UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Synthesis of potential anti-viral agents possessing the tetrahydropentaprismane ring system Tse, Hoi Lun Allan 1982

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-UBC_1982_A6_7 T84.pdf [ 3.71MB ]
Metadata
JSON: 831-1.0060393.json
JSON-LD: 831-1.0060393-ld.json
RDF/XML (Pretty): 831-1.0060393-rdf.xml
RDF/JSON: 831-1.0060393-rdf.json
Turtle: 831-1.0060393-turtle.txt
N-Triples: 831-1.0060393-rdf-ntriples.txt
Original Record: 831-1.0060393-source.json
Full Text
831-1.0060393-fulltext.txt
Citation
831-1.0060393.ris

Full Text

SYNTHESIS OF POTENTIAL ANTI-VIRAL AGENTS POSSESSING THE TETRAHYDROPENTAPRISMANE RING SYSTEM by HOI-LUN ALLAN TSE B.Sc.(Hon.), The University of Bradford, 1979 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF CHEMISTRY We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA May 1982 © Hoi-Lun Allan Tse, 1982 In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t bf the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y a v a i l a b l e f o r reference and study. I further agree that permission for extensive copying of t h i s thesis for s c h o l a r l y purposes may be granted by the head of my department or by his or her representatives. It i s understood that copying or p u b l i c a t i o n of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of c H E r t l S T / ? r The University of B r i t i s h Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date / -7 n \ i i ABSTRACT T h i s t h e s i s d e s c r i b e s t h e s y n t h e s e s o f the m o l e c u l e s 1 1 - a z a - p e n t a c y c l o [ 6 . 2 . 1 . 0 2 ' 7 . 0 l , > 9 . 0 5 » 1 0]decane (28) and 4,5-dimethyl-1 1 - a z a - p e n t a c y c l o [6.2.1 .0 2 •'.O*' 9^ 5 > 1 0]decane ( 2 9 ) . Owing t o t h e i r s t r u c t u r a l s i m i l a r i t i e s t o 1-aminoadamantane (an a n t i - v i r a l and a n t i - P a r k i n s o n ' s d i s e a s e a g e n t ) , they might p o s s e s s a c t i v i t i e s a g a i n s t i n f l u e n z a v i r u s e s and/or P a r k i n s o n ' d i s e a s e . The key i n t e r m e d i a t e s i n v o l v e d were the two cage k e t o l s namely, 1 O - e x o - h y d r o x y t e t r a c y c l o -[5.3.O.O 2» 6.0"» 9]decan-3-one (33a) and 6,7-dimethyl-10-exo-h y d r o x y t e t r a c y c l o [5.3.0.0 2» 6.0"* 9]decan-3-one (33b) which were p r e p a r e d v i a a t h r e e - s t e p sequence s t a r t i n g from p-benzoquinone , 1,3-butadiene and 2 , 3 - d i m e t h y l - 1 , 3 - b u t a d i e n e r e s p e c t i v e l y . The i n c o r p o r a t i o n of the r e q u i r e d n i t r o g e n atoms was done by t r a n s f o r m i n g the ketone groups of compound 33a and 33b i n t o the c o r r e s p o n d i n g oxime and oxime e t h e r . G e n e r a t i o n o f t h e amine f u n c t i o n a l groups and b u i l d i n g of t h e n i t r o g e n b r i d g e s were a c h i e v e d i n a s i n g l e s t e p by r e d u c t i o n of the oxime d e r i v a t i v e s e m p l o y i n g aluminium h y d r i d e as the r e d u c i n g agent. The s y n t h e s e s of compound (28) and (29) were t h e r e f o r e a c c o m p l i s h e d v i a a f i v e - s t e p r e a c t i o n sequence (scheme I I I ) s t a r t i n g from p-benzonquinone and the c o r r e s p o n d i n g b u t a d i e n e s . TABLE OF CONTENTS Abstract Table of Contents L i s t of Figures and Schemes Ac knowledgement Introduction A. Background B. Synthetic Strategy Results and Discussion A. Synthesis of 11-Aza-pentacyclo-[6.2. 1 .0 2 ' 6.0*' 9.0 5 » 1 0]decane (28) B. Synthesis of 4,5-Dimethyl-11-aza-pentacyclo-[6.2.1.0 2' 6.0"» 9.0 5» 1 0]decane (29) Exper imental Bibliography iv LIST OF FIGURES Page Figure 1 A 270 MHz 1H NMR spectrum of the 46 hydrochloride of compound 28 Figure 2 A 400 MHz 1H NMR spectrum of the 53 picrate of compound 2_9 LIST OF SCHEMES Scheme I 18 Scheme II 20 Scheme III 23 Scheme IV 24 Scheme V 27 Scheme VI 37 Scheme VII 39 Scheme VIII 48 Scheme IX 51 V ACKNOWLEDGEMENT I wish to express my deep gratitude to Dr. J . R. Scheffer and Dr. E. Piers for their advice, support and encouragement throughout the course of t h i s work. I would l i k e to thank Dr. A. Cheung, Dr. L. Lau and Mr. H. Wong for their assistance during the preparation of the manuscript of t h i s t h e s i s . Thanks are also due to the technical staff of the Department of Chemistry for their service. F i n a l l y , I wish to thank Dr. S. Sacks of the U.B.C. Faculty of Medicine for performing the b i o l o g i c a l t e s t i n g . The f i n a n c i a l support from the University of B r i t i s h Columbia in the form of a Teaching Assistantship i s gr a t e f u l l y acknowledged. 1 Introduction A. Background Viruses constitute an exceedingly interesting example of nucleoprotein complexes with a defined function. They are capable of dormant existence and r e p l i c a t i o n only inside the c e l l s of their hosts (which, depending on virus species, may be bacteria, plants or animals), fashioning and c o n t r o l l i n g the host's metabolism to their own purposes. In their a b i l i t y to reproduce their own kind, to be capable of mutation and to exchange genetic material provided by more than one parent, they exhibit the most salient c h a r a c t e r i s t i c s of l i v i n g organisms. Yet they can be isola t e d in a pure form and treated as d i s t i n c t chemical e n t i t i e s . Ever since W.M. Stanley's i s o l a t i o n of tobacco mosaic virus in 1 9 3 5 1 by c r y s t a l l i s a t i o n and the analysis of i t s chemical composition which showed that i t was composed mostly of protein as well as some nucleic acid, viruses have been the favourite subject of investigation in molecular biology. In general, viruses can be divided into three categories -b a c t e r i a l viruses (bacteriophages), animal and plant viruses. There are many s i m i l a r i t i e s between these kinds of viruses. Their basic structure i s the same in that a l l contain either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) (never both) which i s surrounded by a layer, or capsid, of protein. A l l viruses are chemically simple when compared to c e l l s since they contain few, i f any, enzymes and the i r actual structure i s r e l a t i v e l y simple. 2 Although the exact mechanisms of i n f e c t i o n by various kinds of viruses are d i f f e r e n t , the general pattern remains the same. The virus i s adsorbed onto the c e l l membrane of the host c e l l (in some cases, the whole virus p a r t i c l e i s incorporated into the c e l l ) , the v i r a l nucleic acid i s then released into the cytoplasm. By c o n t r o l l i n g the host's metabolism, proteins and nucleic acids which are essential for r e p l i c a t i o n are synthesized. Reorganisation of these materials occurs during the l a t e stage of i n f e c t i o n and a large number of virus p a r t i c l e s are formed; the release of newly formed p a r t i c l e s into the environment may or may not be concomitant with host c e l l d i sruption. As demonstrated by Hershey and Chase in 19522 by double l a b e l l i n g experiments ( 3 5S for protein, 3 2 P for deoxyribonucleic a c i d ) , the i n f e c t i v e and reproductive part of bacteriophages was the nucleic acid, the external protein coat apparently functioning mainly as a protective coat. It i s widely believed that the same i s true for animal and plant viruses. It has been known that quite a number of human diseases are caused by viruses, for example smallpox, measles and some tumors. F i f t y to seventy-five per cent of the adult population throughout the world suffers from some form of mucocutaneous lesions produced by herpes v i r u s e s 3 . In addition, the same group of viruses i s responsible for more serious i l l n e s s such as herpetic encephalitis and keratoconjunctivitis. The incidence of herpes progenitalis has increased dramatically in recent years and may be considered as one of the most common types of 3 venereal disease. Although many v i r a l diseases such as the common cold are s e l f - l i m i t i n g , with a low mortality and high morbidity, they cause much discomfort to the individual and represent m i l l i o n s of l o s t hours with serious economic repercussions. A drug which would prevent, cure or shorten the duration of these i l l n e s s would have enormous impact. A virus i s so much simpler in i t s constitution than a bacterium that many of the points of attack on the l a t t e r are just not possible with the former such as the muramic acid type c e l l wall and the enzymes associated with i t . However, the mechanism of v i r a l r e p l i c a t i o n suggests several points of attack for i n h i b i t i o n . An a n t i v i r a l agent may work d i r e c t l y on the virus p a r t i c l e i t s e l f , prevent adsorption onto or incorporation into the host c e l l , i n h i b i t v i r a l r e p l i c a t i o n or inter f e r e with the synthesis of the protein coat. Since the i n f e c t i v e cycle of the virus i s so intimately t i e d up with the host c e l l ' s metabolism, i t i s obvious that any chemotherapeutic agent that would i n h i b i t virus propagation would also i n h i b i t the metabolism of the host c e l l . V i r a l chemotherapy, therefore, i s a quest for se l e c t i v e t o x i c i t y . In order to cover a l l the p o s s i b i l i t i e s of influencing a virus i n f e c t i o n or i t s sequelae, the term " a n t i v i r a l agent" has been defined in very broad terms" as "a substance other than a vir u s , a virus-containing vaccine or s p e c i f i c antibody, which can produce either a protective or therapeutic ef f e c t to the cle a r , detectable advantage of the virus infected host. Any material that can s i g n i f i c a n t l y enhance antibody formation, 4 improve antibody a c t i v i t y , improve non-specific resistance, speed convalescence or depress symptoms would also be considered an a n t i v i r a l agent despite the fact that such an agent has no di r e c t action on the invasion, synthesis or migration of the v i r u s " . Over the past two decades, a n t i v i r a l chemotherapy has presented a major challenge to medical science. Although numerous a n t i v i r a l compounds have been reported from experimental screening programs, only a few have been studied c l i n i c a l l y and even fewer have become commercially available drugs. The need for a broad spectrum a n t i v i r a l agent i s pressing. Unlike the development of a n t i b i o t i c s , the p o s s i b i l i t y of finding a broad spectrum agent such as a " p e n c i l l i n equivalent" i s rather remote. One major reason being the c a p a b i l i t y of the virus to undergo mutation and produce a new type of v i r u s . It i s not uncommon for a virus which i s highly susceptible to a drug to become inert to i t after being treated for some time. Most currently available drugs or those in c l i n i c a l t r i a l s are e f f e c t i v e against only s p e c i f i c viruses and, in some cases, against only one pa r t i c u l a r s t r a i n in a group of viruses. Nevertheless, the search for e f f e c t i v e a n t i v i r a l agents i s continuing. Numerous chemicals have been found to be active towards various kinds of viruses. Some of the more important a n t i v i r a l agents are described below. Interferon and Interferon Inducers Interferon i s a low molecular weight protein produced in 5 the body as a defense against v i r a l i n f e c t i o n . C e l l u l a r synthesis of interferon is stimulated by either v i r a l antigen or by a chemical inducer. In terms of combating v i r a l i n f e c t i o n , natural body defense mechanisms would be the ideal system. It was shown . that interferon was e f f e c t i v e in treating rubella i n f e c t i o n 5 and herpes z o s t e r 6 . Other preliminary results confirmed the e f f i c a c y of interferon as an a n t i v i r a l agent. Interferon inducers are chemicals that can induce the production of interferon when incorporated into the c e l l s . The most widely investigated inducer i s the poly-inosinic acid p o l y - c y t i d y l i c acid complex (poly I:C) which i s a double-stranded polyribonucleotide. The interferon-inducing a b i l i t y of poly I:C was f i r s t demonstrated in c e l l systems in 19687 and was shortly followed by d e t a i l s of i t s curative effects on a herpes infection of a rabbit's eye 8, and on various virus infections of animals 3. Poly I:C had been incorporated into a complex with poly- 1-lysine and carboxymethyl c e l l u l o s e 1 0 and promising results were obtained in monkeys against, among other viruses, yellow fever and r a b i e s 1 1 . Nevertheless, the high t o x i c i t y of poly I:C precluded i t s use in man other than for t o p i c a l a p p l i c a t i o n s 1 2 " 1 " . [CH3(CH2)17]2N-CH2-CH2'CH2-N(CH2CH2OH)2 1 6 Other inducers include N,N-dioctadecyl-N'N'-bis(2-hydroxy-ethyl)-1,3-propane diamine _1_ which provides protection against l e t h a l infections of encephalomyocarditis and Semliki Forest virus and supressed pock formation by vaccinia v i r u s 1 5 . Chemical studies have further indicated that the drug also provides protection against rhinovirus-induced d i s e a s e s 1 6 " 1 7 . 