O-(α-Phenylethyl)hydroxylamine as a ‘chiral ammonia equivalent’: synthesis and resolution of 5-oxopyrrolidine- and 6-oxopiperidine-3-carboxylic acids

An approach to the synthesis and resolution of five- and six-membered lactams (i.e., 5-oxopyrrolidine- and 6-oxopiperidine-3-carboxylic acids) is described. The method relies on the one-pot Michael reaction—cyclization of itaconic acid or diethyl homoitaconate and enantiopure O-(α-phenylethyl)hydroxylamine as a ‘chiral ammonia equivalent’. It is shown that this chiral auxiliary can be used for the separation of diastereomeric lactam products and then easily removed by catalytic hydrogenolysis.     

Conformational model for asymmetric Diels-Alder reactions with chiral dienes

1-(O-methylmandeloxy)dienes have significant advantages for asymmetric Diels-Alder reactions, and we now show that high (90%) diastereofacial selectivities can be obtained with these dienes, permitting considerable choice as to dienophile and the presence of additional functionality. We present experimental support, including X-ray structures showing the conformations of three Diels-Alder adducts, for a transition state model which explains the origin of these selectivities. The distinctive characteristics of this model are that the phenyl group is nearly perpendicular to the ester CO, i.e., the PhCCO dihedral angle is near 90°, and that the methoxy group is close to the carbonyl oxygen. These features may have wider applications for chiral control by α-chiral ester groups in other types of reactions. Our results should renew interest in the use of chiral 1-acyloxydienes.     

Intramolecular ene reaction of a chiral bicyclic lactam

The preparation of bicylic lactam 2 is described, employing an acetoacetate-based synthesis of 1,4-ketoacid 3. The lactam 2 was shown to undergo a thermal ene reaction at 280-300 degrees C to afford tricycle 7. Reduction of the ene product followed by removal of the chiral auxiliary fragment provided the unusual lactam system 9 in highly enantioenriched form.     

Diastereoselective protonation of lactam enolates derived from (R)-phenylglycinol. A novel asymmetric route to 4-phenyl-1,2,3, 4-tetrahydroisoquinolines

Highly diastereoselective protonation of chiral lactam enolates of 4-substituted-1,4-dihydroisoquinolin-3-ones is reported. Protonation and alkylation processes of these lactam enolates derived from phenylglycinol occur with opposite diastereofacial selectivity. This diastereoselective protonation has been applied to the asymmetric synthesis of (4S)-N-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline 9 obtained in up to 97% ee.     

Resolution of α-aminolactams by inclusion complexation with chiral host compounds

3-Aminopiperidin-2-one and α-amino-ε-caprolactam were efficiently resolved by inclusion complexation with a chiral host compound, (R,R)-(−)-trans-4,5-bis(hydroxydiphenylmethyl)-1,4-dioxaspiro[4.5]decane. The amino substituent on the lactam ring was found to play an important role in efficient chiral recognition in the inclusion crystals.     

The synthesis of functionalised chiral bicyclic lactam and lactone N-oxides using a tandem Cope elimination/reverse Cope elimination protocol

Functionalised hydroxylamine derivatives of (S)-proline and (R)-pipecolic acid have been prepared using a Cope elimination. These undergo reverse Cope elimination onto a pendant double bond to give bicyclic lactam and lactone N-oxides containing three contiguous chiral centres, this extends the scope and applicability of the reverse Cope elimination in the synthesis of heterocyclic systems by incorporation of the lactone and lactam structural motifs.     

Total synthesis of (−)-2-epi-lentiginosine by use of chiral 5-hydroxy-1,5-dihydropyrrol-2-one as a building block

We have developed a practical synthesis of the chiral lactam as a new chiral building block for alkaloid synthesis. Lipase-catalyzed kinetic resolution of hydroxylactam 8, followed by isolation-racemization of the chiral acetoxylactam 9 provided the optically pure hydroxylactam 8 in 96.0% yield with >99% ee after five cycles of kinetic resolution-racemization process. Chemical transformation of (S)-hydroxylactam 8 furnished chiral (−)-2-epi-lentiginosine (1) in 20% yield in 10 steps with no loss of enantiomeric excess.     

