Cis Compound Research Articles

Novel cis compound heterozygous variants in MYO6 causes early onset of non-syndromic hearing loss in a Chinese family.

Background: Mutations in the MYO6 gene have been associated with both autosomal dominant non-syndromic hearing loss (ADNSHL) and autosomal recessive non-syndromic hearing loss (ARNSHL), with a cumulative identification of 125 pathogenic variants. To investigate the underlying genetic factor within a Chinese family affected with heriditary hearing loss, prompted the utilization of high-throughput sequencing. Method: A detailed clinical investigation was performed. Genetic testing was performed by using target panel sequencing, and Sanger sequencing. Targeted sequencing identified the variants and Sanger sequencing was employed to validate segregation of the identified variants within family. Additionally, bioinformatics analysis was performed to strengthen our findings. Results: Clinical investigation revealed the family members were affected by progressive and sensorineural hearing loss with an onset around 8-10 years old. Furthermore, genetic testing identified novel MYO6 variants, c.[2377T>G; 2382G>T] p.[Trp793Gly; Lys794Asn], positioned in a cis pattern, as plausible pathogenic contributors to early-onset hearing loss characterized by a severe and progressive course. Moreover, bioinformatics analysis showd disruptin in hydrogen bonding of mutant amino acids with interactive amino acids. Conclusion: Our research uncovered a relationship between mutations in the MYO6 gene and non-syndromic hearing loss. We identified two variants, c.[2377T>G; 2382G>T] p.[Trp793Gly; Lys794Asn] in MYO6 as strong candidates responsible for the observed progressive hereditary hearing loss. This study not only adds to our knowledge about hearing problems related to MYO6 but also reveals the presence of monogenic compound heterozygosity. Our study will provide a new sight for genetic diagnosis in such patients and their management for future use.

Clinicopathological and mutational characteristics of primary double mutant gastrointestinal stromal tumor: a single center study with review of the literature

AimsPrimary double KIT/PDGFRA mutations are very rare in gastrointestinal stromal tumours (GISTs) but have not been comprehensively studied to date. In the present study, we investigated the clinicopathologic and genetic features of eight cases of primary double-mutant GISTs, and we reviewed the literature.Methods and resultsThe tumours occurred in six males and two females (age range 57–83 years) and involved the small intestine (n = 4), stomach (n = 2), rectum (n = 1) and retroperitoneum (n = 1). Clinical manifestations were variable, ranging from indolent (no symptoms) to aggressive disease (tumour rupture and haemorrhage). All patients underwent surgical excision, and six of them were treated with imatinib. No one experienced recurrence or other complications during the follow-up time (10 to 61 months). Histologically, all the tumours exhibited mixed cell types, accompanied by variable interstitial changes. KIT mutations were detected in all cases, and the majority of them were present in different exons (n = 5). No PDGFRA exon 12, 14 or 18 mutations were found. All the mutations were validated by next-generation sequencing, and two additional variants with comparatively low allelic fractions were identified in one case. Two of the cases had available allele distribution data, one with an in cis compound mutation and the other with an in trans compound mutation.ConclusionPrimary double-mutant GISTs have distinctive clinicopathologic and mutational features. Studies of more cases are necessary for a better understanding of these tumours.

Abstract A21: Compound PIK3CA mutations support a mutational dose-response model for oncogene activation and response to PI3K inhibitor targeted therapy in breast cancer

