Asymmetric hydroboration of [E]- and [Z]-2-methoxy-2-butenes. Synthesis of (−)-[2R,3R]-butane-2,3-diol in >97% ee

Asymmetric hydroboration of [E]- and [Z]-2-methoxy-2-butene, using (−)-diisopinocampheylborane at −25°C in THF solvent, followed by oxidation using H₂O₂/NaOH, gave (−)-[2R,3R]- and (+)-[2R,3S]-3-methoxy-2-butanols in >97 and 90% ee, respectively. (−)-[2R,3R]-3-Methoxy-2-butanol was converted to (−)-[2R,3R]-butane-2,3-diol (>97% ee, in an overall yield of 65%).     

Synthesis of 1,1′-methylenedi[(1R,1′R,3R,3′R,5R,5′R)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] and derivatives: precursors of long-chain polyketides

Racemic 1,1′-methylene[(1RS,1′RS,3RS,3′RS,5RS,5′RS)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] ((±)-6) derived from 2,2′-methylenedifuran has been resolved kinetically with Candida cyclindracea lipase-catalysed transesterification giving 1,1′-methylenedi[(1R,1′R,3R,3′R,5R,5′R)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] (−)-6 (30% yield, 98% ee) and 1,1′-methylenedi[(1S,1′S,3S,3′S,5S,5′S)-8-oxabicyclo[3.2.1]oct-6-en-3-yl] diacetate (+)-8, (40% yield, 98% ee). These compounds have been converted into 1,1′-methylenedi[(4S,4′S,6S,6′S)- and (4R,4′R,6R,6′R)-cyclohept-1-en-4,6-diyl] derivatives.     

Stereoselective synthesis of (1R,2S)-2-amino-1,3-diols from (R)-cyanohydrins

Vinyl substituted (1R,2S)-amino alcohols 5 were obtained by addition of vinyl magnesium bromide to the corresponding cyanohydrin O-trimethylsilyl ethers (R)-2. The O- and N-protected vinyl amino alcohols 6 were ozonized at −78°C in methanol yielding (1R,2S)-2-amino-1,3-diols7 in high enantiomeric and diastereomeric excesses. For purification, compounds 7 in some cases were acetylated to give the derivatives (1R,2S)-8. Racemic 6a was converted by oxidative ozonolysis at −78°C in methanolic NaOH solution to the corresponding methyl N-acetyl-β-hydroxy propanoate 9a. The configuration of (1R,2S)-8a was confirmed by x-ray crystallographic analysis.     

Total asymmetric syntheses of d-lividosamine and 2-acetamido-2,3-dideoxy-d-arabino-hexose derivatives.

The “naked sugar” (+)-(1R, 4R)-7-oxabicyclo[2.2.1]hept-5-en-one((+)-2) has been converted to D-lividosamine ((+)-1: 3-deoxy-D-glucosamine) and derivatives via (+)-2-chloro-2,3-dideoxy-5,6-O-isopropylidene-D-arabino-hexono-1,4-lactone ((+)-33) and (+)-2-azido-2,3-dideoxy-5,6-O-isopropylidene-D-ribo-hexono-1,4-lactone ((+)-34) in a highly stereoselective fashion. Similarly, 2-acetamido-2,3-dideoxy-D-arabino-hexose and derivatives were derived from the “naked sugar” (−)-(1S,4S-7-oxabicyclo[2.2.1]-hept-5-en-2-one ((−)-2) via the double hydroxylation of the C=C double bond in (−)-N-benzyl-N-[(1R,2S,4S)-6-bromo-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl] amine ((−)-40).     

Tris-chelate complexes with chiral ligands: In search of diastereoisomeric selectivity with remote stereogenic centres

The chiral ligands, 4,4′-bis{(1S,2R,4S)-(−)-bornyloxy}-2,2′-bipyridine, (1S,2R,4S)-1, and 4,4′-bis{(1R,2S,4R)-(+)-bornyloxy}-2,2′-bipyridine, (1R,2S,4R)-1, have been prepared and characterized by spectroscopic techniques and, for (1S,2R,4S)-1, by single crystal X-ray diffraction. Despite the use of enantiomerically pure ligands, the formation of the complexes [Fe((1S,2R,4S)-1)₃]²⁺, [Ru((1S,2R,4S)-1)₃]²⁺, [Ru((1S,2R,4S)-1)(bpy)₂]²⁺ and [Ru((1R,2S,4R)-1)(bpy)₂]²⁺ proceeds without preference for either the Δ or Λ-diastereoisomers.     

