Twenty-Step Total Synthesis of (+)-Phorbol

Open AccessCCS ChemistryCOMMUNICATIONS6 Aug 2024Twenty-Step Total Synthesis of (+)-Phorbol Kuan Zhao†, Yifu Cheng† and Yanxing Jia Kuan Zhao† State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, and Chemical Biology Center, Peking University, Beijing 100191 , Yifu Cheng† State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, and Chemical Biology Center, Peking University, Beijing 100191 and Yanxing Jia *Corresponding author: E-mail Address: [email protected] State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, and Chemical Biology Center, Peking University, Beijing 100191 Southwest United Graduate School, Kunming 650092 Cite this: CCS Chemistry. 2024;0:1–6https://doi.org/10.31635/ccschem.024.202404505 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail We have accomplished the efficient total synthesis of (+)-phorbol in 20 steps from inexpensive (+)-carvone. This concise synthesis is partly due to the use of two pentamethyldisilyl (PMDS) groups as the masked hydroxyl groups. The significant advantages of the PMDS group over other silyl groups have been firmly demonstrated. This total synthesis features a Shapiro reaction that links two fragments possessing a unique PMDS group. This is followed by a Tamao–Fleming oxidation and a subsequent ring-closing metathesis reaction to construct the 5/7/6/3 tetracyclic skeleton. Download figure Download PowerPoint Introduction Tigliane diterpenes and several biogenetically related families of diterpenoids have attracted the attention of organic chemists and biologists because of their intriguing chemical structures and promising medicinal applications.1 Phorbol ( 1) is the most well-known member of the tigliane diterpenes (Figure 1), and its esters exhibit a broad range of interesting biological activities by modulating protein kinase C,2,3 including antitumor, anti-HIV, immune-modulatory, and inflammatory promotion. For example, tigilanol tiglate ( 2) was evaluated in a phase I clinical trial for the treatment of human cancers and approved to treat nonmetastatic mast cell tumors in dogs by Food and Drug Administration.4 Subtle modification of the oxidation state and substituents on the skeleton have particularly great effects on the biological activities of the analogs. Figure 1 | Phorbol (1) and tigilanol tiglate (2). Download figure Download PowerPoint The total synthesis of phorbol is challenging because it has a unique 5/7/6/3 tetracyclic skeleton, eight contiguous stereocenters, and an array of dense functional groups. In addition, it is sensitive to acid,5 base,6 heat, light. and air oxidation.7 In particular, it undergoes cyclopropanol rearrangement under an acidic environment (for the Flaschenträger reaction, see Supporting Information Scheme S1). Although many synthetic efforts towards 1 have been reported,8 only four total syntheses and two formal syntheses of 1 have been reported by four groups (Figure 1). Wender's group achieved the first total synthesis of phorbol as a racemic mixture in 1989 (in 52 steps),9 1990 (in 42 steps),10 and as an enantiomer in 1997 (in 40 steps).11 In 2001, Cha's group reported the formal asymmetric synthesis of phorbol (in 42 steps).12 In 2016, Baran's group reported an exceedingly concise synthesis by using a two-phase terpene synthesis strategy (in 19 steps).13 Lately, Inoue's group reported unified total syntheses based on radical cyclization.14 Related tigliane diterpenes have also been accomplished by the groups of Inoue,15,16 Li,17 Liu,18 Carreira,19 and Li.20 The installation of the C12/13 antidiols along with the cyclopropane is arguably the most challenging part of the synthesis of phorbol. The groups of Wender9 and Baran13 independently conceived the simple solution to this challenge as late-stage transformations and thus eventually achieved its total synthesis. On the contrary, the group of Fuchs described a novel method for the preparation of the phorbol 6,3-bicyclic system from the readily available (+)-carvone21 in which the allyldimethylsilyl (ADMS) group was selected as the masked hydroxyl group (Scheme 1). Recently, Fadel and Carreira19 shared a similar strategy in the total synthesis of pedrolide, and they obtained a fully functionalized carane fragment through an efficient method. Scheme 1 | Fuchs's synthesis of phorbol 6,3-bicyclic system. Download figure Download PowerPoint Inspired by Fuchs's work and as an extension of our ongoing studies towards the total syntheses of structurally complex diterpenoids,22–28 we endeavored to develop a new strategy for the concise and efficient total synthesis of phorbol utilizing a unique pentamethyldisilyl (PMDS) group. The PMDS group is relatively stable and can exert greater steric influence,29 and the PMDS anion has an inherent "soft" nature in conjugate addition and can potentially undergo oxidative desilylation under mild conditions.30,31 Herein, we report the total synthesis of (+)-phorbol in only 20 longest linear steps and 22 total steps. Results and Discussion