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.     

Preliminary studies on the synthesis of rancinamycins from nitrosugars: first total synthesis of (3S,4S,5S,6R)-5-benzyloxy-6-hydroxy-3,4-(isopropylidendioxy)-cyclohex-1-enecarbaldehyde

The first total synthesis of (3S,4S,5S,6R)-5-benzyloxy-6-hydroxy-3,4-(isopropylidendioxy)-cyclohex-1-enecarbaldehyde from d-glucose is described. The key steps of this synthesis are the stereoselective Michael addition of 2-lithio-1,3-dithiane to 3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-nitro--d-xilo-hex-5-enofuranose followed by the enantioselective two-step transformation of 3-O-benzyl-5,6-dideoxy-5-C-(1,3-dithian-2-yl)-6-nitro-β-l-idofuranose into (1S,2S,3S,4S,5S,6R)-5-benzyloxy-6-hydroxy-3,4-(isopropylidendioxy)-2-nitro-cyclohexanecarbaldehyde propylene dithioacetal, which was finally converted into the target compound.     

Stable hydrazone-linked chiral covalent organic frameworks: Synthesis,modification, and chiral signal inversion from monomers

The designed synthesis of chiral covalent organic frameworks(COFs) featuring intriguing properties is fairly scant and remains a daunting synthetic challenge.Here we develop a de novo synthesis of an enantiomeric pair of 2 D hydroxyl-functionalized hydrazone-linked chiral COFs,(S)-and(R)-HthBta-OH COFs,using enantiopure 2,5-bis(2-hydroxypropoxy)terephthalohydrazide(Hth) as monomers.The fo rmation process of hydroxyl-functionalized chiral COFs was monitored using rigorous time-dependent PXRD,vibrational circular dichroism(VCD),and electronic circular dichroism(ECD) studies.Remarkably,VCD spectra indicated a unique chiral signal inversion from the positive Cotton effect of(S)-Hth monomer to the negative Cotton effect of(S)-HthBta-OH COF,which has never been reported in chiral COFs.Moreover,two unprecedented carboxyl-functionalized chiral COFs,(S)-and(R)-HthBta-COOH,were constructed by a post-synthetic modification of the corresponding hydroxyl chiral COFs with succinic anhydride.Notably,carboxyl-functionalized COFs retained homochirality and crystallinity without linker racemization and structural collapse after the chemical modification due to the chemically robust nature of pristine hydrazone-linked chiral COFs.     

Asymmetric Synthesis via Acetal Templates. 14. Preparation of Enantiomerically Pure (3S,4S)- and (3S,4R)-Statine Derivatives

Several (3S,4S)- and (3S,4R)-statine derivatives have been prepared by attack of nucleophiles on crystalline, epimeric N-BOC-lactams 7a and 7b. The key step in the synthesis of the lactams was the TiCl₄-catalyzed coupling reactions of acetals derived from (R)-1,3-butanediol with allyltrimethylsilane.

Several enantiometrically pure (3S,4S- and (3S, 4R)-statine derivatives were made by sodium cyanide-catalyzed reaction of nucleophiles with the lactams 3a and 3b which were synthesized by the scheme 1 → 2 → 3.     

Chiral Non-racemic Bis(vicinal 1,2-Diamines): 4,5-Diamino-N-(3,4-diaminobutyl)pentanamide Tetrahydrochloride, N,N′-Bis[3,4-bis (t-butoxycarbonylamino)butyl]urea and N,N′Bis

The reaction of (R) or (S)-N⁴,N⁵-bis(t-butoxycarbonyl)-4,5-diaminopentanoic acid (6) with (R) or (S)-N³,N⁴-bis(t-butoxycarbonyl)-3,4-diaminobutylisocyanate (8) catalyzed by 4-dimethylamino pyridine (DMAP), leads to the synthesis of (R,R), (S,S), (R,S) and (S,R) isomeric amides (11 a — d) The addition of adipic acid monomethyl ester to (R) or (S) isocyanate, followed by saponification, acidification and subsequent reaction with the second molecule of (R) or (S) isocyanate allows isolation of the (R,R), (S.S) and the meso isomers of N,N′-bis[3,4-bis(t-butoxycarbonylamino) butyl]hexanediamide (17) Removal of protecting groups with HCl/EtOH affords chiral non-racemic molecules having two free vicinal diamine units.     

Stereoselective hydration of (RS)-phenylglycine nitrile by new whole cell biocatalysts

Five new bacterial isolates with stereoselective nitrile hydratase activity against (RS)-2-phenylpropionitrile and (RS)-phenylglycine nitrile were investigated. The permeabilized whole cell isolates selectively hydrate the (S)-enantiomer of phenylglycine nitrile with E values of 1.2–5.4. One isolate, which was identified as Pantoea endophytica, produced pure (S)-phenylglycine (>99% ee) as a result of hydrolysis of (S)-phenylglycine amide by an (S)-specific amidase. Surprisingly, in the hydrolysis of (RS)-phenylglycine nitrile, it was found that the (R)-amide was accumulated in excess (21% ee) despite the nitrile hydratase produced by Pantoea endophytica was (S)-selective. The synthesis of pure (R)-phenylglycine (>99% ee) was achieved in time course studies using another Pantoea sp. with (R)-selective amidase. In the case of Nocardioides sp. the intermediate product, (S)-phenylglycine amide, could be produced (52% ee) without its subsequent hydrolysis into the acid due to the apparent absence of any amidase activity.     