Abstract PIK3CA mutations represent the most frequent oncogenic driver lesion found across all human cancers. Given that single PIK3CA mutations are a predictive biomarker for response to PI3K inhibition, and that these clinical benefits are small, we hypothesized that additional genomic factors may cooperate with single PIK3CA mutations in oncogenesis and response to PI3K inhibitors. We analyzed several large pan-cancer datasets and have discovered a phenomenon of dual PIK3CA mutations in 15% of all PIK3CA-mutant cancers, including breast cancer. Dual PIK3CA mutations are clonal, are found in both primary untreated and metastatic tumors, and are enriched at conserved amino acid positions. We have proved that the majority of dual PIK3CA mutations—including the most frequent dual PIK3CA mutant combinations in breast cancer—are in cis compound mutations (i.e., on the same allele, resulting in a protein molecule with two mutations) in patient samples and cell lines, as shown through multiple sequencing techniques including long-range single-molecule real-time sequencing (SMRT-seq). Compound PIK3CA mutations increase PI3K pathway signaling and growth proliferation in nontransformed cells and cancer cells in vitro and in vivo. Biochemical experiments using recombinant PI3K complexes reveal a mechanism where compound mutants increase PI3K complex thermal instability, resulting in increased kinase activity and liposome binding as compared to single mutants. Compound PIK3CA mutations render cells more sensitive to the PI3Kα inhibitors BYL719 and GDC-0077 than single PIK3CA mutations. These data translate to the clinic, where patients with dual PIK3CA-mutant metastatic breast cancer exhibit more durable responses to PI3K inhibition versus patients with single PIK3CA-mutant breast tumors. Our data support a novel mutational dose-response model for oncogene activation, where compound mutations amplify PI3K signaling and growth to a greater degree than single mutants, resulting in increased sensitivity to PI3Kα inhibitor targeted therapy. These findings also have therapeutic relevance, where compound PIK3CA mutations may be a superior predictive biomarker for response to PI3Kα inhibitors than single PIK3CA mutations, across PIK3CA-mutant cancers. Citation Format: Neil Vasan, Jared Johnson, Hong Shao, Pedram Razavi, Alexander Gorelick, Erik Ladewig, Alesia Antoine, Hardik Shah, Eneda Toska, Guotai Xu, Abiha Kazmi, Barry Taylor, Komal Jhaveri, Maura Dickler, Elisa de Stanchina, Eduard Reznik, Raul Rabadan, Melissa Smith, Robert Sebra, Lewis Cantley, Maurizio Scaltriti, Jose Baselga. Compound PIK3CA mutations support a mutational dose-response model for oncogene activation and response to PI3K inhibitor targeted therapy in breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A21.

The in cis compound EGFR mutations in Chinese advanced non-small cell lung cancer patients

ABSTRACT Literatures regarding the prevalence and clinical significance of compound EGFR mutations are limited. Until now, none of retrospective or prospective research has focused on in cis compound EGFR mutations except case reports. In this study, we screened a cohort of 3,000 treatment-naïve Chinese advanced NSCLC patients using capture-based ultra-deep targeted sequencing to evaluate the prevalence of EGFR in cis compound mutations and the efficacy of EGFR-TKI in this population. Of the 3,000 patients screened, 1,266 (42.2%) had EGFR mutation; among them, 15 patients (1.2%) harboring in cis compound EGFR mutations, with 10 patients carrying EGFR L858R in combination with a rare mutation and five patients carrying two rare EGFR mutations. No patient with EGFR 19del was observed. Interestingly, no in trans configuration was identified in this cohort. All of the patients harboring in cis compound EGFR mutations were non-smokers, histologically diagnosed with adenocarcinoma and received first-generation EGFR-TKI. Furthermore, our data also revealed that patients with in cis compound EGFR mutations exhibit comparable PFS to first generation EGFR-TKI comparing to patients with single activating EGFR mutation. This observation was further supported by in silico molecular modeling analyses which demonstrated in cis compound mutations do not alter the ATP-binding pocket of EGFR, thus having no effect on the interaction between gefitinib and EGFR.

Triphenylbismuth(v) di[(iso)nicotinates] - transmetallation agents or divergent organometalloligands? First organobismuth(v)-based silver(i) coordination polymers.