2,7-Bis(2-diethylaminoethoxy)-9-fluorenone (tilorone, 2) dihy-drochloride was also found to be able to induce high levels of i n t e r f e r o n 1 8 " 2 3 . However further studies demonstrated that ti l o r o n e f a i l e d to e l i c i t detectable interferon in humans and t o x i c i t y was observed when the compound was administered either o r a l l y or t o p i c a l l y . Therefore the drug was deemed unsuitable for c l i n i c a l t r i a l . Although experimental data confirm the e l i g i b i l i t y of interferon as an a n t i v i r a l drug, several barriers stand in the way of i t s ap p l i c a t i o n . Interferon is species-specific which therefore l i m i t s the source for c l i n i c a l use. Technologically, at the present state of the a r t , i t i s not feasible to produce human interferon on a commercial scale. F i n a l l y , the i n s t a b i l i t y of interferon in body f l u i d s requires doses which 0 2 7 are probably well in excess of the e f f e c t i v e l e v e l . Purine and Pyrimidine Derivatives O HO 3_ A large number of purine and pyrimidine analogues have been synthesized and tested as a n t i v i r a l agents. The most well known of these i s 5-iodo-2' -deoxyur idine _3 (R=I, IDUR). The compound was proved by Herrmann to be a potent v i r a l i n h i b i t o r of herpes simplex and vaccinia v i r u s e s 2 * . Subsequent tests c a r r i e d out by Kaufman 2 5 showed that IDUR was highly e f f e c t i v e against herpetic corneal i n f e c t i o n s . Further c l i n i c a l studies substantiated the ef f i c a c y of IDUR against herpes k e r a t i t i s and currently, i t i s commercially available for the treatment of this disease. Other studies indicated that when IDUR was applied as a dimethyl sulphoxide solution ( t o p i c a l l y ) , the duration of the disease caused by cutaneous herpes was shortened by 63% when compared to untreated placebo c o n t r o l s 2 6 . It was also reported e f f e c t i v e against v a r i c e l l a - z o s t e r (shingles) when applied t o p i c a l l y as a 40% dimethyl sulphoxide s o l u t i o n 2 7 . Numerous IDUR analogues have been synthesized and tested 0 8 against various DNA viruses, for example the 5-methylamino- (3_, R=NHCH 3) and 5-trifluoromethyl- (3, R=CF3) derivatives. 5-Trifluoromethyl-2'-deoxyuridine has been known for quite some time and was found to be more potent than IDUR against herpes k e r a t i t i s in rabbits. Futhermore, the compound i s active against IDUR resistant herpes and i s less toxic than IDUR. Recently two IDUR analogues were synthesized 2 8 namely the E-5-(2-bromovinyl)- (R=CH:CHBr) and E-5-(2-iodovinyl)-(R=CH:CHI) derivatives. Both showed marked in h i b i t o r y effects on the r e p l i c a t i o n of herpes simplex virus type 1. In comparison to IDUR, both compounds were more selective in their a n t i v i r a l a c t i v i t y and did not aff e c t the growth or metabolism of the host (primary rabbit kidney) c e l l s unless drug concentrations used were 5000- to 10,000-fold greater than required. When tested in nude mice, E-5-(2-bromovinyl)-2'-deoxyuridine was found to suppress the development of herpetic lesions and resulting mortality whether the drug was administered t o p i c a l l y or systemically. Under the same conditions, IDUR offered l i t t l e , i f any, protection. Ara A 4ci Ara C 4b 9 Two other n u c l e o s i d e s have a l s o shown promise as a n t i v i r a l agents p a r t i c u l a r l y a g a i n s t herpes k e r a t i t i s - 9-p-D-ar a b i n o f uranosyl adenine (Ara-A) 4_a and 1 - 0 - D - a r a b i n o s y l c y s t o s i n e (Ara-C) 4b. Ara-A was found to be a c t i v e ijn v i t r o a g a i n s t herpes simplex and v a c c i n i a v i r u s e s 2 9 as w e l l as cytomegalovirus both in v i t r o 3 0 and j j i v i v o 3 1 . In a d d i t i o n to the broad spectrum of a c t i v i t y i_n v i t r o a g a i n s t DNA v i r u s e s , a c t i v i t y a g a i n s t herpes k e r a t i t i s in hamsters and i n t r a c e r e b r a l l y i n n o c u l a t e d herpes simplex and v a c c i n i a v i r u s e s i n mice were a l s o o b s e r v e d 3 2 . Ara-A has a l s o e x h i b i t e d a c t i v i t y a g a i n s t herpes k e r a t i t i s i n man 3 3 and i s p r e f e r r e d over IDUR i n t r e a t i n g e p i t h e l i a l k e r a t i t i s due to i t s lower t o x i c i t y . R e c e n t l y , Ara-A was approved by the Food and Drug A d m i n i s t r a t i o n (FDA) of the Un i t e d S t a t e s f o r marketing by Warner-Lambert Co. 3* under the name "Vi d a r a b i n e " and i s h i g h l y e f f e c t i v e i n t r e a t i n g herpes simplex e n c e p h a l i t i s . V i d a r a b i n e was claimed as a true a n t i v i r a l agent by Warner-Lambert Co., probably due to the f a c t that the drug i n t e r f e r e s d i r e c t l y with v i r a l r e p l i c a t i o n . Ara-C has a spectrum of a n t i v i r a l a c t i v i t y s i m i l i a r t o Ara-A. It i s a c t i v e j_n v i t r o a g a i n s t DNA v i r u s e s such as herpes v i r u s e s , v a r i c e l l a - z o s t e r , cytomegaloviruses and v a c c i n i a v i r u s e s 3 5 . R i b a v i r i n 5 ( 1 - 0 - D - r i b o f u r a n o s y l - 1 , 2 , 4 - t r i a z o l e - 3 - c a r -boxamide) i s not a puri n e or p y r i m i d i n e d e r i v a t i v e but due to i t s s i m i l i a r chemical s t r u c t u r e , i s i n c l u d e d here f o r the sake of convenience. 10 o OH 6 H 5 Ribavirin i s a broad spectrum a n t i v i r a l agent which was f i r s t synthesized by Simon et a l . 3 6 and was found to be ef f e c t i v e against both DNA and RNA v i r u s e s 3 7 " 3 8 . It has been shown to be a potent agent against herpes in f e c t i o n s . The mode of action of r i b a v i r i n , according to Jon P. M i l l e r and David G. Streeter of ICN Pharmaceuticals I n c . 3 9 , i s i n h i b i t i o n of an enzyme which has an important function in c e l l s infected by herpes viruses, thus i n t e r f e r i n g with the biosynthesis of v i r a l DNA. Promising results from treatment of herpes zoster (shingles), h e r p a t i t i s A with r i b a v i r i n were obtained in c l i n i c a l t r i a l s . C l i n i c a l studies have also substantiated the ef f i c a c y of r i b a v i r i n against influenza which i s a family of RNA viruses. It has been reported that r i b a v i r i n s p e c i f i c a l l y i n h i b i t s the'synthesis of influenza v i r a l protein while having no d i s c e r n i b l e effects on the h o s t 3 9 . R i b a v i r i n has been registered under the trade name "Varizole" by ICN Pharmaceuticals Inc.of Irvine, C a l i f o r n i a , and is already being marketed in Mexico for v i r a l respiratory infections and in 11 B r a z i l for v i r a l h e r p a t i t i s . Other Heterocyclic Compound 6 Benzimidazoles and thiosemicarbazones are the two most important classes in t h i s group. o-Hydroxybenzylbenzimidazole (HBB) 6 and i t s derivatives have been extensively studied since they were found to i n h i b i t s e l e c t i v e l y the r e p l i c a t i o n of several picornaviruses (for example p o l i o and Echo) by i n t e r f e r i n g with v i r a l RNA s y n t h e s i s 0 0 . A large number of HBB analogues were tested for potency against Echo 6 virus with the result that only two passed the stringent t e s t s . These two were HBB i t s e l f and 2-(c-methyl-o-hydroxybenzyl)-benzimidazole" 1. Studies of the effect of N-substitution in HBB have shown that these derivatives were highly active against p o l i o viruses in tissue c u l t u r e s " 2 as were N-substituted a-methoxybenzyl-benzimidazoles* 3. The N-propyl derivatives are most reactive in both cases. Enviroxime, i s a der i v a t i v e of benzimidazole recently developed by L i l y Research Laboratories*' and i s claimed to be highly potent against the rhinovirus family (which i s responsible for the common cold) vn v i t r o . Although enviroxime has not been tested c l i n i c a l l y , i t 12 h a s been shown t o be e f f e c t i v e a g a i n s t more t h a n 60 t y p e s o f r h i n o v i r u s e s when t e s t e d in v i t r o u s i n g m o s t l y human c e l l c u l t u r e s i n c l u d i n g c e l l s d e r i v e d f r o m t h e human t r a c h e a . s II CH=N-NH-C-NHR 8a X=H , R^H 8b X^p-CH3CONH , R=H 8c X=H , R=CH(CH3)C2H5 8d X=p-CB£ONH , R--CH(CH3)C2H5 The i n i t i a l d i s c o v e r y t h a t t h i o s e m i c a r b a z o n e s p o s s e s s e d a n t i v i r a l a c t i v i t y was made by H a m r e * 5 " * 7 who o b s e r v e d a d r a m a t i c e f f e c t on m o r t a l i t y when b e n z a l d e h y d e t h i o s e m i c a r b a z o n e 8 a , t h e p - a c e t a m i d e h o m o l o g u e 8b and t h e i r N - i s o b u t y l h o m o l o g u e s 8c a n d 8d were a d m i n i s t e r e d t o m i c e i n n o c u l a t e d i n t r a n a s a l l y w i t h v a c c i n i a v i r u s e s . T h i s d e v e l o p m e n t u l t i m a t e l y l e d t o a s t u d y o f o t h e r t h i o s e m i c a r b a z o n e s by Thompson e t a l . * 8 who 13 observed a positive effect against vaccinia viruses with i s a t i n 0-thiosemicarbazones 9. Further studies c a r r i e d out by Bauer led to the discovery of N-methyl i sat in p-thiosemicarbazone (Methi sazone ) J_0 which was found e f f e c t i v e against both DNA and some RNA v i r u s e s " 9 in vivo and _in v i t r o . These included p o l i o virus, certain rhinoviruses, some arboviruses and influenza A and B. C l i n i c a l l y the use of the drug has been confined to DNA viruses where i t has shown a prophylactic e f f e c t against smallpox 5 0. Al i p h a t i c Compounds O II H O - P - C H 9 - C O O H OH 11 Phosphonoacetic acid JJ_ has been known for over 50 years and was studied by Lacy R. Overby and his associates at Abbott Laboratories in Chicago. It was found to be highly 1 4 active against herpes simplex 1 and 2 when screened jjn v i t r o 5 1 . In vivo studies on corneal herpes simplex virus infections in rabbits showed that 5% phosphonoacetic acid prepared as the sodium s a l t suppressed herpes k e r a t i t i s in laboratory a n i m a l s 5 2 . It has also been found e f f e c t i v e in mice against virus infections of the central nervous system when administered by intraperitoneal i n j e c t i o n 5 3 . Like "Vidarabine", phosphonoacetic acid i n h i b i t s the herpes-specific DNA polymerase, but i t appears to bind at a d i f f e r e n t s i t e and works through a d i f f e r e n t mechanism5 *~ 5 5 . O Q CHoCOO" VIOQ^ nn CH3-HC-C-CH • H20 C H 3OOC OCoH 5 12 13 Two other compounds have also attracted attention, namely 3-ethoxy-2-oxobutanal hydrate (Kethoxal) J_2 and calcium elenoate 13. Kethoxal has been known since 1957 as a v i r u c i d a l agent for a wide variety of DNA and RNA viruses. It has been found active in tissue cultures against Cocksackie A 21 virus 'and also has shown a c t i v i t y in hamsters infected with parainfluenza 3 virus intranasally and treated i n t r a n a s a l l y 5 6 . Calcium elenolate i s also a wide spectrum e x t r a c e l l u l a r virus i n a c t i v a t o r . The free acid can be obtained from extracts of o l i v e plants. The s a l t J_3 has a low minimal e f f e c t i v e concentration when treated intranasally in hamsters infected with parainfluenza 3 and 15 showed no t o x i c e f f e c t s 5 7 " 5 9 . A l i c y c l i c Compounds U Adamantane d e r i v a t i v e s a r e t h e most e x t e n s i v e l y s t u d i e d c l a s s of a n t i v i r a l compounds i n t h i s g r o u p and p e r h a p s t h e most t h o r o u g h l y s t u d i e d a n t i v i r a l a g e n t s . The d i s c o v e r y of t h e a n t i v i r a l a c t i v i t y o f 1-aminoadamantane ( A m a n t a d i n e ) _1_4 a g a i n s t c e r t a i n s t r a i n s o f i n f l u e n z a v i r u s and i t s l a c k of t o x i c i t y 6 0 " 6 1 l e d t o q u i t e e a r l y c l i n i c a l s t u d i e s 6 2 . A mantadine i s p a r t i c u l a r l y a c t i v e a g a i n s t t h e A 2 s t r a i n of i n f l u e n z a v i r u s , l e s s e f f e c t i v e a g a i n s t t h e C s t r a i n and i n e f f e c t i v e a g a i n s t t h e B s t r a i n . I n man, t h e e f f i c a c y of a m a n t a d i n e was d e m o n s t r a t e d i n c o n t r o l l e d c l i n i c a l t r i a l s and shown t o be most e f f e c t i v e when a d m i n i s t e r e d p r o p h y l a c t i c a l l y a t t h e t i m e of i n f e c t i o n o r i n t h e e a r l y p h a s e o f t h e d i s e a s e . T h e r a p e u t i c a l l y , i t was r e p o r t e d t o s h o r t e n t h e c o u r s e of t h e d i s e a s e , r e d u c e s e v e r i t y of c l i n i c a l symptoms and s h o r t e n t h e d u r a t i o n of f e v e r . T h i s d r u g i s c u r r e n t l y s o l d i n i t s h y d r o c h l o r i d e form under t h e name "S y m m e t r e l " by Endo L a b o r a t o r i e s . W h i l e n o t y e t a p p r o v e d f o r use i n t h e U n i t e d S t a t e s , t h e d r u g i s w i d e l y u s e d i n E u r o p e and t h e S o v i e t U n i o n . D e t a i l e d s t u d i e s on t h e mode of a c t i o n of t h e d r u g i n d i c a t e d t h a t a d s o r p t i o n of v i r u s o n t o t h e c e l l s u r f a c e s 1 6 was apparently unaffected but that penetration of the virus nucleic acid was b l o c k e d 6 3 " 6 " . '2 15 Rimantadine Y5, a homologue of amantadine, in addition to being more e f f e c t i v e i_n v i t r o against influenza A 2, was also reported to i n h i b i t other RNA viruses such as rubella, rubeola, respiratory syncytial and parainfluenza viruses jjn v i t r o 6 5. A number of 2-substituted adamantanes have recently been claimed as a n t i v i r a l agents. The most outstanding one is the spiro compound _1_6 which was claimed to be three times more active j_n vivo against influenza A 2 Japan and A 2 Hong Kong than amantadine 6 6. A broader spectrum of a c t i v i t y was also observed which included a c t i v i t y against Cocksackie A 21 and rhino 2 viruses. 