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« 2017 Chrysler Pacifica minivan EPA-rated at 28 mpg highway, 22 mpg combined; stop/start and PHEV still to come | Main | Rice study finds using natural gas for electricity and heating, not transportation, more effective in reducing GHGs » Channel NewsAsia recently reported on the case of a Tesla Model S owner in Singapore who, rather than receiving the Carbon Emissions-based Vehicle Scheme (CEVS) rebate he expected of S$15,000 (US$10,841) was hit with a CEVS surcharge of S$15,000 for having high carbon emissions. Under Singapore’s revised Carbon Emissions-Based Vehicle Scheme (CEVS), all new cars and imported used cars registered from 1 July 2015 with low carbon emissions of less than or equal to 135g CO /km qualify for rebates of between S$5,000 (US$3,614) and S$30,000 (US$21,681), which are offset against the vehicle’s Additional Registration Fee (ARF). Cars with high carbon emissions equal to or more than 186g CO /km incur a registration surcharge of between S$5,000 and S$30,000. The revised CEVS is applicable until 30 June 2017, after which it will be subject to further review. As Channel NewsAsia determined, Singapore’s Land Transport Authority (LTA), the agency responsible for planning, operating, and maintaining Singapore’s land transport infrastructure and systems, tested the Models S using United Nations Economic Commission for Europe (UNECE) R101 standards. The result was that the electric energy consumption of was 444 Wh/km. (This figure is approaching twice that of the US EPA’s estimate of 235.6 Wh/km (38 kWh/100 miles) for the Model S 90.) Singapore applies a grid emission factor of 0.5 g CO /Wh to all electric vehicles for CEVS analysis to account for CO emissions during the electricity generation process. As a result, the equivalent CO footprint of the Model S was 222g/km—placing it in the CEVS C3 surcharge band (216 to 230 g/km), along with, for example, the Lexus RX270 and the Maserati Ghibli. The LTA spokesperson said that the Tesla was not the first fully electric car where grid emission factor was applied. Others, however, qualified for the rebate. In the US, the fueleconomy.gov website, the official US government online source for fuel economy information, enables users to calculate the upstream GHG emissions from power generation based on location, for use in estimating the full carbon footprint of an EV. (The calculation for “Tailpipe & upstream GHG” is found under the “Energy and Environment” tab for individual vehicles. As an example, the same Model S with a 90 kWh pack would have a US average carbon footprint of 250 g/mile (155 g/km); 150 g/mile (96 g/km) in North County, San Diego; and 270 g/mile (167 g/km) in Henderson, KY, home to some of the most carbon-intense power generation in the US.


News Article | September 12, 2016
Site: http://www.chromatographytechniques.com/rss-feeds/all/rss.xml/all

Loss of megaherbivores such as elephants and hippos can allow woody plants and non-grassy herbs and flowering plants to encroach on grasslands in African national parks, according to a new University of Utah study, published Sept. 12 in Scientific Reports. The study used isotopes in hippopotamus teeth to find a shift in the diet of hippos over the course of a decade in Uganda's Queen Elizabeth National Park following widespread elephant poaching in the 1970s. Kendra Chritz, study first author and U postdoctoral scholar, says that her method of using hippo enamel isotopes could help scientists reconstruct past changes in vegetation in Africa's national parks, areas with relatively little ongoing scientific observation. The results could give ecologists an idea of what could happen to Africa's grasslands if elephants, whose populations are steeply declining, went extinct or reached near-extinction. "We have a window into what these environments could look like without megaherbivores, and it's kind of grim," Chritz says. Grasslands are an important ecosystem in Africa, hosting many animals and serving as corridors for wildlife movement. Lowland tropical grasses, such as those in elephant ecosystems, are part of the C4 class of plants, a reference to the enzyme used to process carbon dioxide into sugars during photosynthesis. Corn and sugarcane are also C4 plants. C3 plants, which use a different enzyme, include trees, shrubs, flowering plants and herbs. C3 plants compete for resources with C4 grasses in African savannas, including sunlight. Elephants and other megaherbivores help keep woody plant encroachment in check by browsing seasonally on shrubs and trees. But without that herbivore control, C3 plants can advance on grasslands unimpeded. The presence of shrubs and trees, which