic enantioselective alkylation of aldehydes leading to a diverse array of secondary alcohols of high optical purity. A combination of dialkylzinc compounds and certain sterically constrained β-dialkylamino alcohols, such as (–)-3-exo-dimethylaminoiso- borneol [(–)-DAIB], as chiral inducers affords the best result (up to 99% ee). The alkyl transfer reaction occurs via a dinuclear Zn complex containing a chiral amino alkoxide, an aldehyde ligand, and three alkyl groups. The chiral multiplication method exhibits enormous chiral amplification: a high level of enantioselection (up to 98%) is attainable by use of DAIB in 14% ee. This unusual nonlinear effect is a result of a marked difference in chemical properties of the diastereomeric (homochiral and heterochiral) dinuclear complexes formed from the dialkylzinc and the DAIB auxiliary. This phenomenon may be the beginning of a new generation of enantioselective organic reactions.

Preparative polar organometallic chemistry

Abstract: I. Reactivity of Polar Organometallic Intermediates.- 1 Introduction.- 2 Alkylation.- 2.1 Reactivity-A Qualitative Comparison of the Polar Organometallics.- 2.2 Scope of the Alkylation Reaction.- 2.3 Dialkylation.- 2.4 Remarks on the Reaction Conditions of Alkylations.- 3 Hydroxyalkylation with Epoxides.- 4 Hydroxyalkylation with Carbonyl Compounds.- 5 Formylation with Dimethylformamide.- 6 Carboxylation.- 7 Reaction of Organoalkali Compounds with Carbon Disulfide.- 8 Addition of Organoalkali Compounds to Isocyanates and Isothiocyanates.- 9 Sulfenylation.- 10 Trimethylsilylation.- 11 Reactions of Organometallic Compounds with Chloroformates and Dimethylcarbamoyl Chloride.- 12 Reactions of Organoalkali Compounds with Halogenating Agents.- 13 Conjugate Additions.- II. Metallation of Aromatic and Olefinic Hydrocarbons.- 1 Introduction.- 2 Metallation of Alkylbenzenes and Alkylnaphthalenes.- 3 Dimetallation of Aromatic Compounds.- 4 Metallation of Olefinic Compounds.- 5 Stereochemistry of Allylic Metallations.- 6 Dimetallation of Olefins.- 7 Experiments.- 7.1 Metallation of Toluene with BuLi * t-BuOK in Hexane.- 7.2 Metallation of 1- and 2-Methylnaphthalene with BuLi * t-BuOK.TMEDA in Hexane.- 7.3 ?-Metallation of Ethylbenzene.- 7.4 ?,??-Dimetallation of m-Xylene.- 7.5 Lithiation of Toluene, Xylene, Mesitylene with BuLi * TMEDA..- 7.6 Metallation of Propene and Isobutene.- 7.7 Metallation of Various Olefins with Strongly Basic Reagents.- 7.8 Metallation of Cyclohexene.- 7.9 Dimetallation of Isobutene.- 7.10 Metallation of Isoprene.- 7.11 Metallation of ?-Methylstyrene.- 7.12 Metallation of Indene.- 7.13 Metallation of Cyclopentadiene.- 7.14 Preparation of 1,4-Cyclohexadiene.- 7.15 Allylbenzene.- 8 Selected Procedures from Literature.- III. Metallation of Saturated Sulfur Compounds.- 1 Introduction.- 2 Substrates and Metallation Conditions.- 2.1 S,S-Acetals.- 2.2 Methoxymethyl Phenyl Sulfide.- 2.3 Ethythiomethyl Ethyl Sulfoxide.- 2.4 Orthothioformates.- 2.5 Dialkyl Sulfides and Alkyl Aryl Sulfides.- 2.6 Dialkyl and Alkyl Aryl Sulfoxides and Sulfones.- 3 Experiments.- 3.1 Lithiation of Formaldehyde Dimethylthioacetal with BuLi in THF and Hexane.- 3.2 Lithiation of Formaldehyde Dimethylthioacetal with BuLi * TMEDA in Hexane.- 3.3 Reaction of Lithiated Bis(methylthio)methane with Alkyl Halides.- 3.4 Hydroxyalkylation of Lithiated Bis(methylthio)methane with Epoxides.- 3.5 Reaction of Lithiated 1,3-Dithiane with 1-Bromo-3-chloropropane and Ring Closure of the Coupling Product Under the Influence of Butyllithium.