Our retrosynthetic analysis is depicted in Scheme 2. We envisioned that (+)-phorbol ( 1) could be generated from the tetracycle 8 through functional group transformations. Compound 8 resembles the full 5/7/6/3 tetracyclic skeleton of 1 and was obtained by Tamao–Fleming oxidation of intermediate 9 followed by the ring-closing metathesis (RCM) reaction. Intermediate 9 was generated by the Shapiro reaction of trisylhydrazone (trisyl = triisopropylbenzenesulfonyl) 10 with ketone 11. Trisylhydrazone 10 was conveniently prepared from cyclopentenone 12 by conjugate addition of pentamethyldisilyllithium. Ketone 11 was derived from 13, which was prepared from (+)-carvone ( 3) by the modification of Fuchs's approach. Scheme 2 | Retrosynthetic analysis of (+)-phorbol (1). Download figure Download PowerPoint Our synthesis commenced with the preparation of the trisylhydrazone 10 (Scheme 3). Conjugate silyl addition of pentamethyldisilyllithium (prepared in situ by the reaction of hexamethyldisilane with methyllithium in hexamethylphosphoramide, see Supporting Information Scheme S2) to cyclopentenone ( 12) and trapping of the resulting enolates with methallyl bromide ( 14) afforded the desired 15. And the desired trisylhydrazone 10 was obtained quantitatively in the condensation of 15 with TrisNHNH2. Scheme 3 | Preparation of trisylhydrazone 10. Download figure Download PowerPoint Ketone 11 was prepared from (+)-carvone ( 3) by modification of Fuchs's approach (Scheme 4a). (+)-Carvone ( 3) was readily converted to 3,4-epoxy-caranone ( 4) following the known one-pot procedure.32,33 α-Silylation of caranone 4 with chloropentamethyl-disilane provided the desired α-silyl ketone 16 (it was necessary to add substrate very slowly, otherwise a dimer of 4 would be produced, see Supporting Information Figure S3 and Table S4). Reduction of α-silyl ketone 16 with LiAlH4 afforded the desired 1,3-diol 17 (see Supporting Information Figure S4 and Table S5) in 66% yield.34 Scheme 4 | (a) Preparation of ketone 11. (b) Feasibility of Tamao-Fleming oxidation of PMDS. Download figure Download PowerPoint In order to investigate the feasibility of Tamao-Fleming oxidation of the PMDS group to alcohol, protection of 1,3-diol 17 with acetyl was carried out (Scheme 4b). The C9 alcohol was selectively protected in the presence of C12 alcohol to give 21. However, this chemo-selectivity was not found in compound 6 (Scheme 1). This result clearly indicated that the PMDS group exerted greater steric influence than the ADMS group. Methoxymethyl (MOM) protection of alcohol 21 gave 22. Treatment of 22 with tetrabutylammonium fluoride followed by H2O2 gave the desired alcohol 23 in 82% yield, which was confirmed by single-crystal X-ray diffraction analysis (see Supporting Information Figure S1 and Table S2). The result indicated that PMDS was easily converted to tertiary alcohol under mild conditions without affecting cyclopropane. With these encouraging results, we proceeded to convert 17 to 11. As described above, the chemo-selectivity of C9 and C12 alcohol during protection prompted us to investigate the selective oxidation of less hindered C9 alcohol without the protection of C12 alcohol. Gratifyingly, the selective oxidation of C9 alcohol using Mukaiyama's reagent ( 18) smoothly afforded the desired ketone 19.35 MOM protection of ketone 19 gave ketone 13. Aldol reaction between 13 and (phenylseleno)-acetaldehyde ( 20) followed by elimination of the resultant secondary alcohol produced ketone 11 in 60% yield in two steps.36 Having both fragments in hand, we turned our attention to the completion of total synthesis of 1 by the formation of the C9–C10 bond though the addition of vinyl lithium to a ketone followed by RCM to form the seven-membered ring (Scheme 5).18,37,38 Coupling of trisylhydrazone 10 with ketone 11 was achieved by the Shapiro reaction. Treatment of hydrazone 10 with n-BuLi afforded a vinyl anion species, which was then reacted with ketone 11 to produce a mixture of two diastereomers 9a and 9b (dr = 1:1) in 85% yield. Interestingly, both 9a and 9b were found to exist as a mixture of atropisomers in solution, a feature attributed to the hindered rotation of the newly formed C9–C10 bond. The presence of atropisomers continued until the formation of the seven-membered ring. Scheme 5 | Total synthesis of (+)-phorbol (1). Download figure Download PowerPoint Attempts to form the seven-membered ring by RCM reactions of 9a and 9b were then made. However, no desired products were observed, even after screening lots of catalysts and solvents, probably due to the large PMDS groups. Thus, the transformation of two silyl groups was firstly conducted. Tamao–Fleming oxidation of 9a and 9b provided the desired alcohol 24a and 24b in nearly 63% yield. Swern oxidation of alcohol 24a and 24b followed by selective protection of C13 alcohol with MOM gave ketone 25a and 25b. Subsequent reaction of 25a and 25b with the Grubbs-Hoveyda second-generation (GH-II) catalyst followed by olefin isomerization with DBU in one pot