Cis Cyclopropane Research Articles

Molecule confirmation and structure characterization of pentatriacontatrienyl mycolate in Mycobacterium smegmatis

Mycobacterium smegmatis is often used to study the different components of mycobacterial cell wall. Mycolic acids are important components of mycobacterial cell wall that have been associated with virulence. Recently, a novel lipid containing mycolic acids has been described in M. smegmatis. However, some uncertainties regarding the structure of this molecule named mycolate ester wax have been reported. The objective of this work was to perform an in depth structural study of this molecule for its precise characterization. Using 1H and 13C NMR spectroscopy, the molecular structure of mycolate ester wax found in M. smegmatis has been elucidated. The characterization was complemented with MS analyses. This molecule is formed by a carbon chain with three methyl substituted olefinic units and a mycolate structure with trans double bonds and cis cyclopropane rings. The present molecular study will facilitate the detection and identification of pentatriacontatrienyl mycolate in future studies by the performance of a simple 1D 1H NMR experiment.

Discovery of phenyl acetamides as potent and selective GPR119 agonists

The paper describes the SAR/SPR studies that led to the discovery of phenoxy cyclopropyl phenyl acetamide derivatives as potent and selective GPR119 agonists. Based on a cis cyclopropane scaffold discovered previously, phenyl acetamides such as compound 17 were found to have excellent GPR119 potency and improved physicochemical properties. Pharmacokinetic data of compound 17 in rat, dog and rhesus will be described. Compound 17 was suitable for QD dosing based on its predicted human half-life, and its projected human dose was much lower than that of the recently reported structurally-related benzyloxy compound 2. Compound 17 was selected as a tool compound candidate for NHP (Non-Human Primate) efficacy studies.

Mycobacterium tuberculosis-associated synthetic mycolates differentially exert immune stimulatory adjuvant activity.

Mycolic acids (MAs) are highly hydrophobic long-chain α-alkyl β-hydroxy fatty acids present in the cell wall of Mycobacterium tuberculosis (Mtb) as a complex mixture of molecules with a common general structure but with variable functional groups in the meromycolate chain. In this study, we addressed the relationship between the MA molecular structure and their contribution to the development of T-cell immune responses. Hereto, we used the model antigen ovalbumin and single synthetic MAs, differing in oxygenation class and cis versus trans proximal cyclopropane configuration, as immune stimulatory agents. Subcutaneous delivery of liposome-formulated MAs with a proximal cis cyclopropane elicited antigen-specific Th1 and cytotoxic T-cell immune responses, whereas intratracheal immunization elicited pulmonary Th17 responses. These immune stimulatory activities depended not only on the cis versus trans proximal cyclopropane configuration but also on the MA oxygenation class. Our study thus shows that both the presence and nature of the functional groups in the meromycolate chain affect the immune stimulatory adjuvant activity of Mtb mycolates and suggests that Mtb bacilli may impact on the host protective immune response by modulating the cis versus trans stereochemistry of its mycolates as well as by altering the oxygenation class of the meromycolate functional group.

ChemInform Abstract: Synergistic Catalysis: cis‐Cyclopropanation of Benzoxazoles.

In the present paper we report our latest efforts in pushing the boundaries of synergistic catalysis. We propose the use of 3 different catalytic cycles working in concert for the formation of cis cyclopropane derivatives of benzoxazoles with excellent stereoselectivities. This is the proof of concept that synergistic catalysis could be successfully used in cascade reactions.

Synergistic catalysis: cis-cyclopropanation of benzoxazoles.

In the present paper we report our latest efforts in pushing the boundaries of synergistic catalysis. We propose the use of 3 different catalytic cycles working in concert for the formation of cis cyclopropane derivatives of benzoxazoles with excellent stereoselectivities. This is the proof of concept that synergistic catalysis could be successfully used in cascade reactions.

