Pheromone synthesis. Part 249: Syntheses of methyl (R,E)-2,4,5-tetradecatrienoate and methyl (2E,4Z)-2,4-decadienoate,the pheromone components of the male dried bean beetle,Acanthoscelides obtectus (Say)

The enantiomers of methyl (E)-2,4,5-tetradecatrienoate (1), a component of the male pheromone of Acanthoscelides obtectus, were synthesized from the enantiomers of 1-undecyn-3-ol (6), which were obtained via asymmetric acetylation of (±)-1-trimethylsilyl-1-undecyn-3-ol (4) with vinyl acetate as catalyzed by lipase PS (Amano). The ortho ester Claisen rearrangement of 6 with triethyl orthoacetate was the key-step to generate the chiral allenic system. A new synthesis of (±)-1 was also executed starting from (±)-6. Three different syntheses of methyl (2E,4Z)-2,4-decadienoate (2), another component of the male pheromone of A. obtectus, were achieved by means of either palladium-catalyzed Heck reaction or a Claisen and an Al₂O₃ catalyzed thermal rearrangements.     

Anti-inflammatory polyketides from the mangrove-derived fungus Ascomycota sp. SK2YWS-L

A pair of novel 2,3-diaryl indone derivatives (+)- and (?)-ascomindone D [(+)-1 and (?)-1, respectively], as well as two new prenylated polyketides ascomfurans C (2) and ascomarugosin A (3) were obtained from the culture of a mangrove endophytic fungus Ascomycota sp. SK2YWS-L together with three known compounds (4–6). The enantiomers (+)-1 and (?)-1 were purified through chiral HPLC separation, which represented the first example of resolving 2,3-diaryl indone atropisomers in natural products. The structures of the new compounds were determined on the basis of interpretation of spectroscopic data including X-ray diffractions and the absolute configurations of (+)-1 and (?)-1 were elucidated by ECD calculations. The biosynthesis pathway was proposed. In the anti-inflammatory assay, (+)-1 and (?)-1 exhibited potential anti-inflammatory effects by inhibiting against the production of nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW 246.7 mouse macrophages with the IC₅₀ values of 17.0 and 17.1 μM, respectively.     

Preparation of dimethyl (R)- and (S)-2-(2-aminophenyl)-2-hydroxyethylphosphonate from anthranilic acid

An efficient synthesis of both enantiomers of dimethyl δ-amino-β-hydroxyethylphosphonate 6 has been achieved starting from anthranilic acid, through the resolution of dimethyl (±)-2-(2-N,N-dibenzylaminophenyl)-2-hydroxyethylphosphonate 9 with (S)-O-methylmandelic acid. The absolute configuration of the enantiomers 9 was assigned by the Dale and Mosher approach using the extended Newman projections and molecular mechanics.     

Synthesis of 4-aryl-substituted β-lactam enantiomers by enzyme-catalyzed kinetic resolution

Enantiopure 4-phenyl- and 4-(p-tolyl)-2-azetidinones 3a, 3b, 4a and 4b (with e.e.s of ≥96%) were prepared through lipase-catalyzed asymmetric butyrylation of the primary OH group of N-hydroxymethylated β-lactams (±)-5 and (±)-6 at the (R)-stereogenic centre or by lipase-catalyzed asymmetric debutyrylation of O-butyryloxymethyl-2-azetidinones (±)-7 and (±)-8 at the (R)-stereogenic centre. The ring-opening of lactams 5a, 5b, 6b and 8a with HCl/EtOH afforded the corresponding β-amino ester enantiomers 9a, 9b, 10a and 10b with e.e.s of ≥92%.     

