An Efficient Strategy for the Synthesis of α,α′-cis and trans-Disubstituted Medium Ring Ethers

An asymmetric alkylation-ring-closing metathesis strat-egy was developed for the construction of a,a'-disubstituted medi-um ring ethers. The approach features an asymmetric alkylation of highly functionalized a-alkoxy acyl oxazolidinones followed by ring closure effected by Grubbs' ruthenium catalyst. The relation-ship between diene conformation and the rate of ring-closure was examined. Medium ring ethers are a common structural feature of many ladder ether marine toxins, as well as simpler me-tabolites from Laurencia species. This diverse collection of natural products often contains seven, eight, and nine membered ring ethers. 1 The challenge of efficient con-struction of medium ring ethers has led to the develop-ment of numerous strategies for their synthesis. 2-5 The vast majority of these approaches have focused on the a,a'-cis-disubstitution pattern rather than a,a'-trans-di-substituted medium ring ethers, despite their similar fre-quency of occurrence. trans-Isoprelaurefucin (1), 6 isolau-refucin methyl ether (2), 7 chlorofucin (3), 8 bromofucin (4), 9 isolaureatin (5), 10 and obtusenyne (6), 8 for example, all contain a,a'-trans-disubstituted medium ring ethers (Figure 1). Murai's synthesis of obtusenyne (6) 11 and our own recent syntheses of prelaureatin and laurallene 12 con-stitute the only known syntheses of medium ring ether natural products with the a,a'-trans-disubstitution ar-rangement. The investigation of a versatile, general strat-egy for the synthesis of both a,a'-cis and a,a'-trans-disubstituted medium ring ethers is described here. We recently published a total synthesis of the marine nat-ural product (+)-laurencin (9), in which the key steps were an asymmetric alkylation of the sodium enolate of substi-tuted acyl oxazolidinone 7, followed by ring-closing met-athesis of the resultant diene to give cyclic ether 8 (Scheme 1). 2 Previous work in our laboratory has demon-strated that an asymmetric aldol-ring-closing metathesis strategy for the assembly of medium ring ethers was equally adaptable to both the a,a'-cis and a,a'-trans-di-substituted medium ring ethers. 3,12 The asymmetric alky-lation-ring-closing metathesis approach to cyclic ethers also offered the potential for a similar adaptable strategy

From principles to action: Applying the National Research Council's principles for effective decision support to the Federal Emergency Management Agency's watch office

AbstractThe National Research Council (NRC) proposed six principles for effective decision support in its 2009 report Informing Decisions in a Changing Climate. We structured a collaborative project between the Federal Emergency Management Agency Region R9 (FEMA R9), the Western Region Headquarters of the National Weather Service (WR-NWS), and the Climate Assessment of the Southwest (CLIMAS) at the University of Arizona around the application of the NRC principles. The goal of the project was to provide FEMA R9's Watch Office with climate information scaled to their temporal and spatial interests to aid them in assessing the potential risk of flood disasters. We found that we needed specific strategies and activities in order to apply the principles effectively. By using a set of established collaborative research approaches we were better able to assess FEMA R9's information needs and WR-NWS's capacity to meet those needs. Despite our diligent planning of engagement strategies, we still encountered some barriers to transitioning our decision support tool from research to operations. This paper describes our methods for planning and executing a three-party collaborative effort to provide climate services, the decision support tool developed through this process, and the lessons we will take from this deliberate collaborative process to our future work and implications of the NRC principles for the broader field of climate services

Enantioselective Total Synthesis of Spirofungins A and B

The enantioselective total synthesis of spirofungins A (1) and B (2) is reported in 14 steps over the longest linear sequence. Key steps include the use of thiazolidinethione mediated aldol reactions to assemble the major fragments and installation of the C1–C6 side chain using a cross metathesis reaction

Synthesis of (-)-Mucocin

An enantioselective total synthesis of (−)-mucocin has been completed. A combination of asymmetric glycolate aldol additions and ring closing metathesis reactions were exploited to construct the C18−C34 and C7−C17 fragments. A selective cross-metathesis reaction was employed as the key step to couple two complex fragments

Formal Synthesis of (+)-Sorangicin A

The formal synthesis of (+)-sorangicin A was completed by two independent routes. Both approaches feature a cross metathesis reaction to form the C29-C30 bond to arrive at the bicyclic ether/tetrahydropyran fragment. Formation of the C15-C16 olefin to unite the dihydropyran fragment with the rest of the molecule was achieved by either a cross metathesis reaction or a Julia-Kocienski olefination

