Chiral chelate phosphanes: XI. Application of cyclopentane-based C2 chiral bis(phosphane) ligands C5H8(PR2)2 to Pt---Sn-catalyzed styrene hydroformylation

Treatment of [(1,5-C₈H₁₂)PtCl(X)] (X=Cl, CH₃, CH₂CMe₃) with C₂ chiral cyclopentane-1,2-diyl-bis(phosphanes) C₅H₈(PR₂)₂, either as racemic mixtures or as resolved enantiomers, afforded the chelate complexes [C₅H₈(PR₂)₂Pt(Cl)(X)] (X=Cl: R=Ph (1), N-pip (2), OPh (3); X=CH₃: R=Ph (4), N-pip (5), OPh (6); X=CH₂CMe₃: R=Ph (7), N-pip (8), OPh (9); ‘N-pip’=N(CH₂)₅), (+)-[(1R,2R)-C₅H₈{P(OPh)₂}₂PtCl₂] [(R,R)-3], (−)-[(1S,2S)-C₅H₈{P(OPh)₂}₂PtCl₂] [(S,S)-3], (−)-[(1R,2R)-C₅H₈(PPh₂)₂Pt(Cl)(X)], and (+)-[(1S,2S)-C₅H₈(PPh₂)₂Pt(Cl)(X)] (X=CH₃: (R,R)-4, (S,S)-4; X=CH₂CMe₃: (R,R)-7, (S,S)-7). Reacting 4, 6, and 7 with AgO₃SCF₃ led to triflate derivatives [C₅H₈(PR₂)₂Pt(X)(OSO₂CF₃)] [X=CH₃: R=Ph (11), OPh (12); X=CH₂CMe₃: R=Ph (13)] with covalently bonded OSO₂CF₃ ligands. The unusual Pt₂ complex [μ-Cl{C₅H₈(PPh₂)₂PtCH₃}₂]O₃SCF₃ (14) containing an unsupported single Pt---Cl---Pt bridge was also isolated. In the presence of SnCl₂, complexes 1, 3, 4, 6, 7, and 9 are catalysts for the hydroformylation of styrene forming 2- and 3-phenylpropanal together with ethylbenzene. Except for 1, they also catalyze the consecutive hydrogenation of the primary propanals to alcohols. High regioselectivities towards 2-phenylpropanal (branched-to-normal ratios ≥91:9) were obtained in hydroformylations catalyzed by 3 and 4, for which the influence of varied CO/H₂ partial pressures, catalyst-to-substrate ratios and different reaction temperatures and times on the outcome of the catalytic reaction was also studied. When tin-modified complexes (R,R)-3, (S,S)-3, and (S,S)-4 were used as optically active Pt(II) catalysts, an only low stereoselectivity for asymmetric hydroformylation (e.e.<18%) was observed. The Pt---Sn complexes [C₅H₈(PR₂)₂Pt(CH₃)(SnCl₃)] [R=Ph (15), OPh (17)], resulting from SnCl₂ insertion into the Pt---Cl bonds of 4 or 6, undergo rapid degradation in solution, forming mixtures composed of [C₅H₈(PR₂)₂Pt(X)(Y)] with R=Ph or OPh and X/Y=Cl/SnCl₃ (16, 18), Cl/Cl (1, 3), and SnCl₃/SnCl₃ (19, 20), respectively. In the presence of SnCl₂, triflate complex 11 also becomes a catalyst for styrene hydroformylation and consecutive hydrogenation of the aldehydes to alcohols. The crystal structures of 11 complexes — 2, 5, 7, 8, 9, 10 (the previously prepared [C₅H₈{P(N-pip)₂}₂Pt(CH₂CMe₃)₂]), 13, 14, 16, (R,R)-3, and (S,S)-3 — were determined by X-ray diffraction.     