17 B e s i d e s the a f o r e m e n t i o n e d compounds, a l m o s t every c o n c e i v a b l e v a r i a t i o n on n i t r o g e n - c o n t a i n i n g adamantane d e r i v a t i v e s has been c l a i m e d i n the p a t e n t l i t e r a t u r e s t o have a n t i v i r a l a c t i v i t y a g a i n s t i n f l u e n z a s t r a i n s and r e l a t e d RNA v i r u s e s . O c c a s i o n a l l y DNA v i r u s e s were a l s o i n c l u d e d i n the spectrum of a c t i v i t y . B. S y n t h e t i c S t r a t e g y The d i s c o v e r y of the a n t i v i r a l and, perhaps more i m p o r t a n t l y , the a n t i - P a r k i n s o n ' s d i s e a s e p r o p e r t i e s of A m a n t a d i n e 3 9 has s t i m u l a t e d i n t e n s i v e r e s e a r c h i n t h e s y n t h e s i s and b i o l o g i c a l t e s t i n g of o t h e r p o t e n t i a l a n t i v i r a l and a n t i - P a r k i n s o n ' s d i s e a s e a gents r e l a t e d t o i t . In o b v i o u s a n a l o g y t o t h e main s t r u c t u r a l f e a t u r e s found i n Symmetrel, most r e s e a r c h has c e n t e r e d on p o l y c y c l i c s o - c a l l e d "cage" o r g a n i c compounds w i t h pendant n i t r o g e n - c o n t a i n i n g s i d e c h a i n s * ' 6 7 . The amino and a l k y l a m i n o d e r i v a t i v e s of almost e v e r y t r i - , t e t r a -and p e n t a c y c l i c o c t a n e , nonane, decane and undecane have been s y n t h e s i z e d and c l a i m e d i n the p a t e n t l i t e r a t u r e t o p o s s e s s a c t i v i t y a g a i n s t i n f l u e n z a v i r u s * . One example i s t h e s y n t h e s i s of t r i c y c l o [4. 4. 0. 0 3 »8]decan-1 - y l a m i n e _1_7 and o - m e t h y l t r i c y c l o -[4 .4.0.0 3» 8]decan-1-methylamine by Deslongchamps and c o - w o r k e r s 6 8 " 6 9 as i l l u s t r a t e d i n scheme I . Other s y m m e t r i c a l p o l y c y c l i c r i n g s k e l e t o n s which have been i n v e s t i g a t e d w i t h a view towards a n t i v i r a l a c t i v i t y i n c l u d e J_9 (cubane), p e n t a c y c l o -[6.2.0.0 2' 7.0*> 1 0.0 5» 9]decane 20, t e t r a c y c l o [5.3.O.O 2» 6.0*» 9]-decane 2J_ and t r i c y c l o [ 3 . 3 . 0 . 0 3 ' 7 ] o c t a n e 22 t o name a few. SCHEME 1 19 As can be imagined, the syntheses of nitrogen-substituted derivatives of these and other complex p o l y c y c l i c systems i s not a simple task; arduous multistep procedures are often required which severely l i m i t both the amount and variety of compounds which can be produced. In contrast, one major reason for the extensive interest in adamantane-based a n t i v i r a l agents has been their ready synthetic a v a i l a b i l i t y . F a c i l e general synthetic routes to other cage compounds would enable further studies of their properties as a n t i v i r a l and anti-Parkinson's agents. During the course of studying the photochemistry of reduced napthoquinones and their derivatives, Scheffer and co-workers 7 0 discovered a new and remarkably f a c i l e general entry into the tetrahydropentaprismane ( t e t r a c y c l o [ B . S . O . O 2 ' 6 . 0 * ' 9 ] d e c a n e ) ring variations in the compounds produced and in addition w i l l permit" the synthesis of r e l a t i v e large amount of materials. However, before turning into the d e t a i l s of the procedure, i t is appropriate to discuss previous patented work on the tetrahydropentaprismane system. R. J . Stedman at Smith Kline and French Laboratories has described the synthesis of compound 23 as well as a number of related d e r i v a t i v e s 7 1 . The synthetic sequence to 2_3 involves 15 system. This synthetic route allows numerous substituent 23 20 1. H 2 S0 4 6 2. NaOH , Toluene LSOCI2 2. NaN 3 , acetone •3- Toluene, A hi; ACETONE HO~N 1. cone. HCl THF * 2. anhy. pyridine, A 1.H2S04 2.NH2OH-HCl NaoAc MeOH 1.3N HCl, 90 C 2. HO(CH2)20H,A benzene, pTsOH. 3. Li,tBuOH,THF L i A lH A , A ? 2 3 SCHEME II 21 steps of which the key cage compound forming reaction i s the photoconversion of 24 to 25 (scheme I I ) . In addition to being sy n t h e t i c a l l y long, the pathway offers l i t t l e opportunity for substituent v a r i a t i o n ; furthermore, the star t i n g materials are expensive and not readily a v a i l a b l e (1,4-cyclohexadiene and tetrachlorocyclopentadiene ethylene k e t a l ) . Scheffer's approach to the tetrahydropentaprismane system also involves a photochemical step, namely the intramolecular [2 + 2] photocyclisation of 26 leading to 21_ (equation 1). A number of d i f f e r e n t l y substituted compounds of the general structure 2_7 have been successfully synthesized and in a l l cases the y i e l d i s good to excellent. These include 27a (R1=R2=CH 3); 27b (R,=H, R 2=CH 3); 27c (R,=R2=H); 27d (R,=CH3, R2=H). The 22 c o r r e s p o n d i n g a d d u c t s 26a-d a r e r e a d i l y p r e p a r e d v i a the two s t e p sequence shown above ( e q u a t i o n 2 ) . Both r e a c t i o n s l e a d i n g t o 261 a r e w e l l known and a r e e a s i l y p e r formed. In a d d i t i o n , a l a r g e number of 1,3-dienes and q u i n o n e s a r e e i t h e r c o m m e r c i a l l y a v a i l a b l e or r e a d i l y s y n t h e s i z e d , t h u s h i g h l y f u n c t i o n a l i s e d t e t r a h y d r o p e n t a p r i s m a n e s can be p r e p a r e d r e a d i l y . The o b j e c t i v e of t h i s p r o j e c t i s t o s y n t h e s i z e the m o l e c u l e s 1 1 - a z a - p e n t a c y c l o [6.2.1.0 2> 7.0' » 1 0.0 5' 9jdecane 28 and i t s d i m e t h y l analogue 4 , 5 - d i m e t h y l - 1 1 - a z a - p e n t a c y c l o -[6.2.1.0 2» 7.0*> 1 0 , 0 5 > 9 ] d e c a n e 29. Owing t o t h e i r s t r u c t u r a l 28 " 2 9 s i m i l a r i t i e s t o 1-aminoadamantane, t h e s e compounds might p o s s e s s a c t i v i t y a g a i n s t i n f l u e n z a v i r u s e s and/or P a r k i n s o n ' s d i s e a s e . The s y n t h e t i c s t r a t e g y i n v o l v e d i n the s y n t h e s i s of t h e s e two compounds i s based on two key p r o c e s s e s : (1) E x p l o i t a t i o n of the t h r e e - s t e p e n t r y t o the t e t r a h y d r o p e n t a p r i s m a n e s k e l e t o n , and (2) b u i l d i n g t h e heteroatom b r i d g e by t r a n s a n n u l a r c y c l i s a t i o n . The t r a n s a n n u l a r c y c l i s a t i o n methodology has been u l t i l i s e d s u c c e s s f u l l y f o r the s y n t h e s i s of the b r i d g e d e t h e r ( 1 1 - o x a - p e n t a c y c l o [ 6 . 2 . 1 . 0 2 • 7 . 0 " • 1 0.0 5» 9]decane) 30 by S c h e f f e r and c o - w o r k e r s 7 0 as d e p i c t e d by e q u a t i o n 3. The s y n t h e t i c p l a n s d e s i g n e d f o r amines 28 and £9 a r e shown i n scheme I I I . 31b R1-CH3 £ b R,=CH3 28 R,=H 3k R=H , R=H & a R=H £ R,=CH3 34b R,=Cr^ iR=CH3 3& R-=CH3 SCHEME III Transannular c y c l i s a t i o n s of appropriately functionalised molecules often provide a convenient method for preparation of 24 (R=C6H5CH2) ^N~R 1-5eq. L i A l H A A 2eq.NaBH4 O, NR H 1. H 2 Pd/C EtOH 2. HN0 2 NH 2 OH,H 2 0 ,A , EtOH OH N 7 IM^ OH H2,PtO,HCl, EtOH HNO2 NH •OH SCHEME IV 25 h e t e r o c a g e compounds which a r e o t h e r w i s e d i f f i c u l t t o o b t a i n . A w e l l known example i s the s y n t h e s i s of 1 - s u b s t i t u t e d 2-heteroadamantanes. u s i n g b i c y c l o [ 3 . 3 . 1 ] n o n a - 3 , 7 - d i o n e 3_5 as s t a r t i n g m a t e r i a l 7 2 . Both the oxygen and n i t r o g e n b r i d g e d compounds a r e o b t a i n e d i n good y i e l d and o n l y a few s t e p s a r e i n v o l v e d (scheme I V ) . T h i s example f u l l y d emonstrated the v e r s a t i l i t y of the methodology i n c o n s t r u c t i n g h e t e r o c a g e compounds. Another example from the l i t e r a t u r e , which i s more r e l a t e d t o the s y n t h e s e s of compounds 28 and 29, i s the p r e p a r a t i o n of h e t e r o - b i r d c a g e compounds such as 3_7 from p e n t a -c y c l o [ 6 . 2 . 1 . 0 2 ' 7 . 0 " ' 1 0 . 0 5 • 9 ] u n d e c a n - 3 , 6 - d i o n e 36 7 3 » 7 *. The t r a n s a n n u l a r c y c l i s a t i o n of d i k e t o n e 3_6 was f i r s t r e p o r t e d by Cookson and c o - w o r k e r s 7 5 . They r e p o r t e d t h a t c y c l i c h y d r a t e 3_7 was formed s l o w l y when 3_6 was exposed t o a t m o s p h e r i c m o i s t u r e ( e q u a t i o n 4 ) . In c o n t r a s t , S a s a k i and co-workers found t h a t 36 37 even a f t e r h e a t i n g compound 3_6 i n aqueous e t h y l a c e t a t e a t 60°C f o r t h r e e d a y s , the c y c l i c h y d r a t e c o u l d not be i s o l a t e d . I n s t e a d the monohydrate 3_8 was o b t a i n e d . H e a t i n g compound 38 a t 180°C r e c o n v e r t e d i t t o the d i o n e 36 w i t h l o s s of w a t e r , and no t r a c e of the t r a n s a n n u l a r c y c l i z e d h y d r a t e c o u l d be d e t e c t e d ( e q u a t i o n 5 ) 7 3 . In a d d i t i o n , the known k e t o - a l c o h o l 3_97 5 d i d 26 38 not c y c l i z e to the hemi-ketal even on heating at 270°C (equation 6). A l l these data indicated that the diketone 36 has a lower 39 transannular c y c l i s a t i o n r e a c t i v i t y as compared with system 3_5 which i s known to afford 1-hydroxy-2-oxa-adamantane on hydrogenation with Raney-Nickel 7 6, presumably via the i n t e r -mediacy of the keto-alcohol 40 (equation 7). Other trans-H 40 annular c y c l i s a t i o n s involving diketone 36 are i l l u s t r a t e d in scheme V 7 \ An interesting point to note i s the s e l e c t i v i t i e s of 27 SCHEME V 28 43 towards metal hydride reagents. Similar s e l e c t i v i t i e s have also been reported for the bicyclo [3.3 .1 ] nona-3,7-dione 3_5. The f a c i l e dehydration of the glycol type derivatives such as 4J_ and 44 to the corresponding oxa-bridged products could be ra t i o n a l i s e d by considering a r e l i e f of s t e r i c crowding of the two hydroxyl groups which are pointing toward each other. Summarising the results on transannular c y c l i s a t i o n s of dione 3_6, we can conclude that the transannular c y c l i s a t i o n r e a c t i v i t y of the three position OH group or i t s metal complex against the six position CO group i s very low . The i s o l a t i o n of the ketol 3_9, the hydrate 38 and monoamine adduct 42 j u s t i f y t h i s conclusion. On the other hand, very f a c i l e c y c l i s a t i o n is well known for the bicyclo[3.3.1]nona-3,7-dione (scheme IV). One approach to increase the transannular c y c l i s a t i o n r e a c t i v i t y of 3_6, as envisaged by Singh 7*, in order to prepare the oxa-birdcage compounds via a shorter route, is to activate the carbonyl groups with electron withdrawing groups. As expected, incorporation of electron withdrawing groups onto the diketone 36 rendered i t highly susceptible to transannular (8) 4 6 R = R ' = 0 H 4 7 R = 0 H R = O C 2 H 5 43 R = R = N H 0 H " 29 nucleophilic reactions. Thus, tetrachloro cage diketone 4 5 7 5 afforded oxa-birdcages 46-48 in excellent y i e l d when refluxed with aqueous 1,4-dioxane, ethanol, and hydroxylamine r e s p e c t i v e l y 7 * (equation 8 ) . Moreover , the c y c l i c hydrate £6 was also obtained when 45 was exposed to atmospheric moisture for a prolonged period. In contrast to the pentacyclo [ 6 . 2 . 1 . 0 2 ' 7 . 