1450 Send Orders for Reprints to [email protected] Mini-Reviews in Medicinal Chemistry, 2016 , 16, 1450-1461 REVIEW ARTICLE ISSN: 1389-5575 eISSN: 1875-5607 Impact The Chemistry of Galanthamine. Classical Synthetic Methods and Factor: 2.841 Comprehensive Study on its Analogues BENTHAM SCIENCE Péter Keglevich, Csaba Szántay and László Hazai* Department of Organic Chemistry and Technology, University of Technology and Economics, Budapest, Hungary, H-1111 Budapest, Gellért tér 4. Hungary Abstract: Galanthamine as an Amaryllidaceae alkaloid has an important role in the treatment of Alzheimer’s disease. Some efforts were made to elaborate the total A R T I C L E H I S T O R Y synthesis, and hundreds of its derivatives were prepared to find a more effective molecule with advantageous properties. Moreover, almost every part of the Received: September 22, 2015 Revised: January 07, 2016 tetracycle was changed; in members of the rings, in the nature and position of the Accepted: February 30, 2016 heteroatoms, and ring-opened analogues were also synthesized. In this review the DOI: basic synthetic works and the most important derivatives and analogues are 10.2174/13895575166661603211145 overviewed. 56 L. Hazai Keywords: Acetylcholinesterase inhibition, Alzheimer’s disease, butyrylcholinesterase inhibitor, galanthamine, hexahydrobenzofurobenzazepine, structural analogues. 1. INTRODUCTION galanthamine review [3] 3.97 μM is given for IC50, while in a letter published in 2008, however, this value was 1.82 μM 1.1. Galanthamine and Related Amaryllidaceae Alkaloids [11]. While sanguinine (3) is more effective in the AChE (-)-Galanthamine (1), (-)-lycoramine (2), (-)-sanguinine inhibitory activity [11], in fact, galanthamine (1) has come to (3) and their precursor (-)-narwedine (4) (Fig. 1) belong to the front in the treatment of Alzheimer’s disease, because the the family of Amaryllidaceae alkaloids [1]. Among the physiological activity is unfavourably influenced by the Amaryllidaceae alkaloids the acetylcholinesterase (AcChE) phenolic hydroxyl group in the aromatic ring of sanguinine inhibitory activity can be connected to the structures (3). containing galanthamine or galanthamine-like skeleton. Galanthamine (1) is used in the form of hydrobromide Furthermore, it was pointed out, that galanthamine (1) has salt (Nivalin, Reminyl, Razadyne) as a medicine in several butyrylcholinesterase (BuChE) activity as well [2]. countries, e.g. in Austria, in Sweden, or in England. The Nevertheless, galanthamine (1) has an important role in the clinical investigations in connection with galanthamine (1) modulation of nicotine receptors in the brain. are in the last phase all over Europe and also in the United The chemistry, biological properties [3, 4] and States. The important effect of galanthamine (1) in the biosynthesis [5] of galanthamine (1) were reviewed. course of the treatment of Alzheimer’s disease proves to Attempts in developing biotechnology as an alternative retard the progression of the trouble. This compound has a process for galanthamine production [6-8] and in silico unique positive influence to the cognitive activities (learning, screening with molecular docking [9] on its derivatives as remembering, etc.), to the everyday actions and to the potential cholinesterase inhibitors were also investigated. psychological confusions and disturbances. For the IC50 values of the AChE inhibitory effect of Galanthamine (1) has been discovered and isolated from galanthamine (1) there are data in the literature between 1 Galanthus woronowii, but for commercial needs it is and 5 μM, respectively, e.g. in a work [10] from 2006 obtained synthetically or by extraction from Narcissus spp. presenting natural compounds with acetylcholinesterase and Leucojum spp. [5]. The clinical indication is getting inhibitory activity, IC50 1.07 μM can be found. In a more and more topical, the increasing needs, the high cost and the restricted supply of the material justify the efforts of *Address correspondence to this author at the Department of Organic different research laboratories to elaborate efficient industrial Chemistry and Technology, University of Technology and Economics, synthetic procedures, as well as to synthesize new Budapest, Hungary, H-1111 Budapest, Gellért tér 4. Hungary; Tel: +36-1- derivatives with modification of the structure of 463-2208; Fax: +36-1-463-3297; E-mail: [email protected] galanthamine (1). 