Development of Novel Bacteriostatic Agents against Mycobacterium tuberculosis Using In silico Techniques

The cell wall of Mycobacterium tuberculosis is made up of mycolic acids which are found to play important role in pathogenesity by modification of double bonds at specific sites on mycolic acid precursors by the action of cyclopropane mycolic acid synthases (CMASs) that belong to a family of S-adenosyl-methionine-dependent methyl transferases. PcaA is an cyclopropane mycolic acid synthase required for cording, persistence and virulence of Mycobacterium tuberculosis and modifies mycolic acid by cyclopropanation of proximal double bond to cis cyclopropane generating alpha mycolic acid. A molecular docking of selected compounds was performed and the differences in their binding modes were investigated in order to design novel lead compound that can act as better antitubercular agent targeting cyclopropane mycolic acid synthases.

Effect of support properties on the performance of silica-supported bis(oxazoline)–copper chiral complexes

Mesoporous silica materials with different textural properties have been prepared by sol–gel synthesis under mild acidic conditions, and used as supports for chiral IndaBox ligand. After complexation with copper, these solids are catalysts for cyclopropanation reactions. Enantioselectivities in the range of 52–57% e.e. for cis cyclopropanes and 42–48% e.e. for trans cyclopropanes are obtained without any effect of the textural properties. However, these properties show an important effect on the activity and mainly on the recyclability of the catalyst. In contrast with the expected effect, solids with very large pores but low surface area lead to a significant deactivation upon recovery, whereas solids with highly developed surface area lead to the best overall results.

Progress toward the synthesis of the bicyclo (6.3.0) framework using TMM diyls

The ability of a vinylcyclopropyl substituted TMM diradical (e.g. 1) to transform to the bicyclo (6.3.0) framework is not restricted to cis cyclopropanes. Trans substituted systems work well, thereby significantly increasing the scope of the chemistry. Improved levels of regioselection toward the (6.3.0) system were observed. A mechanistic rationale for the increase is presented.

Location of functional groups in mycobacterial meromycolate chains; the recognition of new structural principles in mycolic acids.

Mycobacterial alpha-, methoxy- and keto-mycolic acid methyl esters were separated by argentation chromatography into mycolates with no double bond, with one trans double bond or with one cis double bond. Meromycolic acids were prepared from each methyl mycolate fraction by pyrolysis, followed by silver oxide oxidation, and analysed by high-energy collision-induced dissociation/fast atom bombardment MS to reveal the exact locations of the functional groups within the meromycolate chain. The locations of cis and trans double bonds, cis and trans cyclopropane rings, methoxy and keto groups, and methyl branches within the meromycolate chain were determined from their characteristic fragment ion profiles, and the structures of the meromycolic acids, including those with three functional groups extracted from Mycobacterium tuberculosis H37Ra, Mycobacterium bovis BCG and Mycobacterium microti, were established. Meromycolic acids with one cis double bond were structurally closely related to those with one cis cyclopropane ring, whereas the meromycolic acids with one trans cyclopropane ring were closely related to the corresponding meromycolic acids with one cis cyclopropane ring. A close relationship between methoxy- and keto-meromycolic acids was also implied. The relationship between the meromycolic acids with a trans double bond and the other meromycolic acids was not clearly revealed, and they did not appear to be immediate substrates for trans cyclopropanation.

Stereochemical considerations on the stereoselective cyclopropanation reactions of 3-aryl-2-phosphonoacrylates induced by the (–)-8-phenylmenthylIn this paper, menthyl refers to the menthan-3-yl radical. group as a chiral auxiliary

The cyclopropanation of (−)-8-phenylmenthyl (E)-3-aryl-2-phosphonoacrylates E-3a–d with dimethyloxosulfonium methylide and diazomethane affords the corresponding trans cyclopropane derivatives as the major diastereomers with high diastereoselectivity. On the other hand, the cyclopropanation of (−)-8-phenylmenthyl (Z)-3-aryl-2-phosphonoacrylates Z-3a–d and (−)-menthyl derivative 4 gives mixtures of cis and trans cyclopropane derivatives with low diastereoselectivity. The high diastereoselectivity in the cyclopropanation of (E)-acrylates E-3a–d can be rationalized by considering the π–π interaction between the phenyl ring of the chiral auxiliary and the acrylate moiety in the s-cis conformer. The low selectivity in the cyclopropanation of (Z)-acrylates (Z-3a–d and 4) can be attributed to a low-lying conformer with the acrylate moiety twisted out of conjugation.

