Synthesis of enantiopure (R)-2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-3-methylbutanoic acid—a key intermediate for the preparation of Aliskiren

The enantioselective hydrogenation of (E)-2-(4-methoxy-3-(3-methoxypropoxy)-benzylidene)-3-methylbutanoic acid (1) to (R)-2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-3-methylbutanoic acid (2)—a key intermediate in the synthesis of the pharmacologically important renin inhibitor Aliskiren—is described. The stereochemistry of the catalytic transformation has been studied using a number of homogeneous chiral Rh(I) and Ru(II) complexes bearing ferrocene-based phosphine ligands. The highest enantioselectivity for the homogeneous hydrogenation of 1 (up to 95% ee) was achieved with a [Rh(NBD)₂]BF₄ pre-catalyst (substrate/catalyst ratio 100:1, 10 bar H₂, 40 °C, in MeOH). To bring the enantioselectivity to perfection an effective method for the isolation of the enantiopure carboxylic acid is suggested likewise.     

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.     

Synthesis and characterization of cyclometallated palladium(II) and platinum(II) complexes with amide-thiolate ligands

The redox reaction of bis(2-benzamidophenyl) disulfide (H₂L-LH₂) with [Pd(PPh₃)₄] in a 1:1 ratio gave mononuclear and dinuclear palladium(II) complexes with 2-benzamidobenzenethiolate (H₂L⁻), [Pd(H₂L-S)₂(PPh₃)₂] (1) and [Pd₂(H₂L-S)₂ (μ-H₂L-S)₂(PPh₃)₂] (2). A similar reaction with [Pt(PPh₃)₄] produced only the corresponding mononuclear platinum(II) complex, [Pt(H₂L-S)₂(PPh₃)₂] (3). Treatment of these complexes with KOH led to the formation of cyclometallated palladium(II) and platinum(II) complexes, [Pd(L-C,N,S)(PPh₃)]⁻ ([4]⁻) and [Pt(L-C,N,S) (PPh₃)]⁻ ([5]⁻). The molecular structures of 2, 3 and [4]⁻ were determined by X-ray crystallography.     

PEG-400-H2O as a green and recyclable medium for asymmetric hydrogenations of aromatic ketones catalyzed by RuCl2(TPPTS)2-(S,S)-DPENDS

PEG-400-H₂O was found to be a green and recyclable reaction medium for asymmetric hydrogenations of aromatic ketones catalyzed by a ruthenium achiral monophosphine complex RuCl₂(TPPTS)₂ [TPPTS: P(m-C₆H₄SO₃Na)₃] modified by (S,S)-DPENDS [disodium salt of sulfonated (S,S)-1,2-diphenyl-1,2-ethylene-diamine]. The acetophenone product was obtained with 86.3% ee under the optimized conditions. The resulting products can be easily separated from the catalyst by extraction with n-hexane. The catalyst immobilized in PEG-400-H₂O not only exhibits excellent activity and enantioselectivity, but also can be recycled and reused several times without a loss of activity or enantioselectivity.     

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.     

The synthesis and characterisation of N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides and related pyrrolidin-2-yl-4,5-dihydro-1H-imidazol-5-ones as potential enantioselective organocatalysts