Synthesis and characterization of the two enantiomers of a chiral sigma-1 receptor radioligand: (S)-(+)- and (R)-(-)-[18F]FBFP

Racemic [¹⁸F]FBFP ([¹⁸F]1) proved to be a potent σ₁ receptor radiotracer with superior imaging properties. The pure enantiomers of unlabeled compounds (S)- and (R)-1 and the corresponding iodonium ylide precursors were synthesized and characterized. The two enantiomers (S)-1 and (R)-1 exhibited comparable high affinity for σ₁ receptors and selectivity over σ₂ receptors. The Ca²⁺ fluorescence assay indicated that (R)-1 behaved as an antagonist and (S)-1 as an agonist for σ₁ receptors. The ¹⁸F-labeled enantiomers (S)- and (R)-[¹⁸F]1 were obtained in >99% enantiomeric purity from the corresponding enantiopure iodonium ylide precursors with radiochemical yield of 24.4% ± 2.6% and molar activity of 86–214 GBq/µmol. In ICR mice both (S)- and (R)-[¹⁸F]1 displayed comparable high brain uptake, brain-to-blood ratio, in vivo stability and binding specificity in the brain and peripheral organs. In micro-positron emission tomography (PET) imaging studies in rats, (S)-[¹⁸F]1 exhibited faster clearance from the brain than (R)-[¹⁸F]1, indicating different brain kinetics of the two enantiomers. Both (S)- and (R)-[¹⁸F]1 warrant further evaluation in primates to translate a single enantiomer with more suitable kinetics for imaging the σ₁ receptors in humans.     

Enantiomeric resolution by lipase-catalysed esterification of a trans-5,6-dihydro-1,10-phenanthroline possessing helical and central chirality

Lipase-catalysed enantioselective esterification was carried out to obtain the kinetic resolution of (±)-trans-5-hydroxy-6-methoxy-1,10-phenanthroline (±)-1b. Different lipases from Candida cylindracea, Candida antarctica, Rhizomucor miehei, Pseudomonas fluorescens and Pseudomonas cepacia were tested in an unusual methanol/vinyl acetate (8:92 v/v) reaction mixture P. fluorescens lipase showed good enantiodifferentiation (E = 48) and allowed us to prepare both enantiomers (+)-(5S,6S,M)-1b and (−)-(5R,6R,P)-1b with an enantiomeric excess of >97%.     

Three unprecedented biphenyl derivatives bearing C6-C3 carbon skeleton from the bark of Magnolia officinalis var. biloba

(±)-Magoilgomer A [(±)-1] and magoilgomer B (2) were identified from the bark of Magnolia officinalis var. biloba. (+)-1 and (−)-1 were a pair of novel biphenyl derivatives featuring three C6-C3 subunits. 2 was an unprecedented adduct containing magnolol and honokiol. These three oligomers possessed new parallel mode which should be biosynthesized from the coupling of three or four C6-C3 subunits. The structures of (±)-1 and 2 were elucidated based on the spectroscopic data analyses and electronic circular dichroism (ECD) calculations. 2 exhibited neuroprotective effects of oxygen glucose deprivation-induced SK-N-SH cell injury.     

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.     

Enzymatic resolution of racemic secondary cyclic allylic alcohols

The resolutions of five racemic cyclic alcohols: 6,6-dimethylcyclohex-2-en-1-ol (±)-5, 4,4-dimethylcyclohex-2-en-1-ol (±)-7, 5,5-dimethylcyclohex-2-en-1-ol (±)-11 and isomeric trans-(±)-13 and cis-piperitols (±)-14 are presented. They were resolved by enzymatic esterification with vinyl esters or by enzymatic hydrolysis of their racemic esters in phosphate buffer. The following lipases were used as biocatalysts: Novozyme 435 (Candida antarctica), Amano PS (Burkholderia cepacia) and lipase from Candida cylindracea. All isomers of alcohols were obtained with at least 96% ee.     

Dayaolingzhiols A−E,AchE inhibitory meroterpenoids from Ganoderma lucidum

Ganoderma mushrooms are widely used as effective medicines for treating and preventing chronic diseases. In this study, five new meroterpenoids, dayaolingzhiols A (1) and B (2) featuring a 6/6/6 ring system, dayaolingzhiols C?E (3–5) harboring a γ-lactone motif, along with eight known ones (6–13), were purified from G. lucidum. To clarify their chemical structures, spectroscopic and ECD and OR computational methods were used. In addition, the inhibition of all the new meroterpenoids against AChE was evaluated, disclosing that (+)-4 and (±)-5 possess potent AChE inhibitory activities with respective IC₅₀ values of 8.52?±?1.90?μM and 7.37?±?0.52?μM.     

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.     

