The Frondosins: An Unusual Synthetic and Stereochemical Journey

Abstract

Isolated from the marine sponge Dysidea frondosa, the frondosin family of meroterpenoid natural products were shown to be antagonists of the binding of the cytokine interleukin‐8 to its receptor. With implications of interleukin‐8 management being associated with a wide range of acute and chronic inflammatory disorders, as well as tumor progression and/or metathesis, there have been a multitude of syntheses of these natural products in the hopes of developinging new pharmacological agents. However, assignment of the absolute configurations of these natural products became unclear, because the first two syntheses of frondosin B, by Danishefsky and by Trauner, produced conflicting assignments for the single stereogenic center at C8. Here we describe the initial stereochemical mystery surrounding the Danishefsky and Trauner syntheses and provide evidence through ensuing syntheses of frondosins B and A that resolve this issue. These subsequent asymmetric syntheses have established that (1) the natural product occurs as the R enantiomer, and (2) a late‐stage stereochemical inversion occurred during the Trauner and Wright syntheses of frondosin B.

Beyond optical rotation: what's left is not always right in total synthesis

“…In this work, we describe the direct assignment of absolute configuration of the natural product frondosin B 11 and relevant synthetic intermediates through the combined use of OR, VCD, and ECD. Careful analysis was performed to establish both the chemical and enantiomeric purities of intermediates to ensure that the reported optical rotation values were the result of the compound of interest and not impurities.…”

Bioactive Prenyl- and Terpenyl-Quinones/Hydroquinones of Marine Origin †

“…A different rearrangement of the sesquiterpenoid skeleton led to a 6–7 carbocyclic framework as in frondosins (frondosin A, 250 ) or liphagal ( 251 ) ( Figure 22 ). Although these compounds were described before the period covered by this review, several synthetic studies have been performed during this time to clarify conflicting assignments on some stereocentres [ 107 , 108 , 109 ]. These were well compiled in the Wright’s review [ 108 ].…”

“…In other cases, natural products were used as the starting material. The strategies used in the synthesis of different TQs/THQs were the main subject of previous reviews [ 108 , 161 ], so this section is not intended to be exhaustive, but rather to focus in the idea of using natural products, particularly terpenoids, as the starting point to obtain a variety of bioactive analogues of marine natural products.…”

Total Synthesis of Bioactive Marine Meroterpenoids: The Cases of Liphagal and Frondosin B

“…The Wright synthesis [ 30 , 31 ] was centered on a formal [4 + 3] cycloaddition reaction to generate the key 6,7-fused ring motif ( Figure 13 ). This strategy was utilized on a collective total synthesis of (+)-liphagal and (−)-frondosin A as well.…”

“…There also were many synthetic efforts towards other frondosin members, including Trost’s total synthesis of (+)-frondosin A using Ru-catalyzed [5 + 2] cycloaddition [ 34 , 35 ]. An early review on synthesis of frondosins was summarized in 2011 [ 36 ] as well as in 2015 [ 31 ].…”