Plant natural products and their derivatives are the important reservoirs for the development of medicines, health products and food additives. The synthetic biology technology brings new strategies to manufacture rare plant natural products with complicated structures at large scale by artificially constructing and optimizing the biosynthesis pathway of target compounds in microbial chassis cells. In this paper, the research progress on the artificial syntheses of important plant natural products such as artemisinin, ginsenosides, morphinan alkaloids, paclitaxel and vinblastine is reviewed. These examples not only demonstrate the great potentials of synthetic biology as well as its combination with synthetic chemistry applied in the artificial syntheses of plant natural compounds, but also show us the roadmap for future research and development on de novo synthesis of plant natural products. New technologies developed in synthetic biology and synthetic chemistry would further promote the unveiling of biosynthetic pathways of complex natural compounds, the discovery and characterization of key bioparts, the design and building of novel chassis cells, the strong-strong combination of biosynthesis and chemical synthesis, and thus accelerate the process to transfer the developed technologies to artificially synthesize plant natural products from laboratories to markets.

Heterocycles (α,β/β,γ-unsaturated-γ-lactones, α,β-unsaturated-γ-lactams)-based vinylogous Mannich reactions (VMR) constitute a class of effective C-C bond formation approach to install vicinal aminol-containing α,β-unsaturated-lactones and vicinal diamine-containing α,β-unsaturated-γ-lactams. Possessing multiple functionalities, the latters are versatile building blocks for the synthesis of O-heterocycles, N-heterocycles and the synthesis of alkaloids. The progresses of the asymmetric vinylogous Mannich reactions of silyloxy pyrroles and silyloxy furans from 2011 to mid-2018 are summarized. The methods are organized according to chiral auxiliary-induced asymmetric VMRs, asymmetric VMRs catalyzed by metal-chiral ligand complex or organocatalyst, and the applications of the aymmetric VMRs to the syntheses of complex alkaloids. Some limitations of the developed heterocycles-based VMRs are also briefly discussed.

With the rapid progress of synthetic biology and other related filed, there is a continuous growth of the applications of genetically modified organisms in many aspects, including industry, agriculture, health and environment. However, unintended release or uncontrolled propagation of these genetically modified organisms may cause significant side effects to the nature ecological environment. In order to eradicate the escaping problem and horizontal gene transfer between artificial and natural organisms, many researches have been focused on how to limit genetically modified organisms to a controlled environment. The research progress of biocontainment of genetically modified organisms mainly from three aspects of traditional biocontainment strategies, the orthogonalization of central dogma and the design of complex genetic networks is highlighted. It is believed that the advanced biocontainment technology would promote the further application of synthetic biology.

In order to find novel pyrazole amides having potent bioactivities, a series of novel pyrazole amide compounds carrying substituted pyridyl moiety were designed and synthesized according to the method of active substructure combination. The preliminary bioassay data showed that some title compounds displayed good insecticidal activities. At the concentration of 500 μg/mL, ten compounds exhibited insecticidal activity against Oriental armyworm with 60%~100%, and one compound indicated insecticidal activity against Aphis medicaginis with 100%. When the concentration was reduced to 100 μg/mL, two compounds still showed insecticidal activity against Oriental armyworm with 70%~100%, which were better than that of the control tolfenpyrad. Additionally, one compound displayed 50% insecticidal activity against Oriental armyworm at the concentration of 20 μg/mL.

Monoterpene indole alkaloids (MIAs) are a group of important specialized metabolites that exhibit a broad range of pharmacological activities. However, the contents of MIAs in natural plants are extremely low. It could be produced through advanced synthetic chemistry, but the production scale is very limited, and the further modification of the key scaffold is very difficult. With the full elucidation of MIAs biosynthetic pathway and deeper investigation of biotechnology in synthetic biology, the use of synthetic biology strategies combined with chemical semi-synthesis will be an important development trend for the synthesis of these compounds and their derivatives. Elucidation of MIAs biosynthetic pathway by characterizing involved genes is the prerequisite for synthetic biology. Strictosidine, which was formed by the combination of tryptamine and secologanin, is the key intermediate for MIAs biosynthesis. The discovery of biological parts and research advances of synthetic biology of MIAs based on the upstream biosynthetic pathway, the formation of strictosidine, and downstream biosynthetic pathway, production of divergent MIAs derived from strictosidine over the past three decades are described. This review could provide guidance for further elucidation of other MIAs and promotion of synthetic biology for producing MIAs.

