Syntheses of Bile Pigments. Part 17. Synthesis of a non-racemizable urobilin derivative

The optically active urobilin model compound 7 was synthesized, in which Me groups instead of H-atoms are bound to the asymmetric centers, thus preventing loss of chirality by tautomerization. The key intermediate of the eleven-step synthesis of 7 is the 1,4,5,10-tetrahydro-10-hydroxy-1-oxo-11H-dipyrrin-9-carboxylate rac- 2 , which could be resolved into enantiomers by fractional crystallization of the corresponding methyl N-[1-(naphth-1-yl)ethyl]carbamates 3 and 4 . The absolute configuration of enantiomerically pure (?)- 2 was determined by X-ray diffraction analysis of its camphor-10-sulfonate 5 . As the CD spectrum of the urobilin analogue 7 obtained from (?)-(R)- 2 displays a positive Cotton effect, the present results prove, in connection with previous work, that substitution of Me groups for the H-atoms bound to the asymmetric centers of a chiral urobilin chromophore do not influence the relationship between absolute configuration of the latter and its helicity.     

Enantioselective Deprotonation/Electrophile Addition Reactions of Tricarbonyl(phenyl carbamate)chromium Complexes

Sequential reaction of the tricarbonyl[(η⁶-phenyl) carbamate]chromium complex 3 with chiral amide bases (see 4 and 5 ) and electrophiles yielded planar chiral ortho-substituted complexes 6 with up to 70% enantiomeric excess (ee) (Scheme 2, Table 1 and 2). The enantiomer purity could be increased to >90% ee by fractional crystallization. In all but one case the racemate crystallized selectively, leaving the enantiomerically enriched complex in solution. X-Ray crystal-structure analyses of rac- 6a and (1R)- 6a suggest that this can be ascribed to a more favorable packing of enantiomers of opposite configuration in the solid state than that of the enantiomerically pure solid. Increasing the temperature of the intermediate ortho-lithiated aryl carbamate complex induced an anionic ortho-Fries rearrangement: The 1,3-transposition of the carbamoyl group yielded the ortho-substituted (η⁶-benzamide)tricarbonylchromium complexes 10 in 65% yield, after exposure to the electrophile (Scheme 6), and the use of a chiral amide base 5 in the deprotonation step afforded the product with an ee of 54%.     

Preparation,Structure, and Properties of All Possible Cyclic Dimers (Diolides) of 3-Hydroxybutanoic Acid

In connection with the proposed structure of a trans-membrane cellular ion channel consisting of a complex between poly[(R)-3-hydroxy butanoate] (P(3-HB)) and calcium polyphosphate, CaPP_i (ca. 150 units each), which is supposed to contain s-cis-bonds or even more highly strained ester conformations, we have prepared and studied the properties of the cyclic dimer of 3-HB, the diolide 1 . All possible forms of 1 , the rac-, the meso-, and the enantiomerically pure (R,R)- and (S,S)-compounds were prepared, purified, and characterized. The synthesis (Scheme 1) started from dimethyl succinate with the key step being the Baeyer-Villiger oxidation of the rac- and meso-2,5-dimethylcyclohexane-1,4-diones 5 . The rac-diolide 1 was resolved by preparative chromatography on a Chiralcel OD column (Fig.1). The crystal structures of rac- 1 (Fig.3) and of meso- 1 (Fig.5) were determined by X-ray diffraction: the diolides 1 contain s-cis-ester bonds and an ester group with a conformation half way to the transition state of rotation (Fig.2). Strain energies for the diolides 1 of up to 17.8 kcal/mol are suggested. Accordingly, these compounds show reactivities similar to those of carboxylic-acid anhydrides or even acid chlorides. They cannot be chromatographed on silica gel, and they react with primary, secondary, and tertiary alcohols, and with amines to form derivatives of open chain 3-HB ‘dimers’, hydroxy acids 6 , esters 7 , and amides 8 (Scheme 2). The rate of acid-catalyzed ring opening of the diolides 1 with alcohols has been measured (Fig.6 and 7). From the results described, we conclude that it is unlikely for strained and reactive ester conformations to occur as part of ion channels through phospholipid bilayers of cells.     