can be seen in aerial photographs, give only a partial picture of the balance of power between C3 and C4 plants. Observing herbs and flowering plants requires ground-level observation, and records of such observations in Uganda's Queen Elizabeth National Park, and many national parks in Africa, is sparse. The two plant groups' metabolic processes treat isotopes of carbon differently, so that C4 plants have a higher proportion of heavy carbon isotopes than C3 plants. As animals, such as hippos, eat plants, and the isotopic signatures of the plants in their diet are incorporated into the animals' bodies and preserved in durable tissue, such as teeth. The hippos of Queen Elizabeth National Park, Chritz found, had been indirectly "observing" the plant makeup of the grasslands all along. Queen Elizabeth National Park sits on the border between Uganda and the Democratic Republic of the Congo, and covers the channel that connects two lakes. In 1971, Idi Amin became president of Uganda, and management of the national parks essentially ceased. The Ugandan military killed thousands of elephants between 1971 and the mid-1980s, both to sell ivory to fund the regime and as food. Aggressive poaching continued after Amin's ouster, and by the mid-80s the park's elephant population had dropped from more than four thousand down to around 150. Around 4,000 hippos were poached as well. Studies showed increased areas of woody plants in the park once management resumed in the 1990s. Because the change happened over a span of a few decades, Queen Elizabeth National Park was an ideal ecosystem in which to test whether herbivore teeth could represent the shift from C4 to C3 plants. Hippo teeth are not easy to come by, Chritz says. The teeth haven't been used before for isotope analysis due to the difficulty of obtaining samples from a wide range of time periods. One of Chritz's co-authors, Hans Klingel of Universitaet Braunschweig in Germany, conducted important research on the behavior of hippos in Queen Elizabeth National Park in the 1980s and 90s. He contributed teeth from the 1960s, pre-poaching, and from 2000. Chritz and her colleagues sampled enamel every centimeter along the length of each tooth, using known growth rates to correlate sections of the tooth to different years. All of these samples taken together recorded diet history from approximately the last decade of the animal's life. But analysis showed that the two teeth displayed very different isotopic signatures. Chritz needed a third sample, in between the two time periods. While in Uganda in 2013, Chritz approached the current game warden about obtaining another hippo tooth. The warden showed her a skeleton on display at a park museum from a hippo that died in 1991 - perfectly within the time range Chritz had aimed for. Results showed that the 1960s hippo ate approximately 80 percent C4 plants, and that the percentage of C4 in the later hippos' diets had dropped to around 65 percent. This showed that, within a time scale of only a few decades, C3 plant encroachment had progressed enough to significantly impact the diets of the animals in the park. The results also showed the validity of Chritz's method and reconstructed the progression of vegetation changes since the 1960s. Another surprise in the results was the proportion of C3 plants in the later hippos' diets. Initial studies of hippo diets surmised that hippos only ate grass. "And few researchers have suggested otherwise," Chritz says. "It appears that they're actually quite flexible in their diets and adaptable to environmental change." The clear implication from Chritz's work is that the loss of elephants and other megaherbivores can lead to rapid environmental and ecological change. "We've built a record that shows just how drastic the loss of megaherbivores in a park can be on a very short timescale," she says. "Within ten years, we see a big change in what's happening in this once diverse grassy area of the park. This is a window into the future of what could to happen in East African savannas as elephants continue to be poached at the currently unprecedented rate." Chritz is hopeful that restoring elephant populations could reverse the changes and cause the grasslands to re-emerge. "But when you have too many elephants, they can also decimate forests by over-browsing," she says. "There's a balance you have to reach. The most important thing right now is to work hard at fighting poaching." People can combat poaching by reducing the demand and financial incentive for harvesting the elephants' tusks, Chritz says. "Not purchasing ivory and knowing which products you might use that are made from ivory is the best thing you can do to protect elephants."


