Stereoselective total synthesis of (+)-(6R,2′S)-cryptocaryalactone and (−)-(6S,2′S)-epi cryptocaryalactone

The total synthesis of (+)-(6R,2′S)-cryptocaryalactone and (−)-(6S,2′S)-epi cryptocaryalactone is reported based on stereoselective reduction of δ-hydroxy β-keto ester to install 1,3-polyol system, cis Wittig olefination, and lactonization as the key steps. The synthesis of (−)-(6S,2′S)-epi cryptocaryalactone is also reported using syn-benzylidene acetal formation and a preferential Z-Wittig olefination reaction and lactonization as the key steps.     

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.     

Stereoselective synthesis of (R)-(−)-denopamine, (R)-(−)-tembamide and (R)-(−)-aegeline via asymmetric reduction of azidoketones by Daucus carota in aqueous medium

A simple and efficient stereoselective synthesis of (R)-denopamine and other naturally occurring hydroxy amides from optically active (R)-2-azido-1-arylethanols, is described for the first time via reduction of the corresponding -azidoarylketones with enzymes from Daucus Carota root, under mild and environmentally friendly conditions. The products are formed with high degrees of enantioselectivity.     

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.     

Synthesis of (2R,3S,4S)-4-aryl-3-hydroxyprolinols

Synthesis of (2R,3S,4S)-4-aryl-3-hydroxyprolinols has been established starting from 2-benzyloxymethylpyrrolidin-2-one framework, which is derived from commercially available trans-(2S,4R)-4-hydroxyproline. The single diastereomer having a trans–cis relative configuration with C₂ and C₃ and C₃ and C₄ is constructed in two one-pot functional group transformations of Grignard addition/dehydration and epoxidation/isomerization as the key steps in moderate yield.     

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 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.     

(R)-4-menthen-3-one in the synthesis of (3S)-methylundecand (2S)-methyldec-1-ylbromides, key synthons for (S,S,S)-diprionylacetate

New capabilities for the synthetic use of (R)-4-menthen-3-one were demonstrated using as examples (3S)-methylundec- and (2S)-methyldec-1-ylbromides, key synthons for (S,S,S)-diprionylacetate (sex pheromone of pine sawflies of genera Diprion and Neodiprion).     

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.     

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 Synthesis of （R）- and （S）-Moprolol

A simple and effective procedure for the enantioselective synthesis of （R）- and （S）-moprolol was described. The key step was the asymmetric synthesis of enantiopure （R）- and （S）-guaifenesin, which were synthesized from enantioenriched （R）-3-chloro-l,2-propanediol and （S）-epichlorohydrin via kinetics of hydrolysis resolution of racemic epichlorohydrin by chiral Salen-Co^Ⅲ complex. The e.e. values of both the optical compounds were above 98%, and the chemical structures of the target compounds were confirmed by ^1H NMR, ^13C NMR, IR, and MS.     

Chemoenzymatic synthesis of (R)- and (S)-1-heteroarylethanols

A chemoenzymatic methodology for the synthesis of highly enantiomerically enriched (S)- and (R)-1-heteroarylethanols by enantioselective bioreduction with baker’s yeast of the corresponding 1-heteroarylethanones followed by three racemization free chemical steps including a Mitsunobu reaction was developed.     

Total synthesis of 3,4-dihydroxyprolines, -threo- -norvaline and (2S,3R,4R)-2-amino-3,4-dihydroxytetrahydrofuran-2-carboxylic acid methyl ester

The Henry reaction between -glyceraldehyde and ethyl nitroacetate allowed the practical development of a diastereoselective synthesis of 3,4,5-trihydroxy-2-nitropentanoic acid esters, which were reduced to polyoxamic acids, which were used in a new diastereoselective synthesis of 3,4-dihydroxyprolines and new enantioselective syntheses of -threo- -norvaline and (2S,3R,4R)-2-amino-3,4-dihydroxytetrahydrofuran-2-carboxylic acid methyl ester.     