Enzyme-catalyzed synthesis and absolute configuration of (1S,2R,5S)- and (1R,2S,5R)-2-(1-hydroxyethyl)-1-(methoxymethyloxyethyl)cyclobutane-1-carbonitrile,key intermediates for the preparation of chiral cyclobutane-containing pheromones

Formal synthesis of chiral grandisol and the oleander scale pheromone and their antipodes can be achieved through a convenient lipase-catalyzed enantiodifferentiation process of the common cyclobutane intermediate (±)-2-(1-hydroxyethyl)-1-(methoxymethyloxyethyl)cyclobutane-1-carbonitrile 3. The resolution afforded both enantiomers in almost enantiomerically pure form and their absolute configurations were assigned on the basis of the Δδ values for their (R)- and (S)-MTPA esters.     

Enantioselective Syntheses and Absolute Configurations of Viridiene and Aucantene,Two Constitutents of Algae Pheromone Bouquets

Viridiene ((+)- 6 ; (+)-(3R,4S)-3-((1Z)-1,3-butadienyl)-4-vinylcyclopentene) and aucantene ((+)- 18 ; (+)-(4R,5R)-4-((1E)-1-propenyl)-5-vinylcyclohexene) are constituents of the pheromone bouquets of several brown algae species. Key synthons to the title compounds are optically active γ-lactones with known or experimentally determined absolute configurations. Horse liver alcohol dehydrogenase, which catalyses the oxidation of meso- and racemic non-meso diols to chiral lactones, and pig-liver esterase, which catalyzes the saponification of meso-diesters to chiral half-esters, were utilized for the asymmetric synthesis of such precursors. The racemic non-meso diol rac- 1 is converted to the two stereoisomeric γ-lactones (+)- 2 and (+)- 3 which are readily separated. meso-Diol 12 is oxidized to the chiral γ-lactone (?)- 11 . Its enantiomer (+)- 11 is obtained by enantioselective saponification of the meso-diester 9 with pig-liver esterase. Appropriately designed syntheses lead from these chiral intermediates to both enantiomers (+)- and (?)- 6 of viridiene and (+)- and (?)- 18 of aucantene. In addition, kinetically controlled reduction of the racemic aldehydes rac- 5a and rac- 15 with horse liver alcohol dehydrogenase offers a convenient alternative to the enantioselective preparation of the enantiomers of the two hydrocarbons 6 and 18 . Chromatography of 6 on triacetylated cellulose as a stationary chiral phase confirms the enantiospecificity of the synthetic routes designed.     

Enantioselective Allylic Substitution Catalyzed by Chiral [Bis(dihydrooxazole)]palladium Complexes: Catalyst structure and possible mechanism of enantioselection

Allylpalladium complexes with chiral bis(dihydrooxazole) ligands were studied as catalysts for the enantioselective allylic substitution reaction of rac-1,3-diphenylprop-2-enyl acetate (rac- 5 ) with the anion of dimethyl malonate (Scheme 1). Using enantiomerically pure (S,E)-1-(4-tolyl)-3-phenylprop-2-enyl acatete ((S)- 25 ) as substrate, the reaction was shown to proceed by a clean ‘syn’ displacement of acetate by dimethyl malonate (Scheme 6). The [Pd¹¹(η³-allyl)] complex 18 and the analogous [Pd(η³-1,3-diphenylallyl)] complex 20 , both containing the same bis(dihydrooxazole) ligand, were characterized by X-ray structure analysis and by NMR spectroscopy in solution. The structural data reveal that steric interactions of the allyl system with the chiral ligand result in selective electronic activation of one of the allylic termini. The higher reactivity of one allylic terminus toward nucleophilic attack is reflected in a significantly longer Pd? C bond and a shift of the corresponding ¹³C-NMR resonance to higher frequency.     

