An Approach toward 17-Arylsubstituted Marginatafuran-Type Isospongian Diterpenoids via a Palladium-Catalyzed Heck–Suzuki Cascade Reaction of 16-Bromolambertianic Acid

Isospongian diterpenes are a small but growing family of natural tetracyclic secondary metabolites isolated from marine organisms, primarily sponges and nudibranchs. A palladium-catalyzed domino Heck–Suzuki reaction sequence for the synthesis of the tetracyclic skeleton of marginatafuran-type isospongian diterpenoids with a wide variety of substituents in the C-17 position is reported. The proposed approach was based on selective transformations of the accessible plant diterpenoid lambertianic acid and includes an intramolecular Heck reaction of 16-bromolambertianic and arylation of the palladium intermediate with arylboronic acid. The influence of the nature of the substituent both in arylboronic acids and in the furan ring of 16-bromolambertianic acid on the direction and chemoselectivity of the reaction has been studied. The described derivatization of natural furanolabdanoid lambertianic acid produced new functionalized molecules for biological study and gave novel insights into the reactivity of complex molecular structures.


Introduction
Marine sponges have been considered as a very remarkable field for the discovery of bioactive natural products. Among sponge metabolites, spongian diterpenes have received diverse attention due to their role as eco-physiological mediators. Being devoid of the physical protection, marine sponges are obvious targets for predation, and as a consequence, many spongian diterpenes have been isolated from spongivorous marine opisthobranch mollusks (nudibranchs) that predate upon these sponges. In particular, the furanoditerpenes marginatafuran 1 (Figure 1) presented the first example of an isospongian-type diterpenoid, which was isolated from the skin extract of the northwestern Pacific common dorid nudibranch Cadlina luteomarginata [1]. In fact, compound 1 was later found in minor amounts in sponges from the same area belonging to the genus Aplysilla [2]. Another furanoditerpene marginatone 2 was isolated from the sponge Aplysilla polyrhaphis [3], and A. glacialis [4], together with its derivative 20-acetoxymarginatone 3. Compound 3 was also isolated from skin extracts of a marine gastropod mollusk Cadlina luteomarginata [5].
Owing to the rare marginatane carbon skeleton and biological profiles, these natural products represent attractive targets for the synthetic communities. The first synthetic studies use the polyene substituted furan ambliofuran [6] as the starting compound [7,8]. Using the mercury(II) reagent, ambliofuran was cyclized, leading to the tetracyclic isospongiane in 13% yield. Compound with the marginatane carbon skeleton was obtained after the demercuration treatment with sodium borohydride [7]. Ambliofuran had also been cyclized to furanoditerpene using SnCl 4 as an electrophile initiator [8]. Indium tribromide-promoted epoxy olefin cyclization with the formation of the tetracyclic marginatane-type compound was described in [9]. An oxidative free-radical cyclization of a polyene compound with The palladium-catalyzed domino (cascade) reaction of 16-bromolambertianic acid derivatives, including the intramolecular Heck reaction and cross-coupling Suzuki reaction with arylboronic acids, became the main synthetic method. The effect of the varying substitution pattern of the boronic acid aromatic ring, as well as the nature of the C-15 substituent in the terpenoid skeleton, will be explored. Previously, this Heck-Suzuki cascade reaction strategy has been intensely investigated in the synthesis of a variety of heterocycles, carbocycles [21][22][23][24], and also applied toward the synthesis of various natural products [25]. Due to the formation of a new chiral quaternary stereocenter, at the first stage as a result of the intramolecular Heck reaction, the products of this domino reaction are formed as a mixture of two diastereomers. Obtaining optically active compounds requires the use of chiral catalysts [26][27][28][29][30]. In the case of lambertianic acid, a reaction with high diastereoselectivity is expected due to the higher steric availability of the α-side of the diterpene core [31].

