Chemo-enzymatic enantio-convergent asymmetric synthesis of (R)-(+)-Marmin

Asymmetric biohydrolysis of trisubstituted terpenoid oxiranes (rac-1a-rac-3a) was accomplished by employing the epoxide hydrolase activity Rhodococcus and Streptomyces spp. Depending on the biocatalyst, the biohydrolysis proceeded in an enantio-convergent fashion and gave the corresponding vic-diols in up to 97% ee at conversions beyond the 50%-threshold. In order to avoid a depletion of the ee of product by further oxidative metabolism, bioconversions had to be conducted in an inert atmosphere with exclusion of molecular oxygen. The synthetic applicability of this method was demonstrated by the asymmetric total synthesis of the monoterpenoid coumarin (R)-(+)-Marmin in 95% ee.     

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of common cutworm (Spodoptera litura)

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of Spodoptera litura was carried out. Substrate was converted to three new terpenoids, (+)-(1R,2S)-10-hydroxyfenchol, (+)-(1R,2R,3S)-8-hydroxyfenchol and (−)-(1S,2S,6S)-6-exo-hydroxyfenchol, and one known terpenoid, (−)-(1R,2R,3R)-9-hydroxyfenchol. These structures were established by NMR, IR, specific rotation and mass spectral studies.     

Total syntheses of (R)-argentilactone and (R)-goniothalamin via catalytic enantioselective allylation of aldehydes

The total syntheses of (R)-argentilactone (five steps, 25% overall yield) and (R)-goniothalamin (three steps, 61% overall yield) have been described through the enantioselective catalytic allylation of aldehydes (including a propargylic aldehyde) which provided a rapid access to these natural products that display very interesting biological activities.     

Ru-catalyzed enantioselective preparation of methyl (R)-o-chloromandelate and its application in the synthesis of (S)-Clopidogrel

The preparation of methyl (R)-o-chloromandelate via Ru-catalyzed asymmetric hydrogenation and transfer hydrogenation was investigated. With Ru-(R,R)-2,4,6-triisopropyl C₆H₂SO₂-DPEN as the catalyst and HCOOH-Et₃N azeotrope as the hydrogen donor, up to 92% ee was obtained in an optional condition. The synthesis of (S)-Clopidogrel was also studied.     

(1R,2R)-DPEN-derived triazolium salts for enantioselective oxodiene Diels-Alder reactions

Enantioselective oxodiene Diels-Alder reactions catalyzed by (1R,2R)-DPEN-derived triazolium salts were realized successfully. With 0.5 mol % of (1R,2R)-DPEN-derived triazolium salt C and 150 mol % of Et₃N, the reactions of various α-chloroaldehydes (α-bromoaldehyde) with substituted enones led to 3,4-dihydropyridinones and their derivatives in good yields, diastereoselectivities, and enantioselectivities (up to 97% ee).     

Lipase-catalyzed kinetic resolution of thiotetronic acid derivatives bearing a chiral quaternary carbon: total synthesis of (R)-thiolactomycin and its O-analogue

We have developed a chemoenzymatic synthesis of (R)-thiolactomycin (1) having a chiral quaternary carbon atom at C5. In the kinetic resolution of the thiotetronic acid precursor 4, both enantiomers were obtained with high enantiomeric excess by use of Chirazyme^® L-2. Chemical transformations of the (R)-alcohol 4 provided the chiral (R)-thiolactomycin (1) in 36% yield in five steps.     

Stereoselective synthesis of (+)-(8R,8aR)-perhydro-8-indolizidinol

A highly stereoselective total synthesis of (+)-(8R,8aR)-perhydro-8-indolizidinol is described. Key steps involved in this synthesis are diastereoselective zinc allylation, azido-olefin cyclization and reductive amination followed by cyclization which effectively constructed the indolizidine ring. This contributes a unique approach to the synthesis of indolizidine alkaloids that offers the advantages of brevity and relatively high overall yields.     

Chiral separation of (R,S)-2-phenyl-1-propanol through cellulose acetate butyrate membranes

As the cellulose acetate butyrate possessed multichiral carbon atoms in its molecular structure unit, enantioselective membrane was prepared using cellulose acetate butyrate as membrane material. The flux and permselective properties of membrane using aqueous solutions of (R,S)-2-phenyl-1-propanol as feed solution was studied. The top surface and cross-section morphology of the resulting membranes were examined by scanning electron microscopy. When the membrane was prepared with 15 wt.% cellulose acetate butyrate and 20 wt.% DMF in the casting solution, and the operating pressure and feed concentration of racemate were 2 kgf/cm² and 5 mmol/L, respectively, over 98% of enantiomeric excess (e.e.) was obtained. This is a report, for the first time, that the cellulose acetate butyrate is used as optical resolution membrane material for isolating the optical isomers of (R,S)-2-phenyl-1-propanol.     