The acylation of substituted 2-aminopropanamides with (2S)-Boc-proline, (2S)-Cbz-proline and (2S)-Bn-proline was used to prepare substituted 1-protected N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides (74-89%), whose subsequent deprotection gave N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides (94-95%). The enantiomerically pure N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides obtained were tested as organocatalysts for the aldol reaction of cyclohexanone with 4-nitrobenzaldehyde, with yields ranging from 38% to 79% ee. The highest enantioselectivity (89% ee) was achieved by catalysis with N-(1-carbamoyl-cyclopentyl)-(S)-prolinamide (methanol, l0% HCl). By the action of sodium methoxide, Boc-N-(1-carbamoyl-cyclopentyl)-(S)-prolinamide was quantitatively cyclised to 2-(1-Boc-pyrrolidin-2-yl)-1,3-diazaspiro[4.4]non-1-en-4-one, which was accompanied by racemisation at the stereogenic centre of the proline skeleton. Alternatively, the substituted 4,4-dialkyl-2-pyrrolidin-2-yl-4,5-dihydro-1H-imidazol-5-ones were prepared by oxidation of 4,4-dialkyl-2-((2S)-1-Boc-pyrrolidin-2-yl)-4,5-dihydro-1H-imidazolidin-5-ones (54-69%). In an acid medium, 2-pyrrolidin-2-yl-1,3-diazaspiro[4.4]non-1-en-4-one and (4S)-4-isopropyl-4-methyl-2-pyrrolidin-2-yl-4,5-dihydro-1H-imidazol-5-one underwent racemisation. Conversely, the free base of (2S)-2-pyrrolidin-2-yl-1,3-diazaspiro[4.4]non-1-en-4-one very easily underwent oxidation to give the achiral 2-(4,5-dihydro-3H-pyrrol-2-yl)-1,3-diazaspiro[4.4]non-1-en-4-one.     

A new strategy in enantioselective intramolecular hetero Diels-Alder reaction: catalytic double asymmetric induction during the tandem transetherification-intramolecular hetero Diels-Alder reaction of methyl (E)-4-methoxy-2-oxo-3-butenoate with rac-6-methyl-5-hepten-2-ol

An efficient catalytic double asymmetric induction during the tandem transetherification-intramolecular hetero Diels-Alder reaction has been developed. The enantioselective tandem reaction of methyl (E)-4-methoxy-2-oxo-3-butenoate with rac-6-methyl-5-hepten-2-ol has been achieved to provide methyl (2R,4aS,8aR)-3,4,4a,8a-tetrahydro-2,5,5-trimethyl-2H,5H-pyrano[4,3-b]-pyran-7-carboxylate in good yield with effective kinetic resolution (up to 95% selectivity), high diastereoselectivity (up to 92% de), and high enantioselectivity (up to 97% ee) in the presence of (S,S)-tert-Bu-bis(oxazoline)-Cu(SbF₆)₂ and 5 Å molecular sieves.     

Synthesis of trimethyl (2S,3R)- and (2R,3R)-[2-H1]-homocitrates and the corresponding dimethyl ester lactones—towards elucidating the stereochemistry of the reaction catalysed by homocitrate synthase and by the Nif-V protein

Trimethyl (2S,3R)- and (2R,3R)-[2-²H₁]-homocitrates, 10b and 10c respectively, and dimethyl (2S,3R)- and (2R,3R)-[2-²H₁]-homocitric lactones, 11b and 11c respectively, have been synthesised from shikimic acid and [2-²H]-shikimic acid by a route which defines the stereochemistry of the two chiral centres in each compound. The NMR spectra of these products will enable the stereochemistry of the biological reaction catalysed by homocitrate synthase and by the protein from the nifV gene to be elucidated.     

8-Amino-5,6,7,8-tetrahydroquinolines as ligands in iridium(III) catalysts for the reduction of aryl ketones by asymmetric transfer hydrogenation (ATH)

Aqua iridium(III) complexes with 8-amino-5,6,7,8-tetrahydroquinolines CAMPY L1 and its derivatives as chiral ligands proved to be very efficient catalysts for the reduction of a wide range of prochiral aryl ketones, revealing a variety of behaviours in terms of reaction rate and stereoselectivity. As standard substrates, differently substituted acetophenones were studied and good enantioselectivity (86% ee) was achieved in the reduction of 1-(o-tolyl)ethan-1-one 6. Particularly interesting was the ATH reaction in the case of β-amino keto esters, precursors of β-lactams and azetidinones. The best results were obtained with [Cp¹Ir(H₂O)(L1)]SO₄ affording the corresponding diastereomeric alcohols in an (R,S)-configuration with an excellent 99% ee in the reduction of 2-(benzamido methyl)-3-oxo-3-(4-(trifluoromethyl)phenyl)propanoate 12.     

