Low Diastereoselectivity Research Articles

A molecular electron density theory study of the mechanism, chemo- and stereoselectivity of the epoxidation reaction of R-carvone with peracetic acid.

The epoxidation reaction of R-carvone 8 with peracetic acid 9 has been studied within the molecular electron density theory at the B3LYP/6-311(d,p) computational level. The chemo- and stereoisomeric reaction paths involving the two C–C double bonds of R-carvone 8 have been studied. DFT calculations account for the high chemoselectivity involving the C–C double bond of the isopropenyl group and the low diastereoselectivity, in complete agreement with the experimental outcomes. The Baeyer–Villiger reaction involving the carbonyl group of R-carvone 8 has also been analysed. A bonding evolution theory analysis of the epoxidation reaction shows the complexity of the bonding changes taking place along this reaction. Formation of the oxirane ring takes place asynchronously at the end of the reaction by attack of anionic oxygen on the two carbons of the isopropenyl C–C double bond.

Editors' Choice—Highly Diastereoselective Anodic Fluorination of Organosulfur Compounds Based on Neighboring Participation

Highly diastereoselective and efficient anodic α-fluorination of phenyl, p-chlorophenyl, and 2-naphthyl 3,3,3-trifluoro-2-methoxypropyl sulfides was successfully carried out at platinum electrodes in Et3N-nHF (n = 3–5)/MeCN to provide the corresponding α-fluorinated products in good yields, whereas the corresponding p-methoxyphenyl sulfide derivative gave much lower diastereoselectivity. On the basis of such marked substituent effects on the diastereoselectivity and a previous study of anodic methoxylation of related sulfides, as well as the X-ray analysis of the configuration of the major diastereomer of the electrochemically fluorinated β-naphthyl derivative, it was clarified that the high diastereoselectivity is attributable to the neighboring MeO group participation to the anodically generated cationic intermediate destabilized by an electron-withdrawing CF3 group.

Amino-β-lactams in Ugi reaction: An efficient method for preparation of functionalized peptidomimetics

A synthetic strategy for the Ugi reaction on amino-β-lactam synthon 1 was developed. The Ugi reaction products 5 were obtained in satisfactory yields (47–78%) and generally, low diastereoselectivity (up to 72:28 dr). In case of Ugi products 5 derived from cyclohexylcarbaldehyde and amino-β-lactam 1, the reaction yields were lower (38–61%) but the products were obtained in high diastereoselectivity (>95:5).

Addition of Metalated 3‐Alkyl‐Substituted Alkoxyallenes to Imines: Preparation of Tetrasubstituted 2,5‐Dihydropyrroles, Pyrrolidin‐3‐ones, and Pyrroles

Metalated 3‐alkyl‐substituted methoxyallenes were either generated by lithiation of the corresponding methoxyallenes or, according to a procedure of Brandsma, from 3‐alkyl‐substituted propargyl methyl ethers. Additions of these axially chiral intermediates to various imines afforded the expected allenylamines in good yields, but low diastereoselectivity. The products were cyclized either under basic conditions or with silver nitrate as catalyst to furnish the desired 1,2,3,5‐tetrasubstituted 2,5‐dihydropyrrole derivatives. Under basic conditions the cyclization is stereospecific whereas the presence of silver nitrate can induce partial crossover. The mechanisms of the two cyclization modes are discussed. Two of the N‐tosyl‐substituted dihydropyrroles were subjected to an excess of potassium tert‐butoxide giving the expected aromatized 3‐methoxypyrrole derivatives by elimination of p‐tolyl sulfinate. Acid‐promoted hydrolysis of the enol ether moiety of 2,5‐dihydropyrroles furnished the corresponding pyrrolidin‐3‐ones in good yields. The sodium borohydride reduction of these intermediates gave the corresponding 3‐hydroxypyrrolidine derivatives with high diastereoselectivity that strongly depends on the substitution pattern of the precursor. This study reveals that 3‐alkyl‐substituted methoxyallenes and their propargylic ether equivalents allow an efficient and flexible approach to 1,2,3,5‐substituted pyrrole derivatives that are useful intermediates for subsequent stereoselective elaboration and promising candidates for natural product syntheses.

