Dimethylformamide Acetals and Bredereck’s Reagent as Building Blocks in Natural Products Total Synthesis

Author(s): Franz Bracher*.

Journal Name: Mini-Reviews in Organic Chemistry

Volume 17 , Issue 1 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Dimethylformamide acetals and Bredereck’s reagent (tert-butoxy-bis(dimethylamino) methane) are versatile C1 building blocks due to their ability to undergo condensation reactions with CH-acidic methyl and methylene moieties. Subsequent modulation of the resulting condensation products enables the preparation of open-chain products like aldehydes, ketones, enones, enol ethers, methyl groups, and, most important in alkaloid total synthesis, the annulation of heterocyclic rings like pyridines, pyridine-N-oxides, bromopyridines, aminopyridines, aminopyrimidines, pyrroles and chromenones. In certain cases, these reagents can act as alkylating agents. The applications of these building blocks in natural products total synthesis are reviewed here.

Keywords: Alkaloid, annulation, Bredereck's reagent, condensation, cyclization, dimethylformamide acetal, indole, naphthyridine, pyridoacridine, total synthesis.

Meerwein, H.; Borner, P.; Fuchs, O.; Sasse, H.J.; Schrodt, H.; Spille, J. Reaktionen mit alkylkationen. Ber. Dtsch. Chem. Ges., 1956, 89(9), 2060-2079.
Abdulla, R.F.; Brinkmeyer, R.S. The chemistry of formamide acetals. Tetrahedron, 1979, 35(14), 1675-1735.
Lloyd, D.H.; Nichols, D.E. Nickel boride/hydrazine hydrate reduction of aromatic and aliphatic nitro compounds. Synthesis of 4-(benzyloxy)indole and alpha-alkyltryptamines. J. Org. Chem., 1986, 51(22), 4294-4295.
Rosso, G.B. tert-Butoxy Bis(dimethyl-amino)methane (Bredereck’s reagent). Synlett , 2006, 5, 0809-0810
Haefliger, W.; Knecht, H. Benz[c,d]indoles - I. The use of tert-butoxy-bis(dimethylamino)methane as condensation reagent. Tetrahedron Lett., 1983, 25(3), 285-288.
Abu-Shanab, F.A.; Sherif, S.M.; Mousa, S.A.S. Dimethylformamide dimethyl acetal as a building block in heterocyclic synthesis. J. Heterocycl. Chem., 2009, 46(5), 801-827.
Stanovnik, B.; Tisler, M.; Hribar, A.; Barlin, G.B.; Brown, D.J. Methylation of heterocyclic compounds containing NH, SH and/or OH groups by means of N,N-dimethylformamide dimethyl acetal. Aust. J. Chem., 1981, 34(8), 1729-1738.
Gaber, H.M.; Muhammad, Z.A.; Gomha, S.M.; Farghaly, T.A.; Bagley, M.C. Recent Synthetic approaches to N,N-dimethyl-β-ketoenamines. Curr. Org. Chem., 2017, 21(21), 2168-2195.
Gaber, H.M.; Bagley, M.C.; Muhammad, Z.A.; Gomha, S.M. Recent developments in chemical reactivity of N,N-dimethylenamino ketones as synthons for various heterocycles. RSC Advances, 2017, 7(24), 14562-14610.
Rossignol, E.; Youssef, A.; Moreau, P.; Prudhomme, M.; Anizon, F. Synthesis of aminopyrimidylindoles structurally related to meridianins. Tetrahedron, 2007, 63(41), 10169-10176.
Swarts, H.J.; Verstegen-Haaksma, A.A.; Jansen, B.J.M.; de Groot, A. Total synthesis of drimane sesquiterpenes from S-(+)-carvone (part 5). Tetrahedron, 1994, 50(33), 10083-10094.
Katoh, T.; Nagata, Y.; Kobayashi, Y.; Arai, K.; Minami, J.; Terashima, S. Enantioselective synthesis of 5-substituted- and 3,5-disubstituted-2-formylpyrrolidine derivatives, the key D-ring fragments of (−)-quinocarcin and (−)-10-decarboxyquinocarcin. Tetrahedron Lett., 1993, 34(36), 5743-5746.
Duhamel, P.; Kotera, M.; Monteil, T. New piperidinic synthons via ring contraction. Formal synthesis of (±)-perhydrohistrionicotoxin. Bull. Chem. Soc. Jpn., 1986, 59, 2353-2355.
Gutzwiller, J.; Pizzolato, G.; Uskoković, M.R. Total synthesis of racemic ajmalicine and 19-epi-ajmalicine. Helv. Chim. Acta, 1981, 64(5), 1663-1671.
