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The Synthesis and Rearrangement THE SYNTHESIS AND REARRANGEMENT REACTIONS OF 1-AMINOADAMANTANE ANALOGUES A thesis submitted in part fulfilment of requirements for the degree of MASTER OF CHEMISTRY by Ivy Sio Hang LAU Supervisor: Dr R. Bishop THE UNIVERSITY OF NEW SOUTH WALES July 1985 THE SYNTHESIS AND REARRANGEMENT REACTIONS OF 1-AMINOADAMANTANE ANALOGUES CONTENTS Page 1. SUMMARY 1 2. INTRODUCTION 2.1 Adamantane and 1-aminoadamantane 2 2.2 Synthetic approaches to 1-aminoadamantane analogues 6 3. DISCUSSION 3.1 Synthesis and rearrangement reactions of 10 3.3.7.7- tetramethylbicyclo[3.3.1]nonane-2,6-dione 3.2 Synthesis and rearrangement reactions of 17 3.3.7.7- tetramethyl-6-methylenebicyclo[3.3.1] nonan-2-one 3.3 Synthesis and rearrangement reactions of end.o-2, 21 en<ic>-6-dihydroxy-3,3,7,7-tetramethylbicyclo [3.3.1] nonane 3.4 Hydrolysis of 1,3-bis(acetamido)-4,4,8,8- 23 3 7 tetramethyltricyclo[3.3.1.1 * ]decane 4. CONCLUSIONS AND FUTURE STUDIES 26 5. EXPERIMENTAL 27 6. REFERENCES 42 -1- 1. SUMMARY Three bicyclo[3.3.1]nonane derivatives were prepared in this project and their behaviour under Ritter reaction conditions investigated: 3.3.7.7- tetramethylbicyclo[3.3.1]nonane-2,6-dione (39) 3.3.7.7- tetramethyl-6-methylenebicyclo[3.3.1]nonan-2-one (44), and endo-2, en<i<2-6-dihydroxy-3,3,7,7--tetramethylbicyclo[3.3.1]nonane (82) . Ritter reaction on the tetramethyl dione (39) was found to give endo-6-acetamido-3,3,6,7-tetramethylbicyclo[3.3.1]non-7-en-2-one (54). Under different conditions a closely related hydroxyamide (55) or (56) was formed. The actual isomer produced is still uncertain. The tetramethyl ketoolefin (44) was found to give 1,3-bis(acet- amido)-4,4,8,8-tetramethyltricyclo[3.3.1.l^*^]decane (67) and 3,3,6,6,7- pentamethylbicyclo[3.3.1]non-7-en-2-one (70) under strong and weak Ritter conditions respectively. Reaction pathways are described explaining the formation of these four novel rearrangement products. Ritter reaction on the tetramethyl diol (82) gave a mixture of products in very low yields with none being isolable. Attempts to hydrolyse the diamide (67) to the diamine using basic hydrolysis conditions were unsatisfactory. -2- 2. Introduction 2.1 Adamantane and 1-aminoadamantane Adamantane, the trivial name for the hydrocarbon tricyclo- 3 7 [3.3.1.1 * ]decane (1), is derived from the Greek for diamond. At the turn of the Twentieth Century the structure of diamond was postu­ lated to be the now familiar arrangement of fused chair cyclohexane 12 3 rings (2) * . Decker , in 1924, proposed the synthesis of "dekaterpene" CigHig (1), a tricyclic hydrocarbon which would have the same part-structure as the diamond lattice and would be highly symmet- 4 rical and strain free. In 1933, Landa first isolated this substance from petroleum naphtha, where it constituted about 0.0004%, accompanied by equally small amounts of alkylated adamantanes. The isolation was made possible by the atypically high melting point of adamantane. Investigations into the chemistry of adamantane were hindered by its unavailability since total synthesis involved elaborate stepwise procedures giving very low overall yields^. In 1956 Schleyer and Donaldson who were studying the facile AlCl3-catalyzed isomerization of endo-tetrahydrodicyclopentadiene (3) to its exo-isomer (4), obtained adamantane in yields of 15-20% by chance. Since then, adamantane has become conveniently available because cyclopentadiene is a commercial product and its dimer can easily be hydrogenated. The driving force for the profound skeletal transformation leading to adamantane is the relief of the large amount of strain inherent in the bicyclo[2.2.1]heptane ring system. While an entirely satisfactory mechanism for this transformation is still absent, it is believed to involve a large number of carbonium ions and rearrangement reactions^. There may also be more than one pathway 9 TABLE I. HISTORY OF INFLUENZA 'PANDEMICS Year Virus 1658 1688 1710 1743 1762 1782 1803 1831 1833 1837 1889 1918 HswinelNl 1948 H1N1 1957 H2N2 'Asian' era 1968 H3N2 'Hong Kong' era 1977 H3N2 1978 H3N2 and H1N1 (possibly 'frozen' since 1950 in nature) 1980 H3N2 and H1N1 (possibly 'frozen' since 1950 in nature) Influenza A viruses are designated as type A, B or C. Influenza A viruses alone are able to cause world-wide epidemics or pandemics. Influenza B and C viruses are responsible for more localised outbreaks. Clinically they are not distinguishable, For influenza A viruses an index in the virus description describes the antigenic character of the haemagglutinin and neuraminidase, e.g. HswinelNl indicates that the H or haemagglutinin originated from a swine influenza virus, whilst the neuraminidase N1 had a human origin. -3- leading to adamantane . The discovery that 1-aminoadamantane (5) exhibited anti-viral g activity against several strains of influenza virus was made in the laboratories of E.I. du Pont de Nomours and Co. in