Diastereoselective Ammonium-Directed Epoxidation in the Asymmetric Syntheses of Dihydroconduramines (+)-C-2, (-)-C-2, (+)-D-2, (+)-E-2, (+)-F-2, and (-)-F-2.

Epoxidations (40% aq HBF4 then m-CPBA) of racemic cis-2-( N-benzylamino)cyclohex-3-en-1-ol and racemic cis-2-( N, N-dibenzylamino)cyclohex-3-en-1-ol proceed with very high levels of diastereoselectivity (>95:5 dr). The latter is in direct contrast to the epoxidation of the corresponding trans-diastereoisomer (which proceeds with essentially no selectivity), showing that the relative configuration of the substrate dramatically influences the diastereoselectivity in these instances. Meanwhile, epoxidations of enantiopure (1 R,2 S,α R)-2-[( N-α-methylbenzyl)amino]cyclohex-3-en-1-ol and (1 S,2 R,α R)-2-[( N-α-methylbenzyl)amino]cyclohex-3-en-1-ol [surrogates for the enantiomers of cis-2-( N-benzylamino)cyclohex-3-en-1-ol] proceed with complete diastereoselectivity (>95:5 dr) under the same conditions, showing that neither the presence of the α-methyl group nor the relative configuration of the α-methylbenzyl stereocenter have an effect upon the established level of diastereoslectivity in these cases. In contrast, epoxidations of enantiopure (1 R,2 S,α R)-2-[ N-benzyl- N-(α-methylbenzyl)amino]cyclohex-3-en-1-ol and (1 S,2 R,α R)-2-[ N-benzyl- N-(α-methylbenzyl)amino]cyclohex-3-en-1-ol [surrogates for the enantiomers of cis-2-( N, N-dibenzylamino)cyclohex-3-en-1-ol] proceed with lower diastereoselectivity (∼70:30 dr). Thus, the presence of the α-methyl group has a detrimental effect on the established level of diastereoselectivity in these cases (although again the relative configuration of the α-methylbenzyl stereocenter is unimportant). The diastereoselective epoxidation pathway is used to enable the asymmetric syntheses of six hitherto unknown, enantiopure dihydroconduramines (+)-C-2, (-)-C-2, (+)-D-2, (+)-E-2, (+)-F-2, and (-)-F-2 (>99% ee in each case).

The stereodynamics of macrocyclic succinimide-thioethers.

Maleimide-thiol coupling is a popular bioconjugation strategy, but little is known about the stereoselectivity and the stereodynamics of the succinimide thioether formed in a biopolymer environment. We used thiol 1,4-addition for the macrocyclisation of 5 designed pentapeptides with the ringsize of hexapeptides because they incorporate the succinimide thioether (4-8). Both succinimide diastereomers are observed in the constrained macrocyclic rings in each case. In spite of the low diastereoselectivity of the macrocyclisation reaction, there is a significant influence of the amino acid environment on the epimerization rate of the succinimide. Its half life can be as short as several hours at room temperature when Gly is the amino acid following the succinimide (peptide 8). On the contrary, no epimerization is detectable even after several weeks in the case of d-Phe C-terminal to the succinimide in peptide 4. Already the small selection of examples shows how big the differences in epimerization rates can be and that the local environment has a significant influence. The variation of amino acids in the vicinity of the ligation site points the way towards the synthesis of bioconjugates which are obtained as stable and separable diastereomers.

Dianionic Phase-Transfer Catalyst for Asymmetric Fluoro-cyclization

Inspired by the dicationic nature of the electrophilic fluorinating reagent, Selectfluor (1), we rationally designed a series of dicarboxylic acid precatalysts (2), which, when deprotonated, act as anionic phase-transfer catalysts for asymmetric fluorination of alkenes. Among them, 2a having the shortest linker moiety efficiently catalyzed unprecedented 6-endo-fluoro-cyclization of various allylic amides, affording fluorinated dihydrooxazine compounds with high enantioselectivity (up to 99% ee). In addition to cyclic substrates, acyclic trisubstituted alkenes underwent the reaction with good diastereoselectivity, whereas low diastereoselectivity was observed for linear disubstituted alkenes. Results suggest that the reaction proceeds via a fluoro-carbocation intermediate.

