A green and expedient synthesis of enantiopure diketopiperazines via enzymatic resolution of unnatural amino acids

Dipeptides comprising a d-phenylglycyl moiety coupled to the l-enantiomer of 2-amino butyric acid, norvaline, norleucine, and homocysteine were successfully synthesized from d-phenylglycine amide and the racemate of the corresponding unnatural amino acid. The reaction is catalyzed by an immobilized form of penicillin G acylase in an aqueous medium. The dipeptides were subsequently converted into the corresponding enantiopure diketopiperazines in overall isolated yields of 22–33%.     

Homochiral conglomerates and racemic crystals in two dimensions: tartaric acid on Cu(110)

Two-dimensional lattice structures formed by racemic tartaric acid on a single crystalline Cu(110) surface have been studied and compared with the enantiopure lattices. At low coverage, the doubly deprotonated bitartrate species is separated into two-dimensional conglomerates showing opposite enantiomorphism. At higher coverage, however, a singly deprotonated monotartrate species forms a heterochiral, racemic crystal lattice. While the enantioseparated bitartrate system undergoes decomposition at the same temperature as the enantiopure system, the racemic monotartrate lattice has a lower thermal stability than the enantiopure lattice of identical periodicity and surface density. At monolayer saturation coverage, the pure enantiomers form a denser lattice than the racemate. This is in contrast to the three-dimensional tartaric acid crystals, where the racemate crystallizes in a lattice of higher density, which is also more thermally stable than the enantiopure tartaric acid crystals.     

Regioselective and stereospecific synthesis of enantiopure 1,3-oxazolidin-2-ones by intramolecular ring opening of 2-(Boc-aminomethyl)aziridines. Preparation of the antibiotic linezolid

The amide moiety of several enantiopure unactivated 1-aryl- or 1-alkylaziridine-2-carboxamides were reduced and then N-Boc-protected to afford enantiopure 2-(Boc-aminomethyl)aziridines, which were further converted into enantiopure 5-(aminomethyl)-1,3-oxazolidin-2-ones by means of a stereospecific and fully regioselective BF3.Et2O-promoted intramolecular nucleophilic ring opening. One of these oxazolidinones was transformed into the antibiotic linezolid through a CuI-catalyzed N-arylation reaction at its carbamate moiety.     

Non-racemic (scalemic) planar-chiral five-membered metallacycles: routes, means, and pitfalls in their synthesis and characterization

This critical review provides a systematic classification of the synthetic routes to planar-chiral five-membered metallacycles into several routes, namely C-H bond activation, oxidative addition, transmetallation and optical resolution. As a characteristic of these bulk compounds is that they are synthesized as binary mixtures of enantiomers in proportions varying from the racemate to enantiopure, a review of absolute-configuration determination of the title planar-chiral scalemates is presented. This review is of interest to organic and organometallic synthetic chemists involved in asymmetric synthesis (97 references).     

The preparation and resolution of 2-phenyl-Quinazolinap,a new atropisomeric phosphinamine ligand for asymmetric catalysis

The preparation and resolution of an axially chiral quinazoline-containing phosphinamine ligand is described. The biaryl linkage was formed in a Pd-catalysed coupling of 4-chloro-2-phenylquinazoline 10 with 2-methoxy-1-naphthylboronic acid 11. Demethylation of the product ether 12 afforded alcohol 13 which was converted into the corresponding triflate 14 by treatment with trifluoromethanesulphonic anhydride. An Ni-catalysed phosphinylation gave the required phosphinamine ligand 9 as a racemate. Diastereomeric palladacycles 16, formed from 9 and (+)-di-μ-chlorobis[(R)-dimethyl(1-(1-naphthyl)ethyl)aminato-C₂,N]dipalladium(II) 15 were separated to give diastereomerically pure materials. An X-ray crystal structure of the (R,R)-16 palladacycle was determined and is discussed. Displacement of the resolving agent by reaction with 1,2-bis(diphenylphosphino)ethane gave enantiopure 2-phenyl-Quinazolinap 9, a new atropisomeric phosphinamine ligand for asymmetric catalysis.     

