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Synlett 2023; 34(12): 1529-1533
DOI: 10.1055/a-2002-8680
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Special Issue Honoring Masahiro Murakami’s Contributions to Science

Total Syntheses of Dysidealactams E and F and Dysidealactone B, Drimane-Type Sesquiterpenes Derived from a Dysidea sp. of Marine Sponge

Yuhao Chen
a   Guangdong Key Laboratory for Research and the Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong, 524023, P. R. of China
,
Ping Lan
b   Institute for Advanced and Applied Chemical Synthesis, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P. R. of China
,
Lorenzo V. White
b   Institute for Advanced and Applied Chemical Synthesis, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P. R. of China
,
Weiguang Yang∗
a   Guangdong Key Laboratory for Research and the Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong, 524023, P. R. of China
,
Martin G. Banwell  ∗
a   Guangdong Key Laboratory for Research and the Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong, 524023, P. R. of China
b   Institute for Advanced and Applied Chemical Synthesis, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P. R. of China
› Author Affiliations

We thank the National Natural Science Foundation of China (Grant Nos. 22250410258 and 22250410259), the Science and Technology Planning Program of Zhanjiang (Grant. No. 2021A05247) and the Ministry of Science and Technology of the People’s Republic of China for financial support.
› Further Information
 
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Dedicated to Professor Masahiro Murakami (Kyoto University) in recognition of his profound and ingenious contributions to so many aspects of chemical synthesis.

Abstract

Dysidealactams E and F and dysidealactone B are recently reported marine natural products. Their syntheses from β-cyclocitral are detailed here. The preparation of certain derivatives and analogues of these compounds is also described and single-crystal X-ray analyses of two of these, as well as that of (±)-dysidealactam F, are reported.


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Key words

cycloaddition - drimanes - marine natural products - sesquiterpenes - total synthesis

Drimane-type sesquiterpenes are encountered in numerous plants, fungi, and marine organisms, including mollusks and sponges.[1] They are recognized for their broad array of biological activities that include plant-growth-regulating, phytotoxic, antifeedant, antibacterial, antifungal, anticancer, molluskicidal, and piscicidal effects.[1] [2] New members of the class continue to be identified at an impressive rate.[3] While nitrogen-containing drimanes are known, these normally feature α-amino acid residues appended through ester linkages to the decalin core. Ones that involve nitrogen directly attached to the carbons of the drimane framework are less common,[3d] and are exemplified by the sesquiterpene glycinyllactams and imides 1–5 (Figure [1]) isolated by the Capon Group from a Dysidea sp. of sponge collected in Southern Australian waters.[4] The structures of two of these (1 and 4) were confirmed by single-crystal X-ray analyses. The non-nitrogen-containing co-metabolites 6 and 7 were also isolated from the same organism.[4] [5]

Zoom Image
Figure 1 Structures of the drimane-type sesquiterpenes 1–7 isolated from a Dysidea sp. of marine sponge

Although none of compounds 1–7 displayed any notable antibacterial, antifungal, or cytotoxic activities, γ-lactams[6] and succinimides[7] are, more broadly speaking, recognized as privileged scaffolds in medicinal chemistry. As a consequence, the development of new methods for their synthesis continues apace.[8] Given the foregoing, and as part of a program concerned with developing small libraries of marine natural products that could be subjected to broad screening regimes, we undertook total syntheses of the title compounds, namely dysidealactams E (4) and F (5), and dysidealactone B (7). In doing so, we sought to identify abbreviated and flexible routes to a compound or compounds embodying the drimane framework from which rapid diversification of functionality might be achieved. Details are presented below.