Highly Diastereoselective Synthesis of 2-(1-N-Boc-aminoalkyl)thiazole-5-carboxylates by Reduction of tert-Butylsulfinyl Ketimines.

Positional isomers of naturally occurring peptide subunits were synthesized via highly diastereoselective reduction of tert-butylsulfinyl ketimines as a key reaction. While NaBH4 reduction of ketimines derived from 2-thiazolyl ketones afforded the (RS,R)-isomer with moderate diastereoselectivity, L-Selectride® reduction afforded the (RS,S)-isomer as the sole product. In contrast, ketimines derived from tert-butyl 2-thiazolyl ketone afforded the (RS,R)-isomer with low diastereoselectivity by both NaBH4 and L-Selectride® reduction. Stereochemistry of the reaction was discussed based on calculation of the conformational energies for ketimines.

14-Membered cyclic bis-semicarbazones: Stereoselective synthesis and structural features

Stereoselectivity of acid-catalyzed cyclization of 4-(1-aryl-3-oxobutyl)semicarbazide hydrazones into mixtures of trans- and cis-isomers of 14-membered cyclic bis-semicarbazones has been studied. The isomer ratio is dependent on solvent, catalyst acidity, substrate structure and concentration, reaction temperature and time, catalyst loading. The experimental data show that the macrocyclization of acyclic precursors initially formed from two molecules of substrates proceeds with low diastereoselectivity to give mixtures of trans- and cis-macrocycles followed by slow transformation of cis-isomers into trans-isomers via ring opening by a retro-aza-Michael reaction resulting in high trans-selectivity. The driving force of this isomerization is shown to be a lower solubility of trans-isomers compared with cis-isomers. Some mechanistical aspects of the macrocycle formation were confirmed by calculations performed at the DFT B3LYP/6–311++G(d,p) level of theory. Molecular structure of the obtained hexaaza macrocycles was established using single crystal and powder X-ray diffraction, IR, UV–Vis, 1H and 13C NMR spectroscopy, and DFT calculations.

Stereoselective allylation and reduction of N-tert-butanesulfinyl-α-keto aldimines

A simple methodology for the synthesis of N-tert-butanesulfinyl-α-keto aldimines from both α-keto aldehydes and carboxylic esters has been developed. The addition of an in situ formed allyl indium reagent to these chiral imines was also studied. The addition took place in a sequential manner, first to the imine group with excellent diastereoselectivity and then to the carbonyl group with lower diastereoselectivity. Ruthenium-catalyzed ring closing metathesis of the resulting 5-aminoocta-1,7-dien-4-ol derivatives provided access to 6-aminocyclohex-3-enols. Reduction of the α-keto aldimines led to N-tert-butanesulfinyl-1,2-aminoalcohols as a 1:1 diastereomeric mixture.

Additions of Organomagnesium Halides to α-Alkoxy Ketones: Revision of the Chelation-Control Model.

The chelation-control model explains the high diastereoselectivity obtained in additions of organometallic nucleophiles to α-alkoxy ketones but fails for reactions of allylmagnesium halides. Low diastereoselectivity in ethereal solvents results from no chelation-induced rate acceleration. Additions of allylmagnesium bromide to carbonyl compounds are diastereoselective using CH2Cl2 as the solvent even though rate acceleration is still absent. Stereoselectivity likely arises from the predominance of the chelated form in solution. Therefore, a revised chelation-control model is proposed.