Cis-Selective Asymmetric Cyclopropanation of Olefins Catalyzed by Five-Coordinate [RuCl(PNNP)]+ Complexes

The five-coordinate complex [RuCl(1a)]PF6 (3a; 1a = (S)-N,N‘-bis[2-(diphenylphosphino)benzylidene]-2,2‘-diamino-6,6‘-dimethylbiphenylene) catalyzes the cyclopropanation of styrene by decomposition of diazoesters. The cis cyclopropane derivative is formed with moderate selectivity (cis:trans ratio is 48:52), but high enantioselectivity (90−96% ee). The related species [RuCl(1b)]PF6 (3b; 1b = N,N‘-bis[2-(diphenylphosphino)benzylidene]-(1S,2S)-diaminocyclohexane) gives the cis product with selectivity up to 95% and enantioselectivity up to >99% ee. High cis selectivity is obtained also with 2,5-dimethyl-2,4-hexadiene as substrate. Complex 3a yields ethyl chrysanthemate with 94% cis selectivity and enantioselectivity up to 80% ee. The putative carbene intermediate trans-[RuCl(C(H)COOEt)(1b)]+ (11b) was prepared and characterized spectroscopically in solution. Its reaction with styrene gives the cyclopropane derivative with 98:2 cis:trans selectivity. The steric constraints in the transition states involving 11b and styrene were estimated by means of molecular modeling calculations. The relative total energies of the four diastereomeric aggregates follow the experimental enantio- and diastereoselectivity trends. The model proposed also predicts the correct absolute configuration of both cis and trans cyclopropane products.

Cis-Selective cyclopropanations using chiral 5,5-diaryl bis(oxazoline) catalysts

A series of 5,5-diaryl bis(oxazolines) have been prepared and used as ligands in the copper catalysed asymmetric cyclopropanation of styrene. Unusually, for bis(oxazolines), the diastereoselectivity of the process favoured the cis cyclopropanes with diastereomeric ratios of up to 65:35 being realised. The cis selectivity of the process was rationalised in terms of repulsion between the alkene substituent and the pro-R 5-aryl group of the bis(oxazoline).

Regioselectivity and diastereoselectivity in the indium-mediated homoallyl-cyclopropanation of dibenzylidene acetone (dba)

Abstract Indium mediated reaction of dibenzylidene acetone (dba) with [ 2 H 2 ]-allyl bromide affords 1,1-distyryl-2-(but-3-enyl) cyclopropane 7 (a triene) as a mixture of four isotopomers. Whilst this reaction is not regiospecific, the analogous reaction employing crotyl bromide in place of allyl bromide is highly regioselective and somewhat selective for the cis cyclopropane isomer. When the reaction is performed with dimethylallyl bromide, cyclopropanation fails and tetraene products are obtained instead.

Asymmetric [2 + 1] Cycloaddition Reactions of 1-Seleno-2-silylethene.

The reaction of (E)-1-(phenylseleno)-2-(trimethylsilyl)ethene (1) and vinyl ketones 2a-d in the presence of a chiral Lewis acid prepared from TiCl(4), Ti(O(i)Pr)(4), (R)- or (S)-1,1'-binaphthol (BINOL), and MS4A gave enantiomerically enriched cis cyclopropane products 3a-d. The enantiomeric excess and chemical yield varied depending on the ratio of TiCl(4) and Ti(O(i)Pr)(4) to 1. Reproducible results (43-47% ee/33-41% yields) for cis-1-acetyl-2-[(phenylseleno)(trimethylsilyl)methyl]cyclopropane (3a) were obtained using 1.1 equiv of TiCl(4), 0.54-0.65 equiv of Ti(O(i)Pr)(4), and 1.65 equiv of BINOL. The observed enantioselectivity was explained by consideration of the structure of the postulated intermediates, alkoxy titanium-carbonyl complexes, via ab initio MO calculations.

