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The first total synthesis of sanjoseolide (1), which was originally obtained from Dalea frutescens A, was achieved via an efficient route with a longest linear sequence of six steps from the commercially available 2,4-dihydroxyacetophenone in 8.6% overall yield. Meanwhile, a series of sanjoseolide representative analogues were synthesized and assessed for their antiproliferative potency against cancer cells of different origins. Compound 8e inhibited the survival of all tested cancer cell lines in a dose-dependent manner, the IC50 values of the treatment were about 12.8 μM for human cholangiocarcinoma cell lines RBE and 12.7 μM for human cholangiocarcinoma cell lines HCCC-9810, which was more active than sanjoseolide (1). Analysis of the structure-activity relationships revealed that the presence of a trifluoromethyl group may be beneficial in terms of both RBE and HCCC-9810 inhibition.

(‒)-Morphine, which is selected as an essential medicine by World Health Organization, is widely applied in the treatment of the pain-related diseases. Due to its synthetically challenging molecular architecture and important clinical role, extensive synthetic studies of morphine-type alkaloids have been conducted. However, catalytic asymmetric total synthesis of (‒)-morphine remains a long-standing challenge. Here, we disclose an efficient enantioselective total synthesis of (‒)-morphine in a longest linear sequence of 16 steps. The key transformation features a highly enantioselective Robinson annulation enabled by our spiro-pyrrolidine catalyst to rapidly construct the densely functionalized cis-hydrodibenzofuran framework containing vicinal stereocenters with an all-carbon quaternary center. This asymmetric approach provides an alternative strategy for the synthesis of (‒)-morphine and its analogues., (‒)-Morphine is an essential medicine selected by the World Health Organization, however its catalytic asymmetric syntheses have been rarely reported. Here, the authors developed an intramolecular enantioselective Michael addition leading to (‒)-morphine in a longest linear sequence of 16 steps.

The total synthesis of decarboxyaltenusin (5’-methoxy-6-methyl-[1,1’-biphenyl]-3,3’,4-triol), a toxin produced by various mold fungi, has been achieved in seven steps in a yield of 31% starting from 4-methylcatechol and 1-bromo-3,5-dimethoxybenzene, where the longest linear sequence consists of five steps. The key reaction was a palladium-catalyzed Suzuki coupling of an aromatic boronate with a brominated resorcin derivative.

Herein, we report the synthesis of the entire acyclic carbon framework toward (±)-furanocembranoid 1 via the longest linear sequence of 12 steps from commercially available linalool and diethyl 2-isopropylmalonate. Key to the success of this synthetic approach is a silver-catalyzed enyne-annulation reaction for the formation of 2,4-disubstituted furan motif of unique furanocembranoid 1, isolated from Croton oblongifolius. Construction of macrocycle has also been explored using the ring-closing metathesis reaction.

The first synthesis of the pentasaccharide fragment of the angucycline antibiotic saquayamycin Z is described. By using our sulfonyl chloride mediated reagent controlled dehydrative glycosylation, we are able to assemble the glycosidic linkages with high levels of anomeric selectivity. The total synthesis was completed in 25 total steps, and in 2.5% overall yield with a longest linear sequence of 15 steps.

The kedarcidin chromophore is a formidible target for total synthesis. Herein, we 19 describe a viable synthesis of this highly unstable natural product. This entailed the early 20 introduction and gram-scale synthesis of 2-deoxysugar conjugates of both L-mycarose and L21 kedarosamine. Key advances include: (1) stereoselective allenylzinc keto-addition to form an 22 epoxyalkyne; (2) -selective glycosylations with 2-deoxy thioglycosides (AgPF6/DTBMP) 23 and Schmidt donors (TiCl4); (3) Mitsunobu aryl etherification to install a hindered 1,2-cis24 configuration; (4) atropselective and convergent Sonogashira-Shiina cyclization sequence; 25 (5) Ohfune-based amidation protocol for naphthoic acid; (6) Ce(III)-mediated nine26 membered enediyne cyclization and ester/mesylate derivatisation; (7) SmI2-based reductive 27 olefination and global HF-deprotection end-game. The longest linear sequence from gram28 scale intermediates is 17-steps, and HRMS data of the synthetic natural product was obtained 29 for the first time