The reaction of Ph3BiCl2 with alkali salts of isonicotinic and nicotinic acids afforded Ph3Bi[O(O)CC5H4N-4]2 (1) and Ph3Bi[O(O)CC5H4N-3]2 (2), respectively, which were characterized by multinuclear NMR spectroscopy in solution, mass spectrometry and IR spectroscopy in the solid state. Their molecular structures were established by single-crystal X-ray diffraction. For both 1 and 2 the molecules contain a trigonal bipyramidal C3BiO2 core, with the phenyl groups in equatorial positions. The potential use of 1 and 2 as ditopic organometalloligands was investigated. The reaction of 1 or 2 with Me3SnCl (1 : 2 molar ratio) resulted in carboxylato ligand exchange and the formation of Me3Sn[O(O)CC5H4N-4] (3) and Me3Sn[O(O)CC5H4N-3] (4) besides Ph3BiCl2. The crystals of both 3 and 4 contain 1-D coordination polymers built through intermolecular N → Sn interactions. The treatment of Ni[S2P(OiPr)2]2 with 1 and 2, respectively, resulted, in addition to di(carboxylato)nickel(ii) derivatives, in isolation of Ph3Bi and the disulphane [(iPrO)2P(S)S]2. New coordination polymers were obtained by reacting 1 and 2 with various silver(i) salts: [Ag{Ph3Bi[O(O)CC5H4N-4]2}(OTf)] (5), [Ag{Ph3Bi[O(O)CC5H4N-3]2}(OTf)]·CH2Cl2 (6·CH2Cl2), [Ag{Ph3Bi[O(O)CC5H4N-4]2}](SbF6)·2THF (7·2THF), [Ag{Ph3Bi[O(O)CC5H4N-3]2}](SbF6)·CH2Cl2 (8·CH2Cl2) and [Ag{Ph3Bi[O(O)CC5H4N-3]2}(NO3)]·CH2Cl2 (9·CH2Cl2). The crystal structures of 5 and 6 can be described as 1-D chains linked by triflate bridges in pairs of chains and 2-D networks, respectively. Compound 7 features a 2-D grid-like topology of the network, with tecton 1 acting as a tridentate ligand through both nitrogen and one oxygen atoms. The linker 2 molecules adopt either cis (compound 6) or trans (compounds 8 and 9) conformation. Complexes 8 and 9 are 1-D chain polymers exhibiting zig-zag and wavy motifs, respectively. The dimensionality of the structures is extended by the presence of supramolecular interactions (ππ, AgAg, AgO).

Oxidorhenium(V) Complexes with Tetradentate Iminophenolate Ligands: Influence of Ligand Flexibility on the Coordination Motif and Oxygen-Atom-Transfer Activity.

The synthesis of oxidorhenium(V) complexes 1-3 coordinated by tetradentate iminophenolate ligands H2L1-H2L3 bearing backbones of different rigidity (alkyl, cycloalkyl, and phenyl bridges) allows for the formation of distinct geometric isomers, including a symmetric trans-oxidochlorido coordination motif in complex 3. The complex employing a cycloalkyl-bridged ligand (2) of intermediate rigidity exhibits an interesting solvent- and temperature-dependent equilibrium between a symmetric (trans) isomer and an asymmetric (cis) isomer in solution. The occurrence of a symmetric isomer for 2 and 3 is confirmed by single-crystal X-ray diffraction analysis. Chlorido abstraction from 2 with AgOTf yields the corresponding cationic complex 2a, which does not exhibit an isomeric equilibrium in solution but adopts the isomeric form predominant for 2 in a given solvent. All complexes were, furthermore, employed in three benchmark oxygen-atom-transfer (OAT) reactions, namely, the reduction of perchlorate, the epoxidation of cyclooctene, and OAT from dimethyl sulfoxide (DMSO) to triphenylphosphane (PPh3), to assess the influence of the isomeric structure on the reactivity in these reactions. In perchlorate reduction, a clear structural influence was observed, where the trans arrangement in 3 led to the complete absence of activity. In the epoxidation reaction, all complexes led to comparable epoxide yields, albeit higher catalytic activity but lower overall stability of the catalysts with a trans arrangement was observed. In OAT from DMSO to PPh3, also a clear structural dependence was observed, where the trans complex 3 led to full phosphane conversion with an excess of oxidant, while the cis compound 1 was completely inactive.

Molecular Structure of Cyclopropyl (Isocyanato) Silane: A Combined Microwave Spectral and Theoretical Study.

