L-Phenylalanine Cyclohexylamide: A simple and convenient auxiliary for the synthesis of optically pure α,α-disubstituted (R)- and (S)-amino acids

This work describes L -phenylalanine cyclohexylamide ( 5c ) as a simple, cheap, and powerful chiral auxiliary for the synthesis of a series of optically pure α,α-disubstituted (R)- and (S)-amino acids of type 1 , such as (R)- and (S)-2-methyl-phenylalanine ( 1a ), (R)- and (S)-2-methyl-2-phenylglycine ( 1b ), and (R)- and (S)-2-methylvaline ( 1c ; Scheme 3). These amino acids were efficiently transformed into the suitably protected and activated amino acid building blocks (R)- and (S)- 12b and (R)- and (S)- 12c (Scheme 4) which are ready for incorporation into peptides by solution or solid-phase techniques. Based on the crystal structures of 6b, 6c , and 7a belonging to the diastereoisomeric peptides series 6 and 7 , the absolute configurations of each member of the series were determined. β-Turn geometries of type II′ and I were observed for 6b and 7a , respectively, whereas 6c crystallized in an extended conformation. The impacts of side-chain variation on conformation and crystal packing of these triamides are discussed.     

Synthesis of (R)- and (S)-4-hydroxyisophorone by ruthenium-catalyzed asymmetric transfer hydrogenation of ketoisophorone

The first synthesis of (R)- and (S)-4-hydroxyisophorone by catalytic transfer hydrogenation of ketoisophorone is reported. Ruthenium catalysts containing commercially available chiral amino alcohols afforded 4-hydroxyisophorone in up to 97% selectivity and 97% ee. (R)- or (S)-4-Hydroxyisophorones with >99% ee were isolated by crystallization. The catalyst precursors [RuCl₂((S,R)-ADPE)(η⁶-p-cymene)] ((S,R)-ADPE=(1S,2R)-amino-1,2-diphenylethanol-N) and (R_Ru)-[RuCl((S,R)-ADPE⁻¹)(η⁶-p-cymene)] (ADPE⁻¹=amino-1,2-diphenylethanolato-N,O) were isolated for the first time and the X-ray crystal structure of the latter determined.     

Mammalian alkaloids: Synthesis and O-methylation of (S)- and (R)-3′-hydroxycoclaurine and their N-methylated analogues with S-adenosyl-L-[methyl-14C]methionine in presence of mammalian catechol O-methyltransferase

O-Methylation of the optically active 3′-hydroxycoclaurines 3a and 3b and of the N-methylated analogs 5a,b with S-adenosyl-L -[methyl-¹⁴C]methionine in presence of mammalian COMT was investigated in vitro. The N-unsubstituted (1S)- and (1R )-isomers 3a and 3b , respectively, afforded almost equal amounts of the corresponding N-norreticuline 4 and N-nororientaline 19 , besides two unknown by-products (see Fig. and Table 1). The N-methylated (1S)-isoquinoline 5a , on the other hand, afforded largely (S)-orientaline ((S)- 19 ), while an almost equal mixture of (R)-reticuline ( 6b ) and (R)-orientaline ((R)- 19 ) was obtained from the (1R)-enantiomer 5b . The isoquinolines 3a,b and 5a,b were prepared by a Bischler-Napieralski cyclization yielding O-benzyl-protected isoquinoline 10 (Scheme 1). The optical resolution of 10 was accomplished with 2′-bromotartranilic acid. The N-methylated isoquinolines were prepared by N-formylation of 10a,b and reduction of the formamides 13a,b with diborane (→ 14a,b ). Deblocking of the benzyl-ether moieties of 10a,b and 14a,b was accomplished by catalytic hydrogenation in presence of HCl, affording directly 3a,b ·HCl and 5a,b ·HCl, respectively.     

