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Partial synthesis of porphyrin S411 from protoporphyrin IX DME Sivasothy, Ramani 1978

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PARTIAL SYNTHESIS OF PORPHYRIN SA11 FROM PROTOPORPHYRIN IX DME by RAMANI SIVASOTHY B.Sc.(Hons•). U n i v e r s i t y of London, (1976) A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENT FOR THE DEGREE OF MASTER OF SCIENCE THE FACULTY OF GRADUATE STUDIES i n the Department of Chemistry We accept t h i s t h e s i s as conforming to the re q u i r e d standard 2 A p ^ c THE UNIVERSITY OF BRITISH COLUMBIA i ( ^ „ fa Raman! Sivasothy, Oct. 1978 ' - p/ruw'&o In presenting th i s thes is in pa r t i a l fu l f i lment of the requirements for an advanced degree at the Univers i ty of B r i t i s h Columbia, I agree that the L ibrary shal l make it f ree l y ava i lab le for reference and study. I further agree that permission for extensive copying of th is thesis for scho lar ly purposes may be granted by the Head of my Department or by his representat ives. It is understood that copying or pub l i ca t ion of this thes is for f inanc ia l gain sha l l not be allowed without my written permission. Department of The Univers i ty of B r i t i s h Columbia 2075 Wesbrook P l a c e Vancouver, Canada V6T 1WS Date \ \ * Q c ^ V x ^ VH^T - i i -ABSTRACT This study describes the partial synthesis of porphyrin SA11 (la) from protoporphyrin IX DME (32). Conversion of 2-(2-hydroxyethyl)-A-(2-methoxycarbonylvinyl)-deuteroporphyrin IX DME (Alb) into hardero-porphyrin (3Aa) is also outlined. Photo-oxidation of (32) gives the isomeric photoprotoporphyrins (36a) and (36b); these isomers can be separated by column chromatography. Compounds (36a) and (36b) are transformed into the mono-formyl-mono-vinyl-deuteroporphyrins (33a) and (33b) by reduction with borohydride followed by the cleavage of the resulting glycols with periodate. Treatment of (33a) and (33b) with 2 equivalents of thallium(III) nitrate in methanol affords the mono-acetal-mono-formyl derivatives which, on condensation with malonic acid in the presence of piperidine gives the mono-acetal-mono-acrylie acid-deuteroporphyrins. The mono-acetal-mono-acrylic acid derivatives are converted into the corresponding mono-acrylic acid mono-(2-hydroxyethyl)-deuteroporphyrins (Ala) and (Alb) by hydrolysis and reduction with borohydride. Treatment of (Ala) with CBr^ /Ph-jP affords the 2-bromoethyl derivative (A2a) which, is converted into the corresponding 2-cyanoethyl derivative (A3) by cyanide in 1-methylpyrrolidone. Compound (A3) is transformed into porphyrin SA11 (la) by methanolysis. Hydrogenation of the acrylic acid side-chain of compound (Alb) followed by the dehydration of the 2-hydroxyethyl side-chain effect's the conversion of compound (A5) into harderoporphyrin (3Aa). - i i i -TABLE OF CONTENTS ABSTRACT i i LIST OF SCHEMES i v LIST OF ABBREVIATIONS v ACKNOWLEDGEMENTS v i I. INTRODUCTION 1 1.1 Structure and Nomenclature 2 1.2 Biosynthesis of Heme 5 1.3 Synthesis of Porphyrins 11 A. ^  One-Step Process 11 i ) from Dipyrromethanes 11 i i ) from Dipyrromethenes 14 B. Two-Step Process 15 i) from b-bilenes 15 i i ) from a-oxobilanes 16 i i i ) from b-oxobilanes 16 I I . SYNTHESIS OF PORPHYRIN S411 22 Ap p l i c a t i o n of the P a r t i a l Synthetic Intermediates 36 I I I . EXPERIMENTAL 41 3.1 General Methods 41 3.2 Chemicals and Materials 42 3.3 Preparations 42 BIBLIOGRAPHY $1 - i v -LIST OF SCHEMES 1.1 Biosynthesis of Coproporphyrinogen I and I I I 1.2 A Pos s i b l e Mechanism for the Formation of Uroporphyrinogen I I I 1.3 Biosynthesis of Heme from Coproporphyrinogen I I I 1.4 Synthesis of D i p y r r o l i c Intermediates 1.5 Synthesis of Porphyrins v i a Dipyrromethanes 1.6 Synthesis of Porphyrins v i a Dipyrromethenes 1.8 Porphyrins from b-bilenes 1.9 Porphyrins from a-oxobilanes 1.10/ Porphyrins from b-oxobilan.es 2.1 Oxidation of Protoporphyrin IX DME v i a Photoprotoporphyrins 2.2 Condensation of Mono-formyl-mono-vinyl-deuteroporphyrin IX DME with Malonic a c i d 2.3 A Possible Synthesis of Porphyrin S411 from Mono-acrylic acid-mono-vinyl-deuteroporphyrin IX DME 2.4 A Reaction Sequence f o r the Conversion of 2-formyl-4-vinyl-deutero-porphyrin IX DME into Porphyrin S411 2.5 Reaction Mechanism of TTN i n Methanol with a Double Bond 2.6 Mechanism of Bromination of an Alcohol with CBr./Ph„P 4 3 2.7 Synthesis of Porphyrin S411 from Protoporphyrin IX DME 2.8 Synthetic Scheme for the Transformation of 2-(2-hydroxyethyl)-4 - a c r y l i c acid-deuteroporphyrin IX DME into Harderoporphyrin -v-ABBREVIATIONS Ac a c e t y l Acr. - a c r y l i c a c i d Bu* t e r t i a r y b u t y l DME dimethylester DTBE d i t e r t i a r y b u t y l e s t e r d doublet dd doublet of doublets lo g . logarithm max. / - maximum pMe methoxycarbonyl e t h y l Acr - methoxycarbonyl v i n y l Me methyl DMF N,N-dimethyl formamide Ph phenyl P propionic a c i d py pyr i d i n e q quartet s - s i n g l e t t t r i p l e t V v i n y l ACKNOWLEDGEMENTS I wish to thank the many people who have aided me during the course of t h i s study. I would l i k e to p a r t i c u l a r l y thank David Dolphin f o r h i s s u p e r v i s i o n and understanding. My s p e c i a l thanks are extended to Bob Carls o n f o r h i s c o n t i n u a l counsel and encouragement throughout a l l stages of t h i s work. Thanks are a l s o due to Robert D i N e l l o f o r h i s i n s t r u c t i o n s i n the experimental aspects of t h i s study; C a r l A l l e y n e f o r t a k i n g time to read t h i s manuscript and f o r g i v i n g h i s h e l p f u l comments and suggestions; members of the Dolphin research group f o r t h e i r / a s s i s t a n c e ; Dr.A.H.Jackson f o r p r o v i s i o n of porphyrin S411. F i n a l l y , 1 wish to thank Devi f o r her help and co-operation i n typing t h i s manuscript. INTRODUCTION (la) -CH=CH-COOH -CH2CH2COOH (lb) -CH2CH2COOH -CH=CH-COOH Meconium i s an accumulated end-product of the development and metabolism of the foetus and i s rich in bi l e pigments and porphyrins. 