Reports on the synthesis of drimane-type sesquiterpenes abound, permitting us to draw upon a large body of literature[1b] [9] in establishing a reliable route to the target compounds 4, 5, and 7. The obvious precursor to these targets was the cyclic anhydride 8 (Figure [2]), the dextrorotatory form of which is itself encountered as the natural product (+)-winterin and for which a number of syntheses have been reported.[10]

Zoom Image
Figure 2 The drimane sesquiterpene (+)-winterin (8), a logical precursor to target compounds 4, 5, and 7

The reaction sequence that we first used to obtain (±)-winterin is shown in Scheme [1] and followed, in its opening stages, the work of Watanabe et al.[11] So, the commercially available monoterpene β-cyclocitral (9) was subject to Wittig olefination to give the semicyclic diene 10 in 94% yield. This was engaged in a thermally promoted Diels–Alder reaction with dimethyl acetylenedicarboxylate (DMAD) to afford a mixture of the desired adduct (±)-12 (56%) and the phthalate 13 (39%), the latter product arising from the loss of the elements of methane from the former.[12] [13] These products could only be cleanly separated from one another by using HPLC techniques. Furthermore, because no modification to the experimental conditions that we investigated (including variations in the reaction temperature) completely suppressed the formation of compound 13, this mixture of products was subjected to hydroboration/oxidation conditions. As a result, diene (±)-12 was regio- and stereoselectively converted into the alcohol (±)-14, which could then be separated from the inert phthalate 13 by flash chromatography. Despite the modest yield (34%) of compound (±)-14 obtained by this means, it could be accumulated in sufficient quantity to allow it to be carried forward in the illustrated sequence. Specifically, and as reported by Watanabe and co-workers,[11] it was converted under standard conditions into thiocarbamate (±)-15 (60%). This derivative was then subjected to reduction with Bu3SnH and so affording the deoxygenated compound (±)-16 in quantitative yield. Heating this compound in refluxing trifluoroacetic acid (TFA) resulted in efficient formation of the cyclic acid anhydride (±)-8, the structure of which was confirmed by single-crystal X-ray analysis[14] [see also the Supporting Information (SI)]. Furthermore, all the spectral data acquired on this anhydride matched those previously reported for winterin.[10g] Because Jang and Han have recently reported that alcohol (±)-14 is readily resolved into its constituent enantiomers,[15] the (+)- and (–)-forms of compound 8 are necessarily accessible by using this reaction sequence.

Zoom Image
Scheme 1 First-generation synthesis of (±)-winterin [(±)-8] from β-cyclocitral (9)

An operationally superior route to compound (±)-8 is shown in Scheme [2]. This was inspired by Brieger’s low-yielding synthesis of (±)-winterin,[10a] for which little experimental detail was provided in the original 1965 report. Heating a solution of a mixture of the Diels–Alder adduct (±)-12 and phthalate 13 in TFA under reflux led to the formation of the cyclic anhydride (±)-17 (87%) which was readily purified through successive flash chromatographic and crystallization steps. Upon subjecting a THF solution of compound (±)-17 to catalytic hydrogenation using 10% Pd/C as catalyst then (±)-winterin [(±)-8] was obtained in an unoptimized 55% yield.

Zoom Image
Scheme 2 Second-generation synthesis of (±)-winterin [(±)-8] from the Diels–Alder adduct (±)-12

The acquisition of compound (±)-8 by the means described immediately above enabled its ready examination as a potential precursor to the targeted natural products (±)-4, (±)-5, and (±)-7. In the event, the first of these was readily obtained (Scheme [3]) by treating a solution of substrate (±)-8 in 1:1 v/v acetonitrile–water with 10 molar equivalents of glycine and upon heating the ensuing mixture under reflux for 12 hours, the expected product (±)-4 was obtained in 54% yield after chromatographic purification.[16] All the spectroscopic data for this product were in complete accord with the assigned structure and matched those of dysidealactam E as reported by Capon and co-workers[4] (see the SI for a tabulated comparison of the 13C NMR spectral data sets).

Zoom Image
Scheme 3: The conversion of (±)-winterin [(±)-8] into compounds (±)-4, (±)-5, (±)-7, and (±)-18

On treating compound (±)-8 with 1.2 molar equivalents of urea[17] in methanol in a sealed tube at 165 °C for eight hours, the expected product (±)-5 was obtained. Once again, all the spectral data acquired on this imide were consistent with the assigned structure, which was later confirmed by single-crystal X-ray analysis,[14] details of which are provided in the SI. Additionally, the NMR spectral data obtained on compound (±)-5 matched those reported[4] for dysidealactam F (see the SI for a tabulated comparison of the 13C NMR spectral data sets).

