RSS-Feed abonnieren
Bitte kopieren Sie die angezeigte URL und fügen sie dann in Ihren RSS-Reader ein.
https://www.thieme-connect.de/rss/thieme/de/10.1055-s-00000084.xml
Synthesis 2019; 51(04): 787-815
DOI: 10.1055/s-0037-1611702
DOI: 10.1055/s-0037-1611702
review
Indolylvinyl Ketones: Building Blocks for the Synthesis of Natural Products and Bioactive Compounds
M.G.U. thanks the Ministry of Education and Science of the Russian Federation (Project No. 4.5371.2017/8.9) and Russian Foundation for Basic Research (grant No. 16-03-00513 А). V.T.A. thanks Russian Foundation for Basic Research (grant No. 16-03-00807 А).Weitere Informationen
Publikationsverlauf
Received: 04. Oktober 2018
Accepted after revision: 13. November 2018
Publikationsdatum:
24. Januar 2019 (online)
Dedicated to the memory of Professor Alexander V. Butin
Abstract
Indolylvinyl ketones are valuable building blocks that can be utilized for the synthesis of numerous natural products and bioactive molecules containing an indole core motif. Herein, we describe their application for the total synthesis of some alkaloids, their analogues, and a variety of other important compounds, with an emphasis on biologically active examples.
1 Introduction
2 Functionalization of the Enone C=C Bond
2.1 Reduction
2.2 Michael Addition
2.3 Cycloaddition
3 Transformation of the Carbonyl Group
3.1 Reduction
3.2 Knoevenagel Reaction
3.3 Addition of Organometallic Compounds
3.4 Olefination
4 Reactions Involving the Enone Conjugate System С=С–С=О
4.1 Reactions with 1,2-Dinucleophiles
4.2 Reactions with Compounds Bearing an Active Methylene Group
4.3 Reactions with 1,3-Dinucleophiles
4.4 Reactions with 1,4-Dinucleophiles
5 Functionalization of the Enone Methylene Group C(O)–CH2R
5.1 Acylation/Crotonic Condensation and Related Transformations
5.2 Enolization
6 Functionalization of the Indole Core
6.1 [4+2] Cycloaddition
6.2 [3+3] Annulation
6.3 Electrocyclic Reactions
7 Miscellaneous
8 Conclusions
-
References
- 1a Gribble GW. Indole Ring Synthesis: From Natural Products to Drug Discovery. Wiley & Sons; Chichester: 2016: 704
- 1b Ishikura M, Abe T, Choshi T, Hibino S. Nat. Prod. Rep. 2013; 30: 694
- 2a Chadha N, Silakari O. Eur. J. Med. Chem. 2017; 134: 159
- 2b Sherer C, Snape TJ. Eur. J. Med. Chem. 2015; 97: 552
- 2c Zhang M.-Zh, Chen V, Yang G.-F. Eur. J. Med. Chem. 2015; 89: 421
- 2d Kaushik VN, Kaushik N, Attri P, Kumar N, Kim CH, Verma AK, Choi EH. Molecules 2013; 18: 6620
- 3 Baumann M, Baxendale IR, Ley SV, Nikbin N. Beilstein J. Org. Chem. 2011; 7: 442
- 4 Pettersson B, Hasimbegovic V, Bergman J. Tetrahedron Lett. 2010; 51: 238
- 5 Somei M, Yamada F, Karasawa Y, Kaneko C. Chem. Lett. 1981; 10: 615
