Asymmetric synthesis of triepoxyzerumbol

The achiral sesquiterpene zerumbone 1, which is readily available from wild ginger, has a unique functionality and reactivity making it a convenient starting material for its conversion into useful compounds, such as paclitaxel. Optically active triepoxyzerumbol (−)-3 and its acetate (+)-4 were synthesized by lipase-catalyzed enantioselective transesterification of racemic 3. Under optimized conditions, a lipase from Alcaligenes sp. (Meito QL) catalyzed the reaction of racemic 3 with isopropenyl acetate in THF at 35 °C to afford (1S)-3 and (1R)-4 with an E-value of 79. The absolute configuration of (1R)-4 was determined by single crystal X-ray diffraction of its ester with a chlorine atom using the anomalous dispersion effect.     

Stereoselective and versatile approach for the synthesis of gossyplure and its components

Efficient synthetic routes to gossyplure and its components (1a and 1b) were formulated. The three key units viz the alkynol 3, the bromide 5, and the alkanal 13 were derived from easily accessible starting materials. Alkylation of 3 with 5, and subsequent semihydrogenation followed by oxidation, provided the C₁₁-alkenal 8 which was subjected to a stereocontrolled Wittig reaction with a C₅-phosphonium salt, to yield directly the desired pheromone (1a + 1b). The synthesis of its individual components involved the manipulation via an acetylenic intermediate, viz the alkynol 14 which was obtained through alkylation of 3. A sequence of well-established reactions on 14, then provided the corresponding (E)- and (Z)-alkenylphosphonium salts which upon a (Z)-specific Wittig olefination with the C₇-aldehyde (13), led to the stereoselective synthesis of 1a and 1b.     

Deboronation-induced ratiometric emission sensing of fluoride by 1,3,5-tris-(o-carboranyl-methyl)benzene

1,3,5-Tris-(o-carboranyl-methyl)benzene (closo-1) and its nido-form (nido-1) were synthesized and fully characterized. The solid-state molecular structure of closo-1 was determined by single-crystal X-ray diffraction analysis. Compound closo-1 exhibited an intense single emission in various organic solvents that was red-shifted with increasing solvent polarity. The positive solvatochromic effect and theoretical calculation results at the first excited (S₁) optimized structure of closo-1 strongly suggest that this emissive band can be assigned to an intramolecular charge transfer. Meanwhile, nido-1 showed a pronounced red-shift of the emissive band compared to that of closo-1 and aroused low-energy emission. The specific emissive features of nido-1 were attributed to the elevation of its HOMO level, estimated by cyclic voltammetry. The photophysical changes by conversion from closo-1 to nido-1 allowed the emissive color-tunable sensing of fluoride. Thus, the tris-o-carboranyl compound showed great potential as a chemodosimeter for fluoride anion sensing, detectable by the naked-eye.     

Iridoids in equatorial and tropical flora—III : Isolation and partial synthesis of 6-epiaucubin a new glucosidic iridoid

The structure of a new glucosidic iridoid, 6-epiaucubin 1, isolated from leaves of a tropical tree, Tecoma chrysantha Jacq., was established by analysis of the spectroscopical data of 1 and its hexa-O-acetyl derivative 3. Partial synthesis of 1 from its epimer, aucubin 2, is also reported.     

A straightforward synthesis of both enantiomers of allo-norcoronamic acids and allo-coronamic acids,by asymmetric Strecker reaction from alkylcyclopropanone acetals

Methylcyclopropanone hemiacetal (2S)-3a underwent the asymmetric Strecker reaction induced by a chiral amine to provide a useful synthesis of enantiomerically pure (1R,2S)-(+)-allo-norcoronamic acid 1 in good yield and high enantiomeric excess. From racemic alkyl hemiacetal (±)-3, the same methodology also constituted a useful way to prepare both (+)-1 and (−)-1 and (+)-allo-coronamic acid 2 and its antipode (−)-2 with good yield and high enantiomeric excess.     

Characterization of two chimeric sesterterpene synthases from a fungal symbiont isolated from a sesterterpenoid-producing Lamiaceae plant Leucosceptrum canum

Two chimeric sesterterpene synthases (AaTPS1 and AaTPS2) were functionally characterized from Alternaria alternata MB-30 isolated from the leaves of a sesterterpenoid-producing Lamiaceae plant Leucosceptrum canum. AaTPS1 generated a 5/8/6/5 tetracyclic sesteraltererol (1) and its absolute stereochemistry was determined by X-ray crystallographic analysis of its derivative 10,11-epoxysesteraltererol (2), which enabled revision of the absolute configuration of C7 of sesterfisherol produced by NfSS and PTTS014 characterized previously and its derivative 10,11-epoxysesterfisherol. AaTPS2 produced a 5/15 bicyclic preterpestacin I (3). Site-directed mutagenesis suggested that F192 in AaTPS1 was likely involved in controlling of the hydroxylation of C12, and eight amino acids were important for the enzyme activity of AaTPS1 and AaTPS2. The engineered Escherichia coli and Saccharomyces cerevisiae strains were constructed for the productions of compounds 1 and 3, and the highest titer of compound 1 reached 62.3 mg/L in shake-flask culture. Both compounds 1 and 2 showed anti-adipogenic activity.     

