Efficient preparation of enantiomerically pure (E)-4-(tributylstannanyl)but-3-en-2-ol via lipase-mediated resolution

The practical preparation of enantiomerically pure (E)-4-(tributylstannanyl)but-3-en-2-ol 1 from 3-butyn-2-ol 2 is reported. A modified Guibé's Pd-catalyzed hydrostannation of 2 provided the racemic γ-hydroxy vinylstannane 1 in a good yield. The enzymatic esterification of 1, with an inexpensive lipozyme, afforded (R)-3 and (S)-1 with very high enantiomeric excesses and chemical yields. This procedure is suitable for the multigram scale preparation of the potential chiral building blocks, (R)-1 and (S)-1.     

Efficient synthesis of the cyclopentanone fragrances (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone and Magnolione

This paper describes the selective syntheses of two cis-isomer-enriched cyclopentanone fragrances: (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone (four steps, 62% overall yield, 67% cis) and Magnolione^® (five steps, 60% overall yield, 55% cis). In addition, the asymmetric synthesis of (3aR,7aS)-5-methyl-2,3,3a,4,7,7a-hexahydro-1H-inden-1-one as well as (3a′R,7a′S)-5′-methyl-2′,3′,3a′,4′,7′,7a′-hexahydrospiro[[1,3]dioxolane-2,1′-indene] has been realized by an efficient kinetic resolution, which enables the selective synthesis of the 2S,3R-isomer-enriched 3 and 4.     

Resolution of 7-oxabicyclo[2.2.1]hept-5-en-2-one via cyclic aminals

High yielding resolution of racemic 7-oxabicyclo[2.2.1]hept-5-en-2-one (±)-1 (`7-oxanorbornenone') via aminal formation with (R,R)-1,2-diphenylethylenediamine 2 is reported. Acidic hydrolysis furnishes the enantiomeric ketones (+)-1 and (−)-1 (≥95% ee). The chiral diamine is efficiently recovered.     

Highly efficient double enantioselection by lipase-catalyzed transesterification of (R,S)-carboxylic acid vinyl esters with (RS)-1-phenylethanol

Transesterification of the title compounds using lipase B from Candida antarctica in toluene afforded the corresponding esters in good to excellent diastereomeric excess. (R)-2-Phenylpropionic acid-(R)-1-phenethyl ester 4 was isolated in 45% yield and 64% de after 2.5 h, whereas (R)-2-phenylbutyric acid-(R)-1-phenethyl ester 5 was obtained in 40% yield and 56% de after 35 h. A single recrystallization from n-hexane gave 4 with 98% de. In all reactions CAL-B showed excellent enantioselectivity (E >100) toward (RS)-1-phenylethanol and moderate enantioselectivity (E∼10) toward both carboxylic acid vinyl esters.     

Synthesis of enantiomerically pure (Z)-(2′R)-1-O-(2′-methoxyhexadec-4′-enyl)-sn-glycerol present in the liver oil of cartilaginous fish

Synthesis of enantiopure (Z)-(2′R)-1-O-(2′-methoxyhexadec-4′-enyl)-sn-glycerol 1, the principal methoxylated glyceryl ether found in Nature, is described by a highly convergent five-step process taking place in 27% overall yield. The synthesis is based on an ether bond formation between the chiral synthon (R)-2,3-O-isopropylidene-sn-glycerol and (Z)-(R)-1-chlorohexadec-4-en-2-ol employing ground potassium hydroxide and tetra-n-butylammonium bromide as a catalyst under solvent free conditions.     

Synthesis of optically active 2-fluoroalk-1-en-3-yl esters and chirality transfer in their Claisen-type rearrangements

A series of enantioenriched long chain 2-fluoroalk-1-en-3-ols 1 has been prepared by lipase-catalyzed resolution of the racemic compounds synthesized from terminal alkenes. The lipase of Candida antarctica was shown to be the most efficient one in terms of enantioselectivity. Transesterification of the fluorinated allylic alcohols 1 was superior over the hydrolysis in a phosphate buffer of the corresponding acetates 2. Lipase-catalyzed acetylation of allylic alcohols 1 in organic medium gave (S)-(−)-3-acetoxy-2-fluoroalk-1-enes of chain lengths C₁₀, C₁₆ and C₁₈ with 68-89% yield and 92-96% ee, while the remaining (R)-(+)-2-fluoroalk-1-en-3-ols were isolated with 54-96% yield and 72-86% ee. The absolute configuration was assigned by comparison of measured and calculated CD-spectra, and unambiguously by ¹H and ¹⁹F NMR spectroscopy using a modified Mosher's method. From the optically active fluorinated allylic alcohols 1 corresponding esters 2 such as propionates, 3,3,3-trifluoropropionates and Boc-glycinates were synthesized. These compounds were rearranged to 2-substituted 4-fluoroalk-4-enecarboxylic acids 3 applying modified conditions of the [3,3]-sigmatropic Ireland-Claisen rearrangement. While a complete chirality transfer from C-3 of the allylic esters to C-2 of the carboxylic acids or 2-amino acids, respectively, occurred in rearrangements of the propionates and Boc-glycinates, racemic 2-(trifluoromethyl)alk-4-enecarboxylic acids were formed from the allylic trifluoropropionates. The configurational lability of the latter products is caused by the strongly acidic proton in α-position to the trifluoromethyl and the carboxyl groups under the basic rearrangement conditions.     

