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Synthesis of (–)-melazolide B, a degraded limonoid, from a natural terpene precursor

Open AccessPublished:March 21, 2022DOI:https://doi.org/10.1016/j.tchem.2022.100011

      Abstract

      Degraded limonoids are a subclass of limonoid natural products that derive from ring-intact or ring-rearranged limonoids. Establishment of robust synthetic routes to access them could provide valuable materials to identify the simplest active pharmacophore responsible for the observed biological activities of the parent molecules. This communication delineates the development of a divergent strategy to furnish melazolide B and several other related congeners from a common keto-lactone intermediate, which was rapidly assembled from α-ionone. A chemoselective carbonyl α,β-dehydrogenation and a Wharton reduction were key strategic steps in this synthetic pathway.

      Graphical abstract

      Keywords

      1. Introduction

      Limonoids are a large family of terpenoid natural products with more than a thousand members isolated to date [
      • Tan Q.-G.
      • Luo X.-D.
      ,
      • Taylor a.D.
      In Fortschritte der Chemie organischer Naturstoffe/Progress in the Chemistry of Organic Natural Products.
      ,
      • Zhang Y.
      • Xu H.
      ]. These secondary metabolites display a broad array of biological activities, ranging from anticancer, anti-inflammation, antifeedant, and neurological activities [
      • Tan Q.-G.
      • Luo X.-D.
      ,
      • Taylor a.D.
      In Fortschritte der Chemie organischer Naturstoffe/Progress in the Chemistry of Organic Natural Products.
      ,
      • Zhang Y.
      • Xu H.
      ]. Due to their diverse and intricate structures as well as interesting biological profiles, several synthetic campaigns have targeted this family of natural products [
      • Behenna D.C.
      • Corey E.J.
      ,
      • Faber J.M.
      • Eger W.A.
      • Williams C.M.
      ,
      • Fu S.M.
      • Liu B.
      ,
      • Heasley B.
      ,
      • Lv C.
      • Yan X.
      • Tu Q.
      • Di Y.
      • Yuan C.
      • Fang X.
      • Ben-David Y.
      • Xia L.
      • Gong J.
      • Shen Y.
      • Yang Z.
      • Hao X.
      ,
      • Pinkerton D.M.
      • Chow S.
      • Eisa N.H.
      • Kainth K.
      • Vanden Berg T.J.
      • Burns J.M.
      • Guddat L.W.
      • Savage G.P.
      • Chadli A.
      • Williams C.M.
      ,
      • Schuppe A.W.
      • Huang D.
      • Chen Y.
      • Newhouse T.R.
      ,
      • Schuppe A.W.
      • Newhouse T.R.
      ,
      • Schuppe A.W.
      • Zhao Y.
      • Liu Y.
      • Newhouse T.R.
      ,
      • Yamashita S.
      • Naruko A.
      • Nakazawa Y.
      • Zhao L.
      • Hayashi Y.
      • Hirama M.
      ]. Our group has reported the total synthesis of several rearranged limonoids and pyridine-containing bislactone limonoid alkaloids (12) [
      • Schuppe A.W.
      • Huang D.
      • Chen Y.
      • Newhouse T.R.
      ,
      • Schuppe A.W.
      • Newhouse T.R.
      ,
      • Schuppe A.W.
      • Zhao Y.
      • Liu Y.
      • Newhouse T.R.
      ], which exhibit modest PTP1B inhibitory activity (Scheme 1) [
      • Zhou Z.F.
      • Liu H.L.
      • Zhang W.
      • Kurtan T.
      • Mandi A.
      • Benyei A.
      • Li J.
      • Taglialatela−Scafati O.
      • Guo Y.W.
      ]. The development of these robust synthetic routes has enabled efficient access to them and their analogs for SAR studies [
      • Newhouse T.
      • Schuppe A.
      • Liu Y.
      • Zhao Y.
      • Ibarran S.
      • Huang D.
      • Wang E.
      • Lee J.
      • Loria P.
      ]. These investigations piqued our interest in identifying the active pharmacophore for the observed PTP1B inhibition.
      Degraded limonoids, such as azedaralide (3), pyroangolensolide (4) and (−)-melazolide B (5), are a subclass of limonoid natural products arising from ring-intact or ring-rearranged limonoids (Scheme 1) [
      • D'Ambrosio M.
      • Guerriero A.
      ]. Although highly speculative at this juncture, Guerriero and co-workers hypothesized, based on the co-isolation of pyroangolensolide (4) and melazolide B (5), that they may derive from a common tetranotriterpenoid precursor such as deoxyandirobin (7) (Scheme 2) [
      • D'Ambrosio M.
      • Guerriero A.
      ]. Fragmentation along the C9–C10 bond would yield fragments resembling degraded limonoid natural products (Scheme 2) [
      • D'Ambrosio M.
      • Guerriero A.
      ]. Mechanistic proposals have previously been hypothesized [
      • Almeida A.
      • Dong L.
      • Appendino G.
      • Bak S.
      ,
      • Li W.-S.
      • Mandi A.
      • Liu J.-J.
      • Shen L.
      • Kurtan T.
      • Wu J.
      ].
      Scheme 1
      Scheme 1Selected limonoids and structurally related compounds.
      Scheme 2
      Scheme 2Proposed biosynthesis of (−)-melazolide B.
      Our established approach provided a synthetic pathway to access compounds related to the DE-ring fragments, such as azedaralide (3) and pyroangolensolide (4) [
      • Schuppe A.W.
      • Zhao Y.
      • Liu Y.
      • Newhouse T.R.
      ]. Herein we disclose the development of synthetic routes to access compounds related to the AB-ring fragments, including (−)-melazolide B (5) and actinidiolide (6).

