Asymmetric indium-mediated Barbier-type allylation reactions with ketones to form homoallylic alcohol products

We report a general method for the enantioselective allylation of both aromatic and aliphatic ketones under indium-mediated Barbier-type conditions. Using 2 equiv of a commercially available amino alcohol, either (1S,2R)-(+)-2-amino-1,2-diphenylethanol ((+)-1) or (1R,2S)-(−)-2-amino-1,2-diphenylethanol ((−)-1) as the chiral auxiliary, good yields and enantioselectivities were achieved. To our knowledge, the enantioselectivities reported herein are the highest obtained for the indium-mediated allylations of ketones, specifically the homoallylic alcohol product obtained from the addition to α,α,α-trifluoroacetophenone provided 80% enantiomeric excess.     

Stereoselective synthesis of (R)-(+)-1-methoxyspirobrassinin, (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether and their enantiomers or diastereoisomers

Stereoselective synthesis of cruciferous indole phytoalexin (R)-(+)-1-methoxyspirobrassinin and its unnatural (S)-(−)-enantiomer was achieved by spirocyclization of 1-methoxybrassinin in the presence of (+)- and (−)-menthol and subsequent oxidation of the obtained menthyl ethers. Methanolysis of menthyl ethers in the presence of TFA afforded (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether as well its unnatural (2S,3S)-, (2R,3S)-, and (2S,3R)-isomers.     

Synthesis, resolution and assignment of absolute configuration of trans 3-amino-1-oxyl-2,2,5,5-tetramethylpyrrolidine-4-carboxylic acid (POAC), a cyclic, spin-labelled β-amino acid

Racemic trans 3-(9-fluorenylmethyloxycarbonylamino)-1-oxyl-2,2,5,5-tetramethylpyrrolidine-4-carboxylic acid (Fmoc-POAC-OH), prepared by conventional methods, was resolved upon esterification with (aR)-2,2′-dihydroxy-1,1′-binaphthyl. Separation of the obtained diastereomeric monoesters Fmoc-(±)-trans-POAC-O-(aR)-binaphthol by crystallization/chromatography, and removal of the chiral auxiliary by saponification of the aryl ester function furnished both enantiomers (+)-(3R,4R)-Fmoc-POAC-OH and (−)-(3S,4S)-Fmoc-POAC-OH. The absolute configuration of the asymmetric C³, C⁴ carbons of POAC were assigned from the induced circular dichroism of a flexible biphenyl probe present in the terminally protected dipeptide derivatives Boc-Bip-(+)-POAC-OMe and Boc-Bip-(−)-POAC-OMe (Bip, 2′,1′:1,2;1″,2″:3,4-dibenzcyclohepta-1,3-diene-6-amino-6-carboxylic acid). This assignment was confirmed by X-ray diffraction analysis of the diastereomeric monoester Fmoc-(+)-trans-POAC-O-(aR)-binaphthol, shown to be (aR,3R,4R). Solution synthesis of peptides to the hexamer level, based on the (3R,4R)-POAC enantiomer combined with (1S,2S)-2-aminocyclopentane-1-carboxylic acid, was carried out to examine coupling conditions at both C- and N-termini of the POAC residue, in view of further syntheses and 3D-structural investigations.     

Enantiopure vic-amino alcohols and vic-diamines from (1R,2S)-1,2-dihydroxy-1,2-dihydronaphthalene

(1S,2S)-2-Hydroxy-1-amino-1,2,3,4-tetrahydronaphthalene, (1R,2R)-1-hydroxy-2-amino-1,2,3,4-tetrahydronaphthalene, (1S,2R)-1,2-diamino-1,2,3,4-tetrahydronaphthalene, (2R,3S)-2-hydroxy-3-amino-1,2,3,4-tetrahydronaphthalene and (2S,3S)-2,3-diammino-1,2,3,4-tetrahydronaphthalene have been synthesized from (1R,2S)-1,2-dihydroxy-1,2-dihydronaphthalene. The latter was obtained, using a protocol reported in a previous paper, from naphthalene using an Escherichia coli recombinant strain containing the naphthalene dioxygenase gene cloned from Pseudomonas fluorescens N3.     

Enantioselective synthesis of indolizidine and quinolizidine derivatives from chiral non-racemic bicyclic lactams

Chiral non-racemic bicyclic lactams 2b,c, derived from (R)- and (S)-phenylglycinol, were used in the enantioselective synthesis of (−)-lupinine and 5-epitashiromine, respectively. The efficiency of the synthesis relied on the high diastereoselectivities of formation and reduction of compounds 2b,c.     

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of common cutworm (Spodoptera litura)

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of Spodoptera litura was carried out. Substrate was converted to three new terpenoids, (+)-(1R,2S)-10-hydroxyfenchol, (+)-(1R,2R,3S)-8-hydroxyfenchol and (−)-(1S,2S,6S)-6-exo-hydroxyfenchol, and one known terpenoid, (−)-(1R,2R,3R)-9-hydroxyfenchol. These structures were established by NMR, IR, specific rotation and mass spectral studies.     

