Loss Of Optical Activity Research Articles

Chemoenzymatic synthesis of optically active α-cyclopropyl-pyruvates and cyclobutenoates via enzyme-catalyzed carbene transfer with diazopyruvate.

Cyclopropanes are recurrent structural motifs in natural products and bioactive molecules. Recently, biocatalytic cyclopropanations have emerged as a powerful approach to access enantioenriched cyclopropanes, complementing chemocatalytic approaches developed over the last several decades. Here, we report the development of a first biocatalytic strategy for cyclopropanation using ethyl α-diazopyruvate as a novel enzyme-compatible carbene precursor. Using myoglobin variant Mb(H64V,V68G) as the biocatalyst, this method afforded the efficient synthesis of α-cyclopropylpyruvates in high diastereomeric ratios and enantiomeric excess (up to 99% ee). The ketoester moiety in the cyclopropane products can be used to synthesize diverse optically pure cyclopropane derivatives. Furthermore, the enzymatically obtained α-cyclopropylpyruvate products could be converted into enantiopure cyclobutenoates via a metal-free photochemical ring expansion without loss of optical activity.

Chiral Spirocyclic Phosphoric Acid‐Catalyzed Synthesis of 4‐Alkyl‐3,4‐dihydropyrimidin‐2(1H)‐one Derivatives by Asymmetric Biginelli Reactions

AbstractA chiral spirocyclic phosphoric acid‐catalyzed asymmetric Biginelli reaction based on aliphatic aldehydes has been realized for the synthesis of biologically important and synthetically useful 4‐alkyl‐3,4‐dihydropyrimidin‐2‐(1H)‐one (4‐alkyl−DHPM) skeletons in good yield and with high levels of enantioinduction. The utility of this transformation was further demonstrated by direct thionation and C−C/C−N bond construction to provide a series of 4‐alkyl−DHPMs derivatives without any loss of optical activity, providing streamlined access to the formal synthesis of Batzelladine A.

PdII -Catalyzed Enantioselective C(sp3 )-H Activation/Cross-Coupling Reactions of Free Carboxylic Acids.

PdII -catalyzed enantioselective C(sp3 )-H cross-coupling of free carboxylic acids with organoborons has been realized using either mono-protected amino acid (MPAA) ligands or mono-protected aminoethyl amine (MPAAM) ligands. A diverse range of aryl- and vinyl-boron reagents can be used as coupling partners to provide chiral carboxylic acids. This reaction provides an alternative approach to the enantioselective synthesis of cyclopropanecarboxylic acids and cyclobutanecarboxylic acids containing α-chiral tertiary and quaternary stereocenters. The utility of this reaction was further demonstrated by converting the carboxylic acid into cyclopropyl amine without loss of optical activity.

PdII‐Catalyzed Enantioselective C(sp3)−H Activation/Cross‐Coupling Reactions of Free Carboxylic Acids

AbstractPdII‐catalyzed enantioselective C(sp3)−H cross‐coupling of free carboxylic acids with organoborons has been realized using either mono‐protected amino acid (MPAA) ligands or mono‐protected aminoethyl amine (MPAAM) ligands. A diverse range of aryl‐ and vinyl‐boron reagents can be used as coupling partners to provide chiral carboxylic acids. This reaction provides an alternative approach to the enantioselective synthesis of cyclopropanecarboxylic acids and cyclobutanecarboxylic acids containing α‐chiral tertiary and quaternary stereocenters. The utility of this reaction was further demonstrated by converting the carboxylic acid into cyclopropyl amine without loss of optical activity.

FeCl3-catalyzed tandem Prins and Friedel–Crafts cyclization: a highly diastereoselective route to polycyclic ring structures

Catalytic FeCl3 in the presence of 4Å molecular sieves has been shown to effect highly diastereoselective tandem Prins and Friedel–Crafts cyclization of substituted (E/Z)-6-phenylhex-3-en-1-ol and a variety of aldehydes to provide a range of polycyclic compounds in good to excellent yields. The reaction of an enantioenriched alcohol with an aldehyde provided the cyclization product without loss of optical activity. Furthermore, a Lewis acid catalyzed ring opening resulted in functionalized tetralin derivatives with multiple chiral centers.