- 6 Brown MA, Kerr MA. Tetrahedron Lett. 2001; 42: 983
- 7 Uchuskin MG, Pilipenko AS, Serdyuk OV, Trushkov IV, Butin AV. Org. Biomol. Chem. 2012; 10: 7262
- 8 Black DSt. C, Deb-Das RB, Kumar N. Aust. J. Chem. 1992; 45: 611
- 9 Guo X, Hu W, Cheng S, Wang L, Chang J. Synth. Commun. 2006; 36: 781
- 10 Makarov AS, Merkushev AA, Uchuskin MG, Trushkov IV. Org. Lett. 2016; 18: 2192
- 11 Saikia A, Barthakur MG, Boruah RC. Synlett 2005; 523
- 12 Somei M, Ohnishi H. Chem. Pharm. Bull. 1985; 33: 5147
- 13 Tharra P, Baire B. Org. Lett. 2018; 20: 1118
- 14 Ornstein PL, Bleisch TJ, Arnold MB, Wright RA, Johnson BG, Schoepp DD. J. Med. Chem. 1998; 41: 346
- 15 Hagen SE, Domagala J, Gajda C, Lovdahl M, Tait BD, Wise E, Holler T, Hupe D, Nouhan C, Urumov A, Zeikus G, Zeikus E, Lunney EA, Pavlovsky A, Gracheck SJ, Saunders J, VanderRoest S, Brodfuehrer J. J. Med. Chem. 2001; 44: 2319
- 16 Somei M, Tokutake S, Kaneko C. Chem. Pharm. Bull. 1983; 31: 2153
- 17 Stroba A, Schaeffer F, Hindie V, Lopez-Garcia L, Adrian I, Fröhner W, Hartmann RW, Biondi RM, Engel M. J. Med. Chem. 2009; 52: 4683
- 18 Jin J, Gong J, Qin Y. Angew. Chem. Int. Ed. 2015; 54: 2228
- 19 Edwards PD, Albert JS, Sylvester M, Aharony D, Andisik D, Callaghan O, Campbell JB, Carr RA, Chessari G, Congreve M, Frederickson M, Folmer RH. A, Geschwindner S, Koether G, Kolmodin K, Krumrine J, Mauger RC, Murray CW, Olsson L.-L, Patel S, Spear N, Tian G. J. Med. Chem. 2007; 50: 5912
- 20 Li W, Wu X.-F. Eur. J. Org. Chem. 2015; 331
- 21 Somei M, Karasawa Y, Kaneko C. Heterocycles 1981; 16: 941
- 22 Somei M, Karasawa Y, Kaneko C. Chem. Lett. 1980; 9: 813
- 23a Natsume M, Muratake H. Heterocycles 1980; 14: 445
- 23b For recent review on ergot alkaloids, see: Chen J.-J, Han M.-Y, Gong T, Yang J.-L, Zhu P. RSC Adv. 2017; 7: 27384
- 24 Caruana L, Fochi M, Franchini MC, Ranieri S, Mazzanti A, Bernardi L. Chem. Commun. 2014; 50: 445
- 25 Romanini S, Galletti E, Caruana L, Mazzanti A, Himo F, Santoro S, Fochi M, Bernardi L. Chem. Eur. J. 2015; 21: 17578
- 26 Semenov AA, Kuchkova KI, Styngach EP. Khim. Geterotsikl. Soedin. 1970; 6: 1066; Chem. Heterocycl. Compd. 1970, 6, 993
- 27 Nenajdenko VG, Druzhinin SV, Balenkova ES. Izv. Akad. Nauk, Ser. Khim. 2003; 2332; Russ. Chem. Bull. 2003, 52, 2467
- 28 Wascholowski V, Knudsen KR, Mitchell CE. T, Ley SV. Chem. Eur. J. 2008; 14: 6155
- 29 Lundy BJ, Jansone-Popova S, May JA. Org. Lett. 2011; 13: 4958
- 30 Shih J.-L, Nguyen TS, May JA. Angew. Chem. Int. Ed. 2015; 54: 9931
- 31 Zhu Y, Dong Z, Cheng X, Zhong X, Liu X, Lin L, Shen Z, Yang P, Li Y, Wang H, Yan W, Wang K, Wang R. Org. Lett. 2016; 18: 3546
- 32 Bergman J. Acta Chem. Scand. 1972; 26: 970
- 33 Oh CH, Park HS, Park N, Kim SY, Piao L. Synlett 2014; 25: 579
