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Studies towards Syntheses of Enantiopure 1-Azaadamantane-2- Derivatives.

Verhaar, M.T.

Publication date 2000

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Citation for published version (APA): Verhaar, M. T. (2000). Studies towards Syntheses of Enantiopure 1-Azaadamantane-2- carboxylic Acid Derivatives.

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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 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 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 derivative will presumably lead to mixtures of two diasteromeric adamantanes. Nevertheless,, structures obtained via the former approach may be complementary to those fromm approach 2. Preferably,, intramolecular ./V-acyliminium ion cyclisations will be employed for the formationn of the emboldened C-C bonds in structures 34 and 35. During the last twenty years bothh inter- and intramolecular coupling reactions of iV-acyliminium ions with a wide range of nucleophiless have been investigated.26 Our group has been strongly involved in the application off yV-acyliminium ion chemistry in alkaloid synthesis.27 Examples are the total syntheses of anatoxin,288 peduncularin,29 desoxoprosophylline,30 gelsemine31 and very recently gelsedine.32 AA general reaction scheme for an N-acyliminium ion coupling is outlined in eq 1.9.

^%^VV . ^N^ (1.9) ++ l I

Bothh azabicyclo[3.3.1]nonenes 34 and 35 are interesting in their own right because severall derivatives possess useful biological activity.33 This ring system is also found in the skeletonn of diterpene alkaloids such as aconitine 37.2 Aconitine, the most complicated representativee of the Aconitum alkaloids, has been known since 1833 and belongs to the most toxicc materials of plant origin known to man. The roots and leaves of the Aconitum species weree employed in ancient times as animal poisons, for the treatment of neuralgia, hypertension, goutt and rheumatism for example, and in the medieval trials by ordeal.

OMee H HOpp^J^OCOPh h

Me ^N Me OMe e aconitinee 37

1.55 Purpose of this investigation

Thee main goal of this investigation is to develop general synthetic methodology for the synthesiss of sizable amounts of novel substituted l-azaadamantane-2-carboxylic acid derivatives. .

6 6 J-Azaadamantane-2-carboxylicJ-Azaadamantane-2-carboxylic acid derivatives

Chapterr 2 describes the synthesis of several l-azaadamantane-2-carboxylic acid derivativess using an azabicyclononene as key intermediate (approach 1). These investigations weree aimed at the enantiopure modification and improvement of the aforementioned synthesis. Chapterr 3 deals with the use of radical cyclisations to obtain azabicyclononene-2-carboxylic esters,, which are used in the synthesis of 1-azaadamantanes (approach 2). Studies towards the synthesiss of bicyclic cc-amino acid derivatives using N-acyliminium ion cyclisations are presentedd in Chapter 4. In the final chapter of this thesis, Chapter 5, the work aiming at the synthesiss of 2-substituted 1-azaadamantanones is described.

1.66 References and notes

1.. In this Thesis, stereochemical assignments in the structure drawings are made, when needed, withh emboldened or dashed wedges for non-racemic compounds with known absolute configuration.. Emboldened or dashed lines are used for indicating relative stereochemistry. Wavingg lines indicate a mixture of diastereomers, unless the drawing is used to summarise resultss of two diastereomers.

wedges:: | or ; lines: | or i wave: | 2.. Pelletier, S. W. Chemistry of the Alkaloids; Van Nostrand; New York, 1970. 3.. Fort, R. C. jr. Adamantane. The chemistry of diamond molecules, vol. 5 of Studies in Organic Chemistry,, Marcel Dekker Inc., New York, 1976. 4.. (a) Bok, T. R.; Speckamp, W. N. Heterocycles 1979,12, 343. (b) Speckamp, W. N.; Dijkink, J.; Dekkers,, A. W. J. D.; Huisman, H. O. Tetrahedron 1971, 27, 3143. (c) Bok, T. R.; Speckamp, W.. N. Tetrahedron 1979, 35,267. 5.. Patents on 1-azaadamantanes showing pharmacological activity: (a) Jarreau, F. X.; Koenig, J. J. Eur.. Pat. Appl. EP 76755 (1982); Chem Abstr. 1983, 99, 88055z. (b) Jarreau, F. X.; Koenig, J. J.. French demande FR 2543954 (1984); Chem Abstr. 1985, 102, 131937h. (c) Beecham Group PLC,, Jpn. Kokai Tokyo Koho JP 62 77386 (1987); Chem abstr. 1988,108, 5870s. 6.. (a) Flynn, D. L.; Becker, D. P.; Spangler, D. P.; Nosal, R.; Gullikson, G. W.; Moummi, C; Yang,, D.-C. Bioorg. Med. Chem. Lett. 1992,2,1613. (b) Becker, D. P.; Nosal, R.; Zabrowski, D.. L.; Flynn, D. L. Tetrahedron 1997,53, 1. 7.. (a) Grob, C. A.; Kiefer, H. R.; Lutz, H. J.; Wilkens, H. J. Helv. Chim. Act. 1967, 50, 416. (b) Gleiter,, R.; Stohrer, W.-D.; Hoffman, R. Helv. Chim. Act. 1972, 55, 893. (c) Grob, C. A.; Bolleter,, M.; Kunz, W. Angew, Chem. 1980,92, 734. 8.. (a) Dekkers, A. W. J. D.; Verhoeven, J. W.; Speckamp, W. N. Tetrahedron 1973, 29, 1691. (b) Worrell,, C; Verhoeven, J. W.; Speckamp, W. N. Tetrahedron 1974, 30, 3525.

