(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries in the enantioselective preparation of α-aryloxypropanoic acid herbicides and α-chlorocarboxylic acids

rac-α-Chlorocarboxylic acids, rac-9a–e, were formally deracemized by reaction of the corresponding acyl chlorides with the chiral auxiliaries (R)- and (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone, (R)- and (S)-4, followed by mild alkaline hydrolysis. The highest o.p. (99%) was obtained in the case of (S)-α-chloropropanoic acid, a known precursor for the synthesis of (R)-α-aryloxypropanoic acid herbicides such as dichlorprop-P, (R)-3a, or mecoprop-P, (R)-3b, which, together with their enantiomers, were also obtained in moderate e.e.s by dynamic kinetic resolution from (αRS,3S)-4,4-dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-bromopropanoate, (αRS,3S)-6, by reaction with the corresponding phenoxide followed by mild acid hydrolysis.     

Synthesis and anticonvulsant activities of (R)-(O)-methylserine derivatives

Efficient procedures for the synthesis of (R)-N-benzyl-2-amino-3-methoxypropionamide ((R)-3), 2-acetamido-3-methoxypropionic acid (4), and O-methylserine (5) are described beginning from (R)-Cbz-serine ((R)-7). The reactions proceeded with little or no racemization and permitted the synthesis of the potent anticonvulsant (R)-N-benzyl-2-acetamido-3-methoxypropionamide ((R)-2). The anticonvulsant activities of 2–4 were determined revealing the surprising activity of (R)-2.     

Natural product synthesis from (8aR)- and (8aS)-bicyclofarnesols: synthesis of (+)-wiedendiol A, (+)-norsesterterpene diene ester and (−)-subersic acid

Both enantiomers (8aR)-7 and (8aS)-7 of bicyclofarnesol were synthesized from the enzymatic resolution products (1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-5 (98% ee) and acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aS)-6 (>99% ee), respectively. The formal synthesis of (+)-wiedendiol 1 was achieved via a coupling reaction of an ate complex derived from 1,2,4-trimethoxybenzene with allyl bromide (8aS)-8 derived from (8aS)-7. The total synthesis of (+)-norsesterterpene diene ester 2 was achieved, based on the synthesis of (13E,10S)-α,β-unsaturated aldehyde 12, derived from (8aS)-7, followed by the selective construction of the (3E,5E)-diene moiety including a C(2)-stereogenic centre in (+)-2. The total synthesis of (−)-subersic acid 3 was carried out based on a Stille coupling between allyl trifluoroacetate congener 25c, derived from (8aR)-7, corresponding to the diterpene part, and aryl stannane congener 26 in the presence of Pd catalyst and CuI as an additive.     

Synthesis of oligomers including eight P-chiral centers and the construction of the 12-phosphacrown-4 skeleton

The stepwise oxidative coupling reaction from (S,S)-1 gave optically active oligomers, (S,R,R,S)-2 and (S,R,S,R,R,S,R,S)-3, having four and eight chiral phosphorus atoms, respectively. The behaviors of these oligomers in the solid state and in solution were investigated in detail. The first construction of a 12-phosphacrown-4 skeleton was also reported.     

A straightforward synthesis of both enantiomers of allo-norcoronamic acids and allo-coronamic acids,by asymmetric Strecker reaction from alkylcyclopropanone acetals

Methylcyclopropanone hemiacetal (2S)-3a underwent the asymmetric Strecker reaction induced by a chiral amine to provide a useful synthesis of enantiomerically pure (1R,2S)-(+)-allo-norcoronamic acid 1 in good yield and high enantiomeric excess. From racemic alkyl hemiacetal (±)-3, the same methodology also constituted a useful way to prepare both (+)-1 and (−)-1 and (+)-allo-coronamic acid 2 and its antipode (−)-2 with good yield and high enantiomeric excess.     

