Enantiodivergent syntheses of cycloheptenone intermediates for guaiane sesquiterpenes

The syntheses of enantiomeric 6-isopropenyl-3-methyl-2-cycloheptenones 16 and 22 have been effected starting from (R)-(−)-carvone. In the synthesis of 16, (R)-(−)-carvone was reduced and the resulting dihydrocarvone transformed regioselectively into silyl enol ethers. Cyclopropanation with dibromocarbene and in situ rearrangement gave an α-bromo-cycloheptenone which was reduced to the (R)-(+)-cycloheptenone 16. In the synthesis of 22, (R)-(−)-carvone was cyclopropanated with a sulfur ylide, followed by reduction with LiAlH₄ and acid-catalyzed cyclopropylcarbinyl rearrangement to afford a cycloheptenol. Oxidation and double bond conjugation led to the (S)-(−)-cycloheptenone 22 in a partially racemized form. Four cycloheptenones have been obtained and are suitable intermediates for the enantiodivergent syntheses of guaiane sesquiterpenes.     

Kinetic resolution of 1,2-dihydroxy-3-ferrocenylpropane by sequential lipase-catalysed esterification

One-pot sequential esterification of 1,2-dihydroxy-3-ferrocenylpropane 1, catalysed by lipase from Pseudomonas cepacia, allowed kinetic resolution of the racemate, affording (−)-(R)-1-acetoxy-2-hydroxy-3-ferrocenyl-propane (−)-2, and (+)-(S)-1,2-diacetoxy-3-ferrocenylpropane (+)-3, in high chemical yield and enantiomeric excess.     

Total syntheses of macrosphelides (+)-A, (−)-A and (+)-E

Total syntheses of (+)-macrosphelide A 1 (18.5% overall yield in 11 steps) and (+)-macrosphelide E 2 (23.9% overall yield in 11 steps) have been achieved via the chemoenzymatic reaction product (4R,5S)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 4. The enantiomer (−)-A (1) (14.2% overall yield in 11 steps) of (+)-1 was also synthesized from the chemoenzymatic reaction product (4S,5R)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 4.     

Bone collagen cross-links: an efficient one-pot synthesis of (+)-pyridinoline and (+)-dexoypyridinoline

A one-pot reaction of (2S,5R)-(−)-tert-butyl-[(2-tert-butoxycarbonyl)amino]-5-hydroxy-6-aminohexanoate 2b or (S)-(−)-tert-butyl-[(2-tert-butoxycarbonyl)amino]-6-aminohexanoate 2c with (S)-(−)-tert-butyl-6-bromo-[bis-(2-tert-butoxycarbonyl)amino]-5-oxohexanoate 5 in the presence of K₂CO₃ in MeCN–MeOH followed by hydrolysis gave bone collagen cross-links, (+)-Pyd 1b or (+)-Dpd 1c, in 42–48% yield, respectively.     

Synthesis of both RP and SP enantiomers of unsymmetrical methylphosphonates based on a new approach utilizing a P-ester bond with α-hydroxyacids

Condensation of methyl methylphosphonochloridate with the dilithium salt of 2-methyllactic acid gave P-racemic methylphosphonates which unexpectedly contained two units of α-hydroxyacid linked via carboxylic ester bond. The racemic mixture was chromatographically separated via diastereomeric salts with quinine or cinchonine to give, based on the X-ray analysis, pure (R_P)-(+) and (S_P)-(−) enantiomers. Both enantiomers were immobilized on the ArgoGel^®–OH solid support. Condensation of methyl methylphosphonochloridate with α-hydroxyacid methyl esters [2-methyllactate, (S_C)-(−)-lactate, methyl (S_C)-(+) and (R_C)-(−)-mandelates] gave chromatographically inseparable 1:1 mixtures of diastereomers in 63–69% yields. A basic hydrolysis of the latter resulted in a selective and unexpected cleavage of the P–OMe group in a quantitative yield [(S_C)-(+) and (R_C)-(−)-mandelates, (S_C)-(−)-lactate] or simultaneous cleavages of P–OMe and C(O)OMe groups (2-methyllactate).     