The fragmentation of exo-5-norbornenyl-2-oxychlorocarbene: stereochemistry and mechanism

The fragmentation of (S)-exo-5-norbornenyl-2-oxychlorocarbene (3) affords (S)-exo-5-norbornenyl-2-chloride (4), (R)-endo-5-norbornenyl-2-chloride (5), and (S)-3-nortricyclyl chloride (6) with varying degrees of enantiomeric excess. A weighted blend of S_Ni fragmentation and escape to norbornenyl/nortricyclyl ion pairs rationalizes the stereochemical results.     

Reduced collagen cross links: the first synthesis of all the possible (2S,2′S)-stereoisomers of 5-hydroxylysinonorleucine and of 5,5′-dihydroxylysinonorleucine in enantiomerically pure form

The paper reports the first enantioselective synthesis of all the possible collagen reduced cross links as described: (2S,2′S,5R)- and (2S,2′S,5S)-5-hydroxylysinonorleucine 3a and 3b, (2S,2′S,5R,5′R)-5,5′-dihydroxylysinonorleucine 4a, (2S,2′S,5R,5′S)-5,5′-dihydroxylysinonorleucine 4b and (2S,2′S,5S,5′S)-5,5′-dihydroxylysinonorleucine 4c. The Williams’ glycine template methodology was used both for the introduction of a stereogenic at the α-position and for an easy protection of the amino acidic functionalities during the synthesis of the dimeric amino acids.     

Synthesis of (±)-2R,4R,5S-2-methoxy-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexanone and (±)-2R,4S,5R-2-methoxy-5-nitro-4-(2,3,4-trimethoxyphenyl)cyclohexanone as colchicine mimetics

Colchicine mimetic (±)-4S,5R-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexene (1) was epoxidized to afford a mixture of epoxides. The epoxides were separately converted in two steps, with high stereoselectivity, to two regioisomeric α-methoxyketones. One regioisomer, (±)-2R,4S,5R-2-methoxy-5-nitro-4-(2,3,4-trimethoxyphenyl)cyclohexanone (17), proved to be about 12-fold more potent than synthetic precursor 1 against HCT-116 tumor cells while the other regioisomer, (±)-2R,4R,5S-2-methoxy-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexanone (16), and the synthetic intermediates tested showed no improvement in potency.     

Preparation of chiral diimino- and diaminodiphosphine ligands and their Cu and Ag complexes. X-ray crystal structures of [Cu(1S,2S-cyclohexyl-P2N2)][PF6] and [Ag(1R,2R-cyclohexyl-P2N2H4)][BF4]

