Di-tert-butylsilylene (DTBS) group-directed α-selective galactosylation unaffected by C-2 participating functionalities

We have discovered an unusual α-galactosylation using phenylthioglycoside of 4,6-O-di-tert-butylsilylene (DTBS)-protected galactose derivatives as a glycosyl donor, which was not hampered by the neighboring participation of C-2 acyl functionality such as NTroc and OBz. The power of the DTBS effect has been exemplified by the coupling reaction with various glycosyl acceptors.     

Stereoselective synthesis of 1,2-cis galactosides: synthesis of a glycolipid containing Galα1-6Gal component from Zygomycetes species

An α-selective galactosylation was demonstrated under various conditions. Among these α-galactoside approaches, high α-selectivity was achieved by the virtue of 4,6-O-di-tert-butylsilylene (DTBS) group. Yield was further improved by the influence of a 2-O-benzylated donor compared to 2-O-benzoylated donor. This method was then applied to the first highly stereoselective synthesis of a newly found trisaccharide glycosphingolipid in Zygomycetes species.     

Toward the total synthesis of citreamicin η: Synthesis of the pentacyclic core and GAB-ring annelation model studies

A short 11-step synthesis of the pentacyclic core of the polycyclic xanthone antibiotic citreamicin η has been completed. Although the basic approach was inspired by our previous explorations of polycyclic xanthone chemistry, the present report features some new insights into the Moore rearrangement and offers some improvements to our original methodology that include additions of aryllithiums to squarate esters, additions of cerium acetylides to hindered ketones utilizing PDA as an internal indicator, and the use of cyclic di-tert-butylsilyl (DTBS) ethers to protect electron-rich benzyl alcohols toward ionization under acidic conditions. We also developed an improved protocol for selective o-bromination of phenols utilizing N-bromosuccinimide (NBS) and tetramethylguanidine (TMG) that promises to be generally useful. Finally, we developed a modular approach for the synthesis of isoquinolones and dihydro-5H-oxazolo[3,2-b]isoquinoline-2,5(3H)-diones that features a novel sequence of alkoxycarbonylation, acetone arylation, transamidation.     

Chirality sensing of saccharides using a boronic acid-appended chiral ferrocene derivative

A diboronic acid-appended chiral ferrocene derivative (R)-9 was designed and synthesized. This chiral ferrocene scaffold was obtained by resolution of the diastereomer with a monosaccharide derivative. One can therefore expect that (R)-9 would show d/l selectivity for specific monosaccharides. The complex formation of (R)-9 with various saccharides using the two boronic acid functions was conveniently monitored by a change in the circular dichroism (CD) spectra. The CD spectral change (Δ[θ]) induced by added monosaccharides was chiroselective: in particular, d/l-alloses and d/l-galactoses induced the 8.0- and 7.0-fold difference in the magnitude of the CD spectral change. The association constants for d- and l-saccharides (K_D and K_L, respectively) were determined: among them, (R)-9 showed a significant discrimination ability for mannose (K_L/K_D=2.6) and arabinose (K_L/K_D=1/2.4). The origin of d/l selectivity was discussed on the basis of computational studies on (R)-9·saccharide complexes.     

Enantiopure erythro- and threo-1-aryl-1-[2-pyrrolidyl]-methanols: synthesis from l-proline

Enantiopure (1R,2S)-erythro- and (1S,2S)-threo-isomers of four new aryl-pyrrolidyl alcohols 5aH, 5aMe, 5bH and 5bMe have been obtained in five steps from (−)-(S)-proline and fully characterized. The oxidation of alcohol 8 into aldehyde 9 was the most difficult step and racemization occurs during Swern oxidation but this difficulty can be overcome by using SO₃/pyridine as oxidant. Diastereomer I of the protected amino alcohol 10a crystallized and was shown to be the (1R,2S)-erythro-isomer (e-10a-I) using X-ray crystallography. Therefore the (1R,2S)-erythro structure was assigned to all compounds obtained from e-10a-I, and, as a consequence, the (1S,2S)-threo structure was assigned to diastereomers II.     

Lipase-mediated kinetic resolution of cis-1,2-indandiol and the Ritter reaction of its mono-acetate

Lipase-mediated kinetic resolution of cis-1,2-indandiol 5 in the presence of lipase PS was examined. Enantiomerically enriched (1S,2R)-2-acetoxy-1-indanol 6a was obtained when cis-1,2-indandiol 5 was treated with one equivalent of vinyl acetate. Treatment of 5 with two equivalents of vinyl acetate furnished a mixture of (1R,2S)-2-acetoxy-1-indanol 6a and (1R,2S)-1-acetoxy-2-indanol 6b. A route to both enantiomers of 1 was also developed by using the enantiomerically enriched mono-acetate thus obtained.     

