Synthesis of High-Order and High-Oxidation State Securinega Alkaloids

Abstract

Conspectus Securinega alkaloids, composed of more than 100 members characterized by the compact tetracyclic scaffold, have fascinated the synthetic community with their structural diversity and notable bioactivities. On the basis of the structural phenotype, oligomerizations and oxidations are major biosynthetic diversification modes of the basic Securinega framework. Despite the rich history of synthesis of basic monomeric Securinega alkaloids, the synthesis of oligomeric Securinega alkaloids, as well as oxidized derivatives, has remained relatively unexplored because of their extra structural complexity. In the first half of this Account, our synthetic studies toward high-order Securinega alkaloids are described. We aimed to establish a reliable synthetic method to form C14–C15′ and C12–C15′ bonds, which are prevalent connection modes between monomers. During our total synthesis of flueggenine C (9), we have invented an accelerated Rauhut–Currier reaction capable of forming the C14–C15′ bond stereoselectively. Installation of the nucleophilic functionality to the Michael acceptor, which ushers the C–C bond forming conjugate addition to follow the intramolecular pathway, was the key to success. The C12–C15′ linkage, which was inaccessible via an accelerated Rauhut–Currier reaction, was established by devising a complementary cross-coupling/conjugate reduction-based dimerization strategy that enabled the total synthesis of flueggenines D (11) and I (14). In this approach, the C12–C15′ linkage was established via a Stille cross-coupling, and the stereochemistry of the C15′ position was controlled during the following conjugate reduction step. In the later half of this Account, our achievements in the field of high-oxidation state Securinega alkaloids synthesis are depicted. We have developed oxidative transformations at the N1 and C2–C4 positions, where the biosynthetic oxidation event occurs most frequently. The discovery of a VO­(acac)2-mediated regioselective Polonovski reaction allowed us to access the key 2,3-dehydroallosecurinine (112). Divergent synthesis of secu′amamine A (62) and fluvirosaones A (60) and B (61) was accomplished by exploiting the versatile reactivities of the C2/C3 enamine moiety in 112. We have also employed a fragment-coupling strategy between menisdaurilide and piperidine units, which allowed the installation of various oxygen-containing functionality on the piperidine ring. Combined with the late-stage, light-mediated epimerization and well-orchestrated oxidative modifications, collective total synthesis of seven C4-oxygenated securinine-type natural products was achieved. Lastly, the synthesis of flueggeacosine B (70) via two synthetic routes from allosecurinine (103) was illustrated. The first-generation synthesis (seven overall steps) employing Pd-catalyzed cross-coupling between stannane and thioester to form the key C3–C15′ bond enabled the structural revision of the natural product. In the second-generation synthesis, we have invented visible-light-mediated, Cu-catalyzed cross-d...

Total Synthesis of 4α-Hydroxyallosecurinine and Securingine F, Securinega Alkaloids with a C4-Hydroxy Handle for Biofunctional Derivatizations

“…Furthermore, we envisioned to couple the newly developed strategy that enables the introduction of the hydroxyl group at C4 position of the securinega skeleton with our previously established synthetic chemistry toward various high-order and high-oxidation state securinega alkaloids. 11 It would enable the synthesis of various complex high-order and high-oxidation state securinega alkaloids with a C4-hydroxyl handle. Those congeners can be subjected to biofunctional derivatizations and biological studies.…”

“…Securinega alkaloids have fascinated the chemical community for over six decades because of their promising biological activities and intriguing structures. [9][10][11] They show a potent antitumor activity that is based on cytotoxicity, differentiation-induction activity, and the reversal of multidrug-resistance activity. 12 Securinega alkaloids also exhibit nervous-system-related and cardiovascular-system-related activities.…”

Transformation of (allo)securinine to (allo)norsecurinine via a molecular editing strategy

“…Securinega alkaloids, composed of over 100 members, have fascinated the synthetic community owing to their structural diversity ( Wehlauch and Gademann, 2017 ; Kang et al, 2023 ) and potent bioactivities ( Hou et al, 2023 ) since the isolation of securinine ( 2 ) in 1956 ( Muraveva and Bankovskii, 1956 ). Securinane alkaloids, exemplified by allosecurinine ( 1 ) and securinine ( 2 ), are characterized by an azabicyclo[3.2.1]octane core (B/C rings), fused with a piperidine (A) and butenolide (D) rings ( Scheme 1A ).…”

Re-examining the stereochemistry of polycyclic suffruticosine via TDDFT calculations, ECD spectroscopy, and chemical synthesis

“…Interestingly, structurally complex Securinega alkaloids resulting from the biosynthetic dimerization and oxidation of the fundamental tetracyclic unit have been found. 2 Despite the successful determination of the atom connectivity of highly oxidized Securinega alkaloids, the precise assignment of their stereochemistry has remained a significant challenge.…”