Tris-chelate complexes with chiral ligands: In search of diastereoisomeric selectivity with remote stereogenic centres

The chiral ligands, 4,4′-bis{(1S,2R,4S)-(−)-bornyloxy}-2,2′-bipyridine, (1S,2R,4S)-1, and 4,4′-bis{(1R,2S,4R)-(+)-bornyloxy}-2,2′-bipyridine, (1R,2S,4R)-1, have been prepared and characterized by spectroscopic techniques and, for (1S,2R,4S)-1, by single crystal X-ray diffraction. Despite the use of enantiomerically pure ligands, the formation of the complexes [Fe((1S,2R,4S)-1)₃]²⁺, [Ru((1S,2R,4S)-1)₃]²⁺, [Ru((1S,2R,4S)-1)(bpy)₂]²⁺ and [Ru((1R,2S,4R)-1)(bpy)₂]²⁺ proceeds without preference for either the Δ or Λ-diastereoisomers.     

Preparation of (S)-2-substituted succinates by stereospecific reductions of fumarate and derivatives with resting cells of Clostridium formicoaceticum

Fumarate derivatives have been reduced to (S)-2-methylsuccinate 2a, (S)-2-ethylsuccinate 3a and (S)-2-chlorosuccinate 4a in up to 1 M concentrations with Clostridium formicoaceticum. Formate was the electron donor and viologens or anthraquinone-2,6-disulphonate acted as artificial electron mediators. Reductions with freeze-dried cells in ²H₂O-buffers led to the (2R,3S)-[2,3-2,²H]-dideuterated succinate derivatives. The productivity numbers¹ ranged from 450 to 5000 and the enantiomeric excess of all (S)-2-substituted succinates was 99 %.     

Synthesis, isolation and structural characterization of optically active planar chiral cyclomercurated ferrocenylimines

Asymmetric cyclomercuration of chiral ferrocenylimines (+)-(R)-2 and (−)-(S)-2 with mercuric acetate and subsequent treatment by lithium chloride gave two different pairs of diastereomeric cyclomercurated ferrocenylimines. The four enantiomerically pure compounds with both planar and central chirality were isolated from the two pairs by thin layer chromatography. The structures and absolute configurations of these complexes were determined by single-crystal X-ray analysis and characterized by IR, ¹H NMR, specific rotation and elemental analysis.     

Diastereoselective synthesis of 3,4-disubstituted 5-(p-tolylsulfinyl)-5,6-dehydropiperidin-2-ones: chirality transfer in the enantioselective synthesis of ethyl (+)-(3S,4aS,7aS)-1-oxo-octahydro-1H-cyclopenta[c]pyridine-3-carboxylate

The base-mediated reaction of enantiomerically pure -sulfinylketimine (+)-1 with (E)-,β-disubstituted propenoate esters afforded 3,4-disubstituted-5-(p-tolylsulfinyl)-5,6-dehydropiperidin-2-ones 9-13 and 14 with high or complete diastereoselectivity. A sole diastereomer of the four possible ones, with regard to the nature of ester, was isolated, which revealed the stereocontrol of the chiral sulfinyl group in the Michael reaction and transenolization steps. In addition, the enantioselective synthesis of ethyl (+)-(3S,4aS,7aS)-1-oxo-octahydro-1H-cyclopenta[c]pyridine-3-carboxylates (+)-17 is described (five steps; 47% yield; ee 97%). The absolute configuration of stereocentres introduced in (+)-17 was assigned on the basis of ¹H NMR data.     