Diastereoselektive Alkylierung von 3-Aminobutansäure in der 2-Stellung

Diastereoselective Alkylation 3-Aminobutanoic Acid in the 2-Position The enantiomerically pure 3-aminobutanoic acids (R)- and (S)- 6 are readily available by preparative HPLC separation of the two diastereoisomers 5 obtained from addition of (S)-phenethylamine to methyl crotonate and subsequent hydrogenolysis (Scheme 2). (S)-Methyl 3-(benzoylamino) butanoate ((S)- 3 ) is also available by enzymatic kinetic resolution with pig-liver esterase. The N-benzyl- and N- benzyloxycarbonyl derivatives rac 3 , 8 , and 9 of 3-aminobutanoates are doubly deprotonated with LDA and alkylated or aminated in high selectivity (17 examples, relative topicity like; see Tables 1 and 2). The configuration of three of the products is assigned (Schemes 4–6), and in four cases, the free α-substituted β-amino acid is prepared by acidic hydrolysis (see Table 3). It is shown that the doubly lithiated β-amino-acid derivative is solubilized, and its reactivity may be strongly influenced by the presence of 3 equiv. of LiCl.     

Preparation of β2‐Amino Acid Derivatives (β2hThr, β2hTrp, β2hMet, β2hPro, β2hLys,Pyrrolidine‐3‐carboxylic Acid) by Using DIOZ as Chiral Auxiliary

The title compounds were prepared from valine‐derived N‐acylated oxazolidin‐2‐ones, 1 – 3, 7, 9 , by highly diastereoselective (≥ 90%) Mannich reaction (→ 4 – 6 ; Scheme 1) or aldol addition (→ 8 and 10 ; Scheme 2) of the corresponding Ti‐ or B‐enolates as the key step. The superiority of the ‘5,5‐diphenyl‐4‐isopropyl‐1,3‐oxazolidin‐2‐one’ (DIOZ) was demonstrated, once more, in these reactions and in subsequent transformations leading to various t‐Bu‐, Boc‐, Fmoc‐, and Cbz‐protected β²‐homoamino acid derivatives 11 – 23 (Schemes 3–6). The use of ω‐bromo‐acyl‐oxazolidinones 1 – 3 as starting materials turned out to open access to a variety of enantiomerically pure trifunctional and cyclic carboxylic‐acid derivatives.     

A Reinvestigation of the α-Alkylation of 4-Monosubstituted 2-phenyloxazol-5(4H)-ones (‘azlactones’): A general entry into highly functionalized α,α-disubstituted α-amino acids

Novel, more reliable and general reaction conditions for the α-alkylation of 4-monosubstituted 2-phenyloxazol-5(4H)-ones ( = 4-monosubstituted 2-phenyl-azlactones) rac- 2 to 4,4-disubstituted 2-phenyloxazol-5(4H)-ones rac- 1 were found (Scheme 2). Thus, a whole range of highly functionalized rac- 1 were prepared in medium-to-good overall yields (40-90%, see Table). Azlactones rac- 1 are ideal precursors for the synthesis of optically pure α,α -disubstituted (R)- and (S)-α-amino acids.     

Synthesis of New Chiral Bidentate (Phosphinophenyl)benzoxazine P,N-Ligands

Two new chiral bidentate (phosphinophenyl)benzoxazine P,N-ligands 2a and 2b were synthesized from highly enantiomer-enriched 2-(1-aminoalkyl)phenols 4 . Ligand rac- 2a was obtained on refluxing the t-Bu-substituted (aminomethyl)phenol 4a with 2-(diphenylphosphino)benzonitrile in chlorobenzene in the presence of anhydrous ZnCl₂ followed by decomplexation (Scheme 2). This reaction, when carried out with (+)-(S)- 4a , was accompanied by racemization at the stereogenic center of the alkyl side chain. The enantiomerically pure ligands (+)-(R)- 2a and (−)-(S)- 2a were obtained using a stepwise procedure via the amides (−)-(R)- and (+)-(S)- 5b , respectively, followed by cyclization to benzoxazines (+)-(R)- and (−)-(S)- 7b , respectively, with triflic anhydride and by F-atom substitution by diphenylphosphide (Schemes 3 and 5). In the case of the i-Pr analogue 2b , this last step resulted in racemization (Scheme 6). This was overcome by preparing the bromo derivative and introducing the diphenylphosphine group via Br/Li exchange and reaction with chlorodiphenylphosphine (Scheme 7). The first application of (+)-(R)- 2a in an asymmetric Heck reaction showed high enantioselectivity (91%) (Scheme 8).     

