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Madangamine alkaloids: Madness and tranquility

  • Ye Tang
    Affiliations
    CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China

    The University of Chinese Academy of Sciences, Beijing, 102419, China
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  • Lili Zhu
    Correspondence
    Corresponding author. CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China.
    Affiliations
    CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China

    The University of Chinese Academy of Sciences, Beijing, 102419, China
    Search for articles by this author
  • Ran Hong
    Correspondence
    Corresponding author. The University of Chinese Academy of Sciences, Beijing, 102419, China.
    Affiliations
    CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China

    The University of Chinese Academy of Sciences, Beijing, 102419, China

    Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
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Open AccessPublished:August 13, 2022DOI:https://doi.org/10.1016/j.tchem.2022.100025

      Abstract

      As a small class of complicated 3-alkylpiperidine alkaloids, madangamine alkaloids have received considerable interest from the synthetic community mainly due to their intriguing polycyclic architecture and their biogenetic relevance to other manzamine alkaloids. The synthetic achievements from several groups were highlighted with emphasis on the construction of the diazatricyclic core as well as the macrocycles in the individual approaches. The infancy of the biomimetic strategy leading to the keramaphidin-type alkaloids was realized in Baldwin's inaugural synthesis, followed by improvement in the recent bioinspired approach by Fürstner. The intramolecular Diels-Alder-type reaction remains a formidable challenge for biomimetic synthesis towards manzamine alkaloids. This mini-review also outlines future directions in the development of novel strategies and tactics to inherit Baldwin's legacy.

      Graphical abstract

      1. Background

      Natural products are adapted as indispensable resources to inspire the creation of novel chemical spaces with biological interest. [
      • Newman D.J.
      • Cragg G.M.
      Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019.
      ] Deconstruction of complex natural products is the driving force for synthetic chemistry to develop novel strategies and methods that may find wide applications in various disciplines. [
      • Nicolaou K.C.
      • Rigol S.
      • Yu R.
      Total synthesis endeavors and their contributions to science and society: a personal account.
      ] A plethora of structural variants derived from the synthetic adventure provide unprecedented opportunities to discover molecules with novel functions. On the other hand, interpretation of the biosynthetic pathways in nature would help us to reconstitute the biosynthetic machinery and develop novel biomimetic approaches to overcome labour-intensive routes. [
      ] However, such biomimetic events remain challenging due to the painstaking imprecise control of the reactivity and selectivity of specific functional groups under nonenzymatic conditions.
      Madangamines represent a small class of unique and complicated 3-alkylpiperidine alkaloids derived from the dimerization of tetrahydropyridine (Fig. 1). Madangamines A-E were isolated from the marine sponge Xestospongia ingens van Soest, [
      • Kong F.
      • Andersen R.J.
      • Madangamine A.
      A novel cytotoxic alkaloid from the marine sponge Xestospongia ingens.
      ,
      • Kong F.
      • Graziani E.
      • Andersen R.J.
      • Madangamines B.−E.
      Pentacyclic alkaloids from the marine sponge Xestospongia ingens.
      ] and madangamine F was identified from the marine sponge Pachychalina alcaloidifera. [
      • De Oliveira J.H.H.L.
      • Nascimento A.M.
      • Kossuga M.H.
      • Cavalcanti B.C.
      • Pessoa C.O.
      • Moraes M.O.
      • Macedo M.L.
      • Ferreira A.G.
      • Hajdu E.
      • Pinheiro U.S.
      • Berlinck R.G.S.
      Cytotoxic alkylpiperidine alkaloids from the Brazilian marine sponge Pachychalina alcaloidifera.
      ] All congeners exhibit significant cytotoxicity to a variety of cancer cell lines. [
      • Miura K.
      • Kawana S.
      • Suto T.
      • Sato T.
      • Chida N.
      • Simizu S.
      Identification of madangamine A as a novel lysosomotropic agent to inhibit autophagy.
      ] For instance, madangamine A shows good cytotoxicity ​in vitro ​to the human leukaemia cell line HL-60 (IC50 ​= ​16.7 ​μg/mL) and inhibits autophagy. Interestingly, the olefin groups in the D-ring of various madangamines play an important role in the given cytotoxicity, [
      • Suto T.
      • Yanagita Y.
      • Nagashima Y.
      • Takikawa S.
      • Kurosu Y.
      • Matsuo N.
      • Miura K.
      • Simizu S.
      • Sato T.
      • Chida N.
      Unified total synthesis of madangamine alkaloids.
      ] enriching the medicinal potential of manzamine alkaloids [
      • Faheem P.A.
      • Kumar B.K.
      • Chander S.
      • Sekhar K.V.G.C.
      • Sankaranarayanan M.
      Anti-infective potential of manzamine alkaloids - a review.
      ].