- 3.6 Hydroxymethylation of Bis(methylthio)methane with Paraformaldehyde.- 3.7 Reaction of Lithiated Bis(methylthio)methane with Dimethylformamide and Subsequent Acid Hydrolysis.- 3.8 Reaction of Lithiated Bis(methylthio)methane with Carbon Dioxide.- 3.9 Reaction of Lithiated Bis(methylthio)methane with Dimethyl Disulfide and Trimethylchlorosilane.- 3.10 Lithiation of Methoxymethyl Phenyl Sulfide and Subsequent Reaction with Dimethylformamide.- 3.11 Reaction of Lithiated Bis(methylthio)methane with Methyl Isothiocyanate and N,N-Dimethyl Carbamoyl Chloride.- 3.12 Peterson Olefination Reactions with Lithiated Trimethylsilyl Bis(methylthio)methane. Preparation of Ketene Thioacetals.- 3.13 Conjugate Addition of Lithiated S,S-Acetals and Corresponding S-Oxides to 2-Cyclohexen-1-one and Methyl Acrylate.- 3.14 Lithiation of Dimethyl Sulfide and Methyl Phenyl Sulfide and Subsequent Reaction of the Lithium Compounds with Benzaldehyde and Trimethylchlorosilane.- 3.15 Lithiation of (Trimethylsilylmethyl)Phenyl Sulfide and Subsequent Reaction with Acetone.- 3.16 Dilithiation of Methyl Phenyl Sulfide and Subsequent Trimethylsilylation.- 3.17 Reaction of Bis(methylthio)methane with Potassium Amide in Liquid Ammonia and Subsequent Reaction with Oxirane..- 3.18 Reaction of Dimethylsulfoxide with Sodamide in Liquid Ammonia and Subsequent Alkylation with Bromohexane.- 3.19 Mono-Deuteration of Bis(ethylthio)methane.- 3.20 Lithiation of Methyl Phenyl Sulfoxide with LDA and Subsequent Alkylation with Butyl Bromide.- 3.21 Preparation of Formaldehyde-S,S-Acetals.- 3.22 Preparation of Ethylthiomethyl Ethyl Sulfoxide and Methyl Phenyl Sulfoxide.- 3.23 Preparation of Benzaldehyde Dimethylthioacetal.- 4 Selected Procedures from Literature.- IV. ?-Metallation of Derivatives of Toluene Containing Heterosubstituents.- 1 Scope of this Chapter.- 2 Experiments.- 2.1 Metallation of N,N-Dimethyl-ortho-Toluidine.- 2.2 Synthesis of ortho-Pentylphenol via Potassiation of O-Protected ortho-Cresol.- 2.3 Dimetallation of ortho-Cresol.- 2.4 Metallation of o-and p-Tolunitrile with Alkali Amides in Liquid Ammonia and Alkali Diisopropylamide in THF-Hexane Mixtures.- 2.5 ?-Lithiation of p-Toluene-N,N-Dimethylsulfonamide.- V. Metallation of Heterosubstituted Allylic and Benzylic Compounds.- 1 Introduction.- 2 Substrates and Metallation Conditions.- 2.1 Allylic Amines and Ethers.- 2.2 Allylic and Pentadienylic Sulfur, Silicon and Selenium Compounds.- 2.3 Benzylic Amines, Silanes and Sulfides.- 2.4 Regiochemistry of the Reactions of Allylic Alkali Metal Compounds with Electrophiles.- 3 Experiments.- 3.1 Metallation of N,N-Dialkyl Allylamines with BuLi * TMEDA and BuLi * t-BuOK.- 3.2 Metallation of Allyl t-Butyl Ether with BuLi * t-BuOK.- 3.3 Lithiation of Allyl Trimethylsilane with BuLi * TMEDA.- 3.4 Lithiation of Methyl Allyl Sulfide and Phenyl Allyl Sulfide with BuLi.- 3.5 Metallation of Methyl Isopropenyl Ether with BuLi * t-BuOK.- 3.6 ?-Metallation of Benzyl Dimethylamine with BuLi * t-BuOK.- 3.7 Lithiation of Methyl Benzyl Sulfide and Benzyl Trimethylsilane.- 3.8 Preparation of N,N-Dimethyl Allylamine and N,N-Diethyl Allylamine.- 3.9 Preparation of t-Butyl Allyl Ether.- 3.10 Methyl Allyl Sulfide, Methyl Benzyl Sulfide and Phenyl Allyl Sulfide.- 3.11 Preparation of Allyl Trimethylsilane.- VI. Metallation of Heterocyclic Compounds.- 1 Introduction.- 2 Metallation of Alkyl Derivatives of Pyridine and Quinoline.- 3 Lateral Metallation of 2-Substituted Oxazolines, Thiazolines, Dihydrooxazines and Thiazoles.- 4 Experiments.