The molecular equilibrium structures of two conformers (cis and gauche) of C3H5-SiH2-NCO have been deduced by a combination of microwave (MW) spectra at natural abundance including data from (13)C and (29,30)Si isotopomers and ab initio calculations. The MW rotational constants (RCs) for the most abundant isotopes are cis: A = 4216.3617(64), B = 1225.76654(91), and C = 1037.31468(77) MHz and gauche: A = 4955.55(79), B = 1094.9276(81), and C = 942.7031(80) MHz. The symmetric quartic centrifugal distortion constants have been evaluated for the cis conformer, using the I(r) representation for CS symmetry. Only partial substitution structures (PSSs) could be derived from the spectra after inclusion of the above isotopic combinations at each center. Using the PSSs, the full structures were determined by ab initio calculation of the equilibrium structures using coupled-cluster singles and doubles with selected triples configuration calculations (CCSD(T)); the two conformers have an energy difference of 228 cm(-1) (cis lower than gauche). The similarity of the calculated and MW RC results confirms the identities of the two compounds. The more interesting cis conformer has bond lengths C2-Si3, 1.9072(73), C2-C9 1.464(22), and C9-C10 1.4944(33) Å and angles Si3-C2-C10 119.4(12)° and C9-C2-C10 57.1(12)°, with similar results for the gauche conformer. The Si3N4C5 angle is wide in the cis conformer (145°) and nearly linear in the gauche conformer (179°). New physical insights into the bonding of cis conformers of this type have led the identification of an attractive force between the relatively crowded cyclopropyl and isocyanato groups in the cis conformation. This is demonstrated by three methods: Comparing electronic charges (both AIMALL and Mulliken analyses) in the pair of conformers shows a relative shift of density between these groups in the cis compound. Comparison of the highest occupied molecular orbitals (HOMOs) shows major mixing of density, exemplified by HOMO-1 in these structural units for the cis conformer but which is absent for the gauche conformer. Finally, the nearly linear isocyanate moiety (and the molecular dipole moment) of the cis conformer points closely toward the connected C atom of the cyclopropyl ring, while the gauche conformer dipole moment is significantly different in direction and points toward the midpoint of the C2Si3 bond. Both the HCSiN torsional and Si-N═C bending surfaces connecting these conformers were explored at the Møller-Plesset second-order perturbation theory level (MP2), which led to the exclusion of other conformers. The bending surface shows a very high amount of quartic potential function.

Surface Composition of CIS Compound Affected by Xe⁺ Irradiation

Surface Composition of CIS Compound Affected by Xe⁺ Irradiation

Reactions of ansa fluorodioxy cyclotriphosphazene derivatives with phenol

The reactions of mono ansa fluorodioxy cyclotriphosphazenes {N3P3Cl4[OCH2(CF2)nCH2O] (n=3, 1a; n=4, 1b)} with the sodium salt of phenol in THF solution at different molar ratios were investigated in order to determine the reaction pathways and the mechanism of the nucleophilic substitution at the PCl2 and PCl(OR) phosphorus atoms by phenol and for a comparison with previous work on the reactions of the same starting compounds 1a and 1b with the sodium salt of methanol. Fourteen new products were formed, namely mono-phenoxy derivatives (2a–4a, 3b), di-phenoxy derivatives (5a–7a, 5b), tri-phenoxy derivatives (8a–10a, 8b) and tetra-phenoxy derivatives (11a, 11b). These products, which could be separated, have been characterized by elemental analysis, mass spectrometry, 1H and 31P NMR spectroscopy. A similar result to the reaction with methanol was observed in the first stage of the reaction of compound 1a, containing the 10-membered ansa-ring, with the reaction occurring competitively at both the PCl2 and P(OR)Cl moieties with an approximate 8:1 preference for the PCl2 group. In the second stage of the reaction of compound 1a, the bis non-geminal cis compound (7a) formed as the major product, whilst the major product was the bis gem compound in the similar reaction of 1a with sodium methoxide. Consequently, the tris non-geminal cis compound (9a) might be formed beside the tris geminal compound (8a) in the third stage of the reaction of compound 1a with phenol, unlike the methanol reaction. All the reactions of compound 1b, containing the 11-membered ansa-ring, with the sodium salt of phenol occurred at the PCl2 group before the P(OR)Cl moiety. X-ray crystallographic studies of two compounds (7a and 8b) showed that nucleophilic substitution reactions with the sodium salt of phenol at the ansa-ring PCl(OR) phosphorus atoms of the mono ansa fluorodioxy cyclotriphosphazene compounds 1a and 1b occurred with retention of the configuration.

