Efficient and stereoselective synthesis of threo-β-hydroxy-l-glutamic acid via a tandem (Z)-olefination-conjugate addition

threo-β-Hydroxy-l-glutamic acid 1 is an attractive target as a biologically active compound and as a chiral synthon. The required β-hydroxyl group in 1 was efficiently and stereoselectively introduced via an intramolecular conjugate addition of the N-hydroxymethyl group of γ-amino-α,β-unsaturated (Z)-ester 4. While the corresponding (E)-ester 3 gave a lower selectivity of ca. 5:1 in the intramolecular conjugate addition, a selectivity of up to 70:1 was shown with (Z)-ester 4. The tandem (Z)-olefination-conjugate addition could be achieved by simply changing the reaction conditions to give a selectivity of >20:1. Thus, the target compound 1 was obtained as its hydrochloride salt in 70% overall yield over four steps from lactol 2.     

Emericelactones A-D: Four novel polyketides produced by Emericella sp. XL 029, a fungus associated the leaves of Panax notoginseng

The application of an OSMAC approach on an endophytic fungus Emericella sp. XL 029 has yielded four novel polyketides, emericelactones A-D (1–4).The structures and stereochemistry of 1–4 were elucidated by NMR and MS data analyses, computational methods, as well as by comparison with known compounds. Compound 1 contained an unprecedented linear pentaene substructure ending in an oxabicyclo[2.2.1]heptane moiety, while compounds 2–4 are epimers possessing an unprecedented linear triene structures ending in two cyclic moieties of an oxabicyclo[2.2.1]heptane and a cyclopentan-1-one. Compounds 1–4 showed moderate antimicrobial activities against three agricultural pathogenic fungi (Verticillium dahliae Kleb, Rhizoctonia solani and Gibberella saubinetii) and two human pathogenic bacteria (Micrococcus lysodeikticus and Salmonella typhi) with MIC values of 25–50?μg/mL.     

An efficient enzyme-catalyzed kinetic resolution: large-scale preparation of an enantiomerically pure indole-ethyl ester derivative,a key component for the synthesis of a prostaglandin D2 receptor antagonist,an anti-allergic rhinitis drug candidate

Three racemic esters including indole-ethyl ester 1 as well as its related derivatives 3 and 4 in Scheme 1, all synthetic intermediates for the preparation of chiral compound 5, were used as substrates to evaluate the catalytic potentials of a panel of commercial enzymes for asymmetric hydrolysis. After an extensive evaluation of the conversion rates (C), enantiomeric excesses (ee) and enantioselectivity determination (E), lipase from Pseudomonas fluorescens was identified. This lipase catalyzed the asymmetric hydrolysis of racemic indole-ethyl ester 1 affording the desired enantiomerically pure intermediate 1 with 97% ee and an E value of 425. Indole-ethyl ester 1, with the following attributes: being early in the synthetic scheme, showing resistance to racemization in the later chemical reactions as well as the possibility of the recycling of the unwanted enantiomer, was therefore selected for optimization and establishment of an enzyme-catalyzed reaction for the industrial-scale synthesis of the compound 5, a drug candidate for the treatment of allergic rhinitis.     

Salvihispin A and its glycoside,two neo-clerodane diterpenoids with neurotrophic activities from Salvia hispanica L.

A neo-clerodane diterpenoid, salvihispin A (1), as well as its glycoside, salvihispin A-2-O-β-d-3-keto-glucopyranoside (2) were isolated from the aerial parts of Salvia hispanica. Compound 2 possessed an unusual 3-keto-glucopyranoside moiety. Their structures and absolute configurations were elucidated by extensive spectroscopic methods and confirmed by single crystal X-ray diffraction. Salvihispin A (1) and its glycoside (2) enhanced the neurite outgrowth of NGF-mediated PC12 cells at a concentration of 10?μM.     

Efficient oxidative resolution of a P-stereogenic triarylphosphine and asymmetric synthesis of a P-stereogenic atropoisomeric biphenyl diphosphine dioxide

Racemic 3-methoxyphenyl(1-naphthyl)phenylphosphine 1 was effectively resolved via an oxidative resolution procedure utilizing l-menthyl bromoacetate as the resolving agent to give enantiopure 3-methoxyphenyl(1-naphthyl)phenylphosphine oxide (R)-2 in 41% yield. Reduction of the resolved (R)-4 with HSiCl₃/NEt₃ provided the corresponding phosphine (R)-1 in >97% ee. Ortho-iodination of the enantiopure (R)-4 followed by Ullmann coupling of the resulting iodoarylphosphine oxide gave a P-stereogenic and atropoisomeric biphenyl diphosphine dioxide as a single diastereoisomer. The latter transformation constitutes the first example of an effective transfer of a P-centered chirality to an axial chirality of the atropoisomeric biaryl system. The absolute configurations of the resolved phosphine and the atropoisomeric biaryl system have also been established.     