Chemoenzymatic synthesis of both enantiomers of cispentacin

Based on the lipase-catalysed kinetic resolution of the silyloxyalcohol (1RS,2SR)-5 by transesterification with vinyl acetate in the presence of lipase from Pseudomonas cepacia a synthesis of both enantiomers of the β-amino acid cispentacin (1R,2S)-1 and (1S,2R)-1 using simple functional group interconversions is described.     

Asymmetric reactions catalyzed by chiral metal complexes : XXXII. Efficient asymmetric hydrogenation of itaconic acid derivatives catalyzed by rhodium complexes of improved (2S,4S)-N-(t-butoxycarbonyl)-4-(diphenylphosphino)-2-[(diphenylphosphino)methyl]pyrrolidine (BPPM) analogues

We have prepared analogues of (2S,4S)-N-(t-butoxycarbonyl)-4-(diphenylphosphino)-2-[(diphenylphsphino)methyl]pyrrolidine (BPPM), bearing para-dimethyl-amino groups to prove the utility of our designing concept with regard to electronic effects of the phosphino groups on the enantioselectivity and the activity of the rhodium complex catalysts. Their rhodium complexes are much more effective than those of BPPM and (2S,4S)-N-(t-butoxycarbonyl)-4-(dicyclohexylphosphino)-2-[(diphenylphosphino)methyl]pyrrolidine (BCPM) for the asymmetric hydrogenation of dimethyl itaconate. The hydrogenation has also been used successfully in an efficient asymmetric synthesis of the key intermediate of new human renin inhibitors.     

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.     

Highly stereoselective construction of 4,6-cis-substituted quinolizidine ring core: an application to enantioselective total synthesis of the marine alkaloid clavepictines A, B and pictamine

The enantioselective total synthesis of the marine alkaloids clavepictines A, B and pictamine has been achieved through the highly stereocontrolled quinolizidine ring closure of the conformationally constrained piperidine ring system (2), which bears the chiral centers and appropriate functionality needed for the synthesis of target alkaloids. The absolute stereochemistry of clavepictines and pictamine was verified to be 3R, 4S, 6S, 9aS by the present synthesis.     

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.     

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.     

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.     

Synthesis and absolute stereochemistry of serricornin [(4S,6S,7S)-4,6-dimethyl-7-hydroxy-3-nonanone] : The sex pheromone of the cigarette beetle

The absolute stereochemistry o serricornin (4,6-dimethyl-7-hydroxy-3-nonanone) was established as 4S, 6S, 7S by synthesizing both (4S, 6S, 7S)-isomer and its antipode. Only the natural enantiomer was bioactive.     

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.     

A comparison of ferroelectric liquid crystals containing diastereomeric propionic acids derived from natural ethyl lactate

Two diastereomeric carboxylic acids, 2(S)-[2(R)-methylhexyloxy]propionic acid and 2(S)[2(S)-methylhexyloxy]propionic acid, were prepared from ethyl (S)-lactate and (R)-1-iodo2-methylhexane or (S)-1-iodo-2-methylhexane in the presence of Ag₂O. From these acids two liquid crystals, 2 and 3 , whose configurations are (S , R ) and (S, S) were synthesized and their liquid crystal properties investigated. Although both LCs have the same phase sequence Cr-SmC*-N*-I as well as a wide SmC* phase range, the influence of the relative stereochemistry on their physical properties is clear. The liquid crystal with (S, S)-configuration possesses better properties: lower SmC* phase transition temperature, wider SmC* phase range and higher P_s value. The P_s value difference between the ferroelectric LCs 2 and 3 (97 and 131nCcm^-2, respectively, at T_c - T = 10°C) is unexpectedly large. The consideration, alone, of a zigzag conformation at the chiral molecular part of 2 and 3 is insufficient to explain such a difference.     

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.     

Enzymatic resolution of 3-bromo-cyclohept-2-enol: application to the determination of the absolute configuration of diethyl (3-hydroxy-cyclohept-1-enyl)phosphonate

Enzymatic resolution of racemic 3-bromo-cyclohept-2-enol 2 with lipozyme affords enantiomerically pure (S)-(−)-2 whose absolute configuration was determined by chemical correlation, and further allowed an enantioselective synthesis of (S)-(+)-diethyl (3-hydroxy-cyclohept-1-enyl)phosphonate 1.     

Catalytic and structural studies of Rh complexes of (−)-(2S,4S)-2,4-bis(diphenylphosphino)pentane. Asymmetric hydrogenation of acetophenonebenzylimine and acetophenone

Rhodium(I) complexes formed by (−)-(2S,4S)-2,4-bis(diphenylphosphino)pentane (BDPP) are efficient catalysts for the hydrogenation of acetophenone and acetophenonebenzylimine. The composition of the solvent mixture and the reaction temperature have a marked influenced on the enantioselectivity. These effects are thought to be related to the enhanced conformational flexibility of six-membered rings when simple substrates without functional groups are coordinated to the rhodium. X-ray crystallographic studies reveal that in [Rh((S,S)-BDPP)NBD]⁺ (1) the ligand is in a chair conformation, and that in [Rh((S,S)-BDPP)COD]⁺ (2) the chelate ring is in a δ-skew conformation. Studies of Rh((S,S)-BDPP)(NBD)Cl (3) in solution indicate a trigonal bipyramidal structure with a chair conformation of the ring in aromatic solvents and a conformationally labile ring in methanol.     

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%.