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Total Synthesis and Structural Elucidation of Two Unusual Non-Methylene-Interrupted Fatty Acids in Ovaries of the Limpet Cellana toreuma

Lipids volume 52, pages 1019–1032 (2017)Cite this article

Abstract

In our previous study, unusual odd-numbered dienoic acids with a terminal olefin were found as minor components in ovaries of the Japanese limpet Cellana toreuma, and the synthetic interests have been focused onto their structural confirmation and the inspection into their potential biological activity. Here, we describe an efficient and stereoselective total synthesis of two new unusual dienoic acids, 19:2∆7,18 and 21:2∆7,20, through a common pathway involving the strategic combination of alkyne-zipper reaction and Lindlar hydrogenation for the construction of their unique carbon chains. In our synthetic study, 2-propyn-1-ol was at first subjected to alkylation and alkyne-zipper reaction to form the two fragments, and the subsequent carbon chain elongation was achieved by the usual coupling reaction to obtain the C-19 and C-21 products bearing an internal acetylenic group. Then, the internal acetylenic group of these products was subjected to Lindlar hydrogenation to form a Z-alkenyl moiety, and the subsequent deprotection of the products was carried out under an acidic condition without isomerization of the internal Z-alkenyl group. Total synthesis of target fatty acids, 19:2∆7,18 and 21:2∆7,20, was finally accomplished by two-step oxidation of the resulting alcohols into carboxylic acids in a highly chemoselective manner, and the structures of these unusual natural fatty acids were finally elucidated by identifying the GC–MS spectra of the methyl esters of authentic and synthetic fatty acids.

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Scheme 1
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Scheme 7

Abbreviations

DMPU:

N,N′-Dimethylpropyleneurea

DMSO:

Dimethyl sulfoxide

ECL:

Equivalent chain length

GC–MS:

Gas chromatography–mass spectrometry

HRMS:

High resolution mass spectrometry

IR:

Infrared ray spectroscopy

MIFA:

Methylene-interrupted fatty acid

MOM:

Methoxymethyl

MS:

Mass spectrometry

m.p.:

Melting point

NMIFA:

Non-methylene-interrupted fatty acid

NMR:

Nuclear magnetic resonance spectroscopy

THF:

Tetrahydrofuran

TLC:

Thin-layer chromatography

References

  1. Djerassi C, Lam W (1991) Sponge phospholipids. Acc Chem Res 24:69–75

    Article  CAS  Google Scholar 

  2. Barnathan G (2009) Non-methylene-interrupted fatty acids from marine invertebrates: occurrence, characterization and biological properties. Biochimie 91:671–678

    Article  CAS  PubMed  Google Scholar 

  3. Kornprobst JM, Barnathan G (2010) Demospongic acids revisited. Mar Drugs 8:2569–2577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jefferts E, Morales RW, Litchfield C (1974) Occurrence of cis-5, cis-9-hexacosadienoic and cis-5, cis-9, cis-19-hexacosatrienoic acids in the marine sponge Microciona prolifera. Lipids 9:244–247

    Article  CAS  PubMed  Google Scholar 

  5. Litchfield C, Marcantonio CC (1978) Occurrence of 5,9,19-octacosatrienoic, 5,9-hexacosadienoic and 17-hexacosenoic acids in the marine sponge Xestospongia halichondroides. Lipids 13:199–202

    Article  CAS  Google Scholar 

  6. Walkup RD, Jamieson GC, Ratcliff MR, Djerassi C (1981) Phospholipid studies of marine organisms: 2. Phospholipids, phospholipid-bound fatty acids and free sterols of the sponge Aplysina fistularis (Pallas) from fulva (Pallas) (=Verongia thiona), isolation and structure elucidation of unprecedented branched fatty acids. Lipids 16:631–646

    Article  CAS  PubMed  Google Scholar 

  7. Carballeira NM, Jesús RM (1994) New Δ5,9 fatty acids in the phospholipids of the sea anemone Stoichactis helianthus. J Nat Prod 57:1688–1695