Synthesis of N-Fmoc 3-(4-(di-(tert-butyl)phosphonomethyl)phenyl)pipecolic acid as a conformationally constrained phosphotyrosyl mimetic suitably protected for peptide synthesis

Phosphonomethylphenylalanine (Pmp, 2) has shown wide utility as a hydrolytically stable phosphtyrosyl (pTyr, 1) mimetic, particularly in Src homology 2 (SH2) domain-binding peptides. (2S,3R)-3-(4-(phosphonomethyl)phenyl)pipecolic acid (3) represents a variant of Pmp having φ and χ₁ torsion angles constrained through incorporation into the piperidinyl ring structure contained within pipecolic acid. Reported herein is the enantioselective preparation of 3, in an orthogonally protected form (4) suitable for use in peptide synthesis. Stereochemistries at both the 2- and 3-positions are derived inductively from a single chiral center provided by the commercially available Evans chiral auxiliary, (4S)-4-benzyl-1,3-oxazolidin-2-one. Incorporation of 4 into a Grb2 SH2 domain-directed tripeptide (18) showed that Grb2 SH2 domain-binding affinity was reduced relative to the parent Pmp-containing tripeptide (19). Although conformational constraint did not enhance affinity in this case, novel amino acid analogue 4 may serve as a useful tool for the induction of defined phosphotyrosyl geometry in peptides directed at other signal transduction targets.     

Indenyl complexes of ruthenium(II) containing optically active diphosphines. X-ray structures of (S,S)-(η-C9H7)-Ru{Ph2PCH(CH3)CH(CH3)PPh2}Cl and of its η-C5H5 analogue

The optically active indenyl complexes ((η⁵-C₉H₇)Ru(L---L)Cl (where L---L is either (S,S)-1,2-dimethyl-1,2-ethanediylbis(diphenylphosphine) (chiraphos) or (R,R)-1,2-cyclopentanediylbis(diphenylphosphine) (cypenphos)) have been synthesized and spectroscopically characterized and compared with the corresponding cyclopentadienyl complexes. Reaction of the new complexes with 2-e-donors give cationic adducts in which the pentahaptocoordination of the indenyl ligand is maintained. The crystal structures of (S,S)-(η⁵-C₉H₇)Ru{Ph₂PCH(CH₃)CH(CH₃)PPh₂}Cl (1) and (S,S)-η⁵-C₅H₅Ru{Ph₂PCH(CH₃)CH(CH₃)PPh₂}Cl (3) have been determined.     

Preparation of both enantiomers of malic and citramalic acid and other hydroxysuccinic acid derivatives by stereospecific hydrations of cis or trans 2-butene-1,4-dioic acids with resting cells of Clostridium formicoaceticum

(R)-Malic, (S)-malic, (R)citramalic, (S)-citramalic, (2R,3S)-2-hydroxy-3-methyl-succinic and (2R,3S)-2,3-dimethyl-2-hydroxysuccinic acid were prepared on scales up to 25 mmol by stereospecific addition of water to different 2-butene-1,4-dioic acid derivatives catalyzed by resting cells of Clostridium formicoaceticum (Scheme 1). The (3R)-monodeuterio (R)- and (S)-malic acid as well as (R)- and (S)-citramalic acid were prepared using freeze-dried cells in ²H₂O-buffer. The stereochemical purity of the products was in most cases ≥ 99%.     

开口箭化学成分及抗肿瘤活性

从开口箭新鲜根茎中分离得到8个化合物, 通过理化性质分析、 质谱、 红外光谱及核磁共振波谱检测等方法鉴定了其结构, 分别为开口箭皂苷J(1)、 (25S)-26-O-β-D-吡喃葡萄糖基呋甾-1β,3β,22α,26-四羟基-3-O-β-D-吡喃葡萄糖苷(2)、 洋地黄毒苷元-3-O-α-L-吡喃岩藻糖苷(3)、 弯蕊皂苷元B(4)、 异罗斯考皂苷元(5)、 罗斯考皂苷元(6)、 香豌豆酚(7)及(+)-儿茶素(8). 其中, 化合物1为新化合物, 化合物3, 4, 7和8为首次从该属植物中分离得到. 在抗人结肠癌细胞LoVo和胃癌细胞BGC-823活性评价中, 化合物5和6表现出较强的抗肿瘤活性, 半抑制浓度(IC₅₀)值分别达到0.532和0.757 μmol/L.     

