More than 100 cladiellin diterpenoids (a.k.a. eunicellins) have been isolated from marine invertebrates in diverse locations, and many of them exhibit potent biological activities [1, 2]. As exemplified by the structures of cladieunicellin D (1) [3] and klysimplexin U (2) [4] (Scheme 1), these natural products all possess a characteristic 6/5/9-membered ring skeleton, but differ in their oxidation and unsaturation levels. The intricately fused and highly oxidized structures of cladiellins have inspired chemists to develop new synthetic methods for their efficient assembly. Extensive synthetic studies and various total syntheses have been disclosed to date [5,6,7,8,9,10,11].

Scheme 1
scheme 1

Structure of cladieunicellin D (1) and klysimplexin U (2), and synthetic plan for cladiellin skeleton 3

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Three-component coupling is an extremely useful method for increasing the structural and functional complexity of the molecule in a single step [12]. Radical-based three-component reactions are particularly advantageous for constructing highly oxygenated carboskeletons of terpenoids, because radical reactions enable chemoselective formation of ring-connecting hindered carbon–carbon (C–C) bonds without affecting the preexisting oxygen functionalities of the fragments [13,14,15,16,17,18,19]. In this context, we recently developed Et3B/O2-mediated radical-polar crossover reactions of α-alkoxyacyl tellurides, comprising a sequential radical addition and an aldol reaction [20, 21]. As part of our continuing interest in exploring this powerful method, we decided to devise a new efficient strategy for assembling cladiellin diterpenes. Accordingly, the cladiellin skeleton 3 was selected as an initial synthetic target. Compound 3 was designed to have the six tertiary stereogenic carbons (C1, 2, 4, 9, 10, and 14) that correspond to those of 1 and 2, and to possess the C3-OH, C5-olefin, and C11-ketone that would function as handles for completing the total syntheses. Herein we report the expeditious construction of this complex molecule 3 using the radical-polar crossover reaction as the pivotal transformation.

The three-component coupling reaction allowed for a simple synthetic strategy (Scheme 1). The 6/5/9-tricycle 3 was retrosynthetically dissected into α-alkoxyacyl telluride 6 as a radical precursor, (–)-cryptone (7) as a radical acceptor, and (Z)-4-hexenal (8) as an electrophile. Coupling of these three fragments 6–8 would connect the C1–C2 and C9–C10 bonds with stereoselective installation of the three stereocenters (C1, 9, and 10). Since the entire carbon framework would be assembled in this single reaction, the remaining processes from 5 to 3 would not involve further carbon-chain extension. The C5’-bromo ether and C2-acetal structures of 5 would be utilized to construct the C5-olefin and C2-ether, respectively. After C10-epimerization, the C5- and C6-double bonds of 4 would participate in a ring-closing metathesis reaction to cyclize the nine-membered ring of the target 3.

The requisite α-alkoxyacyl telluride 6 was readily prepared from commercially available diprogulic acid (9) in six steps (Scheme 2). After converting carboxylic acid 9 to benzyl ester 10 using K2CO3 and benzyl bromide, the less-hindered acetonide of 10 was chemoselectively removed to provide diol 11. The primary alcohol of 11 was regioselectively brominated by employing PPh3 and CBr4, and the remaining secondary alcohol was protected as the PMB-ether by the action of PMBOC(=NH)CCl3 and (+)-CSA [22]. The benzyl ester of 13 was in turn hydrolyzed by an aqueous LiOH solution to generate the carboxylic acid of 14. Then, α-alkoxyacyl telluride 4 was derivatized from 14 via a one-pot procedure: formation of the activated ester with i-BuOCOCl and N-methylmorpholine, and subsequent replacement of the i-BuOCO2 group with the TePh group using i-Bu2AlH and (PhTe)2 [23].

Scheme 2
scheme 2

Construction of the cladiellin skeleton. Reagents and conditions: (a) BnBr, K2CO3, DMF, r.t., 93%; (b) 50% aq AcOH, 50 °C, 98%; (c) PPh3, CBr4, pyridine, THF, 50 °C, 99%; (d) PMBOC(=NH)CCl3, (+)-CSA (5 mol%), CH2Cl2, r.t.; (e) 1 M aq LiOH, THF, r.t., 89% (2 steps); (f) i-BuOCOCl, NMM, THF; (PhTe)2, i-Bu2AlH, 87%; (g) Et3B (5 equiv.), air, 7 (3 equiv.), 8 (10 equiv.), hexane, r.t.; (h) NaBH(OAc)3, benzene, r.t., 37% (2 steps); (i) SmI2, Et3N, H2O, THF, r.t., 42%; (j) i-PrMgBr, THF, −78 °C; s-BuLi, −78 to 0 °C, 47% from 15; (k) BiBr3 (25 mol%), Et3SiH, MeCN, 0 °C, 71%; (l) TPAP (20 mol%), NMO, MS 4 A, r.t., 92%; (m) F (20 mol%), p-benzoquinone, toluene, 130 °C, 67%. Bn, benzyl; r.t., room temperature; PMB, p-methoxybenzyl; CSA, 10-camphorsulfonic acid; NMM, N-methylmorpholine; TPAP, tetrapropylammonium perruthenate; NMO, N-methylmorpholine N-oxide; MS, molecular sieve; Mes, mesityl; Cy, cyclohexyl

