Expeditious synthesis of 3,4-dihydroisocoumarins and phthalides using the Heck-Matsuda reaction

Several 3,4-dihydroisocoumarins and phthalides were synthesized by an effective Heck-Matsuda reaction involving an ortho carboxybenzenediazonium salt with a series of styrenes bearing electron donating and electron withdrawing groups, methylvinyl ketone, and methyl acrylate. The reaction was carried out in an open-flask with 1% mol of palladium acetate in aqueous ethanol at ∼80 °C, giving the correspondent 3-aryl-3,4-dihydroisocoumarins and phthalides with good overall yields. The electronic nature of the group attached to the olefin is a key feature for the regioselectivity of the cyclization step.     

Highly diastereoselective alkylation of vicinal dianions of chiral succinic acid derivatives: a new general strategy to (R)-β-arylmethyl-γ-butyrolactones

The vicinal dianions derived from chiral succinic acid derivatives, 1,4-bis[(4R,5S)-3,4-dimethyl-2-oxo-5-phenylimidazolidin-1-yl]butane-1,4-dione and 1,4-bis[(4S,5R)-3,4-dimethyl-2-oxo-5-phenylimidazolidin-1-yl]butane-1,4-dione react with arylmethyl bromides with high diastereo- and regio-selectivity to provide the corresponding chiral α-arylmethylated succinic acid derivatives; the (R)-products are converted into (R)-β-arylmethyl-γ-butyrolactones and (R)-α-arylmethyl-γ-butyrolactones.     

Catalytic asymmetric Michael reactions of dibenzyl malonate to α,β-unsaturated N-acylpyrroles using a La(O-iPr)3/Ph-linked-BINOL complex

Catalytic asymmetric Michael reactions of a malonate to acyclic α,β-unsaturated N-acylpyrroles as ester equivalent acceptors are described. A La(O-iPr)₃/(S,S)-linked-BINOL complex, which is suitable for Michael addition to cyclic enones, is not suitable for acyclic α,β-unsaturated N-acylpyrroles. A new (S,S)-Ph-linked-BINOL chiral ligand was developed to improve enantioselectivity, and a La(O-iPr)₃/(S,S)-Ph-linked-BINOL complex with the addition of HFIP afforded Michael adducts in good yield and enantioselectivity (up to 96% ee).     

Synthesis of 3-substituted 8-hydroxy-3,4-dihydroisocoumarins via successive lateral and ortho-lithiations of 4,4-dimethyl-2-(o-tolyl)oxazoline

Sequential treatment of 4,4-dimethyl-2-(o-tolyl)oxazoline in THF with sec-BuLi, aromatic or aliphatic aldehydes, sec-BuLi, B(OMe)₃, and H₂O₂ produced the laterally alkylated and ortho-hydroxylated oxazolines in one-pot. Treatment of these products with TFA in aqueous THF provided 3-substituted 8-hydroxy-3,4-dihydroisocoumarins in 44-75% overall yields. This procedure allowed the short synthesis of (±)-hydrangenol and (±)-phyllodulcin, naturally occurring 3,4-dihydroisocoumarins of pharmacological interest. A more economical synthesis of (±)-phyllodulcin via the trianion intermediate is also described.     

A practical enantioselective total synthesis of (−)-(S)-stepholidine

A convergent enantioselective total synthesis of (−)-(S)-stepholidine, a drug candidate for the treatment of schizophrenia and/or drug abuse, was described, which represented the first example of successful auxiliary-assisted Bischler–Napieralski cyclization of amide bearing bromine atom at 2-position of the C ring, followed by an introduction of the aryl methyl ester via Br–Li exchange. (−)-(S)-Stepholidine was synthesized in 6 steps, with 52% overall yield and >99% ee. The reported synthesis is practically free from chromatographic separation.     

