Ynamide Protonation-Initiated <i>Cis</i> -Selective Polyene Cyclization and Reaction Mechanism

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLE5 Sep 2022Ynamide Protonation-Initiated Cis-Selective Polyene Cyclization and Reaction Mechanism Jiasheng Yao†, Chen-Long Li†, Xing Fan, Zhou Wang, Zhi-Xiang Yu and Junfeng Zhao Jiasheng Yao† School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436 College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022 , Chen-Long Li† College of Chemistry, Peking University, Beijing 100871 , Xing Fan College of Chemistry, Peking University, Beijing 100871 , Zhou Wang College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022 , Zhi-Xiang Yu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] College of Chemistry, Peking University, Beijing 100871 and Junfeng Zhao *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436 School of Chemistry and Chemical Engineering, Northwestern Polytechnical University, Xi'an 710072 State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071 https://doi.org/10.31635/ccschem.021.202101331 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The diastereoselectivity of conventional polyene cyclization reactions is highly dependent on the configuration of the internal alkenes, where E-polyenes provide trans-decalins, while Z-polyenes offer cis-decalins. Although polyene cyclization has evolved into a reliable and widely used strategy for the construction of trans-decalin frameworks of terpene and steroid natural products, its application for cis-decalin framework is extremely challenging. This is because it not only requires the difficultly approached Z-polyenes but also has usually been accompanied by the formation of undesired trans-isomer. We herein report a universal polyene cyclization approach to cis-decalin frameworks by employing ynamide-capped polyenes (YCPs), which erase the traditional strict requirement for alkene stereochemistry since both E- and Z-YCPs give cis-decalin frameworks with excellent diastereoselectivity. A broad range of YCPs are compatible to furnish the cis-decalin frameworks in good to excellent yields without any detectable trans-isomer. Both experimental and density functional theory (DFT) calculation results reveal that the ynamide protonation-initiated polyene cyclization proceeds in a stepwise manner involving an unprecedented double protonation mechanism wherein the steric repulsion between the iminium and the forming decalin framework in the Friedel–Crafts transition state is responsible for the unusual excellent cis-diastereoselectivity. DFT calculations also showed that an excess of TfOH was essential for the formation of cis-decalin because the catalytic amount of TfOH resulted in the pretermination of this cascade process. Download figure Download PowerPoint Introduction Terpenes and steroids containing complex polycyclic frameworks and continuous multiple stereocenters are ubiquitous natural products with intriguing biological activities.1,2 In nature, their polycyclic frameworks are constructed via enzyme-catalyzed protonation-initiated polyene cyclization reactions, wherein up to five C–C bonds and nine continuous stereocenters can be formed with excellent chemo-, regio-, and stereoselectivities.3–5 The excellent efficiency of polyene cyclization reactions has fascinated organic chemists for more than 60 years and inspired investigations of the reaction mechanism and the design of a variety of fantastic biomimetic polyene cyclization reactions in the laboratory.6–8 To mimic the polyene cyclization occurring in nature, an isopropenyl group was originally employed as the initiator in the polyene cyclization reactions.9–13 In view of the structural diversity of terpenes and steroids as well as the difficulties encountered in the functionalization of the gem-dimethyl group of the final cyclized products, epoxides,14 aldehydes,15 vinyl groups,16 and allylic alcohols,17 among other functional groups,18–20 which can interact with the catalyst or promoter to form a carbenium ion or a radical,21–23 have been employed as initiators for polyene cyclization reactions. It is widely believed that the chemo-, regio-, and stereoselectivities of polyene cyclization are governed by the prearranged conformation of the linear precursors. The stereochemistry outcome of polyene cyclizations is predictable according to the Stork–Eschenmoser hypothesis (Scheme 1b),24,25 which suggests that polyenes containing E-alkene (E-polyenes) give trans-ring junctions while Z-polyenes afford cis-ring junctions.26 Owing to these efforts, biomimetic polyene cyclization of E-polyenes has evolved into a widely applied and highly reliable strategy for constructing trans-decalin frameworks of terpene- and steroid-based natural products and their derivatives.8,27–30 However, this strategy has not been applied in the synthesis of cis-decalin-containing natural products yet, which are also prevalent in nature (Scheme 1a).31–34 This is mainly due to the following two reasons: (1) the