Synthesis of optically active forms of sulcatol : The aggregation pheromone in the scolytid beetle, Gnathotrichus sulcatus

(S)-(+)-Sulcatol (1) and its antipode (1′) were synthesized from (R)-(−)-glutamic acid (2), and its antipode (2′), respectively. This established the absolute configurations of both enantiomers of sulcatol and afforded key materials to study the relationship between pheromone activity and chirality.     

Synthesis and olfactory properties of (−)-(1R,2S)-Georgywood

The enantiomers of Georgywood^® were synthesized from (E)-2-methyl-6-methylene-nona-2,7-diene and methacrylaldehyde followed by oxidation of the Diels–Alder adduct and classical racemate separation of the acid with optically-active N-methylephedrine. Conversion to the final ketone and olfactory evaluation showed that the (−)-(1R,2S)-enantiomer is more powerful by a factor of >100 than its antipode. The absolute configuration was determined by conformational studies and CD-analysis.     

Total asymmetric syntheses of 3- and 4-deoxy-hexoses and derivatives

(1S,4S)-7-Oxabicyclo[2.2.1]hept-5-en-2-one ((−)-5, a “naked sugar”) has been converted to (−)-(1R,4S,6S)-6-endo-benzyloxy-2-bromo-7-oxabicyclo[2.2.1]hept-2-ene ((−)-12) in a highly stereoselective fashion. Double hydroxylation of the C=C double bond of (−)-12, followed by acetylation and Baeyer-Villiger oxidation of the resulting -acetoxyketone (−)-14 afforded (−)-5-O-acetyl-2-O-benzyl-3-deoxy-β-D-arabino-hexofuranurono-6,1-lactone ((−)-15). This compound was converted readily into (+)-methyl 3-deoxy--D-arabino-hexofuranoside ((+)-6 and (+)-methyl 3-deoxy-β-L-xylo-hexofuranoside ((+)-7) and partially protected derivatives. (−)-15 was also converted into 4-deoxy-D-lyxo-hexopyranose (34) and several partially protected derivatives such as (+)-methyl 4-deoxy-2,3-O-isopropylidene--D-lyxo-hexopyranoside ((+)-8).     

Oligomeric flavanoids. Part 13. Synthesis of profisetinidins based on (−) robinetinidol and (+) -epifisetinidol

Acid-catalyzed condensation of (+)-mollisacacidin-[(2R, 3S, 4R)-2, 3-trans-3, 4-trans-flavan-3,3′,4,4′,7-pentaol] with an excess of (−)-robinetinidol[(2R,3S)-2,3-trans-flavan-3,3′,4′,5′,7-pentaol] afforded a novel series of bi-, tri-, and tetraflavanoid profisetinidins. They are accompanied by (−)-fisetinidol-(4,2′)-(−)-robinetinidol which results from the pyrogallol B-ring of (−)-robinetinidol serving as nucleophile competing with its resorcinol A-ring in coupling with a C-4 carbocationic intermediate. Similar condensation with (+)-epifisetinidol[(2S,3S)-2,3-cis-flavan-3,3′,4′,7-tetraol] led to the exclusive formation of [4,6]-interflavanyl bonds, these units being ‘linearly’ arranged in the tetraflavanoid analogue in contrast to the ‘branched’ nature of the (−)-robinetinidol homologue.     

A convenient stereoselective synthesis of (R)-(−)-denopamine and (R)-(−)-salmeterol

β-Adrenoreceptor agonists (R)-(−)-denopamine (R)-1 and (R)-(−)-salmeterol (R)-2 have been prepared in good overall yield and high enantioselectivity through a biotransformative pathway.     

