Enantioselective allyltitanations and metathesis reactions. Application to the synthesis of piperidine alkaloids (+)-sedamine and (-)-prosophylline

An enantioselective synthesis of the piperidine alkaloids (+)-sedamine and (-)-prosophylline is reported. The synthesis of (+)-sedamine has been achieved in 12 steps with an overall yield of 20% from benzaldehyde, and (-)-prosophylline was obtained in 15 steps with an overall yield of 9.2%, starting from D-glyceraldehyde acetonide 14. The key steps are enantioselective allyltitanation reactions and ring-closing or cross-metathesis reactions.     

Synthesis and thermal decomposition of N,N-dialkoxyamides

N,N-dialkoxyamides 1c, a virtually unstudied member of the new class of anomeric amides, amides bearing two electronegative atoms at nitrogen, have been synthesised in useful yields directly from hydroxamic esters using phenyliodine(III)bis(trifluoroacetate) (PIFA). Infrared carbonyl stretch frequencies and carbonyl (13)C NMR properties have been reported, which support strong inhibition of amide resonance in these amides. Their thermal decomposition reactions in mesitylene at 155 °C proceed by homolysis to form alkoxyamidyl and alkoxyl free radicals in preference to HERON rearrangements to esters. The reactions follow first-order kinetics and for a series of N,N-dimethoxy-4-substituted benzamides, activation energies of 125-135 kJ mol(-1) have been determined together with weakly negative entropies of activation.     

Divergent routes to chiral cyclobutane synthons from (-)-alpha-pinene and their use in the stereoselective synthesis of dehydro amino acids

Several polyfunctionalized cyclobutane derivatives have been synthesized using commercial (-)-alpha-pinene and (-)-verbenone as chiral precursors. Thus, oxidative cleavage of these compounds by using ruthenium trichloride afforded quantitatively (-)-cis-pinonic and (-)-cis-pinononic acids, respectively, without epimerization. These products were converted into several types of aldehydes, which are the key intermediates in the synthesis of cyclobutane dehydro amino acids via Wittig-Horner condensations with suitable phosphonates. These reactions are highly stereoselective, affording exclusively (Z) isomers, stereochemistry being assessed by NMR experiments. The obtained dehydro amino acids are polyfunctionalized molecules useful for the synthesis of other alpha-amino acids, with additional chiral centers, whose configuration must be induced by the chirality of the terpene employed as a precursor.     

A practical new chiral controller for asymmetric Diels-Alder and alkylation reactions

[formula: see text] The enantiomerically pure hydroxy sulfones (+)- and (-)-2 have been prepared from 1,2-epoxycyclohexane by a simple and practical procedure. The acrylate esters of these alcohols undergo BCl3-catalyzed Diels-Alder reactions with a variety of dienes at -78 to -55 degrees C in CH2Cl2 or C7H8 with high dienophile face selectivity (Table 1). The chiral esters so formed are readily cleaved with recovery of the controllers (+)- or (-)-2. Esters of (+)- and (-)-2 can be converted to Z-potassium enolates and alkylated with high face selectivity.     

Stereoselective Rh-catalyzed hydrogenation of cyclobutyl chiral enamides: double stereodifferentiation vs catalyst-controlled diastereoselection