preference for the transition state of forming cis product over its trans-counterpart is marginal for Z-polyene substrates, leading to a mixture of cis- and trans-isomers; (2) synthesizing Z-polyene substrates is more difficult than their E-polyene counterparts.35–38 Only recently has the first polyene cyclization approach to enantioenriched cis-decalins from Z-polyenes been accomplished by Gleason and co-workers (Scheme 1c, eq 1).39 Interestingly, scattered reports have illustrated that the cis ring juncture could be obtained as a side product of some very rare polyene cyclizations of E-polyenes albeit with poor selectivity.38,40–43 In such a context, we envisioned that a universal approach to cis-decalin products from both E- and Z-polyenes will be much more attractive because the more easily prepared E-polyenes rather than the difficultly approached Z-polyenes could be used for the challenging cis-polyene cyclization (Scheme 1c, eq 2). Another advantage is that the tedious separation of E- and Z-isomers during the substrate preparation would be unnecessary as the configuration of the alkene in polyenes will not influence the diastereoselectivity. We herein report a universal strategy to solve the long-standing challenge to construct cis-decalin frameworks via polyene cyclization of either ynamide-capped E-polyenes (E-YCPs) or ynamide-capped Z-polyenes (Z-YCPs). Additionally, DFT calculations have been conducted, revealing that a unique double protonation mechanism is involved, and the steric repulsion between the iminium and the forming decalin framework in the Friedel–Crafts (F–C) transition state is responsible for the unusual excellent cis-diastereoselectivity. Scheme 1 | (a) Natural products containing cis-decalin frameworks, (b) the Stork–Eschenmoser hypothesis, and (c) the polyene cyclization approach to the cis-decalin framework. Download figure Download PowerPoint Experimental Methods General procedure for ynamide protonation-initiated cis-selective polyene cyclization To an oven-dried reaction tube (10 mL) equipped with a magnetic stir bar was added E-YCPs 1 (0.1 mmol) in dichloromethane (DCM) (1 mL), and cooled to −40 °C. Then TfOH (2 mmol) was added slowly, and stirred for 10 min. After the reaction was complete, the reaction mixture was treated with saturated aqueous NaHCO3 solution, extracted with DCM, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude extracts were purified by silica gel column chromatography to offer the desired products 2a– 2p and 6a–6m. Computational methods All calculations were performed with the Gaussian 09 program.44 Geometry optimizations of all intermediates and transition states were carried out using the hybrid B3LYP45,46 functional with the 6-31G(d)47 basis set in the gas phase. Frequency calculations at the same level were performed to confirm that each stationary point was either a minimum or a transition state structure and to evaluate its zero-point energy and the thermal corrections at 298 K. To improve their accuracy, single-point energy calculations were carried out using the M06-2X48 functional with the 6-311G(d,p)47 basis set. Solvation energy (ΔGsolvation) for every species was the computed single-point energy difference in DCM and in the gas phase. Single-point energies in DCM (ε = 8.93) were evaluated by SMD49 calculations. Gibbs free energies in solutions were obtained from sums of the large basis set gas-phase single-point energies, solvation energies (ΔGsolvation), and the gas-phase Gibbs free energy corrections (at 298 K). The energy profile was drawn according to Gibbs free energies in the DCM solution (ΔGsol). The standard state of 1.0 mol/L at 298 K for all species was used. The computed structures were illustrated using CYLView.50 Results and Discussion It is well known that the protonation of an ynamide can produce a highly reactive keteniminium ion, which can be used to initiate cationic cascade reactions to construct polycyclic frameworks.51–53 On the other hand, a C–C triple bond has been used as the initiator for polyene cyclization because of its ability to deliver an electrophilic carbon center upon interaction with a carbophilic metal catalyst.54–59 Recently, our group has been interested in both ynamide chemistry60–65 and developing new reactions and strategies for efficient construction of polycyclic compounds.66,67 Based on our previous studies, we hypothesized that an ynamide functional group would be a promising initiator for polyene cyclization (Scheme 1c, eq 2). More importantly, the final polycyclic products bearing an extra amino functionality might be highly useful for the synthesis of terpene alkaloids and further manipulation. Preliminary study demonstrated that our proposal was feasible, and the tricyclic decalin 2a could be obtained as the major product with excellent diastereoselectivity. Optimization of reaction conditions disclosed that solvent, Brønsted acid promoter and its loading, and reaction temperatures had significant influence on reaction outcomes (Table 