Stereoselective synthesis of (−)-allosedamine and (1R,3R)-HPA-12 from β-p-toluenesulfonamido-γ,δ-unsaturated sulfoxide

A stereoselective synthesis of (−)-allosedamine and HPA-12 is disclosed. The key steps of the synthesis include the diastereoselective synthesis of a β-sulfonamido unsaturated sulfoxide, elaboration of a bromohydrin via intramolecular sulfinyl group participation and a ring-closing metathesis reaction for the construction of the piperidine ring of allosedamine.     

Radical mediated stereoselective synthesis of (4R,8R)-4,8-dimethyldecanal, an aggregation pheromone of Tribolium flour beetles

(4R,8R)-4,8-Dimethyldecanal, a common aggregation pheromone of Tribolium flour beetles, has been synthesized from (R)-2,3-O-isopropylideneglyceraldehyde in 11 steps and 7% overall yield. The key step in the synthesis is the highly diastereoselective chelation-controlled radical reaction of ethyl (4S,5R)-4-benzyloxy-5,6-(isopropylidenedioxy)-2-methylenehexanoate with ethyl (R)-5-iodo-3-methylpentanoate performed in the presence of 7 equiv of MgBr₂·OEt₂.     

Biomimetically inspired total synthesis of (12S)-12-hydroxymonocerin and (12R)-12-hydroxymonocerin

A concise asymmetric total synthesis of (12S)-12-hydroxymonocerin (1) and (12R)-12-hydroxymonocerin (2) were efficiently achieved from the known 4-bromo-2,6-dimethoxyphenol. The synthetic approach was inspired by our biomimetic synthesis of (+)-monocerin (3) and 7-O-demethylmonocerin (4). The cis-fused furobenzopyranones of 1 and 2 was efficiently constructed via an intramolecular nucleophilic trapping of a quinonemethide intermediate, which was obtained by benzylic oxidation of compound 10 using 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).     

Syntheses and X-ray structures of Cu(II) and Zn(II) complexes of N,N′-dibenzyl-(R,R)-1,2-diaminocyclohexane and application to nitroaldol reaction

Chiral Cu(II) and Zn(II) complexes with N,N′-dibenzyl-(R,R)-1,2-diaminocyclohexane ligands were synthesized and characterized. X-ray crystal structures of these complexes reveal that Cu complex has the distorted square-planar geometry and the Zn one has the nearly tetrahedral pattern. The coordination of metals to the chiral diamine ligand leads to a 5-membered metallaheterocycle of (S,S)-configuration of nitrogen atoms. Their asymmetric catalytic activities to nitroaldol reaction of benzaldehyde and nitromethane were examined. The difference of the geometry around metals leads to the opposite preferential configuration of alcohol products using these chiral complexes as asymmetric catalysts in the presence of triethylamine or diisopropylethylamine.     

A simple and stereodivergent strategy for the synthesis of 3′-C-branched 2′,3′-dideoxynucleosides exploiting (Z)-but-2-en-1,4-diol and (R)-2,3-cyclohexylideneglyceraldehyde

Barbier type additions of allylic bromide 4, derived from (Z)-but-2-en-1,4-diol 2 to (R)-2,3-cyclohexylideneglyceraldehyde 1 were performed through mediation with Zn employing Luche’s procedure and also with low valent Cu, Co, and Fe which were produced via bimetal redox strategy in THF to afford 5c,d as the major products. From these, 5a,b were prepared following an oxidation-reduction protocol. Compound 5c was exploited as a representative starting material to develop a simple and inexpensive strategy toward the synthesis of 3′-C-branched 2′,3′-dideoxynucleosides having stereodiversity at 3′- and 4′-positions.     

