A concise synthesis of highly enantiomerically enriched 2-alkylparaconic acid esters via ruthenium-catalyzed asymmetric hydrogenation of acylsuccinates

The catalytic asymmetric hydrogenation of acylsuccinates using RuCl₃ as a precatalyst and atropisomeric diphosphines as chiral auxiliaries allows the synthesis of optically active 2-alkylparaconic acid esters in preparative yields with enantioselectivities up to 99.5% ee.     

Transition state analysis of acid-catalyzed dAMP hydrolysis

Multiple kinetic isotope effects (KIEs) on deoxyadenosine monophosphate (dAMP) hydrolysis in 0.1 M HCl were used to determine the transition state (TS) structure and probe its intrinsic reactivity. The experimental KIEs revealed a stepwise (SN1) mechanism, with a discrete oxacarbenium ion intermediate. This is the first direct evidence for the deoxyribosyl oxacarbenium ion in solution. In 50% methanol/0.1 M HCl the products were deoxyribose 5-phosphate (dRMP) and alpha- and beta-methyl dRMP. The alpha-Me-dRMP/beta-Me-dRMP ratio was 8.5:1. Assuming that a free oxacarbenium ion is equally susceptible to nucleophilic attack on either face, this indicated that approximately 20% proceeded through a solvent-separated ion pair complex, or free oxacarbenium ion, a DN+AN mechanism, while approximately 80% of the reaction proceeded through a contact ion pair complex. The oxacarbenium ion lifetime was estimated at 10(-11)-10(-10) s. Computational transition states were found for ANDN, DN*AN, DN*AN, and DN+AN mechanisms using hybrid density functional theory calculations. After taking into account 20% of DN+AN, there was an excellent match of calculated to experimental KIEs for 80% of the reaction having a DN*AN mechanism. That is, C-N bond cleavage is reversible, with dAMP and the {oxacarbenium ion*adenine} complex in equilibrium. The first irreversible step is water attack on the oxacarbenium ion. The calculated 1'-14C KIE for a stepwise mechanism with irreversible C-N bond cleavage (DN*AN) was 1.052, in the range previously associated only with ANDN transition states, and close to the calculated ANDN value, 1.059. The 1'-14C KIE was strongly dependent on the adenine protonation state.     

Asymmetric Diels-Alder and Ene Reactions in Organic Synthesis. New Synthetic Methods (48)

Rapidly accumulating evidence shows the value of asymmetric Diels-Alder and ene reactions for the syntheses of enantiomerically pure molecules. This article presents a systematic and critical treatment of various stereoface-differentiating principles, including very recent spectacular advances. The chiral information is mainly provided by covalently bound auxiliaries, some of which are crystalline, inexpensive, and readily available from naturally occurring monoterpenes, hydroxy acids, amino acids, steroids, and sugars. Non-destructive transfer of chirality leads to the efficient creation of up to four chiral centers with predictable relative and absolute configurations. Regenerative cleavage of the auxilary group from the diastereomerically pure adducts furnishes a range of polyfunctional, optically pure building blocks. Their synthetic potential is illustrated by strategic applications to the syntheses of physiologically interesting, chiral natural products such as prostaglandins, antibiotics, terpenoids, shikimic acid, alkaloids, and kainoids.     

Synthesis of two (S)-indoline-based chiral auxiliaries and their use in diastereoselective alkylation reactions

Two chiral auxiliaries, 2-[(S)-indolin-2-yl]propan-2-ol 1a and (S)-2-(2-methoxypropan-2-yl)indoline 1b, were synthesised from enantiomerically pure (S)-indoline-2-carboxylic acid 3. High diastereoselectivities in alkylations of enolates of the propanoylamides derived from the two auxiliaries are presented. Surprisingly, both auxiliaries induced the same selectivity at the newly created stereogenic centre. The benzyl bromide and n-butyl iodide alkylation reactions showed diastereomeric ratios that were moderate (81:19) to very good (96:4) and with very good yields (86–98%). When LiCl was used as an enolate coordinating agent, in the benzylation of the enolate from propanoylated auxiliary 1a, a very high crude diastereomeric ratio was obtained (99.7:0.3).     

