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Reaction of Diels-Alder adducts of 1-bromo-2-bromomethylcyclopropene and either 1,3-dienes or furans with butyl lithium leads to a 1,3-dehalogenation to produce [4.1.1]propellanes. The oxygen bridged propellane derived from furan reacts with a second mol.equiv. of butyllithium by cleavage of the bridge with allylic rearrangement and the formation of a cis-3-butyl-[4.1.1]propell-4-en-2-ol. © 1997 Elsevier Science Ltd.

Mycolic acids (MAs) occur in the cell wall of Mycobacterium tuberculosis as variable mixtures of different classes and chain lengths. Here, we address the relationship between the structure and its inflammatory function of this virulence factor using single synthetic MA isomers, differing in oxygenation class and cis- versus α-methyl-trans proximal cyclopropane orientation. Analysis of bronchoalveolar inflammation, lung histopathology and alveolar macrophage transcription revealed a strong dependence on these meromycolic chemistries of mouse pulmonary inflammation in response to intratracheal treatments with MAs. Whereas α-MA was inert, oxygenated methoxy- and keto-MA with cis-cyclopropane stereochemistry elicited solid to mild inflammatory responses respectively. In trans-cyclopropane orientation, methoxy-MA partially lost its inflammatory activity and keto-MA exerted anti-inflammatory alternative activation of alveolar macrophages and counteracted cis-methoxy-MA induced airway inflammation. The differential innate immune activities of MAs demonstrated here, dependent on oxygenation class and cis versus α-methyl-trans cyclopropane chemistry, identify a novel means for M. tuberculosis to steer host immune responses during infection.

We report the syntheses of a single enantiomer of an unprotected ketomycolic acids containing a cis-cyclopropane and of related hydroxy-mycolic acids.

Reaction of 3-alkyl-1,2-dibromocyclopropenes with electron-rich or electron-poor alkenes in solution at 0 – 20 °C leads to cyclopropanes apparently derived by stereoselective trapping of a single isomer of a vinylcarbene; in the absence of an alkene, the cyclopropenes rearrange to alknes.

A 23-26-carbon chain length range of omega-19 (1'R,2'S) cyclopropane fatty acids, related to mycobacterial mycolic acids, has been prepared. The key cyclopropyl intermediate, (1'R,2'S)-(Z)-1-formyl-2-octadecylcyclopropane, underwent Wittig chemistry with various reagents to provide vinylic precursors, which were selectively reduced to the corresponding saturated omega-19 cyclopropane fatty acids or esters. The 24-carbon omega-19 cyclopropane ester was made by chain elongation of the 23-carbon ester. Saturated and unsaturated chiral cyclopropane acids and esters were assayed, using wall extracts of Mycobacterium smegmatis; the incorporation of 14C-acetate was used to measure inhibition or stimulation of mycolic acid synthesis. Minor inhibition (2-3%) was shown by the 23- and 24-carbon saturated esters; all the other compounds were stimulants. The most effective (38-55%) stimulators of mycolate synthesis were the unsaturated esters with 23- and 26-carbons and the saturated and unsaturated 25-carbon acids.

We report a synthesis of a single enantiomer of a dicyclopropane containing mycolic acid from Mycobacterium tuberculosis; this method can be simply varied to modify the chain lengths or the absolute stereochemistry of either cyclopropane.

The genes from the oxygenase cluster nagAaGHAbAcAd of naphthalene-degrading Ralstonia sp. strain U2 were cloned and overexpressed. Salicylate 5-hydroxylase (S5H) activity, converting salicylate to gentisate, was present in vitro only in the single extract of cells with overexpressed nagAaGHAb or in a mixture of three cell extracts containing, respectively, NagGH (the oxygenase components), NagAa (ferredoxin reductase), and NagAb (ferredoxin). Each of the three extracts required for S5H activity was rate limiting in the presence of excess of the others but, when in excess, did not affect the rate of catalysis. S5H catalyzed the 5-hydroxylation of the aromatic rings of 3- and 4-substituted salicylates. However, the methyl group of 5-methylsalicylate was hydroxylated to produce the 5-hydroxymethyl derivative and the 6-position on the ring of 5-chlorosalicylate was hydroxylated, producing 5-chloro-2,6-dihydroxybenzoate. In an assay for the nag naphthalene dioxygenase (NDO) based on the indole-linked oxidation of NADH, three extracts were essential for activity (NagAcAd, NagAa, and NagAb). NDO and S5H were assayed in the presence of all possible combinations of the nag proteins and the corresponding nah NDO proteins from the “classical” naphthalene degrader P. putida NCIMB9816. All three oxygenase components functioned with mixed combinations of the electron transport proteins from either strain. The S5H from strain U2 is a unique monooxygenase which shares sequence similarity with dioxygenases such as NDO but is also sufficiently similar in structure to interact with the same electron transport chain and probably does so in vivo during naphthalene catabolism in strain U2.

