Bent π-Conjugation within a Macrocycle: Asymmetric Total Syntheses of Spirohexenolides A and B.

Macrocycles with bent π-conjugation motif are extremely rare in nature and synthetically daunting and anticancer haouamines and spirohexenolides were representative of such rare natural products with synthetically challenging bent π-conjugation within a macrocycle. While the total synthesis of haouamines has been elegantly achieved, spirohexenolides remains an unmet synthetic challenge due to the highly strained bent 1,3,5-triene conjugation within C15 macrocycle. Inspired by the chemical synthesis of cycloparaphenylenes (CPPs) and haouamines, herein we devise a synthetic strategy to overcome the highly strained bent 1,3,5-triene conjugation within the macrocycle and achieve the first, asymmetric total synthesis of spirohexenolides A (>20 mg) and B (>50 mg). Our synthesis features strategic design of ring-closing metathesis (RCM) macrocyclization followed by double dehydration to achieve the C15 macrocycle with the deformed nonplanar 1,3,5-triene conjugation. In addition, we have developed a new enantioselective construction of highly functionalized spirotetronate fragment (northeast moiety) through RCM and Ireland-Claisen rearrangement. Our in vitro bioassay studies reveal that both spirohexenolides are cytotoxic against a panel of human cancer cells with IC50 1.2-13.3 µM and spirohexenolide A is consistently more potent (up to 3 times) than spirohexenolide B, suggesting the importance of alcohol for their bioactivity and for medicinal chemistry development.

Achmatowicz Rearrangement-Inspired Development of Green Chemistry, Organic Methodology, and Total Synthesis of Natural Products.

The six-membered heterocycles containing oxygen and nitrogen (tetrahydropyrans, pyrans, piperidines) are among the most common heterocyclic structures ubiquitously present in bioactive molecules such as carbohydrates, small-molecule drugs, and natural products. Chemical synthesis of fully functionalized pyrans and piperidines is a research theme of practical importance and scientific significance and, thus, has attracted continuous interest from synthetic chemists. Among the numerous synthetic approaches, Achmatowicz rearrangement (AchR) represents a general and unique strategy that uses biomass-derived furfuryl alcohols as the renewable starting material to obtain fully functionalized six-membered oxygen/nitrogen heterocycles, which provides golden opportunities for organic chemists to address various synthetic challenges.This Account summarizes our 10 years of work on exploiting AchR to address some challenges in organic synthesis ranging from green chemistry and organic methodology to the total synthesis of natural products. We enabled the sustainable and safe use of AchR in a small (academia) or large (industrial) scale by developing two generations of green approaches for AchR (oxone-halide and Fenton-halide), which largely eliminate the use of the most popular, but more toxic and expansive, NBS and m-CPBA. This triggered our intensive interest in developing new green chemistry for important organic reactions, in particular, halogenation/oxidation reactions involving reactive halogenating species with the aim of eliminating the use of commonly used toxic halogen agents such as elemental bromine, chlorine gas, and various N-haloamide reagents (NBS, NCS, and NIS). We successfully employed oxone-halide and Fenton-halide as green alternatives to several mechanistically related organic reactions including arene/alkene halogenation, oxidation or oxidative rearrangement of indoles, oxidation of alcohols/thioacetals, and oxidative halogenation of aldoximes for the in situ generation of nitrile oxide. These green reactions are expected to have a solid impact on the future of organic synthesis in academia and industries.We expanded the synthetic utility of AchR by exploring several new transformations of AchR products and developed a cascade reductive ring expansion, reductive deoxygenation/Heck-Matsuda arylation, palladium-catalyzed C-arylation, and regiodivergent [3 + 2] cycloaddition with 1,3-dicarbonyls. These methodologies offer a new avenue to fully functionalized six-membered heterocycles.The synthetic utility of AchR was demonstrated in our total synthesis of 28 natural products with a pyran/piperidine moiety. The AchR-based strategy endows the total synthesis with scalability, sustainability, and flexibility. The green and scalable approaches developed in our lab for AchR allow us to easily obtain decagrams of synthetically valuable pyrans and/or piperidines with low risk and low cost from biomass-derived furfuryl alcohol/aldehyde.

Green Halogenation of Indoles with Oxone-Halide.

