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UvA-DARE (Digital Academic Repository) Studies towards Syntheses of Enantiopure 1-Azaadamantane-2-carboxylic Acid Derivatives. Verhaar, M.T. Publication date 2000 Link to publication Citation for published version (APA): Verhaar, M. T. (2000). Studies towards Syntheses of Enantiopure 1-Azaadamantane-2- carboxylic Acid Derivatives. 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:27 Sep 2021 CHAPTERR 1 1-AZAADAMANTANE-2-CARB0XYLICC ACID DERIVATIVES 1.11 General Introduction Fromm ancient times mankind has used plants for the preparation of potions with healing, poisoningg or magic power. Many of the biologically active ingredients from these plant extracts,, as far as they have been identified, belong to the compound class of the alkaloids. The termm 'alkaloid' was first proposed by the pharmacist W. Meissner in 1819, meaning 'alkali-like'. Onlyy recently, modern chemistry gained knowledge of the chemical structure of alkaloids, whichh are by definition basic, nitrogen-containing compounds of plant origin (with a complex molecularr structure) which manifest significant pharmacological activity. The nitrogen atom is usuallyy in a ring which is often part of a complex polycyclic system. Nicotine 1, cocaine 2 and strychninee 3' are some examples of well-known alkaloids that display reputed pharmacological activity.2 2 Mee fONN NN ^^, l^fv, | /-^^ l\_ /X52Me \\ I f Ü 1 1 M HH Me /^OCOPh O"^"^O nn H nicotinee 1 cocaine 2 strychnine 3 1-azaadamantane 4 Thee synthesis of alkaloids, derivatives thereof and structurally related compounds has gainedd considerable chemical interest, due to their pharmacological potency. An example of a structurallyy appealing and alkaloid-related synthetic structure is the 1-azaadamantane 4. This 4a conformationallyy restricted tertiary amine is strongly basic (pKb = 2.96) and several reports onn the pharmacological activity5'6 of derivatives of 1-azaadamantane have been published. In addition,, 1-azaadamantane has been used as a rigid model for heterolytic fragmentation, intramolecularr charge transfer,8 gas-phase basicity9 and NMR studies.10 Compoundss with an 1-azaadamantane skeleton have not yet been isolated from natural sources.. However, during the course of biomimetic studies towards Aristotelia alkaloids the bridgedd 1-azaadamantane 7" was isolated from the acid-catalysed transformation of synthetic (-)-hobartinee 5 into (+)-aristoteline 6 to corroborate the absolute configuration of 6 (eq 1.1). Thee formation of 7 was rationalised by assuming that C-3 instead of C-18 of the starting l l ChapterChapter 1 materiall is protonated to yield the corresponding indolenine cation, which is attacked by the doublee bond (C-18) to give an intermediate dihydroindole derivative. A consecutive nucleophilicc displacement at C-2 of the protonated N-l by the nitrogen atom of the azabicyclononanee resulted in the formation of the bridged 1-azaadamantane 7. Borschberg suggestedd that it is possible that this transformation also occurs in the Aristotelia plant tissue, providedd that a suitable enzyme is present. (1.1) ) 20%% HCI aq H2N N reflux,, 8 h -)-hobartinee 5 (+)-aristotelinee 6 (70%) neohobartine 7 (15%) Fromm the New Zealand plant Aristotelia fruticosa another interesting aristoteline alkaloid,, (+)-aristofruticosine 8 was isolated by Bick et al.n This alkaloid contains a norazaadamantanee skeleton which strongly resembles 1-azaadamantane, but lacks one bridging methylene.. An enantiopure total synthesis of this alkaloid by Borschberg et al.13 confirmed the structuree and established the absolute configuration. n n 99 10 (+)-aristofruticosinee 8 Thee norazaadamantane core (9) found in (+)-aristofruticosine 8 has also been synthesisedd in our research group,4 while the isomeric norazaadamantane 10 has been synthesisedd by Becker and Flynn et al.6 in enantiopure form. It was shown that the (nor)azaadamantanee part of benzamides 12 and 13 mimics the 2-aminoethyl substituent of serotoninn 11, while the benzamide portion is viewed as an indole isostere. The benzamide 13 provedd to be the more potent agonist for the serotonine receptors 5-HT3 and 5-HT4, probably duee to the somewhat smaller volume and even more basic character of the norazaadamantane (pKbb = 2.61)4a compared to the parent azaadamantane (pIQ, = 2.96).4a N-- RHN7^T7 7 CIYV>yy > =R KfeN^^XlMe e RNH H serotoninn 11 12 2 13 3 l-Azaadamantane-2-carboxyücl-Azaadamantane-2-carboxyüc acid derivatives 1.22 Synthesis of 1-azaadamantanes Thee first synthetic efforts14 to obtain 1-azaadamantane started from trimesic acid 14 (eq 1.2).. This compound was converted in several steps into the