Dielectrically controlled resolution (DCR) of 3-aminopiperidine via diastereomeric salt formation with N-tosyl-(S)-phenylalanine

A useful key intermediate for the dipeptidyl peptidase-4 (DPP-4) inhibitor, 3-aminopiperidine 1, was successfully resolved with an enantiomerically pure resolving agent, N-tosyl-(S)-phenylalanine 2, to give both stereoisomers (R)-1 and (S)-1 as a less-soluble diastereomeric salt with (S)-2, via a dielectrically controlled resolution (DCR) phenomenon.     

Carbon-carbon double bond in pillar[5]arene cavity: Selective binding of cis/trans-olefin isomers

The binding behavior of pillar[5]arenes (P5As) towards a series of olefin guests ((E)-1,4-dichlorobut-2-ene (1E), (Z)-1,4-dichlorobut-2-ene (1Z), (E)-but-2-ene-1,4-diol (2E), and (Z)-but-2-ene-1,4-diol (2Z), as well as an alkyne derivative 1,4-dichlorobut-2-yne (3)) have been studied in organic solution. P5As exhibit considerable selectivities for the trans-olefin isomers (1E and 2E) over their cis-isomers (1Z and 2Z). The cis/trans-selective interactions hold the potential of utilizing P5As to separate olefin isomers.     

Enantiospecific synthesis of a glycoside of d-epi-purpurosamine

2-Propyl d-epi-purpurosaminide dihydrochloride 14 and its di-N-acetylated derivative 15 were synthesized by an enantiospecific sequence which involves the 2-propyl 6-O-acetyl-3,4-dideoxy-α-d-erythro-hex-3-enopyranosid-2-ulose 2 as the key precursor. The first approach through the saturated diol 4, prepared by reduction of the enone system of 2, was unsuccessful as the C-2 position of 2,6-di-O-sulfonyl derivatives 5 and 6 resisted substitution by azide. Therefore, an alternative sequence starting from the allylic alcohol 3, also derived from 2, was developed. In this case, the 2,6-di-O-tosyl derivative 9 gave the expected 2,6-diazide 10 with additional unwanted rearrangement of the double bond to the 2-propyl 4,6-diazido-2,3,4,6-tetradeoxy-α-d-threo-hex-2-enopyranoside 11 isomer. However, the ditriflate derivative 13, analogous to 9, underwent substitution to afford the diazide 10 in good yield. Upon reduction of the azide functions and saturation of the double bond of 10 by catalytic hydrogenation under acidic conditions, the dihydrochloride salt 14 was obtained as a crystalline product (43% overall yield from 3).     

Rearrangement in the reaction of oxindole with o-nitrobenzyl chloride

The alkylation of oxindole with o-nitrobenzyl chloride produces three products, 5a, 6, and 10. The N-hydroxyindoloquinolone 5a probably arises by rearrangement of an initial alkylation product as shown in Scheme 1. The indoloquinolone 6 is formed by base-catalyzed elimination of o-nitrobenzaldehyde from the dialkylation product 10 and also apparently by a thermal process most simply considered as a 1,5-sigmatropic rearrangement of 10 → 12.     

Resolution of racemic cis-1-amino-2-indanol by diastereomeric salt formation with (S)-2-phenylpropionic acid

Resolution of racemic cis-1-amino-2-indanol 1, a key intermediate for the synthesis of indinavir, is reported. The conditions were optimized for an industrial-scale resolution of racemic cis-1 using (S)-2-phenylpropionic acid 6 as the resolving agent and ethanol as the solvent. The less-soluble diastereomeric salt, (1R,2S)-1·(S)-6, was obtained in 35% yield with 99% de (E >69%) by crystallization. Resolving agent 6 was efficiently recovered from the salt and the mother liquor.     