The hydrogenation reactions of several cyclobutyl enamides derived from (-)-alpha-pinene or (-)-verbenone have been investigated by using different catalysts. The chiralities of both the substrate and the catalyst as well as the Z/E stereochemistry of the double bond have been considered, and the observed diastereoselectivity has been rationalized. For enamides with the double bond separated from the cyclobutane by a methylene, the Wilkinson catalyst did not induce any diastereoselection, but excellent diastereoselectivity was observed when using Et-DuPHOS-Rh and ChiraPHOS-Rh. The configuration of the new stereogenic center was catalyst-dependent and can be rationalized according to the Halpern mechanism. For (Z)-enamides with the double bond directly linked to the cyclobutane ring, the chirality of the substrate governed the diastereoselection and the Halpern mechanism seemed not to be operative in the hydrogenation with ChiraPHOS, with the configuration of the new stereogenic center being determined by steric effects. On the contrary, the chirality of the catalyst was the factor determining the stereochemistry of the major products with alkyl-DuPHOS-Rh. Z/E stereochemistry influenced the stereodifferentiation, and a different behavior for each Z or E stereoisomer was found. For both (Z)- and (E)-enamides, some instances of match/mismatch between the chirality of the substrate and that of the catalyst were observed. As a result of all of these studies, a series of new cyclobutyl alpha-amino acids has been synthesized. These products are interesting to incorporate into conformationally constrained peptides.     

Intramolecular general base catalyzed ester hydrolysis. The hydrolysis of 2-aminobenzoate esters

Rate constants have been obtained for the hydrolysis of the trifluoroethyl, phenyl, and p-nitrophenyl esters of 2-aminobenzoic acid at 50 degrees C in H(2)O. The pseudo-first-order rate constants, k(obsd), are pH independent from pH 8 to pH 4 (the pK(a) of the amine group conjugate acid). The 2-aminobenzoate esters hydrolyze with similar rate constants in the pH-independent reactions, and these water reactions are approximately 2-fold slower in D(2)O than in H(2)O. The most likely mechanism involves intramolecular general base catalysis by the neighboring amine group. The rate enhancements in the pH-independent reaction in comparison with the pH-independent hydrolysis of the corresponding para substituted esters or the benzoate esters are 50-100-fold. In comparison with the hydroxide ion catalyzed reaction, the enhancement in k(obsd) at pH 4 with the phenyl ester is 10(5)-fold. Intramolecular general base catalyzed reactions are assessed in respect to their relative advantages and disadvantages in enzyme catalysis. A general base catalyzed reaction can be more rapid at low pH than a nucleophilic reaction that has a marked dependence on pH and the leaving group.     

Acceleration effect of Lewis acid in allylboration of aldehydes: catalytic,regiospecific, diastereospecific,and enantioselective synthesis of homoallyl alcohols

The addition of pinacol allylboronic esters to aromatic and aliphatic aldehydes smoothly occurred at -78 degrees C in toluene in the presence of a catalytic amount of AlCl3 or Sc(OTf)3 (10 mol %) to give the corresponding homoallyl alcohols in high yields. The reactions proceeded regio- and diastereospecifically, yielding the isomerically pure syn- and anti-homoallyl alcohols from (Z)- and (E)-allylboronic esters, respectively. The protocol was also applied to enantioselective reactions by using a chiral Lewis acid catalyst.     

Gas-phase reactions and rearrangements of alkyl esters with H3O+, NO+, and O2*+: a selected ion flow tube study

Selected ion flow tube mass spectrometry (SIFT-MS) has been employed to study the ion-molecule reactions of 17 alkyl esters reacting with the common SIFT-MS reagent ions, H3O+, H3O+.nH2O (n = 1, 2, 3), NO+, and O2+. The majority of reactions were observed to proceed at or near collision rate, with the exception of H3O+.3H2O, which was found to be slow for 8 of 17 alkyl esters. Unexpected product ions in the form of the parent carboxylic acid cation were observed to arise from the H3O+ and NO+ reactions of some alkyl esters. The observed reactions have been probed by the ab initio CBS-4M and G2(MP2,SVP) methods. The postulated reaction pathway involves a 1,5 H atom migration from a beta-carbon onto the carbonyl oxygen.     

