Total Synthesis of (±)-Glyceollin II and a Dihydro Derivative

Abstract

Stressed soybeans produce a group of phytoalexins that belong to the 6a-hydroxypterocarpan family of flavonoids. Certain of the more prominent members, such as the glyceollins I, II, and III, have demonstrated potential antidiabetic properties and promising cytotoxicity in both human breast and prostate cancer cell cultures with preliminary studies in animals further demonstrating antitumor effects in estrogen-dependent, human breast cancer cell implants. Although syntheses of glyceollin I have been reported previously, this work constitutes the first total directed synthesis of (±)-glyceollin II. It involves 12 steps with an overall yield of 7% using practical methods that should be readily scalable to produce quantities needed for advanced biological characterization. Highlights include a novel intramolecular benzoin condensation, a chelation-controlled lithium aluminum hydride-mediated reduction, and an intramolecular cyclization via the formation of a transient epoxide intermediate to cap the construction of the 6a-hydroxypterocarpan system. Additionally, a dihydro analogue has been obtained, and several isolated intermediates have been made available for evaluation of their biological properties and possible contributions toward elaborating key structure-activity relationship data among this family of promising phytoalexins elicited from stressed soybeans.

Advances in N‐Heterocyclic Carbene Catalysis for Natural Product Synthesis

“…Glyceollin II (11) was generated in 7 % overall yield after a total of 12 steps. The sphingoid base D-arabino-phytosphingosine (17) exists widely in marine organisms, plants, mammalian tissues, fungi, and yeasts. [19] In their total synthesis of this natural product, Haghshenas and Gravel relied on a Breslow intermediate for intermolecular benzoin cyclization (Scheme 6).…”

Cytochrome P₄₅₀, CYP93A1, as defense marker in soybean

“…Content of glyceollins I and II were quantified and glyceollin III estimated using the liquid chromatographymass spectrometry (LC-MS) method described in Malik et al (2015). Glyceollin data for 48 h damaged stem tissue was log 10 transformed prior to statistical analysis.…”

Benzoin condensation of aromatic aldehydes catalyzed by N-heterocyclic carbenes under mild conditions

“…However, it was until Breslow demonstrated the mode of reaction and proposed a mechanism for the benzoin condensation that the mechanism was understood [21]. Since then, it has attracted considerable interest because their numerous applications: it is used as a model reaction to study the properties of new NHCs [1,7,22,23], preparation of intermediates for the synthesis of anti-neoplastic agents [24], and in the synthesis of natural products [25]. Benzoin products can also be transformed into 1,2-diketones [26][27][28], key intermediates for the synthesis of compounds with biological activity [29][30][31][32][33].…”