Synthesis of (5R,8S,10R)-6-(Allyloxy)- and (5R,8S,10R)-6-(Propyloxy)ergolines from the 6-Methyl Precursors

Novel (5R,8S,10R)-6-(allyloxy)- and (5R,8S,10R)-6-(propyloxy)ergolines have been synthesized by use of a Meisenheimer [2,3]-sigmatropic rearrangement of a (5R,8S,10R)-6-allyl-ergoline N⁶-oxide as key step.     

New chiral phosphine-phosphonites derived from (2R,3R)-dimethyl tartrate, (S)-binaphthol and (1R,2S)-ephedrine

The reaction of 2-lithiophenyldiphenylphosphine with phosphorus trichloride afforded the new unsymmetric phosphine, dichloro(2-diphenylphosphinophenyl)phosphine (4). Condensation of 4 with (a) (2R,3R)-dimethyl tartrate or (b) (S)-binaphthol in the presence of triethylamine gave new chiral phosphine-phosphonite ligands, (2R,3R)-[2-(2′-(diphenylphosphino)phenyl)-4,5-bis(carbomethoxy)-1,3,2-dioxaphospholane] ((2R,3R)-5) and (S)-[2-(diphenylphosphino)benzene][1,1′-binaphthalen-2,2′-diyl]phosphonite] ((S)-6). The analogous reaction of 4 with (1R,2S)-ephedrine using N-methylmorpholine as the base, gave [2-(2′-(diphenylphosphino)phenyl)-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine] (7) as a 95:5 mixture of diastereoisomers.     

Herstellung enantiomerenreiner cis- oder trans-konfigurierter 2-(tert-Butyl)-3-methylimidazolidin-4-one aus den Aminosäuren (S)-Alanin, (S)-Phenylalanin, (R)-Phenylglycin, (S)-Methionin und (S)-Valin

Preparation of the Enantiomerically Pure cis- and trans-Configurated 2-(tert-Butyl)-3-methylimidazolidin-4-ones from the Amino Acids (S)-Alanine, (S)-Phenylalanine, (R)-Phenylglycine, (S)-Methionine, and (S)-Valine In contrast to α-hydroxy and α-mercapto carboxylic acids, simple α-amino acids do not form acetal-type derivatives ( 2 , X = NH) with pivalaldehyde. For the generation of amino-acid-derived chiral, nonracemic enolates (cf. 3 ), and hence, for the α-alkylation of amino acids without racemization and without an external chiral auxiliary, the imidazolidinones 12–14 were prepared diastereoselectively. To this end, the methyl or ethyl esters of amino-acid hydrochlorides were first converted to N-methylamides of amino acids which in turn were condensed with pivalaldehyde to give (neopentylidenamino)amides ( 11 ). These Schiff bases could be cyclized either to trans-or to cis-imidazolidinones ( 12, 14 and 13 , respectively), which were obtained in enantiomerically pure form after recrystallization. The enantiomeric purities were confirmed by HPLC with chiral stationary phases or by ¹H-NMR spectroscopy in the presence of chiral shift reagents. The configurations (cis, trans) were assigned by NOE measurements on 300- or 360-MHz ¹H-NMR spectrometers.     

Preparation of (R)-11-hydroxyaporphine directly from (R)-10,11-dihydroxyaporphine ((R)-apomorphine)

A Regioselective synthesis of (R)-11-hydroxyaporphine 2 directly from (R)-10,11-dihydroxyaporphine ((R)-apomorphine, 1 ) is described for the first time. The isopropylidene ketal ring of 10,11-(isopropyl-idenyldioxy)aporphine 5 obtained by the isopropylidenation of apomorphine was regioselectively opened by ten equivalents of trimethylaluminum to give (R)-10-hydroxy-11-tert-butyloxyaporphine 6 . The free 10-hydioxyl position of 6 was triflated with N-pbenyltrifluoromethanesulfonimide and potassium carbonate under reflux to give (R)-10-[(trifluoromethyl)sulfonyloxy]-11-tert-butyloxyaporphine 7 . The reduced product, 11-tert-butyloxyaporphine 8 was prepared from 7 by a palladium-catalyzed hydrogenolysis. The ether cleavage of (R)-11-tert-butyloxyaporphine with 48% hydrobromic acid afforded the desired (R)-11-hydroxyaporphine 2 in good yield.     