Synthesis and resolution of diethyl (1S,2S)-1-amino-2-vinylcyclopropane-1-phosphonate for HCV NS3 protease inhibitors

We herein describe an efficient synthesis of optically active diethyl 1-amino-2-vinylcyclopropane-1-phosphonate (analogous to 1-amino-2-vinylcyclopropane-1-carboxylate). The racemic phosphonate diethyl ester was obtained from an imine derived from aminomethylphosphonate diester and trans-1,4-dibromo-2-butene. Crystallizations of the dibenzoyl-l-tartaric acid salt allowed for separation of enantiomers. The enantiomerically pure material was used to synthesize an extremely potent tripeptide phosphonate inhibitor of HCV NS3 protease. X-ray crystal structure of the inhibitor bound to the HCV NS3 protease confirmed the absolute stereochemistry of the title compound.     

Aminoalkohole, 4. Mitt.: Ein Trennverfahren zur Herstellung von enantiomerenreinem Midodrin

Zusammenfassung Das früher präsentierte Verfahren zur Bestimmung der Enantiomerenreinheit von Aminoalkoholen über die N-BOC-O-MBE-Derivate kann auch zur präparativen Trennung von Midodrin eingesetzt werden. Bei Verwendung der N-((Phenylmethoxy)carbonyl)-Schutzgruppe kann die Entfernung der N-Schutzgruppe selektiv vor der Abspaltung der O-MBE-Gruppe erfolgen, so daß die Kontrolle der stereochemischen Einheitlichkeit der Produkte5 und6 sehr leicht möglich ist. Diese können ohne Racemisierung in die enantiomerenreinen MidodrinhydrochlorideR-1 undS-1 übergeführt werden.

---

A separation procedure for the preparation of enantiomerically pure midodrine

Summary Racemic midodrine chlorohydrate (rac-1) was N-protected to yield the racemic productsrac-2a-c. These were converted into the diastereomeric O-acetals3a-c/4a-c, which can easily be separated by chromatography. After removal of the N- and O-protective groups from3a-b/4a-b, respectively, enantiomerically pure midodrine chlorohydrateR-1 andS-1 could be isolated.

Unserem verehrten Lehrer Herrn Prof.O. Hromatka gewidmet     

Variants of Solid-State and Solution Structures of (η3-Allyl)- {2-[2′-(diphenylphosphino)phenyl]-4,5-dihydrooxazole-P,N}palladium(II) hexafluorophosphates and tetraphenylborates

Crystal and solution structures of the enantiomerically pure and the racemic pairs of (η³-allyl) {2-[2′-(diphenylphosphino)phenyl]-4,5-dihydro-4-phenyloxazole}palladium(II) hexafluorophosphates ( 1 , and rac- 1 , resp.) and tetraphenylborates ( 2 , and rac- 2 , resp.) as well as (η³-allyl){2-[2′-(diphenylphosphino)phenyl]-4,5-dihydro-4-isopropyloxazole}palladium(II) tetraphenylborate ( 3 ) were characterized by X-ray crystallography and ¹H-NMR spectroscopy. In the solid state, rac- 1 and rac- 2 proved to be disordered with both diastereoisomeric complexes in the crystal. The complexes 2 and 3 exist only in the ‘exo’ form. The X-ray structures show that the [Pd^II(η³-allyl)] moiety may adopt different configurations between a nearly symmetrical three-electron Pd^II(π³-allyl) system and an asymmetrical allyl group with a η¹- and a η²-bonding to the metal center. The [Pd^II(η³-allyl)] system of rac- 1 and of ‘endo’ rac- 2 is closer to the former, and that of 2 , ‘exo’-rac- 2 , and 3 closer to the later geometry. The ¹H-NMR spectra of the hexafluorophosphates 1 and rac- 1 show two sets of signals of the allylic protons in an ‘exo’/‘endo’ ratio of 2:3. The tetraphenylborates 2, rac- 2 , and 3 give only one set of broad signals of the allylic protons.     

