Carbocyclic nucleosides from enantiomeric, α-pinane-based aminodiols

Starting from (1R,2S,3S,5R)- and (1S,2R,3R,5S)-6,6-dimethylspiro[bicyclo[3.1.1]heptane-2,2’-oxiran]-3-ol (?)-8 and (+)-8, two comparative syntheses were developed for pinane-based chiral carbocyclic nucleosides. The regioselective ring opening of the spiro-oxirane ring of (?)-8 and (+)-8 with NaN₃ resulted in azidodiols (?)-9 and (+)-9. Catalytic reduction of (?)-9 and (+)-9 furnished chiral aminodiols (?)-10 and (+)-10, which were transformed by linear synthesis to purine-type nucleosides 16–18 through pyrimidine intermediates. Regioselective ring opening of the oxirane ring of (?)-8 and (+)-8 resulted in adenine-, cytosine- and uracil-based carbocyclic nucleosides 19–21 in a single-step synthesis.     

Traceless chirality transfer from a norbornene β-amino acid to pyrimido[2,1-a]isoindole enantiomers

The synthesis of two enantiomeric pairs of pyrimidoisoindoles 9a, 9b and 10a, 10b is reported. During a domino ring-closure reaction, followed by cycloreversion, the chirality of diendo-(?)-(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide [(?)-1] was successfully transfered to heterocycles (+)-9a, (+)-10a, (?)-9b, (?)-10b and (?)-10c.     

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.     

Synthesis of mono- and dihydroxy-substituted 2-aminocyclooctanecarboxylic acid enantiomers

(1R,2S,6R)-2-Amino-6-hydroxycyclooctanecarboxylic acid (?)-10 was synthesized from (1R,2S)-2-aminocyclooct-5-enecarboxylic acid (+)-2 via an iodolactone intermediate, while (1R,2S,3R,4S)-2-amino-5,6-dihydroxycyclooctanecarboxylic acid (?)-12 was prepared by using the OsO₄-catalyzed oxidation of Boc-protected amino ester (?)-5. The stereochemistry and relative configurations of the synthesized compounds were determined by 1D and 2D NMR spectroscopy (based on 2D NOE cross-peaks and ³J(H,H) coupling constants) and X-ray crystallography.     

Stereoselective synthesis of pinane-based β- and γ-amino acids via conjugate addition of lithium amides and nitromethane

Michael addition of dibenzylamine to (?)- and (+)-tert-butyl myrtenate, (?)-2 and (+)-2, derived from (?)- and (+)-myrtenal, furnished monoterpene-based β-amino acid derivatives in highly stereospecific reactions. The resultant amino esters (?)-3 and (+)-3 were transformed to unsubstituted, mono- and disubstituted and Fmoc-protected amino acids (?)-6-11 and (+)-6-11, which are promising building blocks for the synthesis of β-peptides and 1,3-heterocycles. The microwave-assisted conjugate addition of nitromethane to α,β-unsaturated esters (?)-12 and (+)-12 likewise resulted in nitro esters (?)-13 and (+)-13 in highly stereospecific reactions. Compounds (?)-13 and (+)-13 were successfully transformed into γ-amino acids (?)-16 and (+)-16 in two steps.     

Biocatalytic oxidation of thiophosphoryl compounds: a new chemo-enzymatic approach to enantiomeric insecticidal thionophosphates and their oxons

The biocatalytic oxidation of racemic O-S-dimethyl O-p-nitrophenyl phosphorodithioate 5 catalyzed by chloroperoxidase from Caldariomyces fumago resulted in the formation of the (?)-(S)-enantiomer of the corresponding oxon 4 and unoxidized substrate 5 with a (+)-(R)-configuration. Both compounds were obtained with very high enantiomeric excesses, 99.6% and 97%, respectively. The thionation reaction of the resulting (?)-(S)-oxon 4 with Lawesson’s reagent gave (?)-(S)-phosphorodithioate 5 with full stereoselectivity, while the oxidation of unreacted substrate (+)-(R)-5 with iodoxybenzene afforded oxon (+)-(R)-4 with 94.9% ee.     

