Synthetic study toward diterpenoid aberrarone

An approach to aberrarone, an antimalarial diterpenoid natural product with tetracyclic skeleton was reported. Key to the stereoselective preparation of the [6-5-5] tricyclic skeleton includes the mediation of Nagata reagent for constructing the C1 all- carbon quaternary centers and gold-catalyzed cyclopentenone synthesis through C-H insertion.

total synthesis; aberrarone; Pauson-Khand; gold; C-H insertion 2

Marine natural product s have found myriad use in new drug development, exemplified by ET-743 and eribulin.1 Back in 1990s, Rodriguez and co -workers isolated a rich array of terpenoid natural products from Caribbean sea whip, Pseudopterogorgia elisabethae with unprecedented carbon skeleton, most of which showed antitumor, antituberculosis and antimalarial activity. 2-6 Among these structurally intriguing natural product s, aberrarone (1), shows antimalarial activity against chloroquine -resistant strain of Plasmodium falciparum (IC50 = 10 ug/mL) .7 Structurally, aberrarone possess an unusual tetracyclic carbon skeleton yet-to-be found in Pseudopterogorgia elisabethae species, although the related cyclohexane- angularly-fused triquinanes system have been found in waihoensene ( 3), conidiogenone (4), lycopodium alkaloids magellamine (5) and lycojaponicumin (6). Its seven stereogenic centers, including two all-carbon quaternary centers, together with the non-enolizable cyclic -diketone moiety collectively render aberrarone as an attractive but challenging synthetic target. Its congener elisabanolide ( 2) with a lactone in D ring shows their potential biosynthetic relationship. 2 These natural products have been popular synthetic targets mainly due to thei r intriguing structural features. For example, several total synthes es of 3-6 have been reported. 8-28 Previously, two synthetic studies of aberrarone were reported 29,30 and more recently, Carreira and co -workers reported31 the first total synthesis of aberrarone through an impressive cascade reaction including gold-catalyzed Nazarov cyclization, cyclopropanation followed by intramolecular aldol reaction to forge the A, B and D rings. Impressed by the structural features and biological profiles, our grou p embarked a project on the total synthesis of this natural product. Herein we reported our stereoselective synthesis of its 6-5-5 tricyclic skeleton. 3 Figure 1: Selected represent natural product with [6-5-5] tricyclic skeleton Our retrosynthetic analysis is shown in Scheme 1. For the formation of D ring with two quaternary centers and 1,2 -dikeone moiety, Nazarov cyclization 32 of 7 was proposed for synthesizing this challenging moiety. The corresponding precursor cyclopentenone 8 would be afforded from alkynone 9 through the gold-catalyzed C-H insertion.33 Alkynone 9 could be achieved through functional transformation from 10, which itself would be prepared through methylation and c onjugate addition from Pauson-Khand adduct 11. This cyclopentenone could be readily accessed from 1,7- enyne 12 which can be obtained through reported procedure 34 from the commercially available 5-hexenoicacid. Scheme 1: Retro-synthetic analysis of aberrarone. 4

and Discussion Our synthetic route commenced from the known compound 12 which are readily accessed from 5-Hexenoicacid through the reported procedure .34 In the mediation of Co2(CO)8, the 6 -5 bicyclic skeleton 35 was constructed with the right configuration at C6, and the explanation of this stereoselectivity is possible through the conformation of 14 that the OTBS group was in pseudo -equatorial position. Therefore, the PKR proceed to afford 11 containing -H at C 6. F rom this intermediate, to our delight, stereoselective attachment of the requisite methyl group through the corresponding lithium enolate occurred from the convex face of the bicyclic ring system .36 After these two continuous stereocenters were successfully installed, the expected challenging all-carbon quaternary center at C1 was constructed utilizing Nagata reagent (Et 2AlCN). By using this strategy , the stereogenic center at C1 was synthesized, along with a smoothly attachment of the cyanate gr oup served for further functional group transformation to construct the C ring through C -H insertion. The stereochemistry finding of this conjugate addition from the convex face of the 6-5 ring system was further confirmed through X-ray crystallographic analysis. Scheme 2: Synthetic study toward aberrarone. 5 With the key intermediate 10 in hand, we were in a position to test the planned two- step transformation including palladium catalyzed reductive cross coupling with HCO2H followed by Pd/C catalyzed hydr ogenation. To our surprise, the hydrogenation turned out to be a difficult transformation due to the steric hinder ed environment of the trisubstituted double bond , mainly caused by the bulky OTBS group. However, direct subjection of compound 16 to hydrogenation 37 afforded reduction of both triflate and double bond. The plausible pathway for this facile transformation might proceed with first hydrogenation followed by the substitution of the labile triflate ester (for details, see Supporting Info rmation). Moving forward, compound 17 was further converted into alkynone 9 through DIBAL-H reduction, nucleophilic addition and Dess-Martin oxidation. At this stage , t he pivotal C-H insertion step was tried under the reported condition, 33 and cyclopentenone 8 was successfully obtained. Further study with cross coupling or halogen -magnesium exchange shows this moiety is stable for functional group transformation. The attempt for constructing the D ring is currently undergoing.

In summary, w e have developed an approach to assemble the tricyclic skeleton of aberrarone through stereoselective methy lation, conjugate addition and gold- catalyzed C-H insertion from the readily accessed cyclopentenone . Further work to access natural product aberrarone from the key intermediate cyclopentenone 8 is currently underway, and will be reported in due course. 6 Supporting Information The crystallographic data of the compound s 10 (CCDC 2 204711) have been deposited at the Cambridge Crystallographic Database Cente r (http://www.ccdc.cam.ac.uk) Supporting Information File 1: Characterization data and 1H NMR, 13C NMR, and HRMS spectra of the compounds. Funding We are grateful for financial support from Natural Science Foundation of China (Grant No. 21901211).

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