Synthesis of some new tertiary amines and their application as co-catalysts in combination with l-proline in enantioselective Baylis-Hillman reaction between o-nitrobenzaldehyde and methyl vinyl ketone

A chiral benzodiazepine derivative 1 was synthesized starting from o-nitrobenzoyl chloride and methyl l-prolinate hydrochloride. Diastereomeric (1R,2R,1′S)-(+)-2-[N-methyl-N-(α-phenylethyl)amino]cyclohexanol 3a and (1S,2S,1′S)-(+)-2-[N-methyl-N-(α-phenylethyl)amino]cyclohexanol 3b were synthesized starting from (S)-α-phenylethylamine and cyclohexene oxide via ring-opening, diastereomer separation and N-methylation. (S,S)-octahydrodipyrrolo[1,2-a:1′,2′-d]pyrazin 5 was synthesized from methyl l-prolinate. Chiral tertiary amines 1, 3a, 3b and 5 almost cannot catalyze the Baylis-Hillman reaction between o-nitrobenzaldehyde and methyl vinyl ketone (MVK). However, they functioned as efficient catalysts for this reaction in the presence of l-proline. The corresponding adducts were obtained in good yields with enantioselectivity of 83% ee, 81% ee, 51% ee and 66% ee, respectively.     

Intramolecular asymmetric C–H insertion of N-arylalkyl,N-bis(trimethylsilyl)methyldiazoamides mediated by chiral rhodium(II) catalysts. Synthesis of (R)-β-benzyl-γ-aminobutyric acid

The enantio- and site-selectivity of the intramolecular C–H insertion reactions of acyclic N-arylalkyl, N-bis(trimethylsilyl)methyl α-diazoacetamides, and α-carboalkoxy-α-diazoacetamides 1a–g, catalyzed by chiral Rh(II) carboxamidates and Rh(II) carboxylates were studied. In general, the reaction showed good to excellent chemoselectivity. Regioselectivity for most of the reactions was high, but was also found to be influenced by the structure of the diazo substrate and the chiral Rh(II) catalyst employed. The highest enantioselectivity for the reactions catalyzed by chiral Rh(II) carboxamidates was 69% and Rh₂(4R-MEOX)₄ was found to be the most effective. For the chiral Rh(II) carboxylate catalyzed reactions, the highest ee obtained was 75% and Rh₂(S-PTTL)₄ is the optimal catalyst. The method was applied toward the synthesis of a GABA analogue, (R)-β-benzyl-γ-aminobutyric acid.     

N-arylammonio- and N-pyridinium-substituted derivatives of dodecahydro-closo-dodecaborate(2-)

We report two methods for preparing N-arylammonio, N-pyridyl and N-arylamino dodecaborates: heating of the tetrabutylammonium salt of dodecahydro-closo-dodecaborate(2-) with aryl and pyridyl amines, or nucleophilic attack of [closo-B₁₂H₁₁NH₂]²⁻ on a strongly deactivated aromatic system. With aryl amines we obtained [1-closo-B₁₂H₁₁N(R¹)₂C₆H₅]⁻ (R¹ = H, CH₃). With 4-(dimethylamino)pyridine, [1-closo-(B₁₂H₁₁NC₅H₄)-4-N(CH₃)₂]⁻, with a bond between the boron and the pyridinium nitrogen, was obtained. A presumable mechanism for this kind of reactions is reported. By nucleophilic substitution, two products, [1-closo-(B₁₂H₁₁NHC₆H₃)-3,4-(CN)₂]²⁻ and [1-closo-(B₁₂H₁₁NHC₆H₂)-2-(NO₂)-4,5-(CN)₂]²⁻, were formed with 4-nitrophthalonitrile and 1-chloro-2,4-dinitrobenzene gave [1-closo-(B₁₂H₁₁NHC₆H₃)-2,4-(NO₂)₂]²⁻. For [1-closo-B₁₂H₁₁N(CH₃)₂C₆H₅]⁻ and [1-closo-(B₁₂H₁₁NHC₆H₃)-2,4-(NO₂)₂]²⁻ single crystal X-ray structures were obtained.     