Resolution,absolute configuration and antifilarial activity of coumarinyl amino alcohols

The resolution of racemic coumarinyl amino alcohols 5–10 was achieved by using the inexpensive and readily accessible chiral resolving agent N-carbethoxy-l-proline (S)-11. Direct esterification of rac-5–10 with (S)-11 furnished diastereomeric esters, which were easily separated by column chromatography. The obtained diastereomers yielded the desired enantiopure coumarinyl amino alcohols (S)-(+)-5–10 and (R)-(?)-5–10 in good yields with high enantiomeric excess on saponification. The absolute configurations were determined by X-ray crystal analysis and/or by comparison of the specific rotations. Furthermore, in in vitro antifilarial motility inhibition assays, enantiopure coumarins (S)-(+)-9, (R)-(?)-9 and (S)-(+)-10, (R)-(?)-10 were found to be less efficient in affecting the viability of macrofilariae of Brugia malayi than their racemic forms 9 and 10, respectively, indicating the synergistic effect of the enantiomers in evoking antifilarial action.     

Preparation of chiral trans-5-substituted-acenaphthene-1,2-diols by baker’s yeast-mediated reduction of 5-substituted-acenaphthylene-1,2-diones

A series of trans-5-substituted-acenaphthene-1,2-diols were obtained in 21–72% yield with 97–100% ee by baker’s yeast-mediated reduction of the corresponding acenaphthylene-1,2-diones, in the presence of DMSO as a co-solvent and under vigorous agitation. The absolute configuration of (?)-trans-5-methoxy-acenaphthene-1,2-diol trans-3b and (?)-trans-5-bromo-acenaphthene-1,2-diol trans-3c was assigned as (S,S) and (?)-trans-5-thiomorpholin-acenaphthene-1,2-diol trans-3d was established as (R,R) by exciton-coupled circular dichroism.     

Asymmetric synthesis of (S)-(−)-tetrahydropalmatine and (S)-(−)-canadine via a sulfinyl-directed Pictet–Spengler cyclization

(S)-(?)-Tetrahydropalmatine 2 and (S)-(?)-canadine 4 were synthesized in three steps from (S)-6, in 33% and 34% overall yield, respectively. Thus, condensation of the (S)-(E)-sulfinylimines 10 and 11 with the carbanion derived from (S)-6 gave the tetrahydroisoquinolines 12 and 13, respectively, which upon TFA induced N-desulfinylation, and subsequent microwave assisted Pictet–Spengler cyclization effected both cyclization and C-desulfinylation producing (S)-(?)-tetrahydropalmatine 2 and (S)-(?)-canadine 4 in optically pure form.     

Enantioselective sorption of some chiral carboxylic acids by various cyclodextrin-grafted iron oxide magnetic nanoparticles

A new enantioselective sorption approach to chiral carboxylic acid molecules such as (R)-(?)-N-(3,5-dinitrobenzoyl)phenylglycine (R)-(?)DNBPG, (S)-(+)-N-(3,5-dinitrobenzoyl)phenylglycine (S)-(+)DNBPG, (R)-(+)-N-(1-phenylethyl)phthalamic acid (R)-(+)PEPA and (S)-(?)-N-(1-phenylethyl)phthalamic acid (S)-(?)PEPA regarding their complexation with three diversely functionalized β-cyclodextrin grafted iron oxide nanoparticles in the aqueous phase, was developed. The sorption efficiencies of these carboxylic acids were carried out by high-performance liquid chromatography (HPLC) with an Ace 5 C18 column. The effects of temperatures on the sorption were also investigated. The results showed that the ether functionalized derivative of β-cyclodextrin Al-CD-MNPs has a specific affinity for (R)-(?)DNBPG at 30 °C and pH 7.0. The amine functionalized derivative of β-cyclodextrin Am-CD-MNPs has a greater affinity towards not only (S)-(?)DNBPG, but also (R)-(+)PEPA compared with their other isomers, which are the (R)-isomer of DNBPG and the (S)-isomer of PEPA at 30 °C and pH 7.0. In addition, although amide functionalized derivatives of β-cyclodextrin (Amd-CD-MNPs) have an affinity towards both isomers of some chiral carboxylic acids; no selective affinity was observed at 30 °C and pH 7.0.     