Meroterpenoids with diverse ring systems and dioxolanone-type secondary metabolites from Phyllosticta capitalensis and their phytotoxic activity

Twenty meroterpenoids with diverse ring systems including five new ones (1, 2, 5, 6, and 15), together with two new (23 and 24) and two known dioxolanone-type secondary metabolites were isolated from Phyllosticta capitalensis, an endophytic fungus from Cephalotaxus fortunei Hook. Compound 1 was the first example with a 9,14-seco ring A and a five-membered ring B in guignardone derivatives. Compound 2 represented a novel guignardone derivative possessing a 5/7/6/5 ring system with CH₂-7 attached to C-4 rather than C-6 in ring D. The structures of all new compounds were elucidated using spectroscopic data analyses and electronic circular dichroism comparison. The phytotoxic effects of compounds 1–24 on Lactuca sativa and Lolium perenne were evaluated. Compound 22 showed inhibition activity on the shoots growth of L. sativa and L. perenne, as well as the roots growth of L. perenne.     

Beobachtungen zum mechanismus der nenitzescu-reaktion—II

The pyrrolo-indoles 9, 10 and 12 have been isolated as by-products. The structure of carbinolamine 13, a potential precurser of pyrrolo [2,3-f] indoles, was examined by chemical and spectroscopic methods. Under Nenitzescu-conditions 13 could not be reduced to the pyrroloindole 11, but the furano-indolenin 16 was isolated. The origin of the pyrrolo [3,2-e] indole 12 from carbinolamin 17 was proved by a corresponding reaction. The course of the reaction via the ring-opening of the indole 19 can be excluded and thus a direct ring-closure of F is made probable. Attempts to reduct 17 show that the carbinolamine can not be considered as a precursor of hydroxyindoles in an apolar, aprotic medium. Thus a reaction corresponding to an oxidation-reduction mechanism is not possible under these conditions. The experiments indicate that another mechanism, namely the direct cyclisation of H in this case leads to indole formation.     

Biogenetically related caged ent-kaurane diterpenoids from Isodon eriocalyx var. laxiflora

Two novel caged ent-kauranoids, neolaxiflorins D (1) and E (2), along with three other new ent-kauranoids, neolaxiflorins F–H (3–5), and a known one, eriocalyxin B (6), were obtained from Isodon eriocalyx var. laxiflora. Neolaxiflorin D (1) is the first 15,16-seco-16,17-dinor-ent-kaurane diterpenoid, and neolaxiflorin E (2) is the first 15,16-seco-17-homo-ent-kauranoid. The absolute configurations of ent-kauranoids 1 and 2 were determined by single-crystal X-ray diffraction analyses. Structural analysis of intermediate compounds 3–5 indicated that eriocalyxin B (6) is a biogenetic precursor of caged ent-kauranoids 1 and 2 as illustrated. The cytotoxic activity of the new compounds was evaluated by an MTT assay.     

Matched and mismatched pairings in B-secotaxane construction: a structure elucidation study

The synthesis of the basic B-seco taxoid skeleton was achieved through a C10–C11 coupling of the A-ring segment (14S)-1 with the C-ring segments (10S) and (10R)-α-alkoxyorganolithium reagents, prepared in situ from 2 and 6 through nBuLi mediated transmetallation. The matched reactions of (14S)-1 with (10S)-2 and (10S)-6 displays an outstanding diastereoselectivity providing 12 and 34, respectively, as single isomers and hence allowing a convenient entry to highly functionalized taxoid diterpene frameworks. Significant mismatching was observed with the (10R)-epimer of 2 and 6 yielding little, if any, diastereoselectivity. The structures of B-secotaxanes were assigned on the basis of spatial proximity effects in the proton NMR spectrum. Assignment of the C10/C11 stereochemistry was made possible through conversion of the B-secotaxoid frameworks, derived from the matched and mismatched adducts, to the corresponding cyclic acetals. Configurational stability of α-alkoxyorganolithium derivatives was verified in all the cases investigated. Structure elucidation of these adducts was essential for the successful C1–C2 bonding via an intramolecular aldol reaction, given the fact that adducts containing a β-MOM substituent at C10 would be disfavored for such an endeavor.     