Loegers, M.; Overman, L.E.; Welmaker, G.S. Mannich biscyclizations. Total synthesis of (-)-ajmalicine. J. Am. Chem. Soc., 1995, 117(36), 9139-9150.
Peng, J.; Clive, D.L. Asymmetric synthesis of the ABC-ring system of the antitumor antibiotic MPC1001. J. Org. Chem., 2009, 74(2), 513-519.
[http://dx.doi.org/10.1021/jo802344t] [PMID: 19067592]
Bracher, F.; Hildebrand, D. β‐carbolin‐alkaloide, II. Tributyl(1‐ethoxyvinyl)stannan als C2‐Baustein für die synthese von β‐carbolin‐alkaloiden. Liebigs Ann. Chem., 1993, (8), 837-839.
Puzik, A.; Bracher, F. A convenient approach to the canthin-4-one ring system: Total synthesis of the alkaloids tuboflavine and norisotuboflavine. J. Heterocycl. Chem., 2009, 46(4), 770-773.
Strödke, B.; Gehring, A.P.; Bracher, F. Synthesis of desaza analogues of annomontine and canthin-4-one alkaloids. Arch. Pharm. (Weinheim), 2015, 348(2), 125-131.
[http://dx.doi.org/10.1002/ardp.201400328] [PMID: 25664630]
Puzik, A.; Bracher, F. New polycyclic ring systems derived from canthin-4-one. J. Heterocycl. Chem., 2010, 47(2), 449-453.
Fresnada, P.M.; Molina, P.; Delgado, S.; Bleda, J.A. Synthetic studies towards the 2-aminopyrimidine alkaloids variolins and meridianins from marine origin. Tetrahedron Lett., 2000, 41, 4777-4780.
Fresnada, P.M.; Molina, P.; Bleda, J.A. Synthesis of the indole alkaloids meridianins from the tunicate Aplidium meridianum. Tetrahedron, 2001, 57, 2355-2363.
Molina, P.; Fresnada, P.M.; Delgado, S.; Bleds, J.A. Synthesis of the potent marine alkaloid variolin B. Tetrahedron Lett., 2002, 43, 1005-1007.
Molina, P.; Fresneda, P.M.; Delgado, S. Carbodiimide-mediated preparation of the tricyclic pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine ring system and its application to the synthesis of the potent antitumoral marine alkaloid variolin B and analog. J. Org. Chem., 2003, 68(2), 489-499.
[http://dx.doi.org/10.1021/jo026508x] [PMID: 12530876]
Walker, S.R.; Carter, E.J.; Huff, B.C.; Morris, J.C. Variolins and related alkaloids. Chem. Rev., 2009, 109(7), 3080-3098.
[http://dx.doi.org/10.1021/cr900032s] [PMID: 19489543]
Bharate, S.B.; Yadav, R.R.; Battula, S.; Vishwakarma, R.A. Meridianins: Marine-derived potent kinase inhibitors. Mini Rev. Med. Chem., 2012, 12(7), 618-631.
[http://dx.doi.org/10.2174/138955712800626728] [PMID: 22512550]
Wasserman, H.H.; Ives, J.L. A novel method for converting ketones to α-diketones. The reaction of enamino ketones with singlet oxygen. J. Am. Chem. Soc., 1976, 98(24), 7868-7869.
De Bernardi, M.; Mellerio, G.; Vidari, G.; Vita-Finzi, P.; Fronza, G. Fungal metabolites. Part 15. Structure and chemical correlations of uvidin C, D, and E, new drimane sesquiterpenes from Lactarius uvidus Fries. J. Chem. Soc. Perkin Trans, 1983, 2739-2743.
Katsumura, S.; Kimura, A.; Isoe, S. Total synthesis of (±)−jolkinolide A, B, and E utilizing a new mild esterification followsd by intramolecular Wittig-Horner reaction. Tetrahedron, 1989, 45(5), 1337-1346.
Nakahara, S.; Kubo, A. Total synthesis of styelsamine C (I), and formal synthesis of norsegoline (II). Heterocycles, 2005, 65(8), 1925-1929.
Müller, C.; Wagner, A.L.; Rockinger, U.; Winter, G.; Bracher, F. Development of a convenient method for the determination of dimethyl sulfoxide in lyophilised pharmaceuticals by static headspace gas chromatography – mass spectrometry. Anal. Methods, 2019, 11, 2119-2122.
Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. Total synthesis of ingenol. J. Am. Chem. Soc., 2003, 125(6), 1498-1500.
