Asymmetric synthesis of gonytolide A: strategic use of an aryl halide blocking group for oxidative coupling

The first synthesis of the chromanone lactone dimer gonytolide A has been achieved employing vanadium(V)-mediated oxidative coupling of the monomer gonytolide C. An o-bromine blocking group strategy was employed to favor para- para coupling and to enable kinetic resolution of (±)-gonytolide C. Asymmetric conjugate reduction enabled practical kinetic resolution of a chiral, racemic precursor and the asymmetric synthesis of (+)-gonytolide A and its atropisomer.We thank the National Institutes of Health (R35 GM-118173) for research support. Work at the BU-CMD is supported by NIH R24 Grant GM-111625. We thank Prof. Scott Miller and Dr. Anthony Metrano (Yale University) for helpful discussions and preliminary experiments. We thank the Uehara Memorial Foundation for a postdoctoral fellowship to T.I., the American Cancer Society for a postdoctoral fellowship to K.D.R. (PF-16-235-01-CDD), Dr. Jeffrey Bacon (Boston University) for X-ray crystal structure analyses, and Prof. Haruhisa Kikuchi (Tohoku University) for providing a natural sample of gonytolide A. NMR (CHE-0619339) and MS (CHE-0443618) facilities at Boston University are supported by the NSF. (R35 GM-118173 - National Institutes of Health; GM-111625 - NIH; Uehara Memorial Foundation; PF-16-235-01-CDD - American Cancer Society; CHE-0619339 - NSF; CHE-0443618 - NSF

Enantioselective Total Synthesis of Macfarlandin C, a Spongian Diterpenoid Harboring a Concave-Substituted cis-Dioxabicyclo[3.3.0]octanone Fragment.

The enantioselective total synthesis of the rearranged spongian diterpenoid (-)-macfarlandin C is reported. This is the first synthesis of a rearranged spongian diterpenoid in which the bulky hydrocarbon fragment is joined via a quaternary carbon to the highly hindered concave face of the cis-2,8-dioxabicyclo[3.3.0]octan-3-one moiety. The strategy involves a late-stage fragment coupling between a tertiary carbon radical and an electrophilic butenolide resulting in the stereoselective formation of vicinal quaternary and tertiary stereocenters. A stereoselective Mukaiyama hydration that orients a pendant carboxymethyl side chain cis to the bulky octahydronapthalene substituent was pivotal in fashioning the challenging concave-substituted cis-dioxabicyclo[3.3.0]octanone fragment

Butenolide from plant-derived smoke functions as a strigolactone analogue: Evidence from parasitic weed seed germination

AbstractThe main germination active compound in smoke, 3-methyl-2H-furo[2,3-c]pyran-2-one (butenolide), has structural similarities with strigolactones that function as germination stimulants for root parasitic plants such as Orobanche spp. and Striga spp. (Scrophulariaceae). Consequently, we tested whether butenolide also functions as a germination stimulant for parasitic weeds. Butenolide stimulated germination of both Orobanche minor and Striga hermonthica to similar levels as the synthetic strigol analogue GR24 and was effective at similar concentrations (10−5 to 10−11 M). Both butenolide and GR24 were more effective than the synthetic strigol analogue Nijmegan-1. Across eight further Orobanche spp., and for species from the root parasitic genera Cistanche, Conopholis and Lathraea, butenolide also had a similar level of activity to GR24. These results suggest that the germination stimulatory activity of butenolide may result from analogy with strigolactones

Acute Toxicity of the Antifouling Compound Butenolide in Non-Target Organisms

Butenolide [5-octylfuran-2(5H)-one] is a recently discovered and very promising anti-marine-fouling compound. In this study, the acute toxicity of butenolide was assessed in several non-target organisms, including micro algae, crustaceans, and fish. Results were compared with previously reported results on the effective concentrations used on fouling (target) organisms. According to OECD's guideline, the predicted no effect concentration (PNEC) was 0.168 µg l−1, which was among one of the highest in representative new biocides. Mechanistically, the phenotype of butenolide-treated Danio rerio (zebrafish) embryos was similar to the phenotype of the pro-caspase-3 over-expression mutant with pericardial edema, small eyes, small brains, and increased numbers of apoptotic cells in the bodies of zebrafish embryos. Butenolide also induced apoptosis in HeLa cells, with the activation of c-Jun N-terminal kinases (JNK), Bcl-2 family proteins, and caspases and proteasomes/lysosomes involved in this process. This is the first detailed toxicity and toxicology study on this antifouling compound

Combined nutritional stress and a new systemic pesticide (flupyradifurone, Sivanto®) reduce bee survival, food consumption, flight success, and thermoregulation.