0 * • 1 0 . 0 5 » 9 ] -undecan-3,6-dione 36, the tetracyclo[5.3.0.0 2» 6.0 *» 9]decan-5, 8-dione 49 undergoes extremely f a c i l e transannular c y c l i s a t i o n s leading to oxa-bridged compounds. As reported by Scheffer and co-workers 7 0 the diketones 49 (R,=R2=H and R,=CH3, R2=H), which are produced by oxidation of the corresponding keto-alcohols 5_0 (R,=R2=H and R,=CH3, R2=H), are extremely sensitive to atmospheric moisture, in fact, the c y c l i z e d hydrates 5J_ (R,=R2=H and R1=CH3, R2=H) are the products isolated (equation 9 ) . (PCC=Pyr ic l in ium chlorochromate) 30 Furthermore, tosylation of 50 (R,=R2=H) followed by sodium borohydride reduction afforded the c y c l i c ether (equation 3) in very high y i e l d . As pointed out e a r l i e r by Cookson 7 5, the formation of the transannular c y c l i z e d hydrate of 52 (equation 10) depends to a 52 large extent on the distance and angle between the two carbonyl groups. Due to the r i g i d i t y of the cage structure, the distance and angle w i l l in turn depend to a certain extent on the size of the bridge X. Cookson has reported that the formation of the c y c l i c hydrate 52 (X=CH2CH2) was a highly f a c i l e process as compared with i t s one carbon-bridged analogue 52 (X=CH2). Examination of the models of compounds 36 and 5_3 reveals that the one-carbon bridge in 3_6 causes the other side of the cage to expand, thus the distance and angle between the two carbonyl groups are greater than those of 53. Moreover, the distance between the sp 2 carbonyl carbon atom and the alkoxy oxygen attached to the sp 3 carbon of the intermediate 31 d u r i n g c y c l i s a t i o n i n 3_6 i s g r e a t e r than t h a t of 5_3 which a g a i n would lower the c y c l i s a t i o n r e a c t i v i t y of 36. 36' S3 F i n a l l y , t r a n s a n n u l a r c y c l i s a t i o n of compound 36 would l e a d t o a b i r d c a g e m o l e c u l e of the s t r u c t u r e 54 which i s h i g h l y s t r a i n e d w h i l e c y c l i s a t i o n of compound 5_3 produces a " h a l f - b i r d c a g e " m o l e c u l e 5_5 which i s o b v i o u s l y l e s s s t r a i n e d and t h e r e f o r e more 54 55 f a v o u r a b l e from a thermodynamic p o i n t of view. The above q u a l i t a t i v e d e s c r i p t i o n p r o v i d e s a s a t i s f a c t o r y e x p l a n a t i o n of the d i f f e r e n c e i n t r a n s a n n u l a r c y c l i s a t i o n r e a c t i v i t y between m o l e c u l e s 3_6 and 5_3 and prompts us t o u l t i l i s e i t f o r the s y n t h e s e s of compounds 2_8 and 29. 32 Results and Discussion A. Synthesis of 11-Aza-pentacyclo[6.2.l.0 2» 7.0*« 1 o.0 8* 9 1decane The f i r s t intermediate of the synthesis, the tetrahydronapthoquinone 31a, was prepared via the Diels-Alder addition of 1,3-butadiene to p-benzoquinone following the procedure of van Tamelen and co-workers 7 7 (71%). Compound 31 a was found to be r e l a t i v e l y ..unstable. Upon standing at room temperature, i t decomposed slowly and changed from yellow needles to greyish white powder. Reduction of 31 a using sodium borohydride as the reducing agent afforded the hydroxycyclohexeneone 7 0 32a (70%). The s t e r e o s p e c i f i c i t y of the reduction can be explained by Baldwin's "approach vector analysis" concept 7 8. H OH 32a As postulated by Baldwin, during the course of hydride reduction of a l i c y c l i c ketones such as cyclohexanone, the hydride reagent would attack the carbonyl group along a plane containing the C-0 bond and orthogonal to the plane containing the ketone and i t s two substituents; the angle between the l i n e of attack of the hydride and the C-0 bond i s approximated to be 110° based on inversions in the bent or banana bond model of 33 u n s a t u r a t i o n 7 9 . The p r o j e c t i o n of the t r a j e c t o r y of the h y d r i d e a t t a c k i s shown as 56. S i n c e the h y d r i d e can a t t a c k from e i t h e r the t o p or bottom f a c e of the m o l e c u l e , i t i s e v i d e n t t h a t a x i a l s u b s t i t u e n t s a t both the a and i p o s i t i o n s , w i t h r e s p e c t t o the k e t o n i c f u n c t i o n , c o u l d impede the motion of the h y d r i d e r e agent on these t r a j e c t o r i e s . For an o , ^ - u n s a t u r a t e d ketone such as c y c l o h e x e n o n e , t h e r e a re two resonance forms. As a r e s u l t t h e r e a r e two modes of h y d r i d e a t t a c k as d e p i c t e d w i t h 57 and 58. The c o r r e s p o n d i n g r e s u l t a n t approach v e c t o r i s d e r i v e d by summation of v e c t o r s f o r the two s t r u c t u r e s 5_7 and 58 ( w e i g h t s c, and c 2 ) as i n 59. P r o j e c t i o n 5_9 shows t h a t approach of the h y d r i d e t o 57 58 59 the enone c a r b o n y l s h o u l d be v e r y s e n s i t i v e t o q u a s i - a x i a l s u b s t i t u e n t s a t C(6) and C ( 5 ) . In B a l d w i n ' s a n a l y s i s of s i x t e e n c a s e s of c y c l o h e x e n o n e r e d u c t i o n 7 8 t h i s approach v e c t o r a n a l y s i s method l e a d s t o e x c e l l e n t agreement w i t h e x p e r i m e n t s , i n t h a t q u a s i - a x i a l s u b s t i t u e n t s a t C(6) and C(5) of 59 appear t o 34 control the stereochemistry of reduction t o t a l l y , whereas those at C(4) show very l i t t l e e f f e c t . The weightings of substituents, formulated by Baldwin based on their size and proximity to the hydride trajectory, are shown below according to t h e i r r e l a t i v e e f f e c t . 6 quasi-axial CH3 > 6 quasi-axial H > 5-quasi-axial H and 5 quasi-axial CH3 > 6 quasi-axial H. Examination of models of 31 a reveals that both the CH2 group at C(4a) and the hydrogen at C(8a) occupy the quasi-axial positions. According to Baldwin's rule, the quasi-axial CH2 at the C(4a) position causes greater impedence to the hydride reagent. As a r e s u l t , the sodium borohydride attacks the ketonic function from the top face and produces the hydroxycyclohexeneone 32a whose OH group i s anti to the bridgehead hydrogens. A similar result for compound 6p_ was also reported by Baldwin 7 8 (the ketone marked by an asterik was reduced to the hydroxyl group). The sodium borohydride reduction of 31a turned out to be a d i f f i c u l t reaction. It was highly sensitive to the purity of the substrate and to a lesser extent, the purity of the solvent 35 used. S m a l l amounts of i m p u r i t i e s (as d e t e c t e d by t h i n l a y e r chromatography) p r e s e n t i n the s u b s t r a t e caused the y i e l d t o d r o p d r a s t i c a l l y . A t t e m p t i n g t o use e t h a n o l i n s t e a d of methanol as s o l v e n t r e s u l t e d i n complete f a i l u r e of the r e a c t i o n f o r unknown r e a s o n s . Futhermore, when t h e s c a l e of the r e a c t i o n exceeded a c e r t a i n l i m i t ( c a . 2g of n a p t h o q u i n o n e ) , a s u b s t a n t i a l drop i n r e a c t i o n y i e l d was o b s e r v e d . Hoping t o improve the p r o d u c t i o n of 32a, o t h e r r e d u c t i o n methods were e x p l o r e d . D i i s o b u t y l a l u m i n i u m h y d r i d e r e d u c t i o n of 31a c a r r i e d out a t 0°c u s i n g benzene as s o l v e n t 8 0 a f f o r d e d o n l y a s m a l l amount of d e s i r e d p r o d u c t . A s u b s t a n t i a l amount of a new p r o d u c t was formed i n s t e a d which was not i d e n t i f i e d . R e d u c t i o n of 31 a employing sodium b o r o h y d r i d e and c e r i u m t r i c h l o r i d e 8 1 gave o n l y minute amounts of 32a. However a new p r o d u c t was produced i n good y i e l d (>90%) which was s u s p e c t e d t o be compound 6_1_. In fact., t h i s method was l a t e r employed t o s y n t h e s i z e the c y c l o h e x e n e d i o l 6 2 8 2 . R e d u c t i o n of 31a u s i n g sodium b o r o h y d r i d e as the r e d u c i n g agent w i t h the presence of ammoniun c h l o r i d e 8 3 a l s o d i d not p r o v i d e any improvement. H O H H O H £1 H OH H O H .62 36 A f t e r t h e s e u n s u c c e s s f u l a t t e m p t s , we d e c i d e d t o f o l l o w the o r i g i n a l method. P h o t o l y s i s of 32a i n benzene (X > 330nm) p r o v i d e d t h e cage k e t o - a l c o h o l 33a i n good y i e l d ( 9 0 % ) . As mentioned e a r l i e r , a number of d i f f e r e n t l y s u b s t i t u t e d cage k e t o - a l c o h o l s such as 27a and 27b were a l s o p r e p a r e d s u c c e s s f u l l y 7 0 . bR fH,R2=CH3 ^ The p h o t o c h e m i s t r y of n a p t h o q u i n o l s and napthoquinones was f i r s t r e p o r t e d by S c h e f f e r and co-workers d u r i n g t h e c o u r s e of t h e i r i n v e s t i g a t i o n of the t e t r a h y d r o n a p t h o q u i n o n e s 63a (R=H) and 63b (R=CH3) 8 1 1. They found t h a t when compounds 63a and 63b were p h o t o l y s e d under the same c o n d i t i o n s as f o r 32a, no cage p r o d u c t s can be o b t a i n e d . I n s t e a d p h o t o p r o d u c t s 64 ( ( a ) R=H, (b) R=CH 3), 6_5 ( ( a ) R=H, (b) R=CH 3) and 66 ( o n l y f o r 63b) were i s o l a t e d (scheme V I ) . In c o n t r a s t , the endo D i e l s - A l d e r adducts of p-benzoquinone w i t h c y c l i c 1,3-dienes a r e w e l l known t o g i v e cage p r o d u c t s upon p h o t o l y s i s v i a i n t e r n a l 2+2 c y c l i s a t i o n 8 5 . The proposed mechanism f o r t h e f o r m a t i o n of t h e s e t r i c y c l i c p r o d u c t s i s summarised i n scheme V I . The e x c i t e d napthoquinone m o l e c u l e undergoes ^-hydrogen a b s t r a c t i o n v i a a five-membered t r a n s i t i o n s t a t e , f o r m i n g a b i r a d i c a l s p e c i e s which then recombines i n d i f f e r e n t f a s h i o n s l e a d i n g t o 37 R* O 63 X > 330nm — (3-Hydrogen Abstraction HO O 1,6-Bonding R \ H 3 C CH 66 3,8-Bonding R HQ SCHEME VI 38 the o b s e r v e d p r o d u c t s 8 * . Thus by t r a n s f o r m i n g one of the c a r b o n y l groups i n compounds 63a and 63b i n t o a h y d r o x y l group, the p h o t o l y s i s pathway was a l t e r e d c o m p l e t e l y . There appear t o be a t l e a s t two p o s s i b l e r e a s o n s f o r t h i s . F i r s t l y , t h e c a r b o n y l group of t h e b i r a d i c a l r e s u l t i n g from hydrogen a b s t r a c t i o n u ndoubtedly e x e r t s a s t a b i l i s i n g i n f l u e n c e on t h i s s p e c i e s through resonance and hence f a c i l i t a t e s hydrogen a b s t r a c t i o n . S e c o n d l y , the enone chromophore of the c y c l o h e x e n o n e s such as 32a i s a p o o r e r e l e c t r o n a c c e p t o r as compared t o the 2-ene-1,4-dione moiety of the p r e c u r s o r , 63a w h ich, i t would be argued, i n d i c a t e s t h a t a c h a r g e - t r a n s f e r i n t e r a c t i o n between the c y c l o h e x e n e double bond and the e x c i t e d ene-dione system i s r e q u i r e d f o r subsequent p-hydrogen t r a n s f e r 7 0 . I n t r a m o l e c u l a r e x c i t e d - s t a t e c a r b o n y l ( a c c e p t o r ) amine(donor) c h a r g e - t r a n s f e r i n t e r a c t i o n s l e a d i n g t o i n t e r n a l hydrogen a b s t r a c t i o n s a r e w e l l e s t a b l i s h e d . The f a c t t h a t amines and d i - , t r i - , and t e t r a s u b s t i t u t e d a l k e n e s have s i m i l a r i o n i s a t i o n p o t e n t i a l s l e n d s s u p p o r t t o the i d e a t h a t i n t r a m o l e c u l a r c h a r g e - t r a n s f e r e x c i p l e x f o r m a t i o n may be i m p o r t a n t i n the p h o t o c h e m i s t r y of 63a and o t h e r r e l a t e d compounds 8 6 . The o r i g i n a l p l a n of the s y n t h e s i s a f t e r o b t a i n i n g 33a was t o p r e p a r e the c o r r e s p o n d i n g oxime m e t h y l e t h e r by c o n d e n s i n g i t w i t h methoxyamine h y d r o c h l o r i d e . M e s y l a t i o n of t h e oxime e t h e r f o l l o w e d by r e d u c t i o n would t h e r e f o r e p r o v i d e the d e s i r e d p r o d u c t 2_8 (scheme V I I ) . Thus by r e f l u x i n g 33a w i t h methoxyamine h y d r o c h l o r i d e i n methanol and water i n the presence 39 33a 28 NH <-67 N - O C H 3 -H OSO2CH3 SCHEME Vn of potassium acetate for 65 hours, the oxime ether was produced. The mesylate 67 was prepared by reacting the oxime ether with methanesulphonyl chloride in methylene chloride at 0°C in the presence of triethylamine and a trace amount of 4-dimethylamino pyridine (70%). Compound 67 was then subjected to reduction using sodium trifluoroacetoxyborohydride as the reducing agent 8 7. The reduction afforded a complex mixture. Attempts to purify t h i s mixture met with f a i l u r e , and th i s reduction method was then abandoned. The next attempt was to reduce 6_7 employing borane-methyl sulphide as the reducing agent 8 8. Again, a mixture was obtained from which