1875-5607/16 $58.00+.00 © 2016 Bentham Science Publishers Mini-Reviews in Medicinal Chemistry The Chemistry of Galanthamine Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 18 1451 OH OH OH O 6 5 c 7 4a 8a 8 10 4 O b N CH3 O N CH3 O N CH3 O N CH3 9 d 11 a 12 H CO 3 1 H CO HO H CO 3 2 3 3 (-)-1 (-)-2 (-)-3 (-)-4 galanthamine sanguinine lycoramine narwedine Fig. (1). The most important Amarylidaceae alkaloids. ring using L-Selectride, (-)-galantamine (1) could be 2. SYNTHESIS AND STRUCTURAL MODIFICA- isolated. TIONS OF GALANTHAMINE AND GALANTHA- MINE DERIVATIVES Node and co-workers [14] also used the method of biomimetic phenolic oxidative coupling. They synthesized 2.1. Synthesis of Galanthamine (-)-galanthamine (1) by means of a remote asymmetric In the course of the synthesis of galanthamine (1) most of induction where conformation of the seven-membered the known synthetic methods involved the biomimetic azepine ring after the coupling reaction was restricted by intramolecular phenolic oxidation to form the quaterner forming a fused chiral imidazolidinon ring. carbon atom resulting in the tetracycle of the galanthamine Among the new synthetic methods for galanthamine (1), skeleton. In developing this procedure the work of Barton the use of Heck-reaction is a very important and elegant [12] played an important role. The next synthesis can be procedure. In the course of the enantioselective synthesis carried out in kilogram scale and presented here [13] as a elaborated by Trost and his research group [15, 16], the classic based on its results. azepine ring was closured after the formation of the a-b-c In the first step, 3,4-dimethoxybenzaldehyde (5) was tricycle containing the benzofurane skeleton obtained by brominated (Scheme 1), then the demethylation reaction of Heck reaction. The starting materials were 2- the bromo-substituted aldehyde (6) resulted in the 6- bromoisovanilline (13) and a cyclohexenol ester (14) bromoisovanilline (7). After condensation of 7 with substituted by trichloroethoxycarbonyl group. The reaction tyramine, Schiff-base (8) was obtained. The reduction of 8 between 13 and 14 in the presence of a palladium catalyst and formylation of saturated amine (9) gave the N-formyl and a chiral ligand (15) resulted in the aryl ether (16) derivative (10). (Scheme 3). The oxidative cyclisation of compound 10 resulted in the Then, the aldehyde function was protected with bromo-formyl-narwedine (11) (Scheme 2). The keto group triethylorthoformate and the ester group was reduced by of 11 was protected with propylene glycol as a ketal, and DIBALH to the corresponding alcohol (17). The unsaturated after reduction of compound 12 racemic narwedine (4) was nitrile (18) was prepared by the modified Mitsunobu obtained. Second-order asymmetric transformation of reaction, and the aldehyde was deprotected. Heck reaction of racemic narwedine (4) in the presence of catalytic amount of compound 18 resulted in the benzofurane (19) which was (-)-narwedine (4) gave the corresponding (-)-narwedine ((-)- oxidized with selenium dioxide under vigorous reaction 4). After reduction of the carbonyl group of the cyclohexene conditions, and in this reaction the 20 hydroxy compound OCH3 OCH3 OH H3CO H3CO H3CO Br2 cc. H2SO4 tyramine MeOH CHO CHO CHO Br Br 5 6 7 OH OH OH OH OH OH H3CO NaBH4 H3CO HCO2C2H5 H3CO N NH N CHO Br Br Br 8 9 10 Scheme (1). Preparation of intermediates for a classical galanthamine synthesis. 1452 Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 18 Keglevich et al. OH CH3 O O O OH propane-1,2-diol 1. LiAlH4 H3CO K3[Fe(CN)6] O N CHO O N CHO 2. HCl N CHO H3CO Br Br H3CO Br 10 11 12 O O OH EtOH/NEt3 L-Selectride O N CH3 O N CH3 O N CH3 cat. (-)-narwedine H3CO H3CO H3CO 4; racemic narwedine (-)-4 (-)-1 Scheme (2). The cyclisation step and second-order asymmetric transformation. OH H3CO Br η3 15, [ -C3H5PdCl2]2 O CO CH + TrocO 2 3 Et N, CH Cl , rt H3CO Br CHO CO2CH3 3 2 2 CHO 13 14 16 Ph Ph O O Troc: 2,2,2-trichloroethoxycarbonyl NH HN η3 [ -C3H5PdCl2]2: allylpalladium chloride dimer 15: PPh2 Ph2P Scheme (3). The Trost’s synthetic method. 1. CH(OCH3)3 p-TsOH, MeOH 16 O 1. Ph3P, acetone cyanohydrin, O 2. DIBAL-H, OH CN H3CO Br DIAD, Et2O H3CO Br toluene, -78oC 2. TsOH, THF, H2O CH(OCH3)2 CHO 17 18 OH H H O SeO2, NaH2PO4, O Pd(OAc)2, dppp, o H3CO 1,4-dioxane, 150 C, H3CO o CN Ag2CO3, toluene, 107 C CN sealed tube, quartz sand CHO CHO 19 20 OH H DIAD: diisopropyl azodicarboxilate one-pot reaction: O N CH 3 dppp: 1,3-bis(diphenylphosphino)propane 1. CH3-NH2, MeOH 2. DIBAL-H, then NaH2PO4 H3CO 3. NaCNBH3 (-)-1 Scheme (4). Enantioselective synthesis using Mitsunobu and Heck reaction. The Chemistry of Galanthamine Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 18 1453 was obtained, in which the configuration of the hydroxy A derivative containing one carbon carbon double bond group was the same as in the galanthamine. After all, (28) was obtained by the oxidation of cyclohexanone (26) galanthamine (1) was obtained in a one-pot reaction as using o-iodoxybenzoic acid; however, in this way, the presented in Scheme 4. Reaction with methylamine in second C=C double bond could not be introduced into the methanol, reduction with DIBALH, and then reaction with cyclohexane ring. The α,β-unsaturated ketone (28) was sodium cyanoborohydride resulted in the product.