Sharon Chow

Hydrolytic kinetic resolution of terminal mono- and bis-epoxides in the synthesis of insect pheromones: routes to (-)-(R)- and (+)-(S)-10-methyldodecyl acetate, (-)-(R)-10-methyl-2-tridecanone, (-)-(R)-(Z)-undec-6-en-2-ol (nostrenol), (-)-(1R, 7R)-1,7-dimethylnonyl propanoate, (-)-(6R, 12R)-6,12-dimethylpentadecan-2-one, (-)-(2S, 11S)-2,11-diacetoxytridecane and (+)-(2S, 12S)-2,12-diacetoxytridecane

Hydrolytic kinetic resolution (HKR) of functionalised epoxides using (salen)Co(OAc) complexes provides enantiomerically enriched epoxides and diols, which have been transformed into important insect sex pheromones. In this general approach, (-)-(R)- and (+)-(S)-10-methyldodecyl acetates from the smaller tea tortrix moth were obtained, as was (-)-(R)-10-methyltridecan-2-one from the southern corn rootworm. The (S)-epoxide obtained from undec-1-en-6-yne was transformed to (-)-(R)-(Z)-undec-6-en-2-ol (Nostrenol) from ant-lions. HKR of appropriate bisepoxides was also investigated, and transformations of the resulting bisepoxides and epoxydiols provided (-)-(1R,7R)-1,7-dimethylnonylpropanoate from corn rootworms, (-)-(6R,12R)-6,12-dimethylpentadecan-2-one from the female banded cucumber beetle, and (-)-(2S,11S)-2,11-diacetoxytridecane and (+)-(2S,12S)-2,12-diacetoxytridecane from female pea-midges

Synthesis of the Sponge-Derived Plakortone Series of Bioactive Compounds

The Caribbean sponges of the genus Plakortis, P. halichondrioides, and P. simplex have provided a series of biologically active furanolactones-the plakortones A-D (1-4) from the former sponge and B-F (2-6) from the latter. The defining motif of the plakortones is a sterically congested 2,6-dioxabicyclo[3.3.0]octan-3-one moiety, the emblematic furanolactone core. This core is efficiently accessed by a palladium(II) mediated hydroxycyclization-carbonylation-lactonization cascade with an appropriate ene-1,3-diol. Total syntheses of plakortones C (3) and F (6) are now described which settle constitutional and stereochemical features in this group of secondary metabolites. Acquisition of plakortone D (4), the most effective activator of SR-Ca(2+)-pumping ATPase, utilized stereodefined lactone cores that resulted from asymmetric dihydroxylation of protected homoallylic alcohol 29. A derived lactone aldehyde was then coupled with an independently generated, sulfone-activated side chain unit, 57. The 11,12-E-double bond, carried through the sequence as a protected, stereodefined diol, was released therefrom by stereospecific syn-elimination via an orthoester derivative. In this way, plakortone D (4) was demonstrated to possess the (3S,4S,6S,10R,11E) configuration. Racemic plakortone E (5) was also acquired by using the Pd(II) induced sequence, but in this case, the required, complete acyclic system 52 was assembled first. Plakortone C (3) resulted from a sequence commencing with (R)-(+)-3-hydroxy-2-methylpropionate, with a derived iodide 76 alkylating the enolate of the butyramide 77 generated from (1S,2S)-(+)-pseudoephedrine. The liberated primary alcohol 79 was converted by standard procedures to key enediol 89 which, with the Pd(II) protocol, afforded the major separable plakortones 90 and 91, with the former being identical with natural plakortone C (3). Very mild hydrogenation of 90 afforded a saturated plakortone, identical with natural plakortone F (6), thus establishing its structure and absolute stereochemistry. Available information on the stereoselective routes to plakortones E (5) and B (2) are also outlined, so that the constitution and absolute stereochemistry of plakortones B-F are now established.

Determining a synthetic approach to pierisformaside C

An efficient route detailing the construction of the central core of pierisformaside C, the first grayanane-type diterpene to possess three central double bonds, is reported.

Analysis of daphnane orthoesters in poisonous Australian pimelea species by liquid chromatography-tandem mass spectrometry.

Cattle grazing in arid rangelands of Australia suffer periodic extensive and serious poisoning by the plant species Pimelea trichostachya, P. simplex, and P. elongata. Pimelea poisoning (also known as St. George disease and Marree disease) has been attributed to the presence of the diterpenoid orthoester simplexin in these species. However, literature relating to previous studies is complicated by taxonomic revisions, and the presence of simplexin has not previously been verified in all currently recognized taxa capable of inducing pimelea poisoning syndrome, with no previous chemical studies of P. trichostachya (as currently classified) or P. simplex subsp. continua. We report here the isolation of simplexin from P. trichostachya and the development of a liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method to measure simplexin concentrations in pimelea plant material. Simplexin was quantified by positive-ion atmospheric pressure chemical ionization (APCI) LC-MS/MS with selected reaction monitoring (SRM) of the m/z 533.3 > 253.3 transition. LC-MS/MS analysis of the four poisonous taxa P. trichostachya, P. elongata, P. simplex subsp. continua, and P. simplex subsp. simplex showed similar profiles with simplexin as the major diterpenoid ester component in all four taxa accompanied by varying amounts of related orthoesters. Similar analyses of P. decora, P. haematostachya, and P. microcephala also demonstrated the presence of simplexin in these species but at far lower concentrations, consistent with the limited reports of stock poisoning associated with these species. The less common, shrubby species P. penicillaris contained simplexin at up to 55 mg/kg dry weight and would be expected to cause poisoning if animals consumed sufficient plant material.

