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Synthesis of the thioester segment. Reagents and conditions: (a) K2CO3 (1.5 eq), MeI (1.5 eq), N,N-dimethylformamide (DMF), 22 °C, 20 h, 99%. (b) MeMgBr (1.05 eq), 0 °C, 10 min; then HMPA (2.0 eq), triethylamine (Et3N; 1.5 eq), chlorotrimethylsilane (TMSCl; 1.5 eq), tetrahydrofuran (THF), 22 °C, 10 min, 94%. (c) EtMgBr (1.5 eq), THF, 50 °C, 1 h; then CS2 (30 eq), 70 °C, 3 h; then MeI (4.0 eq), 22 °C, 8 h, 67%. (d) DMP (1.2 eq), methylene chloride (CH2Cl2), 22 °C, 1 min, 83%. (e) MeONa (10.0 eq), methanol (MeOH), 50 °C, 4 h, 66%.
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Clostrubin is a potent antibiotic against methicillin- and vancomycin-resistant bacteria that was isolated from a strictly anaerobic bacterium Clostridium beijerinckii in 2014. This polyphenol possesses a fully substituted arene moiety on its pentacyclic scaffold, which poses a considerable challenge for chemical synthesis. Here we report the first...
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Cycloaddition reactions between a menthone-based chiral nitrone and alkenes or alkynes under microwave activation afforded a series of enantiopure cycloadducts in good yields and with high stereoselectivity. Removal of the chiral auxiliary under acid-catalysis led to a new series of isoxazolidines and isoxazolines with the control of one, two or th...
Citations
... Solventogenic Clostridium species produce secondary metabolites in addition to ABE. For example, C. beijerinckii produces antibiotic clostrubin, which is active against methicillin-and vancomycin-resistant bacteria [105]. ...
Solventogenic Clostridium species are important for establishing the sustainable industrial bioproduction of fuels and important chemicals such as acetone and butanol. The inherent versatility of these species in substrate utilization and the range of solvents produced during acetone butanol–ethanol (ABE) fermentation make solventogenic Clostridium an attractive choice for biotechnological applications such as the production of fuels and chemicals. The functional qualities of these microbes have thus been identified to be related to complex regulatory networks that play essential roles in modulating the metabolism of this group of bacteria. Yet, solventogenic Clostridium species still struggle to consistently achieve butanol concentrations exceeding 20 g/L in batch fermentation, primarily due to the toxic effects of butanol on the culture. Genomes of solventogenic Clostridium species have a relatively greater prevalence of genes that are intricately controlled by various regulatory molecules than most other species. Consequently, the use of genetic or metabolic engineering strategies that do not consider the underlying regulatory mechanisms will not be effective. Several regulatory factors involved in substrate uptake/utilization, sporulation, solvent production, and stress responses (Carbon Catabolite Protein A, Spo0A, AbrB, Rex, CsrA) have been identified and characterized. In this review, the focus is on newly identified regulatory factors in solventogenic Clostridium species, the interaction of these factors with previously identified molecules, and potential implications for substrate utilization, solvent production, and resistance/tolerance to lignocellulose-derived microbial inhibitory compounds. Taken together, this review is anticipated to highlight the challenges impeding the re-industrialization of ABE fermentation, and inspire researchers to generate innovative strategies for overcoming these obstacles.
... Solventogenic Clostridium species produce secondary metabolites in addition to ABE. For 14 example, C. beijerinckii produce antibiotic clostrubin, which is active against methicillin-and vancomycin-resistant bacteria (Yang et al., 2015). ...
Solventogenic Clostridium species are important for establishing sustainable industrial bioproduction of fuels and important chemicals. The inherent versatility of these species in substrate utilization and the range of solvents produced during acetone butanol-ethanol (ABE) fermentation make solventogenic Clostridium an attractive choice for biotechnological applications such as production of fuels and chemicals. The functional qualities of these microbes have thus been identified to be due to complex regulatory networks that play essential roles in modulating the metabolism of this group of bacteria. Genomes of solventogenic Clostridium species have relatively greater prevalence of genes that are intricately controlled by various regulatory molecules than most other species. Consequently, the use of genetic or metabolic engineering strategies that do not consider the underlying regulatory mechanisms will not be effective. Several regulatory factors involved in substrate uptake/utilization, sporulation, solvent production, and stress responses (Carbon Catabolite Protein A, Spo0A, AbrB, Rex, CsrA) have been identified and characterized. In this review, the focus is on newly identified regulatory factors in solventogenic Clostridium species, the interaction of these factors with previously identified molecules, and potential implications on substrate utilization, solvent production, and resistance/tolerance to lignocellulose-derived microbial inhibitory compounds.
