Synthesis of the Sporolide Ring Framework through a Cascade Sequence Involving an Intramolecular [4+2] Cycloaddition Reaction of an o‐Quinone

Abstract

In a recent publication, Fenical and co-workers [1] reported the structural characterization of the two unique molecular frameworks of sporolides A (1) and B (2; Scheme 1). Isolated from the fermentation broths of a strain of the marine-derived actinomycete Salinispora tropica, these compounds feature molecular architectures that contain 24 carbon atoms (among which only two are not oxygenated or sp 2 hybridized), 10 stereogenic centers, and no less than seven rings. These marine natural products present an intriguing synthetic challenge in view of their unprecedented molecular structures and the opportunity they present for the development of novel synthetic strategies. Herein we report the construction of model system 3, which represents the structural skeleton of sporolide A (1) and B (2) and contains all seven rings of the naturally occurring molecules, through a cascade sequence involving an unprecedented intramolecular [4+2] cycloaddition reaction of an olefinic o-quinone.Scheme 2 shows the retrosynthetic analysis of the sporolide model system 3. Thus, the target molecule was envisioned to arise by selective manipulation of the trioxygenated aromatic nucleus of hexacyclic compound 4 a, whose macrocycle and dioxane moieties were simultaneously dismantled through a retro o-quinone [4+2] cycloaddition reaction to reveal o-quinone ester 5 as a possible intermediate, whose generation from catechol 6 was considered standard. While the origin of precursor 6 was clear (that is, from building blocks 7 and 8), the transformation of o-quinone 5 to macrocycle 4 a through the intended cycloaddition reaction was based on a rather daring hypothesis since we were aware of no precedent for such an intramolecular reaction of an o-quinone. [2,3] Furthermore, should such a scenario be possible, its stereochemical outcome could only be speculated upon at the outset. Encouragingly, both molecular models and molecular mechanics calculations, together with electronic considerations, indicated the desired regio-and diatereoisomer to be favored. Thus, of the four possible isomers of 4 a (4 a-4 d, Scheme 3), the desired isomer 4 a was predicted to be the most favored on the basis of electronic (preferential activation of the C6-carbonyl oxygen atom by the C4'-OBn moiety; conjugated addition of the C6-carbonyl oxygen atom onto C10 of the olefinic bond, Scheme 1. Molecular structures of sporolides A (1) and B (2) as well as sporolide ring framework 3.Scheme 2. Retrosynthetic analysis of sporolide ring framework 3.

Total Synthesis of Sporolide B

“…This strategy was based on two key retrosynthetic disconnections: 1) a thermally induced, intramolecular [4+2] cycloaddition reaction involving an o-quinone and a tetrasubstituted olefin to form the macrocyclic structure of the molecule (2!1 b), [6] and 2) a ruthenium-catalyzed, intermolecular [2+2+2] cycloaddition reaction between two acetylenic units, [7] building blocks 3 and 4, to forge its chlorobenzenoid indane structural motif. The complexity of the substrates involved in these planned reactions and the lack of any precedent for their application in complex natural product synthesis made them risky propositions with regards to both feasibility and topology (regio-and stereoselectivity).…”

Cycloadditionen in der Totalsynthese von Sporolid B

“…Obwohl offensichtlich gewagt, ist es eine Mög-lichkeit zur Entwicklung neuer Synthesestrategien, wie die Autoren betonen. [8] Um die benötigte Effizienz dieser Cycloaddition bezüglich Ausbeute und Stereoselektivität zu gewährleisten, wurden das ortho-Chinon-Heterodien und das Inden-Dienophil in ein im Wesentlichen bereits wie die Naturstoffe funktionalisiertes Molekül eingebettet. In diesem Sinne könnte die Strategie als biomimetisch betrachtet werden.…”

“…[5a,b, 6] Eine frühere Studie zu diesem Ansatz mit einem vereinfachten Modellsubstrat hatte zu vielversprechenden Ergebnissen geführt. [8] Somit dient eine neuartige intramo- [10] entstand das gewünschte Cycloadditionsprodukt innerhalb von 30 Minuten in 87 % Ausbeute als einziges Regioisomer (Schema 2). Die Autoren bezeichnen dies als erfolgreiche Integration einer anspruchsvollen Struktur mit chemischem Design.…”

“…Nach Blitzchromatographie wurde das erwartete Cycloadditionsprodukt in 21 % Ausbeute isoliert (40 % bezogen auf zurückgewonnenes Ausgangsmaterial). Das Resultat war weniger befriedigend als bei der früheren Modellstudie, [8] aber immer noch beachtlich, wenn man die Substratkomplexität bedenkt. Die bemerkenswerte Diastereoselektivität (Seitenselektivität des ortho-Chinons relativ zum Inden-Dienophil) kann durch die sterische Ausrichtung der Substituenten erklärt werden: In 6-TS deuten alle Substituenten an den beiden fünfgliedrigen Ringen nach oben und blockieren so die Oberseite.…”

“…Schwerer zu erklären ist hingegen die Seitenselektivität bezüglich des ortho-Chinons, das theoretisch um die C2'-C3'-Bindung rotieren und eine vergleichsweise günstigere Konformation für die gewünschte [4+2]-Cycloaddition einnehmen könnte. Auf Basis früherer Modellrechnungen [8] könnte eine ungünstige 1,3-Benzylspannung zwischen der 4'-OBn-und der 2'-OMe-Gruppe in dem …”