Loss Of Optical Purity Research Articles

Synthesis and optical properties of chiral dinaphthofuran possessing two methyl groups in the bay region

Abstract 8,8′-dimethyl-1,1′-bi-2-naphthol (7) was synthesized by oxidative dimerization of 8-methyl-2-naphthol (6). Camphorsulfonyl chloride was used as a chiral-resolving agent, followed by the synthesis of chiral dimethyl dinaphthofuran 3 by a dehydration reaction between two hydroxy groups without loss of optical purity. The racemization barrier and optical properties of the chiral compound 3 were scrutinized.

Palladium-catalyzed asymmetric hydrogenation of lactones under base-free conditions.

Asymmetric hydrogenation of esters through homogeneous catalysis is a significantly important transformation in organic synthesis. The systems developed so far mainly focused on chiral iridium and ruthenium catalysts, which required a base to facilitate the activity. Herein, we present a palladium-catalyzed asymmetric hydrogenation of lactones under base-free conditions through dynamic kinetic resolution and kinetic resolution. The reaction exhibits high enantioselectivity and excellent functional group tolerance. Remarkably, the hydrogenation proceeds smoothly at the gram scale, and the products can be transformed into several chiral potential building blocks without loss of optical purity. This work provides a new strategy for asymmetric hydrogenation of esters under base-free conditions.

Ring-opening phosphanylation of oxazolines

The P-nucleophilic ring-opening of oxazolines is a highly desired but rarely reported reaction. We have developed a ring-opening phosphanylation of oxazolines using lithium diphenylphosphanide as the nucleophile without loss of optical purity. This methodology is compatible with various chiral pyridine-oxazolines bearing different substituents and features the advantage of mild conditions with easy operation.

Fast and Cost-Efficient 17 O-Isotopic Labeling of Carboxylic Groups in Biomolecules: From Free Amino Acids to Peptide Chains.

17 O NMR spectroscopy is a powerful technique, which can provide unique information regarding the structure and reactivity of biomolecules. However, the low natural abundance of 17 O (0.04 %) generally requires working with enriched samples, which are not easily accessible. Here, we present simple, fast and cost-efficient 17 O-enrichment strategies for amino acids and peptides by using mechanochemistry. First, five unprotected amino acids were enriched under ambient conditions, consuming only microliter amounts of costly labeled water, and producing pure molecules with enrichment levels up to ∼40 %, yields ∼60-85 %, and no loss of optical purity. Subsequently, 17 O-enriched Fmoc/tBu-protected amino acids were produced on a 1 g/day scale with high enrichment levels. Lastly, a site-selective 17 O-labeling of carboxylic functions in peptide side-chains was achieved for RGD and GRGDS peptides, with ∼28 % enrichment level. For all molecules, 17 O ssNMR spectra were recorded at 14.1 T in reasonable times, making this an important step forward for future NMR studies of biomolecules.

Enantioselective Friedel-Crafts Alkylation Reaction of Pyrroles with N-Unprotected Alkynyl Trifluoromethyl Ketimines.

Developed herein is an enantioselective Friedel-Crafts alkylation reaction of N-unprotected alkynyl trifluoromethyl ketimines with pyrroles catalyzed by chiral phosphoric acid to furnish chiral primary α-trifluoromethyl-α-(2-pyrrolyl)propargylamines with high enantioselectivity. Transformation of the alkynyl group of the adducts afforded optically active α-trifluoromethylated amines bearing various substituents such as alkyl, alkenyl, enyne, and triazole without loss of optical purity.

Asymmetric Construction of All‐Carbon Quaternary Stereocenters via Organocatalytic α‐Hydroxymethylation of Malonic Diesters Using Aqueous Formaldehyde

AbstractAn organocatalyzed α‐hydroxymethylation of α‐monoalkyl malonic diesters using 37% aqueous formaldehyde (formalin) as a one‐carbon electrophilic unit to generate all‐carbon substituted quaternary stereocenters has been developed. In the course of our exploration of catalytic methodologies, a metal‐free cooperative catalytic approach with cinchonidine and squaramide co‐catalysts was found to improve both reactivity and enantioselectivity in this transformation. Our organocatalytic method represents the first example of an enantioselective α‐hydroxymethylation of a malonic diester. The enantioenriched α‐hydroxymethyl products could be recrystallized with high recovery, yielding optically pure materials. Moreover, to demonstrate the utility of this methodology, the all‐carbon substituted α‐quaternary stereogenic malonate was converted to both (S)‐ and (R)‐4,4‐disubstituted oxazolidin‐2‐ones without loss of optical purity.

Pyrrole-Protected β-Aminoalkylzinc Reagents for the Enantioselective Synthesis of Amino-Derivatives.