Highly stereoselective synthesis of (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated esters and (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated amides from 1-bromo-1-fluoroalkenes via palladium-catalyzed carbonylation reactions

The highly stereoselective synthesis of (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated esters and (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated amides is described. 1-Bromo-1-fluoroalkenes (E/Z approximately 1:1), which are readily available starting materials, have been found to isomerize to high E/Z ratios after storage at -20 degrees C for 1 week or by photolysis at 254 nm. Since the (E)-isomers have been found to react faster than the corresponding (Z)-isomers at room temperature in Pd(0)-catalyzed reactions, the palladium-catalyzed carboalkoxylation of high E/Z 1-bromo-1-fluoroalkenes lead to a high Z/E (Z/E >/= 98:2) ratio of the alpha-fluoro-alpha,beta-unsaturated esters. When 1-bromo-1-fluoroalkenes (E/Z approximately 1:1) were reacted with HCOOH/NBu(3)/Pd(II)/DMF, the (E)-isomer was selectively reduced, and the remaining (Z)-1-bromo-1-fluoroalkenes were recovered in essentially pure isomeric form. The resulting mixture of (Z)-1-bromo-1-fluoroalkenes and the reduced products underwent similar palladium-catalyzed carboalkoxylation reactions at 70 degrees C, and the (E)-alpha-fluoro-alpha,beta-unsaturated esters were stereospecifically obtained. This methodology was also successfully applied for the stereospecific synthesis of (Z)- and (E)-alpha-fluoro-alpha,beta-unsaturated amides: the palladium-catalyzed carboamidation reaction of high E/Z and (Z)-1-bromo-1-fluoroalkenes lead to pure (Z)- and (E)-alpha-fluoro-alpha,beta-unsaturated amides, respectively.     

Comparisons of phosphorothioate with phosphate transfer reactions for a monoester,diester, and triester: isotope effect studies

Phosphorothioate esters are sometimes used as surrogates for phosphate ester substrates in studies of enzymatic phosphoryl transfer reactions. To gain better understanding of the comparative inherent chemistry of the two types of esters, we have measured equilibrium and kinetic isotope effects for several phosphorothioate esters of p-nitrophenol (pNPPT) and compared the results with data from phosphate esters. The primary (18)O isotope effect at the phenolic group ((18)k(bridge)), the secondary nitrogen-15 isotope effect ((15)k) in the nitro group, and (for the monoester and diester) the secondary oxygen-18 isotope effect ((18)k(nonbridge)) in the phosphoryl oxygens were measured. The equilibrium isotope effect (EIE) (18)k(nonbridge) for the deprotonation of the monoanion of pNPPT is 1.015 +/- 0.002, very similar to values previously reported for phosphate monoesters. The EIEs for complexation of Zn(2+) and Cd(2+) with the dianion pNPPT(2-) were both unity. The mechanism of the aqueous hydrolysis of the monoanion and dianion of pNPPT, the diester ethyl pNPPT, and the triester dimethyl pNPPT was probed using heavy atom kinetic isotope effects. The results were compared with the data reported for analogous phosphate monoester, diester, and triester reactions. The results suggest that leaving group bond fission in the transition state of reactions of the monoester pNPPT is more advanced than for its phosphate counterpart pNPP, while alkaline hydrolysis of the phosphorothioate diester and triester exhibits somewhat less advanced bond fission than that of their phosphate ester counterparts.     

Carboxylic n,N-diphenylcarbamic anhydrides. New acylating agents

Carboxylic N,N-diphenylcarbamic anhydrides have been isolated from the reaction of carboxylate salts with 1-(N,N-dipheriylcarbamoyl)pyridinium chloride in aqueous or ethanolic solution. These anhydrides have been shown to be stable, crystalline derivatives and to be very reactive in acylation reactions. A comparison of pyrazinecarboxylic acid derivatives demonstrated these products to be more reactive than cyanomethyl esters or the so-called Woodward's esters, acyloxyacrylamides.     