Convenient synthesis of chiral H4-BINOL via direct hydrogenation of BINOL

<正>A simple,highly effective hydrogenation of chiral BINOL to provide H_4-BINOL in multigram scale with good yield(up to 78% yield) was developed.A series of heterogeneous catalysts was tested in the hydrogenation;;the best result was obtained with 5%Pd/ C in EtOH under the H_2 pressure of 50 bar for 2 h.This method is a more useful method for practical synthesis of optically pure H_4- BINOL than other available methods.     

Influence of N7 protonation on the mechanism of the N-glycosidic bond hydrolysis in 2'-deoxyguanosine. A theoretical study

The influence of N7 protonation on the mechanism of the N-glycosidic bond hydrolysis in 2'-deoxyguanosine has been studied using density functional theory (DFT) methods. For the neutral system, two different pathways (with retention and inversion of configuration at the C1' anomeric carbon) have been found, both of them consisting of two steps and involving the formation of a dihydrofurane-like intermediate. The Gibbs free energy barrier for the first step is very high in both cases (53 and 46 kcal/mol for the process with inversion and with retention, respectively). However, the N7-protonated system shows a very different mechanism which consists of two steps. The first one leads to the formation of an oxacarbenium ion intermediate, with a Gibbs free energy barrier of 27 kcal/mol, and the second one corresponds to the nucleophilic attack of the water molecule to the oxacarbenium ion and takes place with a barrier of 1.3 kcal/mol. Thus, these results agree with a stepwise SN1 mechanism (DN*AN), with a discrete intermediate formed between the leaving group and the nucleophile approach, and show that N7 protonation strongly catalyzes the hydrolysis of the N-glycosidic bond, making the guanine a better leaving group. Finally, kinetic isotope effects have been calculated for the protonated system, and the results obtained are in very good agreement with experimental data for analogous systems.     

Enantiopure alkaloid analogues and iminosugars from proline derivatives: stereocontrol in sequential processes

An alternative to the use of expensive auxiliaries or catalysts in the synthesis of chiral 2-substituted pyrrolidines is described. Thus, commercial, cheap 4-(S)-hydroxyproline was readily transformed into optically pure pyrrolidines, using a one-pot decarboxylation-alkylation reaction as the key step. In this reaction, an acyliminium intermediate was generated, which was trapped by carbon nucleophiles. As postulated by Woerpel, the addition of the nucleophiles to the five-membered ring iminium ions took place stereoselectively, affording 2,4-cis-disubstituted pyrrolidines in high de. The hydroxy group at C-4 can then be removed, or alternatively, it can be used to create new functionalities in the molecule. In this way, optically pure alkaloid analogues and iminosugars were prepared.     

Enhanced diastereoselectivity via confinement: diastereoselective photoisomerization of 2,3-diphenyl-1-benzoylcyclopropane derivatives within zeolites

Photochemistry of optically pure trans-2,3-diphenyl-1-benzoylcyclopropane has been examined in isotropic solution and within zeolites. Results suggest that it isomerizes by cleavage of either the C1-C2 or C1-C3 bond. From the perspective of chiral induction, photoisomerization of cis-2,3-diphenyl-1-benzoylcyclopropane derivatives with chiral auxiliaries placed at the meta and para positions of the benzoyl group have been examined both in isotropic solution and within zeolites. Whereas in isotropic solution the chiral auxiliaries placed at the meta position exhibit very little influence during the conversion of triplet cis-2,3-diphenyl-1-benzoylcyclopropane derivatives, they have significant influence within zeolites. For example, alpha-methyl benzylamine placed at the meta position of the benzoyl group (via an amide bond) yields the trans isomer with a diastereoselectivity (de) of 71% within NaY zeolite, whereas in solution no de is obtained. The chiral induction process within zeolites depends on the nature of the alkali ion and on the presence of water. Results suggest that the chiral auxiliary is able to control the bond being cleaved (C1-C2 vs. C1-C3 bond) within a zeolite, but it is unable to do so in an isotropic solution.     