- 4.1 General Procedure for the Metallation of Mono-, Di- and Trimethyl Pyridines and Quinolines in Liquid Ammonia and the Subsequent Alkylation.- 4.2 Conversion of 2-Methylpyridine, 2,4-Dimethylpyridine, 2,6-Dimethylpyridine and 2,4,6-Trimethylpyridine into the 2-Lithiomethyl Derivatives.- 4.3 Regiospecific Generation of 4-Metallomethylpyridines in Organic Solvents.- 4.4 Metallation of 3-Methylpyridine.- 4.5 Lithiation of 2-Methylthiazoline.- 4.6 Lithiation of 2,4,4,6-Tetramethyl-5,6-dihydro-1,3-oxazine.- 4.7 Dimetallation of 2,6-Dimethylpyridine.- 5 Organic Syntheses Procedures.- VII. Metallation of Aldimines and Ketimines.- 1 Introduction.- 2 Conditions for the Metallation.- 3 Experiments.- 3.1 Lithiation of Aldimines and Ketimines with LDA.- 3.2 Alkylation of Lithiated Imines.- 3.3 Metallation of Aldimines by Sodamide in Liquid Ammonia.- 3.4 Trimethylsilylation and Methylthiolation of Lithiated Imines.- 3.5 Conversion of Imines into Aldehydes and Ketones.- 3.6 Synthesis of ?,?-Unsaturated Aldehydes from Trimethylsilylated Aldimines.- 3.7 Preparation of Aldimines and Ketimines.- 4 Organic Syntheses Procedures.- VIII. Metallation of Nitriles and Isonitriles.- 1 Introduction.- 2 ?-Metallation of Nitriles.- 3 Metallation of Isonitriles.- 4 Experiments.- 4.1 Metallation of Nitriles with Alkali Amide in Liquid Ammonia.- 4.2 Lithiation of Nitriles and Isonitriles in a Mixture of THF and Hexane.- 4.3 Alkylation of Metallated Nitriles in Liquid Ammonia and in Organic Solvents.- 4.4 Reaction of Metallated Nitriles with Aldehydes and Ketones.- 4.5 Reaction of Lithioacetonitrile with Epoxides.- 4.6 Reaction of Lithiomethyl Isocyanide with Hexyl Bromide, Oxirane and Cyclohexanone.- 4.7 Conversion of Acetaldehyde into the Cyanohydrine and Protection of the OH-Group of the Cyanohydrine with Ethyl Vinyl Ether.- IX. Generation of Lithium Halocarbenoids.- 1 Introduction.- 2 Methods of Generation of Lithium Halocarbenoids.- 3 Experimental Conditions and Techniques in Carbenoid Chemistry.- 4 Experiments.- 4.1 Lithiation of Dichloromethane.- 4.2 Lithiation of 1,1-Dichloroalkanes.- 4.3 Lithiation of Dibromomethane.- 4.4 Lithiation of Chloroform.- 4.5 Lithiation of Bromoform.- 4.6 Lithiation of 7,7-Dibromonorcarane.- 4.7 Lithiation of Ethyl Bromoacetate.- X. Metallation of Carbonyl and Thiocarbonyl Compounds.- 1 Introduction.- 2 Mono Metallation of Carbonyl and Thiocarbonyl Compounds.- 3 Other Methods for the Generation of Enolates and Enethiolates.- 4 Dimetallation of Carbonyl and Thiocarbonyl Compounds.- 5 Experiments.- 5.1 Conversions of Ketones into Lithium Enolates and Subsequent Trimethylsilylation (General Procedure).- 5.2 Reaction of 1-Trimethylsilyloxy-l-Heptene with Butyllithium.- 5.3 Metallation of Carboxylic Esters with LDA.- 5.4 Metallation of Carboxylic Esters with Alkali Amides in Liquid Ammonia.- 5.5 Metallation of N-Methylpyrrolidine and ?-Butyrolactone with LDA.- 5.6 Lithiation of Methyl Crotonate.- 5.7 Lithiation of Thiolesters, Thionesters and Dithioesters with LDA (General Procedure).- 5.8 Metallation of Dithioesters with Alkali Amides in Liquid Ammonia.- 5.9 Dimetallation of Carboxylic Acids.- 5.10 Dimetallation of Pentane-2,4-dione with Sodamide in Liquid Ammonia.- 5.11 Dimetallation of Pentane-2,4-dione with LDA.- 5.12 1-Trimethylsilyloxy-l -heptene.- Metallation-Functionalization Index (Vol. 2).- Syntheses of Reagents and Starting Compounds (Vols. 1 and 2)..- Complementary Index (Vols. 1 and 2).- Typical Procedures and Special Techniques (Vols. 1 and 2).- Purification and Storage and Some Reagents and Solvents (Vols. 1 and 2).