A novel convergent synthesis of the potent antiglaucoma agent travoprost

The 16-(3-trifluoromethyl)phenoxy PGF_2α analogue travoprost (8a) has potent topical ocular activity. A novel convergent synthesis of 13,14-en-15-ol PGF_2α analogues was developed employing Julia–Lythgoe olefination of the structurally advanced prostaglandin phenylsulfone (5Z)-(+)-15 with a new enantiomerically pure aldehyde ω-chain synthon (S)-(?)-16a. Subsequent hydrolysis of protecting groups and final esterification of fluprostenol (7a) yielded travoprost (8a). The main advantages are the preparation of high purity travoprost (8a) and the application of comparatively cheap reagents. The novel convergent strategy allows the synthesis of a whole series of 13,14-en-15-ol PGF_2α analogues from a common and structurally advanced prostaglandin intermediate 15. The preparation and identification of two synthetic impurities, 15-epi isomer (8b) of travoprost and a new prostaglandin related ester (5Z)-(+)-18, are also described.     

Synthesis of the enantiomers of (3Z,9Z)-cis-6,7-epoxy-3,9-octadecadiene,one of the major components of the sex pheromone of Ectropis oblique Prout

Both enantiomers of (3Z,9Z)-cis-6,7-epoxy-3,9-octadecadiene, one of which is the major component of the sex pheromone of Ectropis oblique Prout, were synthesized in 23% overall yield for the (?)-(6S,7R)-enantiomer and 18% yield for the (+)-(6R,7S)-isomer. This protocol uses a sequential regioselective ring-opening strategy and provides a convenient and reliable access to other structurally related insect sex pheromones. Preliminary biological studies revealed that (?)-(6S,7R)-2a was roughly as active as the natural pheromone, while racemic (±)-2 was less bioactive and (+)-2b was much less bioactive.     

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.     

Novel asymmetric total syntheses of (R)-(−)-pyridindolol, (R)-(−)-pyridindolol K1, and (R)-(−)-pyridindolol K2 via a mild one-pot aromatization of N-tosyl-tetrahydro-β-carboline with (S)-2,3-O-isopropylidene-l-glyceraldehyde as the source of chirality

Novel total syntheses of (R)-(?)-pyridindolol 1, (R)-(?)-pyridindolol K1 2, and (R)-(?)-pyridindolol K2 3 are described. By using l-tryptophan methyl ester and (S)-2,3-O-isopropylidene-l-glyceraldehyde as the starting materials, (R)-(?)-pyridindolol 1, (R)-(?)-pyridindolol K1 2, and (R)-(?)-pyridindolol K2 3 were synthesized in 5–7 steps in 66%, 41%, and 55% overall yields, respectively. The characteristic step of the total syntheses is a mild one-pot aromatization of N-tosyl-1,2,3,4-tetrahydro-β-carboline (N-Ts-THBC), which was obtained via Pictet–Spengler reaction of l-tryptophan methyl ester with (S)-2,3-O-isopropylidene-l-glyceraldehyde, and subsequent N-tosylation.     

An unexpected high erythro-selection in the Grignard reaction with an N,O-acetal: a concise asymmetric synthesis of indolizidine alkaloid (−)-2-epi-lentiginosine

Starting from commercially available lactone 10, a concise and highly diastereoselective synthesis of (?)-(lS,2R,8aS)-2-epi-lentiginosine (2) is described. The synthesis featured an unexpected highly erythro-selective reaction of Grignard reagent 7 with the protected N,O-acetal 8. The stereochemical outcome of this reaction is contrary to the known results involving the reactions with O-benzyl protected aminofuranosides and aminoglycosides. Thus, this method constitutes an extension of the threo-diastereoselective C–C bond formation methodology.     