Molybdenum(V) complexes with formate: Geometric isomerism of the [Mo2O4Cl2(Py)2(HCOO)]− ion

Reactions of (PyH)5[MoOCl4(H2O)]3Cl2 with formate resulted in trans-{(Py)2H}[Mo2O4Cl2(Py)2(HCOO)] (1) and cis-(PyH)[Mo2O4Cl2(Py)2(HCOO)] (2), whereas the bromide starting material (PyH)[MoOBr4], yielded (PyH)3[Mo2O4Br4(HCOO)]·2CH3CN (3) and cis-(PyH)[Mo2O4Br2(Py)2(HCOO)] (4) (where Py stands for pyridine, PyH+ for pyridinium cation and (Py)2H+ for a hydrogen-bonded PyH+⋯Py ion). In all, the dinuclear metal–metal bonded {Mo2O4}2+ core may be recognized with its six coordination sites distributed among halides, pyridine ligands and formate. The latter is coordinated via both oxygen atoms, with each to a different metal ion. The [Mo2O4Cl2(Py)2(HCOO)]− ion exhibits geometric isomerism: the pyridine ligands, on each metal ion one, are either trans or cis to each other. The trans isomer crystallized with (Py)2H+ countercations, whereas the cis isomer as a PyH+ salt. In the crystal lattice of cis-(PyH)[Mo2O4Cl2(Py)2(HCOO)] (2), as confirmed by the X-ray structure analysis, pyridinium cation forms a hydrogen bond with the doubly-bridging oxide of the cis-[Mo2O4Cl2(Py)2(HCOO)]− ion. The countercations of trans-{(Py)2H}[Mo2O4Cl2(Py)2(HCOO)] (1) cannot participate in hydrogen-bonding. The DFT calculations on the isomers of the [Mo2O4Cl2(Py)2(HCOO)]− ion show the trans isomer to be by ca. 15kJ/mol more stable than the cis isomer. The calculations on the hydrogen-bonded PyH+⋯[Mo2O4Cl2(Py)2(HCOO)]− ion-pairs show a reversed order of stability. Hydrogen-bonding and weak CH⋯Cl interactions between PyH+ cations and the cis-[Mo2O4Cl2(Py)2(HCOO)]− ion increase the stability of the cis compound.

A unified synthesis of all stereoisomers of 2-(aminomethyl)cyclobutane-1-carboxylic acid

All four stereoisomers of 2-(aminomethyl)cyclobutane-1-carboxylic acid have been prepared starting from a single chirally derivatized unsaturated γ-lactam. A photochemical [2+2] cycloaddition reaction of this compound with ethylene was employed to create the four-membered ring exclusively with a cis ring configuration. The two diastereoisomers were separated conveniently by chromatography then the chiral appendage replaced by the more convenient Boc protecting group. Base-mediated lactam hydrolysis provided each of the cis target structures as single enantiomers. An efficient, tandem epimerization/hydrolysis protocol was applied to a carboxamide derivative of each cis compound, to furnish the corresponding trans compounds as single isomers, for the first time.

ChemInform Abstract: Syntheses, Structures, and Complexation of cis‐ and trans‐Cycloheptane‐1,2‐diyl‐fused Crown Thioethers ([12]ansS4).

AbstractThe competitive complexation experiment indicates that cis compound (VIII) forms the complex with AgOTf more preferably than trans compound (XI).

ChemInform Abstract: Nucleoside Analogues with a Novel Glycone Based on the Benzo[c]furan Core.

Abstract Routes to novel nucleoside analogues based on 1, 3-dihydrobenzo[c]furan have been investigated. Thus l-(1, 3-dihydro-3-hydroxymethylbenzo[c]furan-1-yl)-thymine, an analogue of d4T, was obtained as two diastereoisomers. The cis compound (quasi β-D/α-L stereochemistry) was obtained pure but the trans compound was only 90% pure. A purine analogue with a four atom spacer group between base and glycone was also prepared. The conformation of these constrained nucleosides was studied by molecular modelling.