Stereochemische Korrelationen zwischen (2R,4′R,8′R)-α-Tocopherol, (25S,26)-Dihydroxycholecalciferol, (–)-(1S,5R)-Frontalin und (–)-(R)-Linalol

Stereochemical Correlations between (2R,4′R,8′R)-α-Tocopherol, (25S,26)-Dihydroxycholecalciferol, (–)-(1S,5R)-Frontalin and (–)-(R)-Linalol The optically active C₅- and C₄-building units 1 and 2 with their hydroxy group at a asymmetric C-atom were transformed to (–)-(1S,5R)-Frontalin ( 7 ) and (–)-(3R)-Linalol ( 8 ) respectively; 1 and 2 had been used earlier in the preparation of the chroman part of (2R,4′R,8′R)-α-Tocopherol ( 6a , vitamin E), and for introduction of the side chain in (25S,26)-Dihydroxycholecalciferol ((25S)- 4 ), a natural metabolite of Vitamin D₃. The stereochemical correlations resulting from these converions fit into a coherent picture with those correlations already known from literature and they confirm our earlier stereochemical assignments. A stereochemical assignment concerning the C(25)-epimers of 25,26-Dihydroxycholecalciferol that was in contrast to our findings and that initiated the conversion of 1 and 2 to 7 resp. 8 for additional stereochemical correlations has been corrected in the meantime by the authors [26].     

Chiral Tetraamines Based on (S)-2-(Aminomethyl)pyrrolidine: Template synthesis and properties of copper(II) complexes

The template reaction of {bis[(S)-2-(aminomethyl)pyrrolidine]}copper(II) with formaldehyde, nitroethane, and base in MeOH yields optically pure {1,7-bis[(S)-pyrrolidin-2-yl]-4-methyl-4-nitro-2,6-diazaheptane}- copper(II) ([Cu((S,S)-mnppm)]²⁺) in high yield. The same reaction with rac-2-(aminomethyl)pyrrolidine is also described. Preparative details and spectroscopic and electrochemical properties of the Cu^II complexes and of the free ligands are reported and compared with structural, spectroscopic and electrochemical data of the Cu^II complex of the unsubstituted parent ligand 1,7-bis[(S)-pyrrolidin-2-yl]-2,6-diazaheptane (ppm). The crystal structure of [Cu(ppm)]Cl ClO₄ has been determined by X-ray diffraction methods.     

Copper(II) complexes of potentially terdentate N2-[(R)-2-hydroxypropyl]- and N2-[(S)-2-hydroxypropyl]-(S)-phenylalaninamide for chiral recognition: Synthesis of the Ligands and Formation Constants

Copper(II) complexes of the ligands N²-[(R)-2-hydroxypropyl]- and N²-[(S)-2-hydroxypropyl]-(S)-phenylalaninamide performed chiral separation of N-dansyl-protected and unmodified amino acids in HPLC (reversed phase). With the aim of investigating which species are potentially involved in the discrimination mechanism, the two ligands were synthesized and their complexation equilibria with Cu²⁺ studied by potentiometry and spectrophotometry in aqueous solution up to pH 11.7. The formation constants of the species observed, [CuL]²⁺, [CuL₂]²⁺, [CuLH_–1]⁺, [CuL₂H_–1]⁺, [CuL₂H_–2], and [CuL₂H_–3]^?, were quite similar for both compounds and were compared to those of (S)-phenylalaninamide. Most probably, in [CuL₂H_–3]^? the ligands behave as terdentate, with the deprotonated OH group occupying an apical position.     