Rapid and efficient synthesis of optically active pyrazoles under solvent-free conditions

2-Formyl glycals undergo rapid condensation with arylhydrazines under solvent-free conditions to give the corresponding optically pure 4-substituted pyrazoles in good yields with high selectivity. The stereochemistry of the products was assigned by various NMR experiments.     

Recent topics of transfer hydrogenation

A number of transition metal catalysts have been developed for transfer hydrogenation of organic molecules. This method provides a useful process for the reduction of unsaturated molecules without the need for explosive hydrogen gas. An important development in this area is the design of new ligands that improve activity and selectivity under mild reaction conditions. Polydentate ligands are good candidates for producing high performance metal catalysts. This digest describes recent developments in transfer hydrogenation as well as asymmetric reactions using metal catalysts containing polydentate ligand systems.     

Synthesis and crystal structure of a novel chiral compound prepared from (-)-borneol as a natural chiral auxiliary

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Integrated Suzuki Cross-Coupling/Reduction Cascade Reaction of meta-/para-Chloroacetophenones and Arylboronic Acids under Batch and Continuous Flow Conditions

Overcoming the incompatibility of a pair of conflicting catalysts via a flow methodology has great significance in the practical applications for multistep organic transformations. In this study, a multiple continuous-flow system is developed, which can boost the reactivity and selectivity in a sequential enantioselective cascade reaction. During this process, a periodic mesoporous organosilica-supported Pd/carbene species as a Suzuki cross-coupling catalyst is packed in the first column reactor, whereas another periodic mesoporous organosilica-supported Ru/diamine species as an asymmetric transfer hydrogenation catalyst is packed in the second column reactor. As we envisioned, the initially Pd-catalyzed cross-coupling reaction of meta-/para-chloroacetophenones and aryl boronic acids followed by the subsequentially Ru-catalyzed reduction provides chiral biarylols with enhanced yields and enantioselectivities. Furthermore, the advantages of the easy handling and the simple procedure make this system an attractive application in a scale-up preparation of optically pure organic molecules under environmentally-friendly conditions.     

Recent developments in the synthesis of prosophylline and its derivatives

Several synthetic efforts are reported towards the optically active (?)-prosophylline and (+)-prosophylline, and their derivatives. Interestingly and surprisingly, although only a few synthesis are reported for the parent molecules, there are more reports for the synthesis of their derivatives such as deoxoprosophyllines, deoxoprosopinines, deoxocassines etc. The three main strategies to procure these molecules in optically pure forms are by using (i) chiral synthons (ii) chiral auxiliaries and (iii) asymmetric catalysis. Among these, the chiral synthons are mainly utilized by a number of researchers. This review summarizes the recent developments in the synthesis of optically active prosophyllines and their derivatives, and covers the literature from the year 2000 onwards.     

Chiral ferrocenyl diphosphines for asymmetric transfer hydrogenation of acetophenone

The synthesis of new optically pure ferrocenyl diphosphines have been realized from (R)-(+)-N,N-dimethylaminoethylferrocene. Particularly, dissymmetric ferrocenyl diphosphines have been synthesized. The diphosphines have been used as ligands in asymmetric transfer hydrogenation of acetophenone in the presence of Ru catalysts.     

A synthesis of optically active α-quaternary α-amino acids and esters by assembling three components, ketones, (R)-chloromethyl p-tolyl sulfoxide, and sodium azide, via sulfinyloxiranes

Treatment of lithium α-sulfinyl carbanion of chloromethyl p-tolyl sulfoxides with ketones at low temperature afforded adducts in almost quantitative yields, which were exposed to t-BuOK to give sulfinyloxiranes in high yields. The sulfinyloxirane was reacted with benzylamine to give α-amino aldehyde, which was oxidized with iodine in methanol to afford α-amino carboxylic ester in moderate yield. The sulfinyloxiranes were treated with sodium azide to afford α-azido aldehydes in good yields. Oxidation with NaClO₂ followed by catalytic hydrogenation of the azido group of the α-azido aldehydes gave α-quaternary α-amino acids in good overall yields. The oxidation of the azido aldehydes with iodine in methanol in the presence of KOH followed by the catalytic hydrogenation resulted in α-quaternary α-amino acid methyl esters in good yields. When these reactions were carried out starting from unsymmetrical ketones and optically pure (R)-chloromethyl p-tolyl sulfoxide, a new method for a synthesis of optically active α-quaternary α-amino acids and esters in good overall yields was realized.     