Resolution of 3-methyl-3-phospholene 1-oxides by molecular complex formation with TADDOL derivatives

The antipodes of 1-phenyl-3-methyl-3-phospholene 1-oxide 1a were separated in good yield and in high enantiomeric excess (∼99% ee) by resolution via formation of diastereomeric complexes with (4R,5R)-(−)- and (4S,5S)-(+)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane 2 (TADDOL) or (−)-(2R,3R)-α,α,α′,α′-tetraphenyl-1,4-dioxaspiro[4.5]decan-2,3-dimethanol 3. The method was also suitable for the resolution of the 1-ethoxy-3-phospholene derivative 1b, suggesting that our novel procedure may be of general value, both for the resolution of chiral phosphine oxides and phosphinates.     

Convenient access to both enantiomers of new azido- and aminoinositols via a chemoenzymatic route

1,2-diacetylconduritol E, (±)-1, through complementary use of Mucor miehei (Lipozyme^® IM) and Candida cylindracea lipases, affords (1S)-1,2-diacetylconduritol E, (+)-1, (1R)-1,2-diacetylconduritol E, (−)-1, (1S)-1,2,4-triacetylconduritol E, (+)-2, (1R)-1,2,4-triacetylconduritol E, (−)-2, with high enantiomeric excesses and chemical yields. Following two different methods, diester (+)-1 has been transformed into azidoinositol (−)-4 to give 1L-4-amino-4-deoxy-chiro-inositol, whereas triester (−)-2 furnished the azidoinositol (+)-13, easily converted into 1L-4-amino-4-deoxy-myo-inositol.     

5a-Carba-β-D-, 5a-Carba-β-L- and 5-Thio-β-L-xylopyranosides as New Orally Active Venous Antithrombotic Agents

Mitsunobu displacement of (−)-(1S,4R,5S,6S)-4,5,6-tris{[(tert-butyl)dimethylsilyl]oxy}cyclohex-2-en-1-ol ((−)- 12 ; a (−)-conduritol-F derivative) with 4-ethyl-7-hydroxy-2H-1-benzopyran-2-one ( 16 ) provided a 5a-carba-β-D -pyranoside (+)- 17 that was converted into (+)-4-ethyl-7-[(1′R,4′R,5′S,6′R)-4′,5′,6′-trihydroxycyclohex-2′-en-1′-yloxy]-2H-1-benzopyran-2-one ((+)- 5 ) and (+)-4-ethyl-7-[(1′R,2′R,3′S,4′R)-2′,3′,4′-trihydroxycyclohexyloxy]-2H-1-benzopyran-2-one ((+)- 6 ). The 5a-carba-β-D -xyloside (+)- 6 was an orally active antithrombotic agent in the rat (venous Wessler's test), but less active than racemic carba-β-xylosides (±)- 5 and (±)- 6 . The 5a-carba-β-L -xyloside (−)- 6 was derived from the enantiomer (+)- 12 and found to be at least 4 times as active as (+)- 6 . (+)-4-Cyanophenyl 5-thio-β-L -xylopyranoside ((+)- 3 ) was synthesized from L -xylose and found to maintain ca. 50% of the antithrombotic activity of its D -enantiomer. Compounds (±)- 5 , (±)- 6 , and (−)- 6 are in vitro substrates for galactosyltransferase 1.     

Synthesis of decalin type chiral synthons based on enzymatic functionalisation and their application to the synthesis of (−)-ambrox and (+)-zonarol

Stereoselective syntheses of (−)-ambrox 2 and (+)-zonarol 3 were achieved based on the enzymatic syntheses of (8aS)- and (8aR)-decalin-type 1,3-diols 1, respectively. Non-racemic intermediates such as (8aS)-1 and (8aR)-1 were obtained based on the enantioselective hydrolyses of the phenolic acetal derivative (±)-7 by acylase I.     

Palladium-catalyzed asymmetric Diels–Alder reactions with novel chiral imino-phosphine ligands

Palladium-catalyzed asymmetric Diels–Alder reactions have been achieved with considerably high enantioselectivity by using chiral imino-phosphine ligands derived from (1S,4R)-(+)-fenchone, (1R,2R,5R)-(+)-2-hydroxy-3-pinanone derivatives, (1S,5R)-(−)-menthone, (1R,4R)-(+)-camphor, and (1S)-(+)-ketopinic acid. A mechanism for the asymmetric induction is proposed on the basis of the stereochemical outcome of the reactions.     