Forsythenethoside A (1) is a structurally unique macrocyclic phenylethanoid glycoside, which was isolated from Forsynthia suspensa and displayed considerable neuroprotective activities. Here, we report its first chemical synthesis via a longest linear sequence of 14 steps in 5% overall yield wherein intramolecular oxidative coupling was successfully employed to realize the pivotal macrocyclization. NMR analysis revealed the existence of an unexpected conformational interconversion of the congested macrocycles.

Synthetic studies into the origins of the alkaloid incargranine A have resulted in the development of a four-step (longest linear sequence) total synthesis. This synthesis has been scaled-up to provide gram-scale quantities of material, which would alternatively require extraction of several metric-tons of driedwholeChinese Trumpet-Creeper plants (Incarvillea mairei var. grandiflora).

Homologation of readily available α-boryl pyrrolidines with metal carbenoids is especially challenging even when good leaving groups (Cl−) are employed. By performing a solvent switch from Et2O to CHCl3, efficient 1,2-metalate rearrangement of the intermediate boronate occurs with both halide and ester leaving groups. The methodology was used in the total synthesis of the Stemona alkaloid (−)-stemaphylline in just 11 steps (longest linear sequence), with high stereocontrol (>20:1 d.r.) and 11 % overall yield. The synthesis also features a late-stage lithiation–borylation reaction with a tertiary amine containing carbenoid.

A catalytic enantioselective synthesis of (+)-eucomic acid is reported. A palladium-catalyzed asymmetric allylic alkylation is employed to access the chiral tetrasubstituted α-hydroxyacid moiety found in the natural product. The protecting group strategy was investigated, and a protecting group manipulation was made without any appreciable deleterious effects in the allylic alkylation reaction. Non-natural (+)-eucomic acid is synthesized in a longest linear sequence of 13 steps.

The first total synthesis of (+)-7-bromotrypargine, a β-carboline alkaloid from Ancornia sp. is reported. The synthesis proceeds in nine steps, eight steps longest linear sequence, in 36.9% overall yield. Biological characterization found that (+)-7-bromotrypargine is a H3 antagonist, and a selective inhibitor of the dopamine transporter (DAT) and norepinephrine transporter (NET), without inhibiting the serotonin transporter (SERT). Moreover, unlike electron rich congeners, (+)-7-bromotrypargine is not cytotoxic and thus represents an attractive starting point for chemical optimization; therefore, we piloted a number of chemistries for the synthesis of unnatural analogues.

An enantioselective total synthesis of (+)-cassiol is reported. The complex derived from Pd(2)(pmdba)(3) and enantiopure t-BuPHOX ligand catalyzes enantioconvergent decarboxylative alkylation to generate the quaternary carbon stereocenter at an early stage. The overall synthetic strategy involves a convergent late-stage coupling of two fragments. The synthesis features a longest linear sequence of eight steps.

The enantioselective synthesis of bistramide A has been achieved with a longest linear sequence of 18 steps. The synthetic strategy involves the use of a distereoselective glycolate alkylation, an aldol addition of a chlorotitanium enolate of N-acylthiazolidinthione, and a Sharpless asymmetric epoxidation to synthesize the three key fragments.

The total synthesis of octalactins A and B has been achieved in 15 steps (longest linear sequence) and 10% overall yield from commercially available materials. Key steps include the Paterson-Aldol reaction for the rapid assembly of the carbonate 46, methylenation of 46 and subsequent Claisen rearrangement of the corresponding alkenyl-substituted cyclic ketene acetal to provide the core unsaturated medium-ring lactone 47, and the use of enzyme-mediated acetate deprotection in the presence of a medium-ring lactone.