1 During an investigation of the ether-soluble porphyrins obtained from meconium using counter-current techniques a porphyrin having a Soret absorption band maximum, in 5% w/v hydrochloric acid, at 410-411nm was detected. 2 This isolate was called porphyrin S411. On the basis of i t s behaviour on a lutidine paper chromatographic system, spectral absorption, molecular weight and catalytic hydrogenation the porphyrin S411 was identified as a mono-acrylate, tri-propionate tetramethyl porphin, 3 -2-and assigned s t r u c t u r e (la) or ( l b ) . The synthesis of both isomers (la) and (lb) through the b-oxobilane route - reference to s e c t i o n 1 . 3 . B ( i i i ) has been accomplished. 1* Mixed melting point and counter-current d i s t r i b u t i o n comparison of the synthetic isomers with the n a t u r a l material has defined the structure of porphyrin S411 as ( l a ) B a s e d upon molecular models and n.m.r. and v i s i b l e s p e c t r a l evidence i t has been shown11 that the a c r y l i c a c i d group on porphyrin S411 has a t r a n s - c o n f i g u r a t i o n . . As a possible intermediate i n the biosynthesis of heme i t assumed some importance for a time. / I . I . STRUCTURE AND NOMENCLATURE Porphin (2) i s the parent compound of the porphyrins. A l l d e r i v a t i v e s of porphin are c o l l e c t i v e l y known as 'porphyrins'. Some examples of n a t u r a l l y occurring porphyrins are l i s t e d i n Table 1. The I.U.P.A.C. system of nomenclature when applied to.the porphyrin macrocycle r e s u l t s i n a p r o l i x naming system. For example, the conventional name for porphyrin S411 (la) i s 2-(2-carboxyvinyl)-4,6,7-tris-(2-carboxyethyl)-l,3,5,8-tetramethyl porphin. As a consequence^ the c l a s s i c a l system used by Hans F i s c h e r 5 i s p r e f e r r e d by those working with porphyrin n a t u r a l products. This system of nomenclature i s i l l u s t r a t e d using porphin (2). If a l l the B-positions of the p y r r o l e rings are s u b s t i t u t e d , and these substituents are of two kinds only, four p o s i t i o n a l isomers are p o s s i b l e . This i s i l l u s t r a t e d i n Figure 1.1, using coproporphyrin as an examplei. Although members o f — a l l four isomer s e r i e s can be -3-'type isomer' I, ( 3 ) ; I I , ( 4 ) ; I I I , ( 5 ) ; IV, ( 6 ) ; Figure 1.1 Type isomers of coproporphyria -4-TABLE 1.' TRIVIAL NAMES AND STRUCTURES OF THE PORPHYRINS OF HEME BIOSYNTHESIS S u b s t i t u e n t s on p o s i t i o n P o r p h y r i n UROPORPHYRIN I UROPORPHYRIN I I I HEPTACARBOXYLIC ACID PORPHYRIN I I I HEXACARBOXYLIC ACID PORPHYRIN I I I PENTACARBOXYLIC ACID PORPHYRIN I I I COPROPORPHYRIN I COPROPORPHYRIN I I I HARDEROPORPHYRIN PORPHYRIN S411 or DEHYDROCOPROPORPHYRIN BIS-(HYDROXYPROPIONATE) COPROPORPHYRIN I I I PROTOPORPHYRIN IX Si d e - c h a i n a b b r e v i a t i o n s ; 1 A A A M M M M M M M M 2 P P P P P V R 3 A A A M M M M M M M 4 P P P P P P P V 5 A A A M M M M •M M 6 P P P P P P P 7 A P P M P P P P A M M M P M M M M M A, -CH2COOH; R, -CH=CHCOOH; M, -CH 3, P, -CH 2CH 2C00H; V, -CH=CH2, R b -CH(0H)CH 2C00H; -5-synthetically prepared, only members of the isomer series I and III are found in nature. Similarly, i f the substituents are of three kinds only fifteen isomers are possible. The naturally occurring porphyrins of this type possess the IX-arrangement of substituents (7). Porphyrins found in hemoproteins may also be described as 2 and/or 4 substituted derivatives of deuteroporphyrin IX (7). e.g. porphyrin S411 may be referred to as 2-(2-carboxyvinyl)-4-(2-carboxyethyl)-deuteroporphyrin IX. 1.2. BIOSYNTHESIS OF HEME5 Although the general pathway of the biosynthesis of heme has been known for some twenty years, 7 the detailed description of the sequence of steps between intermediates has only been recently established. 8' 9 The biosynthetic precursors of porphyrins are the hexahydro derivatives of porphin (2), commonly known as the porphyrinogens (8). The porphyrins encountered in the biosynthesis of heme and their substituition patterns are listed in Table 1. ,(8) The f i r s t step in the biosynthesis of heme is the formation of 5-aminolaevulinic acid (ALA) (11) (Scheme 1.1). It is formed by the condensation of succinyl CoA (10), derived via the Krebs cycle and a-oxoglutarate, with glycine (9) in the presence of the enzyme amino-laevulinic acid synthetase (ALA-S) (Scheme 1.1). Two molecules of ALA are condensed by the enzyme ALA-dehydratase to give the mono-pyrrole porphobilinogen (PBG) (12). Under the influence of the enzyme uro-porphyrinogen synthetase, four molecules of PBG are condensed to give uroporphyrinogen I. When uroporphyrinogen synthetase acts in the presence of uroporphyrinogen co-synthetase, uroporphyrinogen III, in which one of the constituent PBG units i s reversed, i s formed. The formation of uroporphyrinogen III could be considered as a stepwise process in which four PBG molecules are combined in a head-to-tail manner to give the symmetrical bilane (13) (Scheme 1 . 