Synthesis,Structure, and Biological Activity of Products of Reactions of 3,4-Dioxohexane-1,6-dioic Acid Esters with 2-Aminophenol

Bioactive derivatives of 1,4-benzoxazine have been prepared via reactions of 3,4-dioxohexane-1,6- dioic (ketipic) acid esters with 2-aminophenol. (2'Z)-2,2'-(2-Hydroxy-2H-1,4-benzoxazin-2-yl-3-ilidene)diacetic acid esters or (2Z)-[2-oxo-2H-1,4-benzoxazin-3(4H)-ylidene]acetic acid esters can be formed depending on the conditions. The structures of the products of dialkyl ketipate esters reactions with 2-aminophenol were determined by means of X-ray diffraction. It has been demonstrated that the prepared compounds exhibit antimycotic activity against test cultures of plant pathogenic fungi (Fusauium sp., Alternarium sp., and Bipolaris soraciniana).     

Ready Access to Fluorinated Phosphonate Mimics of Secondary Phosphates. Synthesis of the (alpha,alpha-Difluoroalkyl)phosphonate Analogues of L-Phosphoserine, L-Phosphoallothreonine, and L-Phosphothreonine

In addition to the previously recorded reactions of diethyl lithio(difluoromethyl)phosphonate (8) with primary triflates and aldehydes, we report here that 8 reacts with functionalized, but unactivated, methyl esters to give efficient acyl substitution. Thus, 8 reacts cleanly (-78 degrees C, THF) with the following methyl esters (product, yield): methyl (S)-isopropylideneglycerate (14, 99%), methyl (S)-3-O-(tert-butyldimethylsilyl)-2 -O-tetrahydropyranylglycerate (16, 85%), and the Garner ester derived from D-serine (15, 77%). Expeditious treatment of the resultant alpha,alpha-difluoro-beta-keto phosphonates with hydride or Grignard reagents followed by alcohol deoxygenation provides a general method for the synthesis of (alpha,alpha-difluoroalkyl)phosphonate analogues of secondary phosphates. For tertiary alcohols, Dolan-MacMillan deoxygenation conditions are employed. The requisite methyl oxalate esters are obtained by an improved procedure wherein the lithium alkoxide of the hindered tertiary alcohol is irreversibly generated at low temperature and then condensed with methyl oxalyl chloride. Relative stereochemistry is assigned via conversion of the Garner ester derived Boc-amino alcohols to the corresponding cyclic, six-membered phosphonate esters and examination of their (1)H NMR spectra. The relevant vicinal coupling constants are extracted from these spectra by performing double quantum-filtered phase-sensitive COSY experiments. This new (difluoromethylene)phosphonate anion-methyl ester condensation, Grignard (hydride) addition, deoxygenation sequence has been applied to the synthesis of (alpha,alpha-difluoroalkyl)phosphonate analogues of L-phosphoserine (>/=96% ee) and L-phosphoallothreonine (93% ee) from D-serine and of L-phosphothreonine (91% ee) from L-glycerate, respectively.     

BF3-induced cyclobutane-opening of verbenone and its deconjugate homolog. Efficient preparation of o-mentha-1,8-dien-3-one and o-menth-1-en-3-one in optically active forms

Starting with (+)-verbenone, readily obtainable from (+)-nopinone, enantioselective preparation of (S)-(+)-4-isopropenyl-, (S)-(−)-4-isopropyl- and (R)-(+)-4-(1-acetoxy-1-methylethyl)-3-methyl-2-cyclohexen-1-ones was accomplished with little loss of stereochemical integrity via BF₃-induced cyclobutane-opening of (+)-4-(methylene)nopinone. As we have developed an efficient chemical transformation of (+)-nopinone into (−)-verbenone, the present syntheses of the above cyclohexenones are formal syntheses of their enantiomers from (+)-nopinone.     