Experimental and theoretical study of racemization, stability and tautomerism of vitamin C stereoisomers

Experimental degradation of vitamin C (VC) in water was monitored using specific rotation, FT-IR and 1H NMR at room temperature and at 80–90°C. The optical activity was reduced (100%) to zero after 6 and 63days at 80–90°C (≅25% in less than 24h) and room temperature, respectively. 1H NMR and FT-IR was performed after these periods which indicated the formation of a complex mixture at higher stirring time and elevated temperature. These observations indicated that vitamin C is unstable in solution at room temperature or at elevated temperature. The solid VC did not lose optical activity after several mounts at room temperature. The instability of VC was related to isomerization (loss of optical activity) of the l-enantiomer either to d-enantiomer (racemization), degradation to undesired products or tautomerization to other isomers. Theoretical investigation (at B3LYP/6-311++G(d,p) and MP2/6-311++G(d,p) levels of theory in vacuo and aqueous phases) formulated tautomerization for RS-stereoisomers of ascorbic acids (AA). The mechanism for deactivation of VC was examined.

Preparation of Optically Active Six-Membered P-Heterocycles: A 3-Phosphabicyclo[3.1.0] hexane 3-oxide, a 1,2-Dihydrophosphinine 1-oxide, and a 1,2,3,6-Tetrahydrophosphinine 1-oxide

The earlier described a 3-methyl-1-phenyl-3-phospholene 1-oxide (1) → 6,6-dichloro-1-methyl-3-phenyl-3-phosphabicyclo[3.1.0]hexane 3-oxide (2) → 4-chloro-1-phenyl-1,2-dihydrophosphinine 1-oxide (3) → 4-chloro-5-methyl-1-phenyl-1,2,3,6-tetrahydrophosphinine 1-oxide (4) reaction sequence was investigated from the point of view of preparing optically active intermediates/products (2–4). In principle, both the resolution of the corresponding racemic products and the transformation of the optically active starting materials are suitable approaches for the preparation of optically active six-membered P-heterocycles (2–4). Racemization occurred during the dichlorocyclopropanation reaction of (S)-3-methyl-1-phenyl-3-phospholene 1-oxide ((S)-1), but the thermolytic ring opening of (−)-2, and the selective reduction of α,β-double bond of (−)-3 did not cause the loss of optical activity. First in the literature, the resolution of a 3-phosphabicyclo[3.1.0]hexane 3-oxide (2) and a 1,2,3,6-tetrahydrophosphinine 1-oxide (4) was elaborated. © 2013 Wiley Periodicals, Inc. Heteroatom Chem 24:179–186, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.21080

Conversion of L‐Cysteine into D‐α‐Amino Acids and Related Transformations

AbstractNaturally configured cysteine is converted into 4‐substituted thiazolidines via the 4‐carbaldehyde corresponding to the serine derived Garner's aldehyde. The key transformation is the conversion into 5‐thiazolidinones by 1O2 oxidation, and fragmentation of the primary 5‐hydroperoxides under in situ acetylating conditions. Whereas the reagent couple trimethylsilyl halides/phenol selectively cleaves the N‐Boc group, LiOH/H2O2 transforms the thiol lactones into lactones by an unknown mechanism, and, subsequently, also cleaves the acetonide affording N‐Boc‐protected D‐amino acids without loss of optical activity. This sequence tolerates unsaturated residues with sensitive allylic functions. In some cases, double bond isomerization is, however, observed. Thethiazolidine intermediates can be cleaved with 3‐nitro‐2‐pyridinesulfenyl chloride, giving reactive mixed disulfides.

Preparation of bicyclic boroxazolidones from aziridine-2-carboxylic esters

Aziridine-2-carboxylic esters 1 were converted into bicyclic boroxazolidones 3 in a three-step sequence. First, the ester groups were hydrolyzed either by sodium hydroxide or with lithium hydroxide in methanol. The salts thus obtained were acidified with acetic acid or through a weakly acidic ion-exchange resin. Treatment of the zwitterionic aziridine-2-carboxylic acids 2 with triethyl-borane in hexane gave boroxazolidones 3 in high yields. Boroxazolidone 3g, obtained from optically active 1g was reconverted to the starting material by 8-hydroxyquinoline without any loss of optical activity.

