We report herein our synthetic efforts towards the divergent syntheses of (−)‐huperzine Q (1), (+)‐lycopladine B (2), (+)‐lycopladine C (3), and (−)‐lycopladine D (4). The 10‐step total synthesis of (−)‐huperzine Q (1) and the first total syntheses of (+)‐lycopladines B (2) and C (3) were accomplished through a series of cascade reactions. Our approach involved a Michael addition/aldol/intramolecular C‐alkylation sequence to forge the 6/9 spirocycle ring, and this was followed by an ethylene‐accelerated carbonyl–olefin metathesis to construct the common 6/5/9 ring system. Finally, late‐stage enamine bromofunctionalization enabled us to access (−)‐huperzine Q (1), (+)‐lycopladine B (2), and (+)‐lycopladine C (3), and a tandem C4‐epimerization/retro‐Claisen condensation furnished (−)‐4‐epi‐lycopladine D (63).
In this issue of Cell Chemical Biology, Mart?′n-Gago et al. (2017a) disclose a new strategy for the selective covalent?targeting of binding site carboxylic acids within the proteome using the isoxazolium salt as a warhead.?This discovery paves the way for developing newprotein ligation methods as well as covalent drug candidates. http://www.cell.com/cell-chemical-biology/pdf/S2451-9456(17)30143-5.pdf
ABSTRACT: Bile acids (BAs) are a family of endogenous metabolites synthesized from cholesterol in liver and modified by microbiota in gut. Being amphipathic molecules, the major function of BAs is to help with dietary lipid digestion. In addition, they also act as signaling molecules to regulate lipid and glucose metabolism as well as gut microbiota […]
Prof. Lei has served as a guest editor to compile a special Symposium-In-Print on Bioorganic & Medicinal Chemistry to celebrate his 2017 Tetrahedron Young Investigator Award. http://www.sciencedirect.com/science/journal/09680896/25/11
Abstract Glycolipids are important structural components of biological membranes and perform crucial functions in living systems, including signaling transduction and interaction with extracellular environment. However, the mechanistic exploration of glycolipids in vivo is challenging because they are not genetically encoded. Herein, we designed and synthesized a series of bifunctional monogalactosyldiacylglycerol (MGDG) probes as a model […]
Abstract: On the basis of its essential role in driving inflammation and disease pathology, cell necrosis has gradually been verified as a promising therapeutic target for treating atherosclerosis, systemic inflammatory response syndrome (SIRS), and ischemia injury, among other diseases. Most necrosis inhibitors targeting receptor-interacting protein 1 (RIP1) still require further optimization because of weak potency […]
To improve chemical cross-linking of proteins coupled with mass spectrometry (CXMS), we developed a lysine-targeted enrichable cross-linker containing a biotin tag for affinity purification, a chemical cleavage site to separate cross-linked peptides away from biotin after enrichment, and a spacer arm that can be labeled with stable isotopes for quantitation. By locating the flexible proteins […]
Dianrong Li#, Chao Li#, Lin Li, She Chen, Lei Wang, Qiang Li, Xiaodong Wang, Xiaoguang Lei* and Zhirong Shen*
Cell Chemical Biology 2016, 23, 257-266
Highlights ?Kongensin A (KA) is a potent inhibitor of necroptosis and an inducer of apoptosis ?KA inhibits necroptosis by preventing the activation of RIPK3 ?TQ ligation enables the identification of HSP90 as a cellular target of KA ?KA covalently binds to HSP90 and inhibits HSP90 through a novel mode of action Summary RIP3-dependent necroptosis […]
We report our synthetic studies towards the synthesis of the C3-C14 fragment of alchivemycin A. The synthesis featured an asymmetric alkylation with excellent diastereoselectivity and a one-pot Julia-Kocienski olefination with excellent E-selectivity. Intramolecular Diels-Alder reaction was employed to construct the highly functionalized cis-decalin framework. Interestingly, the stereochemical outcome was unexpected to generate two stereoisomers 20 […]
Lei Gao, Jianguang Han, and Xiaoguang Lei*
Org. Lett. 2016, 18, 360-363
ABSTRACT: The first enantioselective total syntheses of?(?)-kuwanon X, (+)-kuwanon Y, and (+)-kuwanol A have been accomplished by using asymmetric Diels?Alder cycloaddition promoted by chiral VANOL or VAPOL/boron Lewis acid. The biosynthesis-inspired asymmetric Diels?Alder cycloaddition shows high exo selectivity (exo/endo = 13/1), which was unprecedented in the previous total syntheses of related prenylflavonoid Diels?Alder natural products. […]
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Divergent Total Syntheses of (-)-Huperzine Q, (+)-Lycopladine B, (+)-Lycopladine C and (-)-epi-Lycopladine D
Hong, B.; Hu, D.; Wu, J.; Zhang, J.; Li, H.; Pan, Y.; Lei, X.
