Daphniphyllum Alkaloids: Recent Findings on Chemistry and Pharmacology

Abstract

The unique polycyclic fused ring systems of Daphniphyllum alkaloids, along with their extensive bioactivities, make this family of alkaloids especially attractive targets for total synthesis and biogenetic studies. Successive discoveries of new alkaloids with unprecedented skeletons have made a great contribution to structural diversities of alkaloids elaborated by plants of the genus Daphniphyllum. By the end of 2008, more than 200 alkaloids belonging to 14 different skeletal types have been isolated from different parts of plants of thirteen Daphniphyllum species. These alkaloids show cytotoxic, antioxidant, vasorelaxant, and antiplatelet activating factor effects. The plausible biosynthetic pathways for Daphniphyllum alkaloids have been proposed and biomimetic total syntheses of some alkaloids completed. To provide an update of the previous reviews published in 2009, new structures, synthesis, and bioactivity of Daphniphyllum alkaloids reported in recent years are presented in this article. In the meantime, an additional 54 novel alkaloids have been isolated and identified. Among them, some possess unprecedented frameworks. Several inspired organic syntheses were completed.

Key words

Daphniphyllum - Daphniphyllaceae - alkaloids - synthesis - biological activity

• References

• 1 Kubitzki K. Daphniphyllaceae flowering plants eudicots. Berlin, Heidelberg: Springer; 2007: 127-128
• 2 Yagi S. Daphniphyllum alkaloid. Kyoto Igaku Zasshi 1909; 6: 208-222
• 3 Fang SD, Zhou W, Chen Y, Chu JH. Alkaloids of the poisonous plant Niu-Er-Fon Daphniphyllum calycinum Benth. Acta Chim Sin 1964; 30: 270-274
• 4 Arthur HR, Chan RPK, Loo SN. Alkaloids of Daphniphyllum calycinum and D. glaucescens of Hong Kong. Phytochemistry 1965; 4: 627-629
• 5 Sakabe N, Irikawa H, Sakurai H, Hirata Y. Isolation of 3 new alkaloids from Daphniphyllum macropodum Miquel. Tetrahedron Lett 1966; 7: 963-964
• 6 Sakabe N, Hirata Y. X-ray structure determination of a new type alkaloid, daphniphylline hydrobromide. Tetrahedron Lett 1966; 7: 965-968
• 7 Sakurai H, Sakabe N, Hirata Y. X-ray structure determination of yuzurimine hydrobromide. Tetrahedron Lett 1966; 7: 6309-6314
• 8 Heathcock CH, Davidsen SK, Mills S, Sanner MA. Total synthesis of (±)-methyl homodaphniphyllate. J Am Chem Soc 1986; 108: 5650-5651
• 9 Ruggeri RB, McClure KF, Heathcock CH. Daphniphyllum alkaloids. Part 5. Total synthesis of (±)-daphnilactone A: a novel fragmentation reaction. J Am Chem Soc 1989; 111: 1530-1531
• 10 Stafford JA, Heathcock CH. Daphniphyllum alkaloids. Part 8. Asymmetric total synthesis of (−)-secodaphniphylline. J Org Chem 1990; 55: 5433-5434
• 11 Heathcock CH, Davidsen SK, Mills SG, Sanner MA. Daphniphyllum alkaloids. 10. Classical total synthesis of methyl homodaphniphyllate. J Org Chem 1992; 57: 2531-2544
• 12 Heathcock CH. Nature knows best: an amazing reaction cascade is uncovered by design and discovery. Proc Natl Acad Sci USA 1996; 93: 14323-14327
• 13 Heathcock CH, Hansen MM, Ruggeri RB, Kath JC. Daphniphyllum alkaloids. 11. Biomimetic total synthesis of methyl homosecodaphniphyllate. Development of the tetracylization reaction. J Org Chem 1992; 57: 2544-2553
• 14 Heathcock CH, Joe D. Daphniphyllum alkaloids. 17. A possibly biomimetic transformation of the secodaphnane to the daphnane skeleton. J Org Chem 1995; 60: 1131-1142
• 15 Heathcock CH, Piettre S, Ruggeri RB, Ragan JA, Kath JC. Daphniphyllum alkaloids. 12. A proposed biosynthesis of the pentacyclic skeleton. proto-Daphniphylline. J Org Chem 1992; 57: 2554-2566
• 16 Heathcock CH, Piettre S, Kath J. Mechanic investigations of a biomimetic polycyclization process that leads to the Daphniphyllum alkaloids. Pure Appl Chem 1990; 62: 1911-1920