Flupyradifurone (FPF, Sivanto®) is a new butenolide insecticide that, like the neonicotinoids, is a systemic nicotinic acetylcholine receptor (nAChR) agonist. However, FPF is considered bee-safe (according to standard Risk Assessment tests), and is thus a potential solution to the adverse effects of other pesticides on beneficial insects. To date, no studies have examined the impact of nutritional stress (decreased food diversity and quality) and FPF exposure on bee health although both stressors can occur, especially around agricultural monocultures. We therefore tested the effects of a field-realistic FPF concentration (4 ppm, FPFdaily dose = 241 ± 4 ng/bee/day, 1/12 of LD50) and nutritional stress (nectar with low-sugar concentrations) on honey bee (Apis mellifera L.) mortality, food consumption, thermoregulation, flight success (unsuccessful vs. successful), and flight ability (duration, distance, velocity). Flight and thermoregulation are critical to colony health: bees fly to collect food and reproduce, and they thermoregulate to increase flight efficiency and to rear brood. We studied the effects across seasons because seasonality can influence bee sensitivity to environmental stress. We demonstrate that, depending upon season and nutritional stress, FPF can reduce bee survival (-14%), food consumption (-14%), thermoregulation (-4%, i.e. hypothermia), flight success (-19%), and increase flight velocity (+13%). Because pesticide exposure and nutritional stress can co-occur, we suggest that future studies and pesticide risk assessments consider both seasonality and nutritional stress when evaluating pesticide safety for bees

Synthetic Studies of 2-Acetoxyfuran and 2(3H)-Furanone as Pronucleophiles in the Asymmetric Synthesis of Butenolides

Enantioselective synthesis of γ-substituted butenolides is desirable due to the prevalence of these functionalities in medicinally important natural products. As organic synthons, butenolides contain four carbon atoms, each of which is capable of undergoing regioselective modification. Two complementary approaches for the construction of γ-substituted butenolides have been developed in the present work. The trapped dienolate, 2-acetoxyfuran, couples with aldehydes under mild conditions with diastereocontrol determined by the nature of catalyst, solvent, and temperature employed.An even more efficient synthesis of the butenolide architecture has been developed by the direct coupling of 2(3H)-furanone to aldehydes. Enantioselectivity is afforded by use of Takemoto\u27s bifunctional thiourea catalysts. The simplicityand versatility of these reactions demonstrate the strong potential that the pronucleophiles 2-acetoxyfuran and 2(3H)-furanone offer for the synthesis of γ-butenolides

Investigation into the Synthesis of Bioactive Butenolides

Previous research done on coprophi lous fungi has revealed the presence of secondary metabolites containing butenol ides sub-structures. These butenol ides show activity against the yeast Candida albicans. In efforts to further these investigations, the synthesis of butenol ide analogs was undertaken. The starting materials, 2-methylacryl ic acid and 1-penten-3-ol, were esterified in the presence of triethyl amine to form an ester, pent-1-en-3-yl-2-methylprop-2-enoate. The formation of ester was confirmed using 13C- NMR. The ester was then subjected to ring-closing metathesis in the presence of Grubb\u27 s catalyst. The formation of the butenol ide was also confirmed using 13C-NMR. The product, 5-ethyl-3-methyl-2-(5H)-furanone obtained from this step has been purified using column chromatography. The butenol ide bioassay was done to test its activity agains

A Labdane Diterpene from Enicosanthum congregatum

A labdane diterpene was isolated from the air-dried leaves of Enicosanthum congregatum. The structure has been established as 8,I6-dihydroxy-ent-Iabd-13en- 15-oic lactone on the basis of spectroscopic data