The substrate specificity of the heat-stable stereospecific amidase from Klebsiella oxytoca

The substrate specificity of the heat-stable stereospecific amidase from Klebsiella oxytoca was investigated. In addition to the original substrate, 3,3,3-trifluoro-2-hydroxy-2-methylpropanamide, the amidase accepted 2-hydroxy-2-(trifluoromethyl)-butanamide and 3,3,3-trifluoro-2-amino-2-methylpropanamide as substrates. Compounds with larger side chains and compounds where the hydroxyl group was substituted with a methoxy group, or in which the CF₃ group was substituted by CCl₃, were not accepted. The biotransformation is a new synthetic route to (R)-(+)-3,3,3-trifluoro-2-amino-2-methylpropanoic acid, and its related (S)-(−)-amide, and to (R)-(+)-2-hydroxy-2-(trifluoromethyl)-butanoic acid and its related (S)-(−)-amide.     

Asymmetric borane reduction using mixtures of homochiral amino alcohol ligands

The asymmetric borane reduction of acetophenone is investigated using mixtures of homochiral β-amino alcohol ligands. With stoichiometric amounts of a mixture of two- or three-amino alcohols, the e.e. remains at the level of the best amino alcohol for a wide composition range. A small but statistically significant enhancement in e.e. is observed when 10 mol% of an amino alcohol mixture of (1S,2R)-1-amino-2-indanol and (S)-phenylglycinol is used as chiral ligand.     

An efficient approach to the synthesis of enantiomerically pure trans-1-amino-2-(hydroxymethyl)cyclopropanephosphonic acids

The synthesis of (1R,2S)- and (1S,2R)-1-amino-2-(hydroxymethyl)cyclopropanephosphonic acids was accomplished using different strategies. The (1R,2S)-stereoisomer could be efficiently obtained by the cyclopropanation of ethyl diethoxyphosphorylacetate with the cyclic sulfate derived from (S)-3-benzyloxy-1,2-propandiol as a key step. The (1S,2R)-stereoisomer was synthesized from a readily available (1S,5R)-3-oxabicyclo[3.1.0]hexan-2-on-1-phosphonate.     

Efficient synthesis of 3,4- and 4,5-dihydroxy-2-amino-cyclohexanecarboxylic acid enantiomers

An efficient method for the synthesis of (1S,2R,4R,5S)- and (1R,2R,4R,5S)-2-amino-4,5-dihydroxycyclohexanecarboxylic acids (?)-6 and (?)-9 and (1R,2R,3S,4R)- and (1S,2R,3S,4R)-2-amino-3,4-dihydroxycyclohexanecarboxylic acids (?)-15 and (?)-18 was developed by using the OsO₄-catalyzed oxidation of Boc-protected (1S,2R)-2-aminocyclohex-4-enecarboxylic acid (+)-2 and (1R,2S)-2-aminocyclohex-3-enecarboxylic acid (+)-11. Good yields were obtained. The stereochemistry of the synthesized compounds was proven by NMR spectroscopy.     

Nucleophilic substitution of (sulfonyloxymethyl)aziridines: an asymmetric synthesis of both isomers of mexiletine

The nucleophilic substitution reactions of 1-[1′(R)-α-methylbenzyl]-(2R)- and (2S)-(sulfonyloxymethyl)aziridines were carried out with various nucleophiles including N₃⁻, MeO⁻, CN⁻, SCN⁻, and diarylcuprates. The reaction pathway is influenced by the stereochemistry of the substrates, nucleophiles, and also the structure of the leaving groups. When the reaction site is less sterically hindered for the reactive nucleophiles to approach to the substrate 1-[1′(R)-α-methylbenzyl]-(2S)-(p-toluenesulfonyloxymethyl)aziridines, product is obtained as a single isomer while all the other starting materials afford a mixture of two isomers from two different reaction pathways. Application of this method enabled us to prepare both isomers of orally effective antiarrhythmic agent mexiletine.     

A new asymmetric synthesis of (2S,3R,4R,5S)-trihydroxypipecolic acid

A novel four step synthesis of enantiomerically pure (2S,3R,4R,5S)-trihydroxypipecolic acid, starting from readily available materials, that is, condensation products of (R)-(−)-phenylglycinol with a mesotrihydroxylated glutaraldehyde, is described. The scope and limitations of the reaction have also been investigated.     

First asymmetric synthesis of an acyclic β,β-dialkylated-γ-aminobutyric acid

Enantiomerically pure (R)-γ-amino-β-benzyl-β-methylbutyric acid, an acyclic β,β-dialkyl GABA derivative, is efficiently synthesised from (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl 2-cyanopropanoate by a sequence based on benzylation, Arndt-Eistert homologation and nitrile reduction. Benzylation of (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl 2-cyanopropanoate using potassium carbonate under not strictly anhydrous conditions occurs diastereoselectively to afford (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl (S)-2-cyano-2-methyl-3-phenylpropanoate, the key chiral intermediate from which the desired γ-amino acid is obtained in five steps in 65% overall yield.     