2 ) . ^ Formation of the unsymmetrical uroporphyrinogen III isomer could then proceed via a 'spiro' intermediate (14). Recent studies by Battersby and co-workers using isotopically labelled intermediates have proved 1 0* 1 1 that the unsymmetrical uro-porphyrinogen III i s formed from the symmetrical uroporphyrinogen I isomer by an intramolecular process. Sequential decarboxylation of the -7-HOCCH 2CH 2COSCoA H J N C H J C O O H H UROPORPHYRINOGEN I 4-HEPTACARBOXYLIC ACID PORPHYRINOGEN I 4-HEXACARBOXYLIC ACID PORPHYRINOGEN I PENTACARBOXYLIC ACID PORPHYRINOGRN I 4-COPROPORPHYRINOGEN I (12) UROPORPHYRINOGEN I I I 4-HEPTACARBOXYLIC ACID PORPHYRINOGEN I I I 4- ' HEXACARBOXYLIC ACID PORPHYRINOGEN I I I 4-PENTACARBOXYLIC ACID PORPHYRINOGEN I I I 4-COPROPORPHYRINOGEN I I I SCHEME 1.1 B i o s y n t h e s i s of coproporphyrinogen I and I I I -8-Uro- T.J.I (Vt) SCHEME 1.2 A P o s s i b l e Mechanism for the Formation of Uroporphyrin I I I -9-four a c e t i c a c i d s i d e - c h a i n s of uroporphyrinogen a f f o r d s the hepta-, hexa-, p e n t a - c a r b o x y l i c a c i d porphyrinogens and f i n a l l y the coproporphyrin-ogen I and I I I (Scheme 1.1). Jackson e t . a l . 9 have demonstrated the above s e q u e n t i a l d e c a r b o x y l a t i o n to be c l o c k - w i s e , s t a r t i n g w i t h the a c e t i c a c i d s i d e - c h a i n on the D-ring of uroporphyrinogen and ending w i t h that on the C-r i n g . Coproporphyrinogen I i s not f u r t h e r metabolised. The next stage i n the b i o s y n t h e s i s of heme i s the conversion of coproporphyrinogen I I I to protoporphyrinogen IX. This i n v o l v e s an o x i d a t i v e d e c a r b o x y l a t i o n r e a c t i o n which converts the propionate s i d e -chains on r i n g s A and B of coproporphyrinogen I I I i n t o v i n y l groups. The enzyme i n v o l v e d i n t h i s process i s coproporphyrinogenase (Scheme 1.3). / COPROPORPHYRINOGEN I I I J HARDEROPORPHYRINOGEN J PROTOPORPHYRINOGEN IX I PROTOPORPHYRIN IX 1 PROTOHEME SCHEME 1.3 B i o s y n t h e s i s of Heme from Coproporphyrinogen I I I -10-Sano d e m o n s t r a t e d 1 2 the p a r t i a l i n c o r p o r a t i o n of the b i s - ( h y d r o x y p r o p i o n a t e ) d e r i v a t i v e of cop r o p o r p h y r i n I I I (Table 1) i n t o p r o t o p o r p h y r i n IX. Subsequently, a v i n y l t r i c a r b o x y l i c a c i d p o r p h y r i n from the r a t h a r d e r i a n g l a n d , 1 3 and a dehydro cop r o p o r p h y r i n from meconium, 2 were i s o l a t e d . The former p o r p h y r i n has been i d e n t i f i e d as h a r d e r o p o r p h y r i n 1 3 and the l a t t e r p o r p h y r i n as p o r p h y r i n S A l l 4 (Table 1). On the b a s i s of t h e i r s t r u c t u r e s they were considered as l i k e l y i n t e r m e d i a t e s i n the c o n v e r s i o n of coproporphyrinogen I I I to protoporphy-r i n o g e n IX. Newman p r o j e c t i o n formulae of the b i s - ( h y d r o x y p r o p i o n a t e ) d e r i v a t i v e of coproporphyrinogen I I I have i n d i c a t e d 1 4 how the fo r m a t i o n of v i ^ y l and a c r y l i c a c i d s i d e - c h a i n s may o c c u r . The s t e r i c a l l y favoured conformer (15b) may undergo t r a n s - e l i m i n a t i o n of water to form an a c r y l i c a c i d group, whereas the l e s s s t e r i c a l l y favoured conformer (15a) may undergo t r a n s - d e c a r b o x y l a t i o n to a v i n y l group. I s o t o p i c l a b e l l i n g s t u d i e s have shown that harderoporphyrinogen i s an i n t e r m e d i a t e i n normal m e t a b o l i s m , 1 5 w h i l e porphyrinogen S411 i s an o f f s h o o t of the main b i o s y n t h e t i c pathway. 1 6 On the b a s i s of t h i s evidence, i t has been suggested that the s t e r i c a l l y unfavourable t r a n s - d e c a r b o x y l a t i o n may occur when the s u b s t r a t e i s attached to the enzyme s u r f a c e , whereas the t r a n s - e l i m i n a t i o n of water may occur spontaneously w i t h i n t e r m e d i a t e s that have become detached from the enzyme. 1 2 (15a) (15b) -11-Th e f i n a l stages in the biosynthesis of heme involve the oxidation of protoporphyrinogen IX to protoporphyrin IX and the incorporation of iron by the enzyme ferrochelatase to give protoheme. 1.3 SYNTHESIS OF PORPHYRINS A detailed discussion of the synthesis of porphyrins i s beyond the scope of this introduction. The interested reader is advised to consult recent reviews.17,18 Synthetic intermediates of the unsymmetrically substituted porphyrins are dipyrrolic compounds. The three basic types of dipyrrolic compounds used, are the dipyrromethanes (16), dipyrromethenes (17) and the dipyrroketones (18). Scheme 1.4 outlines the general synthetic routes for their preparations. The methods for the rational synthesis of the unsymmetrically substituted porphyrins are based upon 2+2 type synthesis, in which two dipyrrolic components are coupled together to give the macrocycle. The coupling may be effected through either a one-step process or a two-step process. A. One-step process In the one-step process two dipyrrolic components are joined at both ends to give a cyclic intermediate which on jln situ oxidation gives the porphyrin. i) From dipyrromethanes The synthetic route to porphyrins from dipyrromethanes was developed by MacDonald1^ and u t i l i s e s the mild acid-catalysed condensation of a 5,5'-diformylpyrromethane (19) with a 5,5'-di-unsubstituted pyrromethane (20) (Scheme 1.5). The cyclic intermediate is^oxidised in situ to the Dipyrromethanes: SCHEME 1.4 Synthesis of D i p y r r o l i c Intermediates N (18) (20) SCHEME 1.5 Synthesis of Porphyrins via Dipyrromethanes -14 -required porphyrin. i i ) From dipyrromethenes Until recently the most widely employed synthetic route to unsymmetrically substituted porphyrins was via dipyrromethenes. It involves the condensation of 5,5'-dibromopyrromethene salts (21) with 5,5'-dimethyl- or 5,5'-di(bromomethyl)pyrromethene salts (22) in organic acid melts at temperatures up to 200° 2 0 (Scheme 1.6). SCHEME 1.6 Synthesis of porphyrins via dipyrromethenes The high temperatures required by this procedure often resulted in low yields. Improvements on this procedure have been reported by Paine, Chang and Dolphin. 