      2. Results and discussion

      Our initial synthetic strategy focused on a bidirectional search between the known degraded limonoids, such as 5 and 6, and our previously reported intermediate 11. The benefit of 11 as a starting material goal is that it already contains the key ring systems, quaternary center, and two stereocenters common to these degraded limonoids [
      • Brill Z.G.
      • Condakes M.L.
      • Ting C.P.
      • Maimone T.J.
      ]. A cyclohexanone would need to be converted to an allylic alcohol wherein the hydroxyl group has formally undergone a reductive transposition. As an added benefit, the route to 11 was robust, and involved conversion of α-ionone (8) by a three-step sequence involving a kinetic resolution via Jacobsen epoxidation [
      • Jacobsen E.N.
      • Zhang W.
      • Muci A.R.
      • Ecker J.R.
      • Deng L.
      ], 1,4-hydrosilylation, and oxidative cleavage, as shown in Scheme 3A [
      • Schuppe A.W.
      • Zhao Y.
      • Liu Y.
      • Newhouse T.R.
      ]. Treatment of ketone 11 with KHMDS and N-phenyl-bis(trifluoromethanesulfonimide) resulted in the formation of an intermediate vinyl triflate (12) in 84% yield, which was then reduced to alkene 13 in 87% yield (Scheme 3A). Other reductants employed in this Pd-catalyzed reduction, including Et3SiH and Bu3SnH, were less effective in this context.
      Scheme 3
      Scheme 3Synthesis of C3-epi-melazolide Ba.
      aReagents and conditions: (1) 5 mol % (S,S)-(+)-N,N′-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride, 4-phenylpyridine-N-oxide (5 mol %), aq. NaOCl (1 equiv), CH2Cl2, 0 to 23 °C, 43%, 89:11 er, 10:1 dr; (2) 1 mol % [Rh(COD)(OH)]2, PhMe2SiH (1.3 equiv), THF, 23 to 60 °C, 2 h, 89%; (3) O3, acetone, 78 °C, 0.5 h, then Jones reagent (2.0 equiv), 0 to 23 °C, 2 h, 51%; (4) KHMDS (1.3 equiv), PhNTf2 (1.3 equiv), THF, −78 to 23 °C, 1 h, 84%; (5) 5 mol % Pd(OAc)2, 10 mol % PPh3, formic acid (2.0 equiv), Et3N (3.0 equiv), DMF, 60 °C, 0.5 h, 87% (6) Mn(OAc)3 (0.7 equiv), TBHP (5.0 equiv), EtOAc, 70 °C, 3 d, 40%; (7) LiBH4 (2.0 equiv), CeCl3 (2.0 equiv), THF/MeOH, 0 °C to rt, 1 h, 72%, 20:1 dr; (6') Zn(TMP)2 (1.0 equiv), diethyl allyl phosphate (1.0 equiv), 2.5 mol % [Pd(allyl)Cl]2, PhMe, 120 °C, 3 h, 85%.
      Conversion of alkene 13 to an intermediate enone was achieved by allylic oxidation utilizing Mn(OAc)3 and t-BuOOH [
      • Shing T.K.
      • Yeung Y.-Y.
      • Su P.L.
      ]. Employing alternative allylic oxidation conditions to furnish 5 or 15 directly, such as SeO2 and Cr-based oxidants, were unsuccessful. A diastereoselective Luche reduction of the enone intermediate (14) resulted exclusively in the formation of C3-epi-melazolide B (15).
      Although 13 was not a viable intermediate to melazolide B (5), considering our laboratory's lactone α,β-dehydrogenation [
      • Chen Y.
      • Huang D.
      • Zhao Y.
      • Newhouse T.R.
      ], we reasoned that subjection of 13 to lactone α,β-dehydrogenation conditions could give rise to (−)-actinidiolide (6), an ionone-related compound that was proposed to be produced from kiwiionoside in nature [
      • Sakan T.
      • Isoe S.
      • Hyeon S.B.
      ]. Indeed, dehydrogenation of the lactone functionality in 13 with our laboratory's allyl Pd-catalyzed dehydrogenation conditions revealed that the conditions originally developed for ketone dehydrogenation were most effective (the Zn(TMP)2 and diethyl allyl phosphate system) to produce actinidiolide (6), as shown in scheme 3B [
      • Chen Y.
      • Huang D.
      • Zhao Y.
      • Newhouse T.R.
      ]. Employing the conditions previously developed by our laboratory for ester [
      • Chen Y.
      • Romaire J.P.
      • Newhouse T.R.
      ] or amide [