Facile Synthesis of Enantiomerically Pure 1-（5-Bromo-2-chlorophenyl）-1-（4-ethoxyphenyl）ethane

A facile 7-step procedure for the synthesis of enantiomerically pure 1-（5-bromo-2-chlorophenyl）-1-（4-ethoxyphenyl）ethanes[（R）-2 and（S）-2] that started from （5-bromo-2-chlorophenyl）（4-ethoxyphenyl）methanone 3 was developed.The key step was the resolution of 2-（5-bromo-2-chlorophenyl）-2-（4-ethoxyphenyl）acetic acid 6 by crystallizations of its L-and D-menthyl esters 7 and 8 from petroleum ether to give optically pure enantiomers 9 and 10,respectively.The absolute configurations of the products were unambiguously determined by single-crystal X-ray diffractions of four key intermediates,9,10,13 and 14.This procedure is characterized by inexpensiveness,scalability and ability to produce two individual enantiomers of a diarylethane with unambiguously determined absolute configurations and high enantiomeric purities.     

Crystal Structure and Absolute Configuration of (+)-(1S, 2R)-5, 6-Dimethylidene-2exo-norbornyl-exo-irontricarbonyl p-Bromobenzoate

The title complex (+)- 13x has been prepared in an enantiomerically pure form. Its absolute configuration has been determined by single-crystal X-ray diffraction and has been correlated chemically to that of the 5, 6-dimethylidene-2-norbornyl derivatives (—)- 1 , (—)- 2 , (—)- 3 and to (—)-(1S, 2R)-benzonorborn-5-en-2-yl acetate (s. Scheme 1), whose configuration was deduced by indirect techniques. A critical analysis of the chiroptical properties of the exocyclic dienes 1–3 is now possible. These compounds are limiting systems for the application of the allylic axial chirality rule, the generalized octant rule and the symmetry rule for βγ-unsaturated ketones.     

Enantioselectivity in Odor Perception

The 3‐methyl‐4‐(tricyclo[5.2.1.0^2,6]dec‐4‐en‐8‐ylidene)butan‐2‐ols (=Fleursandol^®; rac‐ 10 ), a new class of sandalwood odorants, were synthesized in their enantiomerically pure forms by use of tricyclo[5.2.1.0^2,6]dec‐4‐en‐8‐ones 17 and ent‐ 17 and (tetrahydro‐2H‐pyran‐2‐yl)‐protected 4‐bromo‐3‐methylbutan‐2‐ols 22 and ent‐ 22 as starting materials (Schemes 2–4). Only four of 16 possible stereoisomers of rac‐ 10 possess the typical, very pleasant, long‐lasting sandalwood odor (Table 1). The (2S,3R,4E,1′R,2′R,6′R,7′R)‐isomer ent‐ 10a is by far the most important representative, with an odor threshold of 5 μg/l in H₂O.     

Synthesis,Structure, and Antimalarial Activity of Some Enantiomerically Pure,cis-fused cyclopenteno-1,2,4-trioxanes

