Asymmetric Total Synthesis of Phomarol

Abstract

Open AccessCCS ChemistryCOMMUNICATION1 Dec 2021Asymmetric Total Synthesis of Phomarol Jian-Hong Fan, Jing-Jing Wang, Fangfang Li, Guannan Wang, Qiang Guo, Lung Wa Chung and Chuang-Chuang Li Jian-Hong Fan Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen 518055 Institute of Chinese Medical Sciences, University of Macau, Macau 999078 Google Scholar More articles by this author , Jing-Jing Wang Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen 518055 Google Scholar More articles by this author , Fangfang Li Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen 518055 Google Scholar More articles by this author , Guannan Wang Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen 518055 Google Scholar More articles by this author , Qiang Guo Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen 518055 Google Scholar More articles by this author , Lung Wa Chung Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen 518055 Google Scholar More articles by this author and Chuang-Chuang Li *Corresponding author: E-mail Address: [email protected] Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen 518055 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202000721 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The first and asymmetric total synthesis of phomarol, an uncommon C25 steroid, is described. The synthetically challenging benzocycloheptane motif, found in phomarol and some other naturally occurring molecules, was synthesized efficiently using a very mild acid-promoted type I [5 + 2] cycloaddition, followed by regio- and chemoselective cleavage of the C–O bond and aromatization cascade. This work is the first example of using the hydrogen bonding between the hydroxy group and oxidopyrylium ylide to control the stereoselectivity of cycloadditions. The highly functionalized tetrahydropyran ring of phomarol was produced efficiently based on our suggested biomimetic pathway. Download figure Download PowerPoint Introduction Because of their important bioactivity and diverse structures, steroids play an important role in organic synthesis and drug discovery.1–8 Phomarol ( 1) (Figure 1), a C25 steroid with an unusual architecture, was isolated by Jung and co-workers9 in 2016 from a jellyfish-derived fungus. Structurally, phomarol ( 1) contains a sterically compact [7–6–6–5–6]-fused pentacyclic framework, with a highly functionalized tetrahydropyran E-ring (highlighted in blue). Furthermore, phomarol bears a synthetically challenging C12 oxidation, for which there are limited efficient approaches to install.10 Phomarol has eight stereocenters, including two quaternary centers. The two chiral secondary hydroxy groups (C1 and C3) that are seemingly symmetrical in the seven-membered ring, are far away from the rest of stereogenic centers, and it is not obvious how to install them efficiently and stereoselectively. The relative and absolute configurations of phomarol are challenging to determine because of the ambiguity in forecasting the stable conformation of the seven-membered A-ring and no reliable nuclear Overhauser effect (NOE) correlations between H11 and H19 (phomarol numbering throughout).9 This issue needed to be more definitively established.11,12 In addition, phomarol possesses a benzocycloheptane A/B ring system (highlighted in red), which is unprecedented in steroids. Therefore, phomarol presents a significant synthetic challenge. Figure 1 | Structural features of phomarol and selected natural products containing a benzocycloheptane motif (highlighted in red). Download figure Download PowerPoint The synthetically challenging benzocycloheptane motif (multisubstituted benzene ring fused with a seven-membered ring) is a common structural feature in other bioactive natural products, including alkaloids, terpenoids, and polyketides (such as compounds 2– 5, Figure 1). Such a skeleton is also found in some important medicines (including loratadine and amitriptyline, not shown). In particular, natural products with this intriguing skeleton have prompted considerable attention from the synthetic community,13–24 including the groups of Li,15,19,21 Fukuyama,16 Zhai,17 Qiu,18 Anderson,20,22 Snyder,23 and Tang.24 However, the development of a new strategy for the efficient synthesis of the benzocycloheptane skeleton is still highly desirable. Furthermore, the total synthesis of phomarol ( 1) has not been reported. In our ongoing research toward the synthesis of the bioactive abeo-steroid25 and natural products with the benzocycloheptane motif,26 we herein wish to describe the first asymmetric total synthesis of phomarol, based on an acid-promoted [5 + 2] cycloaddition, thus establishing the absolute configuration of 1 unambiguously. Results and