Asymmetric hydrolysis of a meso-diester using pig liver esterase immobilised in hollow fibre ultrafiltration membrane

Pig liver esterase (PLE) was physically immobilised in a polysulphone ultrafiltration hollow fibre membrane reactor and used for the repetitive batch two-phase hydrolysis and separation, on a multigram scale, of the meso-diester dimethyl cis-cycloxex-4-ene-1,2-dicarboxylate 1 to enantiomerically pure (1S,2R)-cyclohex-4-ene-1,2-dicarboxylic acid monomethyl ester 2. After 25 days, the enzyme still retained its initial activity, which corresponds to 62% of its activity in the free form, and the enantiomeric purity of monoester 2 was still higher than 97%. Simple experimental conditions were established for the large laboratory scale preparation of substrate 1 and isolation of product 2 from the aqueous phase.     

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.     

Enantiopure isoplagiochin C by directed deracemization through axis-to-axis chirality transfer

Isoplagiochin C 1 was prepared for the first time in enantiopure form from synthetic racemic material, using a novel stereochemical concept. This macrocyclic bisbibenzyl contains two biaryl axes. Of these, axis A is configurationally stable by its fixation within the macrocyclic framework, while axis B is stereochemically unstable. By diesterification of rac-1 with enantiopure (P)-1,1′-binaphthyl-2,2′-dicarboxylic acid, axis B is locked in its P-configuration, thus allowing the resolution and separate saponification of dilactones (P_A,P_B,P)-3 and (M_A,P_B,P)-3 to give the pure enantiomers of 1. This concept permits recycling of any undesired enantiomer of 1 by thermal equilibration of the respective diastereomer of 3.     

Morusalbanol A,a neuro-protective Diels–Alder adduct with an unprecedented architecture from Morus alba

Morusalbanol A (1), a neuro-protective Diels–Alder adduct with a new carbon skeleton, was isolated from the bark of Morus alba. Compound 1 showed evidence of interesting astropisomerism, and resulted in the absence of a number of key proton and carbon signals in the NMR spectra. Its structure was thus elucidated by spectroscopic analysis of its peracetylated derivative (2) and its absolute configuration established as 1S,3S,4R,5S via experimental and calculated ECD spectra of 1. In a neuro-protective assay, morusalbanol A (1) significantly attenuated the H₂O₂-induced cell damage in a dose-dependent manner.     

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.     

Dopamine β-hydroxylase,a fascinating mammalian copper-containing monooxygenase: enzymatic and biomimetic studies of the O-atom transfer catalysis

This paper summarizes our recent studies on the mechanism of O-atom transfer to a benzylic C–H bond promoted by dopamine β-hydroxylase (DBH) and its biomimetic models. We demonstrate that it is possible to carry out parallel and comparative studies on enzyme (DBH) and its biomimetic models with the same substrate: 2-aminoindane (1). It was chosen because its two stereogenic centers, both in benzylic positions, make it very powerful for studying the stereochemistry of an O-atom transfer reaction. DBH-catalyzed hydroxylation of 1 exclusively produced 14 % of trans-(1S,2S)-2-amino-1-indanol 4a (93 % e.e.). Studies with stereospecifically deuterium labeled 2-aminoindanes (1R,2S)-2 and (1S,2S)-3 showed that the formation of 4a was the result of an overall process with retention of configuration where an O-atom is stereospecifically inserted in the trans pro-S position of the substrate. Addition of 1 and (±)2 to 2-vinylpyridine gave 2-X-IndPY2 ligands 5 and 6, which were transformed into copper(I) and (II) complexes {7}(PF₆) and {8}(CF₃SO₃), respectively. Reaction with dioxygen led to new complexes in which an O-atom transfer to a benzylic C–H bond has been performed in the same manner as that of DBH. With deuterium labeled cis-2-d-IndPY2 ligand 6, we demonstrated that the reaction occurs by a stereospecific process with retention of configuration. In both cases (enzymatic vs. biomimetic) the O-atom transfers occur in a two-step process involving radical intermediates.     

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.     