Chiral recognition in surface explosion

The vast majority of chiral compounds crystallize into racemic crystals. It has been predicted and was experimentally established as a rule that chiral molecules on surfaces are more easily separated into homochiral domains due to confinement into a plane and lower entropic contributions. We investigated the formation and stability of two-dimensional tartrate crystals on a Cu(110) surface for the racemic mixture for the first time by means of temperature-programmed desorption (TPD), low-energy electron diffraction (LEED), and X-ray photoelectron spectroscopy (XPS). At low coverage, a bitartrate species becomes separated into homochiral domains, while at high coverage a monotartrate species forms a racemic mixture. At the same coverage and lateral arrangement, the thermally induced autocatalytic decomposition reaction occurs for the monotartrate racemate at a lower temperature than for the pure enantiomers. The stereochemistry in this so-called "surface explosion" reaction is explained by a higher stability of the enantiopure lattice due to lateral hydrogen-bond formation. The higher stability of the enantiopure two-dimensional lattice is in contrast to the higher stability of racemic three-dimensional tartaric acid crystals but is consistent with the observation that homochirality is preferred in hydrogen-bonded self-assembled biomolecular structures.     

Quasienantiomers and quasiracemates: new tools for identification, analysis, separation, and synthesis of enantiomers

The old adage “never mix pure organic compounds” holds in spades for enantiomers. After going to all the trouble to make enantiopure molecules, who in their right mind would ever mix them to make a racemate? Quasienantiomers are almost enantiomers, but not quite. Yet unlike enantiomers, the interest is not so much in separating them but in mixing them to make quasiracemates. This backwards thinking opens new possibilities for identification, analysis, separation and synthesis of enantiomers. A short history is provided, the terms are defined and illustrated, and recent applications of quasienantiomers, quasiracemates and related species are reviewed.     

A novel general route for the preparation of enantiopure imidazolines

A novel procedure for the preparation of enantiopure 1,4-disubstituted 2-imidazolines is reported. Enantiopure beta-amino alcohols are converted into N-hydroxyethylamides, which are reacted with excess thionyl chloride, or with thionyl chloride followed by phosphorus pentachloride to yield N-chloroethylimidoyl chlorides. These intermediates are treated with amines and anilines to produce N-chloroethylamidines, which are converted into imidazolines upon workup with aqueous hydroxide. The method is simple and efficient and has been used to prepare a wide variety of enantiopure imidazolines, in a modular fashion, from readily available amino alcohols.     

Asymmetric synthesis of 4-deoxyverrucarol via two types of ring expansion reactions

Asymmetric synthesis of a trichothecane analogue, 4-deoxyverrucarol (2), was carried out through two types of ring expansion reactions. First, synthesis of the racemate of 2 was investigated. Thus, 1-[1-(tert-butyldimethylsiloxy)-ethyl]-1-methoxycarbonyl-2-hexen-4-on e (10), prepared by Diels-Alder reaction, was converted into the cyclopropylidene 15. The cyclobutanone (+/-)-18 was obtained from 15 via dihydroxylation, followed by successive treatments with SO(2)Cl(2) in the presence of imidazole and Florisil. After transformation of (+/-)-18 into the vinylcyclobutanol (+/-)-19, the second ring expansion reaction was performed with Pd(OAc)(2) to provide the cyclopentanone (+/-)-20. The product was converted into the racemate of 4-deoxyverrucarol (2) through the cyclohexenone (+/-)-22, but the diastereoselectivity during the introduction of the double bond was unsatisfactory. The selectivity was improved in the case of the asymmetric synthesis. The optically active cyclobutanone (+)-18 was prepared via AD reaction of 15 with 73% ee. After the transformation of (+)-18 into the cyclohexanone (-)-30 through the palladium-mediated ring expansion reaction, (-)-30 was subjected to the diastereoselective deprotonation reaction using the chiral amide. The key synthetic intermediate (-)-25 of 4-deoxyverrucarol (2) was synthesized in an optically pure form by taking advantage of a kind of kinetic resolution that occurred during the deprotonation step.     