Diastereoselective Ugi reaction without chiral amines: the synthesis of chiral pyrroloketopiperazines

The three-component Ugi reaction with chiral 2-(2-formyl-1H-pyrrol-1-yl)acetic acids prepared from natural l-aminoacids was investigated. The reaction opens a new route to chiral substituted pyrroloketopiperazines. One of the first examples of an asymmetric Ugi reaction without chiral amines is described. The reaction proceeds with moderate diastereoselectivity to give the target compounds in good yields. The scope and limitation of the approach are discussed.     

An enantiomerically pure 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan- 2-one as 1H NMR shift reagent for the ee determination of chiral lactams, quinolones, and oxazolidinones

The chiral lactam 1 (or its enantiomer ent-1) was shown to be an effective (1)H NMR shift reagent for the ee determination of chiral lactams, quinolones, and oxazolidinones. It was successfully employed in many cases in which a detection of enantiomers by chromatographic methods failed. The method was extended to a broader range of simple substrates bearing a lactam moiety to evaluate its scope. The NH signals of the substrate enantiomers showed the strongest separation and were used for (1)H NMR integration. In most cases, compound 1 (1.5 equiv; 0.06 M solution) induced a baseline separation of the NH signals and it can consequently be regarded as a generally applicable shift reagent for chiral products with a lactam moiety.     

An optimised synthetic approach to a chiral derivatising agent and the utilisation of a dimerisation reaction in the synthesis of a novel C2-symmetric diphosphine ligand

We report an optimised synthetic approach to the chiral derivatising agent (5R)-methyl-1-(chloromethyl)-2-pyrrolidinone. In addition, the observation of an unwanted dimerisation product is turned to our advantage by providing a method for the synthesis of a new class of C2-symmetric chiral diphosphine.     

A novel approach for LC-MS/MS-based chiral metabolomics fingerprinting and chiral metabolomics extraction using a pair of enantiomers of chiral derivatization reagents

Chiral metabolites are found in a wide variety of living organisms and some of them are understood to be physiologically active compounds and biomarkers. However, the overall analysis of chiral metabolomics is quite difficult due to the high number of metabolites, the significant diversity in their physicochemical properties, and concentration range from metabolite-to-metabolite. To solve this difficulty, we developed a novel approach for chiral metabolomics fingerprinting and chiral metabolomics extraction, which is based on the labeling of a pair of enantiomers of chiral derivatization reagents (i.e., DMT-(S,R)-Pro-OSu and DMT-3(S,R)-Apy) and precursor ion scan chromatography of the derivatives. The multivariate statistics is also required for this strategy. The proposed procedures were evaluated by the detection of a diagnostic marker (i.e., d-lactic acid) using the saliva of diabetic patients. This method was used for the determination of biomarker candidates of chiral amines and carboxyls in Alzheimer's disease (AD) brain homogenates. As the results, l-phenylalanine (L-Phe) and l-lactic acid (L-LA) were identified as the decreased and increased biomarker candidates in the AD brain, respectively. Therefore, the proposed approach seems to be helpful for the determination of non-target chiral metabolomics possessing amines and carboxyls.     

Conformationally rigid chiral ferrocene derivative: Synthesis,resolution and stereochemical assignment

A conformationally rigid chiral molecule LB-I with Lewis basic site has been designed and synthesized in racemic form from ferrocene via Lewis acid mediated diastereoselective cyclization of hydroxy lactam. Both isomers were successfully obtained in enantiomerically pure form through classical resolution using dibenzoyl-d-tartaric acid as the chiral resolving agent in acetone. The nature of the diastereomeric salt formed in the resolution process was investigated by single crystal X-ray crystallographic studies. The absolute configuration of (+)-LB-I was unambiguously assigned as (S,R_p) by single crystal analysis of the salt I obtained from precipitate fraction containing (+)-LB-I and dibenzoyl-d-tartaric acid.     