7 7 ChapterChapter 1

9.9. Dekkers, A. W. J. D.; Nibbering, N. M. M.; Speckamp, W. N. Tetrahedron 1972, 28, 1829. 10.. Morishima, I.; Okada, K.; Yonezawa, T.; Goto, K. J. Am. Chem. Soc. 1971, 93, 3922. 11.. Borschberg, H.-J. Helv. Chim. Acta 1984, 67, 1878. 12.. Bick, I. R. C; Hai, M. A.; Preston, N. W. Tetrahedron Lett. 1988, 29, 3355. 13.. Beerli, R.; Borschberg, H.-J. Helv. Chim. Acta 1991, 74, 110. 14.. (a) Fesco, R.; Bianchetti, G. Atti accac. nazl. Lincei, Rend., Classe sci. Fis., mat. e nat. 1953, 15,15, 420; Chem Abstr. 1955, 49, G26A. (b) Fesco, R.; Bianchetti, G. Gazz. Chim. Ital. 1956, 86, 500.. (c) Newman, M. S.; Lowrie, H. S. J. Am. Chem. Soc. 1954, 76,4598. (d) Lukes, R.; Galik, V.. Coll. Czech. Chem. Comm. 1954,19,712. 15.. (a) Speckamp, W. N.; Dijkink, J.; Huisman, H. O. Chem. Commun. 1970, 197. (b) Speckamp, W.. N.; Dijkink, J.; Dekkers, A. W. J. D.; Huisman, H. O. Tetrahedron 1971, 27, 3143. (c) Dekkers,, A. W. J. D.; Huisman, H. O.; Speckamp, W. N. Tetrahedron Lett. 1971, 489. 16.. Dijkink, J.; Speckamp, W. N. Heterocycles 1974, 2, 291. 17.. (a) Delpech, B.; Khuong-Huu, Q. J. Org. Chem. 1978, 43, 4898. (b) Pancrazi, A.; Kabore, I.; Delpech,, B.; Khuong-Huu, Q. Tetrahedron Lett. 1979, 3729. 18.. Black, R. M. Synthesis 1981, 829. 19.. (a) Risch, N.; Saak, W. Angew. Chem. 1982, 94, 926. (b) Risch, N.; Billerbeck, U.; Krieger, E. Chem.Chem. Ber. 1992,125,459. (c) Risch, N.; Billerbeck, U.; Meyer-Roscher, B. Chem. Ber. 1993, 726,1137. . 20.. Risch, N.; Molm, D. Liebigs Ann. 1995, 1901. 21.. Wagner, I.; Musso, H. Angew. Chem. Int. Ed. Engl. 1983,22, 816. 22.. Tr§ka, P.; Kafka, Z.; Hajek, M. Org. Magn. Reson. 1984, 22, 352. 23.. Hahn, J. M.; le Noble, W. J. J. Am. Chem. Soc. 1992,114, 1916. 24.. Wahl, G. H.; Zemyan, S. E. Tetrahedron Lett. 1982,23,4545. 25.. Udding, J. H.; Papin, N.; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1994,50, 8853. 26.. For reviews on Af-acyliminium ion chemistry: (a) De Koning, H.; Speckamp, W. N. in methods ofof Organic Chemistry (Houben-Weyl); Helmchen, G.; Hoffman, R. W.; Mulzer, J.; Schaumann, E.. Eds.; Georg Thieme Verlag: Stuttgart, 1995; Vol E21b, p 1953. (b) Speckamp, W. N.; Hiemstra,, H. in Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I. Eds.; Pergamon: Oxford,, 1991; Vol 2, p 1047. (c) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367. (d)) Zaugg, H. E. Synthesis 1984, 85. (e) Zaugg, H. E. Synthesis 1984, 181. 27.. (a) De Koning, H.; Moolenaar, M. J.; Hiemstra, H.; Speckamp, W. N. in Studies in Natural ProductProduct Chemistry; Atta-ur-Rahman, Ed.; Bioactive Natural Products (Part A); Elsevier: Amsterdam,Amsterdam, 1993; Vol 13, p 473. (b) Hiemstra, H.; Speckamp, W. N. in The Alkaloids; Brossi, A.,, Ed.; Academic Press: New York, 1988: Vol 32, p 271. l-Azaadamantane-2-carboxylicl-Azaadamantane-2-carboxylic acid derivatives

28.. Klaver, W. J.; Melching, K. H.; Hiemstra, H.; Speckamp, W. N. Tetrahedron Lett. 1986, 27, 4799. . 29.. Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am. Chem. Soc. 1989, 111, 2588. 30.. Luker, T.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997,62, 3596. 31.. Newcombe, N. J.; Fang, Y.; Vijn, R. J.; Hiemstra, H.; Speckamp, W. N. J. Chem. Soc, Chem. Commun.Commun. 1994, 767. 32.. Beyersbergen van Henegouwen, W. G.; Fieseler, R. M.; Rutjes. F. P. J. T.; Hiemstra, H. Angew. Chem.Chem. Int. Ed. 1999, 38, 2214. 33.. For a review on 3-azabicyclononanes see: Jeyaraman, R.; Avila, S. Chem. Rev. 1981,81, 149.

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