Chiral β‐aminoalkylzinc halides were prepared starting from optically pure commercial β‐amino‐alcohols. These amino‐alcohols were converted to the corresponding N‐pyrrolyl‐protected alkyl iodides which undergo a zinc insertion in the presence of LiCl (THF, 25 °C, 10–90 min). Subsequent Negishi cross‐coupling or acylation reactions with acid chlorides produced amino‐derivatives with retention of chirality. Diastereoselective CBS‐reductions of some prepared N‐pyrrolyl‐ketones provided 1,3‐subsituted N‐pyrrolyl‐alcohols with high diastereoselectivity. Additionally, a deprotection procedure involving an ozonolysis allowed the conversion of the pyrrole‐ring into a formamide without loss of optical purity.

Iridium-Catalyzed Asymmetric Hydrogenation of 4,6-Disubstituted 2-Hydroxypyrimidines.

An efficient iridium-catalyzed hydrogenation of 4,6-disubstituted 2-hydroxypyrimidines has been achieved, giving chiral cyclic ureas with excellent diastereoselectivities and up to 96% ee of enantioselectivities. In the presence of the in situ generated hydrogen halide, the equilibrium of the lactame-lactime tautomerism of 2-hydroxypyrimidine is more toward the oxo form with lower aromaticity, which effectively improves the reactivity to facilitate hydrogenation. Moreover, the cyclic ureas could be readily converted into chiral 1,3-diamine derivatives without loss of optical purity.

Bifunctional thiophosphinamide catalyzed highly enantioselective Michael addition of acetone to (E)-2-azido β-nitrostyrenes and the subsequent reductive cyclization

We have proven that primary amine/thiophosphinamide incorporating (1R,2R)-1,2-diphenylethane-1,2-diamine is an efficient catalyst for the asymmetric Michael addition of acetone to (E)-2-azido β-nitrostyrenes. Under the optimal reaction conditions, the corresponding Michael addition products were obtained in excellent yields with almost perfect stereocontrol. Upon treatment with Et3SiH/InCl3, the Michael addition products could be successfully converted to the related 2-methyltetrahydroquinolines in acceptable yields with moderate to excellent diastereoselectivity and without appreciable loss in optical purity. This process provides a highly enantioselective pathway for the synthesis of biologically important 2-methyltetrahydroquinoline derivatives.

Facile Synthesis of Chiral Cyclic Ureas through Hydrogenation of 2-Hydroxypyrimidine/Pyrimidin-2(1H)-one Tautomers.

A facile access to optically active cyclic ureas was developed through palladium-catalyzed asymmetric hydrogenation of pyrimidines containing tautomeric hydroxy group with up to 99 % ee. Mechanistic studies indicated that reaction pathway proceed through hydrogenation of C=N of the oxo tautomer pyrimidin-2(1H)-one, acid-catalyzed isomerization of enamine-imine, and hydrogenation of imine pathway. In addition, the chiral cyclic ureas are readily converted into useful chiral 1,3-diamine and thiourea derivatives without loss of optical purity.

Facile Synthesis of Chiral Cyclic Ureas through Hydrogenation of 2‐Hydroxypyrimidine/Pyrimidin‐2(1H)‐one Tautomers

AbstractA facile access to optically active cyclic ureas was developed through palladium‐catalyzed asymmetric hydrogenation of pyrimidines containing tautomeric hydroxy group with up to 99 % ee. Mechanistic studies indicated that reaction pathway proceed through hydrogenation of C=N of the oxo tautomer pyrimidin‐2(1H)‐one, acid‐catalyzed isomerization of enamine–imine, and hydrogenation of imine pathway. In addition, the chiral cyclic ureas are readily converted into useful chiral 1,3‐diamine and thiourea derivatives without loss of optical purity.

Selective Hydrogenation of Carboxylic Acids to Alcohols or Alkanes Employing a Heterogeneous Catalyst

The chemoselective hydrogenation of carboxylic acids to either alcohols or alkanes is reported, employing a heterogeneous bimetallic catalyst consisting of rhenium and palladium supported on graphite. α-Chiral carboxylic acids were hydrogenated without loss of optical purity. The catalyst displays a reverse order of reactivity upon hydrogenation of different carboxylic functions with esters being less reactive than amides and carboxylic acids. This allows for chemoselective hydrogenation of an acid in the presence of an ester or an amide function.

Synthesis of Chiral TFA-Protected α-Amino Aryl-Ketone Derivatives with Friedel-Crafts Acylation of α-Amino Acid N-Hydroxysuccinimide Ester.