Efficient synthesis of 3,4- and 4,5-dihydroxy-2-amino-cyclohexanecarboxylic acid enantiomers

An efficient method for the synthesis of (1S,2R,4R,5S)- and (1R,2R,4R,5S)-2-amino-4,5-dihydroxycyclohexanecarboxylic acids (?)-6 and (?)-9 and (1R,2R,3S,4R)- and (1S,2R,3S,4R)-2-amino-3,4-dihydroxycyclohexanecarboxylic acids (?)-15 and (?)-18 was developed by using the OsO₄-catalyzed oxidation of Boc-protected (1S,2R)-2-aminocyclohex-4-enecarboxylic acid (+)-2 and (1R,2S)-2-aminocyclohex-3-enecarboxylic acid (+)-11. Good yields were obtained. The stereochemistry of the synthesized compounds was proven by NMR spectroscopy.     

Efficient and practical synthesis of both enantiomers of 6-silyloxy-3-pyranone derivatives

Lipase catalyzed kinetic resolution of racemic cis-6-(tert-butyldimethylsilyloxy)-3,6-dihydro-2H-pyran-3-ol (rac)-1 was achieved in high enantiomeric excess. Transesterification of (rac)-1 with vinylacetate in ^tBuOMe yielded the alcohol (3S,6R)-1 in 99.0% ee, whereas (3R,6S)-1 was obtained, in 99.0% ee, by the lipase catalyzed ester hydrolysis of acetate (3R,6S)-2, which was obtained along with the transesterification. Both (3S,6R)-1 and (3R,6S)-1 were subjected to oxidation to provide the corresponding 6-silyloxy-3-pyranone (6R)-3 and (6S)-3, respectively. Application to the synthesis of 7, which is the key intermediate of asymmetric synthesis of pseudomonic acid A 9 is also described.     

Asymmetric Diels–Alder reaction using a new chiral β-nitroacrylate for enantiopure trans-β-norbornane amino acid preparation

The main nitronorbornene adduct derived from the asymmetric Diels–Alder reaction of (S)-benzyl-4-(3-(3-nitroacryloyloxy)-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoate (S)-1 and cyclopentadiene was isolated and transformed to afford the enantiopure bicyclic β-amino acid (1S,2R,3R,4R)-trans-β-norbornane amino acid 9. The enantiomer (1R,2S,3S,4S)-9 could be obtained by the same synthetic route by using the chiral auxiliary (R)-1.     

Enantioselective hydrolysis of (RS)-2-fluoroarylacetonitriles using nitrilase from Arabidopsis thaliana

The enzymatic resolution of 2-fluoroarylacetonitriles (RS)-3 using nitrilase from the plant Arabidopsis thaliana is described. Racemic 2-fluoronitriles 3 are easily accessible from O-silylated aromatic cyanohydrins 2 by reaction with DAST. The nitriles (RS)-3 were hydrolysed with the nitrilase as a catalyst, not to the expected 2-fluoroarylacetic acids but to the corresponding (R)-2-fluoroarylacetamides (R)-5 as the main products. After optimization of reaction conditions (pH 9, 7°C), the enantiomeric excesses of (R)-5a,c and f (R=H, 3-Me, 3-OMe) could be improved to >99% by one recrystallization. The acid catalysed hydrolysis of (R)-5a,5c and 5f afforded the corresponding (R)-2-fluoroarylacetic acids (R)-4a,4c and 4f without racemization.     

Asymmetric synthesis of isoquinuclidines by Diels–Alder reaction of 1,2-dihydropyridine utilizing a chiral Lewis acid catalyst

The chiral isoquinuclidine derivative, 2-azabicyclo[2.2.2]octane ring system, endo-(7R)-3 was obtained in good yield with excellent diastereoselectivity (up to 92% de) by Diels–Alder reaction of 1-(phenoxycarbonyl)-1,2-dihydropyridine 1 with N-acryloyl-(4S)-4-benzyloxazolidin-2-one (4S)-2 using titanium-(2R,3R)-TADDOLate 4 as a chiral Lewis acid catalyst in toluene at 0 °C. On the other hand, endo-(7S)-3 was obtained in good yield with excellent diastereoselectivity (up to 97% de) by Diels–Alder reaction of 1 with (4R)-2 using Cu(OTf)₂/(4S,4′S)-bis(oxazoline) catalyst 8 as a chiral Lewis acid catalyst in dichloromethane at 0 °C. In these reactions, the choice of solvent and the combination of titanium-(2R,3R)-TADDOLate 4 {or Cu(II)/(4S,4′S)-bis(oxazoline) 8} and dienophile (4S)-2 {or (4R)-2} are very important. The stereochemistry of endo-(7R)-3 has been established to be (1R,4S,7R) and the reaction mechanism is proposed.     