- 34 Kumar A, Gupta LP, Kumar M. RSC Adv. 2013; 3: 18771
- 35 Sommer H, Braun M, Schröder B, Kirschning A. Synlett 2018; 29: 121
- 36 Venkatesh C, Ila H, Junjappa H, Mathur S, Huch V. J. Org. Chem. 2002; 67: 9477
- 37 Yadav AK, Peruncheralathan S, Ila H, Junjappa H. J. Org. Chem. 2007; 72: 1388
- 38 Rajkumar V, Babu SA, Padmavathi R. Tetrahedron 2016; 72: 5578
- 39 Chagarovsky AO, Budynina EM, Ivanova OA, Villemson EV, Rybakov VB, Trushkov IV, Melnikov MYa. Org. Lett. 2014; 16: 2830
- 40 Madugula AK, Mahendran V, Sridhara AM, Rangaiah G. Orient. J. Chem. 2016; 32: 2533
- 41a Black DSt. C, Bowyer MC, Kumar N. Tetrahedron 1997; 53: 8565
- 41b Balamurugan R, Sureshbabu R, Rajeshwaran GG, Mohanakrishnan AK. Synth. Commun. 2009; 39: 531
- 42 Konstantinidou M, Gkermani A, Hadjipavlou-Litina D. Molecules 2015; 20: 16354
- 43 Kinsman AC, Kerr MA. Org. Lett. 2000; 2: 3517
- 44 Dethe DH, Boda R. Org. Biomol. Chem. 2016; 14: 5843
- 45 Ranu BC, Samanta S. Tetrahedron 2003; 59: 7901
- 46 Dombrovskii VA, Gracheva EV, Kochergin PM. Khim. Geterotsikl. Soedin. 1986; 40; Chem. Heterocycl. Compd. 1986, 22, 33
- 47 Barco A, Benetti S, Pollini GP, Baraldi PG, Guarneri M, Simoni D, Vicentini CB, Borasio PG, Capuzzo A. J. Med. Chem. 1978; 21: 988
- 48 He P, Liu X, Zheng H, Li W, Lin L, Feng X. Org. Lett. 2012; 14: 5134
- 49 Chen F, Zhang Y, Yu L, Zhu S. Angew. Chem. Int. Ed. 2017; 56: 2022
- 50 Karymova TM, Dvoinishnikova TA, Abramenko PI, Kalent’ev VK, Kazymov AV. Khim. Geterotsikl. Soedin. 1992; 499 ; Chem. Heterocycl. Compd. 1992, 28, 417
- 51 Biradar JS, Sasidhar BS, Parveen R. Eur. J. Med. Chem. 2010; 45: 4074
- 52 Muratake H, Takahashi T, Natsume M. Heterocycles 1983; 20: 1963
- 53a Ishii H, Murakami Y, Furuse T, Takeda H, Ikeda N. Tetrahedron Lett. 1973; 14: 355
- 53b Ishii H, Murakami Y. Tetrahedron 1975; 31: 933
- 54 Tsukerman SV, Nikitchenko VM, Bugai AI, Lavrushin VF. Khim. Geterotsikl. Soedin. 1969; 5: 268 ; Chem. Heterocycl. Compd. 1969, 5, 203
- 55 Gupta DP, Kumar P, Ahmad S, Shanker K. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1990; 29: 194
- 56a Raman K, Pandey BR, Barthwal JP, Parmar SS. Eur. J. Med. Chem. 1980; 15: 567
- 56b Dandia A, Sehgal V, Singh P. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1993; 32: 1288
- 57 Bhalla M, Naithani PK, Kumar A, Bhalla TN, Shanker K. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1992; 31: 183
- 58 Anekal D, Biradar JS. Heterocycl. Commun. 2009; 15: 411
- 59 El-Shihi TH, Abdel Latif NA, El-Sawy ER. Egypt. J. Chem. 2004; 34: 365
- 60 Kumar A, Sharma S, Bajaj K, Bansal D, Sharma S, Saxena AK. K, Lata S, Gupta B, Srivastava VK. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2003; 42: 1979