      2. Chemical synthesis: State of the art

      The unique polycyclic structure of alkaloids has received considerable interest from many research groups. The key element was to develop novel approaches to access the diazatricyclic core. Chronologically, Weinreb, [
      • Matzanke N.
      • Gregg R.J.
      • Weinreb S.M.
      • Parvez M.
      A concise approach to the tricyclic core of the cytotoxic marine alkaloid madangamine A.
      ] Kibayashi, [
      • Yamazaki N.
      • Kusanagi T.
      • Kibayashi C.
      Synthesis of the diazatricyclic core of the marine alkaloids madangamines.
      ] Marazano, [
      • Tong H.M.
      • Martin M.T.
      • Chiaroni A.
      • Bénéchie M.
      • Marazano C.
      An approach to the tricyclic core of madangamines based upon a biogenetic scheme.
      ] Bonjoch, [
      • Quirante J.
      • Paloma L.
      • Diaba F.
      • Vila X.
      • Bonjoch J.
      Synthesis of diazatricyclic core of madangamines from cis-perhydroisoquinolines.
      ] Wardrop, [
      • Bhattacharjee A.
      • Gerasimov M.V.
      • Dejong S.
      • Wardrop D.
      Oxamidation of unsaturated O-alkyl hydroxamates: synthesis of the madangamine diazatricylic (ABC rings) skeleton.
      ] and Douglas [
      • Eastwood M.
      • Douglas C.
      Synthesis of the madangamine alkaloid core by a C–C bond activation cascade.
      ] embarked upon their synthetic efforts towards the preparation of the diazabicyclic A-B-C ring. For instance, Weinreb and coworkers prepared a tricyclic core based on an intriguing intramolecular aminomercuriation. [
      • Matzanke N.
      • Gregg R.J.
      • Weinreb S.M.
      • Parvez M.
      A concise approach to the tricyclic core of the cytotoxic marine alkaloid madangamine A.
      ] A recent approach contributed by the Douglas group featured Pd-catalysed C–C bond activation and cyanoamidation cascades. [
      • Eastwood M.
      • Douglas C.
      Synthesis of the madangamine alkaloid core by a C–C bond activation cascade.
      ] Nevertheless, only three groups completed the total syntheses of selected madangamine alkaloids, including the Bosch and Amat, [
      • Ballette R.
      • Pérez M.
      • Proto S.
      • Amat M.
      • Bosch J.
      Total synthesis of (+)-Madangamine D.
      ,
      • Are C.
      • Pérez M.
      • Bosch J.
      • Amat M.
      Enantioselective formal synthesis of (+)-madangamine A.
      ,
      • Are C.
      • Pérez M.
      • Ballette R.
      • Proto S.
      • Caso F.
      • Yayik N.
      • Bosch J.
      • Amat M.
      Access to Enantiopure Advanced Intermediates en Route to Madangamines.
      ] Sato and Chida [
      • Suto T.
      • Yanagita Y.
      • Nagashima Y.
      • Takikawa S.
      • Kurosu Y.
      • Matsuo N.
      • Miura K.
      • Simizu S.
      • Sato T.
      • Chida N.
      Unified total synthesis of madangamine alkaloids.
      ,
      • Suto T.
      • Yanagita Y.
      • Nagashima Y.
      • Takikawa S.
      • Kurosu Y.
      • Matsuo N.
      • Sato T.
      • Chida N.
      Unified total synthesis of madangamines A, C, and E.
      ] and Dixon [
      • Shiomi S.
      • Shennan B.D.A.
      • Yamazaki K.
      • de Arriba A.L.F.
      • Vasu D.
      • Hamlin T.A.
      • Dixon D.J.
      A new organocatalytic desymmetrization reaction enables the enantioselective total synthesis of madangamine E.
      ] groups.