Enantioselective addition of diethylzinc to aromatic aldehydes catalyzed by Ti(IV) complexes of C2-symmetrical chiral BINOL derivatives

Enantioselective addition of diethylzinc to a series of aromatic aldehydes is developed using new chiral C₂-symmetric ligand (S)-2,2′-(1,1′-binaphthyl-2,2′-diylbis(oxy))bis(methylene)bis(4-nitrophenol) (S)-2b. The catalytic system employing 10 mol % of (S)-2b and 120 mol % of Ti(OiPr)₄ was found to promote the addition of diethylzinc to a wide range of aromatic aldehydes with electron-donating and electron-withdrawing substituents, giving up to 89% ee and up to 95% yield of the corresponding secondary alcohol under mild conditions.     

A practical and efficient procedure for reduction of carboxylic acids and their derivatives: use of KBH4-MgCl2

The use of KBH₄-MgCl₂ to reduce carboxylic acids and their derivatives to the corresponding alcohols or the respective reduced products is described. Methyl (S)-3,4-O-isopropylidene-3,4-dihydroxy butanoate 2 used as a reference substrate was reduced with KBH₄ and MgCl₂ in 1:1 mol ratio to (S)-1,2-O-isopropylidene-1,2,4-butanetriol 1.     

Organocatalytic asymmetric synthesis of 3(2H)-furanones with adjacent quaternary and tertiary stereocenters

An efficient stereoselective Michael addition of simple 3(2H)-furanones to α,β-unsaturated ketones has been described. The protocol provides a facile and efficient access to complex 3(2H)-furanones containing adjacent quaternary and tertiary stereocenters in high yields (up to 99%) with good diastereoselectivities (up to 86:14) and excellent enantioselectivities (up to 98% ee) under mild conditions.     

Isolation, structural elucidation and synthesis of a novel antioxidative pseudo-di-peptide, Hanasanagin, and its biogenetic precursor from the Isaria japonica mushroom

The entomogenous ‘Hanasanagitake’ mushroom, Isaria japonica, is used as a folk medicine and as a traditional health food choice in Japan. A search for naturally occurring antioxidative compounds from the mushroom led to the isolation of a novel pseudo-di-peptide, named Hanasanagin, and a possible biogenetic precursor. The structures of the pseudo-di-peptides were determined as (R)-3,4-diguanidinobutanoyl-(S)-DOPA and (R)-3,4-diguanidinobutanoyl-(S)-tyrosine by spectral analysis, chemical synthesis and enzymatic conversion.     

Polyhydroxylated macrolide isolated from the endophytic fungus Pestalotiopsis mangiferae

A new polyhydroxylated macrolide, named mangiferaelactone (1) was isolated from a solid culture of the endophytic fungus Pestalotiopsis manguiferae, together with ten known compounds [(6S,1′S)-LL-P880α; (6S,1′S,2′R)-LL-P880β; (1′S,2′R)-LL-880γ; (1′R)-dehydropestalotin; (−)-5-carboxylmellein; (−)-5-methylmellein; (−)-5-hydroxylmethylmellein; arabenoic acid; 5,6-dihydro-4-methoxy-2H-pyran-2-one; and the (−)-2-hexylidene-3-methylsuccinic acid]. P. manguiferae was isolated from Hyptis dilatata, a small shrub common in the central region of Panama. The structure of compound 1 was elucidated by a combination of spectroscopic methods (IR, MS, optical rotation, 1D and 2D NMR spectroscopy). The absolute configuration of 1 was established as 4R,7R,8R,9S by application of vibrational circular dichroism (VCD). Compound 1 showed a minimum inhibitory concentration (MIC) of 1.6863 mg/mL against Listeria monocytogenes, and 0.5529 mg/mL against Bacillus cereus. No activity was observed for compound 1 against Plasmodium falciparum or Trypanosoma cruzi; likewise, no cytotoxic activity was observed against A2058 and H522-T1 cells.     