The interaction of optically pure 1R,2R-diammoniumyclohexane mono-(+)-tartrate and 1S,2S-diammoniumcyclohexane mono-(−)-tartrate with 2 equiv. of o-(diphenylphosphino)benzaldehyde in the presence of 2 equiv. of potassium carbonate in a refluxing ethanol/water mixture gave the optically pure condensation products N,N′-bis[o-(diphenylphosphino)benzylidene]-1R,2R-diiminocyclohexane[1R,2R-cyclohexyl-P₂N₂, (R,R)-I] and N,N′-bis[o-(diphenylphosphino)benzylidene]-1S,2S-diiminocyclohexane [1S,2S-cyclohexyl-P₂N₂, (S,S)-I], respectively, in good yield. Reduction of optically pure (R,R)-I and (S,S)-I with NaBH₄ in ethanol gave the optically pure reduced products N,N′-bis[o-(diphenylphosphino)benzylidene]-1R,2R-diaminocyclohexane[1R,2R-cyclohexyl-P₂N₂H₄, (R,R)-II] and N,N′-bis[o-diphenylphosphine)benzylidene]-1S,2S-diaminocyclohexane[1S,2S-cyclohexyl-P₂N₂H₄, (S,S)-II], respectively, in good yield. The coordination behaviour of I and II toward salts of Cu^I and Ag^I have been examined. The interaction of [Cu(C)₃CN)₄][X] (X = ClO₄⁻, PF₆⁻) with 1 equiv. of optically pure L₄ [L₄ = (R,R)-I, (S,S)-I, (R,R)-II and (S,S)-II] gave the corresponding optically pure [CuL₄][X] complexes, III–VI IIIa, L₄ = (R,R)-I, X = PF₆⁻ IIIb, L₄ = (R,R)-I, X = ClO₄⁻ IV, X = PF₆⁻; Va, L₄ = (R,R)-II, X = PF₆⁻, Vb L₄ = (R,R)-II, X= ClO₄⁻, VI L₄ = (S,S)-II, X = PF₆⁻, in good yield. For the Cu^I complexes, the L₄ ligand acted as a tetradentate ligand. However, a variable-temperature ³¹P[¹H] NMR study of IIIb shows that at ambient temperature one of the imino groups of the tetradentate ligand undergoes rapid dissociation to form a tridentate ligand. The interaction of AgBF₄ with 1 equiv. of otpically pure L₄ [L₄ = (R,R)-I, (S,S)-I, (R,R)-II and (S,S)-II gave the corresponding optically pure [AgL₄][BF₄] complexes, VII–X VII L₄ = (R,R)-I; VIII, L₄ = (S,S)-I; IX,L₄ = (R,R)-II; X, L₄ = (S,S)-II], in good yield. For the Ag^I complexes, the L₄ ligand acted as a tetradentate ligand with the two amino groups coordinated unsymmetrically to the silver. A variable temperature ³¹P [¹H] NMR study of VII suggests that at high temperature the complex exists as a tri-coordinated complex. The structurers of IV and IX were established by X-ray diffraction studies.     

Highly diastereoselective N-nitrosation of chiral (E)-2-(benzylidene-amino)ethanols with nitric oxide

N-Nitrosation of (E)-(S)-2-(benzylidene-amino)ethanols 2 with nitric oxide occurred highly diastereoselectively, to give the (2S,4S)-diastereomer dominant N-nitroso-(2S,4S)-1,3-oxazolidines in good yield. Intermediate 2 was prepared from the reaction of benzaldehyde 1 with (S)-2-aminoethanol.     

Chemo- and diastereoselective control for a flexible approach to (5S,6S)-6-alkyl-5-benzyloxy-2-piperidinones

Chemo- and diastereoselective transformation of the N,O-acetals and their chain tautomers (4/5), readily derived from protected 3-hydroxyglutarimide 1a, was studied. It was uncovered that while the reaction with a combination of boron trifluoride etherate/zinc borohydride led to cyclic products (5S,6S/R)-6-alkyl-5-benzyloxy-2-piperidinones 3/2, and 6 in modest chemo- and diastereoselectivities, the reaction of 4/5 with zinc borohydride led exclusively to the formation of the ring-opening products 6 in excellent anti-diastereoselectivities. On the basis of the latter reaction, a flexible approach to (5S,6S)-6-alkyl-5-benzyloxy-2-piperidinones 3 was disclosed.     

Enantiospecific synthesis of the sugar amino acid (2S,5S)-5-(aminomethyl)-tetrahydrofuran-2-carboxylic acid

An enantiospecific synthesis of the tetrahydrofuran amino acid (2S,5S)-5-(aminomethyl)-tetrahydrofuran-2-carboxylic acid 1 is reported. The sugar enone 2-(S)-octyl 6-O-acetyl-3,4-dideoxy-α-d-glycero-hex-3-enopyranosid-2-ulose 2a, derived from galactose, was employed as a chiral precursor. The enone 2a was converted by chemical manipulation of the functional groups into the 6-azido-2-O-tosyl-3,4,6-trideoxy-d-erythro-hexono-1,5-lactone 9 as key intermediate. Methanolysis of 9 induced the opening of the lactone and the attack of the hydroxyl group at C-5 to C-2 with the displacement of the tosylate. This reaction led to the formation of the tetrahydrofuran ring of methyl (2S,5S)-5-(azidomethyl)-tetrahydrofuran-2-carboxylate 10, which was readily converted into 1. The overall yield of the sequence was 35%, and all the intermediates and the final product have been fully characterized. In addition, the preferential conformations in solution of lactone 9 and target molecule 1 have been established.     