News Article
Site: http://phys.org/biology-news/

Study first author and U postdoctoral scholar Kendra Chritz says that her method of using hippo enamel isotopes could help scientists reconstruct past changes in vegetation in Africa's national parks, areas with relatively little ongoing scientific observation. The results could give ecologists an idea of what could happen to Africa's grasslands if elephants, whose populations are steeply declining, went extinct or reached near-extinction. "We have a window into what these environments could look like without megaherbivores, and it's kind of grim," Chritz says. Grasslands are an important ecosystem in Africa, hosting many animals and serving as corridors for wildlife movement. Lowland tropical grasses, such as those in elephant ecosystems, are part of the C4 class of plants, a reference to the enzyme used to process carbon dioxide into sugars during photosynthesis. Corn and sugarcane are also C4 plants. C3 plants, which use a different enzyme, include trees, shrubs, flowering plants and herbs. C3 plants compete for resources with C4 grasses in African savannas, including sunlight. Elephants and other megaherbivores help keep woody plant encroachment in check by browsing seasonally on shrubs and trees. But without that herbivore control, C3 plants can advance on grasslands unimpeded. The presence of shrubs and trees, which can be seen in aerial photographs, give only a partial picture of the balance of power between C3 and C4 plants. Observing herbs and flowering plants requires ground-level observation, and records of such observations in Uganda's Queen Elizabeth National Park, and many national parks in Africa, is sparse. The two plant groups' metabolic processes treat isotopes of carbon differently, so that C4 plants have a higher proportion of heavy carbon isotopes than C3 plants. As animals, such as hippos, eat plants, and the isotopic signatures of the plants in their diet are incorporated into the animals' bodies and preserved in durable tissue, such as teeth. The hippos of Queen Elizabeth National Park, Chritz found, had been indirectly "observing" the plant makeup of the grasslands all along. Queen Elizabeth National Park sits on the border between Uganda and the Democratic Republic of the Congo, and covers the channel that connects two lakes. In 1971, Idi Amin became president of Uganda, and management of the national parks essentially ceased. The Ugandan military killed thousands of elephants between 1971 and the mid-1980s, both to sell ivory to fund the regime and as food. Aggressive poaching continued after Amin's ouster, and by the mid-80s the park's elephant population had dropped from more than four thousand down to around 150. Around 4,000 hippos were poached as well. Studies showed increased areas of woody plants in the park once management resumed in the 1990s. Because the change happened over a span of a few decades, Queen Elizabeth National Park was an ideal ecosystem in which to test whether herbivore teeth could represent the shift from C4 to C3 plants. Getting and testing the teeth Hippo teeth are not easy to come by, Chritz says. The teeth haven't been used before for isotope analysis due to the difficulty of obtaining samples from a wide range of time periods. One of Chritz's co-authors, Hans Klingel of Universitaet Braunschweig in Germany, conducted important research on the behavior of hippos in Queen Elizabeth National Park in the 1980s and 90s. He contributed teeth from the 1960s, pre-poaching, and from 2000. Chritz and her colleagues sampled enamel every centimeter along the length of each tooth, using known growth rates to correlate sections of the tooth to different years. All of these samples taken together recorded diet history from approximately the last decade of the animal's life. But analysis showed that the two teeth displayed very different isotopic signatures. Chritz needed a third sample, in between the two time periods. While in Uganda in 2013, Chritz approached the current game warden about obtaining another hippo tooth. The warden showed her a skeleton on display at a park museum from a hippo that died in 1991 - perfectly within the time range Chritz had aimed for. (Hear more about the retrieval of the tooth and about sampling it in adverse conditions in the attached sound file). Results showed that the 1960s hippo ate approximately 80 percent C4 plants, and that the percentage of C4 in the later hippos' diets had dropped to around 65 percent. This showed that, within a time scale of only a few decades, C3 plant encroachment had progressed enough to significantly impact the diets of the animals in the park. The results also showed the validity of Chritz's method and reconstructed the progression of vegetation changes since the 1960s. Another surprise