Enantioselective [6pi]-photocyclization reaction of an acrylanilide mediated by a chiral host. Interplay between enantioselective ring closure and enantioselective protonation

The [6pi]-photocyclization of the anilides 1a and 5 was studied in the absence and in the presence of the enantiomerically pure chiral lactam 4. The relative configuration of the products was unambiguously established by single-crystal X-ray crystallography and by NMR spectroscopy. A significant enantiomeric excess was observed upon reaction of compound 1a to its photocyclization products at -55 degrees C employing lactam 4 as a chiral complexing agent in toluene as the solvent (66% yield). The trans product ent-3a was obtained in 57% ee, and the minor diastereoisomer (trans/cis = 73/27), cis product ent-2a, was obtained in 30% ee. DFT calculations were conducted modeling the complexation of intermediates 8 and ent-8 to host 4. In agreement with steric arguments concerning the conrotatory ring closure of 1a, the formation of ent-8 is favored leading to the more stable complex 4.ent-8 as compared to 4.8. Whereas the enantioselectivity in the photocyclization to trans compound ent-3a increased upon reduction in the reaction temperature, the enantiomeric excess in the formation of cis compound ent-2a went through a maximum at -15 degrees C (45% ee) and decreased at lower temperatures. Deuteration experiments conducted with the pentadeuterated analogue of 1a, d(5)-1a, revealed that the protonation of the intermediates 8 and ent-8 is influenced by chiral amide 4. In the formation of ent-3a/3a, both the enantioselective ring closure and the enantioselective protonation by amide 4 favor the observed (6aS,10aS)-configuration of the major enantiomer ent-3a. In the formation of ent-2a/2a, the enantioselective ring closure (and the subsequent diastereoselective protonation) favors the (6aR,10aS)-configuration that is found in compound 2a. Contrary to that, the enantioselective protonation by amide 4 shows a preference for ent-2a with the (6aS,10aR)-configuration.     

Catalytic asymmetric synthesis of a nitrogen analogue of dialkyl tartrate by direct mannich reaction under phase-transfer conditions

[reaction: see text] Phase-transfer-catalyzed direct Mannich reaction of glycinate Schiff base 3 with alpha-imino ester 4 has been accomplished with high enantioselectivity by the utilization of N-spiro C(2)-symmetric chiral quaternary ammonium bromide 2 as a catalyst. This methodology enables the catalytic asymmetric synthesis of differentially protected 3-aminoaspartate, a nitrogen analogue of dialkyl tartrate. The product (syn-5) was converted into a precursor (6) of streptolidine lactam.     

High diastereofacial selectivity in the 1,3-dipolar cycloaddition of chiral azomethine ylides

Excellent diastereofacial and endo/exo stereoselectivities have been obtained in cycloaddition of the chiral azomethine ylide generated from 4-phenyloxazolidine acetic acid (−)-8-phenylmenthyl ester 1e.     

Asymmetric synthesis of 3-substituted pyrrolidones via α-alkylation of a chiral non-racemic γ-lactam

3-Alkyl pyrrolidones 9 were synthesized in good yield and high diastereoselectivity by α-alkylation of the new chiral non-racemic lactam 8 derived from (R)-(−)-phenylglycinol. After debenzylation and introduction of an electron-withdrawing group, 3-methylpyrrolidone 10 is easily hydrolyzed in a basic medium to produce γ-aminobutyric acid (GABA) analogue 13.     

New chiral ionic liquids based on imidazolinium salts

The preparation and application of a new series of chiral ionic liquids are described. The salts are based on imidazolinium cations. Some of the cations also incorporated an axial chirality at the C(2) position next to the central chirality. These cations display a very high rotational barrier along the arene–imidazolinium axis. Furthermore, an analogue with a chiral anion was prepared. The salts have low melting points. Their potential as solvents and as chiral shift reagents was explored, resulting for the first time in an example of a chiral ionic liquid as a shift reagent for a neutral compound.     