Discussion The retrosynthetic analysis of phomarol ( 1) is shown in Scheme 1a. We envisioned that 1 could be generated from 6 by an intramolecular cyclization to construct the tetrahydropyran ring, according to the proposed biosynthetic pathway.9 We expected that 6 could be produced from aromatic compound 7 through the diastereoselective 1,2-addition of lithium compound 8. The tetrasubstituted benzene ring,27–30 the most critical synthetic challenge in 7, could be prepared from 9 through a series of functional group manipulations, including a chemoselective cleavage of the C10–O bond and aromatization cascade. In turn, the tetracyclic core in 9 with the desired stereochemistry at C3 was anticipated to be synthesized from 10, using the Achmatowicz reaction followed by type I intramolecular [5 + 2] cycloaddition with exo selectivity.31–52 Finally, compound 10 could be synthesized from the readily accessible furan 11, 3-butenyllithium, and the known enone 1225 using a Stille coupling and 1,2-addition reaction. Scheme 1 | (a) Retrosynthetic analysis of phomarol (1). (b) Key DFT (M06-2X/6-31G*) calculations (the nonimportant H atoms are omitted for clarity). Download figure Download PowerPoint However, it was difficult to envisage the diastereoselectivity of the [5 + 2] cycloaddition of such a complex precursor. To predict the diastereoselective outcome, density functional theory (DFT; M06-2X/6-31G*) calculations were performed.53 DFT calculations showed the hydrogen bonding between the free C8 hydroxy group and the oxidopyrylium ylide so that the model intermediate 13 would be critical in controlling the diastereoselectivity. The reaction pathway to give the desired product 9a is more favorable than that to form 9b both kinetically (by ∼2.6 kcal/mol) and thermodynamically (see Scheme 1b and Supporting Information for computational details). To quickly address several issues mentioned above and demonstrate the DFT calculations, compound 12 was used as the chiral pool compound, which was proved to be efficient in the asymmetric synthesis of steroid cyclocitrinol.25 Some synthetic transformations in the previous synthesis of cyclocitrinol with an unusual bridged ring system via the type II [5 + 2] cycloaddition at high temperature, will provide a reference for the synthesis of phomarol ( 1). However, the new target molecule phomarol with a unique fused ring system poses new synthetic challenges. First, for example, the synthetically challenging benzocycloheptane motif in 1 cannot be synthesized by the type II [5 + 2] cycloaddition. Second, how to efficiently install the C12 oxidation in phomarol was unknown. Third, whether the type I [5 + 2] cycloaddition of our proposed precursor with several sensitive functional groups could occur under mild instead of harsh conditions was also unknown. In our previous total syntheses, all of the types I and II [5 + 2] cycloadditions without any activating group proceeded under harsh conditions (such as at high temperature)25,26,52 without any activating group. Our synthesis commenced with the asymmetric construction of compound 10 (Scheme 2). The known compound 12 (synthesized from commercially available material in two steps with 80% overall yield)25 was treated with LiBF4 in CH3CN/H2O, followed by direduction with diisobutylaluminium hydride (DIBAL) to give diol 14 in an overall yield of 61%. Selective protection of the primary hydroxy group using a triisopropylsilyl (TIPS) group and subsequent protection of the secondary alcohol with an acetyl (Ac) group in one pot gave 15. Allylic oxidation of 15 (3 g scale) with SeO2, followed by oxidation and diastereoselective reduction in one pot, provided 16 as a single product with the desired C12 hydroxy group. This hydroxyl in compound 16 was protected with a p-methoxybenzyl (PMB) group followed by deprotection of the Ac group to give 17 in 76% yield. Compound 17 was oxidized with Dess-Martin periodinane (DMP) to give the enone, which was treated with iodine, TMSN3, and pyridine (Py) in dichloromethane (DCM)54 to generate iodide 18 in 84% overall yield (5 g scale). Pleasingly, the palladium (Pd)-catalyzed Stille coupling of 18 and 11 with the aid of copper(I) thiophene carboxylate (CuTC) in N-methyl-2-pyrrolidone (NMP) produced 19 in 92% yield (7 g scale). Treatment of 19 with 3-butenyllithium in Et2O and then Et3N-HF provided compound 10 as a single diastereomer in 80% yield (2 g scale). Scheme 2 | Asymmetric synthesis of 10. Download figure Download PowerPoint Following the successful preparation of 10, we continued to explore the construction of the tetracyclic skeleton of phomarol by type I [5 + 2] cycloaddition. Initially, oxidative rearrangement of 10 using meta-chloroperbenzoic acid (m-CPBA) in DCM (Scheme 3) afforded compound 20a