1,2-Dibromo-3-alkylcyclopropenes have been obtained by 1,2-debromination of 1,1,2,2-tetrabromocyclopropanes by reaction with 1 mol equiv. of methyllithium. They ring-open at ambient temperature and, in the presence of an electron-rich or electron-poor alkene, a cyclopropane is formed by apparent addition of an intermediate vinylcarbene; addition to (E)- and (Z)-but-2-enes occurs with retention of alkene relative stereochemistry, indicating that, in this case at least, the carbene is trapped as a singlet.

1,2-Dichloro-3,3-dimethylcyclopropene reacts with a number of nitrile oxides to produce oxazines in moderate to good yield in a reaction which apparently involves an unusual formal 3-centre plus 3-centre cycloaddition of the dipole to an intermediate vinylcarbene. In contrast, 1,2-dichloro-3-chloromethyl-3-methylcyclopropene undergoes a dipolar cycloaddition to produce a 2-oxa-3-azabicyclo[3.1.0]-hex-3-ene in which the 6-chloromethyl substituent occupies the endo-position.

Reaction of a number of halogenocyclopropenes with benzenesulfenyl chloride leads to 2-bromo-2-phenylthio-1 -methylenecyclopropanes

1,1-Dibromo-2-trialkylsilylcyclopropanes, readily prepared by dibromocyclopropanation of vinyltrialkylsilanes, react with methyllithium at –90 to 20 °C to give high yields of trialkylsilylcyclopropenes in which the silicon has apparently migrated to C-1.

1,2-Dehalogenation of tetrachlorocyclopropanes (5, X = Cl, OMe, NPri2, SAllyl) by methyl lithium leads to dichlorocyclopropenes (6, X = Cl, OMe, NPri2, SAllyl); the first two of these react with electron rich and electron poor alkenes at 20°C to give cyclopropanes which are apparently derived by trapping of vinylcarbenes (8) rather than (20). Reaction of the derived vinylcyclopropanes with base leads either to ethyl cyclopropyl ketones or to allylidenecyclopropanes.

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.

The cyclopropenes (6, X = CI, OMe, Ph) ring open at 0 - 20 °C to give vinylcarbenes (11) which are trapped in inter- or intramolecular reactions in preference to the isomers (10). The rate of cyclopropanation of 2,3-dimethylbut-2-ene in the presence of (15) correlates well with the aj constant of the 4-substituent, with a p-value of -0.79, suggesting the development of positive charge at C-3 in the transition state.

1, 2-Dehalogenation of tetrachlorocyclopropanes (2, X = Cl, OMe, NPr i 2 , Ph) and (4, X = OMe) by methyl lithium leads to dichlorocyclopropenes (3, X = Cl, OMe, NPr i 2 , Ph) and the carbene (6) respectively; in contrast, the dibromyclopropane (4, X = Cl) is converted to the cyclobutene (11) by a 1, 3-dehalogenation.

3-Benzyl-1,2-dichloro-3-methylcyclopropene undergoes an apparent cyclopropene to vinylcarbene rearrangement at 20 °C; one stereoisomer of the derived vinylcarbene is trapped selectively in either intra- or inter-molecular processes, and in the latter case trapping by addition to the alkene bond of methyl methacrylate leads to a cyclopropane with vinyl and ester groups cis-related. The stereochemistries of the products of both inter- and intea-molecular processes have been established by X-ray crystallography.

The publisher regrets that the author list of the above paper which appeared in Chemistry and Physics of Lipids, vol. 163, pp. 800–808 contained errors. The correct author list is published above. The publisher would like to apologise for any inconvenience this may have caused to the authors of this article and readers of the journal.