Search

Pseudo natural products (PNPs) are natural product-inspired compounds obtained by unprecedented combination of natural product (NP) fragments in complexity-generating transformations. The pyrrolidine- and tetrahydroquinoline fragments individually occur in numerous NPs with diverse bioactivity, yet not in combination. Herein we report the enantioselectively catalyzed asymmetric synthesis of pyrro[3,4-c]quinoline pseudo-natural products in which these two fragments are combined. The synthesis includes a highly enantioselective 1,3-dipolar cycloaddition between amino acid-derived azomethine ylides and α,β-unsaturated malonic acid esters to yield pyrrolidines followed by a sequence of protection-, reduction- and lactamization steps.

Three benzyl silanes, 1-(benzyldimethylsilyl)methyl-1-methylpiperidin-1-ium iodide (1), 1(dibenzylmethylsilyl)methyl-1-methylpiperidin-1-ium iodide (2) and 1-(2-(benzyldimethyl-silyl)ethyl)-1-methylpiperidin-1-ium iodide (3), have been synthesized and structurally characterized by X-ray crystallography. Compounds 1 and 2 are evaluated to determine what structural influence the positive charge in α-position to silicon has on the silicon atom. Furthermore, the compound 3 is used to compare this effect and to show the structural and electronic differences in comparison to 1 and 2. DFT calculations were performed to investigate the individual electronic environments of the silicon and surrounding atoms in detail, which are discussed in regards to Bent’s rule (Bent, 1960, 1961).

A new representative of hydrolysis-stable zwitterionic ZnHal 2 silanolates (with Hal = I) was obtained by treatment of an aminomethyl-functionalised disiloxane with zinc(II) iodide. The molecular structure was elucidated by X-ray crystallography and NMR spectroscopy.

The inclusion of small molecules, such as amines, into hydrogen-bonded assemblies is an important task for a selective enclathration of substance mixtures. Here we report on a convenient method to entrap a simple monoamine by using the acidic nature of a silanol hydroxyl group. In detail, the co-crystallisation of triphenylsilanol and pyrrolidine leading to a defined host–guest compound (1) with a 4:1 stoichiometric composition is presented. The addition of acetic acid to a mixture of the silanol and the amine resulted in the formation of co-crystals (2) comprising the three substances in a 1:1:1 ratio. The structural features, especially in terms of hydrogen-bonding interactions are discussed for both compounds.

A series of monomeric coordination compounds containing zinc(II) chloride or zinc(II) bromide and the 1,2-diamine ligands TMEDA, TEEDA, (R,R)-TMCDA, (R,R)-TECDA and cis-TMCDA have been synthesised and structurally characterised using X-ray diffraction analysis. All but one complex could be successfully used as initiators for the solvent-free ring-opening polymerisation of d,l -lactide. In particular, the polylactide (PLA) prepared with compounds containing (R,R)-TECDA is obtainable in high yields with molecular weights suitable for industrial applications. Thus a class of stable, easy to synthesise and efficient PLA catalysts with neutral ligands is introduced.

We report optimized synthetic procedures to cis-TMCDA and cis-cyclohexane-1,2-diamine. Our new two-step approach is an efficient and low-cost method for synthesizing the ligand cis-TMCDA. In the preparation of cis-cyclohexane-1,2-diamine, the crystallization of the unexpected intermediate cis-cyclohexane-1,2-diammonium hydrogensulfate ethylsulfate made the subsequent reactions easier in their workup, as nickel(II) chloride impurities were eliminated.

γ-Acetylenic carboxylic acids are cyclized to spirolactones under mild conditions, in the presence of Ag2CO3 catalyst. The corresponding spiro-5-alkylidene-γ-butyrolactones were isolated in high yields, and this process constitutes an easy and efficient route to analogous structures of natural products of biological interest.

An alternative synthesis of (±)-4-ethynyl[2.2]paracyclophane (PCP C CH) (5) and 4,16-diethynyl[2.2]paracyclophane (6) via the Corey–Fuchs reaction has been developed. The olefinic intermediate 4-dibromovinyl[2.2]paracyclophane (3) has been isolated and structurally characterized. The racemic terminal alkyne 5 was employed as starting material for assembling of a luminescent extended π-conjugated system containing a thiophene unit and for a catalytic bis-silylation reaction yielding the olefinic dithioether Z-PhSCH2Me2SiC(H) C(PCP)SiMe2CH2SPh (9). The dimetallatetrahedran [Co2(CO)6(μ-η2–PCP–CCH)] (10) has been prepared and its crystal structure determined by an X-ray diffraction analysis. Alkyne 5 has also been used for the preparation of the Pt(0) complex [Pt(PPh3)2(PCP C CH)] (11) and the heterodinuclear dimetallacyclopentenone [(OC)2Fe{μ C( O)C(PCP) C(H)}(μ-dppm)Pt(PPh3)] (12). The synthesis and reactivity of 4-isocyano[2.2]paracyclophane (15) towards heterobimetallic iron–platinum and palladium–platinum complexes is also presented. Opening of the dative iron → platinum bond of [(OC)4Fe(μ-dppm)PtCl2] (16) occurred upon addition of 15 to a CH2Cl2 solution of 16 leading to [(OC)4Fe{μ-dppm}PtCl2(C N PCP)] (17). Treatment of [ClPd(μ-dppm)2PtCl] (18) with isocyanide 15 in a 1:1 ratio affords the A-frame compound [ClPd(μ-dppm)2(μ-C N PCP)PtCl] (19), resulting from formal insertion of 15 into the Pd–Pt bond. Addition of 2 equiv. of 15–18 leads to the ionic A-frame compound [ClPd(μ-dppm)2(μ-C N PCP)Pt(C N PCP)]Cl (20).