Synthesis of the Bis-tetrahydropyran Core of Amphidinol 3

A convergent synthesis of the C31-C52 bis-tetrahydropyran core of the natural product amphidinol 3 is reported. A common intermediate was synthesized from D-tartaric acid utilizing an asymmetric glycolate alkylation/ring-closing metathesis sequence to construct the THP rings. Differential elaboration of the common intermediate allowed the synthesis of two distinct coupling partners which were joined through a modified Horner-Wadsworth-Emmons olefination to provide the bis-tetrahydropyran core

Inflammatory Gene Variants in the Tsimane, An Indigenous Bolivian Population With a High Infectious Load

The Tsimane of lowland Bolivia are an indigenous forager-farmer population living under conditions resembling pre-industrial European populations, with high infectious morbidity, high infection and inflammation, and shortened life expectancy. Analysis of 917 persons ages 5 to 60+ showed that allele frequencies of 9 SNPs examined in the apolipoprotein E (apoE), C-reactive protein (CRP), and interleukin-6 (IL-6) genes differed from some European, African, and north Asian-derived populations. The apoE2 allele was absent, whereas four SNPs related to CRP and IL-6 were monomorphic: CRP (rs1800947, rs3093061, and rs3093062) and IL-6 (rs1800795). No significant differences in apoE, CRP, and IL-6 variants across age were found CRP levels were higher in carriers of two CRP proinflammatory SNPs, whereas they were lower in carriers of apoE4. Taken together, the evidence for (1) different allele frequencies between the Tsimane and other populations and (2) the correlations of CRP and apoE alleles with blood CRP may suggest that these variants are under selection in response to a high infection environment

Data aggregation, ML ready datasets, and an API: leveraging diverse data to create enhanced characterizations of monsoon flood risk

Monsoon precipitation and severe flooding is highly variable and often unpredictable, with a range of flood conditions and impacts across metropolitan regions or a county. County and storm specific watches or warnings issued by the National Weather Service (NWS) alert the public to current flood conditions and risks, but floods are not limited to the area that is under alert and these zones can be relatively coarse depending on the data these warnings are based on. Research done by the Arizona Institute for Resilient Environments and Societies (AIRES) has produced an Application Programming Interface (API) accessible data warehouse of time series precipitation totals across the state of Arizona which consists of higher resolution geographically disperse data that helped create improved characterizations of monsoon precipitation variability. There is an opportunity to leverage these data to address flood risk particularly where advanced Computer Science methodologies and Machine Learning techniques may offer additional spatial and temporal insight into flood events. This can be especially useful during rainfall events where precipitation station reporting frequencies are increased and near real-time totals are accessible via the AIRES API. A Machine-Learning-ready dataset structured to train ML models facilitates an anticipatory approach to predicting/characterizing flood risk. This presents an opportunity for new inputs into management and decision making opportunities, in addition to describing precipitation and flood patterns after an event. In this paper we will be the first to make use of the AIRES API by taking the initial step of the Machine Learning process and assembling the precipitation data into a ML-ready dataset. We then look closer at the dataset assembled and call attention to characteristics of the dataset that can be further explored through machine learning processes. Finally, we will summarize future directions for research and climate services using this dataset and API

Enantioselective Total Synthesis of Brevetoxin A: Unified Strategy for the B, E, G, and J Subunits

Brevetoxin A is a decacyclic ladder toxin that possesses five-,six-, seven-, eight-, and nine-membered oxacycles, as well as 22 tetrahedral stereocenters. Herein, we describe a unified approach to the B, E, G, and J rings predicated upon a ring-closing metathesis strategy from the corresponding dienes. The enolate technologies developed in our laboratory allowed access to the precursor acyclic dienes for the B, E, and G medium ring ethers. The strategies developed for the syntheses of these four monocycles ultimately provided multigram quantities of each of the rings, supporting our efforts toward the convergent completion of brevetoxin A

Total Synthesis of Brevetoxin A

A total synthesis of brevetoxin A is reported. Two tetracyclic coupling partners, prepared from previously reported advanced fragments, were effectively united via a Horner—Wittig olefination. The resulting octacycle was progressed to substrates that were explored for reductive etherification, the success of which led to a penultimate tetraol intermediate. The tetraol was converted to the natural product through an expeditious selective oxidative process, followed by methylenation