Synthesis of Spongidine A and D and Petrosaspongiolide L Methyl Ester Using Pyridine C–H Functionalization

Abstract

An efficient strategy for the synthesis of the potent phospholipase A2 inhibitors spongidine A and D is presented. The tetracyclic core of the natural products was assembled via an intramolecular hydrogen atom transfer-initiated Minisci reaction.A divergent late-stage functionalization of the tetracyclic ring system was also used to achieve a concise synthesis of petrosaspongiolide L methyl ester.

C–H Functionalization-Enabled 11-Step Semisynthesis of (−)-Veragranine A and Characterization of Synthetic Analogs in Osteoarthritis-related Pain Treatment

“…With compound 20 in hand, we next focused on the HAT-initiated Minisci C–H cyclization. Starting from the previously reported conditions − and after comprehensive optimizations (see the Supporting Information), we identified a combination of Mn­(OAc) 3 , PhSiH 3 , and Ti­(OMe) 4 in mixed THF/MeOH as the optimal conditions to deliver the desired product 21 in 60% yield together with its isomer 22 in 15% yield on 3 × 80 mg scale. 22% yield of 20 was recovered as well.…”

Deoxygenative Intramolecular Minisci‐Type Reaction to Access Fused Heterocyclic Scaffolds

“…[6] This strategy was later exploited by Christmann as the key step in the synthesis of Spongidine A and D, and Petrosaspongiolide L methyl ester. [7] The same year, Laha reported a silver-free protocol to access azafluorenones and fluorenones via an intramolecular Minisci-type acylation reaction. [8] Finally, in 2019, Sherwood and Shiao reported a redox neutral, photoredox strategy to access Csp 3 -rich [9] fused heterocyclic scaffolds using N-(acyloxy)phthalimides as radical precursors.…”

“…For example in 2017, Starr adapted Baran's Fe‐mediated olefin hydrofunctionalisation strategy [5] to develop an efficient olefin hydropyridation reaction [6] . This strategy was later exploited by Christmann as the key step in the synthesis of Spongidine A and D, and Petrosaspongiolide L methyl ester [7] . The same year, Laha reported a silver‐free protocol to access azafluorenones and fluorenones via an intramolecular Minisci‐type acylation reaction [8] .…”

Synthesis of Highly Functionalized Pyridines: A Metal-Free Cascade Process

“…(1) the traditional multicomponent condensations, 4 (2) hetero-[4+2] cycloadditions, 5 (3) transition metal-mediated or organo-mediated cycloadditions, 6 (4) 6π-electrocyclizations, 7 and (5) pyridine ring C−H functionalizations. 8 In addition to these categories, a few other methods have also been reported. 9 Compared to the well-established [3+3], [4+2], and [2+2+2] cycloadditions for the synthesis of pyridines, [5+1] approaches have rarely been investigated, and only a few methods have been documented (Scheme 1).…”

“…In the literature, various synthetic methods have been documented and can be classified mainly into five categories: (1) the traditional multicomponent condensations, (2) hetero-[4+2] cycloadditions, (3) transition metal-mediated or organo-mediated cycloadditions, (4) 6π-electrocyclizations, and (5) pyridine ring C–H functionalizations . In addition to these categories, a few other methods have also been reported …”