Racemization of (S)-(+)-10,11-dimethoxyaporphine and (S)-(+)-aporphine: efficient preparations of (R)-(−)-apomorphine and (R)-(−)-aporphine via a recycle process of resolution

Efficient preparations of (R)-(−)-apomorphine (R)-1 and (R)-(−)-aporphine (R)-2 based on a recycle process of resolution are described. In this recycle process of resolution, (RS)-(±)-10,11-dimethoxyaporphine 3 as the precursor of 1, and (RS)-(±)-aporphine 2 were successfully resolved into both enantiomers with (+)-dibenzoyltartaric acid (DBTA). The desired (R)-3 and (R)-2 were obtained and then, respectively, transformed to compound (R)-1, the hydrochloride salt of (R)-1, diacetate compound 4 and the hydrochloride salt of (R)-2; while the undesired (S)-3 and (S)-2 were racemized to obtain a racemate, which was suitable for further resolution. A method for the racemization of the undesired (S)-3 and (S)-2 was extensively studied, in order to obtain high-yielding racemization conditions. A plausible mechanism for the racemization of (S)-3 and (S)-2 was also proposed.     

Crystal and molecular structure of the levorotatory (1R,2S)-ephedrinium (S)-t-butylsulfinylacetate: a definitive proof of the absolute configuration of enantiomeric t-butyl methyl sulfoxides

The levorotatory enantiomer of t-butylsulfinylacetic acid 3 was obtained in the reaction of the α-carbanion of (+)-t-butyl methyl sulfoxide 1 with carbon dioxide. The same enantiopure form of the acid 3 was isolated from its diastereomerically pure levorotatory salt 5 with (−)-(1R,2S)-ephedrine. The structure of this salt was determined by X-ray analysis and the absolute configuration (S) at sulfur was ascribed to the t-butylsulfinylacetate anion. Consequently, the absolute configuration (S) was assigned to the acid (−)-3 and its precursor (+)-t-butyl methyl sulfoxide 1.     

Efficient and practical synthesis of both enantiomers of 6-silyloxy-3-pyranone derivatives

Lipase catalyzed kinetic resolution of racemic cis-6-(tert-butyldimethylsilyloxy)-3,6-dihydro-2H-pyran-3-ol (rac)-1 was achieved in high enantiomeric excess. Transesterification of (rac)-1 with vinylacetate in ^tBuOMe yielded the alcohol (3S,6R)-1 in 99.0% ee, whereas (3R,6S)-1 was obtained, in 99.0% ee, by the lipase catalyzed ester hydrolysis of acetate (3R,6S)-2, which was obtained along with the transesterification. Both (3S,6R)-1 and (3R,6S)-1 were subjected to oxidation to provide the corresponding 6-silyloxy-3-pyranone (6R)-3 and (6S)-3, respectively. Application to the synthesis of 7, which is the key intermediate of asymmetric synthesis of pseudomonic acid A 9 is also described.     

Facile synthesis of enantiomerically pure tert-butyl(methyl)phenylsilanes

A method for the preparation of both enantiomers of tert-butyl(methyl)phenylsilane 2 is presented. Racemic tert-butyl(methyl)phenylsilyl chloride 3 was allowed to react with (R)-(−)-2-amino-1-butanol 4 to give hydrochloride 5. Diastereomer separation via treatment of the respective free amine 6 with 0.5 mol equivalent of HCl in hexane-2-propanol yielded crystalline diastereomerically pure hydrochloride (R)Si-5. The corresponding free amine (R)Si-6 was reduced with LiAlH₄ to give (S)-2. The mother liquors obtained after separation of (R)Si-5 on treatment with oxalic acid provided a crystalline salt that eventually afforded (R)-2. The optical purity of (S)-2 (98% ee) was documented by its reaction (hydrosilylation) with propargylic alcohol derivative 10 and HPLC analysis of product 11 using a chiral column.     

Isolation of amoenamide A and five antipodal prenylated alkaloids from Aspergillus amoenus NRRL 35600

A new prenylated alkaloid, Amoenamide A (6), was isolated from the fungus Aspergillus amoenus NRRL 35600. Previously, 6 was postulated to be a precursor of Notoamide E4 (21) converted from Notoamide E (16), which was a key precursor of the prenylated indole alkaloids in the fungi of the genus Aspergillus. We previously succeeded in the isolation of two pairs of antipodes, Stephacidin A (1) and Notoamide B (2), from A. amoenus and A. protuberus MF297-2 and expected the presence of other antipodes in the culture of A. amoenus. We here report five new antipodes (7–11) along with a new metabolite (12), which was isolated as a natural compound for the first time, from A. amoenus.     