- 61 Reddy MV. R, Billa VK, Pallela VR, Mallireddigari MR, Boominathan R, Gabriel JL, Reddy EP. Bioorg. Med. Chem. 2008; 16: 3907
- 62a Budakoti A, Bhat AR, Athar F, Azam A. Eur. J. Med. Chem. 2008; 43: 1749
- 62b Budakoti A, Bhat AR, Azam A. Eur. J. Med. Chem. 2009; 44: 1317
- 63 Zhang Y.-L, Qin Y.-J, Tang D.-J, Yang M.-R, Li B.-Y, Wang Y.-T, Cai H.-Y, Wang B.-Z, Zhu H.-L. ChemMedChem 2016; 11: 1446
- 64 Sanin AV, Nenajdenko VG, Kuz’min VS, Balenkova ES. Khim. Geterotsikl. Soedin. 1998; 634 Chem. Heterocycl. Compd. 1998, 34, 558
- 65 Bauer U, Egner BJ, Nilsson I, Berghult M. Tetrahedron Lett. 2000; 41: 2713
- 66 Saundane AR, Mathada KN. Monatsh. Chem. 2016; 147: 1291
- 67 Khan KA, Faidallah HM. J. Enzyme Inhib. Med. Chem. 2016; 31: 619
- 68 Pandey AK, Sharma S, Pandey M, Alam MM, Shaquiquzzaman M, Akhter M. Eur. J. Med. Chem. 2016; 123: 476
- 69 Kumar S, Kaur H, Saxena KK. Yeshowardhana Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2014; 53: 1596
- 70 Ummadi N, Gundala S, Venkatapuram P, Adivireddy P. Med. Chem. Res. 2017; 26: 1574
- 71 Cox CD, Breslin MJ, Mariano BJ, Coleman PJ, Buser CA, Walsh ES, Hamilton K, Huber HE, Kohl NE, Torrent M, Yan Y, Kuo LC, Hartman GD. Bioorg. Med. Chem. Lett. 2005; 15: 2041
- 72 Ismail MM. F, Shmeiss NA. M. M, El-Diwani HI, Arbid MS. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1997; 36: 288
- 73 Cocconcelli G, Diodato E, Caricasole A, Gaviraghi G, Genesio E, Ghiron C, Magnoni L, Pecchioli E, Plazzi PV, Terstappen GC. Bioorg. Med. Chem. 2008; 16: 2043
- 74 Sravanthi TV, Sajitha Lulu S, Vino S, Jayasri MA, Mohanapriya A, Manju SL. Med. Chem. Res. 2017; 26: 1306
- 75 Kim SH, Lee S, Kim SH, Kim KH, Kim JN. Bull. Korean Chem. Soc. 2013; 34: 3415
- 76 Hemamalini A, Nagarajan S, Das TM. Carbohydr. Res. 2011; 346: 1814
- 77 Mahmoodi NO, Ghodsi S. Res. Chem. Intermed. 2017; 43: 661
- 78 Kumar SV, Yadav SK, Raghava B, Saraiah B, Ila H, Rangappa KS, Hazra A. J. Org. Chem. 2013; 78: 4960
- 79 Butin AV, Uchuskin MG, Pilipenko AS, Serdyuk OV, Trushkov IV. Tetrahedron Lett. 2011; 52: 5255
- 80a Röeder E, Pigulla J. Arch. Pharm. (Weinheim, Ger.) 1978; 311: 817
- 80b Chavan RS, Khadke AP. Asian J. Chem. 2012; 24: 2711
- 81 Patil PO, Bari SB. Asian J. Chem. 2013; 25: 3588
- 82 Nenajdenko VG, Sanin AV, Tok OL, Balenkova ES. Khim. Geterotsikl. Soedin. 1999; 395 ; Chem. Heterocycl. Compd. 1999, 35, 348
- 83 El-Latif NA. A, Amr AE.-G. E, Ibrahiem AA. Monatsh. Chem. 2007; 138: 559
- 84 Sayed M, Kamal El-DeanA. M, Ahmed M, Hassanien R. J. Heterocycl. Chem. 2018; 55: 1166
- 85 Donohoe TJ, Bower JF, Baker DB, Basutto JA, Chan LK. M, Gallagher P. Chem. Commun. 2011; 47: 10611
- 86 Saundane AR, Vijaykumar K, Vaijinath AV. Bioorg. Med. Chem. Lett. 2013; 23: 1978