Oxidative functionalization of indoles is one of the most widely used approaches to exploit the synthetic utility of indoles. In continuation of our research interest in the green oxidation of indoles, we further explore the oxidation of indoles with oxone-halide and discover that the protecting group on the nitrogen of indoles plays a decisive role in controlling the pathways of indole oxidation with oxone-halide. An electron-withdrawing group on the nitrogen of indoles (N-EWG) enables C2 halogenation with stoichiometric halide, while C3 halogenation could be selectively achieved by using stoichiometric halide without dependence on the electronic property of the protecting group on the indole nitrogen. Different from our previous results obtained by using catalytic halide, these findings lead to the development of an environmentally friendly, efficient, and mild protocol for access to 2- or 3-haloindoles (chloro and bromo). As compared to the previous synthetic methods for 2-/3-haloindoles, our method exploits the in situ-generated reactive halogenating species from oxone-halide for halogenation of indoles and thus eliminates the use of stoichiometric halogenating agents and the production of toxic and hazardous organic byproducts derived from oxidants.

Two Green Protocols for Halogenative Semipinacol Rearrangement.

Semipinacol rearrangement is a special type of Wagner-Meerwein rearrangement that involves carbocation 1,2-rearrangement to provide carbonyl compounds with an α-quaternary carbon center. It has been strategically used for natural product synthesis and construction of highly congested quaternary carbons. Herein, we report a safe and green protocol that uses oxone/halide and Fenton bromide to achieve halogenative semipinacol rearrangement. The key feature of this method is the green in situ generation of reactive halogenating species from oxidation of halide with oxone or H2O2, which produces a nontoxic byproduct (potassium sulfate or water). Easy operation (insensitive to air and moisture) at room temperature without using special equipment adds additional advantage over previous methods.

BiBr3 -Mediated Intramolecular Aza-Prins Cyclization of Aza-Achmatowicz Rearrangement Products: Asymmetric Total Synthesis of Suaveoline and Sarpagine Alkaloids.

An intramolecular aza-Prins cyclization of aza-Achmatowicz rearrangement products was developed in which bismuth tribromide (BiBr3 ) plays a dual role as an efficient Lewis acid and source of the bromide nucleophile. This approach enables the facile construction of highly functionalized 9-azabicyclo[3.3.1]nonanes (9-ABNs), which are valuable synthetic building blocks and a powerful platform for the synthesis of a variety of alkaloid natural products and drug molecules. Suitable substrates for the aza-Prins cyclization include 1,1-disubstituted alkenes, 1,2-disubstituted alkenes, alkynes, and allenes, with good to excellent yields observed. Finally, we showcase the application of this new approach to the enantioselective total synthesis of six indole alkaloids: (-)-suaveoline (1), (-)-norsuaveoline (2), (-)-macrophylline (3), (+)-normacusine B (4), (+)-Na -methyl-16-epipericyclivine (5) and (+)-affinisine (6) in a total of 9-14 steps. This study significantly expands the synthetic utility of the aza-Achmatowicz rearrangement, and the strategy (aza-Achmatowicz/aza-Prins) is expected to be applicable to the total synthesis of other members of the big family of macroline and sarpagine indole alkaloids.

[2+2+1+1] Cycloaddition for de novo Synthesis of Densely Functionalized Phenols.

A unique benzannulation strategy for regioselective de novo synthesis of densely functionalized phenols is described. Through metal-mediated formal [2+2+1+1] cycloaddition of two different alkynes and two molecules of CO, a series of densely functionalized phenols were obtained. The benzannulation strategy allows efficient regioselective installation up to five different substituents on a phenol ring. The resulting phenols have a substitution pattern different from those obtained from Dötz and Danheiser benzannulations.

Environmentally Benign and User-Friendly In Situ Generation of Nitrile Imines from Hydrazones for 1,3-Dipolar Cycloaddition.

Nitrile imines are highly reactive and versatile dipoles and conventionally generated in situ from unstable hydrazonyl halides under basic conditions. Herein, we report the first green and user-friendly protocol for in situ generation of nitrile imines from Oxone-KBr oxidation of hydrazones and base-promoted dehydrobromination. The nitrile imines were demonstrated for 1,3-dipolar cycloaddition with various dipolarophiles, including alkene and alkyne groups. With its green nature, ease of operation, and air and moisture tolerance, we expect our method will find wide applications in organic synthesis.

Asymmetric Total Synthesis of Indole Diterpenes Paspalicine, Paspalinine, and Paspalinine-13-ene.

Paspaline-derived indole diterpenes (IDTs) are structurally complex mycotoxins with unique tremorgenic activity. Reported are asymmetric total syntheses of three paspaline-derived IDTs paspalicine, paspalinine and paspalinine-13-ene. Our synthesis features a green Achmatowicz rearrangement/bicycloketalization for the efficient construction of FG rings (75 % yield) and a cascade ring-closing metathesis of dienyne for highly regioselective formation of CD rings (72 % yield). Other highlights include four palladium-mediated reactions (Stille, aza-Wacker, Suzuki, and Heck) to forge the BE rings and the installation of two continuous all-carbon quaternary stereocenters via reductive ring-opening of cyclopropane and α-methylation of the conjugate ester. Our new synthetic strategy is expected to be applicable to the chemical synthesis of other paspaline-derived IDTs and will facilitate the bioactivity studies of these agriculturally and pharmacologically important IDTs.