Two pairs of enantiomerically pure cis-fused cyclopenteno-1,2,4-trioxanes ( 7 , ent- 7 and 8 , ent- 8 ) are prepared (Schemes 1–3). Their identities are established by dye-sensitized photo-oxygenation of ent- 7 and 8 , ent- 8 to the allylichydroperxides, reduction to the corresponding alcohols, and conversion to the (1S)-camphanates (Scheme 4), the structures of which are determined by X-ray analysis. The dynamic properties of ent- 7 are investigated by NMR spectroscopy and PM3 calculations. Evidence for an easily accessible twist-boat conformation is obtained. The in vitro and in vivo antimalarial activities of 7 , ent- 7,8 , and ent- 8 as well as those of the racemic mixtures are evaluated against Plasmodium falciparum, P. berghei, and P. yoelii. No correlation is observed between configuration and activity. Racemates and pure enantiomers have commensurate activities. The mode of action on the intraerythrocytic parasite is rationalized in terms of close docking by the twist-boat conformer of the trioxane on the surface of a molecule of heme, single-electron transfer to the O? O σ* orbital, and scission to the acetal radical which then irreversibly isomerizes to a C-centered radical, the ultimate lethal agent (Scheme 5).     

Stereoselective synthesis of γ-lactone fused cyclopentanoids

The stereoselective synthesis of γ-lactone fused cyclopentanoids applying chemoenzymatic methods is described. rac-2-Hydroxymethyl-1,4,5,6-tetrachloro-7,7-dimethoxybicyclo[2.2.1]hept-5-ene and rac-2-hydroxymethyl-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene were successfully resolved by Candida rugosa lipase (CRL), to afford enantiomerically enriched products with an ee of 94 and 97%, respectively. The enantiomerically enriched acetates were then subjected to ruthenium and/or cerium catalyzed oxidation to afford α-diketones and subsequent alkaline H₂O₂ mediated oxidative cleavage reaction of α-diketones, followed by CH₂N₂ esterification, gave enantiomerically enriched γ-lactone fused cyclopentanoids with known absolute configurations.     

An efficient and general method for resolving cyclopropene carboxylic acids

A general method is described for the resolution of cycloprop-2-ene carboxylic acids via diastereomeric N-acyloxazolidines prepared from enantiomerically pure oxazolidinones. Although a number of oxazolidinones were shown to resolve cyclopropene carboxylic acids, the oxazolidinones of S-phenylalaninol, S-phenylglycine and (1S,2R)-cis-1-amino-2-indanol are optimal in terms of resolving power and cost effectiveness. Separations were performed using simple flash chromatography, and because there is typically a large difference in R_f values it is possible to separate gram quantities of pure diastereomers in a single chromatogram. The cycloprop-2-ene carboxylic acids that can be resolved include those that are substituted at the 1-position by H, Ph, α-naphthyl, CO₂Me, CH₂OMOM, and trans-styryl; alkene substituents include Me, n-alkyl, Ph and tethered alkynes. Remarkably, 2-methyl-3-propylcycloprop-2-ene carboxylic acid can also be resolved with ease. The relative configurations of four diastereomerically pure oxazolidines were determined by X-ray crystallography. Reduction of the N-acyloxazolidinones with LiBH₄ give enantiomerically pure derivatives of 3-hydroxymethylcyclopropene that react with either MeMgCl or vinylMgCl and catalytic CuI to give enantiomerically pure products of syn-addition.     

Enzyme-promoted desymmetrization of bis(2-hydroxymethylphenyl) sulfoxide as a route to tridentate chiral catalysts

The desymmetrization of prochiral bis(2-hydroxymethylphenyl) sulfoxide 3 was efficiently performed via acetylation promoted by commonly available lipases. Two lipases, namely, CAL-B and LPL proved particularly efficient to give 2-acetoxymethylphenyl 2-hydroxymethylphenyl sulfoxide 4 in up to 98% yield and with up to 98% ee. On the basis of an X-ray analysis, the absolute configuration of 4 was determined as (+)-(R). The enantiomerically pure product 4 was then transformed into a series of enantiomerically pure diastereomeric 2-aminomethylphenyl 2-hydroxymethylphenyl sulfoxides 8 in which the amino groups originated from enantiomerically pure amines having additional C-stereogenic centres. Compounds 8 were examined as possible tridentate chiral catalysts in a reference reaction of diethylzinc with benzaldehyde to give the expected product, 1-phenylpropan-1-ol, in moderate yields and with ee’s of up to 50%.