光催化下(-)-马鞭烯酮的重排

( )-马鞭烯酮[( )-Verbenone]是Wender研究组全合成紫杉醇(Taxol)的重要起始物．( )-马鞭烯酮可由( )-α-蒎烯在Co(Ⅱ)催化下氧化得到,并且在光照下重排得到( )-菊花烯酮[( )-Chrysanthenone]．但从( )-α-蒎烯到( )-菊花烯酮的总产率较低,约为16．5％．我们在重复由光活性α-蒎烯出发经过光活性马鞭烯酮及菊花烯酮衍生物合成紫杉醇AB环的实验中发现,由α-蒎烯合     

Highly chemoselective methylation and esterification reactions with dimethyl carbonate in the presence of NaY faujasite. The case of mercaptophenols, mercaptobenzoic acids, and carboxylic acids bearing OH substituents

In the presence of NaY faujasite, the reactions of dimethyl carbonate (DMC) with several ambident nucleophiles such as o- and p-mercaptophenols (1a,b), o- and p-mercaptobenzoic acids (2a,b), o- and p-hydroxybenzoic acids (3a,b), mandelic and phenyllactic acids (4, 5), have been explored under batch conditions. Highly chemoselective reactions can be performed: at 150 degrees C, compounds 1 and 2 undergo only a S-methylation reaction, without affecting OH and CO2H groups; at 165 degrees C, acids 3-5 form the corresponding methyl esters, while both their aromatic and aliphatic OH substituents are fully preserved from methylation and/or transesterification processes. Typical selectivities are of 90-98% and isolated yields of products (S-methyl derivatives and methyl esters, respectively) are in the range of 85-96%. A comparative study with K2CO3 as a catalyst is also reported. Although the base (K2CO3) turns out to be more active than the zeolite, the chemoselectivity is elusive: compounds 2a,b undergo simultaneous S-methylation and esterification reactions, and acids 3-5 yield complex mixtures of products of O-methylation, O-methoxycarbonylation, and esterification of their OH and CO2H groups, respectively. Overall, the combined use of a nontoxic reagent/solvent (DMC) and a safe promoter (NaY) imparts a genuine ecofriendly nature to the investigated synthesis.     

Recent syntheses and reactions of cyclic imidic esters

Δ²-Oxazolines and 4H-5,6-dihydrooxazines are readily obtainable from carboxylic acids and 2- or 3-amino alcohols by gas-phase dehydration, and 4H-dihydrooxazines can also be obtained by condensation of N-(hydroxymethyl) carboxamides with olefins. These cyclic imidic esters undergo reactions in which the ring is cleaved; these reactions include a new type of polymerization. The behavior of alkyl groups in position 2 and the cyclodditions in the 2,3-position also have been studied. Reactions in side chains on position 2 and addition experiments on the sulfur analogues of the cyclic imidic esters are also reported. A table shows the principal infrared bands of substituted Δ²-oxazolines.     

General base and general acid catalyzed intramolecular aminolysis of esters. Cyclization of esters of 2-aminomethylbenzoic acid to phthalimidine

Plots of log k(0) vs pH for the cyclization of trifluoroethyl and phenyl 2-aminomethylbenzoate to phthalimidine at 30 degrees C in H(2)O are linear with slopes of 1.0 at pH >3. The values of the second-order rate constants k(OH) for apparent OH(-) catalysis in the cyclization reactions are 1.7 x 10(5) and 5.7 x 10(7) M(-)(1) s(-)(1), respectively. These rate constants are 10(5)- and 10(7)-fold greater than for alkaline hydrolysis of trifluoroethyl and phenyl benzoate. The k(OH) for cyclization of the methyl ester is 7.2 x 10(3) M(-)(1) s(-)(1). Bimolecular general base catalysis occurs in the intramolecular nucleophilic reactions of the neutral species. The value of the Bronsted coefficient beta for the trifluoroethyl ester is 0.7. The rate-limiting step in the general base catalyzed reaction involves proton transfer in concert with leaving group departure. The mechanism involving rate-determining proton transfer exemplified by the methyl ester in this series (beta = 1.0) can then be considered a limiting case of the concerted mechanism. General acid catalysis of the neutral species reaction or a kinetic equivalent also occurs when the leaving group is good (pK(a) 相似文献   