(2-Naphthyl)glycolic acid: a tailored resolving agent for p-substituted 1-arylethylamines

A tailored resolving agent for p-substituted 1-arylethylamines, which was designed on the basis of a criterion derived from our crystal-structure study, namely that the racemate and the resolving agent should have similar molecular lengths, is described. The designed enantiopure (2-naphthyl)glycolic acid (2-NGA) showed excellent resolving ability for a wide variety of p-substituted 1-arylethylamines.     

Efficient approach to the Azaspirane core of FR 901483

[reaction: see text] An efficient approach to the azaspirane core of FR 901483 is described employing lithiated methoxyallene as a crucial C3 building block and a suitably protected enantiopure ketimine as the second component. The resulting dihydropyrrole derivative was smoothly converted into a spiro keto aldehyde which under acidic conditions provided a novel azanorbornane derivative 15. Under basic reaction conditions, the desired 5-azatricyclo[6.3.1.0(1,5)]dodecane skeleton 16 was generated. The ratio of diastereomers strongly depends on the reaction conditions employed with l-proline in DMSO providing the highest selectivity in favor of one azaspirane product.     

New resolution of 2-formyl-1,4-dhp derivatives using CIDR methodology. Facile access to new chiral tricyclic thiolactam

(R)- and (S)-alpha-phenylethylamine (alpha-PEA: 7) have been used separately to resolve successfully a racemate 2-formyl-1,4-DHP derivative 4. The process was based on the difference of the solubility of both Schiff bases (6) since one of them crystallized out from the solution. These imines obtained by condensation of (R)-alpha-PEA (7) or (S)-alpha-PEA (7) with aldehyde (rac-4) were separated and analyzed by X-ray diffraction, and their exposition to an hydrochloric hydrolysis conditions led to the enantiopure (4R)-4 or (4S)-4 in excellent yields. Separate condensation of other chiral (8 and 13) and racemic (18) amino thiols as auxiliary with rac-4, (4S)-4, or (4R)-4 is accompanied by an in situ crystallization-induced dynamic resolution, whereby one distereomer of thiazole template selectively precipitates and can be isolated by simple filtration in 76-82% yield with dr > 99. The thiazole species isolated from this process resulted from an amino aldehyde condensation followed by a spontaneous thiol-imine cycloaddition. Finally, the racemate (+/-)-(4R,2'R)-19 and the diastereomerically pure homologous (4S,2'R)-23 and (4R,2'S)-20 (obtained in good yields (79-82%) from 2-aminoethanethiol (18) and 2-formyl-1,4-DHP derivative rac-4, (4S)-4, or (4R)-4, respectively) were converted conveniently in a one-pot procedure into newly tricyclic thiolactams in the DHP series in racemic ((+/-)-(6R,9bR)-21, 72% yield)) and enantiopure ((6S,9bR)-24, 71% yield); (6R,9bS)-24, 70% yield) forms.     

Synthesis of enantiopure trans-3,4-disubstituted piperidines. An enantiodivergent synthesis of (+)- and (-)-paroxetine

Reaction of (R)-phenylglycinol with methyl 5-oxopentanoate gave either bicyclic lactam cis-1 (the kinetic product) or its isomer trans-1 (under equilibrating conditions) as the major products, which were converted to the corresponding (cis or trans) unsaturated lactams 4 and 5. On treatment with lithium alkyl (or aryl) cyanocuprates, these chiral building blocks undergo conjugate addition to give enantiopure trans-3,4-substituted 2-piperidone derivatives in high yield and stereoselectivity. The synthetic potential of this transformation is illustrated by the synthesis of (+)-femoxetine and the two enantiomers of the known antidepressant paroxetine.     