Two novel one-dimensional (1D) coordination polymers of stoichiometry [{Si(CH2SR)4}HgBr2]n (R = Me, 2a; R = Ph, 2b) have been prepared by treatment of HgBr2 with the functionalized silanes Si(CH2SR)4 (R = Me, 1a; R = Ph, 1b) acting as tetradentate thioether ligands. The extended structures result from intermolecular Hg–S interactions linking the monomeric {Si(CH2SR)4}HgBr2 units, as established for 2a, b using single-crystal X-ray diffraction. The effective coordination around the Hg atoms in both compounds is best described as distorted octahedral.

Insertion of hexafluorobutyne into the Pt–H bond of the heterobimetallic complexes [(OC)3Fe{Si(OMe)3}(μ-Ph2PXPPh2)Pt(H)(PPh3)] (1a X = CH2; 1b X = NH) yields the σ-alkenyl complexes [(OC)3Fe{μ-Si(OMe)2(OMe)}(μ-Ph2PXPPh2)Pt{C(CF3) C(H)CF3}] (3a X = CH2; 3b X = NH). This insertion reaction is accompanied by dissociation of the platinum bound PPh3 ligand and saturation of the vacant coordination site by a dative μ−η2-Si–O → Pt interaction. Addition of the Pt–H bond of 1a across the triple bond of 3,3,3-trifluoropropyne affords in a regiospecific manner [(OC)3Fe{μ-Si(OMe)2(OMe)}(μ-dppm)Pt{C(CF3) CH2}] (2) having the trifluoromethyl substituent on the α-carbon. Addition of RN C to 3 affords the isocyanide adducts [(OC)3Fe{Si(OMe)3}(μ-Ph2PXPPh2)Pt(CNR){C(CF3) C(H)CF3}] (4a R = t-Bu, X = CH2; 4b R = 2,6-xylyl, X = CH2; 4c R = 2,6-xylyl, X = NH). In dichloromethane solution 3a is gradually transformed into the C4F6-bridged compound [(OC)3Fe(μ-dppm)(μ-CF3C CCF3)Pt(CO)] 5. The Pt-bound carbonyl ligand of 5 is displaced by xylylisocyanide or trimethylphosphite affording the derivatives [(OC)3Fe(μ-dppm)(μ-CF3C CCF3)Pt(CNxylyl)] 6 and [(OC)3Fe(μ-dppm)(μ-CF3C CCF3)Pt{P(OMe)3}] 7. The molecular structures of 4a, 5 and 6 have been determined by X-ray diffraction studies.

The ab initio and DFT calculations (structural parameters, electron localization function (ELF)) on 3-silaoxetane 3,3-dimethyl2,2,4,4-tetraphenyl-1-oxa-3-silacyclobutane (1) and 3-silathietane 3,3-dimethyl-2,2,4,4-tetraphenyl-1-sila-3-thiacyclobutane (2) show the cyclobutane ring in 2 as being non-planar with a C–Si–C angle of 89.2 and a C–S–C angle of 93.3, whereas the cyclobutane ring in 1 is planar with an unusual small bond angle at the silicon atom of 74.7, which can only be explained by bent bonds. Since the synthesis was performed in water, small bent angles cannot be indicative for high reactivity. The Raman spectra of 1 and 2 were then recorded and analyzed in the 1800–200 cm � 1 spectral region at various temperatures (300–10 K) with the help of the DFT calculation results (harmonic vibrational wavenumbers, Raman scattering activities). Although the wavenumber shifts are quite small, the subtle changes in the spectral features of the 3-silaoxetane and phenyl rings vibrational modes may indicate a loss of symmetry in 1 (between 200 and 150 K) and a possible phase transition in 2 (at about 200 K). Furthermore, the Raman spectra of 1 and 2 confirmed the ELF calculation results, excluding any bond interaction between the silicon and the oxygen or sulfur atom. 2004 Elsevier B.V. All rights reserved.