Asymmetric synthesis of 3,4-dihydroxyglutamic acids via enantioselective reduction of cyclic meso-imide

Stereoselective synthesis of (3S,4S)- and (3R,4R)-series of 3,4-dihydroxyglutamic acids was investigated. The key reaction in this synthesis is asymmetric reduction of meso-imide derived from meso-tartaric acid. Lewis acid-promoted cyanation of the obtained optically active lactam via the acyliminium intermediate followed by standard deprotection procedure afforded the desired 3,4-dihydroxyglutamic acids.     

Asymmetric synthesis of 3-substituted 8-hydroxy-3,4-dihydroisocoumarins from (S)-4-isopropyl-2-(2-methoxy-6-methylphenyl)oxazoline

Reaction of the laterally lithiated (S)-4-isopropyl-2-(2-methoxy-6-methylphenyl)oxazoline with p-tolualdehyde gave an inseparable mixture of the addition products in low diastereoselectivity. However, the (S,S)-product cyclized to the corresponding 3,4-dihydroisocoumarin faster than the (S,R)-product on silica gel, which allowed to be produced both enantiomers of 8-methoxy-3-(p-tolyl)-3,4-dihydroisocoumarin in moderate to good optical purity [S-enantiomer: 75% ee; R-enantiomer: 96% ee]. This procedure was applied to the short-step synthesis of optically active 3,4-dihydroisocoumarin natural products such as (R)-8-hydroxy-3-(1-tridecyl)-3,4-dihydroisocoumarin and (R)-phyllodulcin.     

Boron trifluoride-induced reactions of phenylglycidyl ethers: a convenient synthesis of enantiopure, stereodefined fluorohydrins

Ring-opening hydrofluorination of enantiomerically pure (2S,3S)-3-arylglycidyl ethers (aryl = phenyl, 4-trifluoromethylphenyl) by boron trifluoride-diethyl ether under mild conditions provides β-fluoro alcohols in good yield in a stereospecific manner with complete regiocontrol.     

Synthesis of platinum-iodo-alkyl/aryl complexes in ligand-exchange reactions: Determination of the structure of Pt{(S,S)-bdpp}(X)I complexes (X = Me, I) by X-ray crystallography

Pt{(S,S)-bdpp}(R)I (bdpp = 2,4-bis(diphenylphosphino)pentane; R = Me, Ph, Bz, 2-Tioph) complexes were formed in alkyl/aryl ligand - iodide ligand-exchange reactions by reacting the corresponding Pt{(S,S)-bdpp}R₂ complexes with methyl iodide. The Pt{(S,S)-bdpp}(Me)I complex was isolated and fully characterised. The influence of the X ligand on the platinum-bdpp chelate conformation was investigated in Pt{(S,S)-bdpp}(X)I (X = I, SnCl₃, Me) complex series by means of X-ray crystallography.     

Lithium enolates from a (−)-quinic acid-derived cyclohexanone with a β-alkoxy leaving group: regioselective preparation and evaluation of enolate stability towards β-elimination

Deprotonation of a (−)-quinic acid-derived ketone {(2S,3S,4aR,8R,8aS)-8-[(tert-butyl(dimethyl)silyl)oxy]-2,3-dimethoxy-2,3-dimethylhexahydro-1,4-benzodioxin-6(5H)-one} using lithium hexamethyldisilazide (LHMDS) at −78 °C gave one regioisomeric enolate. The regiocontrol is governed by the axial β-silyloxy substituent and the resulting lithium enolate is stable towards β-elimination at temperatures up to −40 °C. It was found that the axial β-silyloxy group could be conveniently eliminated using 2.1 equiv of LHMDS at 0 °C for 1 h and that an equatorial β-alkoxy group was much more resistant to β-elimination. A chiral lithium amide base was used to overturn the inherent regioselectivity of ketone deprotonation with LHMDS.     

