Asymmetric synthesis of an enantiomerically pure rivastigmine intermediate using ketoreductase

A novel chemo-enzymatic synthesis of (S)-rivastigmine using ketoreductases with NADH/NADPH as the proton donor has been demonstrated. An exclusive enzymatic process has been developed by exploring the possible ketoreductases by screening to identify enzymes useful for the preparation of the (S)-isomer intermediate, and scaling up of the enzymatic process for the production of an adequate, enantiomerically pure precursor of rivastigmine and for the total synthesis of (S)-rivastigmine.     

Efficient synthesis of enantiomerically pure dihydropyrans

cis- and trans-2-Substituted-3,6-dihydro-2H-pyran-3-ols have been prepared via an aldol condensation/ring-closing metathesis/enzymatic resolution sequence. The process can be scaled up to yield gram quantities of enantiomerically pure material.     

Convenient synthetic route to an enantiomerically pure FMOC alpha-amino acid

A strategy for the facile alpha-amination of carboxylic acid menthyl esters is described. The resulting diastereomers, readily separable, can be individually carried on to each enantiomer of the FMOC alpha-amino acid. A variety of unnatural side chains were compatible with this approach. The menthyl ester was easily removed from the FMOC alpha-amino acid without racemization.     

Molecular tectonics: from enantiomerically pure sugars to enantiomerically pure triple stranded helical coordination network

The self-assembly between a bis-monodentate tecton based on two pyridine units connected to an enantiomerically pure isomannide stereoisomer and HgCl2 leads to the formation of an enantiomerically pure triple stranded helical infinite coordination network which was structurally characterised by X-ray diffraction on single crystal.     

Microwave assisted synthesis of enantiomerically pure allylboronates

Stable allylboronates with a stereogenic centre α to the boronic ester moiety represent versatile reagents for stereoselective synthesis of homoallylic alcohols. Use of microwave irradiation in desilylation and sigmatropic rearrangement reactions allows rapid synthesis of α-chiral allylboronates utilized in the highly diastereo- and enantioselective synthesis of (Z)-configured homoallylic α-hydroxy esters by allyl additions to ethyl glyoxylate.     

Synthesis of enantiomerically pure 3-aminochroman derivatives

Enantiomerically pure (3R)-amino-5-methoxy-3,4-dihydro-2H-1-benzopyran was successfully synthesised in nine steps starting from l-serine. The same synthetic pathway was used to prepare the (3S)-aminochroman derivative starting from d-serine. The enantiomeric purity of the final aminochroman derivatives was determined by capillary electrophoresis using β-cyclodextrin as the chiral selector.     

Two enantiomerically pure cyclic arenesulfonamide hydrochloride salts

The crystal structures of N‐[(1R)‐1‐(1‐naphthyl)ethyl]‐3,4‐dihydro‐2H‐1,2‐benzothiazin‐4‐aminium 1,1‐dioxide chloride, C₂₀H₂₁N₂O₂S⁺·Cl⁻, (I), a six‐membered cyclic sulfonamide, and (1R)‐N‐[(5,5‐dioxo‐6,7‐dihydrodibenzo[d,f][1,2]thiazepin‐7‐yl)methyl]‐1‐(1‐naphthyl)ethanaminium chloride, C₂₆H₂₅N₂O₂S⁺·Cl⁻, (II), a seven‐membered cyclic sulfonamide, both representative of a novel family of agonists of the extracellular calcium sensing receptor (CaSR) of possible clinical importance, are reported. The known chirality of the naphthylethylamine precursor has enabled assignment of the absolute configuration of both compounds, which is crucial for the receptor recognition. The crystal structures, though different, reveal for these agonists a notable absence of intramolecular π–π stacking between their respective aromatic groups. This suggests a common structural feature that allows CaSR agonists to be distinguished from antagonists, since in the latter, such interactions have been shown to be important. The connectivities between molecules in the crystal structures are also different, but both involve hydrogen bonding mediated by chloride ions as a common dominant feature.     

Efficient access to enantiomerically pure rigid diamines

Asymmetric spiro cyclization of a pyrrolidine derivative was used as a key step for constructing novel rigid diamines. A selected example has proved its utility as a chiral nonmetallic catalyst in a Michael reaction.     

