Tri- and tetrasubstituted α-fluorocyclohexanones with enantiomeric excesses in the range of 97–100%

The α-fluorinated trisubstituted ketones (2S,5R)-(−)-7-Ia, (2R,5R)-(+)-7-IIe, (2S,5R)-(−)-8-Ia and (2R,5R)-(+)-8-IIe were synthesised from (+)-dihydrocarvone (99% (R)-configuration at C-5) and fully characterised. α-Fluorinated tetrasubstituted ketones (−)-9-Ia, (+)-9-Ia, (+)-9-IIa and (+)-10-Ia having e.e.s of ≥97% were synthesised as racemates from 3-methyl cyclohexenone then resolved into the pure enantiomers using chiral HPLC and fully characterised.     

Synthesis of novel β-amino alcohols and their application in the catalytic asymmetric sulfoxidation of sulfides

Novel chiral norephedrine-based β-amino alcohol ligands containing a thiophene ring were prepared from norephedrine and substituted furan carbaldehydes (methyl- or ethyl-substituted) and used in combination with VO(acac)₂ for the asymmetric oxidation of aryl methyl sulfides using H₂O₂ as an oxidant. Amino alcohol derived Schiff bases 4,5a–b gave higher enantiomeric excesses than amino alcohol-derived reduced Schiff based ligands 6,7a–b. Of these chiral ligands, (1S,2R)-5b and (1S,2R)-7b gave high yields (90%) with moderate to high enantioselectivities (78%, 96% ee, respectively). The oxidation of other aryl methyl sulfides with (1S,2R)-5b and (1S,2R)-7b as ligands afforded the corresponding sulfoxides in 60–89% yields and with 92–99% ee.     

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.     

Absolute configuration of (−)-4-methylheptan-3-ol,a pheromone of the smaller european elm bark beetle,as determined by the synthesis of its (3R,4R)-(+)- and (3S,4R)-(+)-isomers

Nerol and geraniol were stereoselectively converted to (±)-threo- and (±)-erythro-4-methylheptan-3-ol respectively. (R)-(+)-Citronellic acid was converted to a mixture of (3R,4R)-(+)-threo- and (3S,4R)-(+)-erythro-isomers which was separable by GLC. These syntheses established the absolute configuration of the naturally occurring (?)-4-methylheptan-3-ol to be 3S,4S.     

Effect of α-fluorination on asymmetric epoxidation of trans-olefins using α-fluorinated cyclohexanone dioxiranes

Epoxidations of trans-β-methylstyrene, trans-stilbene and trans-methyl p-methoxycinnamate using chiral dioxiranes derived from both enantiopure diastereomers of α-fluoro cyclohexanones, (2S, 5R)-3a-6a and (2R, 5R)-3e-6e are studied and compared. From ab initio calculations at the HF/6-31G^∗ level of conformational inter-conversion for (2S, 5R)-D5a and (2R, 5R)-D5e dioxiranes it was found that, due to the α-fluorine atom, conformer K1 is more stable in the case of (2S, 5R)-D5a while conformer K2 is more stable in the case of (2R, 5R)-D5e. However, in both cases, the more stable conformers, K1 and K2, undergo rapid inter-conversion. Therefore, based on slow epoxidation reactions and rapid ring inversion of six-membered ring dioxiranes the Curtin-Hammett principle holds. Conformation K2 with axial fluorine having been found to be more reactive, the inversion of configuration observed for the epoxides obtained with ketones 3e-6e (compared with ketones 3a-6a) could be rationalized from competitive reactions of K2 and K1 conformations leading to simultaneous production of both (−) and (+) epoxides in the case of ketones 3e-6e.     

The crystal structure and molecular conformation of threo 5-methylmetadone in relation to opioid receptor binding

Crystals of the hydrochloride salt of the biologically inactive threo isomer of 5-methylmethadone, C₂₂H₃₀ONCl, are monoclinic space group P2₁ with unit cell dimnsionsa = 11.019 Å, b = 8.6153Å, c = 10.680Å and β = 93.026°. The observed conformation is one in which the nitrogen bearing chain is extended with the substituents on C(5) and C(6) nearly eclipsed, a feature compatible with NMR studies and molecular mechanics calculations. The very potent agonist (5S, 6S)-erythro-5-methylmethadone has a solid state conformation in which the N atom is rotated back toward the phenyl rings [C(4)-C(5)-C(6)-N = 97°]in agreement with molecular mechanics calculations. The fact that the more potent enantiomers, (6R)-methadone and (5S)-isomethadone, and the inactive threo isomer are observed in the extended solid state conformation in contrast to (5S, 6S)-erythro-5-methylmethadone is consistent with three different models for their interaction with opioid receptors. It is proposed that the more likely of these involves a receptor bound conformation of (6R)-methadone and (5S)-isomethadone that resembles the conformation of (5S, 6S)-erythro-5-methylmethadone or that opioid receptors recognize both gauche-like and extended conformations.     