in the results was the proportion of C3 plants in the later hippos' diets. Initial studies of hippo diets surmised that hippos only ate grass. "And few researchers have suggested otherwise," Chritz says. "It appears that they're actually quite flexible in their diets and adaptable to environmental change." The clear implication from Chritz's work is that the loss of elephants and other megaherbivores can lead to rapid environmental and ecological change. "We've built a record that shows just how drastic the loss of megaherbivores in a park can be on a very short timescale," she says. "Within ten years, we see a big change in what's happening in this once diverse grassy area of the park. This is a window into the future of what could to happen in East African savannas as elephants continue to be poached at the currently unprecedented rate." Chritz is hopeful that restoring elephant populations could reverse the changes and cause the grasslands to re-emerge. "But when you have too many elephants, they can also decimate forests by over-browsing," she says. "There's a balance you have to reach. The most important thing right now is to work hard at fighting poaching." People can combat poaching by reducing the demand and financial incentive for harvesting the elephants' tusks, Chritz says. "Not purchasing ivory and knowing which products you might use that are made from ivory is the best thing you can do to protect elephants." Explore further: When African animals hit the hay: Fossil teeth show who ate what and when as grasses emerged


« Fleet of 150 Renault ZOE EVs for smart solar charging project | Main | Kawasaki Heavy and Shell to partner on technologies for transporting liquefied hydrogen by sea » US Transportation Secretary Anthony Foxx, joined by Barbara Bennett, President and COO of Paul G. Allen’s Vulcan Inc. and Rick Clemmer CEO of NXP Semiconductors, announced the seven finalists for the US Department of Transportation’s (USDOT) Smart City Challenge. (Earlier post.) The USDOT has pledged up to $40 million (funding subject to future appropriations) to one city to help it define what it means to be a “Smart City “and become the country’s first city to fully integrate innovative technologies—self-driving cars, connected vehicles, and smart sensors—into their transportation network. The finalists are: Austin, TX; Columbus, OH; Denver, CO; Kansas City, MO; Pittsburgh, PA; Portland, OR; and San Francisco, CA. Secretary Foxx was joined by representatives of the seven city finalists, including Austin Mayor Steve Adler, Columbus Mayor Andrew Ginther, Kansas City Mayor Sly James, Pittsburgh Mayor Bill Peduto, and Portland Mayor Charlie Hales for the announcement at the C3 Connected Mobility Showcase being held during the South by Southwest conference (SXSW). When the challenge was issued in December 2015, the Department’s launch partner, Paul G. Allen’s Vulcan Inc., announced its intent to award up to $10 million to the winning city to support electric vehicle deployment and other carbon emission reduction strategies. In this second phase of the competition, the seven finalists will receive a $100,000 grant to further develop their proposals. Whereas the first phase called for a high-level overview, the winning city will be selected based on their ability to “think big”, and provide a detailed roadmap on how they will integrate innovative technologies to prototype the future of transportation in their city. The Department will work with each city to connect them with existing partnerships and support their final proposal with technical assistance. In addition to announcing the seven finalists, Secretary Foxx also announced a new Smart City Challenge partnership with Amazon Web Services (AWS), a secure cloud services platform, which will provide solution architecture and best practices guidance to the finalists to help them leverage AWS services for Smart City solutions, as well as award $1 Million of credits to the Challenge winner for AWS Cloud services and AWS Professional Services. Furthermore, AWS will collaborate with US DOT on efforts to engage the startup community, and bring their ideas to the finalists. The credits, support, and collaboration will help the winning city design and build a Smart City on the AWS Cloud. Other partners that have already joined the Smart City Challenge include: The Department developed the Smart City Challenge as a response to the trends identified in the Beyond Traffic draft report. The report, issued last year, revealed that the US’ aging infrastructure is not equipped to deal with a significantly growing population in regions throughout the country. It also identified a need to increase mobility options in developing mega-regions—specifically mid-sized cities. The winning city will be announced in June 2016.


