Toward a Synthesis of Hirsutellone B by the Concept of Double Cyclization

Abstract

This account describes a strategy for directly forming three of the six rings found in the polyketide natural product hirsutellone B via a novel cyclization cascade. The key step in our approach comprises two transformations: a large-ring forming, nucleophilic capture of a transient acyl ketene and an intramolecular Diels–Alder reaction, both of which occur in tandem through thermolyses of appropriately functionalized, polyunsaturated dioxinones. These thermally induced “double cyclization” cascades generate three new bonds, four contiguous stereocenters, and a significant fraction of the polycyclic architecture of hirsutellone B. The advanced macrolactam and macrolactone intermediates that were synthesized by this process possess key features of the hirsutellone framework, including the stereochemically dense decahydrofluorene core and the strained para-cyclophane ring. However, attempts to complete the carbon skeleton of hirsutellone B via transannular carbon-carbon bond formation were undermined by competitive O-alkylation reactions. This account also documents how we adapted to this undesired outcome through an evaluation of several distinct strategies for synthesis, as well as our eventual achievement of a formal total synthesis of hirsutellone B.

Alkaloids from Marine Fungi: Promising Antimicrobials

“…Through labeling studies, Oikawa elucidated that GKK1032s are produced from l-tyrosine and nine acetate units, as well as l-methionine as a methyl donor [60]; however, more details on the biosynthesis route of these compounds are not known. On the other hand, many chemical syntheses were reported for GKK1032s or their intermediates [61][62][63], as well as for hirsutellones [64][65][66][67][68][69], which are also composed of this unique macroether ether ring. Pyrrospirones and pyrrocidines [70,71] were often neglected since the discovery of these four types of decahydrofluorene-type natural products over 20 years ago.…”

Design and synthesis of molecular scaffolds with anti-infective activity

“…The envisioned four-fragment strategy mentioned above proved amenable to the construction of a variety of advanced precursors, including 119 , 122 and 125, and each of these smoothly underwent the proposed dioxenone-opening/intramolecular Diels–Alder/intramolecular ketene-trapping sequence in respectable yields. 62,63 …”

“…63 Attempts to join C-17 and C-1′ utilizing a multitude of methods to construct the γ -lactam ( 115 to 30 , Scheme 12) failed to produce any of the desired bond formation, a result postulated to arise from a lack of proximity in such a rigid ring system. The variety of synthetic studies towards the hirsutellones and other natural products containing the decahydrofluorene core 64 include two total syntheses of hirsutellone B, reported by the Nicolaou 65a and Uchiro 65b groups, respectively.…”

Our Recent Progress on the Intramolecular Diels–Alder Reaction Approach in Natural Products Synthesis: Synthetic Studies of the Octahydronaphthalene Substructure of Versipelostatins and the A/B/C‐Tricyclic Substructure of GKK1032s

“…The Nay group has been involved in the biomimetic synthesis of hirsutellones and has achieved the formal synthesis of hirsutellones 32 – 33 via an advanced intermediate from the Nicolaou group's total synthesis . Recently, the Sorensen group reported their formal total synthesis of hirsutellone B ( 33 ) by means of an elegant double‐cyclization approach . Halvorsen and Roush have reported a stereoselective and convenient synthesis of the decahydrofluorene core of the hirsutellones …”