(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries in Diels–Alder reactions

A study of the Diels–Alder reactions of the esters derived from acrylic, methacrylic, trans-crotonic and trans-cinnamic acid and the chiral auxiliaries (R)- and/or (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone (4, 17, 25 and 26, respectively) with different dienes [cyclopentadiene 5, isoprene 8, 11,12-dimethylene-9,10-dihydro-9,10-ethanoanthracene 9 and anthracene 10], catalyzed by titanium tetrachloride, is described. Cyclopentadiene gave adducts with esters (R)- or (S)-4 and (R)-25 with high endo- and facial-diastereoselectivities. Diene 5 reacted with (±)-17 without endo-diastereoselectivity and failed to give a cycloadduct with (±)-26. Isoprene reacted only with ester (S)-4 with high facial-diastereoselectivity. The reaction of 9 with (R)-4 failed, because the diene was not stable under the acid reaction conditions. Adducts derived from 10 and esters (S)-4 and (R)-17 could be obtained with high facial-diastereoselectivity. LiOH-hydrolysis of the adducts derived from esters (R)- or (S)-4 and (R)-25 gave the corresponding enantiopure acids, the chiral auxiliaries being completely recovered unchanged. However, hydrolysis of the adduct derived from 10 and (R)-17, required more drastic basic conditions which partially epimerized the chiral auxiliary. X-Ray diffraction analysis of the adducts derived from 10 and esters (S)-4 and (R)-17, let us establish their relative configurations and, taking into account the absolute configuration of the starting chiral auxiliary, their absolute configurations.     

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.     

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.     

Enantioselective synthesis of β-amino acids. Part 10: Preparation of novel α,α- and β,β-disubstituted β-amino acids from (S)-asparagine

Perhydropyrimidinone (S)-1 is alkylated with very high diastereoselectivity to give trans products (2S,5R)-3, (2S,5R)–4 and (2S,5R)-5. Dialkylation of (S)-1 also proceeds with complete stereoselectivity to afford adducts (2S,5R)-6, (2S,5S)-6, (2S,5R)-7 and (2S,5S)-7. Hydrolysis (6N HCl, 100°C) of monoalkylated derivative (2S,5R)-3 gives enantiopure α-substituted β-amino acid (R)-8. Hydrolysis of dialkylated adducts 6 and 7 affords enantiopure α,α-disubstituted β-amino acids (R)- or (S)-9 and (R)- or (S)-10. Related iminoester (2S,6S)-2 is alkylated with complete diastereoselectivity to give products (2S,6S)-11–13 whose hydrolysis under relatively mild conditions (2N CF₃CO₂H, CH₃OH, 100°C) affords enantiopure N-benzoylated β,β-disubstituted β-amino acid esters (S)-14–16, with intact double bonds in the olefinic substituents.     

Preparation of optically active bridged biphenyls via a stereoselective synthesis of their mono (tricarbonylchromium) complexes. Chiroptical properties and absolute chiralities of the complexes and ligands12

Reaction of the mono(tricarbonylchromium) complex 3 of diphenic acid anhydride with chiral amines gave the optically active imides 9-11. 10 and 11, from (S)-(?) and (R)(+)-phenylalaninol, respectively were separated by chromatography into exo- and endo-diastereomers (a and b) with opposite metallocene chiralities but with the same axial chirality. The (S)-(?) amino-alcohol induces (S)_a-chirality and vice versa. The absolute configurations of the metallocene and axial-chiral parts of the biphenyl system were deduced from the circular dichroism spectra, the former [(R)_m or (S)_m] by comparison with the CD of benchrotrenes of known absolute configuration, the latter [(R)_a or (S)_a] by applying the exciton model of coupled oscillators to the optically stable biphenyl ligands [i.e. the imides (?)- and (+)-8 easily accessible from 10 and 11 by photochemical decomplexation]. (R)_m-(S)_a for the complex (+)-10a (exo) and (S)_m-(S)_a for the endo-isomer (?)-10b, and vice versa for the complex 11. The parent ligands have the configurations (S)_a(?)-8 and (R)_a(+)-8, respectively.Photochemical cleavage of the optically active bis(tricarbonylchromium) complex (?)-13 of the biphenyl lactone 12 at ?60°C afforded optically labile 12 with a half-life time of racemization of ca 10 min at ?20°. On the basis of its CD the configuration (R)_a is tentatively proposed for 12.The work described represents the first example of the preparation of optically-active biphenyls via benchrotrene precursors.     

Enantioselective synthesis of β-amino acids. Part 9: Preparation of enantiopure α,α-disubstituted β-amino acids from 1-benzoyl-2(S)-tert-butyl-3-methylperhydropyrimidin-4-one,

Double alkylation of enantiopure N,N-acetal pyrimidinone (S)-1, a masked chiral derivative of β-alanine prepared from (S)-asparagine, proceeds with high stereoselectivity to give C(5) disubstituted adducts (2S,5R)-6, (2S,5S)-6, (2S,5R)-7, and (2S,5S)-7. Acid hydrolysis of these derivatives affords enantiopure α,α-dialkylated β-amino acids (R)-8, (S)-8, (R)-9, and (S)-9 in very good yields.     