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The key radical-polar crossover coupling reaction significantly increased the complexity of the molecule under mild conditions. When 6, 7 (3 equiv.), and 8 (10 equiv.) were treated with Et3B (5 equiv.) [24] in hexane (0.2 M) under air at room temperature, the three-component product 5 was indeed produced by linking the two sterically encumbered C1–C2 and C9–C10 bonds, and introducing the correct C1- and C9-stereocenters of the target 3. As the C11-ketone turned out to be prone to a retro-aldol reaction, the yield was calculated to be 37% yield (two steps) after stereoselective reduction of 5 to 1,3-syn-diol 15 with NaBH(OAc)3 [25]. In the coupling reaction, an ethyl radical generated from Et3B and O2 promotes homolysis of the C–Te bond of 6 to form an acyl radical. The acyl radical expels carbon monoxide to produce C2-acetal radical A [26]. Nucleophilic radical A chemoselectively adds to an electron-deficient double bond of 7 in the presence of the electron-rich disubstituted olefin of 8. Moreover, A stereoselectively establishes the C1-position of the two-component adduct by approaching from the opposite face of the bulky C14-isopropyl group of 7. This radical intermediate is then captured by Et3B to form boron enolate, which reacts with aldehyde 8 through the chair-like six-membered transition state B to install the C9- and C10-stereocenters of ketone 5 [27]. It should be noted that the potentially reactive primary bromides of the intermediates survived treatment with nucleophilic i-Bu2AlTePh (14 → 6) and radical-generating Et3B/O2 (6 → 5), indicating the mildness of the present procedure using α-alkoxyacyl telluride.

Having realized the chemo- and stereoselective three-component coupling reaction, the bromo ether structure of 15 was utilized to unmask the C2-ketone and C5-olefin. Such a ring-opening reaction, however, required us to screen the reductants and conditions. While Zn failed to react with bromide 15, the SmI2/H2O/Et3N mixture in THF [28] reduced the bromide, but did not promote the elimination of the C2-oxygen functionality, thereby furnishing debrominated 16 after aqueous work-up. In contrast to these results, sequential addition of i-PrMgBr and s-BuLi to 15 in THF from -78 °C to 0 °C resulted in reductive cleavage of the bromo ether to produce 17. This reaction would involve the following cascade processes: deprotonation of the C9- and C11-alcohols with i-PrMgBr, bromine-lithium exchange induced by s-BuLi (15 → C), E1cB elimination of the C2-oxygen functionality, C2-ketone generation through the ejection of acetone (C → D), and C2-hemiacetal formation by nucleophilic addition of the C9-alkoxide to the C2-ketone, followed by protonation (D → 17).

Finally, the oxygen-bridged five- and nine-membered ring structure of 3 was constructed using the C2-hemiacetal and C5-olefin as chemical handles. First, reductive etherification of 17 was realized by applying a catalytic amount of BiBr3 and stoichiometric Et3SiH [29], leading to the five-membered ether of 18 as the sole C2-stereoisomer. Thus, as the bulky C9-substituent and C14-isopropyl groups blocked the top side of the molecule, Et3SiH attached on oxocarbenium ion E from the bottom side, introducing the requisite C2-trisubstituted stereocenter of 18. The secondary C11-OH of 18 was then regioselectively oxidized to the C11-ketone of 19 in the presence of the secondary C3-OH by employing TPAP reagent [30]. This C11-oxidation enabled us to epimerize the C10-stereochemistry that was established at the radical coupling reaction. Interestingly, upon purification 19 on silica gel, the 6/5-trans-fused ring system of 19 was readily converted to the thermodynamically more stable 6/5-cis-fused tetrahydrofuran of 4 [31]. In this reaction, the potential E1cB elimination of the C9-oxygen functionality was impeded, presumably due to the orthogonal relationship between the σ*(C9–O) orbital and the π(C10–C11) orbital of the C11-enol intermediate. The thus-obtained diene 4 was treated with 20 mol% of a second-generation Grubbs catalyst (F) at 130 °C in toluene using 1,4-benzoquinone as the additive to prevent unwanted olefin isomerization [32]. The nine-membered ether ring successfully formed, delivering cladiellin skeleton 3 with the 6/5/9-membered ring system. The (Z)-geometry of C5-olefin and the 6/5-cis-fused structure of the tricyclic compound 3 was confirmed by the coupling constant (3JH5H6 = 10.9 Hz) and NOE measurement.

In summary, we synthesized cladiellin skeleton 3 in 12 steps from diprogulic acid (9). The three-component coupling reaction of 6–8 effectively connected the sterically hindered C1–C2 and C9–C10 bonds with introduction of the C1-, C9-, and C10-stereocenters. The present radical-polar crossover coupling reaction allowed access to a densely functionalized structure that is difficult to obtain by conventional polar or radical reactions, thereby simplifying the overall route to 3. The i-PrMgBr/s-BuLi-promoted ring-opening of bromo ether 15 revealed the C2-hemiacetal and the C5-olefin. At the last stage of the synthesis, BiBr3-catalyzed reductive etherification of hemiacetal 17, SiO2-promoted C10-epimerization of ketone 19, and a ring-closing metathesis reaction of diene 4 were performed as key transformations to produce the targeted 3. Because of its multiple reactive functional groups applicable for further derivatization, 3 can serve as an advanced intermediate for the total syntheses of various cladiellin diterpenoids, including 1 and 2.