in high yield and none of the expected 21a. Treatment of 20a with Ac2O/Et3N or various other reaction conditions always gave 20b, and no 21b that would be a good precursor to generate the oxidopyrylium ylide in 22 by a group elimination strategy usually at high temperature. However, compound 20b could not undergo the intramolecular [5 + 2] cycloaddition.31–51 Scheme 3 | Diastereoselective synthesis of 9 by a unique acid-promoted [5 + 2] cycloaddition. Download figure Download PowerPoint We proposed that the C3 hydroxy group in compound 20a could attack the C10 carbonyl group to give 21a in the presence of acid (Scheme 3). The C10 anomeric hydroxy group in 21a would then undergo elimination, followed by enolization of the C2 ketone with acid, to form the desired oxidopyrylium ylide stabilized by the adjacent vinyl group in 22. Intramolecular [5 + 2] cycloaddition of 22 could then form 9. Thus, we explored the [5 + 2] cycloaddition under acidic conditions, although there are few reports related to acid-promoted [5 + 2] cycloaddition. In 1999, Magnus and Shen37 reported the first example of trifluoroacetic acid (TFA)-promoted type I [5 + 2] cycloaddition, with only one substrate. So far, total synthesis of natural products using this remarkable TFA-promoted [5 + 2] cycloaddition has been not reported. Therefore, the study and development of acid-promoted [5 + 2] cycloaddition is still highly desirable. However, there is an acid-sensitive allylic and tertiary C8 alcohol in 22, which makes the acid-promoted [5 + 2] cycloaddition very challenging. After extensive investigations, we determined the following procedure to be best: compound 10 was treated with m-CPBA in DCM for 1.0 h, followed by addition of CF3CO2H (TFA) at 25°C. A very mild and highly diastereoselective type I [5 + 2] cycloaddition occurred to provide the desired compound 9 in 60% overall yield (1 g scale). None of its diastereomer dia- 9b was observed. The structure of 9 was unambiguously determined by X-ray crystallographic analysis of its derivative 23, in which the hydrogen bonding between the C8 hydroxy group and oxa-bridge was found. However, under similar conditions, the undesired product 24b (X = methoxymethyl [MOM]) was isolated from 10a (X = MOM) in 30% yield, and none of the diastereomer 24a (X = MOM) was observed. Compound 24b with undesired C3 stereocenter for the synthesis of phomarol will be challenging. These results were consistent with our DFT results that type I [5 + 2] cycloaddition of 22 proceeded favorably with exo selectivity and was different from the indole [5 + 2] cycloadditions with endo selectivity.41 Notably, the hydrogen bonding between the C8 hydroxy group and the oxidopyrylium ylide, such as in 22, was critical to control the diastereoselectivity of the cycloaddition. This mild acid-promoted and hydrogen-bonding-directed [5 + 2] cycloaddition will provide valuable information for developing new catalytic asymmetric [5 + 2] cycloadditions, as catalytic asymmetric [5 + 2] cycloadditions by chiral acids are still unknown.38 Further study is currently underway in our laboratory. With compound 9 in hand, we continued in our proposed construction of the synthetically challenging tetrasubstituted benzene ring of phomarol (Scheme 4). Treatment of 9 with SOCl2 and Py in DCM at 0 °C, followed by NaBH4 and CeCl3·7H2O in MeOH, gave 25 with the desired C7–C8 double bond in 75% yield. Compound 25 underwent a typical Barton deoxygenation to provide 26 in 91% overall yield (2.5 g scale). After extensive trials, we found the following mild protocol to be the optimal conditions for the chemoselective cleavage of the C10–O bond and aromatization cascade. Compound 26 was treated with trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,6-lutidine in DCM at 25 °C for 0.5 h to give intermediate 27. In a one-pot synthesis, compound 27 underwent a spontaneous aromatization and removal of trimethylsilyl (TMS) group in the presence of 4 N HCl, to generate the desired product 28 in an overall yield of 70% (from 26, 1.2 g scale). Notably, compound 27 could be isolated and the structure was confirmed by two-dimensional nuclear magnetic resonance (2D-NMR) and mass spectrometry (MS) (see Supporting Information for details). Notably, this work represents the first example to construct the benzene ring by aromatization after the intramolecular oxidopyrylium ylide [5 + 2] cycloaddition.31–44, 47–51 Scheme 4 | Asymmetric synthesis of 31. Download figure Download PowerPoint Next (Scheme 4), compound 28 was treated with N-bromosuccinimide (NBS) for bromohydroxylation of the double bond, followed by the cyclization using KOH as a base, to give the desired epoxide 29 in 66% yield. Regioselective reductive cleavage of the epoxide in 29 with LiAlH4, followed