Synthesis of enantiopure cyclobutane amino acids and amino alcohols

(−)-(1R,3S)-3-Amino-2,2-dimethylcyclobutanecarboxylic acid and (+)-(1R,3S)-3-amino-2,2-dimethylcyclobutylmethanol, which can be used to prepare enantiopure oligopeptides and cyclobutane-based carbocyclic nucleosides, were synthesized from (+)-(1R)-α-pinene.     

Synthesis of versatile chiral intermediates by enantioselective conjugate addition of alkenyl Grignard reagents to enamides deriving from (R)-(−)- or (S)-(+)-2-aminobutan-1-ol

Conjugate addition of but-3-enylmagnesium bromide to the chiral crotonamide (R)-(+)- and (S)-(−)-3, followed by hydrolysis and oxidation, afforded enantiopure (R)-(+)- and (S)-(−)-3-methyladipic acids 8, respectively. Conjugate addition of vinylmagnesium chloride to the chiral crotonamide and cinnamamides (R)-(+)-3–5, followed by hydrolysis, gave the alkenoic acids (S)-12–14, respectively. Iodolactonization of the latter led to the 5-iodomethyllactones (+)-15–17, which were reduced by means of n-Bu₃SnH into the trans-disubstituted 5-methyllactones (+)-19–21, respectively. Treatment of the iodomethyllactone (+)-16 with LiMe₂Cu or n-Bu₂CuLi furnished the trans-5-alkyl-4-phenyllactones (−)-22 or (+)-23.     

Synthesis of (−)-(1′S,4aS,8aR)- and (+)-(1′S,4aR,8aS)-4a-ethyl-1-(1′-phenylethyl)-octahydroquinolin-7-ones

A synthesis of the enamine (−)-(1′S)-5-ethyl-1-(1′-phenylethyl)-1,2,3,4-tetrahydropyridine 4 and its application in a synthesis of (−)-(1′S,4aS,8aR)- and (+)-(1′S,4aR,8aS)-4a-ethyl-1-(1′-phenylethyl)-octahydroquinolin-7-ones 5 and 6 is described. In addition, an X-ray study of 6 is reported. Finally, the preparation of (+)-(4aS,8aR)-4a-ethyl-octahydroquinolin-7-one 7 is described.     

Chiral Schiff base derivatives of calix[4]arene: synthesis and complexation studies with chiral and achiral amines

Novel chiral Schiff base derivatives of calix[4]arenes 1–3 have been prepared from the reaction of 5,17-diformyl-25,27-dipropoxy-26,28-dihydroxycalix[4]arene 4 with (S)-(−)-1-phenylethylamine, (R)-(−)-1-cyclohexylethylamine, and (R)-(−)-2-heptylamine, respectively, by a convenient method in 69–80% yields. Spectrophotometric titrations have been performed in CHCl₃ at 20–30 °C in order to obtain the binding constants (K) and thermodynamic quantities (ΔH and ΔS) for the stoichiometric 1:1 inclusion complexation of various amines with these new host compounds. The molecular recognition abilities and enantioselectivity for guests (R)- and (S)-α-phenylethylamine, 3-morpholinopropylamine and n-butylamine are discussed from a thermodynamic point of view.     

Enzymatic resolution of (±)-conduritol-B,a key intermediate for the synthesis of glycosidase inhibitors

Lipases from porcine pancreas, Candida cylindracea and Mucor miehei (adsorbed on support, Lipozyme^® IM) catalysed in t-butylmethylether the alcoholysis of rac-conduritol-B peracetate, (±)-1, by n-butanol to give enantiopure (2S,3S)-diacetoxy-(1R,4R)-dihydroxycyclohex-5-ene, (−)-3, and (1S,2R,3R,4S)-tetraacetoxy-cyclohex-5-ene, (+)-1. The enantioforms (+)- and (−)-conduritol-B, obtained after chemical hydrolysis of (−)-3 and (+)-1, respectively, may be employed to prepare both the enantiomers of conduritol-B epoxide and cyclophellitol, powerful inhibitors of glycosidases.     