Chiral N-protected α-amino aryl-ketones are one of the useful precursors used in the synthesis of various biologically active compounds and can be constructed via Friedel–Crafts acylation of N-protected α-amino acids. One of the drawbacks of this reaction is the utilization of toxic, corrosive and moisture-sensitive acylating reagents. In peptide construction via amide bond formation, N-hydroxysuccinimide ester (OSu), which has high storage stability, can react rapidly with amino components and produces fewer side reactions, including racemization. This study reports the first synthesis and utilization of N-trifluoroacetyl (TFA)-protected α-amino acid-OSu as a potential acyl donor for Friedel–Crafts acylation into various arenes. The TFA-protected isoleucine derivative and its diastereomer TFA-protected allo-isoleucine derivative were investigated to check the retention of α-proton chirality in the Friedel–Crafts reaction. Further utilization of OSu in other branched-chain and unbranched-chain amino acids results in an adequate yield of TFA-protected α-amino aryl-ketone without loss of optical purity.

Catalytic B-H Bond Insertion Reactions Using Alkynes as Carbene Precursors.

Herein, we report transition-metal-catalyzed B-H bond insertion reactions between borane adducts and alkynes to afford organoboron compounds in excellent yields under mild reaction conditions. This successful use of alkynes as carbene precursors in these reactions constitutes a new route to organoboron compounds. The starting materials are safe and readily available, and the reaction exhibits 100% atom-economy. Moreover, an asymmetric version catalyzed by chiral dirhodium complexes produced chiral boranes with excellent enantioselectivity (up to 96% ee). This is the first report of highly enantioselective heteroatom-hydrogen bond insertion reactions of metal carbenes generated in situ from alkynes. The chiral products of the reaction could be easily transformed to widely used borates and diaryl methanol compounds without loss of optical purity, which demonstrates its potential utility in organic synthesis. A kinetics study indicated that the Cu-catalyzed B-H bond insertion reaction is first order with respect to the catalyst and the alkyne and zero order with respect to the borane adduct, and no kinetic isotopic effect was observed in the reaction of the adduct. These results, along with density functional theory calculations, suggest that the formation of the Cu carbene is the rate-limiting step and that the B-H bond insertion is a fast, concerted process.

DEPBT as Coupling Reagent To Avoid Racemization in a Solution-Phase Synthesis of a Kyotorphin Derivative

The synthesis of IbKTP-NH₂ with reduction of racemization up to no detectable level has been achieved using 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3<i>H</i>)-one (DEPBT). Among all coupling systems tested, only DEPBT-mediated amide bond formation between N^α-acylated tyrosine and arginine without loss of optical purity.

An Atom-Efficient Direct Regioselective N(τ)-Allylation of Histidine Deriva­tives

Protected N(τ)-allylhistidine has been been prepared by the first direct regioselective allylation procedure using the sterically bulky N(α)-Boc protection group to shield N(π) and thereby inducing regioselectivity. This afforded the N(τ)-allyl protected histidine building block in excellent yields without loss of optical purity.

ChemInform Abstract: N,N‐Diarylammonium Pyrosulfate as a Highly Effective Reverse Micelle‐Type Catalyst for Hydrolysis of Esters.

AbstractIt is found that the pyrosulfate (APS) efficiently promotes the hydrolysis of a number of esters without loss of optical purity.

Synthesis of Optically Active 4-Substituted 2-Cyclohexenones

Recently, Nicolaou and Baran independently synthesized optically active 4-substituted 2-cyclohexenones via an efficient LiOH-mediated intramolecular aldol condensation. Thus far, application of their cyclization approach has been limited to ketoaldehydes where the R-group is branched. It is demonstrated that the LiOH-mediated cyclization, when applied to substrates containing unbranched R-groups, results in significant erosion of optical purity. A mechanistic justification is provided, and a set of neutral, organocatalyzed conditions is identified that enables cyclization with little loss in optical purity.

Heck–Matsuda Reaction for Allylic Nitro Compounds: A Short Asymmetric Synthesis of an FTY720 Derivative

AbstractThe Heck–Matsuda reaction for allylic nitro compounds effectively afforded cinnamyl nitro compounds in good yields. Aryldiazonium salts that have an electron‐donating substituent underwent a smooth reaction in the presence of Pd2dba3. A palladium complex that coordinated with an electron‐rich ligand was necessary for the reaction to progress with electron‐deficient aryldiazonium salts. An optically active allylic nitro compound underwent reaction without the loss of optical purity at the stereogenic center. A short synthesis of an optically active FTY720 derivative was achieved by this method.

ChemInform Abstract: Phosphine‐Catalyzed Heine Reaction.

AbstractOxazolines (V) are formed as a single regioisomer in all cases and the aziridine (VIII) rearranges without any loss of optical purity.