Tetrahedron Letters最新文献

Two bicyclic hexapeptides RA-XXVII and RA-XXVIII, featuring a phenylpropanoid unit attached to the aromatic ring of the Tyr-6 residue of deoxybouvardin, were isolated from the roots of Rubia cordifolia L. Their structures were determined on the basis of spectroscopic data and X-ray crystallography of the 4-O-methyl derivative of RA-XXVII, and the semisynthesis from deoxybouvardin and coniferyl alcohol. RA-XXVII and RA-XXVIII exhibited cytotoxic activity with IC₅₀ values of 0.051 and 0.18 μM, respectively, against the HL-60 cell line, and 0.18 and 0.78 μM, respectively, against the HCT-116 cell line.

The rational design of atropisomeric small molecules is becoming increasingly common in chemical synthesis as a result of the unique advantages this property provides in drug discovery, asymmetric catalysis, and chiroptical activity. In this study, we designed a synthesis of a configurationally stable β-carboline in six steps. Our synthesis made use of an innovative Grignard addition/elimination reaction that formed an yne-ynamide precursor that then reacted with ethyl cyanoformate in a rhodium(I)-catalyzed [2 + 2 + 2] cyclotrimerization reaction to give the atropisomeric β-carboline in excellent yield, good enantioselectivity, and excellent regioselectivity. Extensive optimization of this transformation is described. Racemization kinetics experiments were also conducted on the individual atropisomers and their absolute configurations were determined by circular dichroism.

It is particularly significant to develop mild and efficient methods to construct 2-aryl-substituted benzoic acids framwork due to their wide existence in many important natural organic compounds. Here, we report a concise and mild method to synthesize ortho-arylation of benzoic acids. In this mild catalytic system, decarboxylation byproducts were not observed. Meanwhile, the high yields could be obtained in the absence of ligands.

ATAD2 has received attention as one of the potential oncogene with tumor-promoting aspects in many malignancies. ATAD2 is a highly conserved bromodomain family protein that exerts its biological functions by mainly AAA ATPase and bromodomain. Several small molecule inhibitors have been described in the literature. AZ13824374 (1) recently reported by Holt and co-workers showed promising in vitro (bio-chemical, cellular) and antiproliferative activity in range of breast cancer models. In this work, we described scalable synthetic route for triazolopyridazine derivative (2), a key intermediate of AZ13824374 (1) without using CO in the process. Triazolopyridazine helps to attain the bioactive conformation for AZ13824374 (1) through its crucial interaction with Tyr 1021 of ATAD2. Additionally, triazolopyridazine is extensively used as an intermediate for anticancer agents. This encouraged us to develop cost-effective and scalable process for it.

A combination of rare-earth metal amides RE[N(SiMe₃)₂]₃ and chiral phenoxy-functionalized amino alcohol proligands was developed to realize the enantioselective Michael addition of malonates with unsaturated ketones. The reactions catalyzed by samarium amide Sm[N(SiMe₃)₂]₃ were performed best together with the chiral proligand H₃L¹ (H₃L¹ = 2,4-di-tert-butyl-6-((((1S,2R)-2-hydroxy-1,2-diphenylethyl) amino)methyl)phenol) in DCE with good group tolerance, mostly in high to excellent yields (85–98 %) and good to excellent ee values (50− >99 %). The possible mechanism was also proposed.

The first concise synthesis of nepodin-1-O-β-d-glucopyranoside (D-1) and its l-glucopyranoside (L-1), as well as torachrysone-1-O-β-d-glucopyranoside (D-2) and its l-glucopyranoside (L-2), was achieved via Fries rearrangement and selective glycosylation. Spectral data, particularly the specific rotation signs of the synthetic l-glucosides, correlated with those of natural products previously isolated from Rumex dentatus. This confirms the presence of naturally occurring l-glucosides, L-1 and L-2, identified through synthetic approaches.

The development of anticancer agents targeting EGFR represents a promising strategy in the field of medicinal chemistry. Consequently, a novel series of 1,2,3-triazole – [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hybrids (7a-i & 8a-f) were designed, synthesized, and screened for their in vitro anticancer activity against three human breast cancer cell lines, MCF-7, MDA-MB-231, and MDA-MB-415. Notably, hybrids 7f and 7h, featuring 4-fluorophenyl and 3,5-dichlorophenyl substitutions, respectively, exhibited superior activity against MCF-7 and MDA-MB-231 cell lines, and comparable activity against MDA-MB-415 cell line, compared to the standard drug Erlotinib. Toxicity studies on the noncancerous breast cell line MCF-10A indicate that these compounds are selective for cancer cell lines. Furthermore, these compounds demonstrated high efficacy in the in vitro EGFR inhibition assay, with IC₅₀ values of 0.419 ± 0.05 μM and 0.312 ± 0.02 μM, respectively, in comparison to Erlotinib (IC₅₀: 0.421 ± 0.03 μM). In silico experiments, including molecular docking studies to elucidate the interaction mode with the EGFR active site and ADMET analysis to verify drug-likeness properties, were also conducted for the potent compounds. Both experimental and in silico investigations suggest that compounds 7f and 7h hold promise as lead compounds for further drug design and development endeavors.

Total synthesis of (±)-applanatumol W, formal syntheses of (±)-spiroapplanatumine O and (±)-applanatumol B were accomplished using a common intermediate, methyl benzoyl cyclopentane carboxylate 9. This intermediate was synthesized through a one-pot reaction involving formation of Michael acceptor cyclopentenone through first Michael addition of malonate to acrolein, Aldol condensation and dehydration, followed by Michael addition of allylcuprate and subsequent demethoxycarboxylation.

We herein describe a nickel-catalyzed cascade cyclization of alkynyl nitriles with tert-butylisocyanide under simple reaction conditions. A couple of polysubstituted pyrroles were obtained in moderate yields and with excellent regioselectivity in some cases. The products from this protocol are synthetically useful since the parent pyrrole ring bears one free amino and two cyano groups which enable diverse late-stage transformations.

An efficient synthesis of lauryl thioglycoside of oxazolidinones derived from N-acetyl neuraminic acid was accomplished from a known thioglycoside of Neu5Ac. The O-glycosidation reactivities of the oxazolidinones were evaluated by means of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and N-iodosuccinimide (NIS) as a combined-mediator system. The glycosidation reaction of the lauryl thioglycoside with simple alcohols proceeded smoothly to yield the corresponding α-glycosides in good yields after isolation. The results suggested that the glycosylation reaction using the oxazolidinone derivative of sialic acid has excellent α-stereoselectivity and enables easy isolation of the desired product from the reaction mixture.