      • Chen Y.
      • Turlik A.
      • Newhouse T.R.
      ] dehydrogenation resulted in lower conversion and diminished yield (23% and 47% yield respectively). These results suggest that the Zn(TMP)2 system may be more general for the dehydrogenation of other basic functionalities.
      In order to obtain melazolide B (5), we undertook an alternative route through enone 17 (Scheme 4). Several ketone dehydrogenation conditions of 11 was first examined. A two-step sequence involving TMS enol ether formation and dehydrogenation was first attempted. Treatment of ketone 11 with KHMDS and TMSCl resulted in 16 in 36% yield (Scheme 4A). Although the original Saegusa-Ito oxidation conditions only led to full decomposition of the sily enol ether starting material (16) [
      • Ito Y.
      • Hirao T.
      • Saegusa T.
      ], subjection of 16 to Tsuji's modified conditions smoothly delivered the enone product (17) in 91% yield (Scheme 4A) [
      • Tsuji J.
      • Minami I.
      • Shimizu I.
      ].
      Scheme 4
      Scheme 4Optimization of ketone dehydrogenationa.
      aReagents and conditions: (1) KHMDS (1 equiv), TMSCl (1.5 equiv), THF, –78 °C to rt, 2 h 36%; (2) 10 mol % Pd(OAc)2, 10 mol % dppe, diallyl carbonate (1.5 equiv), MeCN, 80 °C, 4 h, 91%. bYield of the crude reaction mixture, using 0.05 mmol 11, was determined by 1H NMR using dibromomethane as an internal standard. Conversion of 11 in parenthesis. cReactions conducted on 0.2 mmol scale. dConducted on a 3-gram scale.
      Several one-step dehydrogenation conditions were surveyed (Scheme 4B). Utilizing our laboratory's allyl-Pd-catalyzed dehydrogenation conditions [
      • Chen Y.
      • Huang D.
      • Zhao Y.
      • Newhouse T.R.
      ] (entries 1–3) resulted in overoxidation (18), however, the Ni-catalyzed dehydrogenation conditions only gave partially recovered starting material (entry 4). Employing either Mukaiyama's reagent [
      • Mukaiyama T.
      • Matsuo J.-i.
      • Kitagawa H.
      ] (entries 5–6) or IBX (entry 7) resulted in minimal desired product [
      • Nicolaou K.
      • Zhong Y.-L.
      • Baran P.
      ]. Subjection of 11 to Stahl's Pd-catalyzed aerobic dehydrogenation conditions afforded enone 17 with excellent selectivity (>20:1, entry 8) and upon conducting on a 3-g scale, excellent yield (92% yield, entry 9) [
      • Diao T.
      • Stahl S.S.
      ].
      With enone 17 in hand, we were ready to test the proposed synthesis of melazolide B (5) through Wharton reduction [
      • Wharton P.
      • Bohlen D.
      ]. Treatment of enone 17 with urea·H2O2 effected a nucleophilic epoxidation to furnish epoxide 19 in 67% yield as a 1:1 mixture of diastereomers (Scheme 5) [
      • Schuppe A.W.
      • Zhao Y.
      • Liu Y.
      • Newhouse T.R.
      ]. Reduction of the mixture of diastereomers of the α,β-epoxy ketone (19 with Wharton's hydrazine protocol resulted in the formation of (−)-melazolide B (5), via the intermediacy of hydrazone 20 (Scheme 5) [
      • Wharton P.
      • Bohlen D.
      ]. Interestingly, during the reduction of the α,β-epoxy ketone (19) with hydrazine only the desired diastereomer of the allylic alcohol 5 was observed, whereas the undesired diastereomer was degraded. It is unclear at this juncture what those decomposition pathway or pathways are, however the presence of an electrophilic lactone was possibly a liability. This six-step sequence marks the first reported synthesis of (−)-melazolide B.
      Scheme 5
      Scheme 5Synthesis of (−)-melazolide B through Wharton reductiona.
      aReagents and conditions: (5) Urea·H2O2 (3.0 equiv), DBN (3.0 equiv), H2O (9.0 equiv), THF, 0 to 23 °C, 5 h, 67%, 1:1 dr; (6) N2H4·H2O (3.0 equiv), AcOH (1.5 equiv), MeOH, rt, 24 h, 35%.

