A Total Synthesis of (−)-Hamigeran B and (−)-4-Bromohamigeran B

Abstract

A concise synthesis of (-)-hamigeran B and (-)-4-bromohamigeran B is presented. The key reactions include a Suzuki coupling of enol triflate 15 with arylboronic ester for efficient synthesis of the densely 1,2,3-trisubstituted cyclopentene 23, a coordination-controlled intramolecular Friedel-Crafts cyclization of free phenol 13 for highly regioselective construction of tricyclic core 12, and a LiOH/O-promoted hydrolysis and concomitant aerobic oxidation of 31 for atom- and step-economic accessing of diketone 32. The application of these key transformations allowed for a rapid and efficient synthesis of (-)-hamigeran B and (-)-4-bromohamigeran B in 13 steps from the readily available chiral material 18.

Pd-Catalyzed Aerobic Oxidative Heck Cross-Coupling for the Straightforward Construction of Indole δ-Lactams

“…Accordingly, we shifted our focus to a phosphinamide-based palladacycle catalyst 16, which was developed previously by our group (Du et al., 2015, Guan et al., 2014). A supportive clue, albeit not tightly related with the proposed Heck-type reaction, that encouraged us to inspect this catalyst herein is that 16 exhibited extremely high catalytic activity for mild Suzuki coupling of a broad range of arene ( pseudo )halides (Wu et al., 2015, Wu et al., 2018, Cao et al., 2018). To our delight, the use of 16 as catalyst did improve substantially the yield of 15a to 72% (entry 4).…”

Synthesis and Biological Evaluation of Diversified Hamigeran B Analogs as Neuroinflammatory Inhibitors and Neurite Outgrowth Stimulators

“…The synthetic route for the synthesis of the hamigeran B skeleton is illustrated in Scheme 1. The synthesis of diol 9a commenced with preparation of chiral phenolic compound 7 starting from precursor S1 which was prepared from a readily affordable 2-methyl-1,3-cyclopentanedione over six steps with 13% total yield, according to the previously reported protocol [26]. The compound S1 was treated by OsO 4 and NaIO 4 to give the aldehyde 7 a 70% yield, which was unstable in air [26].…”

“…The synthesis of diol 9a commenced with preparation of chiral phenolic compound 7 starting from precursor S1 which was prepared from a readily affordable 2-methyl-1,3-cyclopentanedione over six steps with 13% total yield, according to the previously reported protocol [26]. The compound S1 was treated by OsO 4 and NaIO 4 to give the aldehyde 7 a 70% yield, which was unstable in air [26]. The tricyclic compound 8 is envisioned as being constructed through a key intramolecular Friedel-Crafts cyclization of aldehyde 7 with 70% yield.…”

“…For the coupled product 14, we preferred to examine the Suzuki cross-coupling of 13 with pinacol boronate instead of the corresponding boronic acid that was used previously in Trost's synthesis [29]. Oxidation of the olefinic 14 was conducted by using a combination of OsO 4 and NaIO 4 to give 90% yield of the aldehyde 15, which was unstable in the air [26]. The compound 16 was envisioned as being constructed via an intramolecular Friedel-Crafts cyclization as the key reaction of 15 followed by protection of the phenol hydroxyl with MeI.…”

“…The two small families of natural products have aroused considerable interest from the research communities of natural products, pharmacology, and synthetic chemistry because of their unique structures with intriguing biological potential [22][23][24][25]. Many synthetic endeavors have been devoted to the synthesis of hamigeran B (2), and our group achieved the total synthesis of hamigeran B in 2018 [23][24][25][26][27]. However, the novel pharmacological properties of hamigeran B analogs have not been assessed in anti-neuroinflammatory and neurotrophic activity so far.…”