(Salen)Ti(IV) complex catalyzed asymmetric ring-opening of epoxides using dithiophosphorus acid as the nucleophile

A series of chiral bis-Schiff bases were synthesized starting from (1R,2R)-(+)-diaminocyclohexane, (+)-cis-1,2,2-trimethyl-1,3-diaminocyclopentane, (R)-2,2^′-diamino-1,1^′-binaphthalene, and (1S,2S)-diphenyl-1,2-ethanediamine. The enantioselective ring-opening of meso epoxides with dithiophosphorus acids catalyzed by a (salen)Ti(IV) complex formed in situ upon the treatment of Ti(OPr-i)₄ and the aforementioned chiral Schiff base was realized. The resulting products were obtained with low to good enantioselectivities (up to 73% ee). The (salen)Ti(IV) complex containing the backbone of 1,2-diaminocyclohexane exhibited the best enantioselectivity. The substituents in dithiophosphorus acids and those on the salen aromatic ring have a significant influence on the reaction. Moderate enantioselectivity were obtained for the (salen)Ti(IV) complex catalyzed ring-opening of racemic monosubstituted epoxides. High regioselectivity was observed for the alkyl substituted epoxides, whereas poor regioselectivity was obtained for the aryl substituted ones.     

Synthesis of enantiopure ethyl (1S,9aS)- and (1S,9aR)-1-phenyl-4,9-dioxohexahydropyrrolo[1,2-d][1,4]oxazepine-9a(7H)-carboxylate by carbenoid/ylide/Stevens-[1,2]-shift with ring enlargement

Enantiomerically pure ethyl (1S,9aS)- and (1S,9aR)-1-phenyl-4,9-dioxohexahydropyrrolo[1,2-d][1,4]oxazepine-9a(7H)-carboxylate were obtained by Cu(II)-catalyzed decomposition of an α-diazo carbonyl tethered to a chiral morpholinone. The reaction occurred with moderate diastereoselectivity but with complete enantioselectivity through the carbenoid/spiro-[5,6]-ammonium ylide/Stevens-[1,2]-shift with ring enlargement sequence.     

Asymmetric Kumada-Corriu cross-coupling reaction with Pd2(dba)3 and an N-Ar axially chiral mimetic-type ligand catalyst

A catalyst comprised of Pd₂(dba)₃·CHCl₃ and an N-Ar axially chiral mimetic-type ligand, (S)-N-[2-(diphenylphosphanyl)naphthalene-1-yl]-2-(piperidinylmethyl)piperidine, provides good enantioselectivities for the asymmetric Kumada-Corriu cross-coupling reaction of 1-phenylethylmagnesium chloride and E-β-bromostyrene derivatives with which it is more difficult to achieve high enantioselectivity. Furthermore, in the case of styrene derivatives bearing both vinyl and aryl bromide groups, the chemoselective asymmetric cross-coupling reaction of the vinyl bromide group is observed. This N-Ar axially chiral mimetic-type ligand allows easy synthesis of a wide variety of analogues, and starting from the initial ligand, the enantioselectivity of coupling products is improved by modifying the structure in the ligand.     

Asymmetric cycloaddition reactions between 2-benzopyrylium-4-olates and 3-(2-alkenoyl)-2-oxazolidinones in the presence of 2,6-bis(oxazolinyl)pyridine-lanthanoid complexes

Highly enantioselective (96% ee) and endo-selective (>99:1) cycloaddition reactions were observed between carbonyl ylides, generated from o-(p-bromobenzyloxy)carbonyl-α-diazoacetophenone, and 3-crotonoyl-2-oxazolidinone using (4S,5S)-Pybox-4,5-Ph₂-Yb(OTf)₃ (20 mol %) as the chiral Lewis acid catalyst. In contrast, high exo-selectivity (exo/endo=82:18; 96% ee, exo) was observed for the reaction of o-methoxycarbonyl-α-diazoacetophenone with 3-acryloyl-2-oxazolidinone under similar conditions as reported previously. In the case of cycloaddition reactions between 2-benzopyrylium-4-olate, generated from o-methoxycarbonyl-α-diazoacetophenone, and 3-cinnamoyl- or 3-[(E)-3-(ethoxycarbonyl)propenoyl]-2-oxazolidinones, using the same chiral Lewis acid, the reaction favored the endo-adduct with relatively good enantioselectivity (72 and 78% ee, respectively).     

