Concise Total Synthesis of Dysoxylactam A and a Simplified Analog

Abstract

Comprehensive Summary A total synthesis of 17‐membered macrocyclolipopeptide dysoxylactam A, a potent agent reversing P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR) in cancer cells, was developed from the starting material (S)‐2‐methylbutanal in a linear sequence of 12 steps with 23.2% overall yield. The key steps include proline‐catalyzed asymmetric aldol reaction, Evans aldol reaction and Krische allylation to construct the multiple stereocenters containing fragment, and ring‐closing metathesis to furnish the macrocycle. This total synthesis facilitates the preparation of large amount samples of dysoxylactam A and the side chain simplified derivatives for further biological tests and preliminary structure‐activity relationship exploration.

Koilodenoids A–G, immunosuppressive spiro dimers of diterpenoids from Koilodepas hainanense: structural elucidation and biomimetic transformation

“…Chemical transformations, especially oxidation and reduction reactions, are very practical in the structural elucidation of complex natural products. [10][11][12][13][14] As shown in Scheme S1, † compound 1 could be biogenetically generated by oxidative cleavage of the Δ 3 double bond of 2. In order to determine the relative and absolute configurations of 1, we attempted to develop selective, high-yielding and operationally simple oxidation methods for the conversion of 2 to 1.…”

“…of chemical transformations in the structural elucidation of complex natural products. [10][11][12][13][14] Biological assays revealed that compounds 1-7 showed moderate immunosuppressive effects against concanavalin A (ConA)-induced proliferation of T lymphocytes and lipopolysaccharide (LPS)-induced proliferation of B lymphocytes.…”

“…1,2 Their structures and absolute configurations were unambiguously established from comprehensive spectroscopic analysis, X-ray crystallography data, and chemical methods, in which, an effective and metal-free aerobic photochemical oxidation allowed the biomimetic transformation of 2 into 1 in a high yield, demonstrating the robust role of chemical transformations in the structural elucidation of complex natural products. 10–14 Biological assays revealed that compounds 1–7 showed moderate immunosuppressive effects against concanavalin A (ConA)-induced proliferation of T lymphocytes and lipopolysaccharide (LPS)-induced proliferation of B lymphocytes.…”

Modular Biomimetic Strategy Enabled Discovery of Simplified Pseudo-Natural Macrocyclic P-Glycoprotein Inhibitors Capable of Overcoming Multidrug Resistance

“…40−43 In this regard, macrocycles offered a promising opportunity for developing novel P-gp inhibitors with both higher potency and better safety profiles. Interestingly, in most cases, the macrocyclic P-gp inhibitors were discovered from natural products (Figure 1A), 44−48 such as jatrophane diterpenoids, 45 dysoxylactam A, 44,49 and cyclolipopeptides. 46 Despite the attractive characteristics offered by them, the difficulty of resupply and limitation of modification sites would hamper the investigations of their structure−activity relationship (SAR) and in vivo antitumor efficacy.…”

“…During recent years, macrocycles as a unique scaffold have received increasing attention in medicinal chemistry due to their 3D conformation and proper flexibility and rigidity, which can favorably alter the biological and physiochemical properties and selectivity in comparison to the acyclic analogue. − In this regard, macrocycles offered a promising opportunity for developing novel P-gp inhibitors with both higher potency and better safety profiles. Interestingly, in most cases, the macrocyclic P-gp inhibitors were discovered from natural products (Figure A), − such as jatrophane diterpenoids, dysoxylactam A, , and cyclolipopeptides . Despite the attractive characteristics offered by them, the difficulty of resupply and limitation of modification sites would hamper the investigations of their structure–activity relationship (SAR) and in vivo antitumor efficacy.…”