afforded the enone 8. Hydroxy-group-directed conjugative reduction of 8 with LiAlH2(OMe)2 provided the desired ketone 27 (see Supporting Information Figure S2 and Table S3) as the sole isomer in 66% yield accompanied with 30% 1,2-reduction product 26 which was quantitatively converted to enone 8 by 2-iodoxybenzoic acid oxidation. With the tetracycle 27 in hand, the installation of the C1–C2 double bond and C2 methyl was conducted. After several trials, we found that treatment of 27 with LiHMDS followed by the addition of Mukaiyama's reagent delivered the desired enone 28 in 80% yield.39 The methyl group was introduced by formation of an α-iodoenone followed by a Stille coupling to provide 29 in 60% overall yield along with 32% recovered 28.13 The C4-hydroxylation of 29 was then investigated, and it proved to be quite a challenge. Under most tested conditions, such as Rubottom oxidation and Davis oxaziridine oxidation, the yield was low, and the reaction gave predominantly or wholly the undesired C4-α-OH- 30. We hypothesized that the gem-dimethyl cyclopropane blocked the attack of oxidizing reagents from the top face. Therefore, attempts to protect C9 hydroxyl group to change the conformation of 29 were initially made. Unfortunately, all attempts failed. We then turned our efforts to direct oxidation. After extensive experimentation, we found that t-BuOK/O2/P(OEt)3 gave the best result, which led to the formation of separable diastereomers 30 and 31 in 90% yield with a ratio of 1.5 to 1. The undesired 30 was also readily transformed to precursor 29 by SmI2-promoted C4-dehydroxylation. The oxidation of C20 of 31 with SeO2 was easily overoxidized to the corresponding aldehyde, which was subsequently reduced with n-Bu4NBH4 to give MOM-protected phorbol 32 in 90% yield. Finally, we focused on the most challenging acid-mediated deprotection of MOM, which has not been used in the total synthesis of phorbol. Various Brönsted acids,40–43 Lewis acids,44–49 and solvents were screened (see Supporting Information Table S1). Most of the tested conditions were too harsh and caused degradation of the substrate. After extensive experiments, we found that treatment of 32 with MgBr2 and n-PrSH in CH2Cl2 provided (+)-phorbol ( 1) in 44% yield accompanied by (+)-crotophorbolone ( 33) in 22% yield. In addition, 1 was smoothly transformed to 33 in 80% yield by employing MgBr2 in CH2Cl2. Conclusion We have accomplished the total synthesis of (+)-phorbol in only 20 steps with 0.7% overall yield. This is the highest yield reported to date. The concise synthesis of 1 is enabled by a fundamentally different route for the synthesis of the 6,3-bicyclic system from (+)-carvone and the use of PMDS group as the masked hydroxyl group. The present synthesis clearly underlines the significant advantages of the PMDS group employed in conjugate addition and one-pot oxidative desilylation. A mild acidic condition for the conversion of phorbol to crotophorbolone is also disclosed. Although phorbol is available in large quantities from natural sources, this synthetic route allows access to tigliane analogs that are otherwise not available to access through isolation and semisynthesis. Supporting Information Supporting Information is available and includes experimental procedures, substrate preparation procedures, optimization details, characterizations and analytical data about products, X-ray structures, and NMR spectra. Conflict of Interest The authors declare no competing financial interests. Funding Information This research was supported by the National Natural Science Foundation of China (grant nos. 21925101 and 22331001), and the Yunnan Provincial Science and Technology Project at the Southwest United Graduate School (grant no. 202302AP370004). Acknowledgments We are indebted to Fuling Yin and Hongli Jia for their kind help with X-ray crystallography. References 1. Wang H.-B.; Wang X.-Y.; Liu L.-P.; Qin G.-W.; Kang T.-G.Tigliane Diterpenoids from the Euphorbiaceae and Thymelaeaceae Families.Chem. Rev.2015, 115, 2975–3011. Google Scholar 2. Zhang G.-Y.; Kazanietz M. G.; Blumberg P. M.; Hurley J. H.Crystal Structure of the Cys2 Activator-Binding Domain of Protein Kinase C δ in Complex with Phorbol Ester.Cell1995, 81, 917–924. Google Scholar 3. Otsuki K.; Li W.Tigliane and Daphnane Diterpenoids from Thymelaeaceae Family: Chemistry, Biological Activity, and Potential in Drug Discovery.J. Nat. Med.2023, 77, 625–643. Google Scholar 4. Wender P. A.; Gentry Z. O.; Fanelli D. 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H.Total Synthesis of Mycalamide A.J. Am. Chem. Soc.2005, 127, 7290–7291. Google Scholar Previous articleNext article FiguresReferencesRelatedDetails Issue AssignmentNot Yet AssignedSupporting Information Copyright & Permissions© 2024 Chinese Chemical SocietyKeywordstotal synthesisditerpenoidsphorbolpentamethyldisilyl groupTamao–Fleming oxidationAcknowledgmentsWe are indebted to Fuling Yin and Hongli Jia for their kind help with X-ray crystallography. Downloaded 829 times PDF downloadLoading ...