Oxidation of bicyclic monoterpene ketones with Caro’s acid

Previously unknown seven-membered lactones, (1R,1??R,5S,5??S)-5,5??-oxybis(1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one), 2,2-dimethyl-1,6-dioxaspiro[2.6]nonan-7-one, 4-(1-hydroxy-1-methylethyl)-7-methyloxepan-2-one, and (4R,4??R,7S,7??S)-4,4??-[oxybis(propane-2,2-diyl)]bis(7-methyloxepan-2-one), were synthesized by the Baeyer-Villiger reaction using Caro??s acid as a result of oxidative and skeletal transformations of bicyclic monoterpene ketones, (+)-camphor, (+)-nopinone, and (?)-isocaranone.     

Asymmetric synthesis of (S)-(−)-acromelobinic acid

A total synthesis of (S)-(−)-acromelobinic acid 2, which was isolated from clitocybe acromelalga, was achieved via an asymmetric hydrogenation protocol. Dehydroamino acid derivative 12 was prepared from 2,5-lutidine 5 and subjected to asymmetric hydrogenation using (S,S)-[Rh(Et-DuPHOS)(COD)]BF₄ to give the (S)-(+)-pyridylalanine derivative 13 in 93% yield and >96% e.e. Removal of the protecting groups in (S)-(+)-13 afforded (S)-(−)-acromelobinic acid 2.     

Total,asymmetric synthesis of ethyl d-ido-4-heptulosuronate derivatives starting from diethyl 4-oxopimelate

Bromination of diethyl 4-oxopimelate, followed by double elimination of HBr and ketalization provided diethyl (E,E)-4,4-(ethylidenedioxy)hepta-2,5-dienedioate 4. Sharpless asymmetric dihydroxylation of 4 produced diethyl (2S,3S)-4,4-(ethylidenedioxy)-2,3-dihydroxyhept-5-enedioate (+)-5, with 78% e.e. The corresponding tetrol could not be obtained in one step. Silylation of (+)-5 and a second asymmetric dihydroxylation, followed by silylation led to 20% of meso-diester 9 and 60% of diethyl (2S,3S,5S,6S)-2,3,5,6-tetrakis[(t-butyl)dimethylsilyloxy]-4,4-(ethylidenedioxy)heptanedioate (−)-10. Reductive desymmetrization of (−)-10 with DIBAL-H furnished, after selective oxidation, ethyl (2S,3S,5S,6S)-2,3,5,6-tetrakis-[(t-butyl)dimethylsilyloxy]-4,4-(ethylidenedioxy)-7-oxoheptanoate (+)-13 which was then converted into ethyl 1,2,3,6-O-tetraacetyl-4,4-ethylidenedioxy-α- and β-d-ido-heptapyranuronate (−)-15α,β and into the corresponding 3-(α-d-pyranosyl)propene (−)-16.     

A chiral 1,4-oxazin-2-one: asymmetric synthesis versus resolution,structure, conformation and VCD absolute configuration

1,4-Oxazin-2-one 3 is obtained from 2-pinanone in 4 steps and 78% overall yield. Enantiopure (e.e. >99%) (R)-(+)-3 and (S)-(−)-3 were obtained through chiral supercritical fluid chromatography (using a semi preparative Chiralpak AS column) with almost quantitative recovery of material. The structure and the boat-conformation of the lactone ring have been determined by NMR and the absolute configuration determined by VCD.     

Stereochemistry of terpene derivatives. Part 8: synthesis of novel terpenoids from (1S,4R)- and (1R,4S)-fenchone and their comparative odour characteristics

O-alkylation of (+) and (−)-fenchone oximes with various alkyl halides led to 20 novel ethers. Better results were obtained when mild reaction conditions were employed (i.e., aprotic, polar solvent and room temperature). The hydrolytic kinetic resolution of the O-glycidyl derivative was carried out using cobalt-salen catalysts. The best results were obtained when using (−)-(R,R)-catalyst: (−)-(R)-isomer was obtained with >90% de. The use of a (+)-(S,S)-catalyst gave the (−)-(S)-epoxide with only 67% de. However, the (S)-epoxide was obtained with >90% de when the (−)-(R)-diol was subjected to the Mitsunobu reaction. Significant fragrance diversity was observed between the homologous series of fenchone oxime ethers. More agreeable are scents of ethers derived from (−)-fenchone oxime. Their odours range from turpentine like and resinous to vegetable, floral or woody whereas the scents of (+)-ethers range from turpentine, resinous to onion like and slightly floral.