Synthesis of enantiomerically pure diethyl (R)- and (S)-2-hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates

The synthesis and ee determination of diethyl 3-azido-2-hydroxypropylphosphonates from 2,3-epoxypropylphosphonates have been optimised. Enantiomerically enriched diethyl (R)- and (S)-2-hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates (R)-3a–j and (S)-3a–h as well as (S)-3j were synthesised from diethyl (R)- and (S)-2,3-epoxypropylphosphonates in a reaction sequence including azidolysis followed by 1,3-dipolar cycloaddition with selected alkynes.     

Total synthesis of (+) methyl β-d-vicenisaminide

The total synthesis of methyl β-d-vicenisaminide 1 has been achieved. In this approach, the synthesis of enantiomerically pure methyl (4R,5S)- and (4S,5R)-4-azido-5-hydroxy-2(E)-hexenoates 2 was established by enzymatic resolution of (±)-anti-5-acetoxy -4-azido-2(E)-hexenoate 4. Another stereogenic center was introduced by base-catalyzed intramolecular conjugate addition of a hemiacetal-derived alkoxide nucleophile obtained by the reaction of methyl (4S,5R)-N-4-tert-butoxycarbonyl-N-methylamino-5-hydroxyl-2(E)-hexenoate 8 and benzaldehyde in the presence of a base.     

Absolute configuration of 2-hydroxy-2-(1-naphthyl)propionic acid as determined by the 1H NMR anisotropy method

Enantiopure 2-hydroxy-2-(1-naphthyl)propionic acid (+)-2 was prepared by the stereoselective Grignard reaction of 1-naphthylmagnesium bromide with (1R,3R,4S)-menthyl pyruvate 3 or (1R,3R,4S)-8-phenylmenthyl pyruvate 4, and the absolute configuration of acid (+)-2 was unambiguously determined to be S by the ¹H NMR anisotropy method.     

First stereoselective synthesis of (4aS,5R)-4,4a,5,6,7,8-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone

The synthesis of enantiomerically pure (4aS,5R)-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone (−)-1 is described for the first time. The synthesis starts from (R)-3-methylcyclohexanone and involves the preparation of Piers enol lactone 6 in its enantiopure form as the key intermediate. Treatment of (+)-6 with methyl lithium followed by an intramolecular aldol reaction gives the bicyclic enone (−)-1.     

Stereospecific synthesis and hydrolysis of optically active diaryl(acylamino)(acyloxy)spiro-λ4-sulfanes and related cyclic diaryl(acylamino)sulfonium salts

The stereospecific synthesis of diaryl(acylamino)(acyloxy)spiro-λ⁴-sulfanes (S)-(+)-2, (R)-(+)-5, (S)-(+)-8, and their conversion into related diaryl(acylamino)sulfonium tetrafluoroborates (R)-(+)-3, (S)-(+)-6, (R)-(+)-9, respectively, is described. The enantiomers of spiro-λ⁴-sulfanes (S)-(+)-2, (R)-(+)-5 and (S)-(+)-8 were prepared by dehydration of the corresponding optically active sulfoxide–carboxylic acids (R)-(+)-1, (R)-(−)-4 and (S)-(+)-7, respectively, which were obtained from the racemic forms by diastereoisomeric salt separation with homochiral organic bases. The stereomechanism of the hydrolysis reaction of spiro-λ⁴-sulfanes and sulfonium tetrafluoroborates that depends on pH, the nature of the axial heteroatom, the size of the spiro rings and carboxyl neighbouring group participation is also discussed.     

