Total Synthesis of Penostatin B

The first total synthesis of penostatin B has been accomplished by using a highly diastereoselective Pauson–Khand reaction and an efficient relay ring-closing metathesis for the construction of the basic carbon skeleton of the natural product as the key steps

Design, Synthesis, and Evaluation of Trivalent PROTACs Having a Functionalization Site with Controlled Orientation

Trivalent PROTACs having a functionalization site with controlled orientation were designed, synthesized, and evaluated. Based on the X-ray structure of BRD protein degrader MZ1 (1) in complex with human VHL and BRD4BD2, we expected that the 1,2-disubstituted ethyl group near the JQ-1 moiety in MZ1 (1) could be replaced by a planar benzene tether as a platform for further functionalization. To test this hypothesis, we first designed six divalent MZ1 derivatives, 2a-c and 3a-c, by combining three variations of substitution patterns on the benzene ring (1,2-, 1,3-, and 1,4-substitution) and two variations in the number of ethylene glycol units (1 or 2). We then tested the synthesized compounds for the BRD4 degradation activity of each. As expected, we found that 1,2D-EG2-MZ1 (2a), an MZ1 derivative with 1,2-disubstituted benzene possessing two ethylene glycol units, had an activity profile similar to that of MZ1 (1). Based on the structure of 2a, we then synthesized and evaluated four isomeric trivalent MZ1 derivatives, 15a-15d, having a tert-butyl ester unit on the benzene ring as a handle for further functionalization. Among the four isomers, 1,2,5T-EG2-MZ1 (15c) retained a level of BRD4 depletion activity similar to that of 2a without inducing a measurable Hook effect, and its BRD4 depletion kinetics was the same as that of MZ1 (1). Other isomers were also shown to retain BRD4 depletion activity. Thus, the trivalent PROTACs we synthesized here may serve as efficient platforms for further applications

Cis-selective double spirocyclization via dearomatization and isomerization under thermodynamic control

Spiro compounds have been considered key scaffolds for pharmaceutical applications. Although many synthetic methods exist for monospirocycles, fewer approaches are known for dispirocycles. Here, we report a highly cis-selective method for constructing a 5/6/5-dispirocyclic structure containing pyrrolidine and γ-lactam rings with various substit-uents from a series of N-arylpropiolamides. The high cis-selectivity would result from isomerization under thermody-namic control. Cis- and trans-diastereomers can be in equilibrium, favoring cis-adducts

Ceramicines M–P from Chisocheton ceramicus: isolation and structure–activity relationship study

Ceramicines are a series of limonoids which were isolated from the bark of Malaysian Chisocheton ceramicus (Meliaceae) and show various biological activities. Ceramicine B, in particular, has been reported to show a strong lipid droplet accumulation (LDA) inhibitory activity on a mouse pre-adipocyte cell line (MC3T3-G2/PA6). With the purpose of discovering compounds with stronger activity than ceramicine B, we further investigated the constituents of C. ceramicus. As a result, from the bark of C. ceramicus four new ceramicines (ceramicines M–P, 1–4) were isolated, and their structures were determined on the basis of NMR and mass spectroscopic analyses in combination with NMR chemical shift calculations. LDA inhibitory activity of 1–4 was evaluated. Compounds 1–3 showed LDA inhibitory activity, and 3 showed better selectivity than ceramicine B while showing activity at the same order of magnitude as ceramicine B. Since 3, which possess a carbonyl group at C-7, showed better selectivity than 5, which possess a 7α-OH group, while showing activity at the same order of magnitude as 5, we also investigated the effect of the substituent at C-7 by synthesizing several derivatives and evaluating their LDA inhibitory activity. Accordingly, we confirmed the importance of the presence of a 7α-OH group to the LDA inhibitory activity

Enantioselective Synthesis of (+)-Penostatin E

The first enantioselective total synthesis of penostatin E has been accomplished. Two highly efficient and diastereoselective reactions, a Hosomi–Sakurai allylation and an intramolecular Pauson–Khand reaction, were utilized for the construction of the basic carbon framework of the target molecule as the key steps. A late-stage introduction of the side chain and a successful base-promoted elimination reaction afforded an efficient synthetic route to (+)-penostatin E

Diastereoselective Intramolecular Carbamoylketene/Alkene [2 + 2] Cycloaddition: Enantioselective Access to Pyrrolidinoindoline Alkaloids

A novel and highly diastereoselective intramolecular carbamoylketene/alkene [2 + 2] cycloaddition has been developed, and the methodology was successfully applied to the enantioselective syntheses of (−)-esermethole and Takayama’s intermediate for (+)-psychotrimine

Total Synthesis of Natural Enantiomers of Heliespirones A and C <i>via</i> the Diastereoselective Intramolecular Hosomi-Sakurai Reaction

A full account of the development of a novel type of the intramolecular Hosomi-Sakurai reactions of the substrates with a <i>p</i>-benzoquinone and an allylsilane moieties connected by an ether linkage is described. This transformation proceeds <i>via</i> an addition–elimination sequence and provides the products with two stereogenic centers through a 1,3­(or 1,4)-asymmetric induction in good to excellent diastereoselectivities. A reasonable mechanistic possibility for the reaction, determination of the stereochemistry for the product, and scope and limitation of the transformation are also discussed. The methodology developed here can successfully be applied to the enantiocontrolled total synthesis of the natural enantiomers of (−)-heliespirone A and (+)-heliespirone C, which have been isolated from sunflower <i>Helianthus annuus</i> L. as allelochemicals

Total Synthesis of Natural Enantiomers of Heliespirones A and C <i>via</i> the Diastereoselective Intramolecular Hosomi-Sakurai Reaction

A full account of the development of a novel type of the intramolecular Hosomi-Sakurai reactions of the substrates with a <i>p</i>-benzoquinone and an allylsilane moieties connected by an ether linkage is described. This transformation proceeds <i>via</i> an addition–elimination sequence and provides the products with two stereogenic centers through a 1,3­(or 1,4)-asymmetric induction in good to excellent diastereoselectivities. A reasonable mechanistic possibility for the reaction, determination of the stereochemistry for the product, and scope and limitation of the transformation are also discussed. The methodology developed here can successfully be applied to the enantiocontrolled total synthesis of the natural enantiomers of (−)-heliespirone A and (+)-heliespirone C, which have been isolated from sunflower <i>Helianthus annuus</i> L. as allelochemicals

Enantioselective Total Syntheses of Pygmaeocins B and C

The first enantioselective total syntheses of pygmaeocins B and C have been accomplished using an efficient and highly diastereoselective intramolecular Heck cyclization for the construction of a quaternary stereogenic center and the functionalized A-ring of the natural products as the key step