Cinchonine-catalyzed in situ generation of unstable and gaseous trifluoroacetaldehyde from its hemiacetal and direct aldol reaction with 2-methoxy-1-phenylethanone

The cinchonine-catalyzed in situ generation of unstable and gaseous trifluoroacetaldehyde from its hemiacetal and successive direct aldol reaction with 2-methoxy-1-phenylethanone proceeded smoothly to give 4,4,4-trifluoro-3-hydroxy-2-methoxy-1-phenylbutan-1-one in good yield with low diastereoselectivity and enantioselectivity.

Vanadium(V)-catalyzed epimerization of isoleucine

All stereoisomers of isoleucine were transformed to the mixtures of the corresponding epimers by epimerization in alkaline aqueous solution. The catalyst was formed in situ by condensation of salicylaldehyde and isoleucine followed by complexation with vanadate. No derivatization of the amino acid was necessary. The tetrabutylammonium salts of [VO2(N-salicylidene-isoleucinato)]− can be used for diastereomeric separation of the epimers providing low yields and moderate diastereoselectivities.

Weakly bounded intermediates as a previous step towards highly-enantioselective iminium type additions of β-keto-sulfoxides and -sulfones

A joined experimental and theoretical study on the addition of β-keto-sulfoxides and -sulfones to enals catalyzed with amine compounds of the Jørgensen-Hayashi type is presented. Theoretically, density functional theory calculations are used to explore the potential energy surface of the reactions, providing insight into the mechanisms. Our combined approach allows us to show that the reactions with the sulfoxides take place with the enolate instead of the enol intermediates. The addition mechanisms are evaluated computing the transition states of the reactions between enolates of β-ketosulfones and β-ketosulfoxides with the iminium ion of different catalysts. In the reactions with β-ketosulfoxides, the experiments found a high enantio – and diastereoselectivity; this is explained with the kinetic control exerted by the difference in the energetic barriers as given by the calculations. In the case of β-ketosulfones a low diastereoselectivity was experimentally observed. In this case, similar energy barriers in the two studied pathways are obtained. In both cases (β-keto-sulfones and -sulfoxides), the interaction of both reactants leads to a weakly bounded complex previous to the reaction, in which the orientation determines the stereoselectivity obtained in the products.

ChemInform Abstract: Diastereoselective Synthesis of trans‐3,5‐Disubstituted Dihydrofuran‐2(3H)‐ones via SmI2‐Mediated Reductive Coupling of 2‐Alkylacrylates of N,N‐Diisopropyl‐2‐hydroxybenzamide with Aldehydes.

Abstract Samarium(II) diiodide has been used to mediate reductive coupling reactions of aldehydes with a variety of substituted acrylates, in both achiral and chiral forms, for accessing substituted dihydrofuran-2(3H)-ones (γ-butyrolactones). Two major issues, concerning with self-dimerization of α-non-branched aliphatic aldehydes and low diastereoselectivity of the products, render limited application of the reductive coupling protocol in total synthesis of natural products. We report here on a novel type of substituted acrylates derived from the 2-amido arenols (HO-Aram) such as N,N-diisopropyl-2-hydroxybenzamide. The acrylates of HO-Aram enable: (a) preferential conjugate reduction of the acrylates than carbonyl reduction of aliphatic aldehydes, leading to diminished aldehyde self-dimerization; and (b) organization of an eight-membered ring among the amide carbonyl oxygen atom and samarium(III) to form a 7/8-bicyclic transition state, resulting in highly diastereoselective protonation of the samarium(III) enolate intermediate. Examples of synthesis of trans-3,5-disubstituted dihydrofuran-2(3H)-ones from 2-alkylacrylates of HO-Aram and aliphatic aldehydes are provided.

ChemInform Abstract: A Direct, Concise, and Enantioselective Synthesis of 2‐Substituted 4,4,4‐Trifluorobutane‐1,3‐diols Based on the Organocatalytic in situ Generation of Unstable Trifluoroacetaldehyde.