A study of the behavior of compound (±)-8 toward certain reducing agents was also undertaken and established that when this was treated with lithium tri-tert-butoxyaluminum hydride (LTBA) in THF at –20 °C, a regioselective monoreduction of the anhydride residue occurred, affording, product (±)-7 as a ~1:1 mixture of epimers in 91% yield. The spectral data matched those reported[4] for the natural product dysidealactone B (see the SI for a tabulated comparison of the 13C NMR spectral data sets, both of which were recorded in CD3OD). Furthermore, the NMR spectral data for compound (±)-7 recorded in CDCl3 permitted a comparison to those reported by Montagnac et al.[5] for the same natural product obtained from a New Caledonian sponge as a single epimer of unspecified configuration. In this instance, the match was a little less convincing, in that the chemical shifts reported for the three methyl-group protons of the natural product (at δH = 1.14, 0.96, and 0.92) seemed marginally at odds with those determined for compound (±)-7 (appearing at δH = 1.14, 0.93 and 0.88). Nevertheless, the relative consistency between the two sets of 13C NMR chemical shift data (see the SI for a tabulated comparison) suggests that the New Caledonian-derived material[5] is also dysidealactone B. That being so, it seems reasonable to suggest that one of the reported co-metabolites[5] is a single epimeric form of dysidealactone A.

When lithium tri-sec-butylborohydride (L-Selectride) was used to reduce anhydride (±)-8, the crystalline lactone (±)-18 was obtained in 51% yield. Its structure was confirmed by single-crystal X-ray analysis,[14] [18] details of which are provided in the SI. The dextrorotatory form of compound 18 [(+)-18], known as (+)-isodrimenin, is naturally occurring[18b] and displays, inter alia, notable insect antifeedant properties.[19] The NMR spectral data for compound (±)-18 matched those reported[18b] for the natural product (see SI for a tabulated comparison of the 13C NMR spectral data sets). Isodrimenin has been the subject of a number of total synthesis studies, and the one detailed here is as concise (five steps) as the shortest of those reported previously.[10c] [d] [20]

In efforts to convert compound (±)-4 into the racemic forms of dysidealactams A–C (1–3, respectively), its response to a range of reducing conditions was examined. However, the only useful outcome obtained was when substrate (±)-4 was treated with lithium aluminum hydride in THF at –78 °C (Scheme [4]). Under these conditions, the previously unreported unsaturated γ-lactam (±)-19 was formed as a ~1:1 mixture of epimers and in 49% combined yield.

Zoom Image
Scheme 4 Reduction of compound (±)-4 leading to derivative (±)-19

The four-step synthesis of drimanoid (±)-8 from commercially available materials provides a C15-synthon with a clear capacity to engage in a range of reactions that will permit the functional diversification of the drimane framework in a multitude of ways. Small libraries of both natural products and various analogues should now become quite accessible and might permit the development of enhanced structure–activity relationship profiles for this privileged molecular scaffold.[21] The establishment of methods for the enantioselective synthesis of the Diels–Alder adduct 12 and thereby providing access to both the (+)- and (–)-forms of anhydride 8, would serve to enhance the capacity to explore drimane-type chemical space.[22] Efforts to realize such an outcome are underway in our laboratories and the results will be reported in due course.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2002-8680.
  • Supporting Information