Asymmetric cyclopropanation reactions via iron carbene complexes having chirality at the carbene ligand

The reaction of Fp [(η5-C5H5)Fe(CO)2] anion (1) with chiral (+) or (−) o-anisaldehyde(tricarbonyl)chromium (2) in the presence of chlorotrimethylsilane produced the optically pure (+) or (−) bimetallic complex 4. Separate treatment of 4 at −78° C with trimethylsilyltriflate in the presence of styrene, followed by decomplexation with iodine, produced the corresponding cyclopropanes (101, cistrans). A 60% ee was indicated for the cis cyclopropanes.

Iron Lewis acid catalyzed reactions of phenyldiazomethane and olefins: Formation of cyclopropanes with very high cis selectivity

The iron Lewis acid, [(η 5-C 5H 5)Fe(CO) 2(THF)] + ( 1) catalyzes the cyclopropanation reaction of phenyldiazomethane with olefins to provide cis cyclopropanes in high selectivity.

A Practical and Efficient Synthesis of Fluorinated Pyrethroids. cis-3-(2-Chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylates

Abstract A practical and efficient route to fluorinated pyrethroids has been developed which involves the selective formation of the cis cyclopropane ring using intramolecular alkylation of the haloaldehyde and a novel transformation of the aldehydes to the corresponding esters via the cyanohydrins.

Stereoselective 1,3-debromination reactions

The metallate, PPN+Cr(CO)4NO−, was used for the 1,3-debrominative reductive cyclization of the (±) and meso isomers of dimethyl 2,4-dibromoglutarate and dimethyl 2,4-dibromo-2,4-dimethylglutarate. In both (±) isomers, the reaction is stereospecific in giving the trans cyclopropane product. In the meso case, the reaction is unselective in the first case, but distinctly favors the cis cyclopropane isomer in the second set of compounds. This (±) and meso pair thus represent the first example of near stereospecificity in the debrominations of both 1,3-dibromo diastereomers. Using an enantiomerically enriched dimethyl 2,4-dibromoglutarate, and determining the absolute stereochemistry of the cyclopropane product, it was found that a strict double inversion [Formula: see text] mechanism is involved in the (±) debromination reaction and presumably also in the near-stereospecific meso case reported above.

Fluorine-19 nuclear magnetic resonance studies of lipid fatty acyl chain order and dynamics in Acholeplasma laidlawii B membranes. A direct comparison of the effects of cis and trans cyclopropane ring and double-bond substituents on orientational order.

The hydrocarbon chain orientational order parameters of membranes of Acholeplasma laidlawii B, enriched with large quantities of fatty acids containing either a cis or a trans cyclopropane ring or a cis or trans double bond, plus small quantities of one of an isomeric series of monofluoropalmitic acids, were determined via fluorine-19 nuclear magnetic resonance spectroscopy over a range of temperatures spanning the corresponding gel to liquid-crystalline phase transitions (determined via differential scanning calorimetry). Membrane orientational order profiles in the liquid-crystalline state were generally similar, regardless of the particular fatty acid structure present, showing a region of relatively constant order preceding a region of progressively decreasing order toward the methyl terminus of the acyl chain. In the gel state, the order profiles in the presence of either a trans cyclopropane ring or trans double-bond substituent were similar and were characterized by a pronounced head to tail gradient of order at temperatures just below the lipid phase transition, while at temperatures far below the lipid phase transition this gradient was less pronounced, all chain positions showing a more uniformly high degree of orientational ordering. In the gel state, the order profiles in the presence of either a cis cyclopropane ring or a cis double-bond substituent were also similar but were highly unusual in that order first increased and only then subsequently decreased toward the acyl chain methyl terminus. In addition, the substituents in the cis configuration, whether a cyclopropane ring or a double bond, were overall more disordered in the gel state than the corresponding substituents in the trans configuration.(ABSTRACT TRUNCATED AT 250 WORDS)

Homo-1,4-addition of Grignard reagents to β-oxothiocarbonyl compounds cis cyclopropane ring closure.

Homo-1,4-addition of Grignard reagents to β-oxothiocarbonyl compounds cis cyclopropane ring closure.