Pheromone synthesis. Part 244: Synthesis of the racemate and enantiomers of (11Z,19Z)-CH503 (3-acetoxy-11,19-octacosadien-1-ol), a new sex pheromone of male Drosophila melanogaster to show its (S)-isomer and racemate as bioactive

The enantiomers of (11Z,19Z)-3-acetoxy-11,19-octacosadien-1-ol were synthesized from the enantiomers of 3,4-epoxy-1-butanol PMB ether. Its racemate was also synthesized. Its (S)-isomer and racemate were shown to possess the same pheromone activity as CH503, a long-lived inhibitor of male courtship in Drosophila melanogaster, although the racemate was less active.     

Synthesis and structural characterization of a dichloro zinc complex of N,N′-bis-(2,6-dichloro-benzyl)-(R,R)-1,2-diaminocyclohexane: Application to ring opening polymerization of rac-lactide

A novel dichloro zinc complex (L¹)ZnCl₂, where L¹ is N,N′-bis-(2,6-dichloro-benzyl)-(R,R)-1,2-diaminocyclohexane, has been synthesized and characterized. The dimethyl derivatives, generated in situ from the well characterized dichloro zinc complexes (L¹)ZnCl₂ and (L²)ZnCl₂, where L² is N,N′-bis-(benzyl)-(R,R)-1,2-diaminocyclohexane, were employed as initiators for the ring opening polymerization (ROP) of rac-lactide (rac-LA). The complexes were found to be highly efficient initiators yielding the polylactide (PLA) with a narrow molecular weight distribution. The catalytic activity and heterotactic selectivity of the Zn(II) complexes were affected by the substituents on the phenyl groups of benzyl moieties in (R,R)-1,2-diaminocyclohexane. The dimethyl derivative of (L²)ZnCl₂ produced highly stereocontrolled PLA with P_r = 0.75 at −25 °C.     

Enantioselective synthesis of (R)-deoxydysibetaine and (−)-4-epi-dysibetaine

Enantioselective synthesis of (R)-deoxydysibetaine and (−)-4-epi-dysibetaine was achieved by employing a samarium iodide-promoted reductive carbon-nitrogen bond cleavage of a proline derivative, as a key reaction.     

Crotylation of (R)-2,3-O-cyclohexylideneglyceraldehyde: a simple synthesis of (+)-trans-oak lactone

Crotylations of (R)-2,3-cyclohexylideneglyceraldehyde (1) were utilized in a simple synthesis of trans-oak lactone (I), a representative example of chiral β,γ-disubstituted-γ-butyrolactones. In this endeavor, crotylations of 1 in THF mediated with four low valent metals were studied. All these reactions took place efficiently producing 2 in good yields but with varied stereoselectivities. Each reaction produced the corresponding secondary alcohol adduct 2b and 2c predominantly with diastereoisomer 2a only in trace amounts. Among these four reactions, only Sn-mediated addition yielded 2b as the major products. Later, 2c was converted into 2d through oxidation-reduction. Finally, 2c was transformed into trans-oak lactone I in a few steps. Following this route, 2a, 2b, and 2d would produce other stereoisomers of oak lactone.     

Formation of chiral 21-helical columnar host system with phenylacetylene unit by using (1R,2S)-2-amino-1,2-diphenylethanol

A tunable supramolecular phenylacetylene host system with a chiral channel-like cavity is developed by using (1R,2S)-2-amino-1,2-diphenylethanol. This host system possesses a chiral 2₁-helical columnar structure; chiral cavities are constructed by the self-assembly of the 2₁-helical column, and guest molecules are included by varying the packing of this column.     

Fungi mediated production and practical purification of (R)-(−)-3-quinuclidinol

A fungal system belonging to Mucoraceae family (Mucor piriformis) was explored for the asymmetric reduction of a prochiral ketone, 3-quinuclidinone (I) in an efficient manner to produce an important pharmaceutical precursor (R)-(−)-3-quinuclidinol (II) with ∼96% enantiomeric excess. The efficiency of the process was improved by developing a cation exchange resin (Amberlite IR-120) which assisted the purification of water soluble metabolite II from fermentation media.     

Practical synthesis of (2S,3R)-3-hydroxy-3-methylproline, a constituent of papuamides, using a diastereoselective tandem Michael-aldol reaction

(2S,3R)-3-Hydroxy-3-methylproline, a constituent of cyclodepsipeptides polyoxypeptins A and B, was efficiently synthesized by lithium chloride-induced diastereoselective tandem Michael-aldol reaction using methyl vinyl ketone and N-1-naphthylsulfonylglycine (R)-binaphthyl ester and subsequent hydrolysis of the product in 39% overall yield and five steps.