The reactions of [Pd{ C H 2 SiPh 2 (CH 2 N C 5 H 10 )-κ 2 C , N }(μ-Cl)] 2 with the tetra-n-butylammonium N n Bu 4 + salts of different deprotonated α-amino acids (N,N-dimethylglycine, ( S )-(+)-alanine, ( R )-(−)-2-phenylglycine, and ( S )-(+)-valine) lead to the amino acidato complexes [Pd{ C H 2 SiPh 2 (CH 2 N C 5 H 10 )-κ 2 C , N }{ N R 2 CH(R′)C(O) O -κ 2 N , O }] (R = Me, R′ = H; R = H; R′ = Me, Ph, i Pr), where both nitrogen donor atoms are coordinated trans , as shows the crystal structure of [Pd{ C H 2 SiPh 2 (CH 2 N C 5 H 10 )-κ 2 C , N }{ N H 2 CH( i Pr)C(O) O -κ 2 N , O }].

Two (aminomethyl)(lithiomethyl)silanes Ph 2 Si(CH 2 Li)(CH 2 NC 5 H 10 ) (NC 5 H 10 =1-piperidinyl) ( 2 ) and Me 2 Si{[ R ]-[CHLiPh]}(CH 2 SMP) {SMP=1-[( S )-2-(methoxymethyl)pyrrolidinyl]} [( R , S )- 17 ] are presented including their solid state structures, the first one non-chiral, the latter highly diastereomerically enriched. By metathesis reactions with metal(II) halides (metal=Mg, Ga, Pd, Cd and Hg), the corresponding bis{[(aminomethyl)silyl]methyl}metal(II) compounds or the [(aminomethyl)silyl]methylmetal(II) halides were obtained. In the case of highly diastereomerically enriched (aminomethyl)(lithiomethyl)silane ( R , S )- 17 , the ‘carbanionic’ fragment could be transferred with high stereoselectivities on the metals Hg and Pd. For all of the compounds, the solid state molecular structures were determined.

Four different syntheses of the potent and selective muscanruc antagonist cyclohexyl( 4fluorophenyl)(3-piperidinopropyl)silanol ( p-fluoro-hexahydro-sila-difenidol, p-F-HHSiD (2b); isolated as hydrochloride 2b· HCl) are described (starting materials: (CH 30hSiCH2CH2CH2Cl and Si(OCH3 ) 4 ). In addition, the synthesis of the corresponding carbon analogue p-fluoro-hexahydro-difenidol ( p-F-HHD (2a); isolated as 2a· HCI) and the syntheses of three p-F-HHSiD derivatives (3-5), with a modified cyclic amino group, are reported (3: piperidinojpyrrolidino exchange, isolated as 3· HCI; 4: piperidinoj hexamethylenimino exchange, isolated as 4 · HCl; 5: quaternization of 2b with methyl iodide). The chiral compounds 2a, 2b, 3, 4 and 5 were prepared as racemates. In functional pharmacological studies, 3-5 behaved as simple competitive antagonists at musearlnie Ml receptors in rabbit vas deferens, M2 receptors in guinea-pig atria, and M3 receptors in guinea-pig iJeaJ smooth rnuscle. The pyrrolidino (3) and hexamethylenimino (4) analogues of the parent drug p-F-HHSiD (2b) displayed the highest affinity for Ml and M3 receptors (pA 2 values: 7.0-7.4) but exhibited lower affinity for cardiac M2 receptors (pA 2 : 5.9 and 6.0). Their affinity profile (Ml- M3 > M2) is different from that of p-F-HHSiD (2b) (M3 > Ml > M2), but qualitatively very similar tothat of p-F-HHD (2a). The methiodide 5 exhibited the highest affinity for Ml receptors (pA 2 : 8.5) but lower affinity for M2 and M3 receptors by factors of 5.6 and 3.6, respectively.

A method was developed to determine the affinities of antimuscarinic drugs at m 1 receptors. [ 3 H](±)-Telenzepine served as radioligand in crude preparations of calf superior cervical ganglia and showed high affinity for a single receptor population, consisting of M 1 receptors (K D = 1.12 nM). Kinetic experiments showed monophasic association (k 1 = 0.017 min −1 nM −1 ) and dissociation (k −1 = 0.017 min −1 ) kinetics, the half-life of dissociation being 41 min at 37°C. The kinetic K D value amounted to 1.00 nM. M 1 affinities for pirenzepine, methoctramine, hexahydro-sila-difenidol and p-fluoro-hexahydro-sila-difenidol determined in competition experiments were similar to those found in functional studies with M 1 receptors in rabbit isolated vas deferons. The binding assay was used to determine the affinities of the (R) and (S) enantiomers of tertiary (trihexyphenidyl, hexahydro-difenidol, hexbutinol, p-fluoro-hexbutinol) and quaternary muscarinic antagonists (trihexyphenidyl methiodide, hexbutinol methiodide). Comparison of results obtained with the rabbit vas deferens suggested that the ionic environment may influence the affinities.