Kinetics of the exchange reactions between Gd(DTPA)2-, Gd(BOPTA)2-, and Gd(DTPA-BMA) complexes, used as MRI contrast agents, and the triethylenetetraamine-hexaacetate ligand

The kinetics of ligand exchange reactions occurring between the Gd(DTPA), Gd(BOPTA), and Gd(DTPA-BMA) complexes, used as contrast agents in MRI, and the ligand TTHA, have been studied in the pH range 6.5-11.0 by measuring the water proton relaxation rates at 25 °C in 0.15 M NaCl. The rates of the reactions are directly proportional to the concentration of TTHA, indicating that the reactions take place with the direct attack of the H(i)TTHA((6-i)-) (i = 0, 1, 2 and 3) species on the Gd(3+) complexes, through the formation of ternary intermediates. The rates of the exchange reactions of the neutral Gd(DTPA-BMA) increase when the pH is increased from 6.5 to 9, because the less protonated H(i)TTHA((6-i)-) species can more efficiently attack the Gd(3+) complex. The rates of the exchange reactions of [Gd(DTPA)](2-) and [Gd(BOPTA)](2-) also increase from pH 8.5 to 11, but from 6.5 to 8.5 an unexpected decrease was observed in the reaction rates. The decrease has been interpreted by assuming the validity of general acid catalysis. The protons from the H(i)TTHA((6-i)-) species (i = 2 and 3) can be transferred to the coordinated DTPA or BOPTA in the ternary intermediates when the dissociation of the Gd(3+) complexes occurs faster. The kinetic inertness of Gd(DTPA), Gd(BOPTA), and Gd(DTPA-BMA) differs very considerably; the rates of the ligand exchange reactions of Gd(DTPA-BMA), thus the rates of its dissociation, are 2 to 3 orders of magnitude higher than those of Gd(DTPA) and Gd(BOPTA). The rates of the ligand exchange reactions increase with increasing concentration of the endogenous citrate, phosphate, or carbonate ions at a pH of 7.4, but the effect of citrate and phosphate is negligible at their physiological concentrations. The increase in the reaction rates at the physiological concentration of the carbonate ion is significant (20-60%), and the effect is the largest for the Gd(DTPA-BMA) complex.     

Transition metal-catalysed organic reactions promoted by chelating or metallacycle-forming substrates

Chelating or metallacycle-forming substrates are very useful for directing organometallic reactions. This review covers the more recent research that has been carried out in the authors' laboratory. Rhodium(I)- and (III)-catalysed reactions of C---C coupling of butadiene with N-allylamides or N-alkylbutenamides are described. These reactions are controlled by the size and strength of the chelate ring formed by double-bond insertion into the crotyl-rhodium bond (formed from butadiene) and their regioselectivity can change with the oxidation state of the metal. Rhodium(I)-catalysed reactions of butadiene with enamides are also chelation controlled and lead to different products, depending on the substituents at nitrogen. Cobalt(II) metallacycles have been utilized for promoting some organic reactions. It has been shown that alkenes can be catalytically incorporated into cobaltacyclopentadiene rings, that spirocycles can be obtained from diynes, carbon monoxide and acrylic esters and that a Pauson-Khand-type reaction can be combined with a Michael-type reaction to prepare catalytically new cyclopentenones. The use of palladacycles, derived from norbornene insertion into aryl-palladium bonds, followed by cyclization, has allowed the selective functionalization of either end of the metallacycle and the formation of condensed rings. Conversion of a palladium(II) into a palladium(IV) metallacycle, and catalytic processes involving these intermediates, have been achieved. The formation of alkylaromatic palladacycles has also been exploited for the selective meta functionalization of the aromatic moiety by means of alkyl groups, accompanied by expulsion of the norbornene molecule.