A stereoselective synthetic route to four androsterone isomers from dehydroepiandrosterone (DHEA) was established. Palladium-catalyzed hydrogenation of DHEA and its oxidized derivatives proceeded with high stereoselectivity at the C5 position. No detectable amounts of the opposite diastereomer were observed, enabling the selective construction of complementary stereoisomers. Reduction of the C3 carbonyl group using classical hydride reagents resulted in a reagent-dependent stereoselectivity, allowing access to the desired isomers with high selectivity. Overall, this protocol provides a practical synthetic process for the preparation of optically active steroids and enables access to defined stereoisomers relevant to pharmaceutical synthesis and hormone research.

The reaction of carbonyl compounds with diethyl phosphorocyanidate in the presence of a catalytic amount of lithium cyanide readily affords cyanophosphates (CPs), which have been utilized as useful intermediates for the introduction of a C-1 unit in a variety of reactions. This short review summarizes the progress made in the application of CPs and the related compounds in organic synthesis over the last decade, in which the following items are covered. 1) Introduction. 2) Synthesis of Succinonitrile by Homocoupling from CPs with Cp2TiI. 3) Dearomative Allylation of Naphthaldehyde CPs by Palladium Catalysis. 4) Efficient Synthesis of a 5 alpha-Reductase Inhibitor, 3-(Tetrazol-5-yl)-3,5-pregnadien-20-one through Allylic Rearrangement of CPs. 5) Generation of Alkylidene Carbenes through Tetrazole Fragmentation Derived from CPs. 6) Transformation of Benzaldehydes to Benzonitriles via CPs without One-Carbon Homologation. 7) Preparation of O-Phosphinoyl-protected Cyanohydrins by Aerobic Oxidation of alpha-Substituted Malononitriles. 8) Miscellaneous Reactions. 9) Summary and Perspective.

The microwave-aided racemic synthesis of six 5-hydroxy-5-vinyl-2-cyclopentenone-type natural products was achieved. A key reaction involving the construction of the α-keto vinyl carbinol function was realized by applying a Mislow–Evans rearrangement of an allylic sulfoxide, which was prepared by conjugate addition of cyclopentane-1,3-dione-derived enolate to alkynyl sulfoxide to afford 5-hydroxy-3-methoxy-5-vinyl-2-cyclopentenone (1). From the common intermediate 1, five other congeneric natural products were synthesized.

Abiraterone (Abi) acetate, an anticancer drug, produces metabolites in the serum of patients with prostate cancer. Three unknown metabolites of Abi are previously discovered and the structures of two of these compounds are determined by comparing their LC‐based retention times with those of synthesized compounds. However, the structure of the third metabolite is not identified. Herein, two new Abi derivatives, 5α‐Δ 1 ‐abiraterone (5α‐D1A) and 5β‐Δ 1 ‐abiraterone (5β‐D1A), with a molecular weight of 348, are successfully synthesized as candidates for the third unknown metabolite. 5β‐D1A is confirmed as this third metabolite based on its retention time in the extracted ion chromatogram. The metabolic pathway may have formed 5β‐D1A rather than 5α‐D1A because of the higher activity of steroid 5β‐reductase compared with that of 5α‐reductase. These findings are expected to lead to the discovery of new metabolic pathways.

The transformation of benzaldehydes into benzonitriles via cyanophosphates (CPs) with tetrabutylammonium azide (Bu4NN-3) was found to afford a range of benzonitriles in modest-to-high yields. As the CN-carbon of benzonitriles arises from the formyl-carbon of benzaldehydes, this is a new type of CP-reaction, distinctly different from the past one-carbon nitrile homologation. In contrast, the reaction of ketone- or aliphatic aldehyde-CPs with Bu4NN-3 resulted in mono-deethylaton forming tetrabutylammonium salts.

