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.     

Efficient synthesis of enantiomerically pure alpha-alkyl cyclopropanecarbonitrile derivatives from pyrazolines

[reaction: see text] Thermolysis of enantiopure sulfonyl pyrazolines 4 and 5, easily obtained from (Z)-3-p-tolylsulfinylacrylonitriles (1), afforded sulfonyl cyclopropanes (6, 7) in a completely stereoselective manner in almost quantitative yields. Both cyclopropanes and alkylidenecyclopropanes, containing one or two chiral carbon atoms, one of them being quaternary, were obtained by hydrogenolysis of the C-S bonding and under the conditions reported by Julia, respectively. The highly stereoselective extrusion of nitrogen suggests a concerted mechanism.     

Efficient synthesis of enantiomerically pure beta2-amino acids via chiral isoxazolidinones

We report a practical and scalable synthetic route for the preparation of alpha-substituted beta-amino acids (beta(2)-amino acids). Michael addition of a chiral hydroxylamine, derived from alpha-methylbenzylamine, to an alpha-alkylacrylate followed by cyclization gives a diastereomeric mixture of alpha-substituted isoxazolidinones. These diastereomers are separable by column chromatography. Subsequent hydrogenation of the purified isoxazolidinones followed by Fmoc protection affords enantiomerically pure Fmoc-beta(2)-amino acids, which are useful for beta-peptide synthesis. This route provides access to both enantiomers of a protected beta(2)-amino acid.     

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.     

Novel synthesis of chiral,enantiomerically pure thiodiglycols and diglycols

Natural α-hydroxy acids have been converted in a sequence of O-protection, reduction, O-activation, thioether and ether formation and deprotection to chiral, non-racemic β,β′-dihydroxy thioethers 1a, 1b and ether 1c. Overall yields are excellent (75%). In an attempt to synthesize the respective dihydroxy ether 1d derived from mandelic acid 1,3-dioxolane derivatives 7 were obtained.     

Benzothiazines in organic synthesis. The preparation of enantiomerically pure 4-substituted quinolones

3,4-Dihydroquinolin-2(1H)-ones have potential biological and pharmacological significance. Enantiomerically pure benzothiazines, readily available via an intramolecular addition of a sulfoximine-stabilized carbanion to an alpha,beta-unsaturated ester, could be used as templates for making a series of enantiomerically pure 3,4-dihydroquinolin-2(1H)-ones under mild conditions.     

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.     

Stereoselective synthesis of enantiomerically pure 1-(E)-alkenylsulfoximines

Optically active (E)-N-tosyl-S-(1-alkenyl)-S-phenylsulfoximines 4 are synthesized stereoselectively in a one pot sequence from readily available 1 via C-silylation, metallation and reaction of the corresponding lithiosulfoximine 3 with various carbonyl compounds. The El-MS spectra of the so prepared alkenylsulfoximines 4 show unexpected fragmentations, pointing to a new, unusual S-O-migration of the 1-alkenyl moiety.     

A concise synthesis of enantiomerically pure aroyl-l-alanines and dihydroaroyl-l-alanines

Straightforward preparation of enantiomerically highly enriched N-substituted aroylalanines has been developed. This process involves the combination of crystallization-induced asymmetric transformation and a conjugate addition of N-nucleophiles to the corresponding aroylacrylic acids. Further transformations to 3,4-dichlorobenzoylalanine and aroyl-l-alanines via periodate oxidation and stereoselective reduction to N-substituted syn-4-aryl-4-hydroxy-2-aminobutanoic acids are also described.     

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.     

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.     

Asymmetric synthesis of β-hydroxythioacetamides mediated by enantiomerically pure sulphiny1 derivatives

Enantiomerically pure $\text{P}$-tolyl sulphinyl-N,N-dimethylthioacetamide (1) was prepared starting from (-)-(S)-menthyl toluene-$\text{p}$-sulphinate. Aldol-type condensation of (1) and subsequent removal of the Sulphinyl group open an entry to optically active β-hydroxy thioacetamides in 40–90% e.e.     

The synthesis of diastereo- and enantiomerically pure beta-aminocyclopropanecarboxylic acids

The synthesis of diastereo- and enantiomerically pure beta-aminocyclopropanecarboxylic acids (beta-ACCs) is described. Starting from pyrrole, (rac)-4 is readily obtained, which was kinetically resolved by enzymatic hydrolysis. Subsequent oxidation of (-)-4 and deformylation gives rise to the cis-beta-ACC derivative (ent)-9, while (+)-10 was converted to the trans-beta-ACC derivative 8. Both 8 and (ent)-9 and their benzyl esters 13 and 16, being conformationally restricted beta-alanine or gamma-aminobutyric acid (GABA) derivatives, represent useful building blocks for peptides containing unnatural amino acids.     

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.     

Asymmetric synthesis via acetal templates. 15. The preparation of enantiomerically pure mevinolin analogs

An efficient asymmetric synthesis of the hydroxylactone moiety of mevinolin 1 is described. The key step is the TiCl₄-catalyzed coupling reaction of acetals 3a and 3b derived from (R)-1,3-butanediol with 1,3-bis(trimethylsilyloxy)-1-methoxybuta-1,3-diene 4 to give the δ-alkoxy-β-keto ester 5.     

Efficient synthesis of enantiomerically pure 2-acylaziridines: Facile syntheses of N-Boc-safingol, N-Boc-D-erythro-sphinganine, and N-Boc-spisulosine from a common intermediate

Various enantiomerically pure 2-acylaziridines were prepared efficiently from the corresponding aziridine-2-carboxylate via Weinreb's amide and the subsequent treatment of organometallic compounds. The carbonyl group of those 2-acylaziridines was stereoselectively reduced by NaBH4in the presence of ZnCl2 to give erythro-1,2-amino alcohols with high diastereoselectivities and chemical yields. Using this methodology, we prepared (1R,2S)-N-Boc-norephedrine 5, N-Boc-safingol 8, N-Boc-D-erythro-sphinganine 9, and N-Boc-spisulosine 10 in high yields.