1). Generally, less polar solvent favored the formation of tricyclic product (entries 1, 4, and 5) while more polar nonprotonic solvent favored the generation of monocyclized product (entries 6 and 7). We found that the acidity and loading of the promoter imposed a remarkable effect on the distribution of products. Finally, we were happy to observe that using 20 equiv of triflic acid for the reaction provided the highest chemoselectivity (entries 8–12). In addition, low temperature was beneficial for the formation of the target tricyclic product. The best result was reached when the reaction was carried out in DCM at −40 °C with 20 equiv of triflic acid as the promoter (entry 13). Further increasing the loading of the promoter did not offer any improvement (entry 14), but reducing the loading of the promoter favored the formation of monocyclized product (entries 11 and 15). Surprisingly, X-ray crystallography analysis of 2a illustrated that the relative configuration of the decalin moiety was cis rather than the commonly expected trans counterpart (Scheme 2, eq 1). This unusual diastereoselectivity motivated us to test the Z-YCP substrate 3. To our surprise and delight, cis-decalin tricyclic product 2a was still delivered (Scheme 2, eq 2). This result suggested that the present polyene cyclization reaction would proceed in a stepwise manner, in which both E- and Z-YCP substrates would proceed via the same key intermediate. Fortunately, the preterminated monocyclized product 4 could be obtained as a major product when E-YCP 1a or Z-YCP 3 or a mixture of these two substrates was treated wtih a catalytic amount of triflic acid (20%), (Table 1, entry 15). Compound 4 could be smoothly converted to the final tricyclic product 2a under the standard cyclization reaction conditions (Scheme 2, eq 3). We therefore proposed that the monocyclized product 4 would be a common intermediate for both the Z- and E-YCP substrates. Notably, the one-pot two-step protocol afforded the target tricyclic product with similar excellent efficiencies. Table 1 | Reaction Conditions Optimizationa Entry Promoter (equiv) Solvent T (°C) Yield (%)b 2a 4 2aa 1 TfOH (10 equiv) DCM 0 36 17 — 2 TfOH (10 equiv) CH3NO2 0 27 9 — 3 TfOH (10 equiv) HFIP 0 37 — — 4 TfOH (10 equiv) CHCl3 0 37 12 — 5 TfOH (10 equiv) Toluene 0 39 — — 6 TfOH (10 equiv) Acetone 0 — 47 — 7 TfOH (10 equiv) DMF 0 — 12 — 8 Tf2NH (10 equiv) DCM 0 13 11 — 9 TFA (10 equiv) DCM 0 8 20 — 10 MsOH (10 equiv) DCM 0 8 — 53 11 TfOH (5 equiv) DCM 0 13 31 — 12 TfOH (20 equiv) DCM 0 62 — — 13 TfOH (20 equiv) DCM −40 90 — — 14 TfOH (40 equiv) DCM −40 91 — — 15 TfOH (0.2 equiv) DCM −40 — 77 — Note: DMF, dimethylformamide; HFIP, hexafluoroisopropanol; TFA, trifluoroacetic acid. Bold format is used to highlight that entry 13 is the best reaction condition. aReaction conditions: 1a (0.05 mmol), solvent (1 mL). bMeasured by using crude 1H NMR with 3,4,5-trimethoxyphene as the internal standard. Scheme 2 | Discovery of cis-selective polyene cyclization. Download figure Download PowerPoint With these exciting results in hand, we envisioned that a broad substrate scope for such a reaction would offer a general approach for constructing the challenging cis-decalin frameworks from the easily available E-YCP substrates. A variety of E-YCPs containing aryl terminal groups were prepared and evaluated under the standard cyclization reaction conditions (Scheme 3). In terms of the ynamide moiety, it was revealed that electron-donating substituents on the phenylsulfonamide group of the substrates led to superior results compared to those with electron-withdrawing substituents (i.e., 2a–2e), and the methylsulfonamide substrate gave a comparable result ( 2f). Substrates bearing both electron-withdrawing and -donating groups on the terminator afforded the target tricyclic products in good to excellent yields ( 2g– 2l). In addition, E-YCPs with heterocycles as well as aryl substituents on the terminal phenyl ring were also suitable substrates ( 2m–2o). We then explored substrates with halide substituents and found that both chloro- and bromo-substituents were compatible to give the target cyclized products in good yields ( 2i, 2k). We noted that both para- and ortho-cyclized products ( 2l, 2l′) were formed in yields of 47% and 26%, respectively, when m-Br-Ph- was employed as the terminator. The compatibility of the halide substituents in such a polyene cyclization reaction offered opportunities for further functionalization via transition metal catalyzed cross-coupling reactions using these halide-containing products, greatly expanding the impact of this method in synthesis. Unfortunately, only monocyclized product 2p was obtained in 51% yield when a 3,4,5,-trimethoxyphenyl group was employed as the terminator in the reaction. Scheme 3 | Substrate scope of the unusual polyene cyclization. aReaction conditions: 1 (0.1 mmol), TfOH (2 mmol), DCM (1 mL), −40 °C, 10 min. Download figure Download PowerPoint To further illustrate the generality of this method, the polyene cyclization