[http://dx.doi.org/10.1021/ja029226n] [PMID: 12568608]
Taniguchi, T.; Tanabe, G.; Muraoka, O.; Ishibashi, H. Total synthesis of (+/-)-stemonamide and (+/-)-isostemonamide using a radical cascade. Org. Lett., 2008, 10(2), 197-199.
[http://dx.doi.org/10.1021/ol702563p] [PMID: 18092788]
Murai, A.; Tanimoto, N.; Sakamoto, N.; Masamune, T. Total synthesis of glycinoeclepin A. J. Am. Chem. Soc., 1988, 110(6), 1985-1986.
Schlessinger, R.H.; Schultz, J.A. Stereoselective synthesis of racemic trichodiene. J. Org. Chem., 1983, 48(3), 407-408.
August, R.A.; Khan, J.A.; Moody, C.M.; Young, D.W. Stereospecific synthesis of (2S,4R)-[5,5,5-2H3]leucine. J. Chem. Soc., Perkin Trans. 1, 1996, (6), 507-514.
Coudert, E.; Acher, F.; Azerad, R. A convenient and efficient synthesis of (2S,4R)- and (2S,4S)-4-methylglutamic acid. Synthesis, 1997, (08), 863-865.
Shimokawa, J.; Harada, T.; Yokoshima, S.; Fukuyama, T. Total synthesis of gelsemoxonine. J. Am. Chem. Soc., 2011, 133(44), 17634-17637.
[http://dx.doi.org/10.1021/ja208617c] [PMID: 21980918]
Hutchinson, J.H.; Money, T. An enantiospecific synthesis of estrone. Tetrahedron Lett., 1985, 26(15), 1819-1822.
Chen, X-T.; Gutteridge, C.E.; Bhattacharya, S.K.; Zhou, B.; Pettus, T.R.R.; Hascall, T.; Danishefsky, S.J. A convergent route for the total synthesis of the eleuthesides. Angew. Chem., 1998, 37(1‐2), 185-186.
Batcho, A.D.; Leimgruber, W. Indoles from 2-methylnitrobenzenes by condensation with formamide acetals followed by reduction: 4-Benzyloxyindole. Org. Synth., 1985, 63, 214.
Siu, J.; Baxendale, I.R.; Ley, S.V. Microwave assisted Leimgruber-Batcho reaction for the preparation of indoles, azaindoles and pyrroylquinolines. Org. Biomol. Chem., 2004, 2(2), 160-167.
[http://dx.doi.org/10.1039/B313012F] [PMID: 14737637]
Ikoma, M.; Oikawa, M.; Sasaki, M. Synthetic studies on dragmacidin D: Synthesis of the left-hand fragment. Tetrahedron Lett., 2008, 49(50), 7197-7199.
Nakahara, S.; Kubo, A.; Mikami, Y.; Mitani, H. Synthesis of arnoamine B (IV) and related compounds (V). Heterocycles, 2007, 71(8), 1801-1806.
Kozikowski, A.P.; Greco, M.N.; Springer, J.P. Synthetic studies in the indole series. Preparation of the unique antibiotic alkaloid chuangxinmycin by a nitro group displacement reaction. J. Am. Chem. Soc., 1982, 104(26), 7622-7626.
Brenneisen, R.; Borner, S.; Peter-Oesch, N.; Schlunegger, U.P. Synthesis of baeocystin, a natural psilocybin analogue. Arch. Pharm. (Weinheim), 1988, 321(8), 487-489.
Chandrasoma, N.; Brown, N.; Brassfield, A.; Nerurkar, A.; Suarez, S.; Buszek, K.R. Total synthesis of (±)-cis-trikentrin B via intermolecular 6,7-indole aryne cycloaddition and Stille cross-coupling. Tetrahedron Lett., 2013, 54(8), 913-917.
[http://dx.doi.org/10.1016/j.tetlet.2012.11.125] [PMID: 25278636]
Somei, M.; Inoue, S.; Tokutake, S.; Yamada, F.; Kaneko, C. The chemistry of indoles. XIII. Syntheses of substituted indoles carrying an amino, nitro, methoxycarbonyl, or benzyloxy group at the 4-position and their 1-hydroxy derivatives. Chem. Pharm. Bull. (Tokyo), 1981, 29(3), 726-738.
Tsotinis, A.; Eleutheriades, A.; Hough, K.; Sugden, D. Design and synthesis of potent N1-substituted indole melatonin receptor agonists. Chem. Comm, 2003, (3), 382-383.
Bracher, F. Polycyclische aromatische alkaloide, I. Synthese von cleistopholin und sampangin. Liebigs Ann. Chem., 1989, (1), 87-88.