      2.1 Bosch-Amat's approach towards madangamines D and A (2014 and 2019)

      The Bosch-Amat group reported the total synthesis of (+)-madangamine D in 2014 as the first member ever synthesized. [
      • Ballette R.
      • Pérez M.
      • Proto S.
      • Amat M.
      • Bosch J.
      Total synthesis of (+)-Madangamine D.
      ] The ring-forming sequence in Bosch-Amat's pioneering work featured a rapid construction of the diazatricyclic core, a successful ring closing metathesis (RCM) reaction to build the D-ring, and furnishing the E-ring via macrolactamization.
      The synthesis commenced from condensation of γ-oxoester 1 with (R)-phenylglycinol 2 to yield caprolactam 3 with a chiral centre at C5 via dynamic kinetic resolution on the decagram scale (Scheme 1a). [
      • Amat M.
      • Pérez M.
      • Minaglia A.T.
      • Casamitjana N.
      • Bosch J.
      An enantioselective entry to cis-perhydroisoquinolines.
      ] After completion of the C-ring and installation of the C9-quaternary carbon centre, bicyclic alkene 4 was subjected to stereoselective epoxidation by mCPBA. The corresponding β-epoxide (C2/C3) was further subjected to the Staudinger reduction to generate an amine, which immediately initiated ring-opening to furnish the diazatricyclic core in 5. After protection of the secondary amine with the tosyl group followed by installation of two terminal alkenes, as shown in 6, the macrocyclic D-ring was smoothly constructed by ring closing metathesis enabled by the Grubbs-I catalyst. The subsequent hydrogenolysis of the carbon–carbon double bond, deprotection of the benzyl group in one pot, and oxidation of the C3-secondary alcohol by Dess-Martin periodinane (DMP) provided tetracyclic ketone 7. To complete the right wing, the long carbon chain of 8 bearing a skipped diene was introduced by Wittig olefination (Z/E ​= ​2/1). After release of the secondary amine and hydrolysis of the methyl ester, macrolactamization was performed to successfully afford the requisite E ring. The final reduction of amides completed the synthesis of (+)-madangamine D.
      Scheme 1
      Scheme 1Total syntheses of madangamine alkaloids by the Bosch-Amat and Dixon groups.
      In 2019, the same group further disclosed the formal synthesis of (+)-madangamine A. [
      • Are C.
      • Pérez M.
      • Bosch J.
      • Amat M.
      Enantioselective formal synthesis of (+)-madangamine A.
      ] Following an identical strategy, diazatricyclic compound 9 was constructed in 14 steps (Scheme 1b). Oxidation of the secondary alcohol and subsequent Wittig olefination afforded methyl ester 10. After hydrolysis to release aldehyde, introduction of a butynyl group at C9 by the Ohira–Bestmann homologation and the subsequent cross-coupling with a skipped Z,Z-octadienyl bromide afforded compound 11. Stereoselective semi-hydrogenation of the alkyne successfully delivered the skipped Z,Z,Z-triene intermediate. Exchange of the protecting groups provided tosylate 12 for the next ring closure by substitution after removal of the Boc group to afford the tetracyclic compound 13. Deprotection revealed a free amine for the subsequent macrolactamization enabled by 2-chloro-1-methylpyridinium iodide (CMPI) and diisopropylethylamine (DIPEA) [
      • Suto T.
      • Yanagita Y.
      • Nagashima Y.
      • Takikawa S.
      • Kurosu Y.
      • Matsuo N.
      • Sato T.
      • Chida N.
      Unified total synthesis of madangamines A, C, and E.
      ] to produce lactam 14, which could be readily converted to (+)-madangamine A by Sato-Chida's protocol. [
      • Suto T.
      • Yanagita Y.
      • Nagashima Y.
      • Takikawa S.
      • Kurosu Y.
      • Matsuo N.
      • Sato T.
      • Chida N.
      Unified total synthesis of madangamines A, C, and E.
      ]