Prostaglandin chemistry—V : Synthesis of new prostaglandin synthons; 4(R)-(+)- and 4(S)-(−)-t-butyldimethylsiloxycyclopent-2-en-1-one

Optically active prostaglandin intermediates, 4(R)-(+)- and 4(S)-(?)-hydroxycyclopent-2-en-1-one derivatives, were synthesized from 3(R),5(R)-diacetoxycyclopent-1-ene, 3(R)-acetoxy-5(R)-hydroxycyclopent-1-ene and 3(S),5(S)-dihydroxycyclopent-1-ene obtained by microbiological hydrolysis of 3,5-diacetoxycyclopent-1-ene. The absolute configurations of all these compounds were determined by the exciton chirality method and the induced CD method. The optical purities were determined by NMR measurements of the diastereomeric esters of a versatile optically pure acid, (+)-α-methoxy-α-trifluoromethylphenylacetic acid.     

A scalable synthesis of (R)-3-(2-aminopropyl)-7-benzyloxyindole via resolution

(±)-3-(2-Aminopropyl)-7-benzyloxyindole 1, assembled from 7-benzyloxyindole 3 in 59% overall yield, is resolved with O,O′-di-p-toluoyl l-(2R,3R)-tartaric acid 7 into (R)-1, a key intermediate of AJ-9677 2 (selective adrenaline β₃-agonist) in 99.5% e.e. and 36% overall yield. The unwanted enantiomer (S)-1 (61.9% e.e.; recovered in 57% yield from the crystallization filtrate) can be reused in another round of resolution after its enantiomeric purity is lowered to 3.7% by Raney Co treatment under a hydrogen atmosphere.     

Preparation of (1R,8S)- and (1S,8R)-9-azabicyclo[6.2.0]dec-4-en-10-one: potential starting compounds for the synthesis of anatoxin-a

9-Azabicyclo[6.2.0]dec-4-en-10-one (±)-2, obtained from cyclooctadiene by addition of chlorosulfonyl isocyanate, was N-hydroxymethylated to (±)-3 and then resolved by lipase-catalysed asymmetric acylation of the primary OH group at the (S)-stereogenic centre. High enantioselectivity (E=94) was observed when lipase PS and vinyl butyrate were used in di-iso-propyl ether at −15°C, resulting in the enantiomerically enriched ester 3a and alcohol 3b (e.e. ≥92%). Treatment of 3a and 3b with NH₄OH/MeOH afforded the corresponding β-lactams (1R,8S)-2a and (1S,8R)-2b (e.e. ≥93%), potential starting compounds in anatoxin-a synthesis. The ring opening of lactams (±)-2, (±)-7, 3a and 3b, followed by reduction, resulted in racemic 4–6 and 8 and enantiomeric 4a, 4b, 5a and 5b eight-membered cyclic β-amino acid derivatives.     

Chemo-enzymatic synthesis of (R)-5-hydroxymethyl-2-isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate,a potential chiral building block for multicyclic terpenoids

The chemo-enzymatic synthesis of (R)-5-hydroxymethyl-2-isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate, a potential chiral building block for polycyclic terpenoids containing a five–membered ring having isopropyl and angular methyl substituents, such as erinacin A and dolatriol, was achieved over 11 steps from ethyl 2-oxocyclopentane-1-carboxylate. The key synthetic precursor for this triflate was ethyl (1S,2R)-2-hydroxycyclopentanecarboxylate (>99% ee), which was prepared by a lipase-catalyzed enantioselective hydrolysis of the corresponding racemic acetate. The antipodal (S)-triflate is expected to be the synthetic intermediate for another group of terpenoids involving hamigeran B and stolonidiol. Enantiomerically pure (1R,2S)-hydroxyester (>99% ee) was prepared in high yield using the asymmetric reduction of the oxoester with commercially available carbonyl reductase, “Chiralscreen® OH”-E001.     

Enantioselective allylation of alkyl glyoxylates catalyzed by (salen)chromium(III) complexes

The enantioselective addition of allylstannanes and allylsilanes to alkyl glyoxylates of type 1, catalyzed by chiral (salen)Cr(III) complexes 3, has been studied. We have found that the reaction proceeded smoothly for low loading (1-2 mol %) of (1R,2R)-(salen)Cr(III)BF₄3a or (1R,2R)-(salen)Cr(III)ClO₄3c, and allyltributyltin under simple, undemanding conditions, affording (R)-2-hydroxypent-4-enoic acid esters 2 in good yield (61-90%) and enantioselectivity (58-76% ee).     