The plants of the genus Isodon and the schisandraceae family are two economically and medicinally important phytogroups, and the research of chemical constituents from these two phytogroups has been recognized as one of the most outstanding achievements in natrural product research recently. So far, over 1200 diterpenoids classified into 11 different groups have been reported from the Isodon species and more than 200 schinortriterpenoids (SNTs) involving more than 20 skeletons have been isolated from the schisandraceae species. Their diverse scffolds and significant bioactivities have aroused great interest among the community of organic synthetic chimistry. In this review, the advances in the synthesis of Isodon diterpenoids and schinortriterpenoids during the past decade will be reviewed.

Rhamnosylation is an important type of glycosylation reaction which is widely involved in organic synthesis and structural modification of natural products. In vivo, rhamnosylation is catalyzed by rhamnosyltransferase that transferred the active rhamnosyl donors to the specific sugar acceptors. A larger number of rhamnosyltransferases have been identified in natural and they often played key roles in the biosynthesis of diverse natural products as well as maintaining the cell structure and physiological functions of biological organisms. Besides, enzymatic rhamnosylation has been an effective complementary method to chemical catalysis in the field of organic glycosylation modifications due to its high catalysis efficiency and specificity, mild reaction conditions as well as environment friendship and so on. In this article, research progresses of rhamnosyltransferase are reviewed based on their enzymatic functions, three dimensional structure investigations, rhamnosyl donors' synthesis, enzymatic catalysis promiscuities, and biochemical catalysis applications. Finally, the future development and application of them are also prospected.

The development of covalent inhibitors plays a major role in recent drug discovery due to their potential excellent pharmacokinetics. Covalent inhibitors are small organic molecules which interact with specific target proteins and form a covalent bond, resulting an alteration of the protein conformation and subsequently inhibit the protein activity. The modifications of proteins by covalent inhibitors are generally irreversible with some exceptions. In this review, the commercial covalent inhibitors that interact with proteins via Michael additions, nucleophilic substitution, or disulfide linkage are reviewed. The discussion on various types of warheads in covalent inhibitors could inspire future rational drug design.

Cyclopropane-containing natural products frequently possess excellent biological activities, and may be developed as drug leads. Although the inherent strain of the cyclopropane greatly challenges both chemical synthesis and biosynthesis, great advances have been made for the construction of the cyclopropane in natural products by chemical synthesis owing to the importance of this kind of compounds. Many enzymes responsible for cyclopropanation have also been unraveled. This review summarizes the cyclopropanation strategies in chemical synthesis and biosynthesis. The strategies used in chemical synthesis mainly consist of three classes:(i) a carbene involved mechanism, (ii) an S_N2 reaction mechanism, and (iii) cycloisomerization. The strategies discovered in nature are reviewed on the basis of the carbon state involved, including (i) a carbocation, (ii) a carbanion, and (iii) a carbon radical. Chemical synthesis and biosynthesis are mutually simulative because the strategies developed in chemical synthesis may inspire enzymologists to discover and design new biochemical reactions and vice versa.

Cytochrome P450 enzymes are widely distributed in nature, which mainly participate in xenobiotics metabolism and natural product biosynthesis. These enzymes are able to recognize various substrates to produce many useful oxidative products through diverse reaction types. P450 enzymes can catalyze selective oxidation of C-H bonds in their substrates under mild conditions. Therefore, a lot of P450 enzymes have been applied in the production of fine chemicals, drugs and chemical intermediates for quite a long time. With the development of protein engineering, redox partner engineering, substrate engineering, metabolic engineering and synthetic biology, it has become possible to obtain the P450 biocatalysts with the desired properties such as high activity, the substrate specificity of interest, and great selectivity to meet the industrial requirements, through rational design and direct evolution of P450 enzymes. Thus, the application scope of P450 enzymes in biosynthesis and organic synthesis has been expanded greatly. The types of reactions that can be catalyzed by P450 enzymes, and the strategies to broaden the reaction scope and to enhance the catalytic efficiency and selectivity are summarized. Finally, the challenges and prospects in the application of cytochrome P450 enzymes in biosynthesis and organic synthesis are discussed.