Synthesis of tadalafil (Cialis) from l-tryptophan

The first synthesis of tadalafil 1 (Cialis) from l-tryptophan is described. The title compound 1 was synthesized via seven steps from l-tryptophan methyl ester hydrochloride in 42.3% overall yield. Two characteristic steps involved in this synthesis are the base-catalyzed epimerization of the C-3 position of (1S,3S)-1,2,3-trisubstituted-tetrahydro-β-carboline 3a and the acid-catalyzed epimerization of the C-1 position of (1S,3R)-1,3-disubstituted-tetrahydro-β-carboline 5. The (S)-configurations at C-1 and C-3 were inverted to (R)-configurations during the epimerization reactions. The base-catalyzed epimerization of C-3 of (1S,3S)-1,2,3-trisubstituted-tetrahydro-β-carbolines 3a–3e was also studied in detail.     

Diastereoselective route to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane, a pheromone component of the wasp Paravespula vulgaris

A diastereoselective approach to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane 1 and 1a is described. The route starts with an alkylation reaction among the cyclopentanone N,N-dimethylhydrazone 6 and the chiral iodides (R)-3 or (S)-3, derived from the enantiomers of ethyl β-hydroxybutyrate, controlling the estereocenter at C-2 of the molecules. The alkylated products 7 and 7a were easily transformed into the 1,8-O-TBS-1,8-dihydroxy-5-nonanones 9 and 9a in four steps, and a subsequent stereoselective spiroketalization, in acidic media, afforded a Z:E mixture (1:2) of compounds 1 and 1a.     

Stereoselective synthesis of 5-[(1S)-N-Boc-amino-(2S)-(3-fluorophenyl)ethyl]-dihydrofuran-2-one

A short, efficient, and highly diastereoselective synthesis of 5-[(1S)-N-Boc-amino-(2S)-(3-fluorophenyl)ethyl]-dihydrofuran-2-one (1) is described. Use of phthalic anhydride as thiolate scavenger effectively preserves the chiral integrity of the α-aminoketone 4 product obtained from the reaction of organozincate 3 with thioester 2.     

Total synthesis of the 5-epimers of naturally occurring (−)-hyacinthacine A5 and unnatural (+)-hyacinthacine A4

(1R,2S,3R,5S,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine 10 [(+)-5-epihyacinthacine A₅] and (1R,2S,3R,5S,7aS)-1,2-dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine 17 [ent-5-epihyacinthacine A₄] have been synthesized by either Horner–Wadsworth–Emmons (HWE) or Wittig methodology using aldehydes 6 and 13, prepared from (2R,3S,4R,5R)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine 5 (partially protected DALDP) and (2R,3S,4R,5S)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2,5-bis(hydroxymethyl)-2′-O-pivaloylpyrrolidine 12 (partially protected DGADP), respectively, and the appropriated ylide, followed by cyclization through an internal reductive amination process of the corresponding intermediate pyrrolidinic ketones 7 and 14 and subsequent deprotection.     

Polyhydroxylated pyrrolizidines. Part 8. Enantiospecific synthesis of looking-glass analogues of hyacinthacine A5 from DADP

(1R,2S,3S,5R,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine[(−)-3-epihyacinthacine A₅, 1a] and (1S,2R,3R,5S 7aS)-1,2-dihydroxy-3-hydroxymethylpyrrolizidine[(+)-3-epihyacinthacine A₅, 1b] have been synthesized either by Wittig's or Horner-Wadsworth-Emmond's (HWE's) methodology using aldehydes 4 and 9, both prepared from (2S,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (2, partially protected DADP), and the appropriate ylides, followed by cyclization through an internal reductive amination process of the resulting α,β-unsaturated ketones 5 and 10, respectively, and total deprotection.     