Synthesis and stereochemistry of ceramide B, (2S,3R,4E,6R)-N-(30-hydroxytriacontanoyl)-6-hydroxy-4-sphingenine, a new ceramide in human epidermis

(2S,3R,4E,6R)-N-(30-Hydroxytriacontanoyl)-6-hydroxy-4-sphingenine (1) and its (6S)-isomer (1′) were synthesized by starting from pentadecan-15-olide, the enantiomers of 1-pentadecyn-3-ol, and (S)-Garner's aldehyde. Comparison of the ¹H NMR spectra of the tetraacetyl derivatives of 1 and 1′ with that of ceramide B, a new protein-bound ceramide in human stratum corneum, revealed it to be (2S,3R,4E,6R)-1.     

Kinetic resolution of racemic secondary aliphatic allylic alcohols in lipase-catalyzed transesterification

Different lipases were screened as biocatalysts in the kinetic resolution process of (±)-hept-1-en-3-ol 1, (±)-5-methylhex-1-en-3-ol 2, (±)-6-methylhept-2-en-4-ol 3, (±)-6,6-dimethylhept-2-en-4-ol 4, and 1-phenylbut-3-en-2-ol 5 by enantioselective transesterification. The acylation of (±)-1 and (±)-2 catalyzed by Novozym 435 (Candida antarctica) was very effective and proceeded with good enantioselectivity. After 4–8 h of reactions the esters formed and the alcohols, which remained were obtained with high enantiomeric excess with 97–100% ee and 91–100% ee, respectively. The lipase Amano PS (Burkholderia cepacia) was the best catalyst in the asymmetric transesterification of (±)-5 affording the (R)-alcohol with 90–95% ee and the (S)-ester with 98–100% ee. Low enantioselectivities were observed in the cases of lipase-catalyzed acylation of (±)-3 and (±)-4.     

Lipase catalyzed acylation of primary alcohols with remotely located stereogenic centres: the resolution of (±)-4,4-dimethyl-3-phenyl-1-pentanol

Enantioselective acylation of some (±)-3-alkyl-3-phenyl-1-propanols was performed with enzymes as catalysts. Moderate enantiomeric ratios (E), ranging up to E = 11.6, were obtained. In the resolution, some of the lipases selectively acylated the (+)-enantiomer while others acylated the (−)-enantiomer of the γ-substituted primary alcohols 1–4. Thus, it is possible to obtain both enantiomers of the alcohols as remaining substrate with high enantiomeric purity. The resolution of (±)-4,4-dimethyl-3-phenyl-1-pentanol 4 was extensively studied and screening experiments were conducted to select suitable lipase(s), reaction medium, acyl donor and appropriate temperature combinations to increase the enantiomeric ratio. Chirazyme^® L-6/chloroform/vinyl propionate/38 °C and Chirazyme^® L-7/di-iso-propyl ether/vinyl propionate/0 °C were chosen to obtain both enantiomers, (R)-(+)-4 and (S)-(−)-4, respectively, via sequential resolutions in excellent enantiomeric excess (>98%) and in 25% and 22% yield, respectively.     

Short syntheses of (S)-pipecolic acid, (R)-coniine,and (S)-δ-coniceine using biocatalytically-generated chiral building blocks

The kinetic resolutions of both (±)-N-(benzyloxycarbonyl-2-(hydroxymethyl)piperidine [(±)-5] and (±)-N-(tert-butoxycarbonyl)-2-(hydroxymethyl)piperidine [(±)-6] catalyzed by the enzyme acylase I from Aspergillus species (AA-I) afforded the chiral building blocks (S)-5 and (S)-6, respectively; which were used for the syntheses of the title natural products and derivatives of (S)-pipecolic acid. The syntheses were short (2–4 steps) and proceeded with satisfactory overall yield.     

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.     