... 12,13 Consequently, there has been extensive research into methods to suppress dendrite formation effectively and, thus, improve the safety and cyclic stability of lithium metal batteries. Examples of these methods include (i) the introduction of a 3D current collector [14][15][16] and a 3D host matrix (scaffold) [17][18][19] having a large specic surface area for lithium deposition, which suppresses volume expansion and reduces the local current density; (ii) the in situ formation of ideal SEIs by optimising the electrolyte 20,21 and the inclusion of additives; [22][23][24] (iii) the formation of uniform Li + -ion ow by modifying the inorganic/ organic particles on the separator; 25,26 and (iv) the physical suppression of dendrite growth by enhancing the mechanical strength of the thin lm by coating with an inorganic/organic solid electrolyte 27,28 or a ceramic thin lm. 8,[29][30][31][32][33] In particular, the introduction of an ex situ protective lm on metallic lithium, that is, the introduction of an articial SEI, is a particularly useful method 34 because undesirable side reactions between metallic lithium and the electrolyte, as well as dendrite growth, can be suppressed. ...
Lithium formed dense and smooth two-dimensional lithium clusters on the Al 2 O 3 film, while needle-like lithium grew three-dimensionally on the bare Cu electrode. This leads to superior coulombic efficiency and cycling behaviour.
... [25,26] Interestingly, a few reported examples indicated that the formation of Rh-carbenoids with Rh 2 (OAc) 4 facilitates challenging Barton-Kellogg olefinations. [27][28][29][30] Related to the formation of the thiirane intermediate, an analogous Rh 2 (OAc) 4 -catalyzed epoxidation was reported by Doyle and co-workers (Figure 1 F). [31] Motivated by our interest in catalyst control over higherorder stereogenicity and the addressability of specific states of halted molecular motors, [32,33] we thus considered the feasibility of stereocontrol with the chiral dirhodium tetracarboxylate catalysts designed by the Davies group. ...
Overcrowded alkenes are expeditiously prepared by the versatile Barton–Kellogg olefination and have remarkable applications as functional molecules owing to their unique stereochemical features. The induced stereodynamics thereby enable the controlled motion of molecular switches and motors, while the high configurational stability prevents undesired isomeric scrambling. Bistricyclic aromatic enes are prototypical overcrowded alkenes with outstanding stereochemical properties, but their stereocontrolled preparation was thus far only feasible in stereospecific reactions and with chiral auxiliaries. Herein we report that direct catalyst control is achieved by a stereoselective Barton–Kellogg olefination with enantio‐ and diastereocontrol for various bistricyclic aromatic enes. Using Rh2(S‐PTAD)4 as catalyst, several diazo compounds were selectively coupled with a thioketone to give one of the four anti‐folded overcrowded alkene stereoisomers upon reduction. Complete stereodivergence was reached by catalyst control in combination with distinct thiirane reductions to provide all four stereoisomers with e.r. values of up to 99:1. We envision that this strategy will enable the synthesis of topologically unique overcrowded alkenes for functional materials, catalysis, energy‐ and electron transfer, and bioactive compounds.
... Additionally, Brassard's, Danishefsky's and other related dienes remain particularly useful building blocks for the synthesis of a,b-unsaturated cyclohexenones, which are readily converted into phenols by oxidation using oxygen, 2,3dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), etc. For example, Li and co-workers 35 reported that the reaction of dibromobenzoquinone 2 with diene 1 and subsequent dehydrobromination gave the northern anthraquinone fragment 3 of clostrubin (5) on a multi-gram scale (Scheme 3). The natural product was shown to have strong antibiotic activities with minimum inhibition concentrations (MIC's) at 0.12 mmol L 71 against methicillin-resistant Staphylococcus aureus and 0.97 mmol L 71 against vancomycin-resistant enterocci. ...