1,5-Allyl Shift by a Sequential Achmatowicz/Oxonia-Cope/Retro-Achmatowicz Rearrangement.

1,3-Allyl and 1,2-allyl shifts through [3,3]- and [2,3]-sigmatropic rearrangements are well-established and widely used in organic synthesis. In contrast, 1,5-allyl shift through related [3,5]-sigmatropic rearrangement is unknown because [3,5]-sigmatropic rearrangement is thermally Woodward-Hoffmann forbidden. Herein, we report an unexpected discovery of a formal 1,5-allyl shift of allyl furfuryl alcohol through a 2-step sequential rearrangement. Mechanistically, this formal 1,5-allyl shift is achieved through a sequential ring expansion/contraction rearrangement: 1) Achmatowicz rearrangement (ring expansion), and 2) cascade oxonia-Cope rearrangement/retro-Achmatowicz rearrangement (ring contraction). This new 1,5-allyl shift method is demonstrated with >20 examples and expected to find applications in organic synthesis and materials chemistry.

Chemical Synthesis of Multifunctional Air Pollutants: Terpene-Derived Nitrooxy Organosulfates.

Nitrooxy organosulfates derived from terpenes (NOSTP) represent an important class of products formed between anthropogenic pollution (e.g., SO2 and NOx) and natural emissions. NOSTP compounds have been consistently detected in atmospheric environments under varying urban influences. Their chemical linkages to both anthroposphere and biosphere make them valuable markers for tracking anthroposphere-biosphere interactions. However, their quantification, formation, and transformation kinetics in atmospheric aerosols are hindered due to the lack of NOSTP standards. In this work, we developed two routes for the first concise chemical synthesis of eight NOSTP from terpenes including α-pinene, ß-pinene, limonene, limonaketone, and ß-caryophyllene. Subsequently, six of the synthesized NOSTP were for the first time positively identified in ambient aerosol samples, clarifying certain misidentifications in previous studies. More significantly, the availability of authentic standards allows irrefutable observation of three carbon skeleton-rearranged NOSTP, two derived from α-pinene, and one derived from ß-caryophyllene, revealing the occurrence of previously unrecognized transformation pathways in the formation of NOSTP. Two synthesized NOSTP from ß-pinene and limonene could not be detected, likely due to rapid hydrolysis of their immediate hydroxynitrate precursors outcompeting sulfation. Such mechanistic evidence is valuable in understanding the atmospheric chemistry of NOSTP and related compounds. This work demonstrates the usefulness of authentic standards in probing the NOSTP formation mechanisms in the atmosphere. Comparison of NOSTP ambient samples collected from four Chinese cities in two winter months indicates that anthropogenic chemical factors could outcompete terpene emissions in the formation of NOSTP.

Catalytic Asymmetric Alkynylation of 3,4-Dihydro-ß-carbolinium Ions Enables Collective Total Syntheses of Indole Alkaloids.

Chiral tetrahydro-ß-carboline (THßC) is not only a prevailing structural feature of many natural alkaloids but also a versatile synthetic precursor for a vast array of monoterpenoid indole alkaloids. Asymmetric synthesis of C1-alkynyl THßCs remains rarely explored and challenging. Herein, we describe the development of two complementary approaches for the catalytic asymmetric alkynylation of 3,4-dihydro-ß-carbolinium ions with up to 96 % yield and 99 % ee. The utility of chiral C1-alkynyl THßCs was demonstrated by the collective total syntheses of seven indole alkaloids: harmicine, eburnamonine, desethyleburnamonine, larutensine, geissoschizol, geissochizine, and akuammicine.

C-Aryl Glycosylation: Palladium-Catalyzed Aryl-Allyl Coupling of Achmatowicz Rearrangement Products with Arylboronic Acids.

The first Pd-catalyzed arylation of Achmatowicz rearrangement products with arylboronic acids under mild conditions (rt) to provide the synthetically versatile C-aryl dihydropyranones is reported. It is found that the 4-keto group of Achmatowicz products is essential to increase the reactivity of the Pd-π-allyl complex toward arylboronic acids and that phosphine as the palladium ligand would be destructive to the reaction. This new coupling method addresses the major limitations of previous Pd-catalyzed allyl-aryl couplings of 2,3-unsaturated glycosides with an aryl Grignard or aryl zinc reagent.