Concise and practical synthesis of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6-iminosugars

The syntheses of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6 iminosugars 1a and 1b, respectively, from d-glucose are described. The key transformations in this reaction sequence include regio-selective epoxide ring opening with N-benzylamine followed by intramolecular reductive amination of amino-aldehyde.     

Synthesis and absolute configuration of two diastereoisomeric (1R,2S,3R)-and (1S,2S,3R)-2-amino-1-(2-furyl)-1,3-butandiols

The synthesis of (1R, 2S, 3R) and (1S, 2S, 3R)-2-(N-benzoylamino)-1-(2-furyl)-1, 3-butandiols (15) and (16) from D-threonine is described. The assignment of absolute configuration of the newly formed asymmetric center at C-1 was based on the ¹H-NMR spectra of O-isopropylidene derivatives 17 and 18.     

Synthesis of (3′R,5′S)-3′-hydroxycotinine using 1,3-dipolar cycloaddition of a nitrone

To synthesize (3′R,5′S)-3′-hydroxycotinine [(+)-1], the main metabolite of nicotine (2), cycloaddition of C-(3-pyridyl)nitrones 3a, 3c, and 15 with (2R)- and (2S)-N-(acryloyl)bornane-10,2-sultam [(2R)- and (2S)-8] was examined. Among them, l-gulose-derived nitrone 15 underwent stereoselective cycloaddition with (2S)-8 to afford cycloadduct 16, which was elaborated to (+)-1.     

Boron complexes of S-trityl- -cysteine and S-tritylglutathione

S-Trityl- -cysteine and S-tritylglutathione have been converted to 1,3,2-oxazaborolidine-5-ones by reaction with B-methoxydialkylborane derivatives. The synthesis of dicyclohexyl[S-trityl-(R)-cysteinato-O,N]boron (2), diisopinocampheyl[S-trityl-(R)-cysteinato-O,N]boron (3) and 9-borabicyclo[3.3.1]non-9-yl[S-tritylglutathionato-O,N]boron (5), dicyclohexyl[S-tritylglutathionato-O,N]boron (6) and diisopinocampheyl[S-tritylglutathionato-O,N]boron (7) from S-trityl- -cysteine and S-tritylglutathione, respectively, with potential application in boron neutron capture therapy is reported. The structure of 9-borabicyclo[3.3.1]non-9-yl[S-trityl-(R)-cysteinato-O,N]boron 1 has been determined by X-ray diffraction.     

Syntheses and pharmacological characterization of achiral and chiral enantiopure C/Si/Ge-analogous derivatives of the muscarinic antagonist cycrimine: a study on C/Si/Ge bioisosterism