    Article  CAS  PubMed  Google Scholar 

  8. Carballeira NM, Reyes M (1995) Identification of a new 6-bromo-5,9-eicosadienoic acid from the anemone Condylactis gigantea and the zoanthid Palythoa caribaeorum. J Nat Prod 58:1689–1694

    Article  CAS  PubMed  Google Scholar 

  9. Ando Y, Kawabata Y, Narukawa K, Ota T (1998) Demospongic acids of the marine sponge Halichondria panicea from the coast of Hokkaido, Japan. Fish Sci 64:136–139

    Article  CAS  Google Scholar 

  10. Kawashima H, Ohnishi M, Uchiyama H (2001) Fatty acid compositions of muscle and viscera lipids in dominant limpet species from Otsuchi Bay in northern Japan. J Oleo Sci 50:607–611

    Article  CAS  Google Scholar 

  11. Kawashima H, Ohnishi M, Uchiyama H (2002) Sexual differences in gonad fatty acid compositions in dominant limpets species from the Sanriku coast in northern Japan. J Oleo Sci 51:503–508

    Article  CAS  Google Scholar 

  12. Kawashima H (2005) Unusual minor nonmethylene-interrupted di-, tri-, and tetraenoic fatty acids in limpet gonads. Lipids 40:627–630

    Article  CAS  PubMed  Google Scholar 

  13. Kawashima H, Ohnishi M (2006) Occurrence of novel nonmethylene-interrupted C24 polyenoic fatty acids in female gonad lipids of the limpet Cellana grata. Biosci Biotechnol Biochem 70:2575–2578

    Article  CAS  PubMed  Google Scholar 

  14. Kawashima H, Ohnishi M, Ogawa S, Matsui K (2008) Unusual fatty acid isomers of triacylglycerols and polar lipids in female limpet gonads of Cellana grata. Lipids 43:559–567

    Article  CAS  PubMed  Google Scholar 

  15. Kawashima H, Ohnishi M, Ogawa S (2009) Difference in sterol composition between male and female gonads of dominant limpet species. Lipids 44:665–669

    Article  CAS  PubMed  Google Scholar 

  16. Kawashima H, Ohnishi M, Ogawa S (2011) Differences in sterol composition of gonads of the lottiid limpets Nipponacmea concinna and Nipponacmea fuscoviridis from northern Japan. J Oleo Sci 60:501–504

    Article  CAS  PubMed  Google Scholar 

  17. Kawashima H, Ohnishi M (2012) Novel heneicosadienoic and tricosadienoic acid isomers in ovaries of marine archaeogastropods. Lipids 47:827–833

    Article  CAS  PubMed  Google Scholar 

  18. Kawashima H, Ohnishi M, Ogawa S (2013) Distribution of unusual cholesterol precursors, 4-methyl- and 4,4-dimethylsterols with Δ8-unsaturation, in gonads of marine archaeogastropods. J Oleo Sci 62:465–470

    Article  CAS  PubMed  Google Scholar 

  19. Kawashima H, Onishi M (2016) An unprecedented occurrence of Δ5,9- and Δ9,15-dienoic acids in ovaries of the archaeogastropod limpet Cellana toreuma. Lipids 51:257–262

    Article  CAS  PubMed  Google Scholar 

  20. Zhukova NV (2007) Lipid classes and fatty acid composition of the tropical nudibranch mollusks Chromodoris sp. and Phyllidia coelestis. Lipids 42:1169–1175

    Article  CAS  PubMed  Google Scholar 

  21. Mishra PM, Sree A (2008) Composition of the lipophilic extract from the sponge Axinella carteri collected from the bay of Bengal of the Orissa coast. Chem Nat Compd 44:282–286

    Article  CAS  Google Scholar 

  22. Carballeira NM (2008) New advances in fatty acids as antimalarial, antimycobacterial and antifungal agents. Prog Lipid Res 47:50–61