Staurosporine derivatives substituted at methylamino nitrogen

Abstract: N-substituted derivatives of staurosporine of the general formula [Stau]--N(CH.sub.3)--R (I) in which [Stau] represents a residue of the partial formula ##STR1## and R represents a hydrocarbyl radical R o or an acyl radical Ac, which radicals preferably have a maximum of 30 carbon atoms, and salts of compounds of the formula I having salt-forming properties, are distinguished as selective inhibitors of proteinkinase C. They are manufactured by conventional alkylation or acylation, respectively, of staurosporine.

Annulation via alkylation-Alder ene cyclizations. Palladium-catalyzed cycloisomerization of 1,6-enynes

Abstract: A Pd(0)-catalyzed alkylation of an allyl substrate with a nucleophile containing a double or triple bond to permit subsequent thermal Alder ene reactions constitutes a novel annulation protocol. In the case of a triple bond, a Pd(2+) complex catalyzes an equivalent of an Alder ene reaction. This new cyclization is probed in terms of the effect of substitution on the olefin, the acetylene, and the tether connecting the two. The reaction produces both 1,4-dienes (Alder ene-type products) and 1,3-dienes. Mechanisms to account for the diversity of products are presented. The Pd(2+)-catalyzed reaction shows an ability to interact with remote nonreactive parts of substrates to affect conformation and thereby selectivity. Several advantages accrue to the Pd(2+)-catalyzed reaction

A new general synthesis of polycyclic aromatic compounds based on enamine chemistry

Abstract: Alkylation of enamines and enamine salts followed by a cyclodehydration and dehydrogenation provides an efficient synthetic approach to a wide range of polycyclic aromatic compounds

Interfacial catalysis by phospholipase A2: dissociation constants for calcium, substrate, products, and competitive inhibitors.

