Colibactin represents an as-yet uncharacterized genotoxic secondary metabolite produced by human gut bacteria. Here we report the biosynthetic discovery of two new precolibactin molecules from Escherichia coli, including precolibactin-886 that uniquely incorporates the highly sought genotoxicity-associated aminomalonate building block in its unprecedented macrocyclic structure. This work provides new insights into the biosynthetic logic and mode of action of this colorectal cancer-linked microbial chemical.

Monoterpenes, a major class of biogenic volatile organic compounds, are known to produce oxidation products that further react with sulfate to form organosulfates. The accurate quantification of monoterpene-derived organosulfates (OSs) is necessary for quantifying this controllable aerosol source; however, it has been hampered by a lack of authentic standards. Here we report a unified synthesis strategy starting from the respective monoterpene through Upjohn dihydroxylation or Sharpless asymmetric dihydroxylation followed by monosulfation with the sulfur trioxide-pyridine complex. We demonstrate the successful synthesis of four monoterpene-derived OS compounds, including α-pinene OS, β-pinene OS, limonene OS, and limonaketone OS. Quantification of OSs is commonly achieved using liquid chromatography-mass spectrometry (LC-MS) by either monitoring the [M-H] ion or through multiple reaction monitoring (MRM) of mass transitions between the [M-H] and m/z 97 ions. Comparison between the synthesized standards and previously adopted quantification surrogates reveals that camphor-10-sulfonic acid is a better quantification surrogate using [M-H] as the quantification ion, while the highly compound-specific nature of MRM quantification makes it difficult to choose a suitable surrogate. Both could be rationalized in accordance to their respective MS quantification mechanisms. The in-house availability of the authentic standards enables us to discover that β-pinene OS, due to the sulfate group at the primary carbon, partially degrades to a dehydrogenated OS compound during LC/MS analysis and a hydroperoxy OS over a prolonged storage period (>5 month) and forms a regioisomer through intermolecular isomerization. Limonene OS was positively identified for the first time in ambient samples and found to be more abundant than α-/β-pinene OS in the Pearl River Delta, China. This work highlights the critical importance of having authentic standards in advancing our understanding of the interactions between biogenic VOC emissions and anthropogenic sulfur pollution.

Oxidation of indoles is a fundamental organic transformation to deliver a variety of synthetically and pharmaceutically valuable nitrogen-containing compounds. Prior methods require the use of either organic oxidants (meta-chloroperoxybenzoic acid, N-bromosuccinimide, t-BuOCl) or stoichiometric toxic transition metals [Pb(OAc)4, OsO4, CrO3], which produced oxidant-derived by-products that are harmful to human health, pollute the environment and entail immediate purification. A general catalysis protocol using safer oxidants (H2O2, oxone, O2) is highly desirable. Herein, we report a unified, efficient halide catalysis for three oxidation reactions of indoles using oxone as the terminal oxidant, namely oxidative rearrangement of tetrahydro-β-carbolines, indole oxidation to 2-oxindoles, and Witkop oxidation. This halide catalysis protocol represents a general, green oxidation method and is expected to be used widely due to several advantageous aspects including waste prevention, less hazardous chemical synthesis, and sustainable halide catalysis.

Reported is a new green protocol for the efficient in situ generation of nitrile oxides through NaCl/ Oxone oxidation of aldoximes and their dipolar cycloaddition.The key feature is the use of a green chemistry approach to address the substrate scope of aldoximes: broad scope (aliphatic, aromatic, and alkenyl aldoximes) without production of organic byproducts derived from oxidant and/or catalyst. Importantly, NaCl/Oxone-promoted three-component cycloaddition of aldehyde, hydroxylamine hydrochloride, and alkene was demonstrated to be competent (63−81%).