An unexpected high erythro-selection in the Grignard reaction with an N,O-acetal: a concise asymmetric synthesis of indolizidine alkaloid (−)-2-epi-lentiginosine

Starting from commercially available lactone 10, a concise and highly diastereoselective synthesis of (?)-(lS,2R,8aS)-2-epi-lentiginosine (2) is described. The synthesis featured an unexpected highly erythro-selective reaction of Grignard reagent 7 with the protected N,O-acetal 8. The stereochemical outcome of this reaction is contrary to the known results involving the reactions with O-benzyl protected aminofuranosides and aminoglycosides. Thus, this method constitutes an extension of the threo-diastereoselective C–C bond formation methodology.     

Synthesis and evaluation of new chiral diols based on the dicyclopentadiene skeleton

The resolution by Lipase PS of rac-5 (from reduction of ketone 6, obtained from dicyclopentadiene with a new environment-friendly synthesis) gives (2S)-5, which was further reduced to the endo(2R)-1a alcohol. The endo(2S)-1b alcohol was obtained from camphor with a multistep synthesis. Pinacol couplings of 3a,b, carried out with Mg/Hg or Corey's general procedure respectively, afforded with high diastereoselectivity the C₂ symmetry diols (2R,2′R)-2a and (2S,2′S)-2b, with endo oriented OH functions. The enantiogenic power of the endo alcohol (2R)-1a and (2S)-1b and of the diols (2R,2′R)-2a and (2S,2′S)-2b was tested towards the LiAlH₄ reduction of acetophenone. The C₂ symmetry appears to play a fundamental role.     

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.     

Photochemische Umsetzung von optisch aktiven 2-(1′-Methylallyl)anilinen mit Methanol

Photochemical Reaction of Optically Active 2-(1′-Methylallyl)anilines with Methanol It is shown that (?)-(S)-2-(1′-methylallyl)aniline ((?)-(S)- 4 ) on irradiation in methanol yields (?)-(2S, 3R)-2, 3-dimethylindoline ((?)-trans- 8 ), (?)-(1′R, 2′R)-2-(2′-methoxy-1′-methylpropyl)aniline ((?)-erythro- 9 ) as well as racemic (1′RS, 2′SR)-2-(2′-methoxy-1′-methylpropyl) aniline ((±)-threo- 9 ) in 27.1, 36.4 and 15.7% yield, respectively (see Scheme 3). By deamination and chemical correlation with (+)-(2R, 3R)-3-phenyl-2-butanol ((+)-erythro- 13 ; see Scheme 4) it was found that (?)-erythro- 9 has the same absolute configuration and optical purity as the starting material (?)-(S)- 4 . Comparable results are obtained when (?)-(S)-N-methyl-2-(1′-methylallyl)aniline ((?)-(S)- 7 ) is irradiated in methanol, i.e. the optically active indoline (+)-trans- 10 and the methanol addition product (?)-erythro- 11 along with its racemic threo-isomer are formed (cf. Scheme 3). These findings demonstrate that the methanol addition products arise from stereospecific, methanol-induced ring opening of intermediate, chiral trans, -(→(?)-erythro-compounds) and achiral cis-spiro [2.5]octa-4,6-dien-8-imines (→(±)-threo-compounds; see Schemes 1 and 2).     

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.     

Lipase mediated enantiomer and diastereomer separation of 2,2′-[1,2- and 1,3-phenylenebis(oxy)]dicyclohexanols

Separation of diastereomeric and enantiomeric mixtures of 2,2′-[1,2- and 1,3-phenylenebis(oxy)]dicyclohexanols rac-3a and meso-3a, and rac-3b and meso-3b—resulting from the reactions of pyrocatechol 1a and resorcinol 1b with cyclohexene oxide 2—were performed using acetylation catalyzed by the highly stereoselective Candida antarctica lipase B (Novozym 435). The absolute configurations of the resulting diols (S,S,S,S)-3a,b, monoacetates (R,R,S,S)-4a,b and diacetates (R,R,R,R)-5a,b were assigned on the basis of the steric analogy to the acetylation of racemic trans-2-phenoxycyclohexanol rac-6 with the same enzyme resulting in the known acetate (−)-(R,R)-7.     

Formation of chiral tertiary homoallylic alcohols via Evans aldol reaction or enzymatic resolution and their influence on the Sharpless asymmetric dihydroxylation

Enantioenriched tertiary homoallylic alcohol derivatives (S)-2c and (S)-2a were obtained via Evans aldol methodology and enzymatic resolution of racemic tertiary acetate 2e, respectively. In order to study asymmetric 1,3-induction of the stereogenic center present in 2, congener (R)-2a as well as its O-protected derivatives (R)-2b-d were submitted to Sharpless asymmetric dihydroxylation to yield the diastereomeric 1,2,4-triol derivatives (2R,4R)- and (2S,4R)-3a-d, revealing that neither the substrate nor the Sharpless catalyst exert any stereocontrol. Similar observations were made for the less bulky alkynyl-substituted derivative 12b. However, by using a directed dihydroxylation, the anti product (2R,4R)-3a was favored.     