Heterotricyclodecane XX (+)-(1S, 3S, 6S, 8S)- und (−)-(1R, 3R, 6R, 8R)-2, 7-Dioxa-twista-4,9-dien

(+)-(1S, 3S, 6S, 8S)- and (?)-(1R, 3R, 6R, 8R)-2,7-dioxa-twista-4,9-diene. A synthesis and the determination of the sense of chirality of (+)-(1S, 3S, 6S, 8S)- and (?)-(1R, 3R, 6R, 8R)-2,7-dioxa-twista-4,9-diene ((+)- 5 and (?)- 5 , respectively) is described.     

C45- and C50-Carotinoide. 1. Mitteilung. Synthese von (R)- and (S)-Lavandulol

C₄₅- and C₅₀-Carotenoids, 1st Communication. Synthesis of (R)- and (S)-Lavandulol Starting with methyl (3 R)-3-hydroxybutanoate ((R)-7) and ethyl (3 S)-3- hydroxybutanoate ((S)- 11 ), respectively, (R)- and (S)-lavandulol ((R)- 1 and (S)- 1 ) were synthesized with high optical purity. The synthesized key intermediates (R)- 6 and (S)- 6 are suitable compounds for the synthesis of optically active acyclic C₄₅- and C₅₀-carotenoids.     

Enantioselective addition of dialkylzinc to aldehydes catalyzed by (S)-2-(N,N-disubstituted aminomethyl)indoline

Chiral di- or triamines, (S)-2-(N,N-disubstituted aminomethyl)indoline 1a–d, derived from (S)-indoline-2-carboxylic acid were efficient chiral catalysts for the enantioselective addition of dialkylzincs to aldehydes. The best results were obtained by employing 15 mol% of (S)-2-(4-methylpiperazin-1-ylmethyl)indoline 1c, and chiral secondary alcohols were obtained in up to 97% ee.     

Synthesis of (R)- and (S)-5-(Hydroxymethyl)-3-isopropyloxazolidin-2-one,intermediates in the preparation of optically active β-blockers

The (R)- and (S)-5-(hydroxymethyl)-3-isopropyloxazolidin-2-ones, ((R)- and (S)- 2 , resp.), pivotal intermediates in the preparation of optically active β-blockers, were synthesized using (R,E)-2-hydroxypent-3-enenitrile ( 1 ) as the chiral starting material. In the synthesis of (R)- 2 , a known cyclization/inversion step was applied.     

Stereoselective Formation of Ternary Copper(II) Complexes of (S)-Amino-acid Amides and (R)- or (S)-Histidine and (R)- or (S)-Tyrosine in Aqueous Solution

Formation constants of ternary complexes of Cu^II with (S)-amino-acid amides ((S)-phenylalaninamide, (S)-prolinamide, and (S)-tryptophanamide) and (R)- or (S)-histidine and (R)- or (S)-tyrosine were determined potentiometrically in aqueous solution. Significant stereoselectivity was presented by all three amides towards histidine, the diastereoisomeric complexes with ‘heterochiral’ ligands being more stable than those with ‘homochiral’ ligands (see Table 3). The stereoselectivity observed with (S)-phenylalaninamide and (S)-tryptophanamide may be explained on the basis of hydrophobic stacking interactions between 1H-imidazole and the aromatic side chain, favoured by the terdentate behaviour of histidine (see Fig.2), whereas repulsive effects seem to be prevalent with (S)-prolinamide. Only (S)-prolinamide and (S)-phenylalaninamide show appreciable stereoselectivity with tyrosine, which is bidentate, probably on account of repulsive interactions. The present results on the stability of ternary complexes in solution allow to draw some conclusions on the mechanism of chiral discrimination performed by Cu^II complexes of (S)-amino-acid amides added to the mobile phase in HPLC (reversed phase).     