      3. Conclusion

      In summary, we have documented efficient synthesis of C3-epi-melazolide B, melazolide B and actinidiolide. Tapping into the natural terpene precursors by utilizing α-ionone as a starting material accelerated the assembly of the core bicyclic structures and led to the first reported synthesis of (−)-melazolide B. Among the reported synthesis of (−)-actinidiolide (6) including those from Jorgensen (7 steps) [
      • Yao S.
      • Johannsen M.
      • Hazell R.G.
      • Jørgensen K.A.
      ], Eidman (7 steps) [
      • Eidman K.F.
      • MacDougall B.S.
      ], and Mori (10 steps) [
      • Mori K.
      • Khlebnikov V.
      ,
      • Mori K.
      • Aki S.
      ,
      • Mori K.
      • Puapoomchareon P.
      ], this six-step sequence represents an alternative and concise asymmetric synthesis of (−)-actinidiolide (6). Our robust and scalable pathway will enable future investigations into the PTP1B inhibition of these and similar compounds.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      Financial support for this work was provided by Yale University , Amgen, the Dreyfus Foundation , the Sloan Foundation , Bristol-Myers Squibb (Graduate Fellowship to A.W.S.), Roberts fellowship (to Y.L.), Dox fellowship (to Y.L.), National Science Foundation (GRFP to A.W.S), NSF CAREER ( 1653793 ), and the NIH ( GM118614 ).

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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