Asymmetric catalysis is the most efficient chiral synthesis strategy. Chemists have already developed a variety of catalysts to achieve many asymmetric transformations. However, most of the deveoped chiral catalysts and the asymmetric catalytic reactions were developed on the basis of trios-errors approaches involving massive random screening. How to effectively obtain catalysts with higher activity and selectivity is still a challenge. In recent years, the rapid development of physical organic chemistry and computational chemistry has greatly facilitated the study of the reaction mechanism and the origin of selectivity, setting basis for rational catalyst design and evolution. This review will briefly introduce some representative works on the rational design of chiral catalysts in recent years, including rational design based on structure-activity relationship analysis, rational design based on reaction mechanism research, and computational design of enzymes.

Most polyketide natural compounds, such as antibiotics, antineoplastics and immunosuppressants, are produced by type I polyketide synthases (PKSs). Type I PKSs are composed of several catalytic modules, each of which contains iterative domains, such as acyltransferase (AT) domain, for one round of polyketide chain elongation. The recent advances on AT domains of type I PKS modules and analyzes their categories, the diverse acyl subunits they transfer, their catalytic mechanisms and their protein structures are summarized. Moreover, the recent progress in AT engineering (AT domains swaps, AT site-directed mutagenesis and trans-AT complementation) for new polyketide derivatives is summarized, to show that the substrate specificity of AT domains is one of the key factors on determining the diversity of polyketide backbones. These works have laid a theoretical foundation for the further development of novel polyketides with multi-functions and in high-yields by AT domain engineering.

Total synthesis of natural products is one of the most important field in organic chemistry. Natural products and derivatives, containing complex structures and potential biological activities, are also indispensable sources of drug discovery. The total synthesis of natural products through the combination of chemical synthesis and biosynthesis strategies is reviewed. The main content includes the chemical and biosynthetic studies of artemisinin, spinosyn A, myceliothernophin E and equisetin.

Triterpenoids and steroids are one of the largest classes of natural products composed of six isoprene units, with various chemical structures as well as wide range of biological activities. Fungi serves as important sources for triterpenoids and steroids. However, compared with plants, the types of triterpenoid skeletons discovered in fungi are much fewer, suggesting that there is a large research space. Genome mining has become an important method of discovering novel natural products in the post-genomic era, which uses the genes with similar functional to identify the target genes with new functions. With the rapid development of high-throughput sequencing and biological information technology, biosynthetic pathways of some triterpenoids and steroids with important biological activities have been elucidated in recent years, which build the foundations for the discovery of new triterpenoids or steroids from fungi via genome mining. The recent advances in the biosynthesis of fungal triterpenoids and steroids are mainly introduced.

The emergence of multi-drug resistant bacteria is one of the major public heath crises. Platensimycin (PTM) and platencin (PTN) are potent antibacterial drug leads against many gram-postive pathogens, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. The past decade has witnessed the systematic study of biosynthesis, total synthesis and semisynthesis of these facinating molecules, due to their novel structures and excellent biological activities in vitro and in vivo. These studies have shed new lights on the disovery of microbial drug leads through novel high throughput strategies. Dedicated enzymes for the formation of PTM and PTN and other metabolites in their biosynthetic pathways, including new-characterized bacterial diterpenoid synthases and thiocarboxylate biosynthetic enzymes, have been revealed. The generation of many analogues of PTM and PTN though organic synthesis and precursor-directed biosynthesis has helped to establish the structure-activity relationships of PTM, PTN and their analgues. This review summarizes the progress in the disovery and development of these outstanding natural product drug leads, which supports the notion to integrate biosynthesis and organic synthesis for rapid microbial drug discovery and development.