2 1 Significant variations and extensions of this route by Johnson and his colleagues 2 2' 2 3' 2 1' have further increased i t s applicability. - 1 5 -Th e above mentioned -one-step processess r e q u i r e one of the d i p y r r o l i c components to be symmetrical about the i n t e r - p y r r o l i c carbon atom, i n order to prevent the formation of a mixture of p r o d u c t s . A •^single "product i s o n l y obtained when a symmetrical d i p y r r o l i c compound i s self-condensed. "~TJse of -two d i f f e r e n t d i p y r r o l i c compounds r e s u l t s i n the formation of three p o r p h y r i n s . B. Two-step process •.}.-.-_ >••-- -The-two—step-.; process- involves the formation of an i s o l a b l e open-chain t e t r a p y . r r o l i c i n t e r m e d i a t e , e.g., b i l a n e ( 23), by j o i n i n g -the d i p y r r o l i c components at one end, f o l l o w e d by c y c l i s a t i o n . T his method i s u s e f u l i n the c o n s t r u c t i o n of unsymmetrical p o r p h y r i n s , as i t dispenses w i t h the symmetry requirements. I t i n c l u d e s r o u t e s through b - b i l e n e s , 2 5 a , c - b i l a d i e n e s , 2 2 a - o x o b i l a n e s 2 6 and b - o x o b i l a n e s . 2 7 i ) From b - b i l e n e s Z 5 The approach to p o r p h y r i n s through b - b i l e n e s (24) i s o u t l i n e d i n Scheme 1.8. -16-/ R= Bu*"; SCHEME 1.8 Porphyrins from b-bilenes Electron-withdrawing substituents on the internal rings (B and C ) of the b-bilene (24) lead to complications. As a result this route is not often used. Cyclisation of (24) using trichloroacetic acid and trimethyl orthoformate gives the porphyrin. 2 5 i i ) From a-oxobilanes (25) 2 6 An application of this route is shown in the synthesis of mesoporphyrin IX DME (26) 2 e (Scheme 1.9). i i i ) Frnm h-nxoh-tlanes (29) 2 7 An example of porphyrin synthesis through b-oxobilanes is given in Scheme 1.10 using porphyrin S411 (29) as an example.4 -17-(26) SCHEME 1.9 S y n t h e s i s of Mesoporphyrin v i a the a-oxobilane route (21) SCHEME 1.10 Synthesis of Porphyrin S411 v i a the b-oxobilane route -19-(29) Acr., -CH=CHCOOH, P, -CH2CH2COOH The direct synthesis of a porphyrin with an acry l i c acid side-chain i s not feasible due to the nature of the reactions involved in the construction of the porphyrin macrocycle (Scheme 1.10). One route by which the synthesis of such a porphyrin may be accomplished involves the construction of the corresponding 6-free porphyrin (28), the 6-free position being protected with a bromine atom in the early stages of the synthesis. The substituent i s then introduced into the macrocycle, For example, formylation of the iron(III) complex of (28) with dichloro-methyl ether i n the presence of tin(IV) chloride (Scheme 1.10), followed by condensation with methyl hydrogen malonate would introduce an acrylic acid group into the g-free position of (28). The a- and b-oxobilane routes have been used for the synthesis of unsymmetric porphyrins, but their main disadvantage i s the complexity of the reaction sequence. Furthermore, isotopic labelling of the side-chains - especially for biochemical studies, i s a major undertaking as there are many steps from mono-pyrrolic precursors. These routes also suffer from the lack of a common intermediate, necessitating the synthesis of appropriate dipyrrolic-precursors for each porphyrin. -20-An a t t r a c t i v e and l e s s l a b o r i o u s a l t e r n a t i v e i s the p a r t i a l s y n t h e s i s of the d e s i r e d p o r p h y r i n from a r e a d i l y a v a i l a b l e n a t u r a l l y o c c u r r i n g porphyrin. As a consequence, the problem i n v o l v e d i n the c o n s t r u c t i o n of the unsymmetrically s u b s t i t u t e d p o r p h y r i n macrocycle i s circumvented. The most r e a d i l y a c c e s s i b l e n a t u r a l porphyrin i s protoporphyrin IX (30) and may be obtained from e i t h e r h e m i n 2 8 or hematoporphyrin IX dihydro-c h l o r i d e ( 3 1 ) , 2 9 both of which are commercially a v a i l a b l e . V, -CH=CH2 (30) R, -CH 2CH 2C0 2H (31) R, -CH(0H)CH 3 (32) R, -CH 2CH 2C0 2CH 3 In t h i s study we rep o r t the p a r t i a l s y n t h e s i s of porphyrin S411 and harderoporphyrin from p r o t o p o r p h y r i n IX DME (32) . P r o t o p o r p h y r i n IX (30) was prepared by the thermal dehydration of hematoporphyrin IX d i h y d r o c h l o r i d e (31) i n r e f l u x i n g DMF.^° E s t e r i f i c a t i o n of (30) was e f f e c t e d w i t h 5% s u l p h u r i c a c i d i n m e t h a n o l . 2 8 Protoporphyrin IX (30) has one p a i r of v i n y l groups s u b s t i t u t e d at p o s i t i o n s 2 and A of the p o r p h y r i n macrocycle. P a r t i a l s y n t h e s i s i n v o l v i n g d e r i v a t i s a t i o n of one of the p a i r of v i n y l groups of -21-protoporphyrin i s commonly accomplished through partial derivatisation. Partial derivatisation involves a reaction in which only one equivalent of the reagent is used. Although i t has been reported 3 1 that the 2-vinyl group is more reactive than the A-vinyl, subsequent studies have not found preferential product f o r m a t i o n . 