Synthesis of C3-substituted enantiopure 2-(p-tolylsulfinyl)-furans: the sulfoxide group as a chiral inductor for furan dienes as precursors of a wide variety of chiral intermediates

(−)-(1R,2S,5R)-Menthyl (S_S)-p-toluenesulfinate and its enantiomer are a common source for a chiral sulfoxide group in organic synthesis, by means of nucleophilic substitution. The replacement of the menthyloxy group, with complete inversion of configuration at the sulfur center of the chiral sulfoxide, allows the inclusion of this organic function into numerous substrates, with defined stereochemistry and high enantiomeric purity. Nine C3-substituted, enantiomerically pure, 2-sulfinylfurans were prepared by this synthetic methodology with moderate to high yields. These enantiopure C3-substituted 2-sulfinylfurans can be used as chiral dienes for [4+3] cycloaddition reactions and in other chemical transformations, in which π-facial selectivity should be induced in order to obtain enantioselective reactions.     

Preparation of chiral bipyridine bis-N-oxides by oxidative dimerization of chiral pyridine N-oxides

The direct preparation of chiral 2,2′-bipyridine bis-N-oxides has been developed. The method involves two stages, first, the deprotonation of substituted chiral pyridine N-oxides and second, the oxidative dimerization of the resulting 2-lithiopyridine N-oxides. Optimization of the reaction conditions led to the selection of LiTMP in THF for the deprotonation and molecular iodine as the oxidant. The corresponding 2-iodopyridine N-oxide is invariably formed as a by-product. A series of 11 chiral pyridine N-oxides was prepared that bear substituents at the C(2) and C(5) positions. Oxidative dimerization of these mono-N-oxides proceeded in 33–77% yield. In all cases, the dimerization was highly diastereoselective for the formation of the P-configuration of the chiral axis.     

MM3 force field prediction of the enantioselective preference in the asymmetric synthesis of a chiral 2-cyclohexen-1-ol using a chiral lithium amide reagent

Enantioselective preference in the asymmetric synthesis where cyclohexene oxide is transformed enantioselectively to chiral (S)- or (R)-2-cyclohexen-1-ol by the reaction with the appropriate chiral lithium amide reagent has been evaluated theoretically using the MM3 force field. The plausible possible structures for each precursor (reaction intermediate complex) leading to a (S)- or (R)-2-cyclohexen-1-ol have been optimized with the extended MM3 force field applicable to the lithium amide functional group, and the populations of their (S)- or (R)-reaction intermediate complexes at an ambient temperature (298 K) were calculated. The initial structure for evaluating the reaction intermediates of this asymmetric synthesis was constructed on the basis of the optimized ab initio transition state structure (MP2/6-31+G^∗) comprising lithium amide LiNH₂ and propene oxide. To the thus obtained transition state structure composed of LiNH₂ and propene oxide, the other remaining Cartesian coordinates for the actual reaction intermediates composed of the chiral lithium amides and cyclohexene oxide were added to make the reaction intermediate structure. The conformational search for the reaction intermediate has been carried out by using the Stochastic search Algorithm, and the optimized geometries and their conformational energies (steric energies) have been calculated by the MM3 force field. The populations calculated from the conformational energies of the reaction intermediate leading to the (S)- or (R)-2-cyclohexen-1-ol were shown to be linearly well correlated with the experimentally reported enantiomer excess (% ee) values. The critical factors to control the enantioselectivity were investigated on the basis of the optimized structures of the reaction intermediate complexes. The MM3 force field approach was shown to be applicable to the theoretical evaluation of the enantioselectivity and be useful for designing a new functional chiral lithium amide reagent for the asymmetric synthesis.