The C/Si/Ge-analogous compounds rac-Ph(c-C₅H₉)El(CH₂OH)CH₂CH₂NR₂ (NR₂=piperidino; El=C, rac-3a; El=Si, rac-3b; El=Ge, rac-3c) and (c-C₅H₉)₂El(CH₂OH)CH₂CH₂NR₂ (NR₂=piperidino; El=C, 5a; El=Si, 5b; El=Ge, 5c) were prepared in multi-step syntheses. The (R)- and (S)-enantiomers of 3a–c were obtained by resolution of the respective racemates using the antipodes of O,O′-dibenzoyltartaric acid (resolution of rac-3a), O,O′-di-p-toluoyltartaric acid (resolution of rac-3b), or 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (resolution of rac-3c). The enantiomeric purities of (R)-3a–c and (S)-3a–c were ≥98% ee (determined by ¹H-NMR spectroscopy using a chiral solvating agent). Reaction of rac-3a–c, (R)-3a–c, (S)-3a–c, and 5a–c with methyl iodide gave the corresponding methylammonium iodides rac-4a–c, (R)-4a–c, (S)-4a–c, and 6a–c (3a–c→4a–c; 5a–c→6a–c). The absolute configuration of (S)-3a was determined by a single-crystal X-ray diffraction analysis of its (R,R)-O,O′-dibenzoyltartrate. The absolute configurations of the silicon analog (R)-4b and germanium analog (R)-4c were also determined by single-crystal X-ray diffraction. The chiroptical properties of the (R)- and (S)-enantiomers of 3a–c, 3a–c·HCl, and 4a–c were studied by ORD measurements. In addition, the C/Si/Ge analogs (R)-3a–c, (S)-3a–c, (R)-4a–c, (S)-4a–c, 5a–c, and 6a–c were studied for their affinities at recombinant human muscarinic M₁, M₂, M₃, M₄, and M₅ receptors stably expressed in CHO-K1 cells (radioligand binding experiments with [³H]N-methylscopolamine as the radioligand). For reasons of comparison, the known C/Si/Ge analogs Ph₂El(CH₂OH)CH₂CH₂NR₂ (NR₂=piperidino; El=C, 7a; El=Si, 7b; El=Ge, 7c) and the corresponding methylammonium iodides 8a–c were included in these studies. According to these experiments, all the C/Si/Ge analogs behaved as simple competitive antagonists at M₁–M₅ receptors. The receptor subtype affinities of the individual carbon, silicon, and germanium analogs 3a–8a, 3b–8b, and 3c–8c were similar, indicating a strongly pronounced C/Si/Ge bioisosterism. The (R)-enantiomers (eutomers) of 3a–c and 4a–c exhibited higher affinities (up to 22.4 fold) for M₁–M₅ receptors than their corresponding (S)-antipodes (distomers), the stereoselectivity ratios being higher at M₁, M₃, M₄, and M₅ than at M₂ receptors, and higher for the methylammonium compounds (4a–c) than for the amines (3a–c). With a few exceptions, compounds 5a–c, 6a–c, 7a–c, and 8a–c displayed lower affinities for M₁–M₅ receptors than the related (R)-enantiomers of 3a–c and 4a–c. The stereoselective interaction of the enantiomers of 3a–c and 4a–c with M₁–M₅ receptors is best explained in terms of opposite binding of the phenyl and cyclopentyl ring of the (R)- and (S)-enantiomers. The highest receptor subtype selectivity was observed for the germanium compound (R)-4c at M₁/M₂ receptors (12.9-fold).     

Determination of the absolute configuration of the male aggregation pheromone, 2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol, of the stink bug Erysarcoris lewisi (Distant) as 2Z,6R,1′S,5′S by its synthesis

Lipase-catalyzed asymmetric acetylation of a mixture of (6R,1′S,4′S,5′R)- and (6R,1′R,4′R,5′S)-7′-norsesquisabinen-4′-ol (3) afforded a separable mixture of the recovered former and the acetate of the latter. The recovered alcohol was oxidized to (6R,1′S,5′R)-sesquisabina ketone (2), whose absolute configuration could be assigned by its CD comparison with (1R,5S)-sabina ketone (4). Conversion of (6R,1′S,5′R)-sesquisabina ketone (2) to the bioactive pheromone revealed the stereostructure of the male aggregation pheromone of the stink bug Erysarcoris lewisi (Distant) to be (2Z,6R,1′S,5′S)-2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol (sesquisabinen-1-ol, 1).     

Stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadec-2-yl acetate and propionate, the sex pheromones of pine sawflies

The stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadec-2-yl acetate (2) and propionate (3) was accomplished by utilizing the cheap and easily available chiron (R)-4-methyl-δ-valerolactone (4). The key steps were chelation-controlled addition of Gilmann reagent to chiral β-alkoxy aldehyde 12 and the Cu(I)-catalyzed coupling of Grignard reagent with bromoester 5 in the presence of NMP.