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.     

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.     

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.     

New methodology for the synthesis of enantiopure (3R,2aR)-(−)-3-phenyl-hexahydro-oxazolo[3,2-a]-pyridin-5-one: a synthesis of (S)-(+)-coniine

A new and efficient methodology for the enantiopure synthesis of (3R,2aR)-(−)-3-phenyl-hexahydro-oxazolo[3,2-a]pyridin-5-one 3 starting from (1′R)-(−)-1-(2′-hydroxy-1′-phenyl-ethyl)-(1H)-pyridin-2-one 1 is described. In addition, the enantiospecific synthesis of (S)-(+)-coniine hydrochloride 6 in good yield from 3 is reported.     

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

An unexpected retro-Michael reaction of (−)-(1′S,4aS,8aR)-and (+)-(1′S,4aR,8aS)-4a-ethyl-1-(1′-phenylethyl)octahydroquinolin-7-ones 1 and 2 is described. In addition, a diastereospecific intramolecular Michael reaction of 3·HCl and 4·HCl is reported.     

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.     

Approaches to (R)- and (S)-1′-(1-aminoethyl)ferrocene-1-carboxylic acid derivatives

Lipase-catalyzed esterification of (±)-methyl 1′-(1-hydroxyethyl)ferrocene-1-carboxylate 4 afforded its (R)-acetate (−)-5 (ee = 99%) and (S)-(+)-4 (ee = 90%). Stereoretentive azidation/amination/acetylation of (R)-(−)-5 gave (R)-(+)-methyl 1′-(1-acetamidoethyl)ferrocene-1-carboxylate (R)-3 (ee = 98%). In a similar manner (S)-(+)-4 was converted into (S)-(−)-3 (ee = 84%). Both enantiomers of 3 were obtained in high chemical yields without a loss of enantiomeric purity. The title compounds can be coupled with natural amino acids and peptides on both C- and N-termini.     

Synthesis of (S)-(−)- and (R)-(+)-O-methylbharatamine using a diastereoselective Pomeranz–Fritsch–Bobbitt methodology

Laterally lithiated (S)-(−)- and (R)-(+)-o-toluamides 6 with a chiral auxiliary derived from (S)- and (R)-phenylalaninol, respectively, were used as the building blocks and chirality inductors in the asymmetric modification of the Pomeranz–Fritsch–Bobbitt synthesis of isoquinoline alkaloids. Their addition to imine 2 proceeded with partial cyclization, giving isoquinolones (+)-7 and (−)-7 along with acyclic products, (−)-8 and (+)-8, respectively. LAH-reduction of (+)-7 and (−)-7, followed by cyclization, afforded both enantiomers of the alkaloid, (S)-(−)- and (R)-(+)-O-methylbharatamine 5, in 32% and 40% overall yield and with 88% and 73% ees, respectively.     

New procedures for the resolution of chiral tert-butylphenylphosphine oxide and some of its reactions

Racemic t-butylphenylphosphine oxide was resolved via formation of diastereoisomeric complexes with (+)-(R)-1,1′-binaphthalene-2,2′-diol and (+)-(S)-mandelic acid. With the latter complexing agent, separation of the essentially enantiopure (−)-(S)-enantiomer was achieved in a single complexation process. Addition of paraformaldehyde to this enantiomer gave α-hydroxymethyl-t-butylphenylphosphine oxide with high stereoselectivity and retention of configuration at phosphorus while its reaction with methyl bromoacetate in methanol/sodium methoxide resulted in the formation of methyl t-butylphenylphosphinate with inversion at phosphorus.     

Enantioselective preparation of (2R,3R)-(+)- and (2S,3S)-(−)-2,3-epoxy-2-methylbutanoic acids and some derivatives

(2R,3R)-(+)- and (2S,3S)-(−)-2,3-epoxy-2-methylbutanoic acids (epoxyangelic acids) were prepared from (Z)-2-methyl-2-butenoic acid using the Sharpless asymmetric epoxidation method in combination with the use of (−)- and (+)-menthol as chiral auxiliaries. Both substances, obtained in high enantiomeric excess, were characterized by spectroscopic and optical activity data. Their absolute configuration was determined by correlation with (R)-(+)-2-methyl-1,2-butanediol.     

Enantioselective acylation of 2-hydroxymethyl-2,3-dihydrobenzofurans catalysed by lipase from Pseudomonas cepacia (Amano PS) and total stereoselective synthesis of (−)-(R)-MEM-protected arthrographol

Lipase Amano PS catalysed acylation of (±)-2-hydroxymethyl-2,3-dihydrobenzofurans using vinyl acetate as the acyl donor in n-hexane gave (−)-(R)-2-acetoxymethyl-2,3-dihydrobenzofurans and (+)-(S)-2-hydroxymethyl-2,3-dihydrobenzofurans in high enantiomeric excess. (−)-(R)-Acetate 18j is converted to (−)-(R)-MEM-protected arthrographol 22.     

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.     

Stereospecific Synthesis of (−)-β-Turmerone and (−)-Bisacurol

The structure of (+)-β-turmerone ((+)- 1a ), a constituent of the rhizomes of Curcuma longa Linn. , and Curcuma xanthorriza, is established as (1′R,6S)-2-methyl-6-(4′-methylenecyclohex-2′-en-1′-yl)hept-2-en-4-one by synthesis of its enantiomer (−)- 1a , and of the corresponding (1′S,6S)-diastereoisomer (+)- 1b as well. In a stereospecific seventeen-step procedure, the monoterpene diols 2a and 2b of well-established configuration are converted into the target compounds (−)- 1a and (+)- 1b , respectively. Moreover, (−)-bisacurol (−)- 3a (II), the enantiomer of another bisabolane sesquiterpene derived from Curcuma xanthorriza, is obtained as a single stereoisomer and shown to be (1′S,6R)-2-methyl-6-(4′-methylenecyclohex-2′-en-1′-yl)hept-2-en-4-ol, the relative configuration at the remaining OH-substituted chiral center C(4) still being unknown.     