Synthesis and evaluation of two mannosamine-derived lactone-type inhibitors of snail β-mannosidase

The inhibition of snail β-mannosidase by the manno-configured amino- and hydroxy-lactams and -imidazoles 7–10 was compared to the inhibition of the β-glucosidases from Caldocellum saccharolyticum and from sweet almonds by the gluco-configured amino- and hydroxy-lactams and -imidazoles 1, 2, 5 and 6 [ΔΔG_diss.(OH → NH₃⁺)]. Substitution in the gluco-configured 1, 3 and 5, of C(2)–OH by an ammonium group strengthens the interaction of the inhibitor with the catalytic nucleophile of retaining β-glucosidases, and weakens the interaction with the catalytic acid. The analogous substitution in the manno-configured inhibitors 7 and 9, leading to 8 and 10, respectively, was expected to only reflect the impaired interaction of the inhibitor with the catalytic acid, as the catalytic nucleophile and the C(2) substituent are located on opposite sides of the average ring plane.The mannonolactam 10 was synthesized from the known hydroxy-lactam 11 by O-mesylation followed by azidation and hydrogenation. Sultone 13 was formed as side product upon mesylation of 11. The imidazole 8 was obtained from 11, similarly to the synthesis of the known gluco-isomer 2, via the hydroxy-imidazoles 22 and 23; best results were obtained by protecting 11 as the triisopropylsilyl ether 29.The resulting inhibition by the imidazoles 7 and 8 was interpreted as reflecting an improved binding of the catalytic nucleophile of snail β-mannosidase with the protonated imidazole ring of 8 and an impaired interaction with the catalytic acid, while a comparison of the inhibition by the lactams 9 and 10 is in keeping with the results that are expected if there is no significant interaction between the catalytic nucleophile of snail β-mannosidase and the C(2)–OH group of β-mannosides. The amino-imidazole 8 is a surprisingly strong inhibitor of the α-mannosidase from Jack beans [K_i = 1.22 μM; mixed-type (α = 2.3)].     

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.     

Chemoenzymatic synthesis of (S)-2-cyanopiperidine,a key intermediate in the route to (S)-pipecolic acid and 2-substituted piperidine alkaloids

The preparation of (S)-2-cyanopiperidine 4 provides a new access to 2-substituted piperidines. This synthesis is based on an enantioselective (R)-oxynitrilase-catalyzed reaction for the preparation of (R)-(+)-6-bromo-2-hydroxyhexanenitrile 1 and the subsequent cyclization of this compound to yield the piperidine ring. The utilization of 4 as the starting material for the synthesis of (S)-2-aminomethylpiperidine 6, (R)-(−)-coniine 10 and (S)-(−)-pipecolic acid 13 is also described.     

Second-generation artificial hydrogenases based on the biotin–avidin technology: Improving selectivity and organic solvent tolerance by introduction of an (R)-proline spacer

We report on our efforts to create efficient artificial metalloenzymes for the enantioselective hydrogenation of N-protected dehydroamino acids using streptavidin as host protein. Introduction of an (R)-proline spacer between the biotin anchor and the diphosphine moiety affords a versatile ligand Biot-(R)-Pro-1 which displays good (S)-selectivities in the presence of streptavidin (91% ee). The resulting artificial metalloenzyme [Rh(Biot-(R)-Pro-1)(COD)]⁺ ⊂ WT-Sav displays increased stability against organic solvents.     

Panisuffrutin A,a highly degraded seco-triterpene derivative from Paeonia suffruticosa var. papaveracea (Andr.) Kerner

Panisuffrutin A (1), a highly degraded seco-triterpene derivative, together with the known palbinone, has been isolated from the whole plant Paeonia suffruticosa var. papaveracea (Andr.) Kerner. The structure with absolute configuration of 1 was determined via comprehensive NMR and MS analyses, as well as NMR and ECD calculations. A plausible biosynthetic pathway for 1 was proposed. Compound 1 showed weak cytotoxicity against Hela cancer cell line with an IC₅₀ value of 26.2 μM, while palbinone exhibited a moderate inhibition on NO production with an IC₅₀ of 18.3 μM.     

A pair of epimeric cassane-type diterpenoids and a new labdane-type derivative from Caesalpinia decapetala

Caesaldecins A and B (1a/1b), a pair of epimeric cassane-type diterpenoids containing an ether linkage between C-6 and C-20 and an α,β-butenolide ring in the northern hemisphere, were isolated from the leaves of the medicinal plant Caesalpinia decapetala (Roth) Alston, along with a new labdane-type diterpenoid, termed as 8(17),11(Z),13(E)-trien-15,18-dioic acid (2). Structures of 1 and 2 were established by extensive spectroscopic analyses, including HRESIMS, 1D and 2D NMR, and electronic circular dichroism (ECD) calculations. The in vitro antibacterial and inhibitory activities against a panel of bacteria and cancer cell lines were evaluated, respectively. Compound 2 displayed moderate antibacterial activity against the methicillin-resistant Staphylococcus aureus subsp. aureus (MRSA) with an MIC₅₀ value of 5.99?μg?mL^?1.