• 17 Ruggeri RB, Heathcock CH. A proposal for biosynthesis of the Daphniphyllum alkaloids. Pure Appl Chem 1989; 61: 289-292
• 18 Piettre S, Heathcock CH. Total synthesis of proto-daphniphylline. Science 1990; 248: 1532-1534
• 19 Yamamura S, Hirata Y. The Daphniphyllum alkaloids. In: Manske RHF, editor The alkaloids, Volume 12. New York: Academic Press; 1975: 41-81
• 20 Yamamura S. Daphniphyllum alkaloids. In: Brossi A, editor The alkaloids, Volume 29. New York: Academic Press; 1986: 265-286
• 21 Kobayashi J, Morita H. Daphniphyllum alkaloids. In: Cordell GA, editor The alkaloids, Volume 60. New York: Academic Press; 2003: 165-205
• 22 Li ZY, Guo YW. Progress in the study of Daphniphyllum alkaloids. Chin J Org Chem 2007; 27: 565-575
• 23 Dong M, Zhang ML, Shi QW, Gu YC, Kiyota H. The Daphniphyllum alkaloids. Curr Org Chem 2009; 13: 646-682
• 24 Kobayashi JI, Kubota T. The Daphniphyllum alkaloids. Nat Prod Rep 2009; 26: 936-962
• 25 Zhang CR, Liu HB, Feng T, Zhu JY, Geng MY, Yue JM. Alkaloids from the leaves of Daphniphyllum subverticillatum . J Nat Prod 2009; 72: 1669-1672
• 26 Kubota T, Suzuki T, Ishiuchi K, Kuhara T, Kobayashi J. Daphnezomines T–V, alkaloids from Daphniphyllum humile . Chem Pharm Bull 2009; 57: 504-507
• 27 Li ZY, Peng SY, Fang L, Yang YM, Guo YW. Two new Daphniphyllum alkaloids from the stems and leaves of Daphniphyllum calycinum . Chem Biodivers 2009; 6: 105-110
• 28 Zhang CR, Liu HB, Dong SH, Zhu JY, Wu Y, Yue JM. Calycinumines A and B, two novel alkaloids from Daphniphyllum calycinum . Org Lett 2009; 11: 4692-4695
• 29 Li ZY, Gu YC, Irwin D, Sheridan J, Clough J, Chen P, Peng SY, Yang YM, Guo YW. Further Daphniphyllum alkaloids with insecticidal activity from the bark of Daphniphyllum macropodum MIQ. Chem Biodivers 2009; 6: 1744-1750
• 30 Li ZY, Xu HG, Zhao ZZ, Guo YW. Two new Daphniphyllum alkaloids from Daphniphyllum macropodum Miq. J Asian Nat Prod Res 2009; 11: 153-158
• 31 Zhang Y, Di YT, Zhang Q, Mu SZ, Tan CJ, Fang X, He HP, Li SL, Hao XJ. Daphhimalenine A, a new alkaloid with an unprecedented skeleton, from Daphniphyllum himalense . Org Lett 2009; 11: 5414-5417
• 32 He T, Zhou Y, Wang YH, Mu SZ, Hao XJ. Two new akaloids from Daphniphyllum angustifolium Hutch. Helv Chim Acta 2011; 94: 1019-1023
• 33 Zhang Y, He HP, Guo LL, Li SF, Di YT, Hao XJ. Daphhimalenines C and D. New alkaloids from Daphniphyllum himalense . Z Naturforsch 2012; 67: 407-410
• 34 Li CS, Di YT, Guo J, Zhang Q, Fang X, Hao XJ. Daphlongamines I and J. New yuzurine-type alkaloids from Daphniphyllum longeracemosum . Z Naturforsch A 2010; 65: 1406-1408
• 35 Yang TQ, Di YT, He HP, Hao XJ. A new alkaloid from the fruits of Daphniphyllum longeracemosum (Daphniphyllaceae). Yunnan Zhiwu Yanjiu 2010; 32: 561-563
• 36 Yang TQ, Di YT, He HP, Zhang Q, Zhang Y, Hao XJ. Further alkaloids from the fruits of Daphniphyllum longeracemosum . Helv Chim Acta 2011; 94: 397-403
• 37 Zhang Y, Di YT, He HP, Li SF, Lu Y, Gong NB, Hao XJ. Daphmalenines A and B: Two new alkaloids with unusual skeletons from Daphniphyllum himalense . Eur J Org Chem 2011; 2011: 4103-4107
• 38 Tan CJ, Wang YH, Di YT, He HP, Mu SZ, Li SF, Zhang Y, Hao XJ. Daphnioldhamine A, a novel alkaloid from Daphniphyllum oldhami . Tetrahedron Lett 2012; 53: 2588-2591
• 39 Cao MM, Zhang Y, He HP, Li SF, Huang SD, Chen DZ, Tang GH, Li SL, Di YT, Hao XJ. Daphmacromines A–J, alkaloids from Daphniphyllum macropodum . J Nat Prod 2012; 75: 1076-1082
• 40 Zhang Y, Di YT, Mu SZ, Li CS, Zhang Q, Tan CJ, Zhang Z, Fang X, Hao XJ. Dapholdhamines A–D, alkaloids from Daphniphyllum oldhami . J Nat Prod 2009; 72: 1325-1327
• 41 Zhang CR, Fan CQ, Dong SH, Liu HB, Zhou WB, Wu Y, Yue JM. Angustimine and Angustifolimine: two new alkaloids from Daphniphyllum angustifolium . Org Lett 2011; 13: 2440-2443