a highly v o l a t i l e pale yellow o i l with a d i s t i n c t v e smell was isolated (35%). The mass spectrum of t h i s compound displayed an intense peak at m/e 177, presumably the molecular ion peak, and suggested a molecular formula of C^H^NO. The 20MHz 1 3C NMR spectrum consisted of eleven peaks located between 6 23 and 8 73 and appeared in the 40 form of f i v e d o u b l e t s and one s i n g l e t . I t s 400 MHz 'H NMR spectrum was f a i r l y s i m p l e , d i s p l a y i n g s h a r p d o u b l e t s and broad s i n g l e t s . Futhermore, t h e r e were two s h a r p s i n g l e t s a t o 3.53 and o 3.59, b o t h i n t e g r a t i n g f o r t h r e e hydrogens, which i n d i c a t e d t h e p r e s e n c e of two methoxy groups. Combining a l l the s p e c t r a l d a t a , i t was deduced t h a t t h i s m a t e r i a l was a m i x t u r e of compounds 68 and 6j). The two s h a r p s i n g l e t s a p p e a r i n g i n the 'H NMR spectrum c o u l d then be a s s i g n e d t o the p r e s e n c e of the two isomers d i f f e r i n g i n c o n f i g u r a t i o n a t the a p i c a l n i t r o g e n atom. 58 69 I t i s known 8 9 t h a t i f an atom p o s s e s s e s a nonbonding p a i r of e l e c t r o n s and i s bonded t o t h r e e o t h e r groups i n a p y r a m i d a l f a s h i o n , i t may undergo u n i m o l e c u l a r i n v e r s i o n of c o n f i g u r a t i o n . At the t r a n s i t i o n s t a t e t o t h i s p y r a m i d a l i n v e r s i o n , the c e n t r a l atom i s t r i g o n a l l y h y b r i d i s e d and the l o n e p a i r i s i n a p o r b i t a l . The n i t r o g e n i n v e r s i o n p r o c e s s has been s t u d i e d e x t e n s i v e l y . In an e a r l y s t u d y , B o t t i n i and R o b e r t s 9 0 observed t h a t n i t r o g e n i n v e r s i o n i n a z i r i d i n e s i s d e t e c t a b l e by v a r i a b l e t e m p e r a t u r e NMR methods. One compound t h a t was s t u d i e d was 1 - e t h y l a z i r i d i n e 70. The NMR spectrum of TO o b t a i n e d a t room temp e r a t u r e showed the c h a r a c t e r i s t i c bands of the e t h y l group and two t r i p l e t band systems which were i n t e r p r e t e d as b e i n g due 41 to the two non-equivalent groups of r i n g hydrogens which are e i t h e r c i s or t r a n s to the N - e t h y l group (equation 11). On H H H 7 0 Et / H H H H \ (11) Et heating to 108°+5°C, the r i n g hydrogens appeared to l o s e t h e i r i d e n t i t y with respect to the e t h y l group and a broad s i n g l e t was observed. As can be imagined, when compound 7_0 undergoes i n v e r s i o n , the energy o f the t r a n s i t i o n s t a t e would be r e l a t i v e l y high as compared to the open c h a i n analogue due to severe bond angle s t r a i n (the n i t r o g e n atom i s s p 2 h y b r i d i s e d ) . One would t h e r e f o r e expect that when the r i n g s i z e i s i n c r e a s e d , the i n v e r s i o n b a r r i e r would be lowered and the process a c c e l e r a t e d . T h i s was indeed observed in the s e r i e s 7J_ - 7 3 9 1 . V 71 72 73 Besides bond angle s t r a i n , the i n v e r s i o n b a r r i e r c o u l d a l s o be r a i s e d by r e p l a c i n g the N - a l k y l s u b s t i t u e n t with one that i s more e l e c t r o n e g a t i v e . By t h i s means the S c h a r a c t e r of the ground s t a t e lone p a i r i s i n c r e a s e d 8 9 ; s i n c e the t r a n s i t i o n s t a t e lone p a i r must s t i l l be p - h y b r i d i s e d , the b a r r i e r i s 42 increased. An example to i l l u s t r a t e t h i s phenomenon i s compound 74 in which . the coalescence temperature of the ring hydrogen signals l i e s above the temperature at which the sample decomposes (>180°C) (cf. Compound 70). I H H 74 The i s o l a t i o n of the syn and anti isomers (compounds 68 and 69) was therefore not unexpected. The t r a n s i t i o n state for the inversion process involves an increase in the C-N-C bond angle in order to obtain a sp 2 configuration, and since the cage structure i s highly r i g i d , the process i s energetically unfavourable. Moreover, the nitrogen atom is attached to the electronegative oxygen which would further increase the inversion barrier for the reason mentioned above. In accord with these observations, the NMR spectrum obtained at 55°C was i d e n t i c a l to that obtained at room temperature. At t h i s stage, we f e l t much relieved and there remained only one step to f i n i s h the synthesis. Several methods were attempted in order to replace the methoxy group by a hydrogen atom. Sodium amalgam r e d u c t i o n 9 2 , hydrogenation over palladium on c h a r c o a l 9 3 and lithium aluminium hydride reduction 9* provided no f r u i t f u l r e s u l t s . In each of the above cases, the starting material was recovered unchanged even after prolonged reaction times and using large excesses of reagents. Zinc-acetic acid 43 reduction 9* afforded a complex mixture, and no attempt at p u r i f i c a t i o n was carried out. F i n a l l y , we decided to abandon the route. After reviewing the o r i g i n a l synthetic plan, we considered a change in strategy. Instead of ef f e c t i n g the preparation of the amino functional group and c y c l i s a t i o n in a single step, i t was f e l t that carrying out these reactions in two separate steps might provide f r u i t f u l r e s u l t s . The new plan was therefore to f i r s t transform the cage keto-alcohol 33a into an amino-alcohol 75, and then to modify the hydroxyl group into a good leaving group such as mesylate which we expected once formed, would c y c l i z e d spontaneously to give 2_8. With this idea in mind, reductive amination of 33a with ammonium acetate in the presence of sodium cyanoborohydride was attempted 9 5. Even by prolonging the reaction time, no reaction was observed, and the star t i n g material was recovered t o t a l l y unchanged. Since the oxime methyl ether of 33a had been prepared successfully, we expected to obtain the oxime 34a by adopting the same method. By refluxing keto-alcohol 33a with hydroxylamine hydrochloride in methanol and water overnight in the presence of potassium acetate, oxime 34a 9 6 was in fact produced (75%). Expecting to obtain the amino-alcohol 75, 34a was subjected 44 t o a l uminium h y d r i d e r e d u c t i o n f o l l o w i n g the p r o c e d u r e of Brown and Y o o n 9 7 . The r e a c t i o n l e d t o a m i x t u r e which was d i f f i c u l t t o p u r i f y . The f i r s t s u c c e s s f u l s e p a r a t i o n was a c h i e v e d by p r e p a r a t i v e gas l i q u i d chromatography ( 8 % 0V17, 150°C) and a compound was i s o l a t e d which was not 75^  but appeared t o be the d e s i r e d f i n a l p r o d u c t 2_8. T h i s compound d i s p l a y e d an i n t e n s e peak a t m/e 147, presumably the m o l e c u l a r i o n peak, i n i t s mass spectrum; i n a d d i t i o n , i t s 270MHz 'H NMR spectrum was almost i d e n t i c a l w i t h t h a t of the c y c l i c e t h e r 30. From th e 1H NMR d a t a (page 6 3 ) , the s t r u c t u r e of t h i s compound was c o n f i r m e d t o be 28 beyond doubt. 30 28 A f t e r much - e f f o r t , i t was found t h a t by chromatographing the r e a c t i o n r e s i d u e on an a l u m i n a column ( n e u t r a l , Woelm, a c t i v i t y grade I I I ) and e l u t i n g w i t h c h l o r o f o r m - m e t h a n o l ( 9 3 : 7 ) , the d e s i r e d amine 28_ c o u l d be i s o l a t e d i n 30% y i e l d . Compound 28 was a. v o l a t i l e s o l i d ; an a ttempt t o r e c r y s t a l l i z e i t from c h l o r o f o r m t u r n e d out t o be d i s a s t r o u s . The amine decomposed and a t l e a s t t h r e e compounds were formed (as d e t e c t e d by gas l i q u i d chromatography) which were not i d e n t i f i e d . To overcome t h i s problem, the p i c r i c a c i d s a l t was p r e p a r e d by m i x i n g a s a t u r a t e d p i c r i c a c i d s o l u t i o n i n benzene w i t h a c o n c e n t r a t e d s o l u t i o n of the amine i n c h l o r o f o r m . The s a l t which was formed 45 precipitated out from the solution and was isolated by f i l t r a t i o n (80%). The picrate of 28_ was extremely stable, non-volatile and was f u l l y characterised. The amine-picrate was reconverted to the free amine by treatment with lithium hydroxide, and dry hydrogen chloride was then bubbled through a chloroform solution of the reliberated amine u n t i l the pH was less than 2. Removal of solvent afforded the hydrochloride of compound 28 (87%). The b i o l o g i c a l testing of the amine-hydrochloride i s being carried out by Dr. Steven Sacks of the U.B.C. Faculty of Medicine. The compound was found to be inactive towards herpes viruses while the results of the tests of potency against influenza yiruses are s t i l l pending. The 270 MHz 'H NMR spectrum of the hydrochloride of 28 is extremely simple and interesting (figure 1 ) . The sim p l i c i t y of the spectrum is explained by the presence of a mirror plane in the molecule. As indicated in the spectrum, the inner C(3) and C(6) hydrogens in thi s ring system experience deshielding via s t e r i c compression res u l t i n g in a r e l a t i v e l y large chemical s h i f t difference between the inner and outer hydrogens at these positions. It is well known 9 6 that when a substituent atom i s held r i g i d l y at a distance from the resonating nucleus that i s less than the sum of the van der Waals r a d i i , the substituent atom w i l l repel electrons from the resonating atom which is therefore deshielded. The magnitude of the effect f a l l s off very rapidly with increasing internuclear distance and i t depends c r i t i c a l l y on the size and p o l a r i s i b i l i t y of the nuclei. A similar deshielding e f f e c t has been observed in the 11 10 CHCl 3 TM5 8 7 6 5 ^ - 3 Figure 1 A 270 MHz 'H NMR spectrum of the hydrochloride of compound 28. 0 47 tetracyclo[4.2.1.1 2' 5.O 3» 7]decane cage structure, for example compound 7_6, in which the chemical s h i f t differences of the inner and outer H's at C(9) and C(10) are 1.01 6 and 0.8 h r e s p e c t i v e l y " . Possibly the most dramatic example which has been observed i s in the cage compound 77_ where the chemical s h i f t s of H, and H 2 are 6 3.55 and 8 0.88 r e s p e c t i v e l y 1 0 0 . The doublet centred at 6 1.25 (J=13HZ) represents the outer hydrogen atoms at C(3) and C(6). The other doublet centred at 5 1.62 (J=13Hz) represents the inner hydrogens at C(3) and C(6). The singlet at 6 4.12 i s assigned to the hydrogen atoms at C(1) and C(8) due to i t s low chemical s h i f t (adjacent to nitrogen). The singlet at S 2.77 is assumed to be the C(4) and C(5) hydrogen signals since they are furthest away from the nitrogen as compared with the C(2), C(7) and C(9), C(10) hydrogens. Defin i t e assignments of the two remaining singlets at 6 2.91 and 6 3.10 were not attempted. Even though a D 20-exchanged spectrum was not obtained, the broad peak centred at 6 9.69 is assigned with confidence to the 48 hydrogens attached to nitrogen. The structure of the compound was further confirmed by i t s 20 MHz 1 3C NMR spectrum which displayed five signals at 8 24.68, S 34.39, 8 40.23, 8 41.24 and 6 64.62. The signal at 8 24.68 was assigned to C(3) and C(6) while the one at & 64.62 was assigned to C(1) and C(8) due to their r e l a t i v e l y low chemical s h i f t s (adjacent to nitrogen). The signal at 8 34.39 was assigned to C(4) and C(5) since they are furthest away from the nitrogen. Definite assignment of the remaining resonances was not attempted. It was unexpected to obtain the amine 28 from the aluminium hydride' reduction of oxime 34a. The proposed mechanism of the reaction i s i l l u s t r a t e d in scheme VIII. We suggest that the f i r s t step i s the reaction of the oxime with the hydride to form a derivative 7_8 with evolution of hydrogen. Addition of another molecule of alumimium hydride to the carbon-nitrogen double bond could then occur, forming 7_9. Cleavage of the nitrogen-oxygen 28 80 SCHEME VIE 49 bond with concomitant hydride transfer to the nitrogen would produce 8Jh The sequence of 34a to 8_0 was o r i g i n a l l y proposed by Brown and Yoon 9 7. Compound 80 could then be attacked by another molecule of aluminium hydride and give the corresponding c y c l i z e d intermediate which on work up, would give the amine 28. Synthesis of 4,5-Dimethyl-11-aza-pentacyclo- [6. 2 . 1 . 0 2 ' 7. 0 4 *1 0 . 