Diastereoselective allylation of N-glyoxyloyl-(2R)-bornane-10,2-sultam and (1R)-8-phenylmenthyl glyoxylate: synthesis of (2S,4S)-2-hydroxy-4-hydroxymethyl-4-butanolide

The diastereoselective addition of allylsilanes and allylstannanes to N-glyoxyloyl-(2R)-bornane-10,2-sultam 1 and (1R)-8-phenylmenthyl glyoxylate 7 in the presence of Lewis acids has been studied. We obtained diastereoselectivities up to 84% and 94% for the allylation of 2 and 7, respectively. The application of the allylation products of 1 or 2 in the synthesis of 4-butanolides, for example (2S,4S)-2-hydroxy-4-hydroxymethyl-4-butanolide 13 is presented.     

(3S,4R,5R)-3-(2-Hydroxyethyl)piperidine-3,4,5-triol as an isofagomine analogue: synthesis and glycosidase inhibition study

The synthesis of (3S,4R,5R)-3-(2-hydroxyethyl)piperidine-3,4,5-triol 10 has been described from d-glucose. The base promoted cyclization for the construction of the piperdine framework is the key step of the synthesis.     

New Synthesis and Chirality of (−)-4,4,4,4′,4′,4′-Hexafluorovaline

(?)-(R)-4,4,4,4′,4′,4′-Hexafluorovaline hydrochloride ((R)- 5 ) of 98% ee is prepared from β,β-bis(trifluoromethyl)acrylic acid (= benzyl 4,4,4-trifluoro-3-(trifluoromethyl)but-2-enoate; 1 ) in 4 steps with an overall yield of 9.6%. Key step is the separation of the TsOH salts of the diastereoisomers obtained by anti-Michael addition of (+)-(R)-1-phenylethylamine ( 2 ) to 1 (→ (R,R)- 3 ). In contrast to the published (S)-chirality, the X-ray structure analysis of (R,S)- 6 reveals, that (R)-chirality has to be assigned to the levorotatory (?)-4,4,4,4′,4′,4′-hexafluorovaline hydrochloride.     

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.     

Fluorescence properties of (R)- and (S)-[1,1′-binaphthalene]-2,2′-diols solutions and their complexes with cyclodextrins in aqueous medium

Steady-state and time-resolved fluorescence techniques were used to study (R)- and (S)-[1,1′-binaphthalene]-2,2′-diol (1,1′-binaphthol or BINOL) dilute solutions of different polarity solvents, as well as their inclusion complexes with α- and βcyclodextrins (CDs) in water. BINOLs in dilute water solutions exhibited a surprisingly high fluorescence anisotropy that was explained as being due to the formation of fairly large order π–π stacking aggregates in aqueous polar media. Stoichiometries, formation constants and the changes of enthalpy and entropy upon inclusion were also obtained by measuring the variation of the fluorescence intensity with [CD] and temperature. Results agree with the formation of 1:1 stoichiometry complexes, but the association constants are rather low and very similar for both enantiomers. Molecular mechanic calculations in the presence of water were employed to study the formation of BINOL complexes with both α- and βCDs. For the most stable structures of any of the complexes only a small portion of the guests, in agreement with thermodynamics parameters and quenching experiments, penetrates inside the CD cavities. Driving forces for 1:1 inclusion processes may be dominated by non-bonded van der Waals host:guest interactions. The low guest:host binding constants and poor enantioselectivity of α- and βCDs for BINOLS may be a consequence of the BINOL aggregation in water.     

Asymmetric synthesis of (R,S)- and (R,R)-4-hydroxy-5-(α-substituted)-hydroxymethyl[2.2]paracyclophane and derivatives by stereoselective addition to (R)-4-hydroxy-5-formyl[2.2]paracyclophane and derivatives

Highly diastereoselective nucleophilic addition reactions of organometallic reagents to formyl[2.2]paracyclophane derivatives which were ortho-substituted by hydroxy-, alkoxy- and trimethylsilyloxy-groups are reported. The absolute configuration of the newly formed secondary alcohols is assigned on the basis of the X-ray diffraction study as well as chemical correlation. The magnitude of the asymmetric induction and even the sense of chirality of the forming asymmetric carbon atoms of the alcohols depended on the nature of the ortho-substituents.