An improved synthesis of deuterated Schöllkopf’s bis-lactim ether and its use for the asymmetric synthesis of (R)-[α-2H]-phenylalanine methyl esters

Treatment of (S)-3-isopropyl-2,5-dimethoxy-3,6-dihydropyrazine with trifluoroacetic acid in MeOD results in regioselective deuteration at its C₆-position affording its corresponding (S)-[6-²H₂]-isotopomer in excellent yield with no loss of stereochemical integrity at its C₃-stereocentre. The lithium aza-enolate of this deuterated chiral template has been alkylated with a range of substituted benzyl bromides to afford (3S,6R)-[6-²H]-3-isopropyl-6-benzyl-bis-lactim ethers that were hydrolysed to afford their corresponding (R)-[α-²H]-phenylalanine methyl esters as hydrochloride salts in good yield.     

Chiral cis-iron(ii) complexes with metal- and ligand-centered chirality for highly regio- and enantioselective alkylation of N-heteroaromatics

Iron-catalyzed highly regio- and enantioselective organic transformations with generality and broad substrate scope have profound applications in modern synthetic chemistry; an example is herein described based on cis-Fe^II complexes having metal- and ligand-centered chirality. The cis-β Fe^II(N₄) complex [Fe^II(L)(OTf)₂] (L = N,N′-bis(2,3-dihydro-1H-cyclopenta-[b]quinoline-5-yl)-N,N′-dimethylcyclohexane-1,2-diamine) is an effective chiral catalyst for highly regio- and enantioselective alkylation of N-heteroaromatics with α,β-unsaturated 2-acyl imidazoles, including asymmetric N1, C2, C3 alkylations of a broad range of indoles (34 examples) and alkylation of pyrroles and anilines (14 examples), all with high product yields (up to 98%), high enantioselectivity (up to >99% ee) and high regioselectivity. DFT calculations revealed that the “chiral-at-metal” cis-β configuration of the iron complex and a secondary π–π interaction are responsible for the high enantioselectivity.

A cis-β Fe^II complex having metal- and ligand-centered chirality catalyzes highly regio- and enantioselective alkylation of indoles (at the N1, C2, or C3 position), pyrroles and anilines with α,β-unsaturated 2-acyl imidazoles (48 examples, up to 99% ee).     

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.     

O-atom transfer biomimetic oxidation of benzoin in the presence of monooxomolybdenum(IV) thiolate complexes

Novel catalytically active monooxomolybdenum(IV) species containing four thiolate ligands obtainable in solution by NaBH₄ reduction of [Mo^vO(SC₆H₅)₄]⁻, [Mo^vO(Z-cys-Val-OMe)₄]⁻, (Z=benzyloxycarbonyl), or [Mo^vO(S₂C₆H₄)₂]⁻ perform the pyridine-N-oxide oxidation of benzoin in N,N-dimethylformamide at 30 °C. The order of catalytic activity is [Mo^vO(Z-cys-Val-OMe)₄]⁻ > [Mo^vO(S₂C₆H₄)₂]⁻ > [Mo^vO(SC₆H₅)₄]⁻ ([benzoin]/[oxidant]/[catalyst]= 20/20/1), while the oxidation by air under the same catalytic conditions gives a different order, [Mo^vO(Z-cys-Val-OMe)₄]⁻> [Mo^vO(SC₆H₅)₄]⁻ >[Mo^vO(S₂C₆H₄)₂]⁻. During the catalytic cycle in the amine-N-oxide oxidation, two intermediate species, [Mo^IVOL₄]²⁻ and [Mo^VIO₂L₄]²⁻, were detected by ¹H NMR, while in the air oxidation an unidentified Mo(VT) species is involved.