We report a convergent synthesis of heteroaryl/aryl-annulated pyridine and quinoline derivatives by a metal-free Povarov reaction. para-Toluene sulfonic acid was used as the catalyst in this reaction, which produced the products in good yields from the corresponding ar-omatic amines and ethyl vinyl ether. A pyridocoumarin and a pyridopy-rimidine product were evaluated for their mosquito larvicidal activity against the third instar larvae of the dengue vector mosquito Aedes aegypti. Examination of morphological changes in the larvae showed dam-age to the target body part after treatment with both the pyridocoumarin and pyridopyrimidine products at the LC50 concentrations. Introduction Early Studies Tetrazole Fragmentation of HATs, Azido-HATs, and 2-Cyanoazeti-dines HAT Synthetic Methods Tetrazole Fragmentation from CPs Summary and Perspective

Prostate cancer is an androgen-dependent malignancy that presents a marked treatment challenge, particularly after progression to the castration-resistant stage. Traditional treatments such as androgen deprivation therapy often lead to resistance, necessitating novel therapeutic approaches. Previous studies have indicated that some of the azolato-bridged dinuclear platinum(II) complexes (general formula: [{cis-Pt(NH3)2}2(μ-OH)(μ-azolato)]X2, where azolato = pyrazolato, 1,2,3-triazolato, or tetrazolato and X = nitrate or perchlorate) inhibit androgen receptor (AR) signaling. Therefore, here we investigated the potential of 14 such complexes as agents for the treatment of prostate cancer by examining their antiproliferative activity in the human prostate adenocarcinoma cell line LNCaP. Several of the complexes, particularly 5-H-Y ([{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N2,N3)](ClO4)2), effectively inhibited LNCaP cell growth, even at low concentrations, by direct modulation of AR signaling, and by binding to DNA and inducing apoptosis, which is a common mechanism of action of Pt-based drugs such as cisplatin (cis-diamminedichloridoplatinum(II)). Comparative analysis with cisplatin revealed superior inhibitory effects of these complexes. Further investigation revealed that 5-H-Y suppressed mRNA expression of genes downstream from AR and induced apoptosis, particularly in cells overexpressing AR, highlighting its potential as an AR antagonist. Thus, we provide here insights into the mechanisms underlying the antiproliferative effects of azolato-bridged complexes in prostate cancer.

Two novel abiraterone (Abi, 3β-OH-Abi) metabolites in human serum were identified as 3α-OH-Abi and Δ5-Abi (D5A). Both metabolites were confirmed by their retention times on LC/MS and their product-ion mass spectra on LC–MS/MS compared to those of authentic compounds, which were chemically synthesized. The plausible metabolic pathways of these two metabolites are as follows: Abi is first oxidized to D5A by 3β-hydroxysteroid dehydrogenase (3β-HSD) and then irreversibly converted to Δ4-Abi (D4A) by ∆5–∆4 isomerase. Presumably, D5A detection is difficult because of its rapid conversion to D4A and its low concentration in serum samples. In contrast, the low concentration 3α-OH-Abi was generated by reducing the remaining D5A using 3α-hydroxysteroid dehydrogenase (3α-HSD).

The enantiomers of 6-fluoro-, 6-bromo-, and 6-iodopericosine A were synthesized. An efficient synthesis of both enantiomers of pericoxide via 6-bromopericosine A was also developed. These 6-halo-substituted pericosine A derivatives were evaluated in terms of their antitumor activity against three types of tumor cells (p388, L1210, and HL-60) and glycosidase inhibitory activity. The bromo- and iodo-congeners exhibited moderate antitumor activity similar to pericosine A against the three types of tumor cell lines studied. The fluorinated compound was less active than the others, including pericosine A. In the antitumor assay, no significant difference in potency between the enantiomers was observed for any of the halogenated compounds. Meanwhile, the (−)-6-fluoro- and (−)-6-bromo-congeners inhibited α-glucosidase to a greater extent than those of their corresponding (+)-enantiomers, whereas (+)-iodopericosine A showed increased activity when compared to its (−)-enantiomer.

