UvA-DARE (Digital Academic Repository) Novel parallel synthesis routes to nitrogen heterocycles via N-acyliminium ions. Veerman, J.J.N. Publication date 2002 Link to publication Citation for published version (APA): Veerman, J. J. N. (2002). Novel parallel synthesis routes to nitrogen heterocycles via N- acyliminium ions. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:08 Oct 2021 CHAPTERR 5 2,6-BRIDGEDD 3-KETOPIPERAZINES VIA N-ACYLIMINIUM ION CHEMISTRY 5.11 Introduction Severall human mood disorders such as depression and schizophrenia are (mainly) causedd by malfunctions in the central nervous system (CNS), which result in neurotransmitterr disregulation. The treatment of (some symptoms of) these diseases involves thee blocking (by antagonists) or stimulation (by agonists) of certain neurotransmitter receptorss (Chart 5.1). Chartt 5.1 1,, haloperidol 2,, fluoxetine Thee blocking of the D2-dopamine receptors in the prefrontal cortex, for example, can bee achieved with haloperidol (1), that is used in the treatment of psychosis.1 The reuptake of serotoninee (3) can be effectively blocked using fluoxetine (2, Prozac®) in the treatment of depression,, eventually leading to higher concentrations of serotonine in the brain.2 A general structurall element found in neurotransmitters such as serotonine (3) and dopamine (4) is the arylethylaminee moiety 5 (Chart 5.2). Chartt 5.2 HO O NH, , % %n nNH , , N N HO O „^ ^ H H QQ 0 HNN N Ar—XX NR ^^ // 8,, X = CH, N Likee haloperidol, many drugs and other bioactive compounds showing CNS activity {i.e.{i.e. eltoprazine (6), flesinoxan (7)) contain an arylpiperidine or arylpiperazine moiety 8.3 77 77 ChapterChapter 5 Thesee structural elements are widely used in CNS research as a bioisosteric replacement for thee arylethylamine moiety in neurotransmitters.4 Chartt 5.3 NH, , PhO O MeO O V^V^N N NC-- jT% jT% N =// N -0 0 MeCT^^N^ ^ ^ ^ r) ) 9,, prazosin O 10 0 Substitutedd piperazines are not only found in CNS active drugs. (Chart 5.3). An examplee is prazosin (9),5 which is used to lower the blood pressure. The 1,4-disubstituted 3- ketopiperazinee 10 is a dual inhibitor of farnesyl transferase/geranyl geranyltransferase I and iss used as a cancer chemotherapeutic agent.6 Consideringg the importance of the piperazine scaffold in a broad range of applications,, we anticipated that it might be worthwhile to rigidity the piperazine core, whichh might provide valuable insight into the biologically active conformation. One way to achievee an enhanced rigidity is by introducing a 2,6-bridge over the piperazine ring, thus loweringg its conformational freedom. In this chapter a very efficient method towards 2,6- bridgedd piperazines is described based on Af-acyliminium ion chemistry. The general retrosyntheticc analysis is depicted in Scheme 5.1. 11 1 12 2 Nu u O O 1 x x R 00 N' "C02H H H 17 7 <= = PGG O OMe e tAtAyKm yKm OO R R R 16 6 15 5 78 8 2,6-Bridged2,6-Bridged 3-ketopiperazines via N-acyliminium ion chemistry Thee desired 2,6-bridged 3-ketopiperazines 11 should be accessible by intramolecular nucleophilicc attack of the side chain at the 2-position onto the transient N-acylirniniurn ion 1277 This irninium ion intermediate will be formed via acid-induced heterolysis of the correspondingg amino alcohol 13, which in turn can be obtained by a chemoselective reductionn of the activated C6 carbonyl of diketopiperazine 14. Finally, these diketopiperaziness should be readily formed upon straightforward condensations of the suitablyy protected commercially available amino acids 16 and 17. The aim of this investigationn was twofold: (i) to determine what type of nucleophiles could be used for the cyclisationn reaction, and (ii) to study the possibilities to stereoselectively introduce groups at thee 5-position of the final ketopiperazine 11. Chartt 5.4 18,, ecteinascidin 743 19, saframycin A 20, quinocarcin A Interestingly,, the 2,6-bridged piperazine moiety is encountered as a key structural elementt in several natural products (Chart 5.4). Examples are the safracins,8 ecteinascidins 18,99 saframycins 1910 and quinocarcin A (20).n All of these compounds show antitumour or antibioticc activity, of which the ecteinascidins 18 are most potent. Remarkably, in all cases thee substituent at the C5-position has a ris-relationship with the 2,6-bridging substituent. In totall syntheses of these natural products the bridge was usually