ds-cyclohexane derivative 15, whichh upon treatment with ammonia in methanol at high temperature and under high pressure resultedd in the formation of small amounts of 1 -azaadamantane 4. Br V V f NH3, MeOH (1.2) ) 15 5 144 C02H Thee method published by Speckamp et al}5 in the seventies allowed the formation of functionalisedd 1-azaadamantanes in larger quantities (eq 1.3). The key step of this procedure wass the condensation of ethyl p\P'-dibromoisobutyrate with the pyrrolidine enamine of N- tosylpiperidonee 16, which afforded 3-azabicyclo[3.3.1]nonane 17 in good yield. Subsequent transformationn into alcohols 18 and treatment with HCl/AcOH afforded the 1-azaadamantanes 19. (1.3) ) NT 0H H f/ V HCl/AcOH H —— ^H /-C02Et RR 18 177 (80%) H RR = H, OH, NH2 Thiss method was extended to the synthesis of quinine (23) analogs16 such as 22. Cyclisationn of 20 in HCl/AcOH afforded the adamantane 21 which upon a Wittig reaction of thee corresponding free ketone and oxidation of C-l 1 led to the quinine analog 22. (1.4) ) ChapterChapter 1 AA very short synthesis of a 1 -azaadamantane was presented by Khuong-Huu et al (eq 1.5).. The a- or P-pinene derived amine 24 smoothly underwent a double Mannich reaction by treatmentt with aqueous formaldehyde and acid catalysis, to yield the adamantane 25. A similar doublee Mannich reaction was applied by Black18 for the synthesis of azaadamantanone8a'18(se e e Sectionn 5.1). """ H20 (1.5) ) CH20 0 dioxane/H20, , ^ ^ A A OH H ^NH2 2 24 4 255 (80%) Rischh et al. described the triple Mannich reaction of substituted 1,3- cyclohexanedioness 26 with hexamethylenetetramine to afford various l-azaadamantane-4,6- dioness 27, which were deoxygenated to give the corresponding 3,5,7-substituted 1- azaadamantaness (eq 1.6). Recently, Risch and Molm20 published the resolution of two racemic l-azaadamantane-3-carboxylicc esters 28 with PLE, which led to the optically active products in moderatee ee's. hexamethylene-- N-- N-- (1.6) ) tetramine e PLEE resolution R1 1 C02Me e o'o' R 28 8 26 6 27 7 :: O: 54% ee :: H, H': 82% ee 1.33 Synthesis of l-azaadamantane-2-carboxylic acid derivatives Derivativess of l-azaadamantane-2-carboxylic acid 30 are all conformational^ constrainedd tertiary oc-amino acids. Well over 500 oc-amino acids have been identified in nature,, showing that this compound class is much more diverse than the 20 amino acids that commonlyy occur in living systems.21 The adamantane amino acid is a very peculiar amino acid becausee the nitrogen is not available for amide bond formation, although the adamantane- *yy*yy tyfy *yy nitrogenn may be quaternised with methyl iodide, allyl bromide, benzyl bromide or chloroaceticc acid23 for example. In spite of their appealing structure and possible applications forr the preparation of biologically active compounds only two racemic syntheses of such compoundss have appeared in the literature.24'25 The first example was published by Wahl et l-Azaadamantane-2-carboxylicl-Azaadamantane-2-carboxylic acid derivatives al.al.2424 (eq 1.7). Using the methodology developed in the group of Speckamp,15 tosylamide 29 wass refluxed in a mixture of concentrated aqueous HC1 and AcOH, to effect the cyclisation to thee adamantane, which was followed by in situ hydrolysis of the cyanide to give the acid 30. ,C02H H refluxx /X^T 30 0 Thee second synthesis, performed in our research group25 proceeded via a Mannich reactionn of azabicyclo[3.3.1]nonene 31 and methyl glyoxylate, affording the two diastereomericc adamantanes 32 in moderate yield (see Section 2.1). r7~~~~\r7~~~~\ Me02CCHO(MeOH) NHH HCÖÖhh - /^'N (1-8) thenn basic work up 311 H C02Me 322 (35%) 1.44 Present synthetic strategies towards l-azaadamantane-2-carboxylic acid derivatives s Thee present investigation is aimed at the synthesis of enantiopure l-azaadamantane-2- carboxylicc acid derivatives. The synthetic strategies to arrive at the adamantane skeleton can be dividedd into two general approaches, as outlined in Scheme 1.1. The adamantane 33 is broken downn retrosynthetically via a Mannich reaction to either the azabicyclononene 34, analogous to thee aforementioned synthesis, or the azabicyclononane-2-carboxylic ester 35. These two intermediatess might be synthesised from enantiopure cyclohexenemethylamines like 36. NH H % % 34 4 approachh 1 NH 2H 2 approachh 2 36 355 C02R ChapterChapter 1 Thee second approach is considered to be the most promising due to the expected stereoselectivee Mannich reaction of 35 with formaldehyde, whereas such a reaction of 34 with aa glyoxylic acid derivative will presumably lead to mixtures of two diasteromeric adamantanes.

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