Diastereo- and Enantioselective Synthesis of α,γ-Diaminobutyric Acid Derivatives via Cu-Catalyzed Asymmetric Michael Reaction

The first highly diastereo- and enantioselective catalytic asymmetric Michael addition of glycine derivatives to nitroalkenes have been developed. The enantioselectivity of ortho-substituted products can be significantly improved by using a new 1,2-P,N-ferrocene ligand L5. The alpha,gamma-diaminoacid derivative was obtained without the loss of optical activity from the adduct.

Ambidextrous optically active copper(ii) phthalocyanine supramolecules induced by peripheral group homochirality

Self-assembling features of the disk-shaped copper(II) phthalocyanine (Pc) molecules carrying four enantiopure (S)- and (R)-1-(p-tolyl)ethylaminocarbonyl groups at their peripheral positions, CuPc-(S) and CuPc-(R), were studied. For comparison, an analogous CuPc carrying racemic 1-(p-tolyl)ethylaminocarbonyl groups, CuPc-(RS), was used. From circular dichroism and visible/infrared spectroscopic studies with wide-angle-X-ray diffraction data, CuPc-(S) and CuPc-(R) were shown to generate optically active π−π stacked assemblies formed in less-polar solvents. CuPc-(RS) produced similar assemblies with a loss of optical activity in the less-polar solvents. Plural interactions of Pcπ/Pcπ stacking, quadruple hydrogen bonding, homochiral stereocenters at the peripheral groups, bulky aralkyl entities and weak coordinating nature of copper(II) of the CuPcs were thought to be responsible for the formation of the optically active CuPc assemblies. The solvent effect was evident: less polar chloroform and tetrahydrofuran helped to generate the optically active CuPc assembly while highly polar N,N-dimethylformamide gave a monomeric Pc species due to the loss of Pc–Pc intermolecular hydrogen-bonding interaction. The self-assembling ability of the CuPcs was similar to NiPc analogues carrying the same chiral peripherals reported previously. Atomic force microscope study revealed that by casting dilute chloroform solutions of CuPc-(S), CuPc-(R) and CuPc-(RS) onto mica surface, worm-like supramolecular polymers were observed while the NiPc-(R) analogue provided needle-like supramolecular polymers.

Pd-Catalyzed Asymmetric α-Arylation and α-Vinylation of Oxindoles

The authors have developed the Pd-catalyzed enantioselective α-arylation and α-vinylation of oxindoles using a ligand with both axial and phosphorus-based chirality. The products having all-carbon quaternary centers were obtained with excellent enantioselectivities and in good yields. Moreover, the α-aryl and α-vinyl oxindole products were further derivatized without any loss of optical activity.

Dual behavior of alcohols in iodine-catalyzed esterification under solvent-free reaction conditions

The dual behavior phenomenon of alcohols in iodine-catalyzed esterification under solvent-free reaction conditions (SFRCs) is described; the governing factor is the stability of the carbonium ion generated from the alcohol; high concentration reaction conditions (HCRCs) or dilute solutions are much less suitable. In the case of benzylic alcohols, loss of optical activity was noted, whereas alkyl alcohols furnished a product with retention of stereochemistry.

Chemospecific Preparation of Both Enantiomers of α‐Terpinyl Trifluoroacetate

(R)‐ and (S)‐α‐Terpinyl trifluoroacetate can easily be prepared in 56–64% yield and high ee by the reaction of (R)‐ and (S)‐limonene with trifluoroacetic acid in cyclohexane. The products were fully characterized by 1H and 13C NMR, IR and MS and theirs Chiral‐HRGC analysis showed there is no loss of optical activity during the reaction.

Self‐Reproduction of Chirality on α‐Aminophosphonates: Asymmetric Synthesis of α‐Alkylated Diethyl Pyrrolidin‐2‐yl‐phosphonate.

AbstractFor Abstract see ChemInform Abstract in Full Text.