Development of a conjugated gadolinium and cisplatin–gelatin possessing properties as an intravascular contrast agent for MR imaging

Purpose The purpose of this study is to create a Gd–DTPA–Gel–Cis compound, which made from gadolinum (Gd), diethylenetriaminepentaacetic acid (DTPA)-dianhydride, cis-diamminedichloroplatinum (Cis) and bovine gelatin (Gel), that makes it possible to visualize Cis as intravascular agent under magnetic resonance imaging (MRI). Materials and methods The amount of DTPA, Gd, and Cis were titrated to determine the new compound's conjugation ratio with gelatin. Considering these functions, Gd–DTPA–Gel–Cis was synthesized, and its stability in bovine serum was evaluated. In addition, the signal intensity of the diluted sample was measured under 1.5 Tesla MRI. Results The synthesized 10 mg/ml of Gd–DTPA–Gel–Cis contained 42.84 μg/ml of Gd and 1.53 μg/ml of platinum. Gd–DTPA–Gel–Cis (100 mg/10 ml) enclosed into the cellulose dialysis tubing was placed in 90 ml of bovine serum and shaken reciprocally at 72 stroke/min at 37 °C. Partial release of free Pt was shown at 6 and 24 h, but no release of Gd occurred for a 24-h period. And high stability of Gd conjugated to DTPA–Gel–Cis. This result suggests possible anti-tumor effectiveness and high stability of Gd conjugated to DTPA–Gel–Cis. The diluted sample presented high signal intensity under 1.5 Tesla MRI. Conclusion Gd–DTPA–Gel–Cis has been developed successfully and we have proven its stability and contrast ability in MRI.

The infrared and Raman spectra of trans- and cis-tetrachloro-tetramethylbicyclopropylidene

The title compounds trans- and cis-2,2,2′,2′-tetrachloro-3,3,3′,3′-tetramethyl-bicyclopopylidene were synthesized, and their infrared and Raman spectra were recorded. Non-coincidence between the IR and Raman bands of the trans compound suggested C 2h symmetry and a planar ring system. In the cis compound most of the IR and Raman bands coincided and a C 2v symmetry seems likely. The exocyclic C C double bond gave rise to a medium/weak Raman band at 1847 cm −1 in the trans compound. In the cis derivative IR and Raman bands both at 1825 cm −1 were observed. From similarities with related molecules, the ring breathing, the antisymmetric ring stretch, the CCl 2 out-of-phase and in-phase stretch and the out-of-plane ring bending modes have been tentatively assigned for the trans and cis compounds.

Coordination Symmetry-Dependent Structure Restoration Function of One-Dimensional MOFs by Molecular Respiration

One-dimensional metal-organic compounds with cis, trans symmetry-controlled counter anions were synthesized (cis compound {[Cu(azpy)(H2O)2(OTs)2]*2H2O*(acetone)} (1) and trans compound {[Cu(H2O)4Cu(azpy)2(OTs)2(H2O)2]*2(OTs)*2H2O*2EtOH} (2)). Only 2, having trans conformation, exhibited a complete structure-restoration effect with a mechanism involving layering of molecular "bricks" of water and solvent molecules.

Efficient Synthesis of Optically Active 4,5-Dihydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine Derivatives Utilizing Lipase-Catalyzed Transesterification

As an efficient and enantioselective synthesis of the 4,5-dihydroxy-benzazepine compounds, the syntheses of optically active 5-0-protected trans-4,5-dihydroxybenzazepine derivatives were accomplished. The trans-7-chloro-4-hydroxy-5-methoxymethoxy-1 -(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine [(±)-4] was kinetically resolved by lipase-catalyzed transesterification. The optically active 4* was isomerized into the cis compound (6*) utilizing the Mitsunobu esterification followed by hydrolysis. The chiral compounds (4* and 6*) were converted to the 4,5-bismethoxymethoxy compounds (7*-10*), which were the intermediates for the compounds (2a, b and 3a, b).