  • References and Notes

  • 4 Khushi S, Salim AA, Elbanna AH, Nahar L, Bernhardt PV, Capon RJ. J. Nat. Prod. 2020; 83: 1577
    CrossrefPubMedSearch in Google Scholar
  • 5 Dysidealactone A (6) and dysidealactone B (7) also appear to have been isolated from the New Caledonian sponge Dysidea fusca; see: Montagnac A, Martin M.-T, Debitus C, Païs M. J. Nat. Prod. 1996; 59: 866
    CrossrefPubMedSearch in Google Scholar
  • 6 For an example, see: Caruano J, Muccioli GG, Robiette R. Org. Biomol. Chem. 2016; 14: 10134
    CrossrefPubMedSearch in Google Scholar
  • 7 For an example, see: Zhao Z, Yue J, Ji X, Nian M, Kang K, Qioa H, Zheng X. Bioorg. Chem. 2021; 108: 104557
    CrossrefPubMedSearch in Google Scholar
  • 8 For an example, see: Zard SZ. Tetrahedron 2021; 79: 131852
    CrossrefPubMedSearch in Google Scholar
  • 12 For a study of the formation of compound 13 from precursor (±)-12, see: Loperfido JC. J. Org. Chem. 1973; 38: 399
    CrossrefSearch in Google Scholar
  • 13 As a referee has pointed out, the aromatization process leading to byproduct 13 is most likely the result of a radical-chain process whereby an initiating radical abstracts the doubly allylic hydrogen from cycloadduct 12, and the ensuing cyclohexadienyl radical then undergoes aromatization by elimination of a methyl radical. The latter, in turn, abstracts the doubly allylic hydrogen of another molecule of 12, thereby propagating the chain; see: Walton JC, Studer A. Acc. Chem. Res. 2005; 38: 794
    CrossrefPubMedSearch in Google Scholar
  • 14 CCDC 2220506, 2220507, and 2220508 contain the supplementary crystallographic data for compounds (±)-5, (±)-8, and (±)-18. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
  • 15 Jang Y, Han S. J. Org. Chem. 2020; 85: 7576
    CrossrefPubMedSearch in Google Scholar
  • 16 (±)-[(5aS,9aS)-6,6,9a-Trimethyl-1,3-dioxo-1,3,4,5,5a,6,7,8,9,9a-decahydro-2H-benzo[e]isoindol-2-yl]acetic acid [(±)-4] A Schlenk tube equipped with a magnetic stirrer bar was charged with compound (±)-8 (500 mg, 2.01 mmol), glycine (1.51 g, 20.1 mmol), and 1:1 MeCN–H2O (6.0 mL). The tube was sealed and the contents were heated at 105 °C (oil-bath temperature) for 8 h. The cooled mixture was then diluted with H2O (10 mL) and the separated aqueous phase was extracted with EtOAc (3 × 25 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure and the resulting residue was subjected to flash chromatography [silica gel, EtOAc–PE (1:3 + 1% AcOH)] to afford, after concentration of the appropriate fractions, a clear yellow oil; yield: 331 mg (54%); Rf = 0.3 (1:3 EtOAc–PE +1% AcOH). FTIR (ATR): 2930, 1703, 1420, 1391, 1233, 1207, 1117, 937, 735 cm–1. 1H NMR (400 MHz, CD3OD): δ = 4.13 (s, 2 H), 2.50 (d, J = 14.0 Hz, 2 H), 2.25 (m, 1 H), 1.97 (m, 1 H), 1.76 (m, 1 H), 1.63–1.45 (complex m, 3 H), 1.38–1.25 (complex m, 3 H), 1.23 (s, 3 H), 0.96 (s, 3 H), 0.93 (s, 3 H); COOH proton not observed. 13C{1H} NMR (100 MHz, CD3OD): δ = 171.8, 171.5, 170.9, 151.4, 141.5, 53.2, 42.9, 39.2, 37.6, 36.3, 34.4, 33.9, 23.0, 22.0, 21.1, 19.5, 19.0. HRMS (TOF ESI, +): m/z [M + H]+ calcd for C17H24NO4: 306.1705; found: 306.1714.
  • 17 For a related example of the use of urea as an ammonia surrogate, see: Naidu PP, Raghunadh A, Rao KR, Mekala R, Babu JM, Rao BR, Siddaiah V, Pal M. Synth. Commun. 2014; 44: 1475
    CrossrefSearch in Google Scholar