by MOM protection and TIPS deprotection, afforded 30 in an overall yield of 71%. The excellent regioselectivity in this epoxide opening reaction with LiAlH4 could be explained by the formation of stable C19 benzylic cation intermediate, followed by hydride attack, to give the desired product. DMP oxidation of 30 gave the aldehyde in 95% yield, which underwent the desired oxidative deformylation reaction, using t-BuOK and O2 in t-BuOH, to afford compound 31 in 88% yield. Next (Scheme 5), treatment of 31 with lithium compound 8 (prepared from iodide 3255 with n-BuLi) in tetrahydrofuran (THF) gave 33 as a single diastereomer in 85% yield, completing the diastereoselective installation of the side chain. Similarly, compound 34 was produced from 31 (see Supporting Information for details). Scheme 5 | Asymmetric total synthesis of phomarol. Download figure Download PowerPoint The final stage of the synthesis is to construct the desired pyran ring, although the diastereoselective formation of a highly functionalized tetrahydropyran ring with five stereocenters, including two quaternary centers, is especially difficult.56–58 Initially (Scheme 5), based on Jung’s biosynthetic hypothesis,9 we tried to construct the tetrahydropyran ring using intramolecular SN2′ cyclization of the C12 hydroxy group in 34. A wide variety of conditions were screened (HCO2H, AcOH, TsOH, H2SO4, HCl, pyridinium p-toluenesulfonate (PPTS), TFA, and CCl3COOH), but none afforded the desired products. These unsuccessful results showed that the construction of the tetrahydropyran ring was very challenging using the proposed biosynthetic intramolecular SN2′ cyclization. After further extensive trials, we envisaged that vinyl epoxide 35 would be a suitable precursor for the desired regio- and stereoselective cyclization (Scheme 5). The acid-catalyzed cyclization of the vinyl epoxide probably proceeded through a SN2 pathway via intermediate 36, through the C12 hydroxy group attacking C22. The developing electron-deficient orbital on C22 in 36 would be stabilized by the adjacent electron-rich double bond.59 Accordingly, exposure of 33 to potassium bis(trimethylsilyl)amide (KHMDS) and Ts (p-toluenesulfonyl)-imidazole in THF produced the anticipated vinyl epoxide 35 in 78% yield. Pleasingly, treatment of 35 using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in DCM/H2O to remove the PMB group and spontaneously undergo the cyclization generated the desired tetrahydropyran ring. The subsequent HCl (aq.) workup afforded 1 as an exclusive diastereomer in 83% yield, completing the first asymmetric total synthesis of phomarol. The structure of synthetic phomarol was unambiguously determined by X-ray crystallographic analysis of the derivative 37. Thus, the structure and absolute configuration of naturally occurring phomarol were unambiguously established by our total synthesis. Conclusion We have achieved the first and asymmetric total synthesis of phomarol ( 1), definitively establishing the absolute configuration. Notably, the synthetically challenging benzocycloheptane motif, which is also found in other natural products (Figure 1) and medicines, was synthesized efficiently using a very mild type I [5 + 2] cycloaddition promoted by acid, followed by regio- and chemoselective cleavage of the C–O bond and aromatization cascade. This work represents the first example of an acid-promoted [5 + 2] cycloaddition applied successfully in the total synthesis of natural products.31–52 This work is also the first example of using the hydrogen bonding between the hydroxy group and oxidopyrylium ylide to control the stereoselectivity of cycloadditions, which was predicted by DFT calculations. Furthermore, the challenging and highly functionalized tetrahydropyran ring of phomarol was successfully installed based on our suggested biomimetic pathway. The eight stereocenters of phomarol, including the C12 hydroxy group which was difficult to install, were constructed in a diastereoselective and efficient fashion. This method could be extended to the total synthesis of other biologically active natural products containing the benzocycloheptane motif, to enable further biological investigation. Such work is ongoing in our laboratory and will be reported in due course. Supporting Information Supporting Information is available and includes computational details and experimental procedures, analytical data for all new compounds. Conflict of Interest There is no conflict of interest to report. Funding Information This work was supported by the Natural Science Foundation of China (grant nos. 21672095 and 21971105), the Shenzhen Science and Technology Innovation Committee (grant no. ZDSYS20190902093215877), and Project KQTD2016053117035204 of the Shenzhen Peacock Plan.