A direct, concise, and enantioselective synthesis of 2-substituted 4,4,4-trifluorobutane-1,3-diols based on the organocatalytic asymmetric direct aldol reaction of an ethyl hemiacetal of trifluoroacetaldehyde with various aldehydes was examined. A catalytic amount (30 mol %) of commercially available and inexpensive l-prolinamide is quite effective as an organocatalyst for the catalytic in situ generation of gaseous and unstable trifluoroacetaldehyde from its hemiacetal, and a successive asymmetric direct aldol reaction with various aldehydes in dichloromethane at 0 °C, followed by reduction with sodium borohydride, gives 2-substituted 4,4,4-trifluorobutane-1,3-diols in moderate to good yields (31–84 %) with low diastereoselectivities and good to excellent enantioselectivities (64–97 % ee).

Threonine aldolases: perspectives in engineering and screening the enzymes with enhanced substrate and stereo specificities.

Threonine aldolases have emerged as a powerful tool for asymmetric carbon-carbon bond formation. These enzymes catalyse the unnatural aldol condensation of different aldehydes and glycine to produce highly valuable β-hydroxy-α-amino acids with complete stereocontrol at the α-carbon and moderate specificity at the β-carbon. A range of microbial threonine aldolases has been recently recombinantly produced by several groups and their biochemical properties were characterized. Numerous studies have been conducted to improve the reaction protocols to enable higher conversions and investigate the substrate scope of enzymes. However, the application of threonine aldolases in organic synthesis is still limited due to often moderate yields and low diastereoselectivities obtained in the aldol reaction. This review briefly summarizes the screening techniques recently applied to discover novel threonine aldolases as well as enzyme engineering and mutagenesis studies which were accomplished to improve the catalytic activity and substrate specificity. Additionally, the results from new investigations on threonine aldolases including crystal structure determinations and structural-functional characterization are reviewed.

Diastereoselective synthesis of trans-3,5-disubstituted dihydrofuran-2(3H)-ones via SmI2-mediated reductive coupling of 2-alkylacrylates of N,N-diisopropyl-2-hydroxybenzamide with aldehydes

Samarium(II) diiodide has been used to mediate reductive coupling reactions of aldehydes with a variety of substituted acrylates, in both achiral and chiral forms, for accessing substituted dihydrofuran-2(3H)-ones (γ-butyrolactones). Two major issues, concerning with self-dimerization of α-non-branched aliphatic aldehydes and low diastereoselectivity of the products, render limited application of the reductive coupling protocol in total synthesis of natural products. We report here on a novel type of substituted acrylates derived from the 2-amido arenols (HO-Aram) such as N,N-diisopropyl-2-hydroxybenzamide. The acrylates of HO-Aram enable: (a) preferential conjugate reduction of the acrylates than carbonyl reduction of aliphatic aldehydes, leading to diminished aldehyde self-dimerization; and (b) organization of an eight-membered ring among the amide carbonyl oxygen atom and samarium(III) to form a 7/8-bicyclic transition state, resulting in highly diastereoselective protonation of the samarium(III) enolate intermediate. Examples of synthesis of trans-3,5-disubstituted dihydrofuran-2(3H)-ones from 2-alkylacrylates of HO-Aram and aliphatic aldehydes are provided.

Synthesis of new spirooxindole derivatives through 1,3-dipolar cycloaddition of azomethine ylides and their antitubercular activity

Non-stabilized azomethine ylides, generated in situ from isatin derivatives and l-proline, have been reacted with (E,E)-1,3-bis(arylidene)indan-2-ones as dipolarophiles in a 1,3-dipolar cycloaddition reaction. Novel functionalized dispiroheterocyclic compounds were obtained with low diastereoselectivity and the regiochemical outcome of the cycloaddition reaction was confirmed by single crystal X-ray analysis. The compounds were investigated by in vitro screening against Mycobacterium tuberculosis (MIC) using the agar dilution method and displayed good activities.

ChemInform Abstract: Intramolecular Palladium‐Catalyzed Alkene Carboalkynylation.

AbstractTriisopropylsilylethynyl bromide reacts with alkene‐tethered activated carbonyl compounds, thus allowing for the formation of five‐membered carbocycles in high yields and six‐membered carbocycles in moderate yields, albeit with low diastereoselectivities.