Stereoselective production of (S)-1-aralkyl- and 1-arylethanols by freshly harvested and lyophilized yeast cells

Substituted (S)-1-phenyl- 2a–h and (S)-1-benzyl-propan-2-ols 4a and b, and (S)-1-phenylethanol 6 were produced from prochiral ketones 1a–h, 3a,b and 5 by reductions with freshly harvested Zygosaccharomyces rouxii and Debaryomyces hansenii cells. The bioreductions were also performed by lyophilized cells. Comparison of the secondary alcohols from the bioreductions 2b–e,g,h and 4a and authentic (S)-alcohols (S)-2b–e,g,h and (S)-4a synthesized from enantiopure (S)-methyloxirane 7 proved the absolute configuration of the products.     

2,2′-Dihydroxy-3,3′-dimethoxy-5,5′-dimethyl-6,6′-dibromo-1,1′-biphenyl: preparation,resolution, structure and biological activity

The preparation and resolution of the titled conformationally stable biphenyl 1 has been performed in high chemical yield starting from creosol 2. Enantiopure biphenyls (aR)-(+)-1 and (aS)-(−)-1 were obtained by the corresponding menthylcarbonate diastereomer and successive reduction. The absolute configuration and specific rotation were correlated by X-ray analysis of the crystal structure of diastereopure menthylcarbonate (aS,1R,1′R,2S,2′S,5R,5′R)-(+)-16. Preliminary biological evaluation of both racemic enantiomers of 1 has been carried out on melanoma cell lines and significant and selective anticancer activity has been observed for the enantiomer (aS)-(−)-1.     

(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.     

Traceless chirality transfer from a norbornene β-amino acid to pyrimido[2,1-a]isoindole enantiomers

The synthesis of two enantiomeric pairs of pyrimidoisoindoles 9a, 9b and 10a, 10b is reported. During a domino ring-closure reaction, followed by cycloreversion, the chirality of diendo-(?)-(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide [(?)-1] was successfully transfered to heterocycles (+)-9a, (+)-10a, (?)-9b, (?)-10b and (?)-10c.     

Polyhydroxylated pyrrolizidines. Part 8. Enantiospecific synthesis of looking-glass analogues of hyacinthacine A5 from DADP

(1R,2S,3S,5R,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine[(−)-3-epihyacinthacine A₅, 1a] and (1S,2R,3R,5S 7aS)-1,2-dihydroxy-3-hydroxymethylpyrrolizidine[(+)-3-epihyacinthacine A₅, 1b] have been synthesized either by Wittig's or Horner-Wadsworth-Emmond's (HWE's) methodology using aldehydes 4 and 9, both prepared from (2S,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (2, partially protected DADP), and the appropriate ylides, followed by cyclization through an internal reductive amination process of the resulting α,β-unsaturated ketones 5 and 10, respectively, and total deprotection.     

Masked constrained cysteines: diastereoselective and enantioselective synthesis of 1-amino-2-mercaptocyclopropanecarboxylic acid derivatives

A diastereoselective and enantioselective synthesis of (Z)-1-benzoylamino-2-tritylsulfanylcyclopropanecarboxylic acid derivatives 8a,b and 9a,b was achieved starting from (−)- or (+)-menthyl 2-benzoylamino-3-tritylsulfanylacrylates 3a,b. Compounds 3 were reacted with diazomethane giving the corresponding pyrazolines 4a,b and 5a,b. These compounds, on melting, were transformed, under steric control, into the cyclopropaneamino acid derivatives (R,R)-8a,b and (S,S)-9a,b. The synthesis of a large class of chiral 2-S-alkyl-1-aminocyclopropanecarboxylic acid derivatives is possible after removing the trityl protecting group and subsequent alkylation reactions.     

Synthesis of mono- and dihydroxy-substituted 2-aminocyclooctanecarboxylic acid enantiomers

(1R,2S,6R)-2-Amino-6-hydroxycyclooctanecarboxylic acid (?)-10 was synthesized from (1R,2S)-2-aminocyclooct-5-enecarboxylic acid (+)-2 via an iodolactone intermediate, while (1R,2S,3R,4S)-2-amino-5,6-dihydroxycyclooctanecarboxylic acid (?)-12 was prepared by using the OsO₄-catalyzed oxidation of Boc-protected amino ester (?)-5. The stereochemistry and relative configurations of the synthesized compounds were determined by 1D and 2D NMR spectroscopy (based on 2D NOE cross-peaks and ³J(H,H) coupling constants) and X-ray crystallography.