the early 1960's. World-wide influenza pandemics have been documented for several 9 hundred years (see TABLE I). About half of the infections caused a febrile respiratory disease, but severe cases were rapidly fatal. The morbidity rate from influenza ( H2N2 strain) in the 1957 pandemic ranged from 18% to 87%^ in various geographic areas. Unlike other viruses such as measles, polio and smallpox, influenza virus has a 9 segmented RNA genome , making genetic recombination between different viruses very frequent. Many influenza A viruses co-exist in animal, 9 avian and human groups . The large genetic pool of influenza viruses makes its control by vaccine very difficult. This, coupled with the time required for vaccine development, makes chemotherapy all the more important. 1-Aminoadamantane (5) is marketed as the hydrochloride with trade names such as "Amantadine" and "Symmetrel". Its therapeutic indications now include influenza A virus strains, influenza A2 11 12 respiratory illness, rubella , Rous sarcoma, Esh sarcoma and 13 Parkinson's Disease . It is a thermostable water soluble solid. In man, the drug is absorbed rapidly after oral administration and there is nearly complete recovery from urine of an administered dose 14 14 in unaltered form . This excretion follows first order kinetics The precise mode of action of 1-aminoadamantane is still unknown. Tissue culture studies^ indicated that 1-aminoadamantane hydrochloride Activity in vivo* (18) ++ (19) + ++ = activity comparable to that of 1-aminoadamantane or better. + = significant activity but less than 1-aminoadamantane. - = inactive. -4- was not virucidal. In the presence of (5), adsorbed infectious viruses remained at the cell surface but were blocked from penetration^. 1-Aminoadamantane has also been reported to inhibit uncoating of viruses and the release of infectious virions^. Industrially, 1-aminoadamantane (5) is prepared from adamantane (1) in several steps. Koch-Haaf reaction on (1) produces the carboxylic acid (6) which is readily converted to the acid chloride (7) and reacted with ammonia to give the amide (8). Hoffmann rearrangement results in the urethane (9) which is hydrolyzed by base to give (5)^. Alternatively, (1) can be monobrominated to give 1-bromoadamantane (10), and this can undergo Ritter reaction to produce the amide (11) which is hydrolyzed to (5)^. Pharmacological screening involving the synthesis of new compounds and in vitro and in vivo testings have picked out those with 18 varying degree of antiviral activity. Aldrich and co-workers conducted a comprehensive study of the structure-activity relationship of some of the compounds related to 1-aminoadamantane. They class­ ified the structure variations into five types (12, 13, 14, 15, 16). In general, the antiviral activity diminished as the size of the N-substituent(s) in (12) increased. The presence of functional groups such as OH, NH2, Cl and COOCH3 on the alkyl moiety reduced activity. Substituents at one or more of the tertiary positions of (13) were highly detrimental to activity. The insertion of a single C as moiety "A" in (14) led to compounds of good activity. One of these, 1-amino- 3 7 ethyl-1'-tricyclo[3.3.1.1 * Jdecane (17) (rimantadine .HC1) was found by Tsunoda and co-workers to be more effective than (12) in vitro 19 against influenza A Japan 305 virus . In (15), the adamantane -5- 3 8 skeleton has been expanded to the tricyclo[4.3.1.1 * ]undecane (homo- adamantane) system. The 3-amino and 3-methylamino derivatives retained antiviral activity. Replacement of the amino group of (12) by H, OH, SH, CN, COOH, Cl or Br gave inactive compounds (16). The basicity of the nitrogen is important since acylation lowered the activity. The antiviral activity of the adamantanespiro-31-pyrrol- 20 idines (18) diminishes with increasing size of the N-substituents. 20 Of the analogous spiro-3'-pyrrolidines (19, 20, 21, 22), activity is highest for (20) which is structurally more related to adamantane. 20 That the cyclohexane derivative (22) is inactive stresses the importance of a bi- or tricyclic nucleus for antiviral activity. In summary, the antiviral activity of 1-aminoadamantane is shared by a whole range of amines attached to multicyclic systems. Thus, compounds related to 1-aminoadamantane are continuously being synthesised by investigators who then assess their activity and attempt to develop the rationale of how they work. c H302^ yPC2CH3 /C02Cn3 CH'CHfCH CK|=C / \ CH302C C02C'H3 ^co2ch3 (26) (23) Michael Addition '•C02CH- CH2Ch ch3o2' Dieckmann c,o2ch3 -------------------- » condensation / \ /C02CH3 ch3o2c CHjCh 'C02ch3 /O2CH3 ChJC Michael Addition >/ Meerwein’s Ester 3 Jones Reagent (26) (31) (33) -6- 2.2 Synthetic approaches to 1-aminoadamantane analogues A simple way of synthesising the bicyclo[3.3.ljnonane system was 21 22 discovered by Meerwein and co-workers * who condensed formaldehyde and dimethyl malonate.
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