Claes, P.; Cappoen, D.; Mbala, B.M.; Jacobs, J.; Mertens, B.; Mathys, V.; Verschaeve, L.; Huygen, K.; De Kimpe, N. Synthesis and antimycobacterial activity of analogues of the bioactive natural products sampangine and cleistopholine. Eur. J. Med. Chem., 2013, 67, 98-110.
[http://dx.doi.org/10.1016/j.ejmech.2013.06.010] [PMID: 23850570]
Jiang, Z.; Liu, N.; Dong, G.; Jiang, Y.; Liu, Y.; He, X.; Huang, Y.; He, S.; Chen, W.; Li, Z.; Yao, J.; Miao, Z.; Zhang, W.; Sheng, C. Scaffold hopping of sampangine: Discovery of potent antifungal lead compound against Aspergillus fumigatus and Cryptococcus neoformans. Bioorg. Med. Chem. Lett., 2014, 24(17), 4090-4094.
[http://dx.doi.org/10.1016/j.bmcl.2014.07.064] [PMID: 25115626]
Mink, K.; Bracher, F. Hetero analogues of the antimicrobial alkaloids cleistopholine and sampangine. Arch. Pharm. (Weinheim), 2007, 340(8), 429-433.
[http://dx.doi.org/10.1002/ardp.200700064] [PMID: 17628034]
Appleton, D.R.; Pearce, A.N.; Copp, B.R. Anti-Tuberculosis natural products: Synthesis and biological evaluation of pyridoacridine alkaloids related to ascididemin. Tetrahedron, 2010, 66(27), 4977-4986.
Bracher, F. Polycyclische aromatische Alkaloide, 2.Mitt. Synthese von Onychin und Eupolauridin. Arch. Pharm. (Weinheim), 1989, 322(5), 293-294.
Pan, E.; Cao, S.; Brodie, P.J.; Callmander, M.W.; Randrianaivo, R.; Rakotonandrasana, S.; Rakotobe, E.; Rasamison, V.E.; TenDyke, K.; Shen, Y.; Suh, E.M.; Kingston, D.G. Isolation and synthesis of antiproliferative eupolauridine alkaloids of Ambavia gerrardii from the Madagascar Dry Forest. J. Nat. Prod., 2011, 74(5), 1169-1174.
[http://dx.doi.org/10.1021/np200093n] [PMID: 21504145]
Bracher, F. Polycyclic aromatic alkaloids. 9. Synthesis and antifungal activity of diazafluoroanthene alkaloids. Pharmazie, 1993, 48(7), 521-523.
[PMID: 8415849]
Plodek, A.; Bracher, F. New perspectives in the chemistry of marine pyridoacridine alkaloids. Mar. Drugs, 2016, 14(2)E26
[http://dx.doi.org/10.3390/md14020026] [PMID: 26821033]
Bracher, F. Total Synthesis of the pentacyclic alkaloid ascididemin. Heterocycles, 1989, 29, 2093-2095.
Bracher, F. Polycyclische aromatische alkaloide, v. synthese von 2-bromleptoclinidinon. Liebigs Ann. Chem., 1990, 2, 205-206.
Bracher, F. Polycyclic Aromatic Alkaloids, 8. The structure of neocalliactine acetate - proof by total synthesis. Liebigs Ann., 1992, (11), 1205-1207.
Nakahara, S.; Tanaka, Y.; Kubo, A. Total synthesis of eilatin (I). Heterocycles, 1993, 36(5), 1139-1144.
Plodek, A.; Bracher, F. A divergent approach to the total synthesis of the marine pyridoacridine alkaloid eilatin and its synthetic isomer isoeilatin. Tetrahedron Lett., 2015, 56(11), 1445-1447.
Bracher, F.; Mink, K. First total synthesis of the 2,7-naphthyridine alkaloid neozeylanicine and unexpected formation of isoquinolines from ethoxyvinyl pyridines. Liebigs Ann. Chem., 1995, (4), 645-647.
Bracher, F. Polycyclische aromatische Alkaloide, 3. Mitt.: Synthese von Perlolidin. Arch. Pharm. (Weinheim), 1989, 322(8), 511-512.
Bracher, F.; Papke, T. Polycyclic aromatic alkaloids, XI. A convenient formal total synthesis of the cytotoxic marine alkaloid amphimedine. Liebigs Ann., 1996, 115-116
Raeder, S.; Bracher, F. A novel approach to the pyridoacridine ring system: Synthesis of the topoisomerase inhibitor 13-deazaascididemin. Arch. Pharm. (Weinheim), 2012, 345(10), 822-826.