0 5 i 9 ] decane The 6,7-dimethyl-4a£,5,8,8ap-tetrahydro-1,4-napthoquinone (31b) was prepared via the Diels-Alder addition of 2,3-dimethyl-1,3-butadiene to p-benzoquinone following the method of Mandelbaum and C a i s 1 0 1 (80%). The problems associated with the sodium borohydride reduction of 31 a were also encountered here. Again by c o n t r o l l i n g the purity of the napthoquinone and the solvent, these problems were minimised and the corresponding hydroxycyclohexenone 32b 7 0 was obtained (70%). I r r a d i a t i o n (X. > 330nm) of compound 32b as a benzene solution provided the cage keto-alcohol 33b (70%). The oxime of 33b was 0» 33b 50 prepared by employing the same method used for preparing 34a and then subjected to aluminium hydride reduction. An unexpected problem arose, namely the r e l a t i v e i n s o l u b i l i t y of the dimethyl oxime in tetrahydrofuran (THF), the solvent recommended for the r e a c t i o n 9 7 . An attempt to use the dimethyl oxime as a suspension in THF was unsuccessful; substantial amounts of the star t i n g material were recovered and only trace amounts of the desired product 2_9 could be iso l a t e d . To overcome th i s problem, i t was decided to use other suitable nitrogen derivatives of 33b as precursors for 29. The f i r s t derivative that was investigated was the corresponding benzylimine, which presumably could be obtained by condensing 33b with benzylamine. Unfortunately, even by prolonging the reaction period and using a large excess of amine, the desired imine could not be obtained and the s t a r t i n g material was recovered. Hoping to improve the reaction, the experiment was repeated using titanium tetrachloride as c a t a l y s t 1 0 2 . A new product was obtained (40%) together with the star t i n g material and small amounts of unidentified side product. This new product displayed an intense absorption band at 1730 cm"1 (C=0) and a weak but sharp band at 3300 cm"1 (N-H) in i t s infrared spectrum. Combining these data with those obtained from a high resolution mass spectrum (m/e 281.1779), 1 3C and 'H NMR spectra, t h i s new compound was tent a t i v e l y assigned the structure 81. Two mechanisms are proposed for the formation of 8_1 which are depicted in scheme IX. For path a, coordination of titanium 51 SI SCHEME IX 52 with the carbonyl oxygen could occur which would f a c i l i t a t e attack of the carbonyl carbon by the amine. Coordination of the hydroxyl oxygen with titanium together with formation of hydrogen chloride might also occur concomitantly. Transannular c y c l i s a t i o n could then follow, forming the c y c l i c ether which might be attacked by the benzylamine and 8J_ would be formed. For path b, we propose that the f i r s t step would be the formation of the imine. Reaction of the hydroxyl group with the Lewis acid might also occur concurrently. Coordination of titanium with the imino nitrogen could then occur followed by intramolecular hydride transfer (analogous hydride transfer process in other s t r u c t u r a l l y similar cage systems had been observed' 0 3) and regenerate the ketone functional group. Cleavage of the titanium and nitrogen bond during work up would give 81. The next nitrogen derivative which was considered to be suitable as a precursor for 2_9 was the oxime methyl ether 34b. Thus, by refluxing 33b with methoxyamine hydrochloride overnight in methanol and water in the presence of potassium acetate, the desired oxime ether was prepared in excellent y i e l d (92%). An interesting point to note i s the apparent higher r e a c t i v i t y of the carbonyl group in 33b as compared with that of 33a; the condensation of 33a with methoxyamine hydrochloride leading to the corresponding oxime ether took a much longer time (more than 60 hours) to complete for unknown reasons. Subjecting 34b to aluminium hydride reduction gave the amine 2_9 after chromatographic p u r i f i c a t i o n (21%) using an alumina column D 20 E X C H A H G E 0 ? N N H 2 0 - \0 / N2° 0 2 N L H 2 0 D M S O J L U 3 2 Fiqure 2 A 400 MHz 'H NMR spectrum of the p i c r a t e of compound 29 54 ( n e u t r a l , Woelm, a c t i v i t y grade I I I ) and e l u t i n g with chloroform-methanol ( 9 2 : 8 ) . The 4 0 0 MHz 1H NMR spectrum of the p i c r a t e of 29 ( f i g u r e 2) resembles that of the h y d r o c h l o r i d e of 28^  ( f i g u r e 1 ) . Again, due to the e x i s t e n c e of a m i r r o r symmetry plane, the spectrum i s s i m p l i f i e d . The doublet c e n t r e d at 8 1 . 0 5 ( J = 1 2 Hz) i s assign e d to the outer hydrogen atoms at C(3) and C ( 6 ) while the doublet c e n t r e d at 8 1 . 5 7 (J=12HZ) i s assign e d as the inner hydrogen atoms at these p o s i t i o n s . The r e l a t i v e l y l a r g e d i f f e r e n c e i n chemical s h i f t between the inner and outer hydrogens can a l s o be e x p l a i n e d by the d e s h i e l d i n g e f f e c t v i a s t e r i c crowding of the inner h y d r o g e n s 9 9 1 0 ° . The sharp s i n g l e t at 8 1 . 1 6 r e p r e s e n t s the two methyl group hydogens at C ( 4 ) and C ( 5 ) . The s i n g l e t at 8 4 . 1 6 i s a s s i g n e d t o the hydrogen atoms at C ( 1 ) and C ( 8 ) due to t h e i r low chemical s h i f t (adjacent to n i t r o g e n ) . Ambiguity a r i s e s i n the assignment of the two broad s i n g l e t s at 8 2 . 4 0 and 8 2 . 5 6 ; undoubtedly these two s i g n a l s represent the C ( 2 ) , C ( 7 ) and C ( 9 ) , C ( 1 0 ) hydrogens but a d e f i n i t e assignment cannot be made without e x t r a i n f o r m a t i o n . A f i n a l p o i n t concerning the spectrum i s the apparent " l o s s " of the amino hydrogen s i g n a l s . The sharp s i n g l e t at 8 8 . 5 7 i s d e f i n i t e l y the two aromatic r i n g hydrogens of the p i c r a t e ; c l o s e r examination r e v e a l s that the 55 base of the peak is somewhat broadened and the t o t a l integration of t h i s signal is between three and four hydrogens. Upon D 20 exchange, t h i s broad shoulder disappeared. Therefore, we suggest that the shoulder i s the signal of the amino hydrogens and since i t i s so broad, the integration i s inaccurate. 56 Exper imental General Melting points were determined on a Fisher-Johns hot-stage or Gallenkamp (sealed tube samples) melting point apparatus and are uncorrected. Infrared (IR) spectra were recorded on Perkin-Elmer Model 701B, 257 and 137 spectrophotometers using potassium bromide discs for s o l i d samples and a thin f i l m pressed between two sodium chloride plates for pure l i q u i d s . The IR spectra were calibr a t e d with the 1601cm"1 band of polystyrene. The assignment of each absorption i s indicated in parentheses after each band. Proton nuclear magnetic resonance (NMR) spectra were recorded with Varian HA-100, Nicolet-Oxford H-270 or Bruker WH-400 spectrometers. 1 3C NMR spectra were recored with Varian CFT-20 and Bruker WP-80 spectrometers. The signal positions are reported using tetramethylsilane as internal standard. For 1H NMR spectra, the m u l t i p l i c i t y , integrated peak area, coupling constant and proton assignments ( i f possible) are indicated in parentheses after the signa l . Mass spectra (ms) were obtained on a Varian/MAT Atlas CH-4B mass spectrometer which was operated at an ionising potential of 70 electron v o l t s . Elemental analyses were performed by the departmental microanalyst, Mr. P. Borda. For gas l i q u i d chromatography (GLC), a Hewlett Packard 5380A flame ionisation model was used; K grade nitrogen was the c a r r i e r gas. The column used was 5% OV 17 on Chromosorb W 80/100 mesh operated at a flow of 30 ml per minute. For s i l i c a gel column 57 chromatography, the "flash chromatography" technique 1 0" was employed. The columns were slurry packed in the eluting solvent with S i l i c a Gel 60 (from E. Merck), 230-400 mesh ASTM. For alumina column chromatography, Woelm alumina (from ICN) of a c t i v i t y grade III (deactivated according to instructions) was used; the column were slurry packed in the eluent and run without application of pressure. Tetrahydrofuran (THF) was p u r i f i e d by refluxing over sodium metal in the presence of benzophenone u n t i l a persistent deep blue colour was observed, then d i s t i l l e d prior to use. Lithium aluminium hydride (LAH) solution in THF was prepared following the procedure of Brown and Yoon 9 7. In one t y p i c a l preparation, about 9g of LAH (95+% pure, Alfa) was added to 125ml of p u r i f i e d THF. The mixture was s t i r r e d overnight under nitrogen and f i l t e r e d through one and a half inches of C e l i t e (previously dried in the oven) and one inch of sand packed on a sintered glass funnel, a s l i g h t l y turbid colourless solution was obtained. The hydride concentration was determined to be 1.45M by allowing 0.5ml aliquots of the solution to react with a 1:1 mixture of THF and 1M sulphuric acid and measuring the volume of hydrogen evloved. 100% Sulphuric acid was prepared by mixing calculated amounts of fuming sulphuric acid (containing 30% sulphur trioxide) and concentrated sulphuric acid (96.7%). The resulting mixture was standardised with 0.1M sodium hydroxide solution. In a t y p i c a l preparation, 10.201g of concentrated sulphuric acid was mixed with 5.007g of fuming sulphuric acid. The r e s u l t i n g acid solution was found to contain 99.87% sulphuric acid by weight. 39 4ai,5,8,8a0-Tetrahydro-1,4-napthoquinone (31a) p-Benzoquinone (32.05g, 0.297mol) ( p u r i f i e d by sublimation) was placed in the c y l i n d r i c a l flask of a Parr hydrogenation apparatus followed by the addition of 225ml of benzene. The quinone was p a r t i a l l y dissolved and the resu l t i n g mixture was cooled in an ice bath. 1,3-Butadiene (35.6ml) was condensed (in dry-ice-acetone) and rapidly introduced into the cooled mixture. The flask was stoppered and secured onto the hydrogenation apparatus. The reaction mixture was allowed to stand for twenty days with occassional shaking. At the end of the reaction period, a yellow solution was obtained. The solution was f i l t e r e d and the benzene removed under reduced pressure to provide a yellow s o l i d which was r e c r y s t a l l i s e d from cyclohexane. The desired napthoquinone (34.08g, 71%) was obtained in form of yellow needles, melting point 51-52°C ( l i t . 7 7 52-54°C). 4a^,5,8,8a0-Tetrahydronapthoquin-1-one-4-o-o1 (32a) Napthoquinone (31 a) (500mg, 3.05mmol) was dissolved in 10ml of methanol and cooled in an ice bath. Sodium borohydride (46.2mg, l.22mmol) suspended in 2ml of ice cold methanol was added slowly over a period of 10 minutes with s t i r r i n g . After s t i r r i n g the reaction mixture at the temperature of the ice bath for 35 minutes, about 15ml of water was added and the resulting pale yellow solution was extracted with six 20ml portions of chloroform. The combined extracts were washed with brine and dried over anhydrous sodium sulphate. Removal of the solvent 60 and r e c r y s t a l l i s a t i o n of the residue from cyclohexane-benzene afforded 350mg (70%) of napthoquinol (32a, melting point 130-131°C ( l i t . 7 0 128-128.5°C). Compound 32a displayed the following spectral c h a r a c t e r i s t i c s : IR (KBr) 3300cm"1 (OH), 1680cm"1 (C=0 conjugated); ms (parent) m/e 164; 1H NMR (CDC13) 8 6.70 (d, 1H, J=l0Hz), 8 5.95 (dd, 1H, J,=10HZ, J 2=2.5Hz), 8 5.70 (m, 2H), 8 4.85-4.95 (m, 1H), 8 2.60-2.95 (m, 3H), 8 2.30 (s, 1H, exc with D 20), 8 1.90-2.30 (m, 3H). 1 0-Exo-hydroxytetracyclo [5.3.0.0 2 > 6.0 a' 9] decan-3-one (33a) Napthoquinol (32a) (400mg, 2.44mmol) was dissolved in 350ml of benzene and the re s u l t i n g solution was purged with nitrogen for 90 minutes. Internal i r r a d i a t i o n (450W Hanovia lamp, uranium glass f i l t e r , Pyrex immersion well) of 32a was monitored by GLC (at 180°C, retention time of 32a i s 3.21 minutes, retention time of 33a i s 3.80 minutes) and stopped after 16 hours (less than 1% of 32a remained). Benzene was removed under reduced pressure to afford a yellow o i l y residue which was p u r i f i e d by s i l i c a gel column chromatography using ethyl acetate-petroleum ether (30-60°C) (7:3) as eluent. In t h i s way 356mg (89%) of 33a was isolated which was then r e c r y s t a l l i s e d from petroleum ether (65-110°C)-benzene; melting point 231-233°C (sealed tube). The cage ketol (33a) displayed the following spectral c h a r a c t e r i s t i c s : IR (KBr) 3400cm"1 (OH), 1730cm"1 (C=0); ms (parent) m/e 164; 'H NMR (CDC13) 8 4.14 (br s, 1H), 8 3.16-3.05 61 (m, 1H), 6 2.86-2.70 (m, 2H), S 2.60-2.50 (m, 2H), S 2.40-2.30 (m, IH), S 2.14 (quasi t r i p l e t , 2H), b 1.83-1.95 (m, 1H), 8 1.58 (s, 1H, exc with D 20), 6 1.30-1.40 (m, 1H). lQ-Exo-hydroxytetracyclo[5.3.0.0 2 6.0" 9]decane-3-ketoxime (34a) The cage keto-alcohol (33a) (1.31g, 8.0mmol) was dissolved in 25ml of methanol with s t i r r i n g in a 100ml round bottom fl a s k . Hydroxylamine hydrochloride (2.63g, 37.9 mmol) and potassium acetate (1.87g, l9.1mmol) were added to the above solution with s t i r r i n g whereupon a white suspension was formed. The flask was then equipped with a reflux condenser and the suspension was heated in an o i l bath with s t i r r i n g while water was introduced slowly u n t i l a clear colourless solution was obtained. After refluxing overnight, methanol was removed under reduced pressure and the oxime precipitated as a'white s o l i d which was co l l e c t e d by f i l t r a t i o n and washed thoroughly with water. The s o l i d was dried in vacuo to give 972mg of desired oxime. The aqueous residue was extracted with four 20ml portions of ethyl acetate and the combined extracts washed successively with d i l u t e hydrochloric acid, saturated sodium bicarbonate solution, water and brine and dried over anhydrous sodium sulphate. Removal of solvent under reduced pressure provided another 95mg of oxime. The t o t a l y i e l d of the reaction was 1.067g (75%). The crude oxime was r e c r y s t a l l i s e d from a mixture of ethyl acetate and small amount of ethyl alcohol, melting point of 34a i s 209.5-211°C. Oxime 34a displayed the following spectral c h a r a c t e r i s t i c s : 62 IR (KBr) 3300cm"1 ( O H ) , 1675cm"1 (C=N); ms (parent) m/e 179; 'H NMR (DMSO d 6) 8 4.53 (s s l i g h t l y s p l i t , 2H, exc with D 20), 8 3.67 (br s, 2H), 8 3.46-3.33 (m, 2H), 8 3.32 (s, superimposed on the multiplet, 2H, exc with D 20), 8 2.84-2.48 (m, 8H), 8 2.30 (br d 1H, J=lOHz), 8 2.23 (br d, 1H, J=10HZ), 8 1.92 (two superimposed doublets, 2H), 8 1.74 (two superimposed doublets, 2H), 8 1.55 (d futher s p l i t , 2H, J=12Hz), 8 0.80-0.90 (m, 2H). Anal. Calcd for C 1 0H 1 3O 2N : C 67.02, H 7.31, N 7.82. Found C 67.20, H 7.34, N 7.76. 