Stereoselective synthesis of biologically active tetronic acids

(4R)-3-Amino-4-trimethylsilyloxy-2-alkenoates (R)-3, obtained from O-trimethylsilyl protected optically active cyanohydrins (R)-1 via the Blaise reaction, are hydrolyzed under mildly acidic conditions to give optically active tetronic acids (R)-4 without racemization. From the follow-up reactions of (R)-4 investigated, only methylation with diazomethane afforded the biologically active tetronic acid derivative (R)-5a without racemization whereas acylation and reductive alkylation, respectively, resulted in partial racemization or failed on the whole.     

Easy access to optically active Hagemann's esters

The synthesis of optically active Hagemann's esters was investigated. The starting materials in this approach were enamino esters (R,Z)-8, prepared through the condensation of keto ester 6 with (R)-1-phenylethylamine 7. Michael addition reaction of the enamino esters (R,Z)-8 with methyl vinyl ketone gave the expected adducts 10 with good e.e.s of 93–96%. Subsequent annulation of the adducts furnished optically active Hagemann's esters.     

The synthesis of some optically active C-methylated 2-oxohexamethyleneimines

Three new, optically active, methyl-substituted 2-oxohexamethyleneimines were prepared by cyclization of the respective optically active C-methylated 6-aminohexanoic acids. The active forms of the amino acids used for the preparation of (?)-3-methyl-2-oxohexamethyleneimine and (?)-7-methyl-2-oxohexamethyleneimine were obtained by resolution of their diastereomeric quinine salts. s-(+)-5-methyl-2-oxohexamethyleneimine was synthesized without racemization from optically pure 2-isopropylidene-5-methyleyclohexanone (pulegone).     

Preparation of optically active bridged biphenyls via a stereoselective synthesis of their mono (tricarbonylchromium) complexes. Chiroptical properties and absolute chiralities of the complexes and ligands12

Reaction of the mono(tricarbonylchromium) complex 3 of diphenic acid anhydride with chiral amines gave the optically active imides 9-11. 10 and 11, from (S)-(?) and (R)(+)-phenylalaninol, respectively were separated by chromatography into exo- and endo-diastereomers (a and b) with opposite metallocene chiralities but with the same axial chirality. The (S)-(?) amino-alcohol induces (S)_a-chirality and vice versa. The absolute configurations of the metallocene and axial-chiral parts of the biphenyl system were deduced from the circular dichroism spectra, the former [(R)_m or (S)_m] by comparison with the CD of benchrotrenes of known absolute configuration, the latter [(R)_a or (S)_a] by applying the exciton model of coupled oscillators to the optically stable biphenyl ligands [i.e. the imides (?)- and (+)-8 easily accessible from 10 and 11 by photochemical decomplexation]. (R)_m-(S)_a for the complex (+)-10a (exo) and (S)_m-(S)_a for the endo-isomer (?)-10b, and vice versa for the complex 11. The parent ligands have the configurations (S)_a(?)-8 and (R)_a(+)-8, respectively.Photochemical cleavage of the optically active bis(tricarbonylchromium) complex (?)-13 of the biphenyl lactone 12 at ?60°C afforded optically labile 12 with a half-life time of racemization of ca 10 min at ?20°. On the basis of its CD the configuration (R)_a is tentatively proposed for 12.The work described represents the first example of the preparation of optically-active biphenyls via benchrotrene precursors.     

Chemoenzymatic route to optically active dihydroxy cyclopenta[b]naphthalenones; precursors for decalin-based bioactive natural products

The development of an efficient chemoenzymatic route for the synthesis of optically active dihydroxy cyclopenta[b]naphthalenones; (+)-1,4a-dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta[b]naphthalen-2(4H)-one (+)-10 and (+)-1,8a-dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta[b]naphthalen-2(4H)-one (+)-11 is described. Different lipases and esterases were tested in the enzymatic hydrolysis of the corresponding acetates (±)-4a-hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-cyclopenta[b]naphthalen-1-yl acetate (±)-8, (±)-8a-hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-cyclopenta[b]naphthalen-1-yl acetate (±)-9, CRL (Candida Rugosa Lipase) and PLE (Pig Liver Esterase) were found to be the most effectual enzymes; for (?)-8 by 47% ee with the corresponding dihydroxy; (+)-10 by 98% ee in the presence of CRL; whereas, (?)-8 was obtained with 40% ee with the corresponding dihydroxy, (+)-10 with 58% ee in the PLE hydrolysis. It was concluded that CRL was the best biocatalyst for the substrate (±)-8. Moreover, enzymatic resolution in the presence of CRL yields, (?)-9 with 46% ee with the corresponding dihydroxy derivative; (+)-11 with 98% ee; however, in the presence of PLE, yields (?)-9 with 36% ee as well as the related dihydroxy derivative; (+)-11 with 49% ee respectively. The study concluded that CRL is the best biocatalyst for compounds (±)-8 and (±)-9.     