Asymmetric addition of trimethylsilylcyanide to N-benzylimines catalyzed by recyclable chiral dimeric V(V) salen complex

Chiral dimeric vanadium (V) salen complex (10 mol%) derived from 5,5-Methylene di-[(S,S)-{N-(3-tert-butyl salicylidine)-N′-(3′,5′-di-tert-butyl salicylidene)]-1,2-cyclohexanediamine] with vanadyl suphate followed by auto oxidation was used as efficient catalyst for enantioselective Strecker reaction of N-benzylimines with TMSCN at −30 °C. Excellent yield (92%) of α-aminonitrile and high chiral induction was achieved (ee up to 94%) in case of 2-methoxy substituted N-benzylimines in 10 h. The catalytic system worked well up to four cycles with retention of enantioselectivity.     

Enantioselective, chemoenzymatic synthesis, and absolute configuration of the antioxidant (−)-gloeosporiol

The natural antioxidant (−)-gloeosporiol, isolated as a peracetylated derivative from a culture of the fungus Colletotrichum gloeosporioides, has been enantioselectively prepared from 3,4-dihydroxybenzaldehyde by means of a chemoenzymatic synthesis. The key intermediate was obtained by resolution with a lipase from Pseudomonas cepacia. Its stereochemistry, initially assigned as R, according to the Kazlaukas empirical rule for secondary alcohols, was independently confirmed by NMR and chirooptic methods. This, in turn, allowed the assignment of compound (−)-1 as (−)-(2S,3R,4R)-2-(3′,4′dihydroxyphenyl)tetrahydrofuran-3,4-diol.     

anti-Selective aldol reactions of chiral alcohol substituted γ-benzyloxyl vinylogous urethanes and the synthesis of 3-benzyloxyl-4-hydroxylalkan-2-ones

The anti-selective aldol reaction of chiral alcohol-substituted γ-benzyloxy vinylogous urethanes is described. The use of (1S,2R,4R)-1-(hydroxydiphenylmethyl)-7,7-dimethylbicyclo[2,2,1]-heptan-2-ol as a chiral auxiliary in the aldol reaction of a vinylogous urethane enolate was found to provide anti-products in good yields with moderate to excellent enantioselectivities. The major anti-vinylogous urethane lactones were transformed into 3-benzyloxyl-4-hydroxylalkan-2-ones in good yields.     

Catalytic enantioselective allylation of aldehydes using β-amido functionalized allylstannanes with chiral In(OTf)3/i-Pr-pybox complexes

The enantioselective allylation of aldehydes using a variety of β-amido functionalized allyltributylstannanes proceeded smoothly with good to high yields and enantioselectivities in the presence of 10 mol % of a chiral catalytic complex prepared from In(OTf)₃ and 2,6-bis[(S)-4-isopropyloxazolin-2-yl]pyridine {(S)-i-Pr-pybox}, providing the corresponding chiral γ-hydroxy amides.     

Sensitive monitoring of monoterpene metabolites in human urine using two-step derivatisation and positive chemical ionisation-tandem mass spectrometry

A gas chromatographic–positive chemical ionisation-tandem mass spectrometric (GC–PCI-MS/MS) method for the simultaneous determination of 10 oxidative metabolites of the monoterpenoid hydrocarbons α-pinene, (R)-limonene, and Δ³-carene ((+)-3-carene) in human urine was developed and tested for the monoterpene biomonitoring of the general population (n = 36). The method involves enzymatic cleavage of the glucuronides followed by solid-supported liquid–liquid extraction and derivatisation using a two-step reaction with N,O-bis(trimethylsilyl)-trifluoroacetamide and N-(trimethylsilyl)imidazole. The method proved to be both sensitive and reliable with detection limits ranging from 0.1 to 0.3 μg L⁻¹. In contrast to the frequent and distinct quantities of (1S,2S,4R)-limonene-1,2-diol, the (1R,2R,4R)-stereoisomer could not be detected. The expected metabolite of (+)-3-carene, 3-caren-10-ol was not detected in any of the samples. All other metabolites were detected in almost all urine samples.