Direct enantiomeric high performance liquid chromatographic separation of aminoglutethimide and its major metabolite on a series of Chiralcel OD and Chiralcel OJ columns and its application to biological fluids

A direct, isocratic, sensitive and precise liquid chromatographic method is presented for the enantiomeric separation of aminoglutethimide (AG) and its acetylated metabolite (AcAG) using cellulose tris-3,5-dimethyl phenyl carbamate (Chiralcel OD) and cellulose tris(4-methylphenyl benzoate) ester (Chiralcel OJ) columns in series. The enantiomeric elution order is determined by separate chromatography of the racemate AG and racemate AcAG and of their separate enantiomers under similar conditions. This method has been used to determine and identify the enantiomers of AG and AcAG in the urine sample collected from a metastatic breast cancer patient after administration of AG for 24 h. Large amounts of (+)-R-AG are excreted unchanged in the urine together with smaller quantities of (+)-R-AcAG, while most of the (-)-S-AG is metabolically converted into (-)-S-AcAG.     

A Triptycene-Based Enantiopure Bis(Diazadibenzoanthracene) by a Chirality-Assisted Synthesis Approach

By applying a chirality-assisted synthesis (CAS) approach enantiopure diaminodibromotriptycenes were converted to rigid chiral helical diazadibenzoanthracenes, which show besides pronounced Cotton effects in circular dichroism spectra higher photoluminescence quantum yields as comparable carbacyclic analogues. For the enantiopure building blocks, a protocol was developed allowing the large scale synthesis without the necessity of separation via HPLC.     

Ethylene in organic synthesis: a new route to anticholenergic pyrrolidinoindolines, and other molecules with all carbon-quaternary centers via asymmetric hydrovinylation

The asymmetric hydrovinylation (1 mol % Ni-cat., 1 atm, ethylene, >98% ee) products from 1-methylenetetralines are readily converted into 3,3-disubstituted oxindoles and subsequently to pyrrolidinoindolines. These hydrovinylation products are also useful for the syntheses of enantiopure benzomorphans.     

Structures of glycine, enantiopure alanine, and racemic alanine adlayers on Cu(110) and Cu(100) surfaces

We have determined the structures of dense adlayers of glycine and alanine on the Cu(110) and Cu(100) surfaces using plane wave density functional theory. These calculations resolve several experimental controversies regarding these structures. Glycine exists on Cu(110) as a single adlayer structure, while on Cu(100) two distinct glycine adlayers coexist. The glycine structures serve as useful starting points for constructing alanine adlayer structures. We considered separately the adsorption of enantiopure alanine and racemic alanine on each surface. Adlayers of enantiopure alanine are found to be closely related to the adlayers observed for glycine. Racemic alanine adlayers on Cu(110) are structurally analogous to those observed for glycine on this surface and adopt a pseudo-racemate ordering. On Cu(100), in contrast to glycine, racemic alanine is found to adopt a single adlayer structure that is an ordered racemate. Spontaneous segregation of molecular enantiomers does not occur in racemic adsorbed mixtures on either surface. Consideration of the orientationally distinct domains that may exist for each adlayer on these surfaces provides important information for the interpretation of the adlayer domain boundaries that are commonly observed in scanning tunneling microscopy images of amino acid adlayers. Examining this set of amino acid adlayers provides useful insight into the range of subtle behaviors that can arise in these and related systems where chiral molecules form ordered adlayers on flat metal surfaces.     

Assignment of the absolute configuration of (+)-5,5′,6,6′-tetrahydro-7,7′-spiro[7H-cyclopenta[b]pyridine], a new inherently chiral spiropyridine,by a nonempirical analysis of its circular dichroism spectrum

The absolute configuration of (+)-spiropyridine 1, obtained in its enantiopure form by chromatographic resolution of the racemate upon the CSP Chiralcel AD, has been assigned as (aS) by simulating the ECD spectrum in the range 320–235 nm both by coupled oscillator (DeVoe) and TD DFT/B3LYP/6-31G¹ calculations.     

A [2+2+2]-cyclotrimerization approach for the synthesis of enantiopure isochromans using a carbohydrate derived dialkyne template

An easy access to enantiopure isochromans through cross alkyne trimerization of a glucose derived dialkyne was developed. One of the synthesized isochromans was converted into a novel tricyclic nucleoside by simple transformations.