Protecting-group-free catalytic asymmetric total synthesis of (−)-rosmarinecine

The protecting-group-free asymmetric total synthesis of (?)-rosmarinecine was achieved in only four steps from the commercially available (±)-3-hydroxypyrrolidine hydrochloride (2a). The key steps include the direct oxidation of (±)-2a to (±)-3-hydroxy-1-pyrroline N-oxide (1a) using the Davis reagent and the domino reaction; viz., the lipase-catalyzed dynamic kinetic resolution of (±)-1a with 1-ethoxyvinyl ethyl maleate followed by the intramolecular [3+2] dipolar cycloaddition reaction of the generated optically active ester. Some insights into the mechanism of the racemization of the optically active 1a, observed during the enzymatic process, were also obtained.     

Synthesis of novel chiral dopants based on optically active p-substituted mandelic acids

Novel esters of optically active p-substituted mandelic acids (+)-1 and (+)-2 were prepared by a convergent synthetic strategy in high enantiomeric excess (99% ee). The esters (+)-1 and (+)-2 induce helical macrostructures in the mesophases of achiral liquid-crystal materials, although neither exhibits mesorphism on its own.     

Stereochemical studies-LVIII: Synthesis of optically active compounds by the novel use of meso-compound-2. efficient synthesis of an optically pure steroid intermediate

In order to explore the general application of a novel method for preparing optically active compounds, synthesis of the optically pure steroid intermediate((?)-1) has been examined by employing the diol(2) as a meso-compound and N-mesyl-(S)-phenylalanyl chloride(3) as a source of the optically active functional group.     

One-pot acylation and fractional crystallization: preparation of optically active serinol monobenzoates

Mono-O-acylation of (R)-2-(α-methylbenzyl)amino-1,3-propanediol 1 with 4-nitrobenzoyl chloride and DMAP in dichloromethane at room temperature gave crystals of optically active (2S,αR)-3-hydroxy-2-(α-methylbenzyl)aminopropyl 4-nitrobenzoate hydrochloride [(2S)-2a·HCl] in 33% yield by fractional crystallization. Optically active oxazolidinones, aziridines, and serinol derivatives were synthesized from the benzoate (2S)-2a.     

Prostaglandin chemistry—VIII : Synthesis of optically active 7-oxoprostaglandins

Regiospecific α-acylation of β-alkenylated enolates generated by conjugate addition of lithium organocuprates to α,β-unsaturated ketones is described. Several new 7-oxoprostaglandin analogues, 7-oxoprostaglandin E₁ (18), 11-deoxy-7-oxoprostaglandin E₁ (23), and their 15-epi enantiomers 17 and 22, were synthesized by conjugate addition-acylation method. From optically active 4(R) -t - butyldimethylsiloxycyclopent - 2 - en - 1 - one (R-11), 7-oxoprostaglandin E₁ (18) was synthesized. Determination of the absolute configuration of 11-deoxy-7-oxoprostaglandin E₁ (23) and its 15-epi enantiomer (22) on the basis of CD study is described. Successful acylation of β-alkenylated lithium copper enolates with reactive acylating agents such as thiol esters and N-acyl imidazole as well as acyl halides is described.     

Chemoenzymatic syntheses of two optically active hexa-azamacrocycles

Two optically active hexa-azamacrocycles with C₂ and D₂ symmetry, respectively, have been efficiently synthesized from the enzymatically prepared (R,R)-cyclohexane-1,2-diamine bis(amidoester) derivative (R,R)-4.     