Paulomycins are a group glycoside antibiotics produced by Streptomyces, which not only show excellent antibacterial activities against gram-positive bacteria, but also display good antitumor activities. The paulic acid moiety is one of the structures that cause the instability of paulomycin. This study aimed to improve the stability of paulomycins. When small molecule thiol compound N-acetylcysteamine (SNAC) was added to the fermentation broth of paulmycin producing strain, four new paulomycin derivatives of palsimycins A, B, C, and D were obtained. The antibacterial activity evaluation showed that the minimal inhibit concentrations (MICs) of palsimycin A and palsimycin B against the tested strains were at the same level as those of paulomycin A and paulomycin B. The stability test revealed that under the same conditions, palsimycin A, B, C, and D were all more stable than paulomycin A and paulomycin B. In conclusion, without scarifying the antibacterial activity, this study increased the stability of paulomycin by the addition of paulic acid with SNAC, which laid a foundation for further research and application of paulomycins.

3,4-Fused indole alkaloids are an important part of naturally occurring indole alkaloids and have attracted considerable interests from synthetic chemists because of their unique structures and various biological activities. In this review, the recent total syntheses of the 3,4-fused indole alkaloids from 2013 are summerized and classified by the ring-closing positions of the indole 3,4-fused ring.

Asymmetric synthesis of the tetracyclic skeleton of arborisidine is reported. Starting from the enantiomerically pure compound 10,9-di-tert-butyl5-ethyl(4S,8R)-6-hydroxy-7,8-dihydro-9H-8a,4b-(epiminoethano)carbazole-5,9,10-tricar-boxylate (11) which was reported earlier by our group, a Krapcho decarboxylation reaction was used to afford the ketone, and then a reductive ring-opening method was applied to open the pyrrolidine ring of the substrate. The C(15)-C(16) double bond and the methyl group at C(16) of A/B/D tricyclic skeleton were introduced via Saegusa oxidation and Michael reaction, respectively. Finally, an intramolecular aza-Michael addition reaction was used as a key reaction to construct the C-ring and C(16) quaternary center, which led to the efficiently asymmetric synthesis of A/B/C/D tetracyclic skeleton of arborisidine.

The study of native proteins with post-translational modifications (PTMs) is one of the main fields of epigenetics. The discovery of novel PTM models and their vital regulatory role for chromatin structure and gene transcription have been one of the current research focuses drawing attention of biologists especially in recent years. However, we still lack efficient strategies for the preparation of sufficient amount of native proteins with certain PTMs. The currently existing chemical biology methods are reviewed, and their advantages and disadvantages are compared, including bioorthogonal reaction technique, non-canonical amino acid incorporation, etc. Furthermore, the draft will mainly focus on the application of bioorthogonal reactions on unnatural functional groups for the incorporation of lysine PTMs.

Using aniline derivatives containing lactone structure and styrenes as the starting materials, a series of lactone substituted quinolines were constructed efficiently by oxidative Povarov reaction, promoted by radical cation salt. This reaction provides a new method to achieve the construction of functionalized quinoline skeletons. The mechanistic study reveales that the oxidation of the saturated C-H bond is mediated by free radical intermediate.

Mirror-image proteins are composed of D-amino acids and glycine. They are the enantiomers of the native L-protein counterparts. Currently mirror-image proteins can not be obtained through recombinant technology and therefore, chemical synthesis is the only way to generate mirror-image proteins. As structurally defined and functionally variable chemical materials, mirror-image proteins have potential applications in racemic crystallography, biomimetic catalysis, soft materials, and diagnostics and therapeutic reagents. The chemical synthesis of mirror-image proteins and the advances in racemic X-ray crystallography, mirror-image drug discovery, as well as mirror-image biological systems are surveyed.

Hydramicromelins A~C are coumarin compounds with unique chemical structure and biological activity. With[2,3]-Meisenheimer rearrangemen as a key reaction which has been developed in our laboratory, the core structures of Hydramicromelin A, B and C were synthesized from L-phenylglycine. The route included Wittig reaction,[2,3]-Meisenheimer rearrangement, epoxidation and dihydroxylation reaction, and it was high-yield and high-enantioselectivity.