Concise Access to the Skeleton of Protoilludane Sesquiterpenes through a Photochemical Reaction Cascade: Total Synthesis of Atlanticone C

Abstract

In asingle photochemical operation (l ! 350 nm) an easily accessible indanone derivative was converted into as tructurally complex precursor of the protoilludane sesquiterpenes.T he product (60 %y ield) contains all 15 carbon atoms of the skeleton in the required connectivity and was transformed into the natural product atlanticone C( 9s teps, 6% overall yield). In addition, it was shown that other protoilludanes,s uch as D 6 -protoilludene and paesslerin A, can be prepared in aconcise fashion via the photochemical key intermediate.T he photochemical reaction cascade comprises an ortho photocycloaddition, athermal disrotatory ring opening and ar egioselective disrotatory [4p]p hotocyclization.The protiolludane skeleton A (Figure 1) represents an intriguing natural product scaffold and is the hallmark of many biologically active sesquiterpenes.Acentral cyclohexane ring is flanked by ac yclobutane ring with aq uaternary carbon center C-3 and by a gem-dimethyl-substituted cyclopentane ring at positions C-2 and C-9. Thep rotoilludane biosynthesis [1] from farnesyl pyrophosphate via cationic intermediates is testimony to the masterful ability of nature to create molecular complexity from simple building blocks. Representative sesquiterpenes with this structure element include atlanticone C( 1), [2] D 6 -protoilludene (2), [3] and paesslerin A( 3). [4] Many synthetic approaches have been described to tackle the challenging core structure of the protoilludanes. [5] One set of syntheses aimed at ac onstruction of the tricyclic skeleton from acyclic or monocyclic precursors in amanner mimicking their biological genesis from humulene. [6] In several other approaches,t he rings were built consecutively, [7] with the construction of the cyclobutane ring requiring particular attention. Notable photochemical strategies [8] to secure formation of the four-membered ring include the common [2+ +2] photocycloaddition [9] but also some less frequently used methods such as the photochemical 1,3-acyl shift reaction of b,g-unsaturated enones. [10] Our interest in protoilludanes was triggered by recent work [11] on ar eaction cascade [12] that is initiated by an ortho photocycloaddition and that generates the bicyclo[4.2.0]octane skeleton, acore element of structure A,inasingle operation. Herein, we disclose aconcise access to protoilludane sesquiterpenes that culminated in the first total synthesis of atlanticone C( 1)a nd in the stereoselective synthesis of two other advanced intermediates that had been previously converted into D 6 -protoilludene (2)a nd paesslerin A( 3).Arenes B (Scheme 1), which have ac arbonyl group in ortho position to an alkenyloxy group,are known to undergo an initial [2+ +2] photocycloadditon at the arene (ortho photocycloaddition [13,14] ). Products C are unstable and form cyclooctatrienes D through ad isrotatory ring opening.I ns ome cases,t hese products have been isolated [15] but the most frequent reaction pathway is ac onsecutive disrotatory [4p] Figure 1. The protoilludane skeleton A and representa...

The Application of Dioxygenase‐Based Chemoenzymatic Processes to the Total Synthesis of Natural Products

“…So, on treating this with 0.25 mole equivalents of SnCl 2 av ery smooth reactiont ook place to afford the tricyclic isomer 43. Hydrogenolytic cleavageoft he associated benzyl ether residue under standard conditions then gave diol 44 that was elaborated over af urther four standard steps, and involving intermediates 45-47,i nto the sesquiterpene patchoulenone ( 48). [39] The Diels-Alder adduct 40 (Scheme 7) derived from diol 2 (X = Me) can be manipulatedi nv ariouso ther ways including through acid-catalyzed cleavage of the associated acetonide unit and thereby affording the trans-diol 49,acompound that presumably arises through ar etro-aldol/re-aldolization process.…”

“…Over af urther three steps this photoproduct could be elaborated to then atural product (+ +)-armillarivin (65). [46] Scheme6.Exploitingc ompound 38 in the synthesis of the sesquiterpene patchoulenone (48).…”

Ciamician‐González‐Vorlesung: N. Martín / Premio a la excelencia investigadora: R. Fernández / Leibniz‐Preis: T. Bach

“…Über Bach war in dieser Rubrik zu lesen, als ihm die Gesellschaft Deutscher Chemiker ihre Emil‐Fischer‐Medaille verlieh . In einer Angewandte‐Chemie ‐Zuschrift stellte er kürzlich eine photochemische Route zum Protoilludan‐Sesquiterpengerüst vor …”

Ciamician–González Lectureship: N. Martín / Premio a la excelencia investigadora: R. Fernández / Leibniz Prize: T. Bach

“…Bach was last featured in this section when he won the Emil Fischer Medal of the German Chemical Society (Gesellschaft Deutscher Chemiker) . In a Communication in Angewandte Chemie he recently proposed a photochemical route to the protoilludane sesquiterpene scaffold …”