      2.2 Dixon's total synthesis of madangamine E (2022)

      In 2022, the Dixon group reported the total synthesis of madangamine E, featuring an organocatalyst-enabled enantioselective desymmetrization to access the bridged A-C ring (Scheme 1c). [
      • Shiomi S.
      • Shennan B.D.A.
      • Yamazaki K.
      • de Arriba A.L.F.
      • Vasu D.
      • Hamlin T.A.
      • Dixon D.J.
      A new organocatalytic desymmetrization reaction enables the enantioselective total synthesis of madangamine E.
      ] At the outset, a 9-step sequence from acetal 15 was applied to prepare nitroolefin 16. Asymmetric Michael addition with a thiourea catalyst was developed to form bicyclic intermediate 17 in 95% yield with 99% ee. After several steps, allylic alcohol 18 was selectively transformed into lactam 19 by Iwabuchi's oxidation. [
      • Sasano Y.
      • Nagasawa S.
      • Yamazaki M.
      • Shibuya M.
      • Park J.
      • Iwabuchi Y.
      Highly chemoselective aerobic oxidation of amino alcohols into amino carbonyl compounds.
      ] The cascade process likely involves hemiaminal as an intermediate, which is further oxidized to release the requisite lactam, providing the diazatricyclic compound 19. Subsequent RCM reaction by the Grubbs-I catalyst furnished the D-ring of compound 20 in 82% yield (Z/E ​= ​3.1:1). Further chain elongation at C3 as well as installation of the alkene chain on the N atom permitted a second RCM to achieve the E ring in the presence of the Hoveyda-Grubbs-II (HG-II) catalyst. Application of the RCM reactions to furnish two peripheral macrocycles compromised the relatively lengthy steps towards intermediates 16 and 18. Accordingly, the corresponding pentacyclic compound 22 was then readily converted to (+)-madangamine E by complete reduction of two amides.

      2.3 Sato-Chida's unified approach (2017)

      The order of ring construction in the Bosch-Amat and Dixon groups was the same after the diazatricycle core construction (A-B-C ring). The identical E-ring in all madangamines A-E inspired the Sato and Chida group to devise an advanced intermediate for divergent synthesis, constituting the total syntheses of (+)-madangamines A-E (Scheme 2). [
      • Suto T.
      • Yanagita Y.
      • Nagashima Y.
      • Takikawa S.
      • Kurosu Y.
      • Matsuo N.
      • Miura K.
      • Simizu S.
      • Sato T.
      • Chida N.
      Unified total synthesis of madangamine alkaloids.
      ,
      • Suto T.
      • Yanagita Y.
      • Nagashima Y.
      • Takikawa S.
      • Kurosu Y.
      • Matsuo N.
      • Sato T.
      • Chida N.
      Unified total synthesis of madangamines A, C, and E.
      ] In their work, alkynoate 24 was first prepared in 11 steps from 2-trimethylsilylethanol 23. Subsequent enyne cyclization catalysed by Pd2(dba)3•CHCl3 produced cis-fused bicyclic ring 25 in 87% yield. After a 5-step sequence to install a propargyl silane, treatment of the N-Boc enamine by TFA induced an iminium cyclization to form allene 28 through a proposed intermediate 27 to establish the correct stereochemistry at C2. A regioselective and stereoselective hydroboration of the allene by HB(Sia)2 from the less hindered face provided allylic alcohol 29 in excellent yield (Z/E ​> ​20:1). Activation by the methyl carbonate group permitted the Migita-Kosugi-Stille coupling with (Z)-vinyltin reagent to furnish the skipped Z,Z-diene 30. Subsequent hydrolysis and deprotection provided free amines and acids for classic macrolactamization. A common intermediate 31 was thus prepared after removal of the TIPS group. From this advanced intermediate, divergent synthesis of all five madangamines (A-E) was successfully achieved, providing several madangamine alkaloids and structural derivatives for preliminary biological investigations. [
      • Suto T.
      • Yanagita Y.
      • Nagashima Y.
      • Takikawa S.
      • Kurosu Y.
      • Matsuo N.
      • Miura K.
      • Simizu S.
      • Sato T.
      • Chida N.
      Unified total synthesis of madangamine alkaloids.
      ]
      Scheme 2
      Scheme 2Unified total synthesis of madangamine alkaloids by Sato and Chida.

