Stereoselective synthesis of methyl branched chiral deoxypropionate units: a new route for synthesis of insect pheromone (−)-lardolure and (2R,4R,6R,8R) 2,4,6,8-tetramethylundecanoic acid

(−)-Lardolure and (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoic acid have been synthesized via lipase catalyzed desymmetrization strategy to create two methyl chiral centers. Other key steps involved in the synthesis are Wittig reaction, Evan’s asymmetric alkylation, Grignard reaction, Pd-catalyzed isomerization of primary allylic alcohol to corresponding saturated aldehyde, and PhNO/proline catalyzed MacMillan α-hydroxylation.     

An efficient synthesis of optically active (2R,3R)-2-methyl-3-[(1R)-1-methylprop-2-enyl]cyclopentanone, a useful chiral building block for synthesis of vitamin D and steroids

An efficient synthesis of optically active (2R,3R)-2-methyl-3-[(1R)-1-methylprop-2-enyl]cyclopentanone, a useful chiral building block for synthesis of vitamin D and steroids, has been developed starting from readily accessible optically active secondary propargyl phosphate (R)-2, where the asymmetric Michael addition of a chiral allenyltitanium to alkylidenemalonate 3 is a key reaction.     

Synthesis of (+)-(1S,2R) and (−)-(1R,2S)-2-aminocyclobutane-1-carboxylic acids

(+)-(1S,2R) and (−)-(1R,2S)-2-aminocyclobutane-1-carboxylic acids have been prepared in >97% ee and in 33% and 20% overall yields starting from a single, chiral, bicyclic compound perceived as a chiral uracil equivalent. Construction of the cyclobutane ring is achieved via a [2+2] photocycloaddition reaction of this chiral precursor with ethylene.     

Enantioselective synthesis of (−)-(1R,2R)-1,2-dihydrochrysene-1,2-diol

A general chiral building block containing the 1R,2R-trans-diol moiety was constructed utilizing the stereoselective Shi-epoxidation reaction on a tetralone scaffold assembled by a Negishi cross-coupling on N,N-diethylbenzamide. Further elaboration of this chiral building block into polycyclic aromatic compounds was demonstrated with the total synthesis of the precursor for the most carcinogenic metabolite of chrysene, (−)-(1R,2R)-1,2-dihydrochrysene-1,2-diol in 87% ee.     

First stereoselective total synthesis of (6R)-6-[(4R,6R)-4,6-dihydroxy-10-phenyldec-1-enyl]-5,6-dihydro-2H-pyran-2-one

A stereoselective total synthesis of (6R)-6-[(4R,6R)-4,6-dihydroxy-10-phenyldec-1-enyl]-5,6-dihydro-2H-pyran-2-one is reported. The strategy utilizes an iterative Jacobsen hydrolytic kinetic resolution, ring opening with a chiral propargylic synthon and a preferential (Z)-Wittig olefination reaction and lactonization as the key steps.     

Synthesis of (4R,8R)- and (4S,8R)-4,8-dimethyldecanal: the common aggregation pheromone of flour beetles

The synthesis of (4R,8R)- and (4S,8R)-4,8-dimethyldecanal 1 and 1a has been achieved connecting the chiral building block (R)-2-methyl-1-bromobutane 4 with (R)- and (S)-citronellol derivatives. The key intermediate 4 was obtained optically pure in five steps from methyl (S)-3-hydroxy-2-methylpropionate 2.     

Synthesis of dihydroxylated prolines and iminocyclitols from five-membered endocyclic enecarbamates. Total synthesis of the potent glycosidase inhibitor (2R,3R,4R,5R)-2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP)

cis- and trans-3,4-Dihydroxylated prolines and the iminocyclitol 1,4-dideoxy-1,4-imino ribitol were synthesized employing a strategy involving the Heck arylation of five-membered endocyclic enecarbamates with aryldiazonium salts followed by oxidative cleavage of the electron-rich aromatic ring. The total synthesis of the potent α- and β-glucosidase inhibitor (2R,3R,4R,5R)-2,5-hydroxymethyl-3,4-dihydroxypyrrolidine (DMDP) was also achieved by the same strategy in ten steps from a chiral five-membered enecarbamate in 12% overall yield.     

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.     

(R,R)-α,α′-Bis(trifluoromethyl)-9,10-anthracenedimethanol: a chiral solvating agent for enantiomeric resolution of β-dicarbonyl compounds

Commercially available (R,R)-α,α′-bis(trifluoromethyl)-9,10-anthracenedimetanol is a very efficient solvating agent for the enantiodifferentiation of a series of chiral Michael adducts and related β-dicarbonyl compounds.     

The exo-selectivity of the new non-natural chiral auxiliary (+)-(1R,endo)-2-benzonorbornenol in an asymmetric aza-Diels-Alder reaction

The recently reported compound (+)-(1R,endo)-2-benzonorbornenol (2) proved to be an efficient chiral auxiliary in the asymmetric aza-Diels-Alder reaction between cyclopentadiene and the N-benzyl imine of its glyoxylate, which afforded a virtually all-exo mixture of cycloaducts with a 1S:1R diastereomeric ratio of 63:37.     