Enantioselective organic syntheses using chiral transition metal complexes V. (2S,3S)-Bis(dibenzophospholyl)butane, a rigid (S,S)-CHIRAPHOS analog

The P–Ph cleavage of phenyldibenzophosphole (1) with lithium in THF gives lithium dibenzophospholide (2). Reaction of 2 with ethyleneglycol ditosylate produces the known chelate ligand 1,2-bis(dibenzophospholyl)ethane (3) in good yield. Similarly, 2 and (2R,3R)-butanediol ditosylate give the new chiral chelate ligand (2S,3S)-bis(dibenzophospholyl)butane (4). Ligand exchange of [CpRu(PPh₃)₂Cl] with 3 or 4 yields the halfsandwich complexes [CpRu(C₁₂H₈PC₂H₄PC₁₂H₈)Cl] (5) and [CpRu((S,S)-C₁₂H₈PCHMeCHMePC₁₂H₈)Cl] (6). Complex 6 was characterized crystallographically (monoclinic, space group P2₁ (no. 4), a=820.6(4), b=1501.0(3), c=1172.8(6) pm, β=108.87(2)°, V=1.367(1)×10⁹ pm³, Z=2). The most conspicuous feature of the structure of 6 is the perfect coplanarity of the two dibenzophosphole moieties imposed by their steric interaction with the Cp ligand. Complex 6 and the thiophene complex [CpRu((S,S)-C₁₂H₈PCHMeCHMePC₁₂H₈)(SC₄H₄)]BF₄ (7) derived therefrom are remarkably unreactive with regard to ligand substitutions. A possible explanation is the lack of intramolecular

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–C stabilization en route to the transition state of ligand substitution. The enantiomeric purity of 6 and 7 could nevertheless be demonstrated by conversion to diastereomerically pure [CpRu((S,S)-C₁₂H₈PCHMeCHMePC₁₂H₈)((S)-CNCHMePh)]BF₄ (8).     

Convenient diastereospecific synthesis of a rociverine precursor and its resolution by lipase-catalyzed transesterification

(±)-1-Cyclohexyl-c-2-hydroxymethyl-r-1-cyclohexanol 3, a precursor of the antimuscarinic drug Rociverine 1, was obtained diastereospecifically in very high yield, from the Grignard reaction between C₆H₁₁MgCl and an appropriately protected 2-(hydroxymethyl)cyclohexanone. The preparation of enantiomerically enriched cis diol (+)-(1R,2S)-3 and the corresponding 2-acetoxymethyl derivative (+)-(1S,2R)-12 was achieved by lipase PPL-catalyzed transesterification of racemic diol (±)-3.     

Asymmetric cyclization of 2-alkenylphenols. A comparative study on the use of palladium(II) and titanium(IV) complexes

The oxidative cyclization of 2-(3-pentenyl)phenol catalyzed by [(η³-pinene)PdOAc]₂ gives optically active (+)-2-vinylchroman (25% e.e.), while (−)-2-(1-hydroxyethyl)chroman (56% e.e.) is formed as a single diastereomer upon treatment with t-BuOOH in the presence of Ti(OⁱPr)₄ and -(+)-diethyl tartrate. 2-(2-Butenyl)phenol also undergoes the Ti-promoted asymmetric cyclization to give (2S,1′R)-(−)-2-(1-hydroxyethyl)-2,3-dihydrobenzofuran (29% e.e.).     

Recent Progress in the Synthetic Applications of Substituted Furans and Pyrroles

In this lecture, I would like to present efficient synthetic routes towards the total synthesis of syringolide 1 (2)^1,2 and secosyrin 1 (3),¹ employing 2,4-disubstituted furan 1 as a common precursor. A modified total synthesis of prehispanolone (6)³ from (S)-(+)-Wieland-Miescher ketone (4) via hispanolone (5) will also be discussed. Our methodology for the synthesis of 3,4-disubstituted-lH-pyrroles⁴ and for the generation of 3,4-didehydrothiophene⁵ has also guided us to the successful identification of 1-tert-butoxycarbonyl-3,4-didehydro-1H-pyrrole (7),which is presumably the most strained heterocyclic cumulene ever recorded.     