• 42 Zhan ZJ, Rao GW, Hou XR, Li CP, Shan WG. Alkaloids from the leaves and stems of Daphniphyllum calycinum . Helv Chim Acta 2009; 92: 1562-1567
• 43 Zhang Y, Di YT, Liu HY, Li CS, Tan CJ, Zhang Q, Fang X, Li SL, Hao XJ. Three new alkaloids, paxiphyllines C–E, from Daphniphyllum paxianum. Helv Chim Acta 2008; 91: 2153-2158
• 44 Guo YW, Kurtán T, Krohn K, Pescitelli G, Zhang W. Assignment of the absolute configuration of zwitterionic and neutral macropodumines by means of TDDFT CD calculations. Chirality 2009; 21: 561-568
• 45 Li CS, Di YT, Zhang Q, Zhang Y, Tan CJ, Hao XJ. Alkaloids from the leaves of Daphniphyllum longeracemosum Rosenth. Helv Chim Acta 2009; 92: 653-659
• 46 Zhang Q, Di YT, Li CS, Fang X, Tan CJ, Zhang Z, Zhang Y, He HP, Li SL, Hao XJ. Daphenylline, a new alkaloid with an unusual skeleton, from Daphniphyllum longeracemosum . Org Lett 2009; 11: 2357-2359
• 47 Cherney EC, Baran PS. Terpenoid-alkaloids: Their biosynthetic twist of fate and total synthesis. Isr J Chem 2011; 51: 391-405
• 48 Kim J, Movassaghi M. Biogenetically inspired syntheses of alkaloid natural products. Chem Soc Rev 2009; 38: 3035-3050
• 49 Weiss ME, Carreira EM. Total synthesis of (+)-daphmanidin E. Angew Chem Int Ed Engl 2011; 50: 11501-11505
• 50 Darses B, Michaelides IN, Sladojevich F, Ward JW, Rzepa PR, Dixon DJ. Expedient construction of the [7-5-5] all-carbon tricyclic core of the Daphniphyllum alkaloids daphnilongeranin B and daphniyunnine D. Org Lett 2012; 14: 1684-1687
• 51 Yao Y, Liang G. Rapid construction of the ABC ring system in the Daphniphyllum alkaloid daphniyunnine C. Org Lett 2012; 14: 5499-5501
• 52 Li HL, Zheng JY, Xu SY, Ma DH, Zhao CG, Fang BW, Xie XG, She XG. Rapid construction of the [6-6-6-5] tetracyclic skeleton of the Daphniphyllum alkaloid daphenylline. Chem Asian J 2012; 7: 2519-2522
• 53 Yang M, Wang L, He ZH, Wang SH, Zhang SY, Tu YQ, Zhang FM. Tandem semipinacol-type 1,2-carbon migration/aldol reaction toward the construction of [5–6–7] all-carbon tricyclic core of calyciphylline A-type alkaloids. Org Lett 2012; 14: 5114-5117
• 54 Ihara M. Cascade reactions for syntheses of heterocycles. Arkivoc 2006; vii: 416-438
• 55 Coldham I, Watson L, Adams H, Martin NG. Synthesis of the core ring system of the yuzurimine-type Daphniphyllum alkaloids by cascade condensation, cyclization, cycloaddition chemistry. J Org Chem 2011; 76: 2360-2366
• 56 Coldham I, Burrell AJM, Guerrand HDS, Oram N. Cascade cyclization, dipolar cycloaddition to bridged tricyclic amines related to the Daphniphyllum alkaloids. Org Lett 2011; 13: 1267-1269
• 57 Ikeda S, Shibuya M, Kanoh N, Iwabuchi Y. Synthetic studies on daphnicyclidin A: enantiocontrolled construction of the BCD ring system. Org Lett 2009; 11: 1833-1836
• 58 Dunn TB, Ellis JM, Kofink CC, Manning JR, Overman LE. Asymmetric construction of rings A–D of daphnicyclidin-type alkaloids. Org Lett 2009; 11: 5658-5661
• 59 Ovchinnikova IG, Fedorova OV, Matochkina EG, Kodess MI, Tumashov AA, Slepukhin PA, Rusinov GL, Charushin VN. The first example of cascade synthesis of alkaloid-like subunit incorporated into crown ethers. Macroheterocycles 2012; 3: 108-113
• 60 Denmark SE, Baiazitov RY, Nguyen ST. Tandem double intramolecular [4 + 2]/[3 + 2] cycloadditions of nitroalkenes: construction of the pentacyclic core structure of daphnilactone B. Tetrahedron 2009; 65: 6535-6548
• 61 Ueda M, Walczak MAA, Wipf P. Formal Alder-ene reaction of a bicyclo[1.1.0]butane in the synthesis of the tricyclic quaternary ammonium core of daphniglaucins. Tetrahedron Lett 2008; 49: 5986-5989
• 62 Zhang X, Zhang J, Tan Y, Liu Q, Liu M. Deoxycalyciphylline B, a hepatotoxic alkaloid from Daphniphyllum calycinum . Molecules 2012; 17: 9641-9651