11-Aza-pentacyclo[6.2.1.0 2' 7.0" ' 1 0.0 s» 91decane (28) An oven-dried two-necked 50ml round bottom flask equipped with a magnetic s t i r r i n g bar, rubber septum, and a reflux condenser attached to a dry nitrogen source was charged with 7.5ml (2.52M, l9mmol) LAH solution in THF v i a a syringe. Sulphuric acid (100%) (503ul, 9.5mmol) was added dropwise over a period of 20 minutes while the solution was vigorously s t i r r e d in a cold water bath (5-l0°C) by means of a magnetic s t i r r e r . Hydrogen was evolved with the p r e c i p i t a t i o n of lithium sulphate and the resulting grey suspension was allowed to s t i r for another hour at room temperature. To t h i s suspension at room temperature was added slowly 450mg (2.5mmol) of oxime dissolved in 20ml of THF. Hydrogen was again evolved vigorously, and when i t ceased the reaction mixture was refluxed for 7 hours. The excess hydride was quenched with 4ml 1:1 aqueous THF while the reaction mixture was cooled in a cold water bath ( 5 - 1 0 o C ) . This was followed by the addition of 10ml of aqueous sodium hydroxide 63 solution (3.75M) at room temperature. The o r i g i n a l voluminous p r e c i p i t a t e coagulated to a smaller gelatinous mass. The THF layer was decanted and the aqueous phase was extracted with three 15ml portions of ether. The combined organic extracts were dried over anhydrous potassium carbonate and then f i l t e r e d . Slow removal of solvent under reduced pressure gave a white s o l i d which was chromatographed on an alumina column using methanol-chloroform (7:93) as eluent. The desired cage amine (28) (Il0mg, 30%) was isolated which proved to be homogeneous on GLC (at 165°C, the retention time of 28 i s 1.40 minutes). Compound 28 displayed the following spectral c h a r a c t e r i s t i c s : ms (parent) m/e 147; 'H NMR (CD3OD) 8 3.74 (br s, 2H, C O ) and C(8) methines), 5 2.65 (br s, 4H, C(2), C(7), C(9) and C(10) methines), 8 2.35 (br s, 2H, C(4) and C(5) methines), 8 1.53 (d, 2H, J=12Hz, C(3) and C(6) inner H'S), 8 1.18 (br d, 2H, J=12HZ, C(3) and C(6) outer H's). Picrate of Compound 28 To 77mg (0.52mmol) of the cage amine in 2ml of chloroform, 4ml of p i c r i c acid solution (prepared by dissolving 1g of crude p i c r i c acid in 15ml of benzene followed by drying over anhydrous calcium chloride) was added. After standing at room temperature for 1-2 minutes, bright yellow needles p r e c i p i t a t e d . The mixture was kept in the r e f r i g e r a t o r overnight; 158mg (80%) of picrate was obtained by f i l t r a t i o n which had a melting point of 228.5-230°C. The picrate of compound 28 displayed the following spectral 64 c h a r a c t e r i s t i c s : IR (KBr) 2900cm"1 (secondary amine s a l t ) , 1320cm"1 ( N 0 2 ) ; 1H NMR (DMSO d 6) 8 8.80-8.60 (br shoulder, 2H, NH 2), 8 8.56 (s, superimposed on the shoulder, 2H, aromatic ring H's), 8 4.09 (s, 2H, CO) and C(8) methines), 8 2.82 (s, 2H, C(2), C(7) or C(9), COO) methines), 8 2.68 (s, 2Hr C(2), C(7) or C(9), COO) methines), 8 2.58 (s, 2H, C(4) and C(5) methines), 8 1.56 (d, 2H, J=13.5Hz, C(3) and C(6) inner H's), 8 1 . 19 (br d, 2H, J=13.5Hz, C(3) and C(6) outer H's); 1 3C NMR (DMSO d 6) (from 8 0-100) 8 24.05 (C(3) and C(6)), 8 33.81 (C(4) and C(5)), 8 39.74 (C(2), C(7) or C(9), COO)), 8 40.65 (C(2), C(7) or C(9), COO)), 8 63.98 (CO) and C(8)). Anal. Calcd fo-r C,«H| SH«0 7 : C 51.07, H 4.29, N 14.89. Found C 50.99, H 4.35, H 15.00. Amine Hydrochloride of Compound 28 The amine picrate of 28 (890mg, 2.37mmol) was suspended in 7ml of chloroform in a 60ml separatory funnel, 2g (83.3mmol) of lithium hydroxide and 15ml of water were added and the contents were mixed thoroughly. The organic phase was removed and the aqueous phase was extracted with three 15ml portions of chloroform. The organic extracts were combined and dried over anhydrous sodium sulphate and then f i l t e r e d . Dry hydrogen chloride gas was bubbled through the solution u n t i l the pH was less than 2 (as indicated by pH paper). Chloroform was removed under reduced pressure whereupon a pale yellow s o l i d was obtained which was redissolved in 10ml methanol and treated with a small amount of Norit. Removal of Norit and solvent gave 65 376mg (87%) of the hydrochloride as a white s o l i d . R e c r y s t a l l i s a t i o n from cyclohexane-ethanol provided the hydrochloride in the~form of white needles. The hydrochloride does not have a d i s t i n c t melting point. It starts to decompose when heated to about 250°C and becomes completely black in colour at 310°C. The hydrochloride displayed the following spectral c h a r a c t e r i s t i c s : IR (KBr) 2900cm'1 (secondary amine s a l t ) ; ms (parent) m/e 147; 1H NMR (CDC13) 6 9.69 (broad shoulder, 2H, NH 2), 8 4.12 (s, 2H, C(1) and C(8) methines), 8 3.10 (s, 2H, C(2), C(7) or C(9), C(10) methines), 8 2.91 (s, 2H, C(2), C(7) or C(9), COO) methines), 5 2.77 (s, 2H, C(4) and C(5) methines), .8 1.62 (d, 2H, J=13HZ, C(3) and C(6) inner H's), 8 1.25 (d, 2H, J=13HZ, C(3) and C(6) outer H's); 1 3C NMR (CDC13) 8 64.62 (CO) and C(8)), 8 41.24 (C(2), C(7) or C(9), C(10)), 8 40.23 (C(2), C(7) or C(9), C(lO)), 8 34.39 (C(4) and C(5)) f 8 24.68 (C(3) and C(6)). For detailed description of assignments, see results and discussion. Anal. Calcd for C 1 0H l f lNCl : C 65.39, H 7.68, N 7.63. Found C 65.51, H 7.59, N 7.57. 6,7-Dimethyl-4ag,5,8,8ai~tetrahydro-1,4-napthoquinone (31b) A 25ml round bottom flask was charged with 2.00g (l8.52mmol) of p-benzoquinone (p u r i f i e d by sublimation) and 2ml of benzene. After s t i r r i n g for 5 minutes at room temperature, 2,3-dimethyl-1,3-butadiene (1.67g, 20.36mmol) was rapidly introduced. The flask was then equipped with a reflux condenser 66 with a drying tube attached and the mixture was heated to 60-65°C in an o i l bath with st i r r i n g . After heating for 10 minutes, an orange solution was formed; on futher heating, a yellow solid was precipitated. After a total heating time of three and a half hours, the reaction mixture was cooled to room temperature. Benzene was removed under reduced pressure, and a yellow solid residue was obtained which was dried further in vacuo. Recrystallisation of the residue from a mixture of cyclohexane and small amount of acetone provided 2.8lg (80%) of napthoquinone (31b) as yellow needles, melting point 110—111.5°C ( l i t . 1 0 1 115-117°C). Compound 31b displayed the following spectral characteristics: IR (RBr) 1680cm"1 (C=0), 1600cm"1 (C=C conjugated); 1H NMR (CDC13) 8 6.58 (s, 2H, C(2) and C(3) H's), 5 3.10 (m, 2H, CUa ) and C(8a) methines), 8 2.20 (m, 4H, C(5) and C(8) methylenes), 8 1.63 (s, 6H, C(6) and C(7) methyls). 6, 7-Dimethyl-4a<3, 5 , 8 , 8a^-tetrahydronapthoquin - 1 -one-4-c-ol (32b) A 50ml round bottom flask was charged with 2.17g (11.42mmol) of 31b and 30ml of methanol. The mixture was stirred magnetically and a pale yellow suspension was formed. To the stirred suspension cooled in an ice bath, sodium bor.ohydride (l73mg, 4.55mmol) suspended in 4ml of ice cold methanol was added slowly over a period of 5 minutes with vigorous s t i r r i n g . After stirring for 1 hour at ice bath temperature, about 2ml of saturated ammonium chloride solution was added arid the reaction mixture was allowed to warm to room 67 temperature; a l i g h t brown solution was obtained. The methanol was removed under reduced pressure and the residue was transferred to separatory funnel with the aid of about 30ml of water and small amount of chloroform. Extraction was c a r r i e d out with seven 30ml portions of chloroform and the combined extracts washed successively with water and dried over anhydrous sodium sulphate. After removal of the drying agent, a yellow solution was obtained. The solvent was stripped off under reduced pressure, and the r e s u l t i n g pale yellow s o l i d r e c r y s t a l l i s e d from cyclohexane-ethyl acetate. This provided the napthoquinol (32b) as white needles (l.56g, 71%) with a melting point of 119-122°C ( l i t . 7 0 122-122.5°C). The napthoquinol displayed the following spectral c h a r a c t e r i s t i c s : IR (KBr) 1685cm"1 (C=0 conjugated); 1H NMR (CDC13) 8 1.59 (s, 3H, C(6) or C(7) methyl), 8 1.66 (s, 3H, C(6) or C(7) methyl), 6 1.91 (s, 1H, exc with D 20), 8 1.88-2.28 (m, 3H, C(4a) methine, C(5) methylene), 8 2.50-2.90 (m, 3H, C(8a) methine, C(8) methylene), 8 4.82-5.02 (m, 1H, C(4) methine), 8 5.99 (dd, IH, J,=l0Hz, J 2=2Hz, C(2) H), 8 6.71 (d of t, 1H, J,=10HZ, J 2=2Hz, C(3) H). 6,7-Dimethyl-1Q-exo-hydroxytetracyclo- [5.3.0.02 < 6.0"' 9]decan-3-one (33b) A solution of napthoquinol 32b (1.l6g, 6.04mmol) in 500ml of benzene was purged with nitrogen for 90 minutes and i r r a d i a t e d i n t e r n a l l y (Pyrex immersion well, 450W Hanovia lamp, uranium glass f i l t e r ) , the photolysis was followed by GLC (at 68 180°C, the retention time of 32b i s 5.12 minutes and the retention time of the photoproduct (33b) i s 3.32 minutes) and stopped aft e r three and a half hours (less than 1% of 32b remained). Benzene was removed under reduced pressure and a yellow o i l y residue was obtained. The residue was p u r i f i e d by s i l i c a gel column chromatography using a 1:1 mixture of ethyl acetate and petroleum ether (65-110°C) as eluent. A white s o l i d was isol a t e d which on r e c r y s t a l l i s a t ion from petroleum ether (65-110°C) and a small amount of ethyl acetate, provided 0.83g (71%) of the cage keto-alcohol (33b) as white cubic shaped c r y s t a l s of melting point 194-196°C (sealed tube). Compound 33b displayed the following spectral c h a r a c t e r i s t i c s : I R (KBr) 1730cm"1 (C=0), 3400cm"1 (O-H); ms (parent) m/e 192; 'H NMR (CDC13) 8 1.05 (dd, 1H, J,=12.5Hz, J 2=3Hz), 8 1.14 (s, 3H, C(6) or C(7) methyl), 8 1.29 (s, 3H, C(6) or C(7) methyl), 8 1.59 (s, 1H, exc with D 20), 8 1.73 (dd, 1H, J,=12.5Hz, J 2=3Hz), 8 2.05 (d, 1H, J=13HZ, C(1) or C(2) methine), 8 2.17 (d, 1H, J=13Hz, C(l) or C(2) methine), 8 2.18 (dd, 1H, J,=9Hz, J 2=2.5Hz), 8 2.30 (dd, 1H, J,=9Hz, J 2=2.5Hz), 8 2.38 (d futher s p l i t , 1H, J=9Hz, C(4) or C(9) methine), 8 2.50 (d futher s p l i t , 1H, J=9Hz, C(4) or C(9) methine), 8 4.06 (br s, 1H, C(10) methine). 6, 7-Dimethyl - 1 Q-exo-hydroxytetracyclo [ 5 . 3 . 0 . 0 2 , 6 . 0 < I , 9 J - decane-3-ketoxime methyl ether (34b) The cage keto-alcohol (33b) (3l8mg, 1.66mmol) was dissolved in 5ml of methanol in a 50ml round bottom fl a s k . Methoxyamine 69 hydrochloride (1.11g, 13.25mmol) and potassium acetate (650mg, 6.63mmol) were added to the above solution with s t i r r i n g whereupon a heavy suspension was formed. The flask was then equipped with a reflux condenser and the suspension was heated with s t i r r i n g with slow addition of water u n t i l a clear colourless solution was formed. This solution was refluxed for 20 hours. After cooling the reaction mixture to room temperature, the methanol was removed under reduced pressure and the residue was di l u t e d with water and extracted with four 20ml portions of ethyl acetate. The combined extracts were washed with water, brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and a yellow o i l was obtained. P u r i f i c a t i o n by d i s t i l l a t i o n using a Kugelrohr oven (oven temperature 140°C, pressure O.lmmHg) afforded 337mg (92%) of the oxime ether 34b as a colourless o i l . Compound 34b displayed the following spectral c h a r a c t e r i s t i c s : IR (film) 1650cm'1 (C=N), 3375cm"1 (O-H); ms (parent) m/e 221; 'H NMR (CDC13) 6 0.84 (dd, 1H, J,=6Hz, J 2=3Hz), 8 0.87 (dd, IH, J,=6Hz, J 2=3Hz), 5 1.02 (quasi doublet, 3H, "J"=4Hz, C(6) or C(7) methyl), 8 1.23 (s, 3H, C(6) or C(7) methyl), 8 1.40-1.60 (br shoulder, 1H, exc with D 20), 8 1.54 (dd, superimposed on the shoulder, 1H, J , = 13Hz, J 2=3Hz), 8 1.82 (dd, 1H, J,=13Hz, J 2=3Hz), 8 1.95-2.04 (two superimposed doublets, 1H), 8 2.23 (quasi t r i p l e t futher s p l i t , 1H), 8 2.41 (d futher s p l i t , 1/2 H, J=9Hz), 8 2.47 (d futher s p l i t , 1/2 H, J=9Hz), 8 2.53 (dd, 1/2 H, J,=9Hz, J 2=2.5Hz), 8 2.73 (d futher s p l i t , 1/2 H, J=10HZ), 8 3.12 (dd, 1/2 H, J,=9Hz, J 2=2.5Hz), 70 8 3.45 (d futher s p l i t , 1/2 H, J=10HZ), 8 3.77-3.82 (two sharp si n g l e t s , ratio=7:5, t o t a l 3H, two non-equivalent 0 -methyls), 8 3.97 (quasi doublet, 1H, "J"=5Hz, C(5) methine). ' , Picrate of 4,5-Dimethyl-11-aza-pentacyclo- [6.2. 