Substrate analog studies of the ω-regiospecificity of Mycobacterium tuberculosis cholesterol metabolizing cytochrome P450 enzymes CYP124A1, CYP125A1 and CYP142A1

We report the synthesis and evaluation of a series of cholesterol side-chain analogs as mechanistic probes of three important Mycobacterium tuberculosis cytochrome P450 enzymes that selectively oxidize the ω-position of the methyl-branched cholesterol side-chain. To probe the structural requirements for the thermodynamically disfavored ω-regiospecificity we compared the binding of these substrate analogs to each P450, determined the turnover rates, and characterized the enzymatic products. The results are discussed in the context of the structure-activity relationships of the enzymes and how their active sites enforce ω-oxidation.

Pimelotides A and B, diterpenoid ketal-lactone orthoesters with an unprecedented skeleton from Pimelea elongata.

A detailed investigation of the minor phytochemical components of Pimelea elongata foliage led to the discovery of two new diterpenoid daphnane ketal-lactone orthoesters with an unprecedented skeleton, pimelotides A (1) and B (2). Their structures and relative configurations were elucidated by NMR spectroscopy.

Concerning the Proposed Structure of (+)-Laurobtusol: Spectral Discrepancies with Synthetic, Racemic Stereoisomers

Laurobtusol, a minor metabolite from Laurencia obtusa, had been assigned constitution 1 and relative stereochemistry, 2. However, several stereoisomers of this novel, cyclopropane-containing system 1 have now been synthesized and spectral correspondence between the synthesized isomers and laurobtusol is lacking.

Effect of Increasing Low-Dose Simplexin Exposure in Cattle Consuming Pimelea trichostachya

Pimelea species (or desert riceflower) are small native plants endemic to the drier inland pastoral regions of Australia, which cause a unique syndrome in grazing cattle characterized by submandibular edema and edema in the brisket area as a result of right-sided heart failure attributed to the toxin simplexin, 1. Field evidence suggests that poisoning can occur through minor, inadvertent consumption of Pimelea plant material, but the minimum simplexin intake required to induce Pimelea poisoning is not known. In this study, mild Pimelea poisoning was induced at a daily dose of 12.5 mg Pimelea/kg body weight per day, equivalent to 2.5 μg simplexin/kg body weight per day, demonstrating the high potential toxicity of these plant species. Effects in all animals diminished with prolonged low-dose feeding, and it is postulated that these animals developed mechanisms for detoxifying simplexin, 1, possibly through rumen microbial adaptation or activation of liver enzymes.

Direct Observation of an Oxepin from a Bacterial Cytochrome P450 Catalyzed Oxidation

The cytochromes P450 are hemoproteins that catalyze a range of oxidative C-H functionalization reactions, including aliphatic and aromatic hydroxylation. These transformations are important in a range of biological contexts, including biosynthesis and xenobiotic biodegradation. Much work has been carried out on the mechanism of aliphatic hydroxylation, implicating hydrogen atom abstraction, but aromatic hydroxylation is postulated to proceed differently. One mechanism invokes as the key intermediate an arene oxide (and/or its oxepin tautomer). Conclusive isolation of this intermediate has remained elusive and, currently, direct formation of phenols from a Meisenheimer intermediate is believed to be favored. We report here the identification of a P450 [P450cam (CYP101A1) and P450cin (CYP176A1)]-generated arene oxide as a product of in vitro oxidation of tert-butylbenzene. Computations (CBS-QB3) predict that the arene oxide and oxepin have similar stabilities to other arene oxides/oxepins implicated (but not detected) in P450-mediated transformations, suggesting that arene oxides can be unstable terminal products of P450-catalyzed aromatic oxidation that can explain the origin of some observed metabolites.

sp-sp(3) Coupling reactions of alkynylsilver cations, RC (equivalent to) CAg2+ (R = Me and Ph) with allyliodide

Alkynylsilver cations, RC≡CAg2(+) (where R = Me and Ph) have been prepared in the gas phase using multistage mass spectrometry experiments in a quadrupole ion trap mass spectrometer. Two methods were used: (i) electrospray ionisation (ESI) of a mixture of AgNO3 (in MeOH/H2O/acetic acid) and the alkyne carboxylic acid to yield the appropriate silver acetylide cations RC≡CAg2(+), via a facile decarboxylation of the RC≡CCO2Ag2(+) precursor; (ii) ESI of silver acetylides, RC≡CAg, which yields a cluster of the type, [(RC≡CAg)12Ag2Cl](+). Regardless of the method of preparation, these alkynylsilver cations, RC≡CAg2(+), undergo ion-molecule reactions with allyliodide to yield the ionic products Ag2I(+) and [(RC≡CCH2CH=CH2)Ag](+). The CID spectrum of [(PhC≡CCH2CH=CH2)Ag](+) was compared to that of an authentic sample of the silver adduct of 5-phenyl-1-penten-4-yne. Both ions fragment to yield Ag(+) and the radical cation, PhC≡CCH2CH=CH2(+)˙, confirming that C-C bond coupling has taken place in the gas phase. DFT calculations were carried out on these C-C bond coupling reactions for the system R = Me. The reaction is highly exothermic and involves the initial coordination of the allyliodide to both silver atoms, with the iodine coordinating to one atom and the alkene moiety coordinating to the other. The overall mechanism of C-C bond coupling involves oxidative addition of the allyliodide followed by reductive elimination of RC≡CCH2CH=CH2, to ultimately yield two sets of reaction products: (i) Ag2I(+) and RC≡CCH2CH=CH2; and (ii) [(RC≡CCH2CH=CH2)Ag](+) and AgI.