Enzyme-catalysed approach to the preparation of triazole antifungals: synthesis of (−)-genaconazole

The work describes a new enzyme-mediated approach to optically active epoxide (2R,3S)-6, which is an important key intermediate in the preparation of single enantiomers of chiral azole antifungals. The conversion of (2R,3S)-6 into (?)-genaconazole is reported as an example of its synthetic relevance.     

Natural product synthesis from (8aR)- and (8aS)-bicyclofarnesols: synthesis of (+)-wiedendiol A, (+)-norsesterterpene diene ester and (−)-subersic acid

Both enantiomers (8aR)-7 and (8aS)-7 of bicyclofarnesol were synthesized from the enzymatic resolution products (1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-5 (98% ee) and acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aS)-6 (>99% ee), respectively. The formal synthesis of (+)-wiedendiol 1 was achieved via a coupling reaction of an ate complex derived from 1,2,4-trimethoxybenzene with allyl bromide (8aS)-8 derived from (8aS)-7. The total synthesis of (+)-norsesterterpene diene ester 2 was achieved, based on the synthesis of (13E,10S)-α,β-unsaturated aldehyde 12, derived from (8aS)-7, followed by the selective construction of the (3E,5E)-diene moiety including a C(2)-stereogenic centre in (+)-2. The total synthesis of (−)-subersic acid 3 was carried out based on a Stille coupling between allyl trifluoroacetate congener 25c, derived from (8aR)-7, corresponding to the diterpene part, and aryl stannane congener 26 in the presence of Pd catalyst and CuI as an additive.     

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.     

Chemoenzymatic total synthesis of cryptocaryalactone natural products

A new chemoenzymatic route for the preparation of cryptocaryalactones natural products using a kinetic resolution process as the key step is described. Novozyme-435 catalyzed hydrolysis of the prochiral (±)-monoester 7 afforded the precursors of cryptocaryalactones with high enantiomeric excess and excellent yields. The compounds (4S,6S)-7 and (4R,6R)-7 were converted to (+)-(6R,2′S)-cryptocaryalactone (1) and (?)-(6S,2′R)-cryptocaryalactone (2), respectively by employing Wittig-olefination, lactonization and acylation reactions.     

Constrained cycloalkyl analogues of glutamic acid: stereocontrolled synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) and its 6-phosphonic acid analogue

A new stereocontrolled synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2.6-dicarboxylic acid (LY354740) 1, a potent and selective 2mGluR agonist, has been accomplished in four steps with an overall yield of 27% starting from the enantiopure (+)-(R)-2-(p-tolylsulfinyl)cyclopent-2-enone 3. The key steps include asymmetric cyclopropanation of 3 with (dimethylsulfuranylidene)acetate (EDSA) and removal of the chiral p-tolylsulfinyl auxiliary from the cycloadduct ent-4c upon treatment with iso-propylmagnesium chloride. The stereoselective hydantoin formation from the bicyclic ketone 6 formed (Bucherer–Bergs reaction) and subsequent hydrolysis completed the synthesis of 1. The same reaction sequence has been applied in the first synthesis of enantiopure (+)-2-amino-6-phosphonobicyclo[3.0.1]hexane-2-carboxylic acid 2, a structural 6-phosphono analogue of 1. The starting bicyclic ketophosphonates 9–11 have been obtained by asymmetric cyclopropanation of (?)-(S)-3 with phosphoryl sulfonium ylides, producing only two endo-isomers. The major endo-isomer (+)-11a containing the 6-diisopropoxyphosphoryl group has been converted in three steps into (+)-endo-2 in 46% overall yield.