      3. Biomimetic challenge

      3.1 Baldwin's legacy (1992)

      At the time with only three congeners of manzamines reported and a pessimistic statement of no obvious biogenetic path, [
      • Sakai R.
      • Higa T.
      • Jefford C.W.
      • Benardinelli G.
      Manzamine A, a novel antitumor alkaloid from a sponge.
      ] Baldwin and Whitehead ingeniously proposed a biosynthetic hypothesis for the manzamine alkaloids from partially reduced bis-3-alkylpyridine 32 (Scheme 3a). [
      • Baldwin J.E.
      • Whitehead R.C.
      On the biosynthesis of manzamines.
      ] Three simple building blocks, including ammonia, acrolein equivalent and saturated or unsaturated linear long-chain dialdehydes, were assembled to deliver a macrocyclic bispyridinium derivative (i.e., 32), which then proceeds through intramolecular endo-Diels–Alder reaction and upon subsequent reduction yields the keramaphidin-type pentacyclic intermediate 33a as a key biogenetic precursor for other manzamine alkaloids, such as manzamines A and B. The anticipation of the biogenetic hypothesis was incredible for the late identification of ircinols and keramaphidins. [
      • Tsuda M.
      • Kawasaki N.
      • Kobayashi J.
      Ircinols A and B, first antipodes of manzamine-related alkaloids from an Okinawan marine sponge.
      ,
      • Kobayashi J.
      • Tsuda M.
      • Kawasaki N.
      • Matsumoto K.
      • Adachi T.
      • Keramaphidin B.
      A novel pentacyclic alkaloid from a marine sponge Amphimedon sp.: a plausible biogenetic precursor of manzamine alkaloids.
      ,
      • Tsuda M.
      • Kawasaki N.
      • Kobayashi J.
      Keramaphidin C and keramamine C plausible biogenetic precursors of manzamine C from an Okinawan marine sponge.
      ] To interpret the origin of madangamine A, Andersen and coworkers suggested that advanced intermediate 33a could undergo oxidative fragmentation to cleave the C3–C8 bond. [
      • Kong F.
      • Andersen R.J.
      • Madangamine A.
      A novel cytotoxic alkaloid from the marine sponge Xestospongia ingens.
      ] After redox exchange, newly formed iminium species 35 ​at C2 will be trapped by alkene (ΔC3-C20) via aza-Prins-type cyclization, resulting in the completion of madangamine alkaloids.
      Scheme 3
      Scheme 3Biogenetic proposal of madangamine and biomimetic synthesis of keramaphidin B.
      The inaugural biomimetic synthesis of keramaphidin B was reported by the Baldwin group via an intramolecular Diels-Alder reaction based on their earlier hypothetical biogenesis (Scheme 3b). [
      • Baldwin J.E.
      • Claridge T.D.W.
      • Culshaw A.J.
      • Heupel F.A.
      • Lee V.
      • Spring D.R.
      • Whitehead R.C.
      • Boughtflower R.J.
      • Mutton I.M.
      • Upton R.J.
      Investigations into the manzamine alkaloid biosynthetic hypothesis.
      ] The Wittig reaction of pyridine-linked aldehyde 36 and alkyl ylide derived from 37 was carried out to deliver Z-olefin 38, which immediately performed an exchange of the protecting groups to yield tosylate 39. Subsequent macrocyclization via substitution was promoted by in situ iodination, followed by reduction of pyridinium salt to yield bis-tetrahydropyridine 40. The formation of N-oxides 41 proceeded by mCPBA with contaminated elimination to deliver the bis-dihydropyridinium salt 42 by addition of trifluoroacetic anhydride. In an aqueous tris(hydroxymethyl)aminomethane (Tris) buffer (1 ​M, pH 7.3) in MeOH, intramolecular Diels-Alder reaction gave an intermediate 43b, followed by reduction with NaBH4 to yield a detectable amount of keramaphidin B (0.2–0.3% yield) along with compound 40 recovered in 60–85% yield. Although the yield was very low, the successful isolation of the Diels-Alder adducts proved the chemical feasibility in the hypothetical biogenesis of 3-alkylpiperidine alkaloids.