Preparation of both enantiomers of malic and citramalic acid and other hydroxysuccinic acid derivatives by stereospecific hydrations of cis or trans 2-butene-1,4-dioic acids with resting cells of Clostridium formicoaceticum

(R)-Malic, (S)-malic, (R)citramalic, (S)-citramalic, (2R,3S)-2-hydroxy-3-methyl-succinic and (2R,3S)-2,3-dimethyl-2-hydroxysuccinic acid were prepared on scales up to 25 mmol by stereospecific addition of water to different 2-butene-1,4-dioic acid derivatives catalyzed by resting cells of Clostridium formicoaceticum (Scheme 1). The (3R)-monodeuterio (R)- and (S)-malic acid as well as (R)- and (S)-citramalic acid were prepared using freeze-dried cells in ²H₂O-buffer. The stereochemical purity of the products was in most cases ≥ 99%.     

Determination of absolute configuration of a metabolite (−)-hydroxyhexamide from acetohexamide, syntheses of (−)- and (+)-hydroxyhexamides and (−)- and (+)-acetoxyhexamides

Enantioselective acetylation of (±)-4-(1-hydroxyethyl)benzenesulfonamide 6 with ‘Acylase I’ (No. A 2156) from Aspergillus melleus in the presence of vinyl acetate gave (R)-4-(1-acetoxyethyl)benzenesulfonamide 7 (98% ee) and (S)-6 (98% ee). Both (S)-6 and (R)-7 were individually converted to the (S)-hydroxyhexamide 2 (>99% ee) and (R)-hydroxyhexamide 2 (>99% ee), respectively. The absolute configuration of a metabolite (−)-hydroxyhexamide 2 from acetohexamide 1 was found to be S based on unequivocal chemical methods including X-ray analysis.     

Asymmetric hydroformylation with Pt-phosphine-SnCl2 and Pt-bisphosphine-CuCl2 (or CuCl) catalytic systems

A study has been made of asymmetric hydroformylation of styrene with PtCl₂(PPh₃)₂ + bisphosphine + SnCl₂ (bisphosphine: BDPP = (−)-(2S,4S)-2,4-bis(diphenylphosphino)pentane or DIOP = (−)-(4R,5R)-2,2-dimethyl-4,5-bis(diphenylphosphinomethyl)-1,3-dioxolane) and PtCl₂(bisphosphine) + PPh₃ + SnCl₂ catalysts prepared “in situ”. The presence of an excess of the phosphine ligand slightly lowered the reaction rate, but the enantioselectivity of these systems is significantly higher than those involving PtCl(SnCl₃)(bisphosphine) catalysts. Under mild reaction conditions 88.8% enantiomeric excess was achieved. Replacing SnCl₂ in these catalysts by CuCl₂ or CuCl gave a new homogeneous catalytic system which is active at higher reaction temperature (> 100°C), but has a rather moderate enantioselectivity.     

Synthesis and application of new chiral bidentate phosphine, 2,7-di-tert-butyl-9,9-dimethyl-4,5-bis(methylphenylphosphino)xanthene

New optically active bidentate phosphines, (S,S)- and (R,R)-2,7-di-tert-butyl-9,9-dimethyl-4,5-bis(methylphenylphosphino)xanthenes ((S,S)-1 and (R,R)-1), were prepared through resolution of the corresponding phosphine oxides using (R,R)-(−)-dibenzoyl-tartaric acid and a preliminary experiment on asymmetric synthesis using an allyl substrate proved the utility of the new bidentate phosphines.     

Enzymatic production of (3S,4R)-(−)-4-(4′-fluorophenyl)-6-oxo-piperidin-3-carboxylic acid using a commercial preparation from Candida antarctica A: the role of a contaminant esterase

The enantioselective hydrolysis of (3RS,4RS)-trans-4-(4′-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylate (±)-2 was effected using a commercial preparation of lipase from C. antarctica A (CAL-A). We found that the hydrolytic activity of the lipase (immobilized on a number of very different supports) with this substrate was negligible. However, a contaminant esterase with Mw of 52 KDa from this commercial preparation exhibited much higher activity with (±)-2. This enzyme was purified and immobilized on PEI-coated support and the resulting enzyme preparation was highly enantioselective in the hydrolysis of (±)-2 (E >100), hydrolyzing only the (3S,4R)-(−)-3, which is a useful intermediate for the synthesis of pharmaceutically important (−)-paroxetine. Optimization of the reaction system was performed using a racemic mixture with a substrate concentration of 50 mM. This enzyme preparation was used in three reaction cycles and maintained its catalytic properties.     