Preparation and reactions of optically active cyanohydrins using the (R)-hydroxynitrile lyase from Prunus amygdalus

Cyanuration of 2-naphthaldehyde (1) and 5-methyl-2-furaldehyde (2) yielded the racemic 2-hydroxy-2-(β-naphthyl)ethanenitrile (R,S)-3 and 2-hydroxy-2-(5-methyl-2-furyl)ethanenitrile (R,S)-5, respectively. The same reaction can be completed by using acetone cyanohydrin (4) as a transcyanating agent. The optically active (R)-3 and (S)-5 could be respectively obtained by hydrocyanation of 1 and 2 using (R)-hydroxynitrile lyase (R)-PaHNL [EC 4.1.2.10] from almonds (Prunus amygdalus) as a chiral catalyst. Cyanohydrins 3 and 5 in their racemic and optically active forms undergo a number of transformations which involve either the hydroxyl group or the cyanide function. Moreover, derivatization of 3 and 5 with (S)-Naproxen®chloride (S)-14 gave the respective diastereoisomers. The optical activity of (R)-3 and (S)-5 as well as their derivatives were recorded. The postulated structures for the new products were supported with compatible elementary and spectroscopic (IR, ¹H NMR, ¹³C NMR, MS, and single crystal X-Ray crystallography) analyses. The antimicrobial activity of some selected racemic new products and their respective optically active analogues were also undertaken.     

Synthesis of optically active (+)-19-nortestosterone by asymmetric bis-annulation reaction

Michael reaction of 1,7-pctadien-3-one with 2-methylcyclopentane-1,3-dione, followed by intramolecular aldol condensation promoted by L-amino acids produced the optically active (+)-4-(3-butenyl)-7a-methyl-5,6,7,7a-tetrahydroindane-1,5-dione in high chemical and optical yields. The PdCl₂-catalyzed oxidation of the terminal double bond gave the methyl ketone, which had 76% optical purity and was made 100% optically pure by recrystallization. Then aldol condensation afforded the tricyclic ketone, which was alkylated with 3-butenyl iodide to afford (?)-3β-t-butoxy-2,3,3a,4,5,7,8,9,9aβ,9bα-decahydro-6-(3-butenyl)-3aβ-methyl-1H-benz[e]inden-7-one. The synthesis of this compound means the total synthesis of (+)-19-nortestosterone.     

Practical synthetic protocols of enantiopure 1,1-binaphthyl-2,2-dicarboxylic acid and 2,2-dicyano-1,1-binaphthyl starting from optically active dibromide precursor

Dilithiation of optically active 2,2^′-dibromo-1,1^′-binaphthyl 2 with t-BuLi followed by carboxylation of the resulting dilithio-intermediate 3 with CO₂ gave optically active 1,1^′-binaphthyl-2,2^′-dicarboxylic acid 1, which was further transformed to its dicyano derivative 4. Both of these transformations were carried out in a one-pot operation and the products were obtained in excellent yields with no observable racemization.     

Molecular structures and ab initio molecular orbital calculations of the optically active derivatives of 1-aminocyclopropane-1-carboxylic acid

The novel optically active derivatives of 2,2′-disubstituted-1-aminocyclopropane-1-carboxylic acid (−)-2 and (+)-3 were synthesised from the spiro-azlactone (+)-1. Oxidation of the diol moiety of (+)-3 gave by ring enlargement the racemic mixture of 2,3-dihydrofuran derivative (±)-6. This conversion is explained by stepwise rearrangement of the initially formed tetrasubstituted cyclopropanecarbaldehyde 4 through zwitterionic's reactive intermediate 5. The formation of (±)-6 is preferred energetically as established by ab initio calculations of the ground states and possible intermediates for that rearrangement. The crystal structure and absolute configuration of the compounds (+)-1, (−)-2, (+)-3 and (−)-7 were determined by single-crystal X-ray diffraction method. All four compounds possess Z-configuration of the cyclopropane ring. The dioxolane ring in the structures (+)-1 and (−)-2 adopts half-chair conformation, while the cyclopropane ring and geminally substituted groups in the structures (−)-2, (+)-3 and (−)-7 possess the anticlinal conformation. The molecules of the compound (+)-1 are connected by very weak intermolecular hydrogen bond of C-H?O type. In the compounds (−)-2, (+)-3 and (−)-7inter- and intramolecular hydrogen bonds of N-H?O type were observed. The spiro-compound (+)-1 exhibited a more pronounced inhibitory activity against the proliferation of murine leukemia and human T-lymphocytes cells than other type of tumor cell lines and normal human fibroblast cells.     