Enantioselective [6pi]-photocyclization reaction of an acrylanilide mediated by a chiral host. Interplay between enantioselective ring closure and enantioselective protonation.

The [6pi]-photocyclization of the anilides 1a and 5 was studied in the absence and in the presence of the enantiomerically pure chiral lactam 4. The relative configuration of the products was unambiguously established by single-crystal X-ray crystallography and by NMR spectroscopy. A significant enantiomeric excess was observed upon reaction of compound 1a to its photocyclization products at -55 degrees C employing lactam 4 as a chiral complexing agent in toluene as the solvent (66% yield). The trans product ent-3a was obtained in 57% ee, and the minor diastereoisomer (trans/cis = 73/27), cis product ent-2a, was obtained in 30% ee. DFT calculations were conducted modeling the complexation of intermediates 8 and ent-8 to host 4. In agreement with steric arguments concerning the conrotatory ring closure of 1a, the formation of ent-8 is favored leading to the more stable complex 4.ent-8 as compared to 4.8. Whereas the enantioselectivity in the photocyclization to trans compound ent-3a increased upon reduction in the reaction temperature, the enantiomeric excess in the formation of cis compound ent-2a went through a maximum at -15 degrees C (45% ee) and decreased at lower temperatures. Deuteration experiments conducted with the pentadeuterated analogue of 1a, d(5)-1a, revealed that the protonation of the intermediates 8 and ent-8 is influenced by chiral amide 4. In the formation of ent-3a/3a, both the enantioselective ring closure and the enantioselective protonation by amide 4 favor the observed (6aS,10aS)-configuration of the major enantiomer ent-3a. In the formation of ent-2a/2a, the enantioselective ring closure (and the subsequent diastereoselective protonation) favors the (6aR,10aS)-configuration that is found in compound 2a. Contrary to that, the enantioselective protonation by amide 4 shows a preference for ent-2a with the (6aS,10aR)-configuration.

Synthesis of biologically active dicarba analogues of the peptide hormone oxytocin using ring-closing metathesis.

Facile synthesis of cis and trans olefinic analogues of oxytocin 1 that have carbon in place of sulfur is achieved via ring-closing metathesis (RCM) on a resin-bound linear precursor peptide. Hydrogenation of the cis olefin, 3, proceeds selectively to generate the previously reported saturated derivative 5. Biological testing on rat uterus strips shows that cis compound 3 has an EC50 value of 38 ng/mL (EC50 for oxytocin is 2.7 ng/mL) whereas 5 and trans olefin 4 are less active. [reaction--see text]

Vibrational and Quantum Chemical Studies of 1,2-Difluoroethylenes: Spectra of 1,2-13C2H2F2 Species, Scaled Force Fields, and Dipole Derivatives

Infrared and Raman spectra are reported for cis and trans 1,2- 1 3 C 2 H 2 F 2 . Quantum chemical calculations at B3LYP and MP2 levels have been made for cis and trans 1,2-difluoroethylenes, using 6-311G** and 6-311++G** bases. The resulting harmonic force fields for each compound were scaled with nine independent factors, using frequency data corrected, where necessary, for Fermi resonances and for liquid/gas shifts. The previously accepted assignments for v 7 and v 1 2 in the trans isomer are interchanged. Several scale factors for bending motions differ markedly between the cis and trans compounds. Centrifugal distortion constants observed with significant accuracy are predicted within 6%. Harmonic contributions to the vibrational dependence of the rotational constants and perpendicular amplitudes are calculated. The C=C and C-H bonds in the cis and trans isomers are essentially identical in respect to length, force constant, and isolated CH stretching frequency. However, the C-F bond is slightly stronger in the cis compound. A revised allocation of observed infrared intensity between the overlapping trans v 7 and v 1 2 bands is needed. Directions of ∂p/∂Q for the trans B u bands are given, which differ from those reported earlier. Magnitudes and directions of the bond dipole derivatives ∂μ/∂r for the CH and CF bonds are obtained from calculated atomic polar tensors. In both cis and trans isomers, the vector ∂μ/∂r C F lies within 17° of the bond direction, but for the CH bond, ∂μ/∂r is roughly perpendicular to the CH direction.