Asymmetric hydrogenations of ketones catalyzed by Ru–achiral phosphine-enantiopure diamine complexes

Five novel ruthenium complexes, RuCl₂(MOTPP)₂[(S,S)-DPEN] [MOTPP = tris(4-methoxyphenyl)phosphine] (1), RuCl₂(TFTPP)₂[(S,S)-DPEN] [TFTPP = tris(4-trifluoromethylphenyl)phosphine] (2), RuCl₂(PPh₃)₂[(S,S)-DPEN] (3), RuCl₂(BDPX)[(S,S)-DPEN] [BDPX = 1,2-bis(diphenylphosphinomethyl)benzene] (4), RuCl₂(BISBI)[(S,S)-DPEN][BISBI = 2,2′-bis((diphenylphosphino)methyl)-1,1′-biphenyl]] (5) were synthesized and used for the hydrogenation of aromatic ketones. The complexes showed high catalytic activities, especially that the catalytic activity of complex 5 containing the diphosphine with large bite angle and complex 1 containing triarylphosphine with electron-donating group were higher than the other three complexes. The enantioselectivities of products were almost not influenced by the electron factors of phosphine.     

cis,cis-Spiro[4.4]nonane-1,6-diol: A new chiral auxiliary for the asymmetric Diels-Alder reaction

The use of a mono-pivalate mono-acrylate bis-ester of (+)-1S,5S,6S-spiro[4.4]nonane-1,6-diol in an asymmetric Diels-Alder reaction with cyclopentadiene (2 equiv. BCl₃, −85°C, CH₂Cl₂) provided the expected endo bicyclo adduct in >97% de. Iodolactonization of the bicyclo adduct provided the (+)-lactone (5) with a 1S,4S,6S,8R,9S configuration (97% ee). The de's obtained from using various types and amounts of Lewis acids, and both chiral and racemic bis-esters in the Diels-Alder reaction with cyclopentadiene are also reported.     

(S)-(+)-1-Methyl-2-(6,7,-dimethoxy-2,3-naphthalimido)ethyl trifluoromethanesulfonate as a fluorescence chiral derivatizing reagent for carboxylic acid enantiomers in high-performance liquid chromatography

A new triflate-type fluorescence chiral derivatizing reagent, (S)-(+)-1-methyl-2-(6,7-dimethoxy-2,3-naphthalimido)ethyl trifluoromethanesulfonate, [S-(+)-MDNE-OTf], has been developed for the determination of the enantiomers of carboxylic acids. By introducing the two methoxy groups on the naphthalimido ring moiety, the red shift in the fluorescence spectrum and a high resolution in reversed-mode separation of the diastereomers of chiral carboxylic acids have been achieved. The detection limits (S/N=3) with ultraviolet and fluorescence detection are 8 fmol (λ_max=283 nm) and 4 fmol (λ_ex=283 nm, λ_em=467 nm), respectively.     

Catalytic and structural studies of Rh complexes of (−)-(2S,4S)-2,4-bis(diphenylphosphino)pentane. Asymmetric hydrogenation of acetophenonebenzylimine and acetophenone

Rhodium(I) complexes formed by (−)-(2S,4S)-2,4-bis(diphenylphosphino)pentane (BDPP) are efficient catalysts for the hydrogenation of acetophenone and acetophenonebenzylimine. The composition of the solvent mixture and the reaction temperature have a marked influenced on the enantioselectivity. These effects are thought to be related to the enhanced conformational flexibility of six-membered rings when simple substrates without functional groups are coordinated to the rhodium. X-ray crystallographic studies reveal that in [Rh((S,S)-BDPP)NBD]⁺ (1) the ligand is in a chair conformation, and that in [Rh((S,S)-BDPP)COD]⁺ (2) the chelate ring is in a δ-skew conformation. Studies of Rh((S,S)-BDPP)(NBD)Cl (3) in solution indicate a trigonal bipyramidal structure with a chair conformation of the ring in aromatic solvents and a conformationally labile ring in methanol.     