Synthesis of a variety of optically active hydroxylated heterocyclic compounds using epoxide hydrolase technology

Novel epoxide hydrolases in Yarrowia lipolytica have been shown to hydrolyse a variety of functionalised epoxides with good to excellent stereoselectivity and at high volumetric productivities. Individual biotransformation products have been converted into optically active (R)-(tetrahydrofuran-2-yl)methanol (6), (S)-N-benzyl-3-hydroxypyrrolidine (7), (S)-3-hydroxytetrahydrothiophene (8), (S)-N-benzyl-3-acetoxypiperidine (10), (S)-3-hydroxytetrahydrofuran (16) and (R)-[(S)-N-benzylpyrrolidin-2-yl](phenyl)methanol (20).     

Chemoenzymatic preparation of optically active trans- and cis-cyclohex-4-ene-1,2-diamine and trans-6-aminocyclohex-3-enol derivatives

Lipase from Burkholderia cepacia (PSL-C) effectively catalyzed the kinetic resolution of both racemic trans-N,N-diallylcyclohex-4-ene-1,2-diamine (±)-6 and its precursor trans-6-(diallylamino)cyclohex-3-enol (±)-5. The resulting optically active vicinal diamine and β-amino alcohol were converted into a precursor of oseltamivir and a cis-cyclohex-4-ene-1,2-diamine derivative, respectively.     

Asymmetric cyclization of meso-diepoxides using chiral (salen)Co(III)OAc catalyst forming optically active 1,4-anhydropentitols and 2,5-anhydrohexitols

The asymmetric hydrations of meso-diepoxides, 1,2:4,5-dianhydro-3-O-methylxylitol 2, 1,2:5,6-dianhydro-3,4-di-O-methylallitol 3 and 1,2:5,6-dianhydro-3,4-di-O-methylgalactitol 4, were carried out using (R,R)-1 and (S,S)-1. An optically active five-membered cyclic compound was selectively produced in good yield from 2, but a mixture of the five- and six-membered cyclic compounds was obtained in the cases of 3 and 4. The ees of all cyclic products exceeded 90%.     

Synthesis of optically active forms of ipsenol,the pheromone of IPS bark beetles

(S)-(?)-Ispenol 1′ and its antipode 1″ were synthesized from (S)-(+)-leucine 10 and its antipode 10′, respectively. This established the S-configuration of the naturally occurring (-)-ipsenol. Only the natural (S)-(?)-enantiomer was biologically active on Ips grandicollis.     

One step synthesis of aziridines by the Michael type addition of free sulfimides: Preparation and absolute configuration of optically active acylaziridines

The Michael type additions of diphenyl N-unsubstituted sulfimide (free sulfimide) to various electrophilic olefins were carried out. The reaction with cis- and trans-dibenzoylethylene, dimethyl-fumarate, dimethylmaleate, benzalacetophenone and benzalacetone gave mainly the corresponding trans-2-acylaziridines and trans-enaminoketones. However, phenyl vinyl sulfone or acrylonitrile afforded not the corresponding aziridine but diphenyl-N-2-cyano or N-2-phenylsulfonylethylsulfimide, a simple Michael adduct When optically active (+)-(R)-o-methoxyphenyiphenyl free sulfimide was treated with such an α,β-unsaturated carbonyl compound as benzalacetopbenone, an optically active 2-acylazindine, i.e., (-)-trans-2-benzoyl-3-phenylaziridine was obtained in ca 30% optical purity and its absolute configuration was assigned as (2R,3S) upon chemical transformation to the configuration-ally known 2-phenyl-2-benzoylamino-1-ethanol or by comparing its CD spectrum with that of (1R,2R)-1-phenyl-2-benzoyl-cyclopropane. Meanwhile, (-)-(S)-o-methoxyphenylphenyl free sulfimide was found to react with benzalacetophenone to afford (+)-trans-2-benzoyl-3-phenylaziridine of 25% optical purity. Effects of solvent and temperature on both die distribution of the products ratio and the optical yield were examined.