Enantioselective Preparation of (2R)- and (2S)-Azetidine-2-carboxylic Acids

The enantiomerically pure amino ketones 13 and 31 were prepared starting from the commercially available amino diol 9 and D -serine ( 21 ), respectively. Irradiation afforded highly functionalized azetidinols 15 and 33 in a fully stereoselective manner and in high yields, whereas N-phenacylglycine 5 gave only the secondary products of a Norrish-Type-II cleavage. Compounds 15 and 33 were converted into (2R)- and (2S)-azetidine-2-carboxylic acids 20 and 37 , respectively, in several steps. The influence of H-bonds on efficiency, chemo-, and stereoselectivity of the photochemical cyclization of 5 , 13 , and 31 was discussed. It was shown that conformational analysis of corresponding triplet biradicals is often valuable in understanding the photochemistry of amino ketones.     

(R)- and (S)-N-(Benzyloxycarbonyl)-3,4-epoxybutylamine. New 4-amino-2-hydroxybutyl synthons for the synthesis of hypusine reagents and (R)-6- and (S)-7-hydroxyspermidine

The synthesis and application of the chiral reagents (R)- and (S)-N-(benzyloxycarbonyl)-3,4-epoxybutylamine is described for the first time. These 4-amino-2-hydroxybutyl synthons are successfully employed in the assembly of two hydroxylated triamines, (R)-6- and (S)-7-hydroxyspermidine, and a previously described hypusine reagent, (2S,9R)-11-[(benzyloxycarbonyl)amino]-7-(benzyloxycarbonyl)-2-[(9-fluorenylmethoxycarbonyl)amino]-9-(tetrahydropyran-2-yloxy)-7-azaundecanoic acid, useful for solution- and solid-phase peptide synthesis.     

Stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine

The stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine from (R)-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)piperidin-2-one is described. The key steps involved are α-hydroxylation of quiral lactam with O₂, stereoconvergent reduction of (R)- or (S)-3-(benzyloxy)-piperidin-2-one with Red-Al® which afforded in both cases the trans-bicyclic oxazolidine in high stereoselectivity after chromatographic purification and a stereospecific Grignard addition to chiral bicyclic oxazolidine.     

C45- and C50-Carotehoids. Part 8. Synthesis of (all-E,2S,2′S)-bacterioruberin, (all-E,2S,2′S)-monoanhydrobacterioruberin, (all-E,2S,2′S)-bisanhydrobacterioruberin, (all- E,2R,2′R)-3,4,3′,4′-tetrahydrobisanhydro- bacterioruberin,and (all-E,S)-2-isopentenyl-3,4-dehydrorhodopin

Starting from (R)-3-hydroxybutyric acid ((R)- 10 ) the C₄₅- and C₅₀-carotenoids (all-E,2S,2′S)-bacterioruberm ( 1 ), (all-E,2S,2′S)-monoanhydrobacterioruberin ( 2 ), (all-E,2S,2′S)-bisanhydrobacterioruberin ( 3 ), (all-E,2R,2′R)-3,4,3′,4′-tetrahydrobisanhydrobacterioruberin ( 5 ), and (all-E,S)-2-isopentenyl-3,4-dehydrorhodopin ( 6 ) were synthesized. By comparison of the chiroptical data of the natural and the synthetic compounds, the (2S)- and (2′S)-configuration of the natural products 1–3 and 6 was established.     

Novel open-chain and cyclic conformationally constrained (R)- and (S)-α,α-disubstituted tyrosine analogues

A series of novel open-chain and cyclic conformationally constrained (R)- and (S)-α,α-disubstituted tyrosine analogues 1a–e were synthesized in good yields and high optical purities (Schemes 1 and 2). The absolute configurations of these tyrosine analogues were unambiguously determined based on the X-ray structures of the precursor diastereoisomeric peptides of type 4 and 5 . Four of these structures are described (Figs. 1–4), showing β-turn type-I geometries for dipeptides 4a, 5b , and 4c and an extended conformation for peptide 5c (Table 3). The conversion of the free amino acids 1a–c into suitably protected building blocks 11a–d and 15d,e for peptide synthesis is discussed (Schemes 3 and 4).