News Article
Site: http://www.nature.com/nature/current_issue/

Tigliane diterpenes have been viewed as promising leads in many different medicinal applications including immunomodulatory9, anti-viral10 and anti-cancer11 applications. The most progressed compound in this class of natural products is phorbol 12-myristate 13-acetate, which is currently in phase II clinical trials for treatment of acute myeloid leukaemia. Subtle perturbations of their structures can have a marked effect on their biological profiles, perhaps as a result of differing protein kinase C subtype selectivity9, 10. As such, phorbol esters and related terpenes have been a focus of natural products research1. Our interest in this family stemmed from the anti-cancer effects of certain phorbol analogues whose access was limited. Numerous eudesmane family members have previously been accessed in a concise way via a strategy for the chemical synthesis of complex terpenes that follows the underlying logic of biosynthesis2. This strategy has subsequently been successfully applied to germacrenes3, complex taxanes4, 5 and ingenanes6, 7, 8. In particular, the two-phase synthesis of (–)-ingenol (2, Fig. 1) is only 14 steps from (+)-3-carene (6) and has enabled access to a variety of analogues that were not accessible by any other means6, 7, 8. Because ingenanes (4) and tiglianes (3) are closely related in nature, we hypothesized that intermediate 5, which is available in quantities of more than 100 g, might serve as an ideal starting point for a short route to 1. The execution of this plan depended on the invention of a simple solution to the challenge of incorporating the C12 and C13 oxygen atoms of 1; the difficulty in installing this functionality is well known in the field of organic chemistry. So far, only two total syntheses12, 13, 14 and two formal syntheses15, 16 of 1 have been reported in 40–52 steps (see Supplementary Information for a summary)12, 13, 14, 15, 16. In these studies, an α-oxygenated enone was prepared from a ketone and subsequently cyclopropanated to build in the C13 oxidation via a six-step sequence. Many other efforts towards 1 have also been reported17, 18 (for a full listing of the 36 papers in this area, see Supplementary Information). The route described in refs 17 and 18 is particularly instructive and illustrates the inherent challenge of using (+)-3-carene (6) as a starting material to (+)-phorbol (1): 38 steps were required to reach a phorbol analogue lacking the C11 methyl and C13 oxygen from 6 (refs 17, 18). (Here we define a reaction step as one in which a substrate is converted to a product in a single reaction flask (irrespective of the number of transformations) without intermediate workup or purification.) Our studies, outlined below, culminated in a two-phase, 19-step synthesis of 1 that solves these problems in a concise way. The synthesis commenced with intermediate 5 (Fig. 2), provided in large quantities using a previously described route6. Installation of the C4 oxygen was accomplished using a Mukaiyama hydration and in situ silyl group installation to furnish 7 in 70% yield (gram scale). At this juncture, we pursued installation of the C12 oxygen atom, which required the selective oxidation of a methylene position in the presence of an enone, six tertiary C–H bonds and two other competing methylene sites. To choose the proper oxidant for this transformation, we analysed the structure computationally (Fig. 3a) and by inference of innate reactivity using NMR (Fig. 3b). Thus, we predicted the pseudo-equatorial C–H bond at C12 to be the most reactive on the basis of the following considerations19: (1) steric shielding of the C6, C7, C8 and C11 positions would decrease their rate of oxidation; (2) the higher s-character of the tertiary cyclopropane C–H bonds (C13/14) makes them very difficult to oxidize; (3) of the remaining carbon centres, 13C NMR indicated that C12 is the most ‘nucleophilic’; (4) hyperconjugation from the π-like cyclopropane system should facilitate oxidation of the pseudo-equatorial C–H bond on C12; and (5) strain-release might, to a small extent, accelerate such an oxidation20. Therefore, we chose the