- 87 Mohamed SF, Hosni HM, Amr AE, Abdallad MM. Russ. J. Gen. Chem. 2016; 86: 672
- 88 Manna F, Chimenti F, Bolasco A, Bizzarri B, Filippelli W, Filippelli A, Gagliardi L. Eur. J. Med. Chem. 1999; 34: 245
- 89 Kidwai M, Thakur R, Saxena S. J. Heterocycl. Chem. 2005; 42: 1181
- 90 Kumar A, Sharma S, Tripathi VD, Maurya RA, Srivastava SP, Bhatia G, Tamrakar AK, Srivastava AK. Bioorg. Med. Chem. 2010; 18: 4138
- 91 Liu W, Zhao G. Org. Biomol. Chem. 2014; 12: 832
- 92 Kidwai M, Thakur R, Mohan R. Bull. Chem. Soc. Jpn. 2004; 77: 2265
- 93 Nofal ZM, Soliman EA, Abd El-Karim SS, Elzahar MI, Srour AM, Sethumadhavan S, Maher TJ. Acta Pol. Pharm. 2011; 68: 519
- 94 Giles D, Roopa K, Sheeba FR, Gurubasavarajaswamy PM, Divakar G, Vidhya T. Eur. J. Med. Chem. 2012; 58: 478
- 95 Agarwal A, Srivastava K, Puri SK, Chauhan PM. S. Bioorg. Med. Chem. Lett. 2005; 15: 3133
- 96 Singh TP, Khan R, Noh YR, Lee S.-G, Singh OM. Bull. Korean Chem. Soc. 2014; 35: 2950
- 97 Dandia A, Sehgal V, Upreti M. Phosphorus, Sulfur, Silicon, Relat. Elem. 1995; 105: 93
- 98a Tanitame A, Oyamada Y, Ofuji K, Fujimoto M, Iwai N, Hiyama Y, Suzuki K, Ito H, Terauchi H, Kawasaki M, Nagai K, Wachi M, Yamagishi J. J. Med. Chem. 2004; 47: 3693
- 98b Tanitame A, Oyamada Y, Ofuji K, Terauchi H, Kawasaki M, Wachi M, Yamagishi J. Bioorg. Med. Chem. Lett. 2005; 15: 4299
- 99 Tanitame A, Oyamada Y, Ofuji K, Suzuki K, Ito H, Kawasaki M, Wachi M, Yamagishi J. Bioorg. Med. Chem. Lett. 2004; 14: 2863
- 100 Costi R, Crucitti GC, Pescatori L, Messore A, Scipione L, Tortorella S, Amoroso A, Crespan E, Campiglia P, Maresca B, Porta A, Granata I, Novellino E, Gouge J, Delarue M, Maga G, Di Santo R. J. Med. Chem. 2013; 56: 7431
- 101 Obydennov DL, Pan’kina EO, Sosnovskikh VY. J. Org. Chem. 2016; 81: 12532
- 102 Sri Ramya PV, Angapelly S, Guntuku L, Digwal CS, Babu BN, Naidu VG. M, Kamal A. Eur. J. Med. Chem. 2017; 127: 100
- 103 Nakatani S, Yamamoto Y, Hayashi M, Komiyama K, Ishibashi M. Chem. Pharm. Bull. 2004; 52: 368
- 104 Hasegawa H, Yasuaki Y, Komiyama K, Hayashi M, Ishibashi M, Sunazuka T, Izuhara T, Sugahara K, Tsuruda K, Masuda M, Takasu N, Tsukasaki K, Tomonaga M, Kamihira S. Blood 2007; 10: 1664
- 105 Huang H, Wu W, Zhu K, Hu J, Ye J. Chem. Eur. J. 2013; 19: 3838
- 106 Caballero E, Alonso D, Peláez R, Álvarez C, Puebla P, Sanz F, Medarde M, Tomé F. Tetrahedron Lett. 2004; 45: 1631
- 107 Caballero E, Alonso D, Peláez R, Álvarez C, Puebla P, Sanz F, Medarde M, Tomé F. Tetrahedron 2005; 61: 6871
- 108 Caballero E, Longieras N, Zausa E, del Rey B, Medarde M, Tomé F. Tetrahedron Lett. 2001; 42: 7233
- 109 Caballero E, Figueroa J, Puebla P, Peláez R, Tomé F, Medarde M. Eur. J. Org. Chem. 2008; 4004