... Yang and co-workers reported similar reactivity of a 1,8-dimethoxyanthraquinone with benzylmagnesium bromide as an obstacle during their total synthesis of clostrubin. 17 In the case of anthraquinone 7, we suspect that the steric bulk of the MOM groups is countered by their ability to direct addition of lithioanthracene 10 to C9. This issue was addressed by the use of the noncoordinating tert-butyldimethylsilyl (TBDMS) protecting group in 8. 18 Treatment of 8 with anthryllithium 10 afforded only one regioisomer, adduct 13. ...
The first approaches to the 10'-anthronyl-2-anthraquinone skeleton have been devised, allowing two syntheses of the marine natural product albopunctatone. Both routes involve regioselective addition of a nucleophilic masked anthraquinone to a protected chrysazin derivative; the best affords albopunctatone in five steps and 35% overall yield. Albopunctatone exhibits potent inhibitory activity against Plasmodium falciparum and negligible toxicity to a range of other microbial pathogens and mammalian cells.
Acremolactone B is a pyridine‐containing azaphilone‐type polyketide. The first total synthesis of this molecule was achieved on a gram scale, based on an aza‐6π electrocyclization–aromatization strategy for construction of the tetra‐substituted pyridine ring. A bicyclic intermediate was expeditiously prepared by using [2+2] photocycloaddition and chemoselective Baeyer–Villiger oxidation, which was further elaborated to a densely substituted aza‐triene. An electrocyclization–aromatization cascade was utilized to forge the tetracyclic core of this natural product, and the side chain was introduced through diastereoselective acylation and reduction.
The genus Clostridium is a large and diverse group within the Bacillota (formerly Firmicutes), whose members can encode useful complex traits such as solvent production, gas-fermentation, and lignocellulose breakdown. We describe 270 genome sequences of solventogenic clostridia from a comprehensive industrial strain collection assembled by Professor David Jones that includes 194 C. beijerinckii, 57 C. saccharobutylicum, 4 C. saccharoperbutylacetonicum, 5 C. butyricum, 7 C. acetobutylicum, and 3 C. tetanomorphum genomes. We report methods, analyses and characterization for phylogeny, key attributes, core biosynthetic genes, secondary metabolites, plasmids, prophage/CRISPR diversity, cellulosomes and quorum sensing for the 6 species. The expanded genomic data described here will facilitate engineering of solvent-producing clostridia as well as non-model microorganisms with innately desirable traits. Sequences could be applied in conventional platform biocatalysts such as yeast or Escherichia coli for enhanced chemical production. Recently, gene sequences from this collection were used to engineer Clostridium autoethanogenum, a gas-fermenting autotrophic acetogen, for continuous acetone or isopropanol production, as well as butanol, butanoic acid, hexanol and hexanoic acid production.
Cytochrome P450 (CYP450)‐catalyzed oxidative coupling is an efficient strategy for using simple building blocks to construct complex structural scaffolds of natural products. Among them, heterodimeric coupling between two different monomers is relatively scarce, and the corresponding CYP450s are largely undiscovered. In this study, we discovered a fungal CYP450 (CpsD) and its associated cps cluster from 37208 CYP450s of Pfam PF00067 family member database and subsequently identified a group of new skeleton indole piperazine alkaloids (campesines A−G) by combination of genome mining and heterologous synthesis. Importantly, CYP450 CpsD mainly catalyzes intermolecular oxidative heterocoupling of two different indole piperazine monomers to generate an unexpected 6/5/6/6/6/6/5/6 eight‐ring scaffold through the formation of one C−C bond and two C−N bonds, illuminating its first dimerase role in this family of natural products. The proposed catalytic mechanism of CpsD was deeply investigated by diversified substrate derivatization. Moreover, dimeric campesine G shows good insecticidal activity against the global honeybee pest Galleria mellonella . Our study shows a representative example of discovering new skeleton monomeric and dimeric indole piperazine alkaloids from microbial resources, expands our knowledge of bond formation by CYP450s and supports further development of the newly discovered and engineered campesine family compounds as potential biopesticides.