3 2 - 3 5 As a consequence, partial derivatisation would result in a mixture of porphyrins consisting of the two isomeric (2-or A-derivatised protoporphyrin) mono-derivatives and the di-derivative. Utilisation of this method not only necessitates the separation of the resulting porphyrin mixture, but also gives•low yields for the mono-derivatives due to the formation of the undesired d i -derivative. Furthermore, i t is not easy to assign an absolute struc-fcure / to each of the two isomeric mono-derivatives. Total synthesis, however, has the advantage of being able to unequivocally distinguish between isomers. -22-II. SYNTHESIS OF PORPHYRIN S411 The synthesis of porphyrin S411 (la), from protoporphyrin IX DME (32) involves the transformation of the vinyl groups at positions 2 and 4 of the latter porphyrin into an acrylic acid group and a propionic acid group respectively. The major problem encountered in syntheses involving differently substituted deuteroporphyrins is selective derivatisation of one of the pair of vinyl groups. As no marked difference in reactivity between the 2 and 4 vinyl groups was found 3 2 _ 3 5selective derivatisation is not possible. An alternative method is partial derivatisation which would result in a mixture consisting of the two isomeric mono-derivatised porphyrins. Therefore, i f this method is to be synthetically attractive an efficient method for the separation of the porphyrin mixture is essential. -23-Reports on the partial synthesis of spirographis porphyrins, (mono-formyl-mono-vinyl-deuteroporphyrins) (33a) and (33b) ,33-37 harderoporphyrins (34a) and (34b) 34 and pemptoporphyrins (35a) and (35b) 34 from protoporphyrin IX DME (32) have appeared in the literature. The most outstanding of these is the synthesis of the isomeric spirographis porphyrins (33a) and (33b) by Inhoffen.37 The mono-derivatisation of proto-porphyrin IX DME (32) was effected via the photoprotoporphyrins (36a) and (36b). Exposure of protoporphyrin IX to sunlight gave the isomeric photoprotoporphyrins in a yield of 75%. (a) (b) Rj R2 Ri R2 (33) ; -CHO. -CH=CH2; -CH=CH2, -CHO; (34) -CH=CH2, -CH2CH2C02H; -CH2CH2C02H, . -CH=CH2; (35) ; -CH=CH2, -H; -H, -CH=CH2: -24-The reaction involves the 1,4-addition of singlet oxygen to either of the vinyl substituted pyrrolenine rings (A or B) followed by decomposition of the peroxide (Scheme 2.1). Mono-derivatisation is achieved through the inhibitory effect exerted by the electrophilic formyl ethylidene group on the oxidation of the second vinyl group. This procedure, after chromatography of the isomeric photoprotoporphyrins, gave a 35% yield for each isomer. The greater mobility compound on silica gel using dichloromethane as eluent was identified with the 4-photo-protoporphyrin (36a). Borohydride reduction of the photoprotoporphyrins, followed by rearrangement and cleavage of the resulting glycols with periodate gave the corresponding formyl-vinyl derivatives in an 80% yield (Scheme 2.1). The efficiency of the synthesis is due to mono-derivatisation, which is effected by the formation of the photoproto derivatives, and the facile separation of the two photoproto isomers on silica gel. The usual mode in which a trans-acrylic acid group is introduced into the porphyrin macrocycle is via the condensation of a formyl group with malonic acid in the presence of a strong base. Therefore, the mono-formyl-mono-vinyl-deuteroporphyrins (33a) and (33b) are potentially useful intermediates in the synthesis of porphyrin S411. The high yields reported by Inhoffen for the synthesis of the isomeric formyl-vinyl derivatives (33a) and (33b) could not be reproduced using the cited reaction conditions. 3 8' 3 9 Clezy 3 8 was able to obtain a yield of 25% from the photoprotoporphyrin II DME by changing the solvent from dichloromethane-benzene to dioxane. A 60% yield was reported by Hamilton,1*0 who used a modification of Clezy's method. In the present study, a procedure similar to that used by Hamilton was employed. An average yield of 75% was achieved. N 1 SCHEME 2.1 Photo=oxidation of Protoporphyrin IX DME i -26-Th e condensation of the mono-formyl-mono-vinyl-deuteroporphyrins with malonic acid was achieved according to the method of Hamilton1*0 (Scheme 2.2). The acrylic acid substituent was esterified with 5% sulphuric acid in methanol. Hydration of the acrylic acid double bond was not observed. Conversion of the vinyl group of mono-acrylic acid-mono-vinyl-deuteroporphyrin IX DMEs (37a) and (37b) into a propionic acid group would transform the latter porphyrins into isomeric S411 porphyrins. A sequence of reactions to effect this conversion i s outlined in Scheme 2.3. This synthetic scheme relies on the preferential photo-oxidation of the vinyl group. If the photo-oxidation i s a Diels-Alder type reaction, as has been suggested, 0 7 the acrylic acid diene component should be de-activated by the electronegative carboxyl group. Consequently, the preferential photo-oxidation of the vinyl group was expected, but at a slower rate due to the effect of the acrylic acid group. 3 1 Separation of the isomeric photoprotoporphyrins by column chromatography gives three fractions: the 4-photoprotoporphyrin isomer eluted f i r s t , the mixed isomers and the 2-photoprotoporphyrin isomer. The mixed fractions may be rechromatographed to obtain the pure isomers. Accumulation of adequate supplies of the pure isomers for exploratory studies was limited due to the tedious and costly nature of the chroma-tographic separation technique. The mixed isomers were, therefore, used for preliminary studies to conserve supplies of the pure isomers. The mono-acrylic acid-mono-vinyl-deuteroporphyrins in dichloro-methane containing 10% pyridine were exposed to direct sunlight. After three days a colour change from red to green was observed. The thin-layer chromatogram of the green solution revealed there were four (two pairs) SCHEME 2.3 -29-and not, as expected, two (one pair) products of the reaction. This observation was not shared by Hamilton*40 who reported the presence of only two products. The observed four products indicated that both the vinyl and the acrylic acid diene components were susceptible towards photo-oxidation. The fact that the reaction had occurred at the acrylic acid diene component further indicated that the expected de-activating effect at this reaction site was removed. Ionisation of the carboxyl group in the presence of pyridine could, however, account for the absence of this de-activating effect. Spectral studies of the reaction mixture were not possible, because separation of the products by TLC could not be accomplished. Reduction of the acrylic acid group prior to photo-oxidation would overcome the above drawback but would require the protection of the vinyl group. Protection of the vinyl group may be achieved by either Markownikoff-1*1 or anti-Markownikoff hydration.1*2 The Markownikoff procedure was preferred to the latter, because of the facile dehydration of the mono-(l-hydroxyethyl)-derivative (38). 