Microwave irradiation of 2-alkynyl-5-(phenyl or alkyl)tetrazoles affords 2-(phenyl or alkyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles via intramolecular [3+2] cyclization of nitrile-imine intermediates. In the present method, the use of 5-alkyltetrazoles as the starting materials is more advantageous because of the difficulties associated with conventional photoreactions. From 2-phenylalkynyl-5-methylthio-1H-tetra-zoles, the reaction efficiently produces 2-methylthio-3-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles. The procedure using the methylthio group is applied to the total synthesis of three naturally occurring withasomnines. The method is also extended to the construction of molecules in which bicyclic pyrazoles are fused to six-to eight-membered rings.

Chiral high-performance liquid chromatography (HPLC) analysis of natural pericosine A, which appeared in literature first in 1977, from Periconia byssoides was conducted using a column CHIRALPAK® AD-H to determine the enantiomeric composition of the original mixture which was found to be 68: 32 mixtures of (+)- and (-)-enantiomer, respectively. Furthermore, two independently isolated samples of pericosine A from the same fungus were also analyzed to show the two peaks in the HPLC charts at approximate 1:1 ratio. These results concluded that pericosine A derived from Periconia byssoides was indeed an enantiomeric mixture. Synthesized enantiomers were subjected to evaluation of antitumor activity against three kinds of tumor cells (p388, L1210, HL-60), indicating moderate cytotoxicity against all three kinds of tumor cell lines, but significant difference in potency between the enantiomers was not observed. In contrast, when both the enantiomers of pericosine A were evaluated against five kinds of glycosidases-inhibitory activities (α- and β-glucosidases, α- and β-galactosidases, and α-mannosidase), an apparent difference on anti-glycosidase assay was found between the enantiomers: (-)-pericosine A inhibited α-glucosidase at IC50 : 2.25 mM, and β-galactosidase at IC50 : 5.38 mM, albeit the (+)-enantiomer showed inactivity against these five enzymes.

Background: Acute kidney injury (AKI) is associated with incomplete recovery after the onset of the disease. However, there is no fundamental treatment for this disease. Previously, we identified vanin-1, which appears on the cell surface of proximal tubules early after oxidative stress and induces various inflammatory responses. In this study, we developed and evaluated vanin-1 inhibitors. We synthesized novel vanin-1 inhibitors (OMP compounds) by chemical modification of pantetheine analogues RR6 (IC50 = 0.54 μM), which was reported by Schalkwijk J et al. To evaluate the candidate compounds, vanin-1 activity in serum and renal tissues collected at 1 and 4 hours after subcutaneous administration of 10 mg/kg of RR6 or OMP7 to hamsters was compared with that in the normal group. Results/Conclusions: Serum vanin-1 activity was significantly decreased at 1 hour after subcutaneous administration of RR6, but there was no significant difference at 4 hours. On the other hand, vanin-1 activity was significantly suppressed at 1 and 4 hours after subcutaneous administration of the OMP7. Vanin-1 activity in renal tissue was also not inhibited at 1 hour after subcutaneous administration of RR6. In contrast, the OMP7 significantly inhibited vanin-1 activity at 1 hour after subcutaneous administration. These results suggest that compared to RR6, the OMP7 has a sustained inhibitory effect on vanin-1 activity in serum, and a certain inhibitory effect can be expected in renal tissues as well.

Fourteen novel vanin-1 inhibitors coded OMP-# were designed from RR6 and successfully synthesized by a nucleophilic addition-elimination reaction of the pantetheinic acid-derived Weinreb amide as a key step under Barbier conditions. The synthesized OMP compounds exhibited inhibitory activity against human serum vanin-1 in vitro. Among the synthesized compounds, OMP-7, which possesses a trifluoromethoxy group at the para-position on the phenyl ring, exhibited the most potent activity, approximately 20 times that of the mother compound RR6. OMP-7 was further subjected to an in vivo assay using a normal hamster. More potent activity was observed than that of RR6 against both serum and renal vanin-1. The activity lasted for 4 h after injection against serum vanin-1 and 1 h after injection against renal vanin-1, whereas RR6 did not show the desired activity.