Organosulfates (OSs) derived from biogenic volatile organic compounds are important compounds signifying interactions between anthropogenic sulfur pollution and natural emission. In this work, we substantially expand the OS standard library through the chemical synthesis of 26 α-hydroxy OS standards from eight monoterpenes (i.e., α- and β-pinene, limonene, sabinene, Δ3-carene, terpinolene, and α- and γ-terpinene) and two sesquiterpenes (i.e., α-humulene and β-caryophyllene). The sulfation of unsymmetrically substituted 1,2-diol intermediates produced a regioisomeric mixture of two OSs. The major regioisomeric OSs were isolated and purified for full NMR characterization, while the minor regioisomers could only be determined by liquid chromatograph–mass spectrometer (MS). The tandem mass spectra of the molecular ion formed through electrospray ionization confirmed the formation of abundant bisulfate ion fragments (m/z 97) and certain minor ion fragments characteristic of the carbon backbone. A knowledge of the MS/MS spectra and chromatographic retention times for authentic standards allows us to identify α-hydroxy OSs derived from six monoterpenes and β-caryophyllene in ambient samples. Notably, among two possible regioisomers of α-hydroxy OSs, we only detected the isomers with the sulfate group at the less substituted carbon position derived from α-pinene, limonene, sabinene, Δ3-carene, and terpinolene in the ambient samples. This observation sheds light on the atmospheric OS formation mechanisms.

Union of Type II Anion Relay Chemistry (ARC) with Pd-induced Cross Coupling Reactions (CCR) has been achieved, in conjunction with the design, synthesis, and evaluation of a new class of bifunctional linchpins, comprising a series of vinyl silanes bearing β-or γ-electrophilic sites. The synthetic tactic permits both alkylation and Pd-mediated CCR of the anions derived via 1,4-silyl C (sp 2 )→O Brook Rearrangements.Type I and II Anion Relay Chemistry (ARC), 1 exploiting Brook Rearrangements (Scheme 1A and 1B), 2 comprises a powerful linchpin tactic for the rapid assembly of high levels of molecular complexity, as demanded by natural product total synthesis. Extension of the Type II ARC process (Scheme 1B) to include transition metal promoted Cross-Coupling Reactions (CCR), as the culminating event in the Type II ARC process (cf. 8→9) would, in general, greatly extend the scope of this evolving synthetic tactic. Recently, we recorded a single example employing ortho-TMS benzaldehyde 10 as linchpin that demonstrated the feasibility of uniting Anion Relay Chemistry with Pd-mediated cross coupling (Scheme 2). 3 The reaction sequence involved treatment of 10 with n-BuLi followed in turn by addition of CuI and HMPA to induce 1,4-silyl C(sp 2 )→O migration, vinyl bromide with a catalytic amount of Pd(PPh 3 ) 4 for the CCR, and TBAF to remove the TMS group; tricomponent adduct 10a was produced in 56% yield.Convinced that this "one-flask" multicomponent protocol would hold considerable potential, in general, we initiated a program to unite Anion Relay Chemistry with the cross coupling tactic. We quickly recognized, as reported by Takeda et al. 4 for ortho-TMS benzyl alcohol, that the use of CuI, and in our case a mixture of HMPA and THF (1:1), is required to trigger the 1,4-Brook rearrangement. Towards this end, addition of n-BuLi to 10, followed by CuI/ HMPA:THF induced silyl migration. the presence of 3 mol % Pd(PPh 3 ) 4 in THF at room temperature then, led to a series of cross coupled adducts (10a-10h) with yields ranging from 50-67% (Table 1).Having established the initial scope of the combined ARC-II/Pd-mediated CCR protocol, we turned to the design, synthesis and evaluation of a new class of bifunctional vinyl silanes, with electrophilic sites β or γ to the silane (Figure 1), first to explore their utility as linchpins for the Type II ARC tactic and then as linchpins in the combined ARC-II/Pd-mediated CCR process.Linchpin 11 was readily available via oxidation of known alcohol 17, 5 while 12 was prepared from epoxide 18 6 and commercial vinyl bromide 19 (Scheme 3).To explore the ARC tactic with 11, we selected conditions that proved effective with 10. 3 As illustrated in Table 2, addition of n-BuLi in Et 2 O, followed by CuI (1.2 equiv) in a mixture of HMPA/THF (1:1), and then a variety of carbon-and heteroatom-based electrophiles furnished adducts 21a-21d in 63-68% yield. Under these conditions, the 1,4 silyl migration proceeded rapidly (ca. 30 min). Equally important, palladium-mediated cross coupling rea...

The discovery of iron(ii) bromide and cerium(iii) bromide as a bifunctional catalyst enables the oxidative rearrangement of indoles with hydrogen peroxide as the terminal oxidant.

An environmentally friendly protocol for halocyclization of tryptamine/tryptophol derivatives was developed and demonstrated with 28 examples and synthesis of protubonines.