Synthesis of the antiepileptic (R)-Stiripentol by a combination of lipase catalyzed resolution and alkene metathesis

The enantiopure (ee >99%) antiepileptic (R)-(+)-Stiripentol has been stereoselectively synthesized via cross metathesis of 5-vinylbenzo[d][1,3]dioxole 1 and (R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2. A novel one-pot two-step pathway for the synthesis of 5-vinylbenzo[d][1,3]dioxole 1 starting from 3,4-dihydroxycinnamic acid has been introduced. A lipase catalyzed kinetic resolution access to enantiopure (R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2 (ee >99%) has also been developed.     

Kinetic resolution of 1-(benzofuran-2-yl)ethanols by lipase-catalyzed enantiomer selective reactions

Kinetic resolution of racemic 1-(benzofuran-2-yl)ethanols rac-1a–d was performed by lipase-catalyzed enantiomer selective acylation (E≫100) yielding (1R)-1-acetoxy-1-(benzofuran-2-yl)ethanes (R)-2a–d and (1S)-1-(benzofuran-2-yl)ethanols (S)-1a–d in highly enantiopure form. The degree of enantiomer selectivity for enzymatic alcoholysis/hydrolysis processes starting from racemic 1-acetoxy-1-(benzofuran-2-yl)ethane rac-2 was also tested under various conditions including supercritical CO₂ medium. Racemization-free lipase-catalyzed ethanolysis of the (1R)-1-acetoxy-1-(benzofuran-2-yl)ethanes (R)-2a–d yielded almost quantitatively the enantiopure (1R)-1-(benzofuran-2-yl)ethanols (R)-1a–d.     

Efficient preparation of (1′R)-(−)-1-(2′-hydroxy-1′-phenylethyl)piperidin-2-one: synthesis of (2′S,3R)-(+)-stenusine

An efficient oxidation of (2′R)-(−)-2′-phenyl-2′-(piperidin-1-yl)ethanol 2 with bromine to generate the corresponding piperidin-2-one 3 in 96% is described. In addition, starting from 3, (2′S,3R)-(+)-stenusine 8 was synthesized in 70% overall yield. The X-ray analysis of piperidine 6·HCl is also reported.     

Novel synthesis of 3-(3,3,3-trifluoroprop-1-en-2-yl)furans via stereoselective processing and palladium-catalyzed cycloisomerization

The 3,3,3-trifluoroprop-1-en-2-yl-substituted furans (4) were synthesized via palladium-catalyzed cyclization-isomerization of 1,1,1-trifluoro-2-[(tert-butyldimethylsilyloxy)methyl]-3-alkynylbut-2-en-1-ols (3), which were readily obtained from 1,1,1-trifluoro-2-[(tert-butyldimethylsilyloxy)methyl]-3,3-dibromoprop-2-ene (1) in three steps.     

A practical chemoenzymatic process to access (R)-quinuclidin-3-ol on scale

(±)-3-Butyryloxyquinuclidinium butyrate 6 (2 M, 571 g/L), prepared from (±)-quinuclidin-3-ol 1 and butyric anhydride, undergoes enantioselective hydrolysis by an Aspergillus melleus protease {1.0% (w/v)} in water in the presence of Ca(OH)₂ to keep the reaction at pH 7 and trap butyric acid that is introduced as part of (±)-6 and generated by the enzymatic hydrolysis. After a 24 h period, extraction with n-heptane provides (R)-quinuclidin-3-yl butyrate 5a, which, on methanolysis with Na₂CO₃, is converted into (R)-1, a common pharmacophore of neuromodulators acting on muscarinic receptors, in 96% ee and 42% overall yield from (±)-1. The unwanted antipode (S)-1, which is extracted into n-butanol and purified via its hydrochloride salt in 89% ee and 40% overall yield from (±)-1, can be racemized by the catalysis of Raney Co at 140°C under an atmosphere of H₂ (5 kg/cm²) to regenerate (±)-1 in 97% yield.     

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.     

A new chiral oxazoline derived from camphor and its conversion to (R)-2-methylalkanoic acids

(1S,5R,7R)-(−)-10,10-Dimethyl-3-ethyl-4-oxa-2-azatricyclo[5.2.1.0^1,5]dec-2-ene 2 was prepared in 95% yield from (1S)-1-amino-2-exo-hydroxyapocamphane 1. The chiral oxazoline could be alkylated (LDA/THF/−78°C/RX, RX=ethyl, n-propyl, n-butyl iodides or benzyl bromide) to 3 in 95% yield and >95% diastereoselectivity, and the products hydrolysed to (R)-2-methylalkanoic acids 4 (43–47% yield, 93–98% e.e.).     

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.     

Chemo-biological preparation of the chiral building block (R)-4-acetoxy-2-methyl-1-butanol using Pseudomonas putida

In order to develop new methyl substituted chiral building blocks which are useful for the synthesis of methyl branched natural products, the enantioselective bioreduction of an exo-methylene to a methyl group was investigated. 4-Acetoxy-2-methylene-1-butanol 3 was prepared from itaconic acid over four steps and converted to the chiral alcohol (R)-4-acetoxy-2-methyl-1-butanol 4, by growing cells of Pseudomonas putida. The bioconversion achieved a high enantioselectivity (92% ee) and a high chemical yield (65%) within a relatively short reaction time (18–20 h).