    Article  CAS  PubMed  Google Scholar 

  23. Zhukova NV (2014) Lipids and fatty acids of nudibranch mollusks: potential sources of bioactive compounds. Mar Drugs 12:4578–4592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang HY, Yamakawa Y, Matsuya Y, Toyooka N, Tohda C, Awale S, Li F, Kadota S, Tezuka Y (2014) Synthesis of long-chain fatty acid derivatives as a novel anti-Alzheimer’s agent. Bioorg Med Chem Lett 24:604–608

    Article  CAS  PubMed  Google Scholar 

  25. Yoshida J, Uesugi S, Kawamura T, Kimura K, Hu D, Xia S, Toyooka N, Ohnishi M, Kawashima H (2017) (4Z,15Z)-Octadecadienoic acid inhibits glycogen synthase kinase-3β and glucose production in H4IIE cells. Lipids 52:295–301

    Article  CAS  PubMed  Google Scholar 

  26. Kawashima H, Ohnishi M (2017) Novel odd-chain fatty acids with a terminal double bond in ovaries of the limpet Cellana toreuma. Lipids 52:375–381

    Article  CAS  PubMed  Google Scholar 

  27. Maryanoff BE, Reits AB (1989) The Wittig olefination reaction and modifications involving phosphoryl-stabilized carbanions. Stereochemistry, mechanism, and selected synthetic aspects. Chem Rev 89:863–927

    Article  CAS  Google Scholar 

  28. Mena PL, Pilet O, Djerassi C (1984) Phospholipid studies of marine organisms. 7. Stereospecific synthesis of (5Z,9Z)-, (5Z,9E)-, (5E,9Z)-, and (5E,9E)-5,9-hexacosadienoic acids. J Org Chem 49:3260–3264

    Article  CAS  Google Scholar 

  29. Carballeira NM, Emiliano A, Guzma A (1990) Facile syntheses for (5Z,9Z)-5,9-hexadecadienoic acid, (5Z,9Z)-5,9-nonadecadienoic acid, and (5Z,9Z)-5,9-eicosadienoic acid through a common synthetic route. Chem Phys Lipids 100:33–40

    Article  Google Scholar 

  30. Reyes ED, Carballeira NM (1997) Total synthesis of the antimicrobial fatty acid (5Z,9Z)-14-methylpentadeca-5,9-dienoic acid and its longer-chain analogue (5Z,9Z)-24-methylpentacosa-5,9-dienoic acid. Synthesis 1997:1195–1198

    Article  Google Scholar 

  31. Kulkarni BA, Sharma A, Gamre S, Chattopadhyay S (2004) Synthesis of the marine compound (2R,5Z,9Z)-2-methoxyhexacosa-5,9-dienoic acid via a lipase-catalyzed resolution and a novel O-alkylation protocol. Synthesis 2004:595–599

    Article  Google Scholar 

  32. D’yakonov VA, Makarov AA, Makarova EK, Dzhemilev UM (2013) Novel organomagnesium reagents in synthesis. Catalytic cyclomagnesiation of allenes in the synthesis of N-, O-, and Si-substituted 1Z,5Z-dienes. Tetrahedron 69:8516–8526

    Article  Google Scholar 

  33. D’yakonov VA, Dzhemileva LU, Makarov AA, Mulyukova AR, Baev DS, Khusnutdinova EK, Tolstikova TG, Dzhemilev UM (2015) Stereoselective synthesis of 11-phenylundeca-5Z,9Z-dienoic acid and investigation of its human topoisomerase I and IIα inhibitory activity. Bioorg Med Chem Lett 25:2405–2408

    Article  PubMed  Google Scholar 

  34. Dyakonov VA, Dzhemileva LU, Makarov AA, Mulyukova AR, Baev DS, Khusnutdinova EK, Tolstikova TG, Dzhemilev UM (2015) 11-Phenylundeca-5Z,9Z-dienoic acid: stereoselective synthesis and dual topoisomerase I/IIα inhibition. Curr Cancer Drug Targets 15:504–510