The direct 4-alkoxylation of 4-iodo-1H-pyrazoles with alcohols was achieved by a CuI-catalyzed coupling protocol. The optimal reaction conditions employed excess alcohol and potassium t-butoxide (2 equiv) in the presence of CuI (20 mol%) and 3,4,7,8-tetramethyl-1,10-phenanthroline (20 mol%) at 130 °C for 1 h under microwave irradiation. The present method was efficiently applied to the synthesis of withasomnine and its six- and seven-membered cyclic homologs.

3-Trifluoromethanesulfonyloxy-4,7-dihydropyrazolo[1,5-alpha]pyridine (9) was successfully synthesized from the starting material, pyrazole, via a sequence of reactions containing ring-closing metathesis as a key step. Suzuki-Miyaura coupling of 9 with various arylboronic acids, followed by oxidation or hydrogenation, readily afforded pyrazolo[1,5-alpha] pyridines (11) or 3-aryl-4,5,6,7-tetrahydropyrazolo[1,5-alpha]pyridines (12), respectively. Compounds 12 were found to be withasomnine homologs.

The reaction of cyanophosphates, which are readily derived from γ-ketoaldehyde acetals, with TMSN3 (3 eq)/Bu2SnO (0.3 eq) in refluxing toluene directly furnished 3-substituted-2-cyclopentenones in modest to good yield under mild conditions. The present method was further applied toward the synthesis of dechlorotrichodenone C isolated from Trichoderma asperellum.

Alkylamino coupling reactions at the C4 positions of 4-halo-1H-1-tritylpyrazoles were investigated using palladium or copper catalysts. The Pd(dba)2 catalyzed C-N coupling reaction of aryl- or alkylamines, lacking a β-hydrogen atom, proceeded smoothly using tBuDavePhos as a ligand. As a substrate, 4-Bromo-1-tritylpyrazole was more effective than 4-iodo or chloro-1-tritylpyrazoles. Meanwhile, the CuI mediated C-N coupling reactions of 4-iodo-1H-1-tritylpyrazole were effective for alkylamines possessing a β-hydrogen atom.

Treatments of various nitrites with TMSN3 and Bu2Sn(OAc)(2) at 30 degrees C in benzene for 60 h yielded the corresponding 5-substituted 1H-tetrazoles in good to excellent yields. This method is a mild and efficient alternative reagent system for Wittenberger tetrazole-synthesis that uses TMSN3 and Bu2SnO in toluene at high temperature (93-110 degrees C) for 24-72 h. (C) 2019 Elsevier Ltd. All rights reserved.

Inspired by the significant α-glucosidase inhibitory activities of (+)- and (−)-pericosine E, we herein designed and synthesized 16 analogs of these marine natural products bearing a methoxy group instead of a chlorine atom at C6. Four of these compounds exhibited moderate α-glucosidase inhibitory activities, which were weaker than those of the corresponding chlorine-containing species. The four compounds could be prepared by coupling reactions utilizing the (−)-pericosine B moiety. An additional in silico docking simulation suggested that the reason of reduced activity of the C6-methoxylated analogs might be an absence of hydrogen bonding between a methoxy group with the surrounding amino acid residues in the active site in α-glucosidase.

Novel pyrazole-fused heterobicyclic systems, i.e., trihydrooxocino[3,2-c]pyrazoles, tetrahydrooxonino[3,2-c]pyrazoles, and pentahydrooxecino[3,2-c]pyrazoles, were synthesized starting from 3-or 5-allyl-4-hydroxy-1H-pyrazoles via ring-closing metathesis (RCM) as the key step for the construction of the medium-sized rings (8-to 10-membered rings).The RCM reactions at room temperature required longer times and gave lower yields than those in our previous studies on the preparation of normal RCM products with 6-or 7-membered rings.The microwave-assisted RCM generally afforded double-bond migrated products or ring-contracted products along with normal RCM products.