Chem. Asian J. 2017, 12, 1557-1567. (VIP paper)
We report herein our synthetic efforts towards the divergent syntheses of (−)‐huperzine Q (1), (+)‐lycopladine B (2), (+)‐lycopladine C (3), and (−)‐lycopladine D (4). The 10‐step total synthesis of (−)‐huperzine Q (1) and the first total syntheses of (+)‐lycopladines B (2) and C (3) were accomplished through a series of cascade reactions. Our approach involved a Michael addition/aldol/intramolecular C‐alkylation sequence to forge the 6/9 spirocycle ring, and this was followed by an ethylene‐accelerated carbonyl–olefin metathesis to construct the common 6/5/9 ring system. Finally, late‐stage enamine bromofunctionalization enabled us to access (−)‐huperzine Q (1), (+)‐lycopladine B (2), and (+)‐lycopladine C (3), and a tandem C4‐epimerization/retro‐Claisen condensation furnished (−)‐4‐epi‐lycopladine D (63).
Covalent Probe Finds Carboxylic Acid
Jones, A.; Zhang, X.; Lei, X.*
Cell Chem. Biol. 2017, 24, 537-538
In this issue of Cell Chemical Biology, Mart?′n-Gago et al. (2017a) disclose a new strategy for the selective covalent?targeting of binding site carboxylic acids within the proteome using the isoxazolium salt as a warhead.?This discovery paves the way for developing newprotein ligation methods as well as covalent drug candidates. http://www.cell.com/cell-chemical-biology/pdf/S2451-9456(17)30143-5.pdf
Chemoproteomic Profiling of Bile Acid Interacting Proteins
Zhuang, S.; Li, Q.; Cai, L.; Wang, C.*; Lei, X.*
ACS Cent. Sci. 2017, 3, 501-509
ABSTRACT: Bile acids (BAs) are a family of endogenous metabolites synthesized from cholesterol in liver and modified by microbiota in gut. Being amphipathic molecules, the major function of BAs is to help with dietary lipid digestion. In addition, they also act as signaling molecules to regulate lipid and glucose metabolism as well as gut microbiota […]
Small Molecule Enabled Chemical Biology and Drug Discovery
Lei, X.
Bioorganic & Medicinal Chemistry 25 (2017) 2815–2816
Prof. Lei has served as a guest editor to compile a special Symposium-In-Print on Bioorganic & Medicinal Chemistry to celebrate his 2017 Tetrahedron Young Investigator Award. http://www.sciencedirect.com/science/journal/09680896/25/11
Exploring the Binding Proteins of Glycolipids with Bifunctional Chemical Probes
Liu, X.; Dong, T.; Zhou, Y.; Huang, N.; Lei, X.*
Angew. Chem. Int. Ed. 2016, 55, 14330-14334.