3 0 The method employed was that reported by Clezy and Barrett.1*1 However, the yield was poor. Short reaction periods increased the yield to 40%, but further attempts to improve the efficiency of the reaction were not successful. (38) -30-Kenner, McCorabie and Smith,1*2 made use of the anti-Markownikoff hydration as an intermediate step in the conversion of protoporphyrin IX to coproporphyrin III. The 2-hydroxyethyl derivative was converted to the 2-cyanoethyl derivative via the 2-bromoethyl derivative. Hydrolysis of the 2-cyanoethyl derivative gave the required propionic acid group. Using a similar approach the vinyl group of mono-formyl-mono-vinyl-deuteroporphyrin could be converted to a propionic acid group with the condensation of the formyl group with malonic acid being effected at an appropriate stage in the conversion. In view of this direct route the sequence outlined in Scheme 2.3 was abandoned. Scheme 2.4 illustrates the sequence of reactions leading to the synthesis of porphyrin S411 from 2-formyl-4-vinyl-deuteroporphyrin IX DME. Treatment of (33a) with two equivalents of thallium (III) nitrate (TTN) in methanol gave the 2,2-dimethoxyethyl derivative (39a) . 3 4 » 1 + 2 S t r i c t adherence to the literature procedure, 3 4 resulted in a 70% yield whereas a modified procedure gave a yield of 90%. The f i r s t equivalent of TTN is consumed in the formation of the thallium complex of (33a) (Scheme 2.5). Demetallation of the thallium complex was achieved by passing sulphur dioxide through the solution (T1(III)->T1(I)) and precipitating the T1(I) with acid. Condensation of (39a) with malonic acid in pyridine with a trace of piperidine, as mentioned earlier, gave (40a).1* Acid-hydrolysis of (40a) in tetrahydrofuran followed by borohydride reduction and re-esterification gave (41a) . 3t*»1*2 Conversion of (41a) to (42a) may be effected with either thionyl bromide in dichloromethane-DMF1*2 or carbon tetrabromide-triphenyl phosphine. 3 4 The former method was found unsatisfactory in the presence -32--H H MeO-SCHEME 2.5 -33-of a vinyl group,3** owing to the formation of by-products arising from Markownikoff addition of hydrogen bromide to the vinyl group. The latter method was chosen in consideration of the unsaturated acrylic acid substituent on porphyrin (41a). The mechanism1*3 of the reaction is generally accepted to proceed via an oxophosphonium intermediate as portrayed in Scheme 2.6. The corresponding chlorination, however, i s postulated to proceed via a different mechanism,1+33 as no chloroform was detected 1* 3 3 in the reaction mixture. The porphyrin (41a) in dichloromethane was treated with with a large excess of carbon tetrabromide and triphenyl phosphine and refluxed. The bromo derivative was obtained i n a 72% yiel d . The yield could probably be improved as no attempts were made to determine optimum conditions. The reaction was also carried out with thionyl bromide in a yield of 55%. R Me R R i .(40a); -CH=CHCOOH -CH2CH(OCH3) 2(40b); -CH2CH(0CH3)2 -CH=CHC00H (41a); " -CH=CHC00H -CH2CH20H (41b); -CH2CH20H -CH=CHC00H (42a); -CH=CHC00H -CH2CH2Br (42b); -CH2CH2Br -CH=CHC00H (43) ; -CH=CHC00H -CH2CH2CN -34-i RBr + Ph 3P = O SCHEME 2.6. As mentioned e a r l i e r , the preliminary reactions were carried out on the mixed isomers. A separation of the isomeric mono-methylacrylate-mono-(2-bromoethyl)-deuteroporphyrins were observed on thin-layer chromato-grams. A preparative scale separation was effected, but the resolution obtained was not as good as for the two photoproto isomers. A y i e l d of 15% for each isomer was obtained. The 2-methylacrylate-A-(2-bromoethyl)-isomer was found to be the greater mobility compound on s i l i c a gel when dichloromethane-ether was used as eluent. Treatment of (42a) with cyanide i n 1-methylpyrrolidone gave the corresponding cyano-derivative (43) i n a y i e l d of 70%. Methanolysis of (43) gave the porphyrin S411. CHCHO (32) (36a) CHO M* (33a) T1(IIT)N03 -CH2CH(OCH2)3 (39a) CH2(C02H^2 Py/piperldlne I I SCHEME 2.7 Synthesis of Porphyrin S411 from Protoporphyrin IX DME "36-Dr.A.H.Jackson made available to us a sample of porphyrin S411 obtained by the b-oxobilane route for comparative studies. The melting point behaviour, spectral characteristics - NMR, visible and mass spectroscopy, 4 and TLC mobility of the two specimens were in good agreement. In addition, no significant melting point depression was observed upon admixture. APPLICATIONS OF THE PARTIAL SYNTHETIC INTERMEDIATES An attractive feature of par t i a l synthesis is that the synthetic intermediates, lik e the natural porphyrins derived from hemoproteins, are 2 and/or 4 derivatives of deuteroporphyrin IX. As a consequence, some of the synthetic intermediates are potentially useful in the synthesis of biosynthetically interesting porphyrins. One of the many biosynthetically interesting porphyrins is harderoporphyrin. Harderoporphyrin was f i r s t isolated from the Harderian gland of the r a t . 