An efficient approach to enantiomerically pure fluorhydrins

optically pure α′-monofluoro-α-sulphinyl ketones have been reduced with high diastereoselection to give α′-fluoro-α-sulphinyl alcohols which upon removal of the sulphinyl residue produced enantiomerically pure fluorhydrins.     

Dithiophosphorylation of racemic and enantiomerically pure 1-phenylethanamines

N,N′-Bis[(RS)-, (S)-, and (R)-1-phenylethyl]phosphorodiamidodithioic acids were synthesized by reactions of racemic and enantiomerically pure 1-phenylethanamines with tetraphosphorus decasulfide.     

Synthesis of novel enantiomerically pure tetra-carbohydrazide cyclophane macrocycles

A total of twelve novel enantiomerically pure tetra-carbohydrazide cyclophane macrocycles have been synthesised in quantitative yields by reacting chiral (4R,5R)- and (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazides with aromatic bis-aldehydes in a [2 + 2]-cyclocondensation reaction. The compounds show a dynamic behaviour in solution, which has been rationalized in terms of an unprecedented conformational interconversion between two conformers one stabilised by intramolecular hydrogen bonding and π-π stacking interactions.     

Chemoenzymatic synthesis of enantiomerically pure terminal 1,2-diols

A new practical method for the enzymatic synthesis of 1,2-diols has been developed by employing a lipase catalyzed one-pot transesterification protocol. A series of substituted -acetoxyphenylethanones 3a–g have been reduced to the corresponding alcohols under mild conditions employing sodium borohydride and moist neutral alumina, and further subjected for lipase catalyzed irreversible transesterification in the same pot to give mono- and diacetate diols (R)-4 and (S)-5, which on hydrolysis afforded terminal 1,2-diols, (R)- and (S)-6 in high enantiomeric excess.     

Synthesis of enantiomerically pure vinylcyclopropylboronic esters via cross-metathesis

The potent antibiotic ambruticin caused us to investigate two new aspects of cyclopropylboronic ester chemistry: we established the analytical basics for all 1,2,3-trisubstituted diastereoisomers as well as the cross-metathesis as a tool to synthesise vinylcyclopropylboronic esters.     

A large-scale synthesis of enantiomerically pure γ-hydroxy-organochalcogenides

Enantiomerically pure (R)- and (S)-γ-hydroxy-organochalcogenides are prepared using poly-[R]-3-hydroxybutanoate (PHB) as the starting material.     

Synthesis of 1-deoxy-D-galactohomonojirimycin via enantiomerically pure allenylstannanes

1-Deoxy-D-galactohomonojirimycin was synthesized in seven steps from optically pure allenylstannane 4 and L-lactate-derived aldehyde 5 in 48% overall yield. The key step was the Lewis acid catalyzed reaction of 4 and 5 to give the syn-amino alcohol in excellent yield and very high diastereoselectivity.     

Chemoenzymatic synthesis of enantiomerically pure tricyclic benzomorphan analogues

The key step in the synthesis of enantiomerically pure benzomorphan analogous tricyclic amines 2 is the kinetic resolution of secondary alcohol 7 using the lipase from Pseudomonas fluorescence. The (S)-configured alcohol (S)-7 and the (R)-configured ester (R)-8 were obtained in good yield (40% and 46%, respectively) and excellent enantiomeric excess (99% ee and 98.4% ee, respectively). A diastereoselective oxa-Pictet-Spengler reaction of (S)-7 with ethyl glyoxalate (OHC–CO₂Et) followed by a Dieckmann cyclization provided the tricyclic ring system 11, which allowed the diastereoselective introduction of an amino group at the 6-position. The absolute configuration of alcohol (S)-7 was determined with the tricyclic alcohol 13. The quantum mechanically calculated specific optical rotation of (S,S,S)-configured alcohol 13 is in accordance with the measured specific rotation of the synthesized compound. Moreover, X-ray crystal structure analysis of the synthesized compound, determined with the three-beam interference method, proved the (S,S,S)-configuration of 13. The enantiomerically pure dimethylamine 12 showed moderate affinity toward σ₂ receptors.