Towards the Synthesis of Massadine: A Unified Strategy for the Stereoselective Synthesis of the Carbocyclic C,D‐Ring Subunit

Abstract

Massadine is a hexacyclic marine natural product, which belongs to the family of pyrrole-imidazole alkaloids. Herein, we describe a unified approach to the C,D-ring subunit of this sponge metabolite based on the exploitation of a norbornene scaffold for the stereocontrolled construction of massadine's carbon skeleton. Highlights of the sequence presented include the application of a stereospecific norbornyl rearrangement for facile introduction of an oxygen at the C7-position within the norbornene nucleus, a highly regioselective and end group differentiating ozonolytic scission of a C-C double bond, and an oxidative decarboxylation reaction for the installation of the hindered secondary C2-alcohol function. Furthermore, the iterative assembly of the two guanidine entities as well as the implementation of the spirocyclic junction between the C- and the D-rings are described. Collectively, these key transformations permit an entry to an appropriately functionalized carbon framework, which will serve as a starting point for our efforts toward the completion of the synthesis of massadine.

End‐Group‐Differentiating Ozonolysis of Norbornene Systems To Afford Highly Substituted Cyclopentane Rings

“…More recently, Carreira's group published a series of three contributions relating to the enantioselective synthesis of fragments of massadine, in which regioselective ozonolytic end‐group differentiation cleavage of a norbornene skeleton was used as the key reaction 7,19,20. In their first example, they reported that ozonolytic cleavage of the norbornene 84a (Scheme ) distinguished between the two sp 2 ‐hybridized carbons.…”

“…They subjected the acetal 89a (Scheme ) to the ozonolytic cleavage conditions to isolate the ester/aldehyde 90a as the only isomer, in yields ranging from 44 to 54 % 20. This transformation suffered from undesired side reactions, predominantly during the second stage of the sequence.…”

Recent advances in deep-sea natural products

“…165 Compound 130 displayed signicant growth inhibitory activity against the Gram-positive bacteria S. aureus and B. subtilis; Gram-negative bacteria E. coli and Pseudomonas aeruginosa; and the fungus C. albicans. [169][170][171][172] Wright and co-workers screened the extracts of 65 sponges, gorgonians, hard corals and sponge-associated bacteria from depths of 50 and 1000 m, giving rise to a 42% bioactivity hit rate overall, and an impressive 72% for sponge and gorgonian extracts. [169][170][171][172] Wright and co-workers screened the extracts of 65 sponges, gorgonians, hard corals and sponge-associated bacteria from depths of 50 and 1000 m, giving rise to a 42% bioactivity hit rate overall, and an impressive 72% for sponge and gorgonian extracts.…”

“…The structurally unique compound exhibited potent antimitotic activity (IC 50 < 10 nM) against human A549 lung adenocarcinoma, PANC-1 pancreatic carcinoma, DLD-1 colorectal carcinoma, and murine P388 leukemia cell lines. 187 The marine sponge T. swinhoei, obtained from Uchelbeluu Reef in Palau at a depth of 100 m, was reported to produce three new anabaenopeptin-like peptides, paltolides A-C (168)(169)(170). 185,186 The deep-sea sponges Theonella swinhoei and Theonella cupola, obtained at a depth of 100-120 m and 90 m, respectively, yielded the new sulfated cyclic depsipeptide, mutremdamide A (161), and six new highly N-methylated peptides, koshikamides C-H (162)(163)(164)(165)(166)(167).…”

Syntheses of cyclic guanidine-containing natural products

“…125,126 They also successfully constructed a fully functionalized massadine synthetic intermediate in 2011. 127,128 Specifically, they prepared ketone 24 from allyldimethylsilyl cyclopentadiene and dimethyl fumarate by a Diels–Alder reaction followed by Tamao oxidation (Fig. 6).…”