1 3 The harderian gland is located at the rear of the eye and i s found in animals possessing a 'membrana nictitans' or 'third eyelid'. Preliminary studies on this isolate by Kennedy 1 3 have identified harderoporphyrin as a mono-vinyl-tricarboxylic acid porphyrin. Its structure was formulated as (34a) and proved by the total synthesis of i t s trimethyl ester. 4 1* Subsequently, the corresponding porphyrinogen was established as an intermediate in the biosynthesis of heme between coproporphyrinogen III and protoporphyrinogen IX.. A method for the generation of a vinyl group involves an elimination reaction of a 2-hydroxyethyl substituent. 2 9 Conversion of the 2-hydroxyethyl derivative into the 2-chloroethyl derivative, followed -37-by the dehydrochlorination of the porphyrin zinc chelate with potassium t-butoxide generates the v i n y l group. More recently, Clezy has generated the v i n y l group from either the 2-chloroethyl or methane sulphonate derivative using sodium hydroxide i n aqueous pyridine. 1* 5 The above reactions highlight the s u i t a b i l i t y of 2-(2-hydroxy-ethyl)-4-methylacrylate-deuteroporphyrin IX DME (41b) as a potential precursor for the synthesis of harderoporphyrin (34a). Hydrogenation of the methylacrylate side-chain, followed by the dehydration of the hydroxy-ethyl side-chain would result i n harderoporphyrin (34a) (Scheme 2.7). Cata l y t i c hydrogenation was carried out on the acetate derivative (44) of porphyrin (41b) . In so doing possible hydrogenolysis of side-chains were eliminated. The porphyrin 2-(2-acetoxyethyl)-4-(2-methoxycarbonylethyl)-deuteroporphyrin IX DME (45) has been a key intermediate i n the t o t a l synthesis of harderoporphyrin. 1*'*»1*^  As such, the conversion of porphyrin (4 into porphyrin (45) would accomplish the synthesis of harderoporphyrin. Preliminary studies proved the v a l i d i t y of this synthetic sequence. The transformation of 2-methylacrylate-4-(2-hydroxyethyl)-deutero-porphyrin IX and 2-(2-hydroxyethyl)-4-methylacrylate-deuteroporphyrin IX into porphyrin S411 and harderoporphyrin respectively, i l l u s t r a t e s the e f f i c i e n t u t i l i s a t i o n of the two isomeric mono-(2-hydroxyethyl)-mono-methylacrylate-deuteroporphyrins. The exact mechanism by which coproporphyrinogen I I I i s trans-formed into protoporphyrinogen IX i s yet unclear. The transformation i s established to be s e q u e n t i a l , 1 3 with harderoporphyrinogen as an intermediate. The decarboxylation-elimination of the propionate side-chain i s postulated to proceed v i a the hydroxypropionate derivative -reference to section 1.2, although no evidence for the existence i n nature for the hydroxy propionate derivative i s available. Further investigation into the mechanism of the N (34a) SCHEME 2.8 \ Route for the Synthesis of Harderoporphyrin decarboxylation-elitnination may require the synthesis of the hydroxy propionate derivative and could be readily obtained by the hydration of porphyrin S411 with hydrobromic acid-acetic a c i d . 3 8 Digressing from the main theme of t h i s study, diagnosis of the porphyrias - a group of diseases a r i s i n g from disorders of heme metabolism, requires the separation and quantitative determination of the uro- to protoporphyrin precursors of heme i n blood, urine and faeces. The ready achievement of complex separations by high pressure l i q u i d chromatography (HPLC) has found favour as an e f f i c i e n t a n a l y t i c a l technique i n the c l i n i c a l . investigation of the porphyrias. 4* 7 U t i l i s a t i o n of HPLC i n such a capacity requires the presence of an in t e r n a l standard for a continual check on column and integrator e f f i c i e n c y . The in t e r n a l standard should be stable and rea d i l y a v a i l a b l e . More importantly, i t should be completly resolved from a l l unknowns and yet elute near the peak of i n t e r e s t . The above requirements were met by the f i r s t eluted isomer of mono-hydroxymethyl-mono-vinyl-deuteroporphyrin. The isomeric mono-hydroxymethyl-mono-vinyl-deuteroporphyrins were prepared by the borohydride reduction of the mono-formyl-mono-vinyl-derivatives. The two isomeric mono-hydroxymethyl-mono-vinyl derivatives (46a) and (46b) were separated by column chromatography using dichloromethane-ether as eluent. The greater mobility isomer was i d e n t i f i e d with the 2-vinyl-4-hydroxymethyl-deuteroporphyrin IX DME. Due to the s o l u b i l i t y properties of compounds (46a) and (46b), these compounds were converted to their acetates (47a) and (47b) for characterisation. - A n -I l l . EXPERIMENTAL 3.1. GENERAL METHODS E l e c t r o n i c Spectroscopy V i s i b l e s p e c t r a were obtained on a Cary 17 spectrophotometer. Dichloromethane - s p e c t r o grade was used as s o l v e n t , unless o t h e r w i s e s p e c i f i e d . Nuclear Magnetic Resonance Nuclear magnetic resonance F o u r i e r - t r a n s f o r m spectra, were taken at e i t h e r 100 MHz or 270 MHz w i t h a V a r i a n XL-100 or N i c o l e t Model NIC-80 spectrometer. D e u t e r i o c h l o r o f o r m was the s o l v e n t used. \ Resonances are quoted on the S-scale r e l a t i v e to t e t r a m e t h y l s i l a n e (6=0). M^ss Spectroscopy Mass s p e c t r a were recorded i n an A t l a s CH-4 spectrometer or an A.E.I. MS-902 spectrometer. M e l t i n g P o i n t Determination M e l t i n g p o i n t s were measured w i t h a Thomas-Hoover c a p i l l a r y m e l t i n g p o i n t apparatus and are uncorrected. A n a l y s i s Elemental a n a l y s i s f o r carbon, hydrogen, n i t r o g e n and bromine were determined by Mr.P.Borda of t h e " M i c r o a n a l y t i c a l L a b o r a t o r y , U.B.C. -42-Chromatography Column chromatography was performed using s i l i c a gel (Woelm-A c t i v i t y I) purchased from ICN Pharmaceuticals. The s i l i c a gel was de-activated to A c t i v i t y IV before use. Thin-layer chromatography (TLC) was performed using S i l i c a Gel GF precoated plates (Analtech-Uniplate, 250u) . Precoated 2000u thick plates were used for preparative scale TLC. 3.2 CHEMICALS AND MATERIALS A l l chemicals were reagent grade unless otherwise s p e c i f i e d . Hematoporphyrin IX dihydrochloride was obtained from Sigma Chemical Company. Methanol Dry. methanol was obtained by d i s t i l l a t i o n f TOTH- magnesium methoxide. Dichloromethane Dry dichloromethane was obtained by d i s t i l l a t i o n from calcium hydride. 