Skipped diynes—VII : Stereospecific thermal isomerization of a tetraethynyldimethylenecyclobutane

1,1-Bis(t-butylethynyl)-3-t-butylchloroallene (1) dimerizes stereospecifically at ca 25° to give Z - 1 - (t - butylchloromethylene) - 2- bis(t - butylethynylmethylene) - 3 - t - butyl - 3 - chloro - 4,4 -bis(t - butylethynyl)cyclob Z-I in the solvent bis(2 - ethoxyethyl) ether. Rate data for 100° are k = 111 × 10^?6 sec^?1, ΔH^≠ = 30·8 ± 1 kcal/mole and ΔS^≠ = 15 ± 3 eu. It is proposed that the dimerization of 1 produces a bisallyl diradical in an orthogonal conformation from which conrotatory paths lead to Z-I or trans-II. The observations on this system are used to construct a useful, if simplistic, approach to rationalize or predict product distributions in reactions such as allene dimerizations, 1, 2 - dimethylenecyclobutane rearrangements, etc, which proceed through the bisallyl diradical. On the graph which connects all of the species (or on the energy surface which contains all of the species) the first products should be those which are one allowed reaction step away from a given diradical. Applications and exceptions to this concept of favored kinetic control are discussed.     

Parallel or classical kinetic resolution of a planar chiral ferrocenylketone through asymmetric reductions

Racemic 1-acetyl-2-methoxymethylferrocene, (±)-1 was subjected to asymmetric reduction with two different methodologies and complementary results were obtained. When the reduction of (±)-1 was carried out in the presence of CBS-oxazaborolidine catalyst and BH₃·Me₂S as the hydrogen source, both enantiomers of the substrate were converted with comparable reaction rates and selectivities. The corresponding diastereoisomeric ferrocenylalcohols 3a and 3b were obtained in a 1:1 ratio and >90% enantiomeric excess; this reaction profile being related with a parallel kinetic resolution with high ds₁ and ds₂ diastereofacial selectivities. On the contrary, the transfer hydrogenation of (±)-1 with HCOOH/triethylamine in the presence of (R,R)-Noyori’s catalyst proceeded via classical kinetic resolution, so that the formed (?)-3b or unreacted (+)-1 could be obtained in highly enantiopure form before or beyond 50% of the substrate conversion, respectively. Alcohol 3b with an (1R_p,S)- or (1S_p,R)-configuration is not easily accessible by the diastereoselective metallation/electrophilic quenching sequence routinely applied in the synthesis of planar chiral ferrocenes. As a result, the described procedures provide a valuable access to this useful starting material for the synthesis of homochiral related derivatives.     

Arylnaphthalide lignans from Saussurea medusa and their anti-inflammatory activities

Five new arylnaphthalide lignans (1 ? 4a/4b), together with five known analogues (5–9), were isolated from whole plants of Saussurea medusa. Compound 4 was characterized as an aryltetralin lignan with an unusual C-7′-C-9 oxygen bridge group, and a chiral HPLC analysis was carried out to afford one pair of enantiomers (4a/4b). Structures of the new compounds were elucidated by extensive spectroscopic and electronic circular dichroism (ECD) calculations. All compounds were firstly isolated from S. medusa, and compounds 1–5, 7 and 8 had never been obtained from the genus Saussurea previously. Furthermore, this is the first report of arylnaphthalide lignans isolated from S. medusa. anti-inflammatory activities of the compounds were evaluated by determining their inhibitory activities on the production of NO by LPS-stimulated RAW 264.7 cells. Compounds (?)-4a and 5 exerted the significant inhibition activities with IC₅₀ values of 13.4 ± 1.5 and 15.7 ± 1.1 μM, respectively, which even exceeded the positive control quercetin (IC₅₀ = 15.9 ± 1.2 μM). Compounds 2, (+)-4b, 6 and 9 exhibited moderate inhibitory activities with IC₅₀ values ranging from 19.7 ± 1.9 to 47.4 ± 3.1 μM. Further analysis by molecular docking showed that almost all the active compounds could interact with the amino acid residues of iNOS proteins, which also supported their anti-inflammatory activities.     

Synthesis of racemic and optically active forms of lineatin,the unique tricyclic pheromone of trypodendron lineatum (olivier)

(±) - 33,7 - Trimethyl - 2,9 - dioxatricyclo[3.3.1.0^4,7]nonane 1 and (±) - 3,3,7 - trimethyl - 2,9-dioxatricyclo [4.2.1.0^4,7]nonane 2 were synthesized. The former was shown to be (±)-lineatin, an ambrosia beetle pheromone. A selective synthesis of (±)-lineatin was devised, which was modified to yield the both enantiomers of lineatin via optical resolution of an intermediate.