was investigated by using substrates containing ether linkages. As shown in Scheme 4, oxygen-containing E-YCP substrates could be transformed to the cis-decalin ring systems with excellent chemo-, stereo-, and regioselectivities. The structures of the tricyclic products 6c and 6i were unambiguously confirmed by NMR and X-ray crystallography. Similarly, both electron-withdrawing and -donating groups on the terminal phenyl ring in the substrates were compatible in the reaction ( 6b–6k); however, the preterminated monocyclized products 6l and 6m were obtained when the strong electron-withdrawing group of –NO2 or two electron-donating –OMe groups were present on the terminal phenyl ring of the substrates. Moreover, the target tricyclic product 6k and its deprotected product 6k′ were both obtained in 39% and 36% yields, respectively, for the substrate with a benzyloxy group on its aryl terminal group. Scheme 4 | Substrate scope of the oxygen-containing E-YCPs. aReaction conditions: 5 (0.1 mmol), TfOH (2 mmol), DCM (1 mL), −40 °C, 24 h. bTfOH (3 mmol), DCM (1 mL), −20 °C, 2 d. cTfOH (3 mmol), DCM (1 mL), −40 °C, 4 d. Download figure Download PowerPoint To study the synthetic application of this methodology, further transformations of the polycyclic products were conducted (Scheme 5). For example, the enamide double bond of cis-decalin 2a could be reduced smoothly to furnish 7, which is an attractive intermediate for terpene alkaloid synthesis, with excellent diastereoselectivity (dr > 99:1). In addition, we observed that the α-bromo-ketone 8, in which the bromo and ketone functional groups offer tags for further functionalization, could be obtained in a good yield and diastereoselectivity by treating 2a with N-bromosuccinimide. Notably, the E-YCPs could be easily prepared from Corey's terminal alkynyl E-polyenes, which afforded the trans-decalin framework upon treatment with In(III) reagent,54 via an oxidative cross-coupling reaction.68 This means that both trans- and cis-decalin frameworks are approachable from the same terminal alkynyl E-polyene substrates by employing Corey's method54 directly (Scheme 5, left part) or by capping the terminal alkyne group with ynamide followed by the polyene cyclization of E-YCPs (Scheme 5, middle part). Scheme 5 | Synthetic application of the cyclized product. Download figure Download PowerPoint DFT calculations were carried out to understand the unusual cis-diastereoselectivity of the ynamide protonation-initiated polyene cyclization. A plausible reaction mechanism, which was also supported by DFT calculations, was proposed in Scheme 6. Protonation of the E-YCP ( 1a) or Z-YCP ( 3) by one TfOH molecule (two TfOH molecules were used to mimic the presence of a cluster of TfOH molecules in the reaction system in our calculations) gave the highly reactive keteniminium ion I, which then underwent electrophilic addition toward the alkene, giving the carbenium ion II.Then this intermediate, via cyclization, afforded III′. This step was followed by deprotonation, delivering cis-product 2a (the formation of trans-product from this step was disfavored compared to that of cis-product, see the Supporting Information Scheme S2). However, this pathway was disfavored because there was another competing and much more favored pathway in which intermediate II could easily be trapped by the OTf anion in the TfOH cluster, forming intermediate II-OTf. This species was then transformed to compound 4 via elimination. Actually 4 was observed when a catalytic amount of TfOH was used (Table 1, entry 15 and Scheme 2, eq 2), giving experimental support to this proposal. Scheme 6 | Proposed reaction mechanism. Download figure Download PowerPoint When excess triflic acid was used, compound 1a or 3 still gave II-OTf by the same processes. But II-OTf then underwent further protonation to give a dicationic intermediate, IV (via protonation of the OTf group, a barrierless C–O dissociation process to lose a TfOH molecule, and then protonation of the enamine moiety, see Supporting Information Scheme S5), which then underwent F–C alkylation with the aryl ring and deprotonation followed to afford the final tricyclic product 2a. When Z-polyene 3 was used as the substrate, it experienced the same double protonation processes to give IV and the final tricyclic product 2a. DFT calculations were performed to explain why dication IV favored giving cis-product (Figures 1a and 1b). We started our calculations from the intermediate I, which was generated by an exergonic protonation of substrate 1a or 3. The cyclization was easy with an activation free energy of 0.5 kcal/mol. This step gave cationic intermediate II. Theoretically, II can undergo cyclization to give the cis-product 2a, which only requires an activation free energy of 2.4 kcal/mol (trans-product formation is not favored, see the Supporting Information Scheme S2). Therefore, these calculations imply that cyclization from II is faster than a diffusion process and cannot be intercepted by another reagent, if the