Efficient preparation of (1′R)-(−)-1-(2′-hydroxy-1′-phenylethyl)piperidin-2-one: synthesis of (2′S,3R)-(+)-stenusine

An efficient oxidation of (2′R)-(−)-2′-phenyl-2′-(piperidin-1-yl)ethanol 2 with bromine to generate the corresponding piperidin-2-one 3 in 96% is described. In addition, starting from 3, (2′S,3R)-(+)-stenusine 8 was synthesized in 70% overall yield. The X-ray analysis of piperidine 6·HCl is also reported.     

Stereoselective synthesis of α-substituted serines from protected erythrulose oximes

The additions of organolithium reagents to the CN bond of several chiral oxime ethers derived from erythrulose afforded protected amino polyols with high diastereoselectivity. Four of the latter compounds have been converted into the α,α-disubstituted α-amino acids (R)-2-(−)-methylserine, (S)-2-(+)-methylserine, (R)-(+)-2-phenylserine and (R)-(−)-2-n-butylserine.     

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.     

BF3-induced cyclobutane-opening of verbenone and its deconjugate homolog. Efficient preparation of o-mentha-1,8-dien-3-one and o-menth-1-en-3-one in optically active forms

Starting with (+)-verbenone, readily obtainable from (+)-nopinone, enantioselective preparation of (S)-(+)-4-isopropenyl-, (S)-(−)-4-isopropyl- and (R)-(+)-4-(1-acetoxy-1-methylethyl)-3-methyl-2-cyclohexen-1-ones was accomplished with little loss of stereochemical integrity via BF₃-induced cyclobutane-opening of (+)-4-(methylene)nopinone. As we have developed an efficient chemical transformation of (+)-nopinone into (−)-verbenone, the present syntheses of the above cyclohexenones are formal syntheses of their enantiomers from (+)-nopinone.     

Asymmetric Phase-Transfer Catalysis by Quaternary Ammonium Ions Derived from Cinchona-Alkaloid Analogs Containing 1,1′-Binaphthalene Moieties

The synthesis and catalytic properties of a new type of enantioselective phase-transfer catalysts, incorporating both the quinuclidinemethanol fragment of Cinchona alkaloids and a 1,1′-binaphthalene moiety, are described. Catalyst (+)-(aS,3R,4S,8R,9S)- 4 with the quinuclidine fragment attached to C(7′) in the major groove of the 1,1′-binaphthalene residue was predicted by computer modeling to be an efficient enantioselective catalyst for the unsymmetric alkylation of 6,7-dichloro-5-methoxy-2-phenylindanone ( 1 ; Scheme 1, Fig. 1). Its synthesis involved the selective oxidative cross-coupling of two differently substituted naphthalen-2-ols to afford the asymmetrically substituted 1,1′-binaphthalene derivative (±)- 17 in high yield (Scheme 3). Chromatographic optical resolution via formation of diastereoisomeric camphorsulfonyl esters and functional-group manipulation gave access to the 7-bromo-1,1′-binaphthalene derivative (−)-(aS)- 11 (Scheme 4). Nucleophilic addition of lithiated (−)-(aS)- 11 to the quinuclidine Weinreb amide (+)-(3R,4S,8R)- 8 afforded the two ketones (aS,3R,4S,8R)- 27 and (aS,3R,4S,8S)- 28 as an inseparable mixture of diastereoisomers (Scheme 6). Stereoselective reduction of this mixture with DIBAL-H (diisobutylaluminum hydride; preferred formation of the C(8)−C(9) erythro-pair of diastereoisomers with 18% de) or with NaBH₄ (preferred formation of the threo-pair of diastereoisomers with 50% de) afforded the four separable diastereoisomers (+)-(aS,3R,4S,8S,9S)- 29 , (+)-(aS,3R,4S,8R,9R)- 30 , (−)-(aS,3R,4S,8S,9R)- 31 , and (+)-(aS,3R,4S,8R,9S)- 32 (Scheme 6). A detailed conformational analysis, combining ¹H-NMR spectroscopy and molecular-mechanics computations, revealed that the four diastereoisomers displayed distinctly different conformational preferences (Figs. 2 and 3). These novel Cinchona-alkaloid analogs were quaternized to give (+)-(aS,3R,4S,8R,9S)- 4 , (+)-(aS,3R,4S,8S,9S)- 5 , (+)-(aS,3R,4S,8R,9R)- 6 , and (−)-(aS,3R,4S,8S,9R)- 7 (Scheme 7) which were tested as phase-transfer agents in the asymmetric allylation of phenylindanone 1 . Without any optimization work, (+)-(aS,3R,4S,8R,9S)- 4 was found to catalyze the allylation of 1 yielding the predicted enantiomer (+)-(S)- 3b in 32% ee. The three diastereoisomeric catalysts (+)- 5 , (+)- 6 , and (−)- 7 gave access to lower enantioselectivities (6 to 22% ee's), which could be rationalized by computer modeling (Fig. 4).     

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.     

Synthetic studies of didemnaketal analogue—construction of the (+)- and (−)-5,6-dihydroxy-3,7-dimethyl-octanal intermediates

A synthetic procedure for construction of the (+)-(3R,5R,6R)-5,6-dihydroxy-3,7-dimethyl-octanal and (−)-(3S,5S,6S)-5,6-dihydroxy-3,7-dimethyl-octanal derivatives, the intermediates for synthesis of the HIV-active didemnaketal analogue, was developed via a series of reactions from the natural (−)-menthone.