Results
Bromination of lambertianic acid 4 (the main component of the pine oleoresin of P. sibirica J. Mayr) [32] in a CH 2 Cl 2 solution with NBS at room temperature afforded 16-bromolambertianic acid 5 (isolated yield 40-64%). The reaction of bromide 5 with phenylboronic acid 6a (1.2 equiv.) in the presence of Pd(PPh 3 ) 4 (2 mol%) as catalyst and K 2 CO 3 (3.6 equiv.) as the base in aq. DMF proceeds by heating at 80-85 • C for 24 h with the formation of 17-phenylisospongian-13(16),14-dien-18-oic acid 7a as the main product in the isolated yield 71% (Scheme 1). In the found conditions, the reaction of bromide 5 with 2-fluorophenylboronic acid 6b or 4-fluorophenylboronic acid 6c led to the formation of two products: corresponding cascade reaction products 7b,c and the Suzuki cross-coupling product 8b,c (Table 1, entries 1,2). The reaction products were separated by column chromatography. A significant effect of the position of the substituent in the aromatic ring of boronic acid on the direction of the reaction was observed. Thus, in the reaction of 5 with 2-fluoroboronic acid 6b, the product of arylation 8b and domino reaction 7b were isolated in 45% and 23% yields, respectively (entry 1). In cross-coupling of 5 with 4-fluoroboronic acid 6c, the isospongiantype compound 7c was isolated as the main product (40% yield). The yield of the Suzuki coupling reaction product 8c was about 20%. When carrying out the reaction of bromide 5 with 6b at 60-65 • C, incomplete conversion of the starting compound 5 (60-70%) was observed, while the ratio of the resulting products 7b,8b remained practically unchanged. A low conversion of 16-bromolambertianic acid 5 was observed in the reaction with 3substituted arylboronic acids (3-methoxyphenyl-and 3-fluorophenylboronic acids).
The optimization of reaction conditions was exemplified by the reaction of the bromide 5 with 4-methoxyphenylboronic acid 6d (Table 1, entries 3-15). It was observed that no crosscoupling reaction products were obtained when reaction was carried out under Pd(PPh 3 ) 4 catalyst in the presence of cesium carbonate or tripotassium phosphate as the base. These bases along with potassium carbonate were often used in cross-coupling reactions with bromofurans [33,34]. By performing the Pd-catalyzed reaction at high temperature, the competing process of hydrodehalogenation of furanolabdanoid 5 become favored, and only lambertianic acid 4 was formed (Table 1, entry 4, conditions a).
It has been known that various phosphine ligands are effective in stabilizing the Pd(0) species during the cross-coupling reaction of arylboronic acid, and an increase in the steric hinderance of the ligand in the palladium complex promotes a more rapid occurrence of the stage of incorporation into the alkene in the catalytic cycle of the Heck reaction [35,36]. It was found that sterically demanding and electron-rich monophosphine ligands -di-(1-adamantyl)-benzylphosphine ((1-Adm) 2 PBn) or 2-dicyclohexylphosphino-2',4,'6'-triisopropylbiphenyl (XPhos) were not active in this Heck-Suzuki cascade reaction (Table 1, entries 5,6). In the reaction of terpenoid 2-bromofuran 5 with 4-methoxyphenylboronic acid 6d under catalyst by a Pd(OAc) 2 -P(Tol) 3 system in DMF-water, only the domino reaction product 7d was obtained ( Table 1, conditions b). We have shown that using bidentate ligands (chelating ligands), which can provide a predominance of reductive elimination over β-hydride shift [37], ensured an increase in the isolated yield of both compounds 7d and 8d (Table 1, conditions c-e). The selectivity in compound 7d formation was increased by using sterically more demanding ligands -(R)-1,1 -bis(ditolylphosphino)-2,2-binapthyl (TolBINAP) (conditions d). The increase in the overall yield of compounds 7d and 8d under the catalysis by Pd(OAc) 2 -(R)-BINAP system (conditions e) was characteristic. Using a Pd(OAc) 2 -(S)-BINAP system led to the increasing of the yield of the tetracyclic compound 7d; the stereoconfiguration of the formed product was the same, as in the reaction, it proceeds by using a Pd(OAc) 2 -(R)-BINAP system (conditions e*). We next examined other parameters, including the study of influence of the temperature, nature of the base and solvent on the yield of the domino reaction product (conditions f-i). It was found that the reaction in DMF-water at a lower temperature (60-65 • C) under the Pd(OAc) 2 -(R)-BINAP system resulted in an increase in the selectivity of the reaction and the yield of compound 7d (isolated yield 56%, conditions f ). The reaction employing Cs 2 CO 3 as the base proceeded with lower selectivity for the domino reaction product 7d (yield 35 and 21%, conditions g). The further lowering of reaction temperature led to a decrease in the conversion (30%) and the