Abstract: Interpretation of the kinetics of interfacial catalysis in the scooting mode as developed in the first paper of this series [Berg et al. (1991) Biochemistry 30 (first paper of six in this issue)], was based on the binding equilibrium for a ligand to the catalytic site of phospholipase A2. In this paper, we describe direct methods to determine the value of the Michaelis-Menten constant (KMS) for the substrate, as well as the equilibrium dissociation constants for ligands (KL) such as inhibitors (KI), products (KP), calcium (KCa), and substrate analogues (KS) bound to the catalytic site of phospholipase A2 at the interface. The KL values were obtained by monitoring the susceptibility to alkylation of His-48 at the catalytic site of pig pancreatic PLA2 bound to micellar dispersions of the neutral diluent 2-hexadecyl-sn-glycero-3-phosphocholine. The binding of the enzyme to dispersions of this amphiphile alone had little effect on the inactivation rate. The half-time for inactivation of the enzyme bound to micelles of the neutral diluent depended not only on the nature of the alkylating agent but also on the structure and the mole fraction of other ligands at the interface. The KL values for ligands obtained from the protection studies were in excellent accord with those obtained by monitoring the activation or inhibition of hydrolysis of vesicles of 1,2-dimyristoyl-sn-glycerophosphomethanol. Since only calcium, competitive inhibitors, and substrate analogues protected phospholipase A2 from alkylation, this protocol offered an unequivocal method to discern active-site-directed inhibitors from nonspecific inhibitors of PLA2, such as local anesthetics, phenothiazines, mepacrine, peptides related to lipocortin, 7,7-dimethyleicosadienoic acid, quinacrine, and aristolochic acid, all of which did not have any effect on the kinetics of alkylation nor did they inhibit the catalysis in the scooting mode.

Chemical modification of an antitumor alkaloid camptothecin: synthesis and antitumor activity of 7-C-substituted camptothecins.

Abstract: A radical substitution reaction of 20(S)-camptothecin (1) with methanol furnished 7-hydroxymethylcamptothecin (2). Reaction of 1 with primary alcohols higher than methanol gave 7-alkylcamptothecins (4), of which alkyl groups were one carbon less than the alcohols used and also 7-hydroxyalkylcamptothecins (5). For the preparation of 7-alkylcamptothecin (4), aldehydes were used as a radical source and several alkylated derivatives were synthesized. 7-Acyloxymethyl derivatives (6), 7-carbaldehyde (7), iminomethyl derivatives (10), acid (11), esters (12) and amides (13) were synthesized starting from 2. 7-Ethyl- (4b) and 7-propylcamptothecin (4c), acyloxymethyl compounds 6a, 6c and ethyl ester (12b) exhibited higher antitumor activity than 1 against L1210 in mice.

Asymmetric allylic alkylation catalyzed by palladium-sparteine complexes

Abstract: The cationic complex [Pd(η 3 -C 3 H 5 )(sparteine)]PF 6 ( 6 ) was found to be a suitable catalyst precursor for the asymmetric alkylation of allylic acetates with Na[CH(COOMe) 2 ] as the nucleophile. This constitutes one of the first and still rare examples of a phosphine-free system for this type of Pd-catalyzed reaction. Using 5 mol % of 6 , alkylation products were obtained in up to 90% isolated yield and 85 % enandomeric excess. The alkylation reaction was shown to occur with overall retention of configuration, indicating an analogous mechanism to the one previously proposed for phosphine-containing catalysts. The reactivity of allylic acetates is strongly dependent upon the nature of the substituents, open-chain aliphatic substrates being unreactive.

Alkylation of aromatic compounds.

Abstract: Monoalkylated benzene such as ethylbenzene and cumene or monoalkylated substituted benzene are produced by alkylation in the presence of an acidic mordenite zeolite catalyst having a silica/alumina molar ratio of at least 40:1, preferably 160:1. In a subsequent, optional process, the polyalkylated benzene or polyalkylated substituted benzene produced in the alkylation is transalkylated in the presence of an acidic mordenite zeolite catalyst.

