Formal Enantioselective Synthesis of Aplykurodinone‐1

Abstract

Aplykurodinone-1 (1) is a degraded sterol that can be isolated from the skin of Syphonota geographica, a mollusc that belongs to the Aplysiidae family (Scheme 1). [1] While the biological profile of this molecule remains unknown to date, the closely related aplykurodinone-B (2) exhibits mild cytotoxic activities. [2] Noteworthy, the structure of 1 features six contiguous stereocenters, including a stereogenic quaternary center, embedded in an intriguing hydroindenone system. As a typical feature of steroids, aplykurodinones contain a lipophilic side chain with the stereocenter at C13 connected to the core. On the other hand, this class of molecules features a cis hydrindane moiety (C7-C8 configuration), a structural framework that is also found in pavidolide B (3). [3] The continued interest in steroids [4] is highlighted by a recent total synthesis of rac-1 by Danishefsky and coworkers, who employed an elegant strategy featuring an ionic Diels-Alder reaction to form the racemic hyndrindane core. [5] "Hajos-Parrish-type" ketones [6] are versatile scaffolds for the formation of complex target molecules, as they are often available in enantioenriched form. [7] As part of our current program of natural product synthesis, we were interested in the development of an oxidative process to expand the potential of the Hajos-Parrish methodology to the synthesis of chiral hydrindenediones with quaternary carbon stereo-centers. [8] Herein, we report the successful implementation of this strategy, resulting in the concise formal enantioselective synthesis of 1.The structure of 1 inspired a synthetic approach in which the formation of the quaternary carbon center C7 is pivotal to the stereoselective assembly of the complete skeleton (Scheme 2). In accordance with this plan, we envisaged the preparation of 7 by Michael coupling of 4 and 5, followed by the enantioselective Robinson annulation of adduct 6. Next, oxidation of 7 at C9 followed by the formal deoxygenation at C11 was planned in order to access 8. A chemoselective reduction of the olefin would lead to the stereocenters at C8 and C3 in 9. Our assumptions were that the cis relationship at C8-C7 could be thermodynamically favored, while the trans relationship at C8-C3 could be changed by epimerization. Then, chemo-and diastereoselective reduction of 9 followed by oxidative lactonization would lead to the known tricyclic system 10. Overall, the stereocenter at C7 of 7 would control the formation of the three other stereogenic centers.To evaluate this strategy, rac-7 was produced on a multigram scale from readily available 4 and 5. [9] In order to perform the formal deoxygenation of 7, the reduction of the ketone moiety at C11 was followed by the mesylation of the resulting hydroxy group to facilitate the elimination step (Scheme 3). Regarding the oxidation of C9, we anticipated that a dienolate formed in the presence of bases such as 1, 8diazabicyclo[5.4.0]undec-7-ene (DBU) would steer the regioselectivity of the process. As it is compatible with this base, molecular oxyg...

The Furan Shuffling Hypothesis: A Biogenetic Proposal for Eremophilane Sesquiterpenoids

“…Zuschriften diazabicycloundecene (DBU) or the guanidine base triazabicyclodecene (TBD), this reaction had been accompanied by oxidation of the C1 À C2 bond of the Bn-or PMB-protected (C7 À OPG) tricarbonyl compounds to give the desired diene dione function prior to cyclization. [13] We applied the same reaction conditions to 12 (Scheme 2) with the aim of not only dehydrogenating the C1ÀC2 bond, but also epimerizing the stereogenic center at C4, that is, a to the carbonyl moiety to form both 1 and microsphaeropsisin C ( 13). Initial attempts by using DBUi nC H 2 Cl 2 only led to trace amounts of the desired compounds.Significantly higher yields of both natural products were achieved by applying TBD as the base.A fter work-up,a nalysis of the 1 HNMR spectra of the crude reaction mixture still indicated the presence of unidentified side products.T herefore,w em onitored this transformation by means of 1 HNMR spectroscopy:w ithin 15 minutes, 1 HNMR signals indicating the formation of an unknown intermediate were observed, and disappeared with prolonged reaction time.Only traces of this intermediate were detected after 4hours,which prompted us to extend the reaction time from 30 minutes to 5hours.T his modification not only gave better yields,i ta lso proved to be the key for the successful isolation of pure 1,after attempts to separate this intermediate from microsphaeropsisin Bh ad been unsuccessful using column chromatography or RP-HPLC.…”

“…Microsphaeropsisin B( 1)h ad already been isolated in 2009 from the endophytic fungi Botryosphaeria rhodina PSU-M35 by the group of Rukachaisirikul, named botryosphaerihydrofuran, and assigned an incorrect structure. [15] Recently,K utateladze and collaborators revised this structure based on computational predictions of its 13 CNMR spectrum and comparison with the reported spectrum for microsphaeropsisin. [16] With our measured 1 Ha nd 13 CNMR spectra of synthetic 1 in CDCl 3 matching those reported for natural botryosphaerihydrofuran, we provide additional supporting evidence to the structural revision by Kutateladze and collaborators.…”

“…TBS = tertbutyldimethylsilyl. Synthesis of the natural products microsphaeropsisins B(1)and C( 13). DMP = Dess-Martin periodinane, TBD = triazabicyclodecene, THF = tetrahydrofuran.…”

Antitumor Effects of Sea Hare-Derived Compounds in Cancer

“…Aplykurodinone-1 possesses a cis-fused C-D ring and an unsaturated side-chain. The total synthesis of aplykurodinone-1 was accomplished as a racemic form [211], followed by an enantiopure form [212].…”

The Furan Shuffling Hypothesis: A Biogenetic Proposal for Eremophilane Sesquiterpenoids

“…[10] Themain challenge for the transition of 7 to 1 was to find asuitable sequence for achieving the desired oxidation states on the functionalized positions,t hat is,too ptimize the order in which these reactions were carried out on the Aring and on the side-chain. [13] We applied the same reaction conditions to 12 (Scheme 2) with the aim of not only dehydrogenating the C1ÀC2 bond, but also epimerizing the stereogenic center at C4, that is, a to the carbonyl moiety to form both 1 and microsphaeropsisin C ( 13). Although different fluoride sources were screened, removal of the TBS group was still low-yielding under optimized reaction conditions using Et 3 N·3 HF in THF.I nadifferent approach, we fully oxidized the Aring prior to modification of the side-chain: removal of the TBS group of (11S)-7 using HF in MeCN/THF was followed by DMP-mediated oxidation of the secondary alcohol to install the carbonyl moiety at C3 so that 10 was obtained with 89 %y ield (Scheme 2).…”