      3.2 The keramaphidin Saga (Fürstner, 2021)

      In parallel with the intramolecular Diels-Alder reaction towards keramaphidin B, the Diels-Alder or Mannich reaction of truncated 3-alkylpyridines is also inspirational. Shortly after the hypothesis, Baldwin and coworkers designed 3-methyl-N-ethyl-5,6-dihydropyridinium salt to execute the requisite dimerization (Scheme 4a). [
      • Baldwin J.E.
      • Claridge T.D.W.
      • Heupel F.A.
      • Whitehead R.C.
      A biomimetic approach to the manzamine alkaloids; model studies.
      ,
      • Baldwin J.E.
      • Claridge T.D.W.
      • Culshaw A.J.
      • Heupel F.A.
      • Smrcková S.
      • Whitehead R.C.
      A biomimetic approach to the manzamine alkaloids.
      ] Upon treatment with a buffer (pH 8.3), endo-adduct 44a was isolated in 10% yield after reduction by NaBH4, along with vinylogous Mannich adduct 44b in 4% yield. [
      • Baldwin J.E.
      • Claridge T.D.W.
      • Culshaw A.J.
      • Heupel F.A.
      • Smrcková S.
      • Whitehead R.C.
      A biomimetic approach to the manzamine alkaloids.
      ] The Marazano and Das group also adapted a similar pyridinium salt derived from elimination of MeOH to the DA-adduct 45a in 25% yield along with Mannich adduct 45b in 7% yield. [
      • Gil L.
      • Baucherel X.
      • Martin M.T.
      • Marazano C.
      • Das B.C.
      Model studies towards a biomimetic synthesis of keramaphidin B and halicyclamine A.
      ] Baldwin later improved the synthesis of unstable pyridinium salt from α-aminonitrile and was able to expand the dimerization of side-chain functionalized pyridinium in a reproducible 22% yield. [
      • Baldwin J.E.
      • Claridge T.D.W.
      • Culshaw A.J.
      • Heupel F.A.
      • Lee V.
      • Spring D.R.
      • Whitehead R.C.
      Studies on the biomimetic synthesis of the manzamine alkaloids.
      ] Very recently, Oguri and coworkers observed a dimerization of 1,6-dihydropyridines to afford a vinylogous Mannich-type adduct to access the core skeleton towards halicyclamine-type alkaloids, [
      • Wayama T.
      • Arai Y.
      • Oguri H.
      Regiocontrolled dimerization of densely functionalized 1,6-dihydropyridines for the biomimetic synthesis of a halicyclamine-type scaffold by preventing disproportionation.
      ] representing interesting progress upon the Baldwin-Marazano-Das observation. [
      • Gil L.
      • Baucherel X.
      • Martin M.T.
      • Marazano C.
      • Das B.C.
      Model studies towards a biomimetic synthesis of keramaphidin B and halicyclamine A.
      ]
      Scheme 4
      Scheme 4Bioinspired synthesis of keramaphidin B.
      Given the model studies on the dimerization of various alkylated pyridiniums, Baldwin and coworkers elaborated the construction of diazatricyclic core 48 via bioinspired Diels-Alder addition of pyridinium salt 47 (Scheme 4b). [
      • Baldwin J.E.
      • Claridge T.D.W.
      • Culshaw A.J.
      • Heupel F.A.
      • Lee V.
      • Spring D.R.
      • Whitehead R.C.
      Studies on the biomimetic synthesis of the manzamine alkaloids.
      ] After reduction of the intermediate by NaBH4, polyene 48 was isolated in 22% yield. The following ring closing event proved to be very challenging due to the formation of oligomers and E-double bond isomers. However, the preparative scale of the given cyclization event enabled by the Grubbs-I catalyst generated several cyclized products, including mono-cyclized 49/50 (10–20%) and keramaphidin B (1–2%). It appeared that the formation of 11- and 13-membered rings was an appealing step, although the current approach was indeed stepping forward to the desired target.
      The Fürstner group recently implemented an alkyne tether into the bridged core via a double Michael addition (literally a Diels-Alder reaction), which eventually led to the complete synthesis and validation of the absolute configuration of keramaphidin B. [
      • Meng Z.C.
      • Spohr S.M.
      • Tobegen S.
      • Farès C.
      • Fürstner A.
      A unified approach to polycyclic alkaloids of the ingenamine estate: total syntheses of keramaphidin B, ingenamine, and nominal njaoamine I.
      ] The preinstalled stereogenic centre at C11 in 52 controlled the stereochemical outcome of the critical ring construction (Scheme 4c). The following transformations produced bisalkyne 54, which was appropriate for ring-closing alkyne metathesis (RCAM) by the novel Mo-catalyst to afford macrocycle 55 in 83% yield. The second 11-membered ring in 57 was readily established by the RCM reaction enabled by the Grubbs-I catalyst in 83% yield, albeit with a low stereoselectivity (Z/E ​= ​1:1). The subsequent partial reduction of alkyne by “P-2 nickel” (in situ generated by Ni(OAc)2•4H2O, NaBH4 and H2) delivered the Z,Z-isomer 58 in 37% isolated yield as a single stereoisomer. Reduction of two amides by DIBAL-H completed the synthesis of (+)-keramaphidin B. In this work, the efficiency of the construction of two macrocyclic rings was greatly improved via RCAM and RCM. The elegance of Baldwin's biomimetic approach and Fürstner's improvement enlighten the strategic modification to be merged with novel synthetic methods in the synthesis of complex natural products.