Abstract Glycolipids are important structural components of biological membranes and perform crucial functions in living systems, including signaling transduction and interaction with extracellular environment. However, the mechanistic exploration of glycolipids in vivo is challenging because they are not genetically encoded. Herein, we designed and synthesized a series of bifunctional monogalactosyldiacylglycerol (MGDG) probes as a model […]
Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome
Ren, Y.; Su, Y.; Su, L.; He, S.; Meng, L.; Liao, D.; Liu, X.; Ma, Y.; Liu, C.; Li, S.; Ruan, H.; Lei, X.; Wang, X.*; Zhang, Z.*
J. Med. Chem. 2017, 60, 972-986
Abstract: On the basis of its essential role in driving inflammation and disease pathology, cell necrosis has gradually been verified as a promising therapeutic target for treating atherosclerosis, systemic inflammatory response syndrome (SIRS), and ischemia injury, among other diseases. Most necrosis inhibitors targeting receptor-interacting protein 1 (RIP1) still require further optimization because of weak potency […]
Trifunctional Cross-Linker for Mapping Protein-Protein Interaction Networks and Comparing Protein Conformational States
Tan, D.; Li, Q.; Zhang, M.; Liu, C.; Ma, C.; Zhang, P.; Ding, Y.; Fan, S.; Tao, L.; Yang, B.; Li, X.; Ma, S.; Liu, J.; Feng, B.; Liu, X.; Wang, H.; He, S.; Gao, N.; Ye, K.; Dong, M.*; Lei, X.*
eLife 2016; 5:e12509
To improve chemical cross-linking of proteins coupled with mass spectrometry (CXMS), we developed a lysine-targeted enrichable cross-linker containing a biotin tag for affinity purification, a chemical cleavage site to separate cross-linked peptides away from biotin after enrichment, and a spacer arm that can be labeled with stable isotopes for quantitation. By locating the flexible proteins […]
Natural Product Kongensin A is a Non-Canonical HSP90 Inhibitor that Blocks RIP3-dependent Necroptosis
Dianrong Li#, Chao Li#, Lin Li, She Chen, Lei Wang, Qiang Li, Xiaodong Wang, Xiaoguang Lei* and Zhirong Shen*
Cell Chemical Biology 2016, 23, 257-266
Highlights ?Kongensin A (KA) is a potent inhibitor of necroptosis and an inducer of apoptosis ?KA inhibits necroptosis by preventing the activation of RIPK3 ?TQ ligation enables the identification of HSP90 as a cellular target of KA ?KA covalently binds to HSP90 and inhibits HSP90 through a novel mode of action Summary RIP3-dependent necroptosis […]
Studies towards the Synthesis of the Functionalized C3-C14 Decalin Framework of Alchivemycin A
Ma, K.; Liao, D.; Yang, S.; Li, X.; Lei, X.*
Org. Chem. Front. 2016, 3, 251-258
We report our synthetic studies towards the synthesis of the C3-C14 fragment of alchivemycin A. The synthesis featured an asymmetric alkylation with excellent diastereoselectivity and a one-pot Julia-Kocienski olefination with excellent E-selectivity. Intramolecular Diels-Alder reaction was employed to construct the highly functionalized cis-decalin framework. Interestingly, the stereochemical outcome was unexpected to generate two stereoisomers 20 […]
Enantioselective Total Syntheses of Kuwanon X, Kuwanon Y and Kuwanol A
Lei Gao, Jianguang Han, and Xiaoguang Lei*
Org. Lett. 2016, 18, 360-363
ABSTRACT: The first enantioselective total syntheses of?(?)-kuwanon X, (+)-kuwanon Y, and (+)-kuwanol A have been accomplished by using asymmetric Diels?Alder cycloaddition promoted by chiral VANOL or VAPOL/boron Lewis acid. The biosynthesis-inspired asymmetric Diels?Alder cycloaddition shows high exo selectivity (exo/endo = 13/1), which was unprecedented in the previous total syntheses of related prenylflavonoid Diels?Alder natural products. […]