Enantiodivergent synthesis of 3-amino-4,4-dimethyl-1-phenylpyrrolidin-2-one and derivatives: amino analogues of pantolactone

An enantiodivergent preparation of (+)-(R)- and (−)-(S)-3-amino-4,4-dimethyl-1-phenylpyrrolidin-2-one, (R)- and (S)-9, and several derivatives, from 4,4-dimethyl-1-phenylpyrrolidin-2,3-dione, 4, and (R)- or (S)-1-phenylethylamine, (R)- or (S)-5, as the chirality transfer agents, is described. Amine (S)-9 has also been used as a chiral auxiliary in a diastereoselective Michael reaction.     

Studies on the synthesis of biphenylneolignans. Part 1: Enantioselective synthesis of (S,S)- and (R,R)-2,2′-dimethoxy-4-(3-hydroxy-1-propenyl)-4′-(1,2,3-trihydroxypropyl)diphenyl ether

Two erythro-isomers of 2,2′-dimethoxy-4-(3-hydroxy-1-propenyl)-4′-(1,2,3-trihydroxypropyl)diphenyl ether, (7′S, 8′S)-9 and (7′R, 8′R)-9, were synthesized in seven steps, in which an improved method for the synthesis of the key intermediate 3 was developed. The absolute configuration of the target molecules was also confirmed.     

cis,cis-Spiro[4.4]nonane-1,6-diol: A new chiral auxiliary for the asymmetric Diels-Alder reaction

The use of a mono-pivalate mono-acrylate bis-ester of (+)-1S,5S,6S-spiro[4.4]nonane-1,6-diol in an asymmetric Diels-Alder reaction with cyclopentadiene (2 equiv. BCl₃, −85°C, CH₂Cl₂) provided the expected endo bicyclo adduct in >97% de. Iodolactonization of the bicyclo adduct provided the (+)-lactone (5) with a 1S,4S,6S,8R,9S configuration (97% ee). The de's obtained from using various types and amounts of Lewis acids, and both chiral and racemic bis-esters in the Diels-Alder reaction with cyclopentadiene are also reported.     

Asymmetric syntheses of protected (2S,3S,4S)-3-hydroxy-4-methylproline and 4′-tert-butoxyamido-2′-deoxythymidine

Described herein is a versatile approach to (i) (2S,3S,4S)-3-hydroxy-4-methylproline 3, a constituent of echinocandins and related oligopeptide antibiotics; (ii) (2S,3S)-3-hydroxyproline 1; (iii) (2R,3S)-3-hydroxyprolinol 5, and (iv) 4′-tert-butoxyamido-2′-deoxythymidine 6b. The method features a stepwise regio- and diastereoselective reductive furylation of the protected (3S,4S)-4-methylmalimide 10, (S)-malimide 9, and a chemoselective oxidative transformation of the furyl group to the carboxyl group as the key steps.     

Enantioselektive Katalyse VII. Komplexe von (P(R,S),3R,4R,P′(R,S))-3,4-Bis(phenylphosphino)pyrrolidinen. Die Darstellung optisch reiner 1,2-Bisphosphanliganden mit vier Stereozentren, die zusätzliche funktionnelle Gruppen enthalten

Diastereomeric mixtures of the palladium, the platinum, and the rhodium complexes were prepared from [P(R,S),3R,4R,P′(R,S)]-3,4-bis(phenylphosphino)pyrrolidine (1a). The phosphorus atoms in bis[(P(R,S),3R,4R,P′(R,S))-1-(t-butoxycarbonyl)-3,4-bis(phenylphosphino)pyrrolidine-P,P′]dihalogenopalladium (2) can be alkylated stereoselectively with iodomethane. The P---H bonds in 2 open epoxides, and add to Michael systems, to give new ligands, which can be split off from the palladium with cyanide. The three isomerically pure [(PR,3R,4R,P′R)(PS,3R,4R,P′S)(PR,3R,4R,P′S)]-1-(t-butoxycarbonyl)-3,4- bis[(2-cyanoethyl)phenylphosphino]pyrrolidines were prepared via the neutral diiodopalladium complexes. [(PS,3R,4R,P′S)1-(t-butoxycarbonyl)-3,4-bis[(2-cyanoethyl)phenylphosphino]pyrrolidine-P,P′]diiodopalladium(II) (14-1) was characterised by X-ray crystallography.