Highly conjugated π-electron donors for organic metals: synthesis and redox chemistry of new 1,3-dithiole and 1,3-selenathiole derivatives

Abstract: The bis(1,3-dithiolium) dication salts 8a–c have been synthesised in three steps (31–51% overall yields) starting from 1,4-bis(bromomethyl)naphthalene, 9,10-bis(chloromethyl)anthracene and 4,4′-bis(chloromethyl)biphenyl, respectively. The bis(halogenomethyl) compounds 5 were converted into the dipiperidiniumbis(dithiocarboxylate) salts 6, which on alkylation with 3-chlorobutane-2-one yielded bis(dithioesters)7; cyclisation of 7 occurred on treatment with concentrated sulphuric acid to give dication salts 8. Dimethyl 1,3-dithiol-2-ylphosphonate 20, dimethyl 4,5-dimethyl-1,3-dithiol-2-ylphosphonate 21 and dimethyl 1,3-selenathiol-2-ylphosphonate 22 were treated with butyllithium in the presence of a range of carbonyl compounds and quinones, e.g., cyclopentanone, cyclohexanone, benzophenone, acetophenone, benzaldehyde, thioxanthen-9-one, anthraquinone, bianthrone and naphthacene-5,12-quinone to yield Wittig–Horner products, e.g., alkenes 26–34 and the anthracenediylidene derivatives 35, 36, 40–43 and 53. Unsymmetrical derivatives 37–39 were prepared in two steps as follows: anthrone reacted with 2-methylthio-1,3-dithiolium iodides 45 and 46 in pyridine-acetic acid to yield ketones 48 and 49 which were then treated with the Wittig–Horner reagents 23–25. Cyclic voltammetric data for the new tetrathiafulvalene, selenatrithiafulvalene and diselenadithiafulvalene derivatives 35–43and 53, show that these systems undergo two-electron redox behaviour which is observed as a single wave. Complexes of these donors with electron acceptors, e.g. 7,7,8,8-tetracyano-p-quinodimethane (TCNQ), have been obtained, some of which are organic semiconductors.

Synthesis of 2',3'-dideoxy-3'-C-hydroxymethyl nucleosides as potential inhibitors of HIV

Abstract: A novel synthesis of 2',3'-dideoxy-3'-C-hydroxymethyl nucleosides is described. (2S,3R)-3-[[(4-Bromo-benzyl)oxy]methyl]oxirane-2-methanol (1) was regioselectively alkylated using allylmagnesium bromide. The allyl double bond was oxidatively cleaved, and the product was treated with acidic methanol to give a requisite methyl furanoside derivative which was subsequently condensed with purine and pyrimidine bases. Deblocking and separation of the anomers by chromatography afforded the α- and β-nucleoside analogues

Alkylations of (R,R)-2-t-Butyl-6-methyl-1,3-dioxan-4-ones which are not Possible with Lithium Amides may be Achieved with a Schwesinger P4 Base

Abstract: Enolates A of the dioxanones specified in the title, when generated with lithium amide bases, can only be alkylated with highly reactive electrophiles, and only once. With Schwesinger's t-Bu-P 4 base (a very strong, so-called neutral base, containing 4P and 13N atoms capable of bearing a positive charge in the conjugate P4H+ cation) the dioxanone 1 can be doubly alkylated even with iodobutane (products 16, 17). The 5,6-dimethyl- and 5-benzyl-6-methyldioxanone 2 and 3 can be alkylated diastereoselectively with the formation of quaternary centers at C(5) (products 4, 8—14). In one case, the configuration of the product 4 obtained was determined by conversion to a β-lactone 6 and an olefin 7 (a previous assignment had to be revised). Even the 2,5,6,6-tetraalkyl-substituted dioxanone 19 could be further alkylated ( 20 + 21). Five of the new alkylation products were hydrolyzed to the parent 3-hydroxy-carboxylic acids 5, 22 — 25. The enormous reactivities achieved with the inherently labile enolates and the P411+ counterions are discussed.