[http://dx.doi.org/10.1002/ardp.201200019] [PMID: 22760790]
Lotter, M.; Schilling, J.; Reimann, E.; Bracher, F. First total synthesis of the 2,7-naphthyridine alkaloids lophocladine a and B. Arch. Pharm. (Weinheim), 2006, 339(12), 677-679.
[http://dx.doi.org/10.1002/ardp.200600134] [PMID: 17109463]
Zhang, A.; Ding, C.; Cheng, C.; Yao, Q. Convenient synthesis of 2,7-naphthyridine Lophocladines A and B and their analogues. J. Comb. Chem., 2007, 9(6), 916-919.
[http://dx.doi.org/10.1021/cc700135h] [PMID: 17927143]
Fedorov, O.; Huber, K.; Eisenreich, A.; Filippakopoulos, P.; King, O.; Bullock, A.N.; Szklarczyk, D.; Jensen, L.J.; Fabbro, D.; Trappe, J.; Rauch, U.; Bracher, F.; Knapp, S. Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing. Chem. Biol., 2011, 18(1), 67-76.
[http://dx.doi.org/10.1016/j.chembiol.2010.11.009] [PMID: 21276940]
Villemin, D.; Cheikh, N.; Liao, L.; Bar, N.; Lohier, J-F.; Sopkova, J.; Choukchou-Braham, N.; Mostefa-Kara, B. Two versatile routes towards Cerpegin and analogues: Applications of a one pot reaction to new analogues of Cerpegin. Tetrahedron, 2012, 68(24), 4906-4918.
Wetzel, I.; Allmendinger, L.; Bracher, F. Revised structure of the alkaloid drymaritin. J. Nat. Prod., 2009, 72(10), 1908-1910.
[http://dx.doi.org/10.1021/np900515b] [PMID: 19848436]
Tois, J.; Vahermo, M.; Koskinen, A. Novel and convenient synthesis of 4(1H)quinolones. Tetrahedron Lett., 2005, 46(5), 735-737.
Sun, Q-H.; Zhang, Y.; Chou, G-X. Synthesis and anti-obesity effects in vivo of Crotadihydrofuran C as a novel PPARγ antagonist from Crotalaria albida. Sci. Rep., 2017, 7, 46735.
[http://dx.doi.org/10.1038/srep46735] [PMID: 28436456]
Plodek, A.; Raeder, S.; Bracher, F. Regioselective homolytic substitution of benzo[c][2,7]naphthyridines. Tetrahedron, 2012, 68(24), 4693-4700.
Plodek, A.; König, M.; Bracher, F. Synthesis of the azaoxoaporphine alkaloid sampangine and ascididemin-Type pyridoacridines through TMPMgCl·LiCl‐mediated ring closure. Eur. J. Org. Chem., 2015, 1302-1308.
Tyrrell, N.D.; Tremayne, N.; Evans, G.R. Process for preparing 1- halo-2,7-naphthyridinyl derivatives. US 20090221828 A1, September 3, 2009.
Baldwin, J.J.; Mensler, K.; Ponticello, G.S. A novel naphthyridinone synthesis via enamine cyclization. J. Org. Chem., 1978, 43(25), 4878-4880.
Sureshbabu, R.; Balamurugan, R.; Mohanakrishnan, A.K. Synthesis of substituted carbazoles via electrocyclization of in situ generated enamines from 1-phenylsulfonyl-2/(3)-methyl-3/(2)-vinylindoles and DMF·DMA/ DMA·DMA. Tetrahedron, 2009, 65(18), 3582-3591.
Sureshbabu, R.; Mohanakrishnan, A.K. An improved synthesis of carbazoles via domino reaction of N-protected-2-methylindoles with DMF-DMA/DMA-DMA. J. Heterocycl. Chem., 2012, 49(4), 913-918.
Boisse, T.; Gautret, P.; Rigo, B.; Goossens, L.; Hénichart, J-P.; Gavara, L. A new synthesis of pyrrolo[3,2-b]quinolines by a tandem electrocyclization–oxidation process. Tetrahedron, 2008, 64(30-31), 7266-7272.
Alazard, J.P.; Brayer, J.L.; Thal, C. Alcaloides monoterpeniques I. Fonctionnalisations regioselectives de la N-methyl cyclopentadienyl-2-propylamine. Tetrahedron, 1990, 46(5), 1587-1598.
Fang, F.G.; Feigelson, G.B.; Danishefsky, S.J. A total synthesis of magallanesine: DMF acetal mediated cyclodehydration of a methyl ketone thioimide. Tetrahedron Lett., 1989, 30(21), 2743-2746.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [47 - 66]
Pages: 20
DOI: 10.2174/1570193X16666181204122143
Price: $65

Article Metrics

PDF: 22