2-Methoxy-2-(1-naphthyl)propionic acid,a powerful chiral auxiliary for enantioresolution of alcohols and determination of their absolute configurations by the 1H NMR anisotropy method

Racemic 2-methoxy-2-(1-naphthyl)propionic acid (1, MαNP acid) was enantioresolved as its esters derived from various chiral alcohols. For example, a diastereomeric mixture of esters prepared from (±)-1 and (1R,3R,4S)-(−)-menthol was easily separated by HPLC on silica gel yielding esters (−)-2a and (−)-2b, the separation factor α=1.83 being unusually large. The ¹H NMR chemical shift differences, Δδ=δ(R)–δ(S), between diastereomers 2a and 2b, are much larger than those of conventional chiral auxiliaries, e.g. Mosher’s MTPA and Trost’s MPA acids. This acid 1 is therefore very powerful for determining the absolute configuration of chiral alcohols by the ¹H NMR anisotropy method. Solvolysis of the separated esters yielded enantiopure acids (S)-(+)-1 and (R)-(−)-1, which are useful for enantioresolution of racemic alcohols.     

Optically active 1-(benzofuran-2-yl)ethanols and ethane-1,2-diols by enantiotopic selective bioreductions

Enantiotopic selective reduction of 1-(benzofuran-2-yl)ethanones 1a–d, 1-(benzofuran-2-yl)-2-hydroxyethanones 4a–c and 2-acetoxy-1-(benzofuran-2-yl)ethanones 3a–c was performed by baker's yeast for preparation of optically active (benzofuran-2-yl)carbinols [(S)-5a–d, (S)-6a–c and (R)-6a–c, enantiomeric excess from 55 to 93% ee].     

Enzyme-catalysed approach to the preparation of triazole antifungals: synthesis of (−)-genaconazole

The work describes a new enzyme-mediated approach to optically active epoxide (2R,3S)-6, which is an important key intermediate in the preparation of single enantiomers of chiral azole antifungals. The conversion of (2R,3S)-6 into (?)-genaconazole is reported as an example of its synthetic relevance.     

Synthesis of (1R,cis,αS)-cypermethrine via lipase catalyzed kinetic resolution of racemic m-phenoxybenzaldehyde cyanohydrin acetate

A technical scale preparation of optically active (1R,cis,αS)-cypermethrine 4 from racemic m-phenoxybenzaldehyde cyanohydrin acetate (RS)-1 and (1R,cis)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid chloride (1R,cis)-3 is described. Key steps of the new procedure are a lipase catalyzed enantioselective transesterification of (RS)-1 with n-butanol and direct acylation of the mixture of (R)-1 and (S)-cyanohydrin (S)-2 with (1R,cis)-3 to give enantiomerically pure (1R,cis,αS)-4. The unchanged (R)-1 is removed from (1R,cis,αS)-4 by distillation, and is racemized with triethylamine to give (RS)-1 which is returned to the process. The total yield of (1R,cis,αS)-4 referred to (RS)-1 is 80%.     

ω-Amino acids and lactams with chiral biaryl axis

The optically active amino acids (R)-7 and (S)-8 were prepared as the first representatives of ω-amino acids possessing a biaryl axis as the sole element of chirality.     

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.     

Reactions of β-substituted amines-IV: Kinetics and stereochemistry of the thermal to (r) 3-chloro-1-ethylpiperidine,and the stereo-chemical course of their reactions with nucleophiles

The rate of the thermal rearrangement of (S) 2 chloromethyl-1-ethylpyrrolidine [(S)-1a] to (R)-3-chloro-1-ethylpiperidine [(R) 2a] has been examined at three temperatures in benzene by PMR and polarimetry. The rearrangement was shown to be completely stereospecific and to obey a simple first order rate law. The calculated E_a ΔH3 and ΔS3 were 22 ± 2 $\text{kcal}\text{mole}$ (25°), 21 ± 2.5 $\text{kcal}\text{mole}$ (25°) and - 10 ± 2 e.u. (0°K) respectively. The effect of solvents having differing dielectric constants was also studied. A transition state 9'a and an ion pair intermediate 3a are suggested for the rearrangement. The stereochemical course of the reactions of (S)-1a, (R)-2a and (S)-2a with hydroxide and methoxide ions have been shown to be 100% stereospecific with an uncertainty of about 1%. The absolute configurations of all optically active reactants and products [(S)- and (R)-4a, (S)-4b (R)- and (S)-5a, (R)-5b, (S,S')-6a, (S,R')-7a and (R,R')-8a] were established by chemical correlations with known compounds or by ORD and chemical inference. The ring opening of both the primary and secondary aziridinium ion positions of 1-azonia-1-ethylbicyclo [3.1.0]hexane [(S)-3a] by nucleophiles proceeds entirely by S_N2 processes. The conversion of (R)-1-ethyl-3-hydroxypiperidine [(R)-5a] to (S)-2a. HCl with thionyl chloride in chloroform proceeds by inversion with 4.8% racemization, whereas the thermal rearrangement of (S)-1a to (R)-2a occurs with complete retention of absolute configuration.     