      • Single-crystal X-ray analyses of the naturally occurring enantiomeric form of compound 18 have been reported, see:
    • 18a Escobar C, Wittke O. Acta Crystallogr., Sect. C: Struct. Chem. 1988; 44: 154
      CrossrefSearch in Google Scholar
    • 18b Narbutas PT, Pierens GK, Clegg JK, Garson MJ. Nat. Prod. Commun.
      Crossref
  • 19 For example, see: Messchendorp L, van Loon JJ. A, Gols GJ. Z. Entomol. Exp. Appl. 1996; 79: 195
    CrossrefSearch in Google Scholar
  • 21 For a conceptually related approach using the naturally derived drimane polygodial, see: Rhak KJ, Bissember AC, Smith JA. Tetrahedron 2018; 74: 1167
    CrossrefPubMedSearch in Google Scholar
  • 22 For a chiral-auxiliary-based method leading to the formation of homochiral Diels–Alder adducts of diene 10, see: Hendersen JR, Parvez M, Keay BA. Org. Lett. 2009; 11: 3178
    CrossrefPubMedSearch in Google Scholar

Corresponding Authors

Weiguang Yang
Guangdong Key Laboratory for Research and the Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University,
Zhanjiang, Guangdong, 524023
P. R. of China   

Martin G. Banwell
Institute for Advanced and Applied Chemical Synthesis, College of Pharmacy, Jinan University
Guangzhou, Guangdong 510632
P. R. of China   
Email: mgbanwell@gmail.com   

Publication History

Received: 06 December 2022

Accepted after revision: 21 December 2022

Accepted Manuscript online:
21 December 2022

Article published online:
13 February 2023

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References and Notes

  • 4 Khushi S, Salim AA, Elbanna AH, Nahar L, Bernhardt PV, Capon RJ. J. Nat. Prod. 2020; 83: 1577
    CrossrefPubMedSearch in Google Scholar
  • 5 Dysidealactone A (6) and dysidealactone B (7) also appear to have been isolated from the New Caledonian sponge Dysidea fusca; see: Montagnac A, Martin M.-T, Debitus C, Païs M. J. Nat. Prod. 1996; 59: 866
    CrossrefPubMedSearch in Google Scholar
  • 6 For an example, see: Caruano J, Muccioli GG, Robiette R. Org. Biomol. Chem. 2016; 14: 10134
    CrossrefPubMedSearch in Google Scholar
  • 7 For an example, see: Zhao Z, Yue J, Ji X, Nian M, Kang K, Qioa H, Zheng X. Bioorg. Chem. 2021; 108: 104557
    CrossrefPubMedSearch in Google Scholar
  • 8 For an example, see: Zard SZ. Tetrahedron 2021; 79: 131852
    CrossrefPubMedSearch in Google Scholar
  • 12 For a study of the formation of compound 13 from precursor (±)-12, see: Loperfido JC. J. Org. Chem. 1973; 38: 399
    CrossrefSearch in Google Scholar
  • 13 As a referee has pointed out, the aromatization process leading to byproduct 13 is most likely the result of a radical-chain process whereby an initiating radical abstracts the doubly allylic hydrogen from cycloadduct 12, and the ensuing cyclohexadienyl radical then undergoes aromatization by elimination of a methyl radical. The latter, in turn, abstracts the doubly allylic hydrogen of another molecule of 12, thereby propagating the chain; see: Walton JC, Studer A. Acc. Chem. Res. 2005; 38: 794
    CrossrefPubMedSearch in Google Scholar
  • 14 CCDC 2220506, 2220507, and 2220508 contain the supplementary crystallographic data for compounds (±)-5, (±)-8, and (±)-18. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
  • 15 Jang Y, Han S. J. Org. Chem. 2020; 85: 7576
    CrossrefPubMedSearch in Google Scholar
  • 16 (±)-[(5aS,9aS)-6,6,9a-Trimethyl-1,3-dioxo-1,3,4,5,5a,6,7,8,9,9a-decahydro-2H-benzo[e]isoindol-2-yl]acetic acid [(±)-4] A Schlenk tube equipped with a magnetic stirrer bar was charged with compound (±)-8 (500 mg, 2.01 mmol), glycine (1.51 g, 20.1 mmol), and 1:1 MeCN–H2O (6.0 mL). The tube was sealed and the contents were heated at 105 °C (oil-bath temperature) for 8 h. The cooled mixture was then diluted with H2O (10 mL) and the separated aqueous phase was extracted with EtOAc (3 × 25 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure and the resulting residue was subjected to flash chromatography [silica gel, EtOAc–PE (1:3 + 1% AcOH)] to afford, after concentration of the appropriate fractions, a clear yellow oil; yield: 331 mg (54%); Rf = 0.3 (1:3 EtOAc–PE +1% AcOH). FTIR (ATR): 2930, 1703, 1420, 1391, 1233, 1207, 1117, 937, 735 cm–1. 1H NMR (400 MHz, CD3OD): δ = 4.13 (s, 2 H), 2.50 (d, J = 14.0 Hz, 2 H), 2.25 (m, 1 H), 1.97 (m, 1 H), 1.76 (m, 1 H), 1.63–1.45 (complex m, 3 H), 1.38–1.25 (complex m, 3 H), 1.23 (s, 3 H), 0.96 (s, 3 H), 0.93 (s, 3 H); COOH proton not observed. 13C{1H} NMR (100 MHz, CD3OD): δ = 171.8, 171.5, 170.9, 151.4, 141.5, 53.2, 42.9, 39.2, 37.6, 36.3, 34.4, 33.9, 23.0, 22.0, 21.1, 19.5, 19.0. HRMS (TOF ESI, +): m/z [M + H]+ calcd for C17H24NO4: 306.1705; found: 306.1714.
  • 17 For a related example of the use of urea as an ammonia surrogate, see: Naidu PP, Raghunadh A, Rao KR, Mekala R, Babu JM, Rao BR, Siddaiah V, Pal M. Synth. Commun. 2014; 44: 1475
    CrossrefSearch in Google Scholar