Asymmetric synthesis of .beta.-amino acids. 1. Highly diastereoselective addition of a racemic .beta.-alanine enolate derivative to electrophiles

Abstract: β-Alanine, an inexpensive α-amino acid, was converted into the 2-tert-butylperhydropyrimidin-4-one derivative 2, which can be alkylated with high diastereoselectivity via the corresponding enolate. The high stereoselectivity observed for the reaction of 2-Li with electrophiles seems to be due to steric hindrance generated by an axial disposition of the tert-butyl group at C(2), which directs addition from the enolate face opposite to this group. The hydrolysis of the resulting adducts proceeds with 6N hydrochloric acid to afford α-substituted β-amino acids in good yields. These results pave the road to the development of a new asymmetric synthesis of enantiomerically pure α-substituted β-amino acids

C-alkylation of peptides through polylithiated and LiCl-solvated derivatives containing sarcosine Li-enolate units

Abstract: The tripeptide and hexapeptide derivatives Boc-Gly-Sar-MeLeu-OH (5b), Boc-Ala-Sar-Sar-OH (6b), Boc-Ala-Sar-MeLeu-OH (7b), and Boc-Abu-Sar-MeLeu-Val-MeLeu-Ala-OH (12b) can be poly-deprotonated (tri- and pentalithio derivatives K and P, respectively), and thus C-alkylated on sarcosine (Sar) moieties with MeI and allyl or PhCH2Br. The polylithiated species are solubilized in THF, and their reactivity modified by excess base (lithium diisopropylamide (LDA)), by added LiCl, and/or the cosolvent N,N′-dimethylpropyleneurea (DMPU). Optimization of the reaction conditions for methylation in the cases of 7b (Table 3) and 12b (Scheme 8) gave products in which the Sar residue of the educt has been transformed into a Me-D-Ala unit in yields of 80 (9c/8c) and 67% (14c/13c), respectively, and with a diastereoselectivity of ca. 4:1. Less selective methylations and benzylations were observed with the tripeptides 5b and 6b containing only one stereogenic center; also, excess base and alkyl halide may lead to double alkylations in those latter two cases (Tables 1 and 2). No epimerization of stereogenic centers was detected under the strong-base conditions. The analysis of the products was accomplished by a combination of NMR and FAB-MS spectroscopy, as well as by hydrolysis to the parent amino acids, subsequent formation of derivatives with isopropyl isocyanate, and GC analysis on the chiral column Chirasil-Val®.

Identification of epoxide- and quinone-derived bromobenzene adducts to protein sulfur nucleophiles.

Abstract: Bromobenzene (BB) hepatotoxicity is widely attributed to the alkylation of cellular proteins by chemically reactive metabolites, particularly BB-3,4-oxide. This laboratory recently reported the first conclusive evidence that BB epoxides actually do alkylate proteins; i.e., acid hydrolysates of hepatic proteins from phenobarbital-(PB-) induced BB-treated rats contain S-(o-, S-(m-, and S-(p-bromophenyl)cysteine [Weller, P.E., and Hanzlik, R.P. (1991) Chem. Res. Toxicol. 4, 17-20]. However, these three compounds account for less than 0.5% of total protein covalent binding. Bromoquinone metabolites of BB are also suspected of alkylating proteins. To search for such adducts to protein cysteinyl or methionyl residues, we heated hepatic proteins from PB-induced BB-treated rats with a two-phase mixture of 16 N KOH and CH3I ("alkaline permethylation"). Under these conditions S-alkylated residues are cleaved via elimination and the phenoxide and thiophenoxide groups on the fragments are methylated. Product analysis by 14C HPLC and GC/MS revealed o-, m-, and p-bromothioanisoles in amounts comparable to the content of S-(bromophenyl)cysteines found by acid hydrolysis (para much greater than meta, ortho). This, too, clearly implicates protein-SH alkylation by BB-2,3- and 3,4-oxides. In addition, 2,3-dimethoxy-5-bromothioanisole and another unidentified isomer were observed. However, by far the major adduct (5-6% of total covalent binding) was 2,5-dimethoxythioanisole (i.e., a debrominated adduct). When BB-d5 was administered, the latter contained mostly 3 deuterium atoms/mol. These latter results clearly show that alkylation of protein sulfur nucleophiles in vivo by quinone metabolites is 10-15 times more extensive than their alkylation by BB epoxides. After BB-d5 was administered, the bromothioanisoles and dimethoxybromothioanisoles contained 4 and 2 deuterium atoms/mol, respectively. A weighted average calculation of deuterium retention across the six major sulfur adducts agreed well with 3H/14C retention ratios determined earlier for total liver protein covalent binding of dual-labeled [3H/14C]BB, indicating that the overall pattern of BB metabolite binding to all protein nucleophiles may closely parallel that seen here specifically for protein sulfhydryl groups. The identification of a variety of specific BB-derived adducts to protein now affords the opportunity to investigate their relative contributions to the toxicity of bromobenzene.