Application of chiral tetrahydropentalene ligands in rhodium-catalyzed 1,4-addition of (E)-2-phenylethenyl- and (Z)-propenylboronic acids to enones

Chiral tetrahydropentalenes (3aR,6aR)-1 have been prepared and used as ligands in the Rh-catalyzed 1,4-addition of 1-alkenylboronic acids to cyclic enones 5. It has been discovered that the stereochemistry of the reaction was controlled by the steric properties of the aryl groups in 1 rather than their electronic nature. In the vinylation with (E)-2-phenylethenylboronic acid 5, ligands (3aR,6aR)-1 provided enantioselectivity up to 87% ee and gave high yields of ethenylketones 6 in the presence of 1 (6.6 mol %). The configuration of all ketone products obtained with (3aR,6aR)-1 is (S). Rh-catalyzed reaction of cyclopentenone 4a and (Z)-propenylboronic acid 7 in the presence of ligands (3aR,6aR)-1 yielded at 50 °C an inseparable mixture of (Z)- and (E)-ketones 8 with (Z)-8 as the major product and both in only moderate enantiomeric excess.     

Resolution of C2-symmetric 2,3-diphenylbutane-1,4-diol and purification of diastereomeric 1,4-diphenylbutane-1,4-diol using (S)-proline and boric acid

Racemic 2,3-diphenylbutane-1,4-diol (±)-1 is resolved to obtain the corresponding (R,R)-isomer in 98% e.e. through reaction with (S)-proline and boric acid. Partially resolved (R,R)-(−)-1 and (S,S)-(+)-1 have been enriched to obtain samples of 95 and 97% e.e. through reaction with (S)-proline and boric acid. Diastereomeric 1,4-diphenylbutane-1,4-diol 2 has been purified to obtain the (R,R)-isomer in 98% e.e. using (S)-proline and boric acid.     

Highly enantioselective preparation of C2-symmetrical diols: microbial hydrolysis of cyclic carbonates

A new type of microbial enantioselective hydrolysis of C₂-symmetrical cyclic carbonates is disclosed. During the screening test of the five-membered substrate (4,5-dimethyl-1,3-dioxolan-2-one 5), Pseudomonas diminuta was selected as the best strain to perform the stereoselective hydrolysis. The reaction of dl-5 with this microorganism in aqueous media containing THF as the co-solvent afforded (S,S)-5 and (R,R)-butanediol 1 in excellent yields. It was found that the ring size did not affect the reactivity and enantioselectivity although the enzyme had a high substrate specificity for the side chain. A six-membered cyclic carbonate, dl-4,6-dimethyl-1,3-dioxan-2-one 6, was smoothly hydrolyzed with higher enantioselectivity to afford the optically active (S,S)-6 and (R,R)-2,4-pentanediol 2.     

Matched and mismatched pairings in B-secotaxane construction: a structure elucidation study

The synthesis of the basic B-seco taxoid skeleton was achieved through a C10–C11 coupling of the A-ring segment (14S)-1 with the C-ring segments (10S) and (10R)-α-alkoxyorganolithium reagents, prepared in situ from 2 and 6 through nBuLi mediated transmetallation. The matched reactions of (14S)-1 with (10S)-2 and (10S)-6 displays an outstanding diastereoselectivity providing 12 and 34, respectively, as single isomers and hence allowing a convenient entry to highly functionalized taxoid diterpene frameworks. Significant mismatching was observed with the (10R)-epimer of 2 and 6 yielding little, if any, diastereoselectivity. The structures of B-secotaxanes were assigned on the basis of spatial proximity effects in the proton NMR spectrum. Assignment of the C10/C11 stereochemistry was made possible through conversion of the B-secotaxoid frameworks, derived from the matched and mismatched adducts, to the corresponding cyclic acetals. Configurational stability of α-alkoxyorganolithium derivatives was verified in all the cases investigated. Structure elucidation of these adducts was essential for the successful C1–C2 bonding via an intramolecular aldol reaction, given the fact that adducts containing a β-MOM substituent at C10 would be disfavored for such an endeavor.     

Stereoselective synthesis of biologically active tetronic acids

(4R)-3-Amino-4-trimethylsilyloxy-2-alkenoates (R)-3, obtained from O-trimethylsilyl protected optically active cyanohydrins (R)-1 via the Blaise reaction, are hydrolyzed under mildly acidic conditions to give optically active tetronic acids (R)-4 without racemization. From the follow-up reactions of (R)-4 investigated, only methylation with diazomethane afforded the biologically active tetronic acid derivative (R)-5a without racemization whereas acylation and reductive alkylation, respectively, resulted in partial racemization or failed on the whole.