An Unusual Domino Retro‐Ene–Conia Reaction: Regio‐ and Stereoselective One‐Carbon Ring Expansion of Fenchol Derivatives

AbstractThe 2‐exo‐substituted fenchol derivatives 1–7, easily prepared from (−)‐fenchone in good‐to‐excellent yields, were pyrolyzed by dynamic gas‐phase thermo‐isomerization (DGPTI). At temperatures of ca. 620°, the substrates with a hydroxyallyl (1–4) or a hydroxypropargyl moiety (6) underwent an initial retro‐ene reaction under cleavage of the C(2)C(3) bond to form enol‐ene intermediates with no loss of optical activity. These intermediates then experience either tautomerization to the corresponding α,β‐unsaturated ketones or subsequent Conia rearrangement under one‐carbon ring expansion of the fenchone system to a bicyclo[3.2.1]octane framework. In the case of the isopropenyl substrate 3, the sterically crowded Conia product underwent a new type of ‘deethanation’ reaction by stepwise loss of two Me radicals, giving rise to the thermodynamically favored enone 21. A similar relaxation behavior was observed in the case of the ethynyl substrate 6, which showed a remarkable 1,3‐Me shift after the Conia reaction, leading to the α,β‐unsaturated cyclic ketone 25. The homolytic cleavage of the weakest single bond in 1–3 turned out to be a competing reaction pathway. Intramolecular H‐abstraction within the generated diradical intermediates produced the monocyclic ketones 8, 16, and 19, besides the products obtained by tautomerization and Conia reaction. In contrast, a Ph substituent at C(2) in 7 allowed only the passage through a diradical species to provide phenone 26, which was converted by regioselective Baeyer–Villiger oxidation to the optically active cyclopentanol 29. Both reaction channels, the domino retro‐ene–Conia rearrangement and the diradical‐promoted H‐transfer, have been shown to proceed highly stereoselectively. The absolute configuration of the newly formed stereogenic centers in all compounds was assigned by 1H‐NOE experiments. The reaction mechanism of the novel domino retro‐ene–Conia reaction was established by both a series of 2H‐ and 13C‐labeling experiments, as well as by a detailed computational analysis.

Chemospecific Preparation of Both Enantiomers of α‐Terpinyl Trifluoroacetate.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Self-reproduction of chirality on α-aminophosphonates: asymmetric synthesis of α-alkylated diethyl pyrrolidin-2-yl-phosphonate

A simple method for the asymmetric synthesis of α-substituted diethyl pyrrolidin-2-yl-phosphonate is described. The chiral oxazolopyrrolidine phosphonate was alkylated diastereospecifically with an alkyl halide. The key intermediate is an α-phosphonate-stabilized carbanion that can be alkylated without loss of optical activity and a single enantiomer of product was formed exclusively in 10–80% yield. The configurational assignment of the products relied on 1H– 1H NOESY analysis of the alkylated oxazolopyrrolidine phosphonates. This represents an unprecedented case of self-regeneration of stereocenters (SRS) of cyclic aminophosphonates. The enantiomerically pure α-aminophosphonate diethyl-(2 S)-(2-methylpyrrolidin-2-yl)-phosphonate, a surrogate of 2-methyl proline, was obtained upon hydrogenolysis of the chiral auxiliary in 83% yield.

Photochemistry of racemic and resolved 2-iodooctane. Effect of solvent polarity and viscosity on the chemistry.

The photochemistry of racemic and resolved 2-iodooctane was examined in cyclopentane, methanol, and 2-methyl-2-propanol, media with differing polarities and viscosities. The photochemistry of racemic 2-iodooctane was also examined in the gas phase. The photochemistry of 2-deuterio- and 1,1,1-trideuterio-2-iodooctane in cyclopentane and methanol was also studied. The photoreactions in cyclopentane, 2-methyl-2-propanol, and the gas phase occurred exclusively through homolytic reactions, while in methanol, they occurred predominantly (>53%) through heterolytic reactions. By comparing the disappearance of the optically active substrate with its loss of optical activity, F, the fraction of the initially formed radical pair (RP) or ion pair (IP) resulting in product was determined for the three solvents. Because F contains contributions of both escape of the partners in the RP or IP into the bulk of the solvent and reaction within the RP or IP to yield products other than the substrate, there was no correlation between F and solvent viscosity. The F values will be valuable in assessing the photochemistry of 2-iodooctane in the same media with circularly polarized light.

Synthesis of Optically Active Tricyclic Ethers by Reactions of (−)--Pinene with Phenols in Organized Media

The reactions of (−)-β-pinene (1) with some methyl- and hydroxy-substituted phenols on Hβ-zeolite yield optically active products – tricyclic terpenyl phenyl ethers – in contrast to reactions in homogeneous media, which occur with loss of optical activity. The formation of these products is promoted by the presence of meta-substituents in the phenol molecule.