small, reactive, electrophilic oxidant methyl(trifluoromethyl)dioxirane (TFDO), owing to its straightforward preparation and success in other challenging methylene oxidations21. As predicted, TFDO cleanly achieved C–H oxidation at C12 to deliver the intermediate cyclopropyl carbinol intermediate 8 (single diastereomer), which could be isolated and fully characterized on a gram scale. In practice, however, it was directly treated in the same flask with MgI /ZnI to elicit a dehydrative ring opening22 to furnish diene 9 along with unreacted enone 7. We did not observe the anticipated tertiary iodide product, presumably owing to rapid elimination to form a diene system. The mixture of 7 and 9 was directly subjected to another Mukaiyama hydration to furnish the tertiary carbinol 10 in 34% isolated yield from 7 along with 62% recovered 7. The addition of PPh to this type of reaction has not previously been reported and was found to be essential to prevent the reactive intermediate peroxide adduct from generating an unwanted by-product (see Supplementary Information for details). With the cyclopropane ruptured, the next step was to install the C12/13 oxygenation pattern along with reclosure of the cyclopropane. This manoeuvre has no precedent, and needed to be accomplished rapidly and in a scalable fashion. To this end, chemoselective oxidation of the C12/13 olefin to diketone 11 took place in near quantitative yield using Ru/NaBrO . To reform the gem-dimethylcyclopropane moiety and access the correct oxidation state, a two-electron reduction of the diketone to an enediol would need to take place followed by intramolecular cyclization. Whereas attempts at acetylation of the hindered tertiary alcohol were fruitless and mesylation led to rapid elimination (as with the putative iodide intermediate in 8 → 9), treatment with trifluoroacetic anhydride smoothly led to an intermediate trifluoroacetate. This ester could be treated in the same flask with Zn to deliver an intermediate (12) whose structure was confirmed with the aid of X-ray crystallography. Although the desired reduction took place, it was accompanied by the formation of an additional, unwanted and bizarre C–C bond between C13 and the carbonyl group of the trifluoroester. Although aldol additions of enediols to aldehydes23 and ketones24 are known, there is no precedent for such reactivity with esters. We reasoned that this product originated from a highly reactive enediol intermediate (such as A; R = H) that might be regenerated under equilibrating conditions. In support of this hypothesis was the empirical observation that conversion of 11 to 12 initially resulted in the formation of an approximately 1:1 mixture of 12 along with an isomeric species tentatively assigned as the diastereomeric aldol adduct. Over 24 h this mixture equilibrated to 12 exclusively, perhaps owing to stabilizing intramolecular hydrogen bonding interactions. We evaluated various sets of conditions with the aim of reintroducing the enediol (retro aldol) in the hope that concomitant irreversible cyclopropane formation (via attack at C15) would take place. However, treatment of 12 with catalytic Sc(OTf) in DMF led instead to the cyclobutanone 13. Although clearly undesired, this was encouraging because 13 must have been derived from the desired hydroxy-cyclopropane B via a 1,2-shift, which in turn was produced via the enediol intermediate A (R = H). Indeed, the formation of cyclobutanones such as 13 from hydroxycyclopropanes has a precedent25. To circumvent this undesired pathway, intermediate 12 was converted to hemiorthoester 14 by simple treatment with Ac O followed by exposure to Et N and gentle heating to 60 °C to deliver 15. The single flask conversion of 11 to 15 can be conducted on a gram scale, and presumably succeeds owing to the in situ formation of intermediate A (R = Ac), which prevents 1,2-shift after cyclopropanation. We believe that the conversion of A to the desired cyclopropane is concerted because no elimination products were observed (see above). This reaction cascade consists of thirteen discreet events occurring in the same flask, forming two new C–C bonds, three new ring systems and three C–O bonds, along with