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.     

Asymmetric synthesis of enantiomerically pure zingerols by lipase-catalyzed transesterification and efficient synthesis of their analogues

The achiral zingerone 1, readily available from ginger, can be easily transformed into chiral derivatives. Zingerol 2, a reduced product of zingerone 1 is expected to be an important new medicinal lead compound. We have achieved a concise synthesis of optically active zingerol (R)-2 and (S)-2 by the lipase-catalyzed stereoselective transesterification of racemic 2. Under the optimized conditions, a lipase from Alcaligenes sp. (Meito QLM) and vinyl acetate in i-Pr₂O or hexane at 35 °C within 1 h gave the alcohol (S)-2 and the acetate (R)-9 with high enantioselectivity without producing acetylated by-products. Since optically active (S)-2 and (R)-9 were obtained through lipase-catalyzed transesterification, other enantiomerically pure novel compounds could all be synthesized.     

Diastereoselective schenck ene reaction of singlet oxygen with chiral allylic alcohols; access to enantiomerically enriched 1,2,4-trioxanes

A series of antimalarial chiral 1,2,4-trioxanes (1-8) were synthesised in high enantiomeric purities. Enantioselective addition of R₂Zn reagent to 3-methyl-2-butenal catalysed by (+)-MIB or (−)-MIB yielded both the enantiomers of the chiral allylic alcohols 9-11 (90-98% ee), which were subjected to diastereoselective photooxygenation in the presence of tetraphenylporphine (TPP) to obtain (R,R)-threo- or (S,S)-threo-β-hydroperoxy alcohols (12-14). Reaction of β-hydroperoxy alcohols (12-14) with different cyclic ketones produced optically active trioxanes 1-8.     

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.     

Chemoenzymatic syntheses of two optically active hexa-azamacrocycles

Two optically active hexa-azamacrocycles with C₂ and D₂ symmetry, respectively, have been efficiently synthesized from the enzymatically prepared (R,R)-cyclohexane-1,2-diamine bis(amidoester) derivative (R,R)-4.     

Acid-catalyzed rearrangement of α-hydroxytrialkylsilanes

Cationic rearrangement of several α-hydroxysilanes is described. Treatment of both (1R,1′R,2′S)-α-hydroxycyclopropylsilane syn-9 and (1S,1′R,2′S)-anti-9 under aqueous H₂SO₄ underwent rearrangement via a common α-silyl cation intermediate A to give a mixture of the ring-opened (R)-vinylsilane 13, the tandem [1,2]-CC bond migration product (1R,2S,1′R)-14, and its 1′S isomer 15. On the other hand, the acidic treatment of (R,E)-α-hydroxyalkenylsilane 8 or (R,Z)-8 was each accompanied with partial racemization to give an enantiomeric isomer of allylic alcohol 23 via a preferential syn-facial S_N2′ reaction, respectively. Both α-hydroxyalkynylsilane 6 and α-hydroxyalkylsilane 12 were inert to the acidic conditions; however, treatment of (R)-α-mesyloxyalkynylsilane 26 under aqueous H₂SO₄ gave a mixture of the optically active rearranged allene 27, α,β-unsaturated ketone 28, and (S)-α-hydroxyalkynylsilane 6 with partial racemization. Comparisons of the reactivities of these α-hydroxysilanes under acidic conditions are also disclosed.     

Practical method for crystalline-liquid resolution of chrysanthemic acids utilizing chiral 1,1′-binaphthol monoethyl ethers directed for process chemistry

We have developed an efficient practical resolution method for (1R,3R)-trans-chrysanthemic acid 1 and (1R,3S)-trans-2,2-dimethyl-3-(2,2-dichloroethenyl)cyclopropanecarboxylic acid 2, based on the preliminary results of the simpler analogues, (1R)-2,2-dichlorocyclopropanecarboxylic acid 3 and (1R)-2,2-dimethylcyclopropanecarboxylic acid 4, using a crystalline-liquid separation procedure (without column chromatography) with chiral 1,1′-binaphthol monoethyl ethers (R)-5b as the key auxiliary. Direct esterifications of 1, 2, 3, and 4 with (R)-5b gave four sets of (1R)- and (1S)-diastereomeric esters 8, 9, 6, and 7, respectively, with markedly different melting points. All of these diastereomers were easily obtained using a simple and one-step crystalline-liquid separation. The separated diastereomers 8 and 9 were easily hydrolyzed to the desired enantiopure acids 1 (>98%) and 2 (>99%), respectively, with recovery of (R)-5b (>90%).