Enantiopure trans-1-amino-2-(arylsulfanyl)cyclohexanes: novel chiral motifs for ligands and organocatalysts

In order to obtain the title compounds (1R,2R)-cyclohexane-1,2-diol was stereoselectively converted into cis-(1R,2S)-2-(arylsulfanyl)cyclohexanols and these products were submitted to the nucleophilic substitution via the Mitsunobu reaction (HN₃, DEAD). Reduction of the isolated azides gave the desired trans-(1S,2S)-1-amino-2-(arylsulfanyl)cyclohexanes. The (1S,2S)-1-amino-2-(2-aminophenylsulfanyl)cyclohexanes thus prepared were reacted with 3,5-bis(trifluoromethyl)phenyl isothiocyanate to furnish the respective bis-thiourea compounds. An application of a derivative of this type as an organocatalyst (20 mol %) in the Baylis–Hillman reaction gave the respective product in up to 93% ee.     

Enantioselective, chemoenzymatic synthesis, and absolute configuration of the antioxidant (−)-gloeosporiol

The natural antioxidant (−)-gloeosporiol, isolated as a peracetylated derivative from a culture of the fungus Colletotrichum gloeosporioides, has been enantioselectively prepared from 3,4-dihydroxybenzaldehyde by means of a chemoenzymatic synthesis. The key intermediate was obtained by resolution with a lipase from Pseudomonas cepacia. Its stereochemistry, initially assigned as R, according to the Kazlaukas empirical rule for secondary alcohols, was independently confirmed by NMR and chirooptic methods. This, in turn, allowed the assignment of compound (−)-1 as (−)-(2S,3R,4R)-2-(3′,4′dihydroxyphenyl)tetrahydrofuran-3,4-diol.     

Stereocontrolled synthesis of a potent agonist of group II metabotropic glutamate receptors, (+)-LY354740, and its related derivatives

Efficient synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740: 1) and its structurally related analogs (−)-2 and (−)-3 has been accomplished starting with (1S,2R)-1-amino-2-hydroxycyclopentane- or cyclohexanecarboxylic acid (4 or 17 ) via an intramolecular cyclopropanation of α-diazo acetamide.     

Determination of the absolute structure of albaconol

The concise synthesis of (8aR)-(−)-albaconol (1) from (8aR)-albicanol (2) obtained from the lipase-assisted asymmetric acetylation of rac-2, was achieved in 45% overall yield (eight steps). By comparison of the sign of specific rotation of between synthetic (8aR)-(−)-albaconol (1) and natural (+)-albaconol (1), the absolute structure of natural (+)-1 was determined to be 1R,2R,4aS,8aS configuration.     

Synthesis and quadratic molecular hyperpolarizabilities of two new chiral boronates: Computational and experimental study

A monomeric boronate and an oxobridged chiral dimer were obtained by reaction of the ligand derived from 4-diethylaminosalicylaldehyde with (R)-(−)-phenylglycinol, and phenyl boronic acid or boric acid. The compounds were fully characterized by spectroscopic techniques (¹H, ¹³C, ¹¹B NMR, elemental analyses, IR and masses spectrometry); and their molecular hyperpolarizabilities were investigated by the electric field induced second harmonic (EFISH) technique and semi-empirical calculations. The experimental quadratic hyperpolarizability which is equal to 9.8 × 10⁻³⁰ cm⁵ esu⁻¹ at 1.064 μm for the monomeric derivative rises to 19.5 × 10⁻³⁰ cm⁵ esu⁻¹ in the dimeric specie.     

First asymmetric synthesis of pyrrolizidine alkaloids, (+)-hyacinthacine B1 and (+)-B2

An enantiomerically and diastereomerically pure route has been developed for the first asymmetric synthesis of (1S,2R,3R,5R,7aR)- and (1S,2R,3R,5S,7aR)-1,2-dihydroxy-3,5-dihydroxymethylpyrrolizidine, hyacinthacine B₁ and B₂, featuring efficient and stereodefined elaboration via the asymmetric dihydroxylation (AD) of the functionalized homochiral pyrrolidine derivative prepared from (S)-(−)-2-pyrrolidone-5-carboxylic acid.     

Absolute configuration of bioactive furanogermacrenones from Commiphora erythraea (Ehrenb) Engl. by computational analysis of their chiroptical properties

Absolute configurations (+)-(4S), (+)-(3S,4R), (−)-(2S,4S), and (−)-(1R,2R,4S) were assigned, for the first time, to bioactive furanogermacranes extracted from Commiphora erythraea resin by DFT computational analysis of their ORD curves and ECD spectra. This analysis established that all of these compounds share the same absolute configuration at the methyl-substituted carbon thus allowing us to hypothesize a biosynthetic relationship among these structurally related metabolites.