    Article  CAS  Google Scholar 

  35. Adrian J, Stark CB (2016) Flexible approach to (5Z,9Z)-dienoic fatty acids relevant to synthesis of demospongic acids and related natural products. Eur J Org Chem 2016:4607–4610

    Article  Google Scholar 

  36. Brown CA, Yamashita A (1975) Saline hydrides and superbases in organic syntheses. IX. Acetylene zipper. Exceptionally facile contrathermodynamic multipositional isomerization of alkynes with potassium 3-aminopropylamide. J Am Chem Soc 97:891–892

    Article  CAS  Google Scholar 

  37. Chinnababu B, Purushotham-Reddy S, Kumar-Reddy D, Chandra-Rao D, Venkateswarlu Y (2012) Stereoselective concise total synthesis of leodomycin C and D. Synthesis 44:311–315

    CAS  Google Scholar 

  38. Hoye RC, Anderson LG, Brown SG, Schultz EE (2010) Total synthesis of clathculins A and B. J Org Chem 75:7400–7403

    Article  CAS  PubMed  Google Scholar 

  39. Reddy CR, Suman D, Rao NN (2012) Alkyne-assisted approach to the formal synthesis of antibiotic macrolide (−)-26771B. Synlett 23:272–274

    Article  CAS  Google Scholar 

  40. Liu FP, Zhong J, Zheng B, Li S, Gao G, Wang Z, Li M, Hou S, Wang M, Bian Q (2015) Catalytic asymmetric synthesis of (S,4E,15Z)-docosa-4,15-dien-1-yn-3-ol, an antitumor marine natural product. Tetrahedron Asymmetry 26:961–965

    Article  CAS  Google Scholar 

  41. Liu FP, Zhong J, Li S, Wu L, Wang Q, Mao J, Liu S, Zheng B, Wang M, Bian Q (2016) Total synthesis of (R)-strongylodiols C and D. J Nat Prod 79:244–247

    Article  CAS  PubMed  Google Scholar 

  42. Avocetien KF, Li JJ, Liu X, Wang Y, Xing Y, O’Doherty GA (2016) De novo asymmetric synthesis of phoracantholide. J. Org Lett 18:4970–4973

    Article  CAS  PubMed  Google Scholar 

  43. Calzada JG, Hooz J (1974) Geranyl chloride [2,6-Octadiene, 1-chloro-3,7-dimethyl, (E)-]. Org Synth 54:63–69

    Article  CAS  Google Scholar 

  44. Gericke KM, Chai DI, Lautens M (2008) The versatile role of norbornene in C-H functionalization processes: concise synthesis of tetracyclic fused pyrroles via a threefold domino reaction. Tetrahedron 64:6002–6014

    Article  CAS  Google Scholar 

  45. Bayer AA, Maier ME (2004) Synthesis of enamides from aldehydes and amides. Tetrahedron 60:6665–6677

    Article  CAS  Google Scholar 

  46. Aursnes M, Tungen JE, Vik A, Colas R, Cheng CYC, Dalli J, Serhan CN, Hansen TV (2014) Total synthesis of the lipid mediator PD1n-3 DPA: configurational assignments and anti-inflammatory and pro-resolving actions. J Nat Prod 77:910–916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mancuso AJ, Huang SL, Swern D (1978) Oxidation of long-chain and related alcohols by dimethyl sulfoxide “activated” by oxalyl chloride. J Org Chem 43:2480–2482

    Article  CAS  Google Scholar 

  48. Marx M, Tidwell TT (1984) Reactivity-selectivity in the Swern oxidation of alcohols using dimethyl sulfoxide-oxalyl chloride. J Org Chem 49:788–793

    Article  CAS  Google Scholar 

  49. Lindgren B, Nilsson T (1973) Preparation of carboxylic acids from aldehydes (including hydroxylated benzaldehydes) by oxidation with chlorite. Acta Chem Scand 27:888–890

    Article  CAS  Google Scholar 

  50. Jakobsen CG, Vik A, Hansen TV (2012) Concise synthesis of ω-3 polyunsaturated fatty acids. Tetrahedron Lett 53:5837–5839