Asymmetric Total Syntheses of Rhynchophylline and Isorhynchophylline.

The asymmetric total syntheses of (-)-rhynchophylline and (+)-isorhynchophylline were achieved in 17 and 16 steps, respectively, from butanal and ethyl acrylate. Our synthesis features Carreira ring expansion to construct the tetracyclic spirooxindole core in high diastereoselectivity and the use of Bosch's chiral lactam for preparation of enantioenriched cyclic imine.

Monoterpene and Sesquiterpene α-Hydroxy Organosulfates: Synthesis, MS/MS Characteristics, and Ambient Presence.

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 ß-pinene, limonene, sabinene, Δ3-carene, terpinolene, and α- and γ-terpinene) and two sesquiterpenes (i.e., α-humulene and ß-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 ß-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.

Divergent biosynthesis yields a cytotoxic aminomalonate-containing precolibactin.

Colibactin is 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, which uniquely incorporates the highly sought genotoxicity-associated aminomalonate building block into its unprecedented macrocyclic structure. This work provides new insights into the biosynthetic logic and mode of action of this colorectal-cancer-linked microbial chemical.

Recent Developments in Total Syntheses of Cephalosporolides, Penisporolides, and Ascospiroketals.

The possible biogenetic connection of the 10-membered lactone (decanolide) and the tricyclic [5,5]-spiroacetal-cis-fused-γ-lactone (SAFL) natural products was proposed by Hanson in 1985. Mimicking such biosynthetic hypothesis led us to develop a general synthetic strategy for the total syntheses of both decanolide-type cephalosporolides and SAFL-type natural products. This biomimetic strategy features two key transformations: i) oxidative ring expansion of bicyclic ß-hydroxy tetrahydropyrans to the decanolides and ii) ring contraction rearrangement of the decanolides to the tricyclic SAFLs. In particular, the phenol derivatives are exploited as the starting materials for the decanolides and then the SAFLs. The successful biomimetic total synthesis allows us to revise the structures and biosynthetic hypothesis of several natural products, along with development of an NMR analysis method for determination of the relative stereochemistry of SAFL-type compounds. In addition, this account will summarize recent synthetic work by other research groups.

Asymmetric Total Syntheses of (-)-Hedycoropyrans A and B.

The first and asymmetric total synthesis of (-)-hedycoropyrans A (1) was accomplished in 18 steps with 5.4% overall yield. The key features of our strategy include (1) construction of the unusual trans-2-aryl-6-alkyl tetrahydropyran core via Achmatowicz rearrangement, Zn-mediated reductive deoxygenation, and Heck-Matsuda coupling reaction, and (2) installation of 3,4-anti-dihydroxy from the corresponding 3,4-syn-dihydroxy THP through chemo- and regioselective IBX oxidation and Evans-Saksena reduction. In addition, C2 epimerization of (-)-hedycoropyan A (1) under the acidic condition furnished (-)-hedycoropyan B (2) with 71% yield. This finding might suggest the biogenetic origin of hedycoropyran B.

Synthesis of Four Monoterpene-Derived Organosulfates and Their Quantification in Atmospheric Aerosol Samples.

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, ß-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 ß-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-/ß-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.

Total Syntheses of Sesterterpenoid Ansellones†A and B, and Phorbadione.

Ansellane-type sesterterpenoids including, ansellones A-G and (+)-phorbadione are structurally novel marine secondary metabolites which exhibit anticancer and anti-HIV activity. The first, asymmetric total syntheses of three structurally representative members, (-)-ansellones A and B and (+)-phorbadione, were accomplished in 16-23 steps from (+)-sclareolide. The route features the first regioselective cyclization of vinyl epoxides with internal alcohol nucleophiles in a 1,4-addition manner (SN 2'). Additionally, the allylic C-H oxidation was exploited at a late stage of the synthesis of (-)-ansellone A and (+)-phorbadione. This strategy is expected to be applicable to the synthesis of other ansellane sesterterpenoids.

Unified Asymmetric Total Syntheses of (-)-Alotaketals†A-D and (-)-Phorbaketal†A.

The novel tricyclic spiroketal alotane-type sesterterpenoids showed strikingly different biological activities and potency with subtle structural alterations. Asymmetric total syntheses of the tricyclic sesterterpenoids (-)-alotaketals A-D and (-)-phorbaketal A were accomplished [29-31 steps from (-)-malic acid] in a collective way for the first time. The key features of the strategy included 1) a new cascade cyclization of vinyl epoxy δ-keto-alcohols to forge the common tricyclic spiroketal intermediate, 2) a late-stage allylic C-H oxidation, and 3) olefin cross-metathesis to install the different side chains.