above proposal is correct. But TfOH was used in 20%, and a cluster of TfOH molecules was formed in the solvent, suggesting that intermediate II was actually surrounded by TfOH-OTf anion. This implies that once intermediate II is formed, it can be quickly quenched by its adjacent OTf anion to form II-OTf. This neutral intermediate then underwent an elimination reaction to form 4, with a computed activation free energy of 20.3 kcal/mol. Although II-OTf is more stable than 4 by 8.2 kcal/mol in terms of free energy, 4 can still be generated considering the quick consumption of generated TfOH by 1a (see Supporting Information Scheme S1). Moreover, the direct formation of 4 via deprotonation by OTf anion from II is a barrierless process, although this is less feasible because intermediate II-OTf is more stable (see the Supporting Information Schemes S3 and S4). Figure 1 | (a) DFT-computed energy surface for the generation of 4 and (b) DFT-computed energy surface for the formation of cis- and trans-products (bond distances in angstrom). Download figure Download PowerPoint When TfOH was used in excess amounts, both the OTf group and the enamine moieties in II-OTf were protonated, followed by liberation of a TfOH molecule to afford the dicationic intermediate IV (see the Supporting Information Schemes S5–S7). Two electrophilic transition states, starting from IV, leading to cis- and trans-products, respectively, were located. We found that the dication in the cis-pathway via TS-IV-V, required only an activation free energy of 1.1 kcal/mol to give V, which then furnished the cis-product by deprotonation. In contrast, two steps were required in the trans-pathway. DFT calculations showed that a bicyclic cation intermediate VI was firstly generated from IV via TS-IV-VI with an activation free energy of 13.7 kcal/mol. This step was endergonic by 6.5 kcal/mol. Secondly, an easy C–C bond migration via with an activation free energy of only 6.5 to give a more stable intermediate The DFT results in Figure that trans-product will not be formed because this pathway an activation free energy of 13.7 which is kcal/mol less favored than that required in the The final step of deprotonation from and is expected to be as suggested by our calculations of deprotonation by OTf anion (see the Supporting Information Scheme Therefore, DFT calculations that the trans-product will not be generated in with the experimental Two steric can be to explain the It was firstly found that the group showed a strong with the group in the TS-IV-VI and in Figure the between and is only The could from the repulsion of groups A and in in which the of two is However, the steric cannot be found in the cis-decalin formation transition in which A and groups are in a and A and groups are in a two to the result that state TS-IV-VI is greatly disfavored compared to the state by kcal/mol. A to the unusual cis-diastereoselectivity of the ynamide protonation-initiated polyene cyclization is in Scheme 1c, where double protonation and F–C reaction are shown to have a quick and easy of the process. it was observed that substrate bearing a group to furnish the final tricyclic and this could be to the F–C reaction of the aryl ring in the For substrates and containing or two poor experimental results could be by protonation of the group by strong acid which the aryl ring for the F–C reaction. We have a general synthetic approach to cis-decalin frameworks via an unprecedented ynamide protonation-initiated polyene cyclization by using ynamide-capped polyenes the conventional polyene cyclization reactions wherein E-polyenes to while Z-polyenes offer both E- and Z-YCPs furnish the cis-decalin frameworks with excellent chemo-, regio-, and in the present cyclization and an easy and general to cis-decalin frameworks, a long-standing challenge in the polyene cyclization the that the ynamide-capped polyene substrates could be easily prepared from Corey's E-polyene substrates, which afford the by the traditional method, present method an advantage that it the cis- as well as trans-decalin frameworks approachable from the same available Corey's E-polyene substrates. DFT study that this ynamide protonation-initiated polyene cyclization via a double protonation pathway the keteniminium ion and iminium The DFT calculations disclosed that the steric between the iminium and the forming decalin framework in the F–C transition state a in the unusual cis-diastereoselectivity. the diversity of polycyclic frameworks in natural products and reactions and strategies for constructing polycyclic frameworks are highly The present method, with our previous catalyzed our in this Supporting Information Supporting Information is available experimental and results and of The competing This was supported by the Natural of and and the Natural of Jiangxi We this to the of at Nankai in 3. on in into from the of K. for 6. in to Terpenes and Polyene in Polyene and in Natural Cyclization of of by of Zhao Polyene

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