- 110 Eitel M, Pindur U. J. Org. Chem. 1990; 55: 5368
- 111 Conchon E, Anizon F, Aboab B, Prudhomme M. J. Med. Chem. 2007; 50: 4669
- 112 Arslan T, Sadak AE, Saracoglu N. Tetrahedron 2010; 66: 2936
- 113 Sadak AE, Arslan T, Celebioglu N, Saracoglu N. Tetrahedron 2010; 66: 3214
- 114 Reddy CR, Valleti RR, Dilipkumar U. Chem. Eur. J. 2016; 22: 2501
- 115a Knölker H.-J, Reddy KR. Chem. Rev. 2002; 102: 4303
- 115b Schmidt AW, Reddy KR, Knölker H.-J. Chem. Rev. 2012; 112: 3193
- 116 Sha F, Tao Y, Tang C.-Y, Zhang F, Wu X.-Y. J. Org. Chem. 2015; 80: 8122
- 117 Wu L, Huang H, Dang P, Liang Y, Pi S. RSC Adv. 2015; 5: 64354
- 118 Ozaki K, Zhang H, Ito H, Lei A, Itami K. Chem. Sci. 2013; 4: 3416
- 119 Chen W, Zhang H.-H, Luo Y.-C. Synlett 2015; 26: 1687
- 120 Zhang K, Xu X, Zheng J, Yao H, Huang Y, Lin A. Org. Lett. 2017; 19: 2596
- 121 For recent review, see: Rossi E, Abbiati G, Pirovano V. Eur. J. Org. Chem. 2017; 4512
- 122a Pindur U, Adam R. Helv. Chim. Acta 1990; 73: 827
- 122b Pindur U, Adam R. Heterocycles 1990; 31: 587
- 123a Sureshbabu R, Balamurugan R, Mohanakrishnan AK. Tetrahedron 2009; 65: 3582
- 123b Sureshbabu R, Mohanakrishnan AK. J. Heterocycl. Chem. 2012; 49: 913
- 124 Mohanakrishnan AK, Srinivasan PC. J. Org. Chem. 1995; 60: 1939
- 125 Erba E, Gelmi ML, Pocar D. Tetrahedron 2000; 56: 9991
- 126 Teuber H.-J, Schumann K, Reinehr U, Gholami A. Liebigs Ann. Chem. 1983; 1744
- 127 Teuber H.-J, Gholami A, Reinehr U, Bader H.-J. Liebigs Ann. Chem. 1979; 1048
- 128 Su T, Han X, Lu X. Tetrahedron Lett. 2014; 55: 27
- 129 Babu M, Pitchumani K, Ramesh P. Helv. Chim. Acta 2013; 96: 1269
- 130 Chen J, Morita H, Wakimoto T, Mori T, Noguchi H, Abe I. Org. Lett. 2012; 14: 3080
- 131 Xing Q, Li P, Lv H, Lang R, Xia C, Li F. Chem. Commun. 2014; 50: 12181
- 132 Hassanin HM, Ibrahim MA, Alnamer YA.-S. Turk. J. Chem. 2012; 36: 682
- 133 Ashok D, Rangu K, Gundu S, Lakkadi A, Tigulla P. Med. Chem. Res. 2017; 26: 1735
- 134 Ashok D, Srinivas G, Kumar AV, Gandhi DM. Russ. J. Bioorg. Chem. 2016; 42: 560
- 135 Yang H, Feng J, Tang Y. Chem. Commun. 2013; 49: 6442
- 136 Marsch N, Jones PG, Lindel T. Beilstein J. Org. Chem. 2015; 11: 1700
- 137 Lin T.-Y, Wu H.-H, Feng J.-J, Zhang J. ACS Catal. 2017; 7: 4047
- 138 Swaroop TR, Ila H, Rangappa KS. Tetrahedron Lett. 2013; 54: 5288
- 139a Venkatesan P, Maruthavanan T. Bull. Chem. Soc. Ethiop. 2011; 25: 419
- 139b Venkatesan P, Maruthavanan T. Asian J. Chem. 2011; 23: 2121
- 140 Sangeetha S, Muthupandi P, Sekar G. Org. Lett. 2015; 17: 6006
- 141 Yue G, Lei K, Hirao H, Zhou J. Angew. Chem. Int. Ed. 2015; 54: 6531
- 142 Kumar SV, Saraiah B, Misra NC, Ila H. J. Org. Chem. 2012; 77: 10752
For selected reviews, see:
For excellent reviews, see: