Asymmetric ring-opening of cyclohexene oxide with trimethylsilyl azide in the presence of titanium isopropoxide/chiral ligand

trans-2-Azidocyclohexanol of enantiomeric excess up to 24% is obtained in the ring opening of cyclohexene oxide by use of trimethylsilyl azide in the presence of stoechiometric amount of titanium tetraisopropoxide and chiral diols or aminoalcohols.     

Über die Methylierung der diastereomeren (±)-1-Amino-1,2-diphenyl-3-propanole

Zusammenfassung Die diastereomeren (±)-1-Amino-1,2-diphenyl-3-propanole führen beim Methylieren mit Formaldehyd und Ameisensäure je nach ihrem räumlichen Aufbau zu (±)-erythro-1-Dimethylamino-1,2-diphenyl-3-propanol bzw. (±)-trans-3-Methyl-4,5-diphenyl-tetra-hydro-1,3-oxazin. Aus der letztgenannten Verbindung entsteht durch Behandlung mit LiAlH₄(±)-1-Dimethylamino-1,2-diphenyl-3-propanol. Sowohl die beiden Dimethylaminopropanole als auch deren O-Benzoyl-Derivate werden bei Umsetzung mit Methyljodid mit ziemlich unterschiedlicher Geschwindigkeit quar tärisiert, was durch sterische Verhältnisse bedingt sein dürfte.Methylation of the diastereomeric (±)-1-amino-1,2-diphenyl-3-propanols with formaldehyde and formic acid yields, according to configuration, (±)-erythro-dimethylamino-1,2-diphenyl-3-propanol and (±)-trans-3-methyl-4,5-diphenyl-tetrahydro-1,3-oxazine, respectively. On reduction with LiAlH₄ the latter gives (±)-1-dimethylamino-1,2-diphenyl-3-propanol. The two dimethylaminopropanols as well as their O-benzoyl derivatives, yield quaternary salts with methyl iodide at rather different rates, which differences may be of steric origin.     

1,2-Disubstituted cyclohexane nucleosides: comparative study for the synthesis of cis and trans adenosine analogues

A new class of adenosine analogues with 1,2-disubstituted carbocycles (with cis and trans stereochemistry) have been synthesized. Construction of the base on the amino group of (±)-cis-(2-aminocyclohexyl)methanol was more efficient than the Mitsunobu condensation between the purine base and protected (±)-trans-(2-hydroxymethyl)cyclohexanol. The latter strategy gave the final compound with cis stereochemistry in a short number of steps with the overall yield depending on the nature of the protecting group on the hydroxymethyl group of the diol. However, Mitsunobu condensation between a purine base and the protected (±)-cis-(2-hydroxymethyl)cyclohexanol is not an ideal method to obtain trans purine derivatives because the elimination reaction is faster than the substitution reaction.     

Chiral amines in the diastereoselective Mannich-related multicomponent synthesis of diarylmethylamines, 1,2-diarylethylamines, and β-arylethylamines

The multicomponent synthesis of diarylmethylamines, 1,2-diarylethylamines and β-arylethylamines has been undergone starting from aryl- or benzylzinc reagents, aldehydes, and primary or secondary chiral amines. Good to high diastereoselectivities have been obtained from both l-proline ester derivatives 1 and (±)-trans-1-allyl-2,5-dimethylpiperazine (4). The use of R-(+)-1-phenylethylamine (7) provides important diastereoisomeric excesses (∼60%) in conjunction with very high chemical yields. This work constitutes a preliminary entry to the intended development of a more flexible reaction system, involving easily cleavable chiral amines.     

A variation of the Pictet-Spengler reaction via a sequential reduction-cyclization reaction of N-acylcarbamates: synthesis of 1-substituted tetrahydroisoquinoline derivatives

A new variation of the Pictet-Spengler reaction for the synthesis of 1-substituted tetrahydroisoquinoline derivatives has been developed. The reaction employs the reduction of N-acylcarbamates by DIBAL-H followed by simultaneous cyclization mediated by BF₃·OEt₂. The synthetic potential of this method has been illustrated by the synthesis of the tetrahydroisoquinoline alkaloids, (±)-xylopinine, (±)-laudanosine, (±)-8-oxo-O-methylbharatamine, and (±)-isoindoloisoquinolone.     

Stereochemistry of the Inhibition of δ-Chymotrypsin with Optically Active Bicyclic Organophosphates: 31P-NMR studies

The inhibition of δ-chymotrypsin with optically active, axially and equatorially substituted trans-3-(2,4-dini-trophenoxy)-2,4-dioxa-3λ⁵-phospbubicyclo[4.4.0]decan-3-ones ( = hexahydro-4H-1,3,2-benzodioxaphosphorin 3-oxides) was investigated. Their inhibitory power was determined by kinetic measurements, and the stereochemical course of the reaction of stoichiometric amounts of the enzyme and inhibitor was monitored with ³¹P-NMR spectroscopy at pH 7.8. The irreversible inhibitors show significant enantioselectivity (the (S_p)-enantiomer reacting faster) and yield diastereoisomeric, covalently phosphorylated derivatives of δ-chymotrypsin. ³¹P-NMR Spectroscopic studies of the inhibition by the axially substituted inhibitor revealed for the racemic (±) -2a first a resonance at –4.4 ppm and later, while inhibition proceeded, a second one at –4.5 ppm. The reaction with optically active (+) -2a showed only one signal at –4.4 ppm and its enantiomer (–) -2a only one signal at –4.5 ppm. Using the equatorially substituted racemic epimer (±) -2b , we observed the main resonance at –5.3 ppm and two minor ones at –4.4 and –4.5 ppm. The optically active compound (+) -2b showed two peaks at –4.5 and –5.3 ppm, whereas its antipode (–) -2b revealed two signals at –4.4 and –5.3 ppm. Comparing the ³¹P chemical shifts of the corresponding covalent phosphoserine derivatives 4a (-5.7 ppm, axial) and 4b (-4.5 ppm, equatorial) shows the inhibition with the axial compounds 2a to proceed via neat inversion of the configuration at the P-atom, whereas the equatorial epimers 2b with a higher conformational flexibility seem to follow a different stereochemical pathway which results in both inversion and retention.     

Preparation of Stereodefined Secondary Alkyllithium Compounds

We have developed a practical stereoretentive iodine/lithium‐exchange process that allows the stereodefined preparation of cis‐ and trans‐cycloalkyllithium compounds from their corresponding stereodefined iodides. Quenching with electrophiles offers stereospecific access to both cis‐ (up to 96 % cis) and trans‐cycloalkyl derivatives (up to 99 % trans). A detailed study of the thermodynamic stabilities, stereochemical behavior, and reactivities of axially and equatorially substituted cyclohexyllithium reagents is reported. Ab initio calculations demonstrate that the formation of oligomeric cyclohexyllithium structures is pivotal for explaining the observed stereochemical preference.     

Synthesis and properties of 1,2-dihydropyridazino[4,5-b]indole II

The possibility of the synthesis of substituted 1,2-dihydropyridazino[4,5-b]indoles by the reaction of 1-methyl-2-carbomethoxy-3-(α-halobenzyl)indole or 1-methyl-2-carbomethoxy-3-(α-acetoxybenzyl)indole with hydrazines was demonstrated. The oxidation, reduction, and acylation reactions of the resulting 1,2-dihydropyridazino[4,5-b]indoles were studied.     

An efficient chemoenzymatic method to prepare optically active primary-tertiary trans-cycloalkane-1,2-diamines

Optically active trans-N-Boc-cyclopentane- and cyclohexane-1,2-diamines (7) were prepared by a chemoenzymatic method from the corresponding (±)-trans-N,N-diallylcycloalkane-1,2-diamine. These mono-carbamates 7 (ee=99%) were used as the starting materials in the syntheses of different vicinal primary-tertiary diamines. Thus, by means of a simple three-step sequence involving a reductive-amination of an aromatic aldehyde with 7, N-methylation and finally, cleavage of the Boc group, several trans-N-(arylmethyl)-N-methylcyclopentane- and cyclohexane-1,2-diamines were obtained in high yields.     

Recyclable 1,2‐bis[3,5‐bis(trifluoromethyl)phenyl]diselane‐catalyzed oxidation of cyclohexene with H2O2: a practical access to trans‐1,2‐cyclohexanediol

1,2‐Bis[3,5‐bis(trifluoromethyl)phenyl]diselane‐catalyzed oxidation of cyclohexene by hydrogen peroxide affords a quick, clean and practical access to the important compound trans‐1,2‐cyclohexanediol under mild conditions. The highly atom‐economic properties, clean procedures, high reaction concentration, short reaction time, mild conditions and eco‐friendly, recyclable and low loading catalysts facilitate this methodology for possible future practical industrial production. Copyright © 2014 John Wiley & Sons, Ltd.     

Stereocontrolled transformation of cyclohexene β-amino esters into syn- or anti-difunctionalized acyclic β-amino acid derivatives

A stereocontrolled approach to functionalized acyclic β^2,3-amino acid derivatives was accomplished from cis- or trans-2-aminocyclohexenecarboxylates derived from bicyclic β-lactam regioisomers. The transformations were based on oxidative ring cleavage through the ring C–C double bond of the cyclohexene β-amino esters, followed by functionalization of the dialdehyde intermediates with different phosphoranes. This stereospecific and stereocontrolled procedure was applied to the synthesis of acylic β^2,3-amino acid derivatives functionalized with ester, nitrile, keto, alkyl or arylalkyl groups.     

(-)-Menthol as a source of new N,N-diamine ligands for asymmetric transfer hydrogenation

The synthesis of new chiral N-monotosylated-1,2-diamines based on the (-)-menthol skeleton is presented. The elimination of HCl from neomenthyl chloride obtained from an Appel reaction led to p-menth-3-ene in excellent yield. Further functionalization of the double bond in p-menth-3-ene with chloramine-T gave the corresponding N-tosylaziridines, which upon reaction with sodium azide and subsequent reduction of the azide functional group, formed the 1,2-diamine system. The synthesized chiral ligands proved effective in the asymmetric transfer hydrogenation of aromatic ketones and an endocyclic imine.     

Preparation of chiral trans-5-substituted-acenaphthene-1,2-diols by baker’s yeast-mediated reduction of 5-substituted-acenaphthylene-1,2-diones

A series of trans-5-substituted-acenaphthene-1,2-diols were obtained in 21–72% yield with 97–100% ee by baker’s yeast-mediated reduction of the corresponding acenaphthylene-1,2-diones, in the presence of DMSO as a co-solvent and under vigorous agitation. The absolute configuration of (?)-trans-5-methoxy-acenaphthene-1,2-diol trans-3b and (?)-trans-5-bromo-acenaphthene-1,2-diol trans-3c was assigned as (S,S) and (?)-trans-5-thiomorpholin-acenaphthene-1,2-diol trans-3d was established as (R,R) by exciton-coupled circular dichroism.     

Stereoselective synthesis of cis- and trans-3-fluoro-1-phenylcyclobutyl amine

A stereoselective approach to the synthesis of cis- and trans-3-fluoro-1-phenylcyclobutylamine has been developed. Excellent stereoselectivity was obtained by the reduction of the appropriately substituted cyclobutanone to give either cis- or trans-isomers of 3-hydroxyl-1-phenylcyclobutylamine, which was stereoselectively converted to the 3-fluoro derivative.     

Novel (R)-(+)-limonene-derived ligands: synthesis and application in asymmetric transfer hydrogenations

(R)-(+)-Limonene was transformed into mono-N-tosylated-1,2-diamine derivatives using an N-tosylaziridination procedure followed by sodium azide treatment and reduction on Pd/C. The ligands obtained proved effective in the asymmetric transfer hydrogenation protocol on aromatic ketones.     

The first total synthesis of the (±)-17-methyl-trans-4,5-methyleneoctadecanoic acid and related analogs with antileishmanial activity

The first total synthesis of the marine cyclopropane fatty acid (±)-17-methyl-trans-4,5-methyleneoctadecanoic acid was accomplished in eight steps and in 9.1% overall yield starting from 1-bromo-12-methyltridecane. The cis analog (±)-17-methyl-cis-4,5-methyleneoctadecanoic acid was also synthesized but in seven steps and in 16.4% overall yield. With the two isomeric cyclopropane fatty acids at hand it was possible to unequivocally corroborate the trans relative configuration of the naturally occurring fatty acid by gas chromatographic co-elution of the corresponding methyl esters. The cis isomer was cytotoxic to Leishmania donovani promastigotes with an IC₅₀ of 300.2 ± 4.2 μM.     

Application of phosphorylated reagents derived from N,N′-di-[(S)-α-phenylethyl]-cyclohexane-1,2-diamines in the determination of the enantiomeric purity of chiral alcohols

The synthesis of two new N-[(S)-α-phenylethyl] substituted P-chloro-1,3-diazaphospholidines derived from C₂-symmetric trans-1,2-diaminocyclohexanes, and their application as chiral derivatizing agents in the determination of enantiomeric purities of chiral alcohols by means of ³¹P NMR spectroscopy is described.     

Enantioselective synthesis of cis-α-substituted cycloalkanols and trans-cycloalkyl amines thereof

The diastereo- and enantioselective syntheses of trans-cycloalkyl amines was accomplished through a three-step sequence consisting of: (1) asymmetric transfer hydrogenation through dynamic kinetic resolution of bicyclic and monocyclic α-substituted ketones using HCO₂H/Et₃N as the hydrogen source and TsDPEN-based Ru(II) catalysts, (2) nucleophilic hydroxyl to azide substitution of the resulting cis-cycloalkanols using diphenyl phosphoryl azide under modified Mitsunobu conditions, and (3) reduction of the trans-azide intermediates with LiAlH₄ of PPh₃/H₂O to the desired targets.     

Highly Stable trans‐Cyclooctene Amino Acids for Live‐Cell Labeling

trans‐Cyclooctene groups incorporated into proteins via non‐canonical amino acids (ncAAs) are emerging as specific handles for bioorthogonal chemistry. Here, we present a highly improved synthetic access to the axially and the equatorially linked trans‐cyclooct‐2‐ene isomers ( 1 a , b ). We further show that the axially connected isomer has a half‐life about 10 times higher than the equatorial isomer and reacts with tetrazines much faster, as determined by stopped‐flow experiments. The improved properties resulted in different labeling performance of the insulin receptor on the surface of intact cells.     

Enantioselective synthesis of (1S,2S)-1,2-di-tert-butyl and (1R,2R)-1,2-di-(1-adamantyl)ethylenediamines

An enantioselective synthesis of sterically congested 1,2-di-tert-butyl and 1,2-di-(1-adamantyl)ethylenediamines has been developed. Thus, diastereomerically pure trans-1-apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinones 6 and 7 were successfully prepared by optical resolution of (±)-trans-4,5-dimethoxy-2-imidazolidinone using apocamphanecarbonyl chloride (MAC-Cl) followed by stereospecific and stepwise substitution of the dimethoxyl groups using tert-butyl or 1-adamantyl cuprates to provide (4S,5S)-4,5-di-tert-butyl and (4R,5R)-4,5-di-(1-adamantyl)-2-imidazolidinones 12 and 15, respectively. Furthermore, N-acetyl 4,5-di-tert-butyl and 4,5-di-(1-adamantyl)-2-imidazolidinones 16a,b were enantioselectively deacetylated using a catalytic oxazaborolidine system to provide enantiopure 1-p-tolylsulfonyl-4,5-di-tert-butyl-2-imidazolidinones 12 and 19 and 1-p-tolylsulfonyl-4,5-di-(1-adamantyl)-2-imidazolidinones 18 and 20, respectively. Finally, N-p-tolylsulfonyl-2-imidazolidinones 12 and 15 were treated with 30 equiv of Ba(OH)₂·8H₂O to achieve ring cleavage and to provide (1S,2S)-1,2-di-tert-butylethylenediamine 3 and (1R,2R)-1,2-di-(1-adamantyl)ethylenediamine 4.