Enzymatic resolution of (±)-2-(Nβ-t-butoxycarbonyl-Nα-methylhydrazino)cycloalkanols

Racemates of cis- and trans-2-(N_β-t-butoxycarbonyl-N_α-methylhydrazino)cyclopentanols and -cyclohexanols 1–4 were resolved through lipase PS- or Novozym 435-catalysed asymmetric acylation of the secondary OH group at the (R)-stereogenic centre. High enantioselectivity (E >200) was observed when vinyl acetate or vinyl butyrate was used in diisopropyl ether, resulting in the enantiopure hydrazino esters 1a–4a and hydrazino alcohols 1b–4b. Methanolysis of the esters 1a–4a afforded the corresponding 2-hydrazinocycloalkanols 1c–4c (ee usually >95%).     

Synthesis of amino sugars via isoxazolines DL- and D-lividosamine (2-amino-2,3-dideoxy-ribo-hexose) derivatives from 4-vinyl-1,3-dioxolanes and nitroacetaldehyde acetals

1,3-Dipolar cycloaddition of nitrile oxides, generated from nitroethanol and nitroacetaldehyde derivatives 3, 21 and 22, respectively, and of benzonitrile oxide to 4-vinyldioxolanes 1, 2 gave ca 4:1 erythro/threo mixtures of corresponding isoxazolines. LAH reduction of erytho isoxazolines proceeded with similar (ca 4:1) selectivity to furnish protected ribo-amino-polyols 11, 15,19, DL- and D-lividosamines 31 and 33, respectively, as main products. The DL-lividosamine derivative 33 was obtained pure by crystallization. In the D-series, the corresponding ribo/arabino mixture D-31/D-32 was transformed to the known α-methyl D-lividosaminide D-37.     

Highly stereoselective synthesis of C2-chiral and meso nitroxides from an optically active pyrrolidine

Starting from (2R,5R)-2,5-bis(methoxymethyl)pyrrolidine 1, hydroxylamine cis-3 was synthesized with high stereoselectivity by successive oxidation and addition of PhMgBr. By using PhLi, trans (C₂-chiral) pyrrolidine nitroxide trans-7 was obtained from nitrone 5 derived from hydroxylamine 3. The cis (meso) counterpart cis-7 was produced along with trans-7 when PhMgBr was employed in place of PhLi. Moreover, cis-7 was also obtained selectively by using PhLi and Et₂AlCl with nitrone 5. The change of stereochemical bias observed when EtMgBr and/or nitrone 10 bearing an ethyl group were employed is also discussed.     

Chromatographic enantioseparation of racemic α-(1-naphthyl)ethylammonium perchlorate by a Merrifield resin-bound enantiomerically pure chiral dimethylpyridino-18-crown-6 ligand

Three novel chiral pyridino-18-crown-6 ligands (S,S)-1, (S,S)-2 and (S,S)-3 were prepared and (S,S)-1 was attached to a Merrifield resin. The resulting adsorbent (S,S)-5 was used as a chiral stationary phase in the chromatographic enantioseparation of racemic α-(1-naphthyl)ethylammonium perchlorate. Also, a new chiral pyridono-18-crown-6 ligand (S,S)-6, used for the synthesis of (S,S)-1 and (S,S)-2, was prepared in two different ways.     

Lipase mediated resolution of 1,3-butanediol derivatives: chiral building blocks for pheromone enantiosynthesis. Part 3