1 .0 2 ' 7.O a » 1°.0 5 ' 9]decane An oven-dried 25ml two necked flask equipped with a rubber septum, a magnetic s t i r r i n g bar, and a reflux condenser connected to a source of dry nitrogen was charged with 3.37ml of LAH solution (1.45M, 4.88mmol) in THF. Sulphuric acid (100%) (130ul, 2.46mmol) was added dropwise over a period of 10 minutes while the LAH solution was vigorously s t i r r e d in a cold water bath (5-10 o C). A white p r e c i p i t a t e of lithium sulphate was produced together with vigorous evolution of hydrogen, and a grey suspension was formed which was allowed to s t i r for one hour at room temperature. To t h i s suspension at room temperature was added slowly with s t i r r i n g I80mg (0.8lmmol) of oxime ether (34b) dissolved in 5ml of THF. The reaction mixture was then refluxed for 8 hours. After the reaction had cooled to room temperature, the flask was immersed in a cold water bath (5-10 o C) and 1ml of 1:1 aqueous THF was introduced slowly to decompose the excess hydride. This was followed by the addition of 4ml (3.13M) aqueous sodium hydroxide solution. The o r i g i n a l voluminous p r e c i p i t a t e coagulated to a much smaller gelatinous mass. The THF solution was decanted and the aqueous phase was extracted with three 10ml portions of ether. The combined organic extracts were dried over anhydrous sodium sulphate and 71 the solvent evaporated under reduced pressure to afford a white s o l i d residue. The residue was p u r i f i e d by alumina column chromatography using methanol-chloroform (8:92) as eluent. In this way, 30mg (21%) of the desired cage amine (29) was isolated which was homogeneous by GLC (at 165°C, the retention time of 29 is 1.66 minutes). To 30mg (O.l7mmol) of the cage amine dissolved in 2ml of chloroform , 60mg (0.26mmol) of dry p i c r i c acid dissolved in 1ml of benzene was added. The picrate was precipitated in the form of yellow needles which were found to have a melting point of 262-265°C. The picrate displayed the following spectral c h a r a c t e r i s t i c s : IR (KBr) 2950cm"1 (secondary amine s a l t ) , 1320-1360cm"1 (N0 2); 1H NMR (DMSO d 6) 8 1.05 (d, 2H, J=12HZ, C(3) and C(6) outer H's), 8 1..16 (s, 6H, C(4) and C(5) methyls), . Cr 8 1.57 (d, 2H, J=12HZ, C(3) and C(6) inner H's), 8 2.40 (s, 2H, C(2), C(7) or C(9), C(10) methines), 8 2.56 (s, 2H, C(2), C(7) or C(9), C O O ) methines), 8 4.16 (br s, 2H, C O ) and C(8) methines), 8 8.57 (s, 2H, aromatic ring H's), 8 8.55-8.75 (broad shoulder, 2H, exc with D 20, NH 2). For detailed description of assignments, see results and discussion. Anal. Calcd for C i eH 2 0N a0 7 : C 53.46, H 4.99, N 13.85. Found C 53.26, H 4.79, H 13.63. 72 References W.M.Stanley, Science, 8J_, 644( 1 935). A.D.Hershey and M.Chase, J. Gen. Physiology, 36, 39(1952). A.B.Sabin, N. Engl. J. Med., 293, 986(1975). D.W.Swallow, "Progress in Medicinal Chemistry", vol.8, G . P . E l l i s and G.B.West editors, chapter 4, London, Butterworths, 1971. J.M.Best and J.E.Banatvala, J . B i o l . Stand., 3, 107(1975). G. Emodi, T . R u f l i , M.Just and R.Hernadez, Scand. J . Infec. Dis. , 7, 1(1975) A.K.Field, A.A.Tytell, G.P.Lampson and M.R.Hilleman, Proc. Nat. Acad. S c i . (U.S.), 6J_, 340(1968). J.H.Park and S.Baron, Science, 162, 811(1968). M.Nemes, A.A.Tytell, G.P.Lampson, A.K.Field and M.R.Hilleman Proc. Soc. Exp. B i o l . Med., 132, 776(1969). H. B.Levy, G.Baer, S.Baron, C.F.Gibbs, M.Idarola, W.London and J.M.Rice, I_. R. C. S. , 2, 1643(1974). E.L.Stephen, W.L.Pannier, M.L.Sammons, S.Baron, H.B.Levy and R.O.Spertzel, Fed. Proc., 3_4, 960(1975). R.H.Adamson and S.Fabro, Nature, 223, 718(1969). A.D.Steinberg, S.Baron and N.Talal, Proc. Nat. Acad. S c i . (U.S.) 63, 1102(1969) . P.J.Price, W.A.Suk, E.M.Zimmerman, G.J.Spahn, A.F.Gazdar and S.Baron, J. Nat. Cancer Inst., 5_0, 1299(1973). W.W.Hoffman, J.J.Korst, J.F.Niblack and J.H.Cronin, 73 Antimicrob. Agents Chemotherapy, 3, 498(1973). 16. C.Panusarn, E.D.Stanley, V.Dirda, M.Rubenis and G.G.Jackson, N. Eng_. J. Med., 291 , 57( 1974). 17. R.G.Douglas, J r . And R.F.Betts, Infect. Immun., 9, 506(1974). 18. R.F.Krueger and G.D.Mayer, Science, 169, 1213(1970). 19. R.F.Krueger and G.D.Mayer, Science, 169, 1214(1970). 20. W.L.Albrecht, E.R.Andrews, R.W.Fleming, J.M.Grisar, S.W.Horgan, A . D . S i l l , F.W.Sweet and L.Wenstrup, Abstract No. 160, Nat. Meeting Am. Chem. Soc. Chicago, I I I . , Sept. 1970. 21. W.L.Albrecht, E.R.Andrews, R.W.Fleming, J.M.Grisar, S.W.Horgan, A . D . S i l l , F.W.Sweet and L.Wenstrup, paper presented at the Int. Colloq. On Interferon and Interferon Inducers, Louvain, Sept. 1971. 22. R.Krueger, G.D.Mayer, K.P.Camyre and Yoshimura, paper presented at the 11th I n t e r s c i . Conf. Antimicrob. Agents Chemotherapy, Alantic City, N.J., Oct. 1971. 23. J.F.Niblack, paper presented at the 23rd Int. Congress of Pure and Applied Chem., Boston, Mass. 1971. 24. E.C.Herrman, J r . , Proc. Soc. Exp. B i o l . Med., 107, 1 42( 1961>. 25. H.E.Kaufman, Proc. Soc. Exp. B i o l . Med., 109, 251(1962). 26. F.O.MacCllum and B.E.Juel-Jensen, B r i t . Med. J . , 2, 805(1966). 27. F.O.MacCllum, B.E.Juel-Jensen, A.M.R.Mackenzie and M.C.Mike, B r i t . Med. J., 4, 776(1970). 74 28. E.De Clerg, J.Descamps, P.De Somer, P.J.Barr, A.S.Jones and R.T.Walker, Proc. Nat. Acad. S c i . (U.S.), 76, 2947-2951(1979). 29. M.P. de Garilhe and J.de Rudden, C. R. Acad. S c i . 259, 2725(1964). 30. R.W.Sidwell, G.Arnett and D.J.Dixon, 7th I n t e r s c i . Conf. Antimicrob. Agents Chemotherapy Abstract No. 64 (1967). 31. R.W.Sidwell, G.J.Dixon, S.M.Sellers and E.M.Schabel, J r . , Appl. M i c r o b i o l . , 1 6 , 370(1968). 32. F.M.Schabel, J r . , Chemotherapy, 13, 321(1968). 33. D.Pavan-Langston and C.H.Dohlman, Am. J . Opthalmol., 74, 81(1972). 34. Chem. Eng. News, Oct. 30th, 8(1978). 35. J.M.Campell, R.F.Maes, T.J.Wiktor and H.Koprowski, Virology, 34, 701(1968). 36. L.N.Simon, R.W.Sidwell, G.P.Khare, D.G.Streeter, J.P.Miller, J.T.Witkowski, J.H.Huffman and R.R.Robins, Virus Res. Symp. Mol. B i o l . Proc., 415-428(1973). 37. L.N.Simon, R.W.Sidwell, G.P.Khare, J.P.Miller, J.T.Witkowski, and R.K.Robins, Antimicrob. Agents Chemotherapy, 3, 517(1973). 38. L.N.Simon, R.W.Sidwell, G.P.Khare, L.B.Allen, J.T.Witkowski, J.H.Huffman and R.K.Robins, Antimicrob. Agents Chemotherapy, 3, 242(1973). 39. Thomas H. Maugh II , Science, 192, 128-132( 1976). 40. H.J.Eggers and I.Tamm, J. Exp. Med., 113, 657(1961). 41. H.J.Eggers and I.Tamm, R.Bablanian, A.F.Wagner and 75 K.Folkers, Nature, 223, 785(1969). 42. D.G.O'Sullivan, D.Pantic and A.K.Wallis, Experientia, 23, 704(1967). 43. D.G.O'Sullivan, D.Pantic and A.K.Wallis, Experientia, 24, 1185(1968). 44. Chem. Eng. News, Sept. 1st, 5(1980). 45. D.Hamre, J.Bernstein and R.Donvick, Proc. Soc. Exp. B i o l . , 73, 275(1950). 46. K.A.Brownlee and D.Hamre, J. B a c t e r i o l . , 61, 127(1951). 47. K.A.Brownlee , D.Hamre and R.Donvick, J. Immunol., 67, 305(1951). 48. R.L.Thompson, S.A.Minton, J.E.Officer and G.H.Hitchings, J. Immunol., 70, 229(1953). 49. D.J.Bauer, K.Apostolov and J.W.T.Selway, Ann. N.Y. Acad. S c i . , 173, 314(1970). 50. G.H.Werner, Norw. Press. Med. , j_, 805(1972). 51. N.L.Shipowitz, R.R.Bower, R.N.Appell, C.W.Nirdeen, L.R.Overby, W.R.Roderick, J.B.Schleicher and A.M.Von Esch, Appl. Microbiol., 26, 264(1973). 52. D.D.Gerstein, C.R.Dawson and J.O.Oh, Antimicrob. Agents Chemotherapy, 1_, 285( 1975). 53. R.G.Duff, N.L.Shipowitz and L.R.Overby, 15th I n t e r s c i . Conf. Antimicrob. Agents Chemotherapy, paper No. 241, Sept. 1975. 54. J.C.H.Mao, E.E.Robinshaw and L.R.Overby, J . V i r o l . , 15, 1281(1975). 55. J.C.H.Mao, E.E.Robinshaw and L.R.Overby, J.B.Schleicher, 76 A.Reuter and N.L.Shipkowitz, Antimicrob. Agents Chemotherapy, 6, 360( 1974). 56. H.E.Renis, Ann. N.Y. Acad. Sci . , 173, 527(1970). 57. M.G.Soret, Ant imicrob. Agents Chemotherapy, 160(1969). 58. H.E.Renis, Antimicrob. Agents Chemotherapy, 167(1969). 59. G.A.Elliot, D.A.Buthala and. E.N.DeYoung, Ant imicrob. Agents Chemotherapy, 173(1969). 60. C.E.Hoffman, R.F.Haff and E.M.Neumayer, Fed. Proc., 23, Abstract No. 1716-1720 (1964). 61. W.L.Davis, R.R.Grunert, R.F.Haff, J.W.McGahen, E.M.Neumayer, M.Paulshock, J.C.Watts, T.R.Wood, E.C.Herrmann, J r . And C.E.Hoffmann, Science, 144, 862(1964). 62. G.G.Jackson, R.C.Muldoon and L.K.Akers, Ant imicrob. Agents Chemotherapy, 703(1963). 63. T.R.Wood, Ann. N.Y. Acad. S c i . , 130, 419(1965). 64. N.Kato and H.J.Eggers, Virology, 3_7, 632(1969). 65. A.A.Tsunoda, H.F.Maassab, K.W.Cochran and W.C.Eveland, Antimicrob. Agents Chemotherapy, 553(1965). 66. K.Lundahl, J.Schut, J.L.M.A.Schlatmann, G.B.Paerels and A.Peters, J. Med. Chem. , J_5, 129(1972). 67. D.L.Swallow, "Progress in Drug Research", v o l . 22, E.Jucker editor, Birkhauser, Basel and Stuttgart, p. 268-326(1978). 68. P.Delongchamps, Chemical Abstracts, 75, 76469D(1971). 69. P.Delongchamps, Chemical Abstracts, 83, 9327H(1975). 70. W.K.Appel, T.Greenhough, -J.R.Scheffer, J.Vrotter and 77 L.Walsh, J . Am. Chem. Soc., 102, 1159(1980). 71. (a). R.J.Stedman, Chemical Abstracts, 7J_, 10141 8P( 1 969). (b). R.J.Stedman, Chemical Abstracts, 76, 72123J(1972). 72. Andre R.Gagneux and Rene Meier, Tetrahedron Lett., 1365-1368(1969). 73. T.Sasaki, S.Eguchi, T.Kiriyama and O.Hiroaki, Tetrahedron, 30, 2707(1974). 74. P. Singh, J. O r e Chem., 44, 843( 1979). 75. R.C.Cookson, E,Grundwell, R.R.Hill and J.Hudec, J. Chem. Soc., 3062(1964). 76. H.Setter, P.Tacke and J.Gartner, Chem. Ber., 93_, 3480(1964). 7 7 . E.E.van Tamelen, M.Shamma, A.W.Burgsthaler, J.Wolinski, R.Tamm and P.E.Aldrich, J . Am. Chem. Soc., 91, 7315(1969). 78. J.E.Baldwin, J . Chem. Soc. Chem. Comm., 738(1976). 79. L.Pauling, "The Nature of Chemical Bond", 3rd ed i t i o n , Cornell University Press, New York, 1960, p. 136. 80. K.E.Wilson, R.T.Seidner and S.Masamune, J. Chem. Soc. Chem. Comm., 213(1970). 81. Jean-Louis Luche, J . Am. Chem: Soc., 100, 2226(1978). 82. J.R.Scheffer and S.Shephard, unpublished r e s u l t s . 83. GlW.K.Cavill and R.J.Quinn, Australian Journal of Chemistry, 26, 595(1973). 84. J.R.Scheffer, K.S.Bhandari, R.E.Gayler and R.A.Wostradowiski, J. Am. Chem. Soc., 97, 2178(1975). 85. (a), reference 75. 78 (b) . P.E.Eaton and S.A.Cerefice, J. Chem. Soc. Chem. Comm., 1494(1970). (c) . J.C.Barborak, L.Watts and R.Petit, J. Am. Chem. Soc., 88 , 1328(1966). 86. Reference 70 and references c i t e d therein. 87. N.Umino, T.Iwakuma, M.Ikezaki and N.Itoh, Chem. Pharm. B u l l . , 26, 2897(1977). 88. H.Feuer and D.M.Braustein, J. Orq_. Chem. , 34, 1817(1969). 89. J.Lambert, H.F.Shurvell, L.Verbit, R.G.Cooks and G.H.Stout "Organic Structural Analysis", Macmillan, N.Y., 1976, p. 126-129. 90. A.T.Bottini and J.D.Roberts, J. Am. Chem. Soc., 80, 5203(1958). 91. H.Gunther, "NMR Spectroscopy (An Introduction)" translated by R.W.Gleason, John Wiley and Sons, 1980, p. 225. 92. G.E.Keck, S.Fleming, D.Nickell and P.Weider, Syn. Comm., 9, 281(1979). 93. A.P.Kozikowski and H.Ishida, J. Am. Chem. Soc., 102, 4265(1980). 94. J . J . T u r f a r i e l l o , G.B.Mullen, J.T.Tegeler, E.J.Trybulski, S.C.Wong and Sk.Asrof A l i , J . Am. Chem. Soc., 101, 2435(1979). 95. R.F.Borch, M.D.Berstein and D.H.Durst, J. Am. Chem. Soc., 93, 2897(1971). 96. W.Appel and J.R.Scheffer, unpublished r e s u l t s . 97. N.M.Yoon and H.C.Brown, J . Am. Chem. Soc., 90, 2927(1968). 98. (a), reference 89, p. 33-34. 79 (b). reference 91, p. 86-89. 99. D.J.Herbert, J.R.Scheffer, A.S.Secco and J.Trotter, Tetrahedron Lett., 22, 2941(1981). 100. S.Winstein, P.Carter, F.A.L.Anet and A.J.R.Bourn, J . Am. Chem. Soc., 87, 5247(1965). 101. A.Mandelbaum and M.Cais, J . Org. Chem., 27, 2243(1962). 102. H.Weingarten, J.P.Chupp and W.A.White, J . Org. Chem., 32, 3246(1967). 103. Gabrielle-Anne Craze and I.Watt, J. Chem. Soc. Chem. Comm., 147(1980). 104. W.C.Still, M. Kahn and A.Mitra, J . Org. Chem., 43, 2923(1978). 

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0060393/manifest

Comment

Related Items