Simplified syntheses of the water-soluble chiral shift reagents Sm-(R)-pdta and Sm-(S)-pdta

The chiral shift reagents Sm-(R)-pdta and Sm-(S)-pdta, which are based on (R)- or (S)-1,2-diaminopropane-N,N,N′,N′-tetraacetic acid were synthesized from easily accessible compounds in three simple steps, which makes the method suitable for laboratory-scale production. In addition, a new and efficient method for the preparation of pure anhydrous (R)- or (S)-1,2-diaminopropane-N,N,N′,N′-tetraacetic acid was developed.     

Synthesis of (R)-propane-1,2-diol from lactides by dynamic kinetic resolution

The dynamic kinetic resolution (DKR) of rac-1-tert-butoxypropan-2-ol with isopropenyl acetate in the presence of Novozyme 435 and a ruthenium catalyst produces enantiomerically pure (R)-1-tert-butoxy-2-acetoxy-propane (>99.5 %ee) in a good yield. The product can be easily transformed into (R)-propane-1,2-diol without loss of stereoselectivity. Together with recently published procedures, the herein described DKR offers the possibility to use any lactide source as starting material for the production of (R)-propane-1,2-diol. The chiral diol may serve as the chiral building block for the synthesis of important enantiopure esters, like propylene carbonate, chiral polymers, etc.     

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.     

Asymmetric reduction of prochiral ketones using in situ generated oxazaborolidine derived from (1S,2S,3R,4R)-3-amino-7,7-dimethoxynorbornan-2-ol. An efficient synthesis of enantiopure (R)-tomoxetine

Catalytic asymmetric reduction of prochiral ketones was examined in the presence of chiral oxazaborolidine catalyst 2 prepared in situ from (1S,2S,3R,4R)-3-amino-7,7-dimethoxynorbornan-2-ol (1). The optically active secondary alcohols were generally obtained in moderate to high enantiomeric excesses (ee 43-95%) and good yields (75-94%), except for ketones bearing electron-withdrawing groups. The methodology was applied to the synthesis of enantiopure (R)-tomoxetine, a potent anti-depressant drug.     

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.     

Asymmetric syntheses of (1R,1R,5R,7R) and (1S,1R,5R,7R)-1-hydroxy-exo-brevicomin and a formal synthesis of (+)-exo-brevicomin

Asymmetric syntheses of (1R,1^′R,5^′R,7^′R) and (1S,1^′R,5^′R,7^′R)-1-hydroxy-exo-brevicomins 1 and 2, volatiles of the male mountain pine beetle, and a formal synthesis of (+)-exo-brevicomin 3, a component of the attracting pheromone system of several bark beetles have been achieved. The key steps are Birch reduction of commercially available α-picoline, selective Wittig olefination, and Sharpless asymmetric dihydroxylation.     

Synthetic studies on homophymine A: stereoselective synthesis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid

An efficient and highly stereocontrolled synthesis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid, the β-hydroxy acid unit that acylates the N-terminus of homophymine A, has been devised starting from iodoethane and (S,S)-pseudoephedrine propionamide in 9 steps and 36% average overall yield. Comparison of the ¹H and ¹³C NMR and optical rotation data of the resulting β-hydroxy acid with the natural fragment unambiguously verifies the configurational assignment as (2R,3R,4R,6R).     

Enantioselective diethylzinc addition to aromatic and aliphatic aldehydes using (3R,5R)-dihydroxypiperidine derivatives catalyst

A series of chiral (3R,5R)-dihydroxypiperidine derivatives 3a-f were conveniently prepared from trans-4-hydroxy-l-proline and applied to the catalytic enantioselective addition of diethylzinc to benzaldehyde and heptanal. Among them, 3d was found to show the best asymmetric induction in promoting the addition of Et₂Zn to various aldehydes, providing (R)-secondary alcohols in up to 98% ee.     

Predicting the R/S absolute configuration in asymmetric bifunctional catalysis (ABC)

A predictive model for assigning the R/S absolute configuration in chiral Lewis base-dependent asymmetric bifunctional catalysis (ABC) has been developed. Chiral Lewis base (LB^∗)-dependent ABC abolishes the chiral Lewis acid (LA^∗) component as the stereochemical determining factor in asymmetric catalysis. By correlating the constant LB^∗ chirality to the facial preference for the LA^∗-bound carbonyl group for nucleophile delivery, the R/S absolute configuration of the products can be predicted a priori.     

Synthesis of the two enantiomers of the sex pheromone of Diabrotica Undecimpunct at a Howardi and of chiral precursors of other pheromones starting from enantiomerically pure methyl hydrogen (R)-3-methylglutarate

Readily available methyl hydrogen (R)-3-methylglutarate(2) is a useful chiral building block for the synthesis of several biologically active compounds. Enantiomerically pure (R)-2 has been employed to synthesize stereospecifically each of the two enantiomers, 1a and 1b, of 10-methyl-2-tridecanone, the sex pheromone of the southern corn rootworm, Diabrotica undecimpunctata howardi Barber. Compound (R)-2 has been also used to prepare 99% optically pure (R)-3-methyl-1-pentanol (6) and enantiomerically pure (R)-5-methyl-i-tricosyne (7). These compounds are useful building blocks suitable for the further elaboration to other chiral insect pheromones.