      4. Conclusions: Back to the future

      The intriguing polycyclic core and macrocyclic rings in manzamine alkaloids have emerged as inspirational points for the method development in past decades. [
      • Amat M.
      • Pérez M.
      • Ballette R.
      • Proto S.
      • Bosch J.
      ,
      • Kubota T.
      • Kurimoto S.I.
      • Kobayashi J.
      ] In the first synthesis of madangamine D and formal synthesis of madangamine A, Bosch and Amat devised a cascade process of the Staudinger reduction and subsequent epoxide ring-opening. Sato and Chida unified the total synthesis of madangamines A-E by applying N-acyliminium cyclization to construct the diazatricyclic core. The organocatalytic Michael addition was highlighted in Dixon's synthesis to secure the core structure in a highly enantioselective manner.
      The enlightening Baldwin-Whitehead hypothesis of manzamine alkaloids [
      • Baldwin J.E.
      • Whitehead R.C.
      On the biosynthesis of manzamines.
      ] has attracted a decade-long effort to exploit the fascinating reactivity of alkylpyridinium salts in bioinspired dimerization, providing insights into the structural origin of manzamine alkaloids. Although the rigor of the Diels-Alderase [
      • Jeon B.-s.
      • Wang S.-A.
      • Ruszczycky M.W.
      • Liu H.-w.
      Natural [4 + 2]-cyclases.
      ] in the biogenetic proposal remains elusive, the reactivity preference for the transannular Diels-Alder reaction is worthy of further exploration and will certainly be the inevitable assessment for any biomimetic approach in the future. Additionally, the proposed oxidative fragmentation and redox exchange in Andersen's proposal [
      • Kong F.
      • Graziani E.
      • Andersen R.J.
      • Madangamines B.−E.
      Pentacyclic alkaloids from the marine sponge Xestospongia ingens.
      ] could be truly miserable steps that have never been executed by simplified models (Scheme 3a). Given the difficulty of the oxidative cleavage of the requisite C6–N7 bond in the model Diels-Alder adduct, Marazano and coworkers suggested an alternative biogenesis hypothesis [
      • Kaiser A.
      • Billot X.
      • Olesker A.G.
      • Marazano C.
      • Das B.C.
      Selective entry to the dimeric or oligomeric pyridinium sponge macrocycles via aminopentadienal derivatives. Possible biogenetic relevance with manzamine alkaloids.
      ,
      • Jakubowicz K.
      • Abdeljelil K.B.
      • Herdemann M.
      • Martin M.T.
      • Olesker A.G.
      • Mourabit A.A.
      • Marazano C.
      • Das B.C.
      Reactions of aminopentadienal derivatives with 5,6-dihydropyridinium salts as an approach to manzamine alkaloids based upon biogenetic considerations.
      ,
      • Salvatori M.D.R.S.
      • Marazano C.
      An access to the bicyclic nucleus of the sponge alkaloid halicyclamine A by successive condensation of malondialdehyde units, aldehyde derivatives, and primary amines.
      ,

      Baldwin and coworkers also revised the original proposal by the oxidative cleavage of the C6-N7 bond prior to the Diels-Alder reaction, see ref. 32.