    Article  CAS  Google Scholar 

  51. Angulo-Pachón CA, Diaz-Oltra S, Murga J, Carda M, Marco JA (2010) Stereoselective synthesis and structural correction of the naturally occurring lactone stagonolide G. Org Lett 12:5752–5755

    Article  PubMed  Google Scholar 

  52. Morrison WR, Smith LM (1964) Preparation of fatty acid methyl esters and dimethylacetals from lipids with boron fluoride-methanol. J Lipid Res 5:600–608

    CAS  PubMed  Google Scholar 

  53. Destaillats F, Wolff RL, Angers P (2002) Saturated and unsaturated anteiso-C19 in the seed lipids from Hesperopeuce mertensiana (Pinaceae). Lipids 37:325–328

    Article  CAS  PubMed  Google Scholar 

  54. Wu M, Lee C, Wu Y, Chen C (2008) Synthesis of (4R,15R,16R,21S)-Rollicosin and Its 4S epimer. Eur J Org Chem 2008:854–861

    Article  Google Scholar 

  55. Neef AB, Schultz C (2009) Selective fluorescence labeling of lipids in living cells. Angew Chem Int Ed 48:1498–1500

    Article  CAS  Google Scholar 

  56. Shen Z, Huang M, Xiao C, Zhang Y, Wang PG (2007) Nonlabeled quartz crystal balance biosensor for bacterial detection using carbohydrate and lectin recognitions. Anal Chem 79:2312–2319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mames A, Stecko S, Mikolajczyk P, Soluch M, Furman B, Chmielewski M (2010) Direct catalytic synthesis of carbapenams via cycloaddition/rearrangement cascade reaction: unexpected acetylenes’ structure effect. J Org Chem 75:7580–7587

    Article  CAS  PubMed  Google Scholar 

  58. Trost BM, Livingston RC (2008) An atom-economic and selective ruthenium-catalyzed redox isomerization of propargyl alcohols. An efficient strategy for the synthesis of leucotrienes. J Am Chem Soc 130:11970–11978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cheng X, Li L, Uttamchandani M, Yao SQ (2014) In situ proteome profiling of C75, a covalent bioactive compound with potential anticancer activities. Org Lett 16:1414–1417

    Article  CAS  PubMed  Google Scholar 

  60. Fenlon EE, Ito BR (2008) The thread and cut method: synthesis of molecular knot precursors. Eur J Org Chem 2008:3065–3068

    Article  Google Scholar 

  61. Nguyen TB, Castanet AS, Nguyen TH, Nguyen KPP, Baedeau JF, Gibaud A, Mortier J (2006) Synthesis of model long-chain ω-alkenyltrichlorosilanes and triethoxysilanes for the formation of self-assembled monolayers. Tetrahedron 62:647–651

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Chemistry and Biosciences, Faculty of Science and Engineering, Iwate University, Morioka, Iwate, 020-8551, Japan

    Kazuaki Shimada, Ayako Sugawara & Toshinobu Korenaga

  2. Miyako College, Iwate Prefectural University, Miyako, Iwate, 027-0039, Japan

    Hideki Kawashima

Authors
  1. Kazuaki Shimada
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  2. Ayako Sugawara
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  3. Toshinobu Korenaga
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  4. Hideki Kawashima
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Correspondence to Kazuaki Shimada.

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Shimada, K., Sugawara, A., Korenaga, T. et al. Total Synthesis and Structural Elucidation of Two Unusual Non-Methylene-Interrupted Fatty Acids in Ovaries of the Limpet Cellana toreuma . Lipids 52, 1019–1032 (2017). https://doi.org/10.1007/s11745-017-4303-9

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  • DOI: https://doi.org/10.1007/s11745-017-4303-9

Keywords

  • Limpet
  • Non-methylene-interrupted fatty acid
  • Synthesis
  • Alkyne-zipper reaction
  • Lindlar hydrogenation