constructed via an N- acyliminiumm ion cyclisation. AA typical example is the synthesis of the tricyclic core of saframycin by Sakai et al. as depictedd in Scheme 5.2.6 In a study to determine the optimal conditions for the conversion of precursorr 21 into the cyclic product 22, the best results were obtained by reduction of the isopropyll carbamate activated endocyclic imide with lithium tri-terf-butoxy aluminum hydridee followed by formic acid mediated cyclisation to give the 2,6-bridged 5- ketopiperazinee 22. Hydrogenation of the exocyclic double bond from the sterically least hinderedd side provided the all as substituted product 23. When starting from precursors wheree the C5 substituent was already in a cis position with respect to the C2 center, reduction/cyclisationn of the precursor resulted in cis/ trans mixtures at the C5 position with respectt to the 2,6-bridge. Additionally, the cyclisations were only studied with the terra substitutedd aromatic ring. 79 9 ChapterChapter 5 Schemee 5.2 OMe e OMe e OMe e OMe e OMe e OMe e a,b b MeO^J-X..I C0I2 'Pr MeO^V'^OMe e 21 1 key:key: a) Li('BuO)3AlH, THF; b) HCOOH; c) H2. AA small systematic study of the scope with respect to the nucleophile was reported by Kuriharaa and Mishima (eq 5.1).12 C5-closure e Co-closure e // (5.1) ) 24a:: R = R1 = H 24b:: R = H,R1 = OMe 24c:: R = OMe,R1 = H 25a-c c Usingg unsubstituted (25a) and activated benzylic side chains (25b and 25c) as the nucleophile,, they demonstrated that only closure onto the C6-carbon took place to form the productss 26a-c. No cyclisation onto the C5-carbon resulting in products 24a-c was observed. Cyclisationn onto the C5 position, however, has been observed as a side reaction by Ottenheijmm et al. in the synthesis of neoechinulin and sporidesmin analogues where cyclisationn onto the C6 position was impossible due to the presence of a carbonyl group (eq. 5.2).» » TFA A (5.2) ) O O 27 7 28,, 50% 29,, 26% 80 0 2,6-Bridged2,6-Bridged 3-ketopiperazines via N-acyliminium ion chemistry TFAA treatment of 27 induced cyclisation, which followed by dehydration led to the desiredd enone 28 in 50% yield. As a side product the 2,5-bridged-3,6-diketopiperazine 29 was alsoo isolated in 26% yield. Formation of this side product can be explained by protonation of thee exocyclic methylene, generating a tertiary N-acyliminium ion that was trapped by the N- methylindolee to give 29. Indeed, prolonged stirring with TFA led to almost quantitative formationn of 29. Somee other bridged piperazines have also been reported in literature. The 3,6-bridged diketopiperazinee derivatives 30 reported by Weigl and Wiinsch were synthesised starting fromm (S)-glutamate (Chart 5.5).14 Chartt 5.5 O O f^OEt t OyV0 0 II N I et/-" " 300 31 32 Thesee compounds were developed as core structures, which were further functionalisedd to provide compounds used to inhibit the neurokinin receptor. The 2,6- bridgedd 3,5-diketopiperazine 31 was used as a starting material for the synthesis of Ag 5473, aa compound diplaying immunosuppressant activity.15 The 1,2-bridged ketopiperazine 32 (praziquantel)) was also synthesised using an N-acyliminium ion cyclisation to construct the isoquinolinee ring system.16 5.22 Diketopiperazine Synthesis 5.2.11 The Cbz Route Thee synthesis of the required methyl carbamate derivatised diketopiperazines 14 (Schemee 5.1) started with the coupling of a benzyloxycarbonyl (Cbz)-protected amino acid (33a-c)) to N-benzyl glycine methyl ester (34), which was obtained by reductive amination of glycinee methyl ester with benzaldehyde (Scheme 5.3).17 Cbz-protected (S)-phenylalanine 33a andd (S)-4-fert-butyltyrosine 33b were commercially available. (S)-N-methyltryptophane was synthesisedd according to a literature procedure18 and subsequently protected under Schotten/Baumannn conditions to give 33c. 81 1 ChapterChapter 5 chemee 5.3 R R EDCI I H ,, Pd/C Cbz. rX.OH H HOAt t Cbz z 2 N ++ HN^Y°Me CH2C12,, rt, 24 h MeOH,, rt, 20 h HH 0 Bnn 0 MeO O 33a-c c 34 4 35a-c c Bn n Bn n MeOC(0)Cl l a:: R = Ph DMAP,, DIPEA f b:: R = 4-O BuC6H4 Yl l CH C1 ,, rt, 20 h Yl l 2 2 c:: R = 3-(N-methylindolyl) RR H RR O^OMe 36a:: 76% 37a:: 76% 36b:: 57% 37b:: 82% 36c:: 50% 37c:: 50% Thee amino acids were coupled using standard peptide coupling protocols with 34 to providee the dipeptides 35a-c, which were, without further purification, dissolved in MeOH andd subjected to H2 and Pd/C to remove the Cbz-group.