The regio- and stereoselectivities of the reaction of allyl acetates and silyl ketene acetals catalyzed by palladium(0) complexes: a new route to cyclopropane derivatives

Abstract: Pd(0) complexes of chelating phosphines catalyzed the coupling of allyl acetates and ketene silyl acetals to yield α-allylated carboxylic acid esters. Unexpectedly alkylation of the central carbon atom (C2) of the allyl groups was also observed with concomitant formation of cyclopropane derivatives. In both cases the silyl enolate attacked the allyl group from the side opposite Pd. The yield of the reaction was sensitive to the nature of the ligand coordinated with palladium. The 1,1'-bis(diphenylphosphino) ferrocene-Pd complex was the most effective catalyst

Synthesis of a novel type of chiral phosphinocarboxylic acids. The phosphine-palladium complexes catalyzed asymmetric allylic alkylation

Abstract: A novel type of chiral cycloalkylphosphines bearing the carboxy group at the β-position were developed, and used for palladium catalyzed asymmetric allylic alkylation of allylic substrates such as 2-cyclohexenylacetate and 1,3-disubstituted-propenyl acetates (R1CHCHCH(OAc)R2: R1=R2=Ph; R1=Ph, R2=(CH2)4OAc; R1=Ph, R2=(CH2)6OAc; R1=Ph, R2=(CH2)10OAc). Reaction of the propenyl acetates with soft carbon nucleophiles such as triethyl sodiophosphonoacetate and sodiomalonic acid esters in the presence of a palladium catalyst prepared in situ from Pd(OAc)2 and chiral (2-diphenylphosphino)cycloalkanecarboxylic acids (7a,b) gave high yields of alkylation products (PhCH=CHCH(X)Ph: > 77 %ee for X=CH(CO2Et)P(O)(OEt)2 and > 72 %ee for X=CH(CO2Me)2). The alkylation products 15 and 28a–c were converted into optically active α-methylene-γ-lactone and α-methylene macrolide derivatives. The high stereoselectivity demonstrated by the chiral phosphinocarboxylic acid-palladium catalyzed allylic alkylation suggested to be caused by an electronic repulsion between the carboxy group on the ligand and the incoming soft carbon nucleophile, which directs the nucleophilic attack on one of the π-allyl carbons.

Palladium-catalyzed asymmetric allylic alkylation using dimethyl malonate and its derivatives as nucleophile

Abstract: Palladlum-catalyzed asymmetric allylic alkylatlon of 1,3-dlphenyl-2-propenyl acetate with sodium salt of dimethyl malonate and its derivatives has been successfully carried out in the presence of optically active diphosphine, such as (S)-BINAP. High enantioselectivity of up to 90% ee was obtained with dimethyl malonate.

Selective Monoalkylation of Acyclic Diols by Means of Dibutyltin Oxide and Fluoride Salts.

Abstract: Fluoride anion was found to promote monoalkylation reaction of diols by the stannylene acetal method, and selective monoalkylation of various acyclic diols was accomplished in good yields under mild conditions by employing this new method. Functional groups such as carboxylic acid ester, carboxamide, carbamate, nitrile, alkyl chloride, and ether were not affected under the reaction conditions.