Transition-state analysis of the DNA repair enzyme MutY

The transition state (TS) structure of MutY-catalyzed DNA hydrolysis was solved using multiple kinetic isotope effect (KIE) measurements. MutY is a base excision repair enzyme which cleaves adenine from 8-oxo-G:A mismatches in vivo, and also from G:A mismatches in vitro. TS analysis of G:A-DNA hydrolysis revealed a stepwise S(N)1 (D(N)*A(N)(double dagger)) mechanism proceeding through a highly reactive oxacarbenium ion intermediate which would have a lifetime in solution of <10(-10) s. C-N bond cleavage is reversible; the N-glycoside bond breaks and reforms repeatedly before irreversible water attack on the oxacarbenium ion. KIEs demonstrated that MutY uses general acid catalysis by protonating N7. It enforces a 3'-exo sugar ring conformation and other sugar ring distortions to stabilize the oxacarbenium ion. Combining the experimental TS structure with the previously reported crystal structure of an abortive Michaelis complex elucidates the step-by-step catalytic sequence.     

A novel synthesis, including asymmetric synthesis, of α-quaternary α-amino acid methyl esters from ketones via sulfinyloxiranes

Sulfinyloxiranes were synthesized from ketones and chloromethyl p-tolyl sulfoxide in two steps in almost quantitative yields. The sulfinyloxiranes were treated with NaN₃ in the presence of NH₄Cl to afford α-azido aldehydes, which were oxidized with iodine in the presence of KOH in methanol to give α-azido methyl esters in good overall yields. Catalytic hydrogenation of the α-azido esters afforded α-quaternary α-amino acid methyl esters in quantitative yields. Starting from β-tetralone and optically pure (R)-chloromethyl p-tolyl sulfoxide, an asymmetric synthesis of optically pure (R)-(+)-methyl 2-aminotetraline-2-carboxylate was realized in good overall yields.     

Highly Enantioselective Hydrogenation of N‐Aryl Imines Derived from Acetophenones by Using Ru–Pybox Complexes under Hydrogenation or Transfer Hydrogenation Conditions in Isopropanol

The asymmetric reduction of N‐aryl imines derived from acetophenones by using Ru complexes bearing both a pybox (2,6‐bis(oxazoline)pyridine) and a monodentate phosphite ligand has been described. The catalysts show good activity with a diverse range of substrates, and deliver the amine products in very high levels of enantioselectivity (up to 99 %) under both hydrogenation and transfer hydrogenation conditions in isopropanol. From deuteration studies, a very different labeling is observed under hydrogenation and transfer hydrogenation conditions, which demonstrates the different nature of the hydrogen source in both reactions.     

Chiral tetrathiafulvalene based phosphine- and thiomethyl-oxazoline ligands. Evaluation in palladium catalysed asymmetric allylic alkylation

New chiral redox active ligands based on ethylenedithio-tetrathiafulvalene (EDT-TTF) bearing racemic or optically pure oxazolines have been synthesised. These auxiliaries possess an additional functionality on the TTF unit, namely a thiomethyl residue or a diphenylphosphino moiety. All ligands have been tested in asymmetric allylic substitutions. The enantioselectivity reached is 85% ee.     

Synthesis of optically active 2-aminotetraline derivatives via enantioselective ruthenium-catalyzed hydrogenation of ene carbamates

The enantioselective hydrogenation of prochiral ene carbamates, directly derived from 2-tetralone, was completed using a catalytic ruthenium system generated from Ru(COD)(methallyl)₂, an optically pure diphosphine and a strong acid containing a non-coordinating counter anion.