An enantiomerically pure bilirubin. Absolute configuration of (αR,α′R)-dimethylmesobilirubin-XIIIα

Enantiomerically pure (+)-(αR,α′R)-dimethylmesobilirubin-XIIIα 1 and its (αS,α′S) enantiomer ent-1 were synthesized in ten steps from simple precursors. Resolution was achieved at an early stage in the synthesis, with a racemic monopyrrole precursor rac-6 being converted to its amides 8 with (1S)-camphor-2,10-sultam. Resolution of 8 to 99% d.e. was accomplished in three crystallizations, and the absolute configuration of the acid 6 was deduced by X-ray crystallography of the more crystalline, diastereomerically pure amide 7. Circular dichroism spectroscopy of 1 showed intense bisignate Cotton effects: Δε^max₄₃₅=+344, Δε^max₃₉₁=−193 (CHCl₃), as expected for a molecular exciton, and consistent with a P-helical intramolecularly hydrogen-bonded ridge-tile conformation. The Cotton effect magnitudes of 1 match almost exactly those found for (−)-(βS,β′S)-dimethylmesobilirubin-XIIIα 11 and (+)-(αR,β′R)-dimethylmesobilirubin-XIIIα. However, the Cotton effect of the pseudo-meso diastereomer (αR,β′S)-dimethylmesobilirubin-XIIIα 12 is not zero. Its large positive exciton couplet and ¹H NMR NOE analysis confirm that an α-CH₃ exerts a greater steric demand than a β-CH₃—by a factor of ∼3.     

The first highly stereoselective approach to the mitotic kinesin Eg5 inhibitor HR22C16 and its analogues

A general method for the synthesis of the mitotic kinesin Eg5 inhibitor HR22C16 1 and its analogues based on protecting group (PG)-modulated highly diastereoselective Pictet–Spengler reaction of l-tryptophan methyl ester hydrochloride with meta-(RO)-benzaldehyde is described. By using the enantiomerically pure (1R,3S)-1,3-disubstituted tetrahydro-β-carboline trans-4c as a common chiral synthon, HR22C16 1 and its analogues 2 and 3 were synthesized in 90.1%, 90.2%, and 86.5% overall yields, respectively.     

Synthesis of nor-sesquiterpene spirolactones and their steroidal hybrids revisited. The neopentyl dilemma: misassignment of one stereocentre may necessitate a completely new approach

Inversion at the highly congested C1 position of 1-epi-pathylactone A (1-epi-1), or its corresponding steroidal hybrid 8a, using a diverse range of published procedures including microwave assisted Mitsunobu reaction or via oxidation to the corresponding ketone and subsequent reduction, was unsuccessful in our hands. Attempts to convert the C1 hydroxyl group into its corresponding chloride, en route to napalilactone 2a, also failed. Precursors with the C1α configuration installed at early stage proved not to be amenable to the targets under a broad range of conditions.     

The structures and ultraviolet spectra of the bromination products of 6,6-diphenylfulvene

Bromination of 6,6-diphenylfulvene 1 gives trans-trans-trans-1,2,3,4-tetrabromo-1,2,3,4-tetrahydro-6,6-diphenylfulvene 3 via trans-1,2-dibromo-1,2-dihydro-6,6-diphenylfulvene 2. Compound 3 in cyclohexane or carbon tetrachloride is converted by heating or exposure to sunlight to its trans-cis-trans stereoisomer 4. The structures of 3 and 4 have been established by X-ray crystallography. Compound 3 is converted to a third stereoisomer 5 on standing in chloroform or dichloromethane solution. Anomalies in the ultraviolet spectra of 3–5 can be interpreted in terms of an interaction of the π system with the bromine atoms at C(1) and C(4). The formation of addition products from 1 is indicative of its olefinic rather than aromatic character.     

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.     

Application of pig liver esterase catalyzed transesterification in organic media to the kinetic resolution of glycerol derivatives

The PLE/MPEG catalyzed transesterification of the glycerol ketals rac-1a and rac-1d–f with vinyl propionate in toluene proceeded with good selectivities (E=24–34) and gave the enantiomerically enriched S-alcohols 1a and 1d–f, and the S-esters 2a and 2d–f. High selectivities (E=99 and E≥200) were observed in the transesterification of the glycerol ether rac-3 and its desoxy analog rac-5, both having a secondary hydroxy group, with PLE/MPEG. In transesterifications in organic media PLE exhibited a much higher enantioselectivity than in hydrolysis in water.     

Total synthesis,reactivity, and structural clarification of lindenatriene

The synthesis of lindenatriene (1) and iso-lindenatriene (12) were achieved, along with the des-hydroxy model compounds (10 and 18, respectively), and compared to reported ¹H NMR spectra in the literature (1a and 10a). These comparisons clarify the correct initial assignment of lindenatriene (1) as well as its instability and propensity to isomerize into the more thermodynamically favored iso-lindenatriene (12).