selectivity and yield of reaction products 7d and 8d to 6% (Table 1, conditions h). The reaction in the CH 3 CN-H 2 О solvent system at 60-65 • C proceeds selectively but with lower yield of the domino reaction product 7d (yield 24%, conditions i); additionally, at the same reaction time, the observed conversion was about 90%. Characteristically, the reaction of 16-bromolambertianic acid 5 with arylboronic acids 6b,c in the optimized reaction conditions (f ) afforded the cascade reaction products 7b,c (yield 52-68%, entries 16,17). Conditions (f ) were then employed for reaction of 16-bromolambertianic acid 5 with various arylboronic acids 6e-j. The reaction with 4-trifluoromethyl-and 4-cyano-substituted phenylboronic acids 6e,f proceeded smoothly, preferring the formation of compounds 7e,f (yield 73-81%) (Scheme 2). Similar results were obtained in the reaction of bromofuran 5 with arylboronic acids having a substituent in the meta position of the aromatic ring-3-fluorophenyl-and 3-methoxy-phenylboronic acids 6g,h. The yield of domino reaction products 7g,h reaches 61-72%. The reaction of 5 with 2-methylphenylboronic acid 6i was carried out at 80-85 • C (conditions e) (Scheme 2); the reaction did not proceed well at a lower temperature. The isolated yield of compound 7i reached 48%. In these experiments, the amount of Suzuki coupling product was as low as 3-5% (from the NMR spectrum of the reaction mixture), and by subsequent column chromatography on silica gel, no fraction containing the arylation product was isolated. The reaction of diterpenoid bromide 5 with 3,4,5-trimethoxyphenylboronic acid 6j under conditions e afforded a mixture of domino reaction 7j and arylation 8j products in 61% and 6% yields, respectively (Scheme 2). When this reaction was carried out at 60-65 • C (conditions f ), only the tetracyclic compound 7j was obtained with the yield 67%.
The results indicated that the Pd-catalyzed interaction of 16-bromolambertianic acid 5 with arylboronic acids predominantly proceeds via the intramolecular Heck reaction followed by arylation of the resulting palladium intermediate. A high level of activity of 5 with arylboronic acid containing electron-withdrawing groups 6c,e-h can be apparently concerning due to their higher acidity, which favors the quaternization of the boron atom at the trans-metalation stage [38]. Substitution at the ortho-position (compounds 6b,i) suppressed the reactivity and the yield of 17-arylisopongian diterpenoids 7b,i, and the formation of Suzuki coupling product can be caused by unfavorable stereochemical interactions both at the stage of formation of the boronate anion and during the course of intramolecular cross-coupling. Other studies on domino palladium-catalyzed Heck cyclization/Suzuki coupling have also observed direct couplings [26].
In line with those previously postulated for the Pd-catalyzed domino Heck cascade reactions [23,24], we propose a plausible mechanism (Scheme 3). The oxidative addition of terpenoid bromofuran 5 to palladium(0) formed intermediate A, which was annulated through carbopalladation to form palladium(II) intermediate B. The high diastereoselectivity of the carbopalladation forming B is consistent with the previous literature: the transadduct is thought to form exclusively from the minimized axial-axial interactions [26,39]. The control over the diastereoselectivity of the formation of 7 is provided by the structural features of the labdanoid core, which consist in a higher steric accessibility of the α-side of the diterpene core. The process has been proceeding from the less hindered α-side. The trapped palladium species B reacts with the aryl boronic acid in a transmetalation step, forming intermediate C, which after reductive elimination afforded the desired tetracyclic compound of type 7 with the β-disposition of the C-17 aryl substituent. A direct Suzuki coupling of intermediate D led to the formation of 16-aryllambertianic acid derivatives 8. To study the nature of the substituent in the furan ring on the course of the above domino Heck-Suzuki reaction, we obtained several new derivatives of 16-bromolambertianic acid 5 with both electron-donating and electron-withdrawing substituents at the C-15 carbon atom of the furan ring. The key compound in the synthesis was 16-bromo-15-formyllambertianic acid 9 synthesized by the formylation of terpenoid 2-bromofuran 5 under the described Vilsmeier-Haack reaction conditions for methylambertianate [40]. Complete conversion of starting compound 5 was observed by using an 18-fold excess of phosphorus oxychloride. The isolated yield of aldehyde 9 reached to 89% (Scheme 4). It should be noted that in the methods for the synthesis of furfural bromide in the literature, using furfural as the starting compound was described in [41]. The preparation of 5-bromofuran-2-carbaldehyde from bromofuran is limited by the example of formylation in DMF in the presence of butyllithium. The key compound, 16-bromo-15-cyanolambertianic acid 10 (yield 93%), was synthesized by treating aldehyde 9 with water solution of ammonia in the presence of iodine (3 equiv.) in tetrahydrofuran as described in [42] for the preparation of 16cyanoderivatives of methyllambertianate; for comparison, the complete conversion of 16-formyl methyllambertianic acid was achieved using 1.2 equiv. of iodine [42]. The reduction in aldehyde 9 with sodium borohydride in methanol yielded 16-bromo-15hydroxymethyllambertianic acid 11. 