the cleavage of one C–C bond, two ring systems and two C–O bonds. It unravels a complex polycyclic network to a kinetic endpoint using simple reagents thereby overcoming the greatest challenge posed by 1. The final eight steps of the synthesis served to install two additional oxygen atoms, one methyl group and the proper C12 and C10 stereochemistry. Attempts to install the key C10 stereocentre by way of conjugate reduction were met with failure despite extensive experimentation (see Supplementary Information for details). Thus, to achieve allylic transposition of 15, the weakest point of the synthesis from an efficiency standpoint, we used TsNHNH under reductive conditions, which led to 16 in 40% yield. Allylic oxidation with CrO (ref. 26) delivered enone 17 in 46% yield. A two-step methyl group introduction was accomplished by formation of an α-iodoenone (TMSN , I )27 followed by a Stille coupling28, which afforded 18 in 64% overall yield along with 33% recovered 17. Selective removal of the C7 and C9 silyl groups with the HF ⋅ pyridine complex led to a diol that could be selectively dehydrated using the Martin Sulfurane reagent to an unstable olefin that was directly oxidized using SeO to aldehyde 19 in 51% overall yield. The selective cleavage of the C7 and C9 silyl groups could stem from the inductive effect of the C3 carbonyl group, which could make the C4 silyl group less reactive to acids. X-ray crystallographic analysis of 19 confirmed the structural assignments made thus far. To complete the synthesis, 19 was reduced to the allylic alcohol and shielded as the acetate ester. Attempts to directly reduce the C20 aldehyde and the C12 ketone in 19 were unsuccessful, owing to the rapid rate of the C3 enone carbonyl reduction in the presence of the C20 free primary alcohol (the C20 hydroxy group is actually proximate to C3 as judged by molecular models). Stereoselective ketone reduction using NaBH(OAc) followed by successive treatment with fluoride and hydroxide sources (TBAF and Ba(OH) , respectively) led to optically pure (+)-1 (synthetic, [α]26 105.37 (c 0.23, CH OH); natural, [α]27 104.25 (c 0.20, CH OH)) in 72% isolated yield (15 mg prepared by this route). The concise route to 1 is enabled by a fundamentally different retrosynthetic approach to terpene synthesis in the laboratory, rather than by focusing on the invention of a new synthetic method; the newest method used in this synthesis is a Stille coupling, invented in the 1980’s28. Although the development of new synthetic methodologies are necessary to push the field of organic chemistry forward, this work emphasizes the equal importance of strategy design in the total synthesis of complex natural products29. By holistically mimicking the biosynthesis of ingenol (2) in the laboratory6, 7, we exploited the interrelationship between ingenanes and tiglianes by using the same building block for both synthetic routes. Because two-phase terpene synthesis builds the carbon skeleton with a strategically planned redox state, the majority of steps can focus on installing key oxidations rather than repositioning functional groups and C–C bonds. Access to phorbol (1) requires only five additional steps compared to ingenol (2), owing to the presence of two additional oxygen atoms (C12/13) placed at particularly challenging locations on the carbon skeleton. Successful installation of these oxygenations and two others directly or indirectly relied on the application of C–H functionalization logic to pinpoint both the location and sequence of reactions19, 30. This artificial oxidase phase will enable the synthesis of analogues containing deep-seated modifications in the same fashion that has recently been reported for ingenol (2)8. Although the route, in its current concise form, cannot compete with isolation for the procurement of large quantities of phorbol (1), we argue that it could be adapted to become truly scalable if the need arose. Rather, the purpose of this synthesis is to enable rapid access to new tigliane family members with exciting bioactivity that are either difficult or impossible to access through isolation or semisynthesis.

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