Synthesis of Pt compounds containing chiral (2S,4S) -pentane-2,4-diyl-bis(5H-dibenzo[b]phosphindole) as ligand and their use in asymmetric hydroformylation of styrene derivatives

Unlike bis(diphenyl)phosphine derivatives in general, (2S,4S)-pentane-2,4-diyl-bis(5H-dibenzo[b]phosphindole), S,S-BDBPP, gives a trans oligomeric compound [PtCl₂(S,S-BDBPP)]_n, 1, in reaction with dichloro-Pt precursors such as PtCl₂(PhCN)₂, PtCl₂(CH₃CN)₂ and PtCl₂(COD) at room temperature. Compound 1, which could be readily isolated, slowly rearranges in solutions at room temperature to the expected cis-monomer PtCl₂(S,S-BDBPP), 3. Heating or the presence of PtCl₂(COD) accelerates the transformation of compound 1 to 3. SnCl₂ adducts of both compounds, trans-[PtCl(SnCl₃)(S,S-BDBPP)]_n, 2, and cis-PtCl(SnCl₃)(S,S-BDBPP), 4, as well as the known cis-PtCl(SnCl₃)(S,S-BDPP), 5, (S,S-BDPP = (2S,4S)-2,4-bis(diphenylphosphino)pentane) have been tested as catalysts in the asymmetric hydroformylation of p-isobutylstyrene. The phenyl analog 5 provides up to 75% e.e. but moderate yields to chiral 2-(4-isobutylphenyl)-2-propanal. Compared to this, the regioselectivity to the branched aldehyde is remarkably increased; however, the enantioselectivity is drastically decreased by the use of both dibenzophosphole derivatives 2 and 4. The similarities in the selectivities provided by 2 and 4 indicate that the trans oligomer 2 transforms to the cis-monomer 4 during the catalytic process. X-ray crystal structure determination of compound 3 shows a half-chair conformation for the chelate ring with a symmetric arrangement of dibenzophosphole groups. Besides a preference for the latter achiral conformation, the planar structure of the dibenzophosphole groups can also be considered as reason for the moderate enantioselectivities provided by 4.     

Edulisones A and B, two epimeric benzo[b]oxepine derivatives from the bark of Aglaia edulis

Two benzo[b]oxepine derivatives, edulisones A (1) and B (2), were isolated from the bark of Aglaia edulis, collected in Indonesia. The relative stereochemistry of 1 was determined by single-crystal X-ray diffraction analysis. Treatment of compounds 1 and 2 with lithium hydroxide produced the same hydrolysis products, 1a and 1b, as a result of cleavage of the pyrrolidine ring to an alkylated amide mixture in each case, which demonstrated that these substances are epimeric at their 2-aminopyrrolidine moiety.     

Serendipitous synthesis of a ditwistane: a one-step access!

4-tert-Butyl-2-cyclohexen-1-one dimerizes in THF solution via its kinetic enolate, leading to di-tert-butylditwistane 8 in up to 36% yield (−78 °C → room temp., protonolysis, flash chromatography). X-ray crystallography shows that 8 incorporates one R and one S enantiomer of the starting ketone; none of the diastereomeric ditwistanes epi-8, epi’-8 or iso-8 was isolated. This means that the formation of 8 proceeds with mutual kinetic resolution and 100% induced diastereoselectivity.     

The properties of phenyl cyclohexyl ferroelectric liquid crystals

To continue the search for novel series of ferroelectric liquid crystals, an additional two series of compounds, C S(+)-4-[(2-methylbutyl)phenyl]4'-trans-n-alkylcyclohexyl) benzoates and D S(+)-4-[(4-methylhexanoyl)phenyl]4'(4'-trans-n-alkylcyclohexyl) benzoates, where alkyl = C₅-C₆ are reported in this paper. Their mesomorphic properties have been characterized by optical textural observations and DSC. Some of these compounds show a C-S*_C-S_A-N*-I phase transition sequence. The effects of the alkyl chains on transition temperatures and optically active terminal groups on phase behaviour are discussed.