16-Bromo-15-(methylaminomethyl)lambertianic acid 12 was obtained by the reductive amination of 16-bromo-15-formyllambertianic acid 9. This transformation was carried out in three stages: treatment of methylamine hydrochloride with triethylamine, reaction of the free amine with aldehyde 9 in methylene chloride in the presence of magnesium sulfate, and subsequent reduction in the resulting imine with sodium borohydride in methanol. Conditions (e) ( Table 1) were then employed for the reaction of 15,16-disubstituted furanolabdanoids 9-10 with arylboronic acids 6a,f,j. The reaction of compounds 9 or 10 with phenylboronic acid 6a proceeded smoothly with the formation of Suzuki reaction coupling products 13a or 14 (isolated yield 52-69%) (Scheme 5). The reaction of 9 with arylboronic acids 6f,j differed in the electronic nature of the substituent, and it also gave only the product of Suzuki cross-coupling reaction 13b,c (yield 49-58%). Apparently, in the reaction of furanolabdanoids with an electron-withdrawing substituent at the C-15 carbon atom of the furan ring with arylboronic acids, direct Suzuki coupling was the major pathway. Disubstituted furanolabdanoids 11 or 12 gave no products with phenylboronic acid 6a in the indicated conditions; the electron-donating substituent in the furan ring completely suppressed the reaction, and only the starting compounds were isolated.
The experimental results have revealed a significant influence of the nature of the substituent in functionalized furanolabdanoid 5,9-14 on the direction of the cross-coupling/domino Heck cascade reactions. The unsuccessful reaction of arylboronic acids with 16-bromolambertianate derivatives 11 and 12, having an electron-donating substituent in the furan ring, can be explained by the deactivating effect on the activity of the initial bromofuran in the oxidative addition step of palladium(0) (formation of intermediate A) (Scheme 3). The presence of an electron-withdrawing substituent in the furan ring promotes both oxidative addition and trans-cis rearrangement of the palladium complex formed as a result of transmetalation in the Suzuki reaction. The latter effect can be explained by an increase in the trans-effect of furan in the palladium complex as a result of enhancement of the π-electron-withdrawing properties.
The structure of all synthesized compounds 5, 7a-j, 8b-d,j, 9-12, 13a-c and 14 was confirmed by IR, 1 H and 13 C spectroscopy and mass-spectrometry data. The 1 H and 13  The mass spectra of tetracyclic compounds 7a-j contain a weak peak of the molecular ion. All of the spectra were characterized with the main-ion peak with a mass of 301 (100%), which corresponded to the fragmentation of М+ with the loss of the arylmethyl substituent.

Conclusions
In summary, we have described an efficient protocol for the Heck cyclization-Suzuki coupling cascade reaction toward the synthesis of 17-aryl derivatives of marginatafurantype isospongian diterpenoids. The latter are formed as an individual stereoisomer, with an axial arrangement of the aryl substituent, using both chiral and achiral phosphine ligands. (R)-BINAP has been shown to be the most efficient chiral phosphine ligand. The choice of the base (K 2 CO 3 , K 3 PO 4 , Cs 2 CO 3 ) and solvent (DMF-H 2 O, CH 3 CN-H 2 O) is crucial to lead the direction of the reaction. Electron-rich and electron-deficient arylboronic acids can be used in this domino reaction, although coupling with arylboronic acid containing electron-withdrawing groups provides higher yields of tetracyclic compound. The study of the influence of the nature of the substituent in the furan ring of 16-bromolambertianate showed that derivatives with an electron-donating substituent, under the conditions found, are not active in cross-coupling reactions, and derivatives with an electron-withdrawing substituent give exclusively the furan ring arylation products.
Overall, this domino process allows the synthesis of interesting 17-arylsubstituted marginatafuran-type isospongians, which is a common structural motif among a rare group of biologically interesting diterpenoids.