(R,S)-1,3-Butanediol 5 was kinetically resolved by enzymatic acetylation with vinyl acetate under the presence of Chirazyme™ L-2, c–f, yielding (S)-1-O-acetyl-1,3-hydroxybutane 6 and (R)-1,3-di-O-acetyl-1,3-butanediol 7 with enantiomeric excesses of 91% (E=67.3). Compounds 6 and 7 were easily transformed into the corresponding (S)-3-O-(2-methoxyethoxymethyl)-3-hydroxybutanal 10 and (R)-3-benzyloxybutanal 19, through a protection–deprotection and functional group interchange methodology. Subsequent reaction of 10 and 19 with 3-(methoxycarbonylpropionylmethylene)triphenylphosphorane afforded methyl (E,S)-8-O-(2-methoxyethoxymethyl)-4-oxo-5-nonenoate 12 and (E,R)-8-benzyloxy-4-oxo-5-nonenoate 20. The alkenes 19 and 20 were then catalytically hydrogenated to the corresponding saturated esters 13 and 21. Treatment of 13 and 21 with 1,2-ethanedithiol/F₃B·OEt₂ afforded dithioketals 14 and 22, which were respectively reduced to (S)-1,8-dihydroxy-4-nonanone ethylidenedithioketal 15 and (R)-8-O-benzyl-1,8-dihydroxy-4-nonanone ethylidenedithioketal 23. Finally, deprotection of 15 by catalytic hydrogenation under acidic conditions gave the expected (5S,7S)-(−)-7-methyl-1,6-dioxaspiro[4.5]decane 1. The (5R,7R)-(+)-1 enantiomer was analogously prepared from 23. Both compounds were formed by this procedure with an e.e. of 91%.     

(E)-Selective hydrolysis of (E,Z)-α,β-unsaturated nitriles by the recombinant nitrilase AtNIT1 from Arabidopsis thaliana

From stereoisomeric α,β-unsaturated nitriles (E,Z)-1, the recombinant nitrilase AtNIT1 from Arabidopsis thaliana hydrolyses the (E)-isomers exclusively to the corresponding (E)-carboxylic acids (E)-2 with high specificity. The (E)-selectivity can also be utilised for the preparation of the isomerically pure nitriles (Z)-1. From (E,Z)-2-hydroxycinnamonitrile (E,Z)-3, the otherwise difficult obtainable (Z)-3 was prepared in 66% isolated yield. With β,γ-unsaturated (E,Z)-3-heptenenitrile (E,Z)-4, however, (E)-selectivity was not observed. AtNIT1 exhibits not only diastereoselectivity but also regioselectivity. From a mixture of the four isomers A–D of 3-(2-cyanocyclohex-3-enyl)propenenitrile 6, exclusively isomer D ((E)-cis-6) was hydrolysed to 3-(2-cyanocyclohex-3-enyl)propenoic acid (E)-cis-7, as stated by X-ray crystal structure. Only after complete conversion of D and high enzyme concentrations, isomer C ((E)-trans-6) was hydrolysed to a small extent.     

Double asymmetric induction in 1,3-dipolar cycloaddition of five-membered cyclic nitrones to 2-(5H)-furanones

The 1,3-dipolar cycloaddition of nitrones 1–4 and their enantiomers 2ent–4ent to α,β-unsaturated γ-lactones, such as achiral 9 and d-glycero 10 provides an interesting example of a double asymmetric induction. The reactions are kinetically controlled. Upon heating and prolonged reaction time, however, the reversibility of the cycloaddition was observed and the presence of more stable thermodynamic products detected. Moreover, in the case of lactone 10, a partial racemization did occur and consequently adducts derived from 10ent were formed. Contrary to the corresponding additions involving δ-lactones, where only the exo approach of the reactants was observed, γ-lactones added nitrones in both exo and endo modes. The high preference of an anti addition to the terminal hydroxymethyl group in lactone 10 and to the 3-tert-butoxy group of the nitrone was observed; the 4-tert-butoxy substituent plays a secondary role. The endo addition of the reactants is energetically more demanding than the exo addition and occurs if none of the substituents present in the lactone or nitrone hinders such an approach. Due to the complex steric interactions a single product was formed in two cases only, 2ent/10 and 3/10. In one case, 3/9, a high preponderance of a single adduct was observed.     

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%.     

Resolution of 1-phenyl-2-(p-tolyl)ethylamine via diastereomeric salt formation

(S)-1-Phenyl-2-(p-tolyl)ethylamine (S)-1, used for the industrial scale resolution of chrysanthemic acids, was obtained via resolution of the racemate with the hemiphthalate of (S)-isopropylidene glycerol (R)-2. The maximum experimental efficiency [69% yield and >99% e.e. of (S)-1] was achieved by a simple precipitation of (S)-1·(R)-2 from the solution of the 1:1 diastereomeric salt mixture in 93/7 isopropanol/water at saturation of the more soluble (R)-1·(R)-2 salt. Such an experimental efficiency was consistent with 0.79 maximum theoretical resolvability, derived from the solubilities of the two diastereomeric salts, and with DSC data, which indicated that the (S)-1·(R)-2/(R)-1·(R)-2 system is a binary mixture exhibiting an eutectic with composition approximately corresponding to a 0.2 molar ratio of (S)-1·(R)-2.