      ] in which malonaldehyde, rather than acrolein, participated as a primary three-carbon unit in the Baldwin-Whitehead proposal (Scheme 5a). The open-chain aminopentadienal moiety in dihydropyridinium derivatives 59 would be effective in the Diels-Alder reaction, resulting in an ircinal-type tetracyclic intermediate 60 rather than the keramaphidin-type pentacycle 33a in the previous hypothesis [
      • Baldwin J.E.
      • Whitehead R.C.
      On the biosynthesis of manzamines.
      ] (Scheme 3a). Cleavage of the C3–C8 bond via a vinylogous retro-Mannich reaction forms tricyclic intermediate 61. Accordingly, madangamines can be obtained by a set of transformations, such as cyclization, vinylogous aza-Mannich reaction and isomerization of the carbon–carbon double bond. The Marazano group thus performed a new model study [
      • Tong H.M.
      • Martin M.T.
      • Chiaroni A.
      • Bénéchie M.
      • Marazano C.
      An approach to the tricyclic core of madangamines based upon a biogenetic scheme.
      ] to access the diazatricyclic core (Scheme 5b). As a double-nucleophilic reagent, dicarboxylate 67 enabled a [3 ​+ ​3]-nucleophilic addition to yield bridged intermediate 68, which was readily cyclized to afford core skeletons 69a and 69b. This leaves an open question regarding the validity of the modified proposal if two long tethers are introduced prior to the key [3 ​+ ​3] nucleophilic addition. Moreover, several manzamine alkaloids derived from enantiomers of hypothetical biogenetic precursors also engendered the enticing objective of understanding the biogenesis of complex alkaloids by harvesting the detailed structural features of enzymes. [
      • Tsuda M.
      • Kawasaki N.
      • Kobayashi J.
      Ircinols A and B, first antipodes of manzamine-related alkaloids from an Okinawan marine sponge.
      ,
      • Finefield J.M.
      • Sherman D.H.
      • Kreitman M.
      • Williams R.M.
      Enantiomeric natural products: Occurrence and biogenesis.
      ]
      Scheme 5
      Scheme 5Bioinspired synthesis toward the diazatricyclic core of madangamines.
      The principles of retrosynthetic analysis encourage us to undertake any possible bond disconnection in the synthetic design, while nature elegantly assembles complex molecules with simple building blocks and a handful of reaction types. Therefore, a deep understanding of the reactivity of specific functional groups, especially for reactive and short-lived intermediates, deserves thought-provoking exploration. To simulate natural blueprints, the biogenetic hypothesis should be followed as strategic guidance instead of stringent instruction.[
      • Zheng K.
      • Hong R.
      The fruit of gold: Biomimicry in the syntheses of lankacidins.
      ,
      • Zhou X.
      • Li W.
      • Zhou R.
      • Wu X.
      • Huang Y.
      • Hou W.
      • Li C.
      • Zhang Y.
      • Nie W.
      • Wang Y.
      • Song H.
      • Liu X.-Y.
      • Zheng Z.
      • Xie F.
      • Li S.
      • Zhong W.
      • Qin Y.
      Bioinspired scalable total synthesis of opioids.
      ,
      • Ruan Z.
      • Wang M.
      • Yang C.
      • Zhu L.
      • Su Z.
      • Hong R.
      Total synthesis of (+)-hinckdentine A: Harnessing noncovalent interactions for organocatalytic bromination.
      ] Any adjustment would be necessary to realize the key transformation and preclude side pathways. A compromised narrative ratified in the sensation of biomimetic synthesis was that practical considerations become secondary to theoretical success if the isolated yield is extremely low. [
      • van Tamelen E.E.
      Biogenetic-type syntheses of natural products.
      ] However, in the age of scalability, [
      • Kuttruff C.A.
      • Eastgate M.D.
      • Baran P.S.
      Natural product synthesis in the age of scalability.
      ] biomimetic synthesis has been elevated along with other dimensions, such as availability, diversity, and sustainability, enabled by pragmatic and effective methods to realize selective transformations, thus inspiring us to forge new frontiers beyond the capabilities of enzymes in nature.

      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.

      Acknowledgements

      We are grateful for the financial support from the National Natural Science Foundation of China ( 22171281 to L.Z.), the Program of Shanghai Academic Research Leader ( 20XD1404700 to R.H.), and the Key Research Program of Frontier Sciences ( QYZDY-SSWSLH026 to R.H.) of the Chinese Academy of Sciences .

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