      • Single-crystal X-ray analyses of the naturally occurring enantiomeric form of compound 18 have been reported, see:
    • 18a Escobar C, Wittke O. Acta Crystallogr., Sect. C: Struct. Chem. 1988; 44: 154
      CrossrefSearch in Google Scholar
    • 18b Narbutas PT, Pierens GK, Clegg JK, Garson MJ. Nat. Prod. Commun.
      Crossref
  • 19 For example, see: Messchendorp L, van Loon JJ. A, Gols GJ. Z. Entomol. Exp. Appl. 1996; 79: 195
    CrossrefSearch in Google Scholar
  • 21 For a conceptually related approach using the naturally derived drimane polygodial, see: Rhak KJ, Bissember AC, Smith JA. Tetrahedron 2018; 74: 1167
    CrossrefPubMedSearch in Google Scholar
  • 22 For a chiral-auxiliary-based method leading to the formation of homochiral Diels–Alder adducts of diene 10, see: Hendersen JR, Parvez M, Keay BA. Org. Lett. 2009; 11: 3178
    CrossrefPubMedSearch in Google Scholar

   Permissions and Reprints All articles of this category
Zoom Image
Figure 1 Structures of the drimane-type sesquiterpenes 1–7 isolated from a Dysidea sp. of marine sponge
Zoom Image
Figure 2 The drimane sesquiterpene (+)-winterin (8), a logical precursor to target compounds 4, 5, and 7
Zoom Image
Scheme 1 First-generation synthesis of (±)-winterin [(±)-8] from β-cyclocitral (9)
Zoom Image
Scheme 2 Second-generation synthesis of (±)-winterin [(±)-8] from the Diels–Alder adduct (±)-12
Zoom Image
Scheme 3: The conversion of (±)-winterin [(±)-8] into compounds (±)-4, (±)-5, (±)-7, and (±)-18
Zoom Image
Scheme 4 Reduction of compound (±)-4 leading to derivative (±)-19