3.3 PREPARATIONS PROTOPORPHYRIN IX (30) Protoporphyrin IX (30) was prepared from hematoporphyrin IX dihydrochloride (31) according to the method of D i N e l l o 3 0 i n almost quantitative y i e l d s . --- ~--43-Absorption Spectrum A 409 506 542 576 632 max P y r i d i n e : L i t . 2 8 A 409 506 542 576 63] max NMR 3.62 (16H,m) ( r i n g methyls, propionic a c i d BCH 2) y 4.66 (3H,t) (propionic a c i d aCH 2), 6.3 (4H,dd) ( v i n y l CH 2), 8.4 (2H,m) ( v i n y l CH), 10.19, 10.34, 10.68 (4H, a l l s) (meso-H). PROTOPORPHYRIN IX DME (32) Pfotoporphyin IX (30) was e s t e r i f i e d using 5% s u l p h u r i c a c i d i n methanol 2 8 i n a y i e l d of 75%. / Meltin g Point 221* - from CHC1 3-methanol L i t . 2 8 231* - from CHCl 3-methanol Absorption Spectrum A 407 505 541 575 630 max L i t . 2 8 A 407 505 541 575 630 max NMR 3.20 (4H,t) (propionate gCH 2), 3.48 (12H,t) ( r i n g methyls), 3.66 (6H,s) (methyl ester CH 3) , 4.28 (4H st) (propionate aCH 2), 6.16 (4H,m) ( v i n y l CH 2), 8.10 (2H,m) ( v i n y l CH), 9.72, 9.78, 9.82, 9.88 (each lH,s) (meso-H). Mass Spectrum (%) 590 (100) (parent), 531 (55) (l o s s of -C0 2CH 3), 517 (82) ( l o s s of -CH 2C0 2CH 3), 444 (66) (l o s s of -CH 2C0 2CH 3 twice). -44-PHOTOPROTOPORPHYRIN DMEs (36a) and (36b) Porphyrins (36a) and (36b) were prepared from (32) according to the method of D i N e l l o 3 0 in a combined yield of 72%. The average yi e l d of each pure isomer, after chromatography, was 22%. Isomer I (36b) Melting Point 220-222* - from CH 2Cl 2-methanol L i t . 3 7 222-223* - from CHC13 -methanol Absorption Spectrum A 388 436 568 613 671 max / L i t . 3 7 A 436 565 613 671 ' max NMR 1.26 (3H,s) (aliphatic CH 3), 3.26 (4H,m) (propionate 6CH2), 3.36, 3.42, 3.62 (each 3H, s) (ring methyls), 3.71 (6H,d) (methyl ester CH 3), 4.28 (4H,m) (propionate aCH2), 6.14 (2H,m) (vinyl CH2) , 6.54 (lH,d) (olefinic CH), 7.60 (lH,m) (vinyl CH), 7.60, 8.42, 9.66, 9.76 (each IH, s) (meso-H), 9.97 (lH,s) (aldehyde H). Mass Spectrum (%) 622 (100) (parent), 579 (48) (loss -CH2CH0), 549 (19) (loss of -CH2C02CH3). Isomer II (36a) Melting Point 241-243 T from CH 2Cl 2-methanol 37 L i t . 7 244 - from CHC13 -methanol A b s o r p t i o n Spectrum L i t . 3 7 610 668 608 668 NMR 1.38 (3H,s) ( a l i p h a t i c CH 3), 2.72, 3.27, 3.39 (each 3H,s) ( r i n g m e t h y l s ) , 3.27 (4H,m) (propionate BCH 2), 3.73 (6H,s) (methyl e s t e r CH 3), A.24 (4H,m) (4H,m) (propionate aCH 2), 5.91 (lH,d) ( o l e f i n i c CH), 6.17 (2H,m) ( v i n y l CH 2), 7.93 (lH,m) ( v i n y l CH), 7.49, 8.19, 9.59, 9.62 (each lH,s) (meso-H), 10.06 (l H , s ) (aldehyde H). Mass Spectrum (%) 622 (100) ( p a r e n t ) , 579 (44) ( l o s s of -CH 2CH0), / 549 (15) ( l o s s of -CH 2C0 2CH 3). 2- f o r m y l - 4 - v i n y l - d e u t e r o p o r p h y r i n IX DME (33a) 2-v i n y l - 4 - f o r m y l - d e u t e r o p o r p h y r i n IX DME (33b) The procedure used was a m o d i f i c a t i o n of Hamilton's method. 1* 0 To a s o l u t i o n of (36a) or (36b) (250mg) i n dry dichloromethane (125ml) was added sodium borohydride (250mg) i n dry methanol (10ml). The r e a c t i o n mixture was s t i r r e d a t room temperature f o r one hour. TLC at the end of t h i s r e a c t i o n p e r i o d - methylacetate-heptane 1:1 v/v, R f , s t a r t i n g m a t e r i a l - 0 . 4 6 , product-0.25, i n d i c a t e d the completion of the r e a c t i o n . Excess sodium borohydride was destroyed by the dropwise a d d i t i o n o f a c e t i c a c i d . The r e a c t i o n mixture was washed w i t h water (200ml x 2 ) , d r i e d over sodium sulphate and the s o l v e n t removed i n vacuo. The dark brown re s i d u e was d i s s o l v e d i n dioxane (125ml) and sodium p e r i o d a t e (400mg) i n hot water (0.75ml) was added f o l l o w e d by concentrated s u l p h u r i c a c i d (0.5ml). The r e a c t i o n was monitored by TLC-methylacetate-heptane 1:1 v/v, R f - s t a r t i n g m a t e r i a l - 0 . 2 5 , product-0.75. -46-Th e reaction was complete in one hour. The reaction mixture was worked up and the product purified according to the method of Hamilton. The yield of the reaction was 75%. Isomer (33a) Melting Point Lit. 37 Lit 37 275-278 - from CH2Cl2-petr6lei.m ether (30-60) 278-279* - from CHC13 -methanol Absorption Spectrum A max max 418 518 558 583 642 420 518 559 584 642 NMR Mass Spectrum (%) 3.26 (4H,t) (propionate BCH2), 3.52, 3.58, 3.70,3.76 (12H,s) (ring methyls), 3.66 (6H,s) (methyl ester CH3) 4.35 (4H,m) (propionate aCH2), 6.32 (2H,m) (vinyl CH2), 8.21 (lH.dd) (vinyl CH), 9.78, 9.86, 9.92, 10.66 (each lll,s) (meso-H), 11.32 (lH,s) (aldehyde H). 592 (100) (parent), 446 (18) (loss of CH2C02CH3 twice) 519 (81) (loss of CH2C02CH3). Isomer (33b) Melting Point Lit 37 Lit 37 223 - from CH2Cl2-pet.ether 225* - from CHC13 -methanol Absorption Spectrum A max max 420 518 558 583 642 418 518 559 584 642 -47-NMR 3.20 (4H,m) (propionate 6CH2), 3.30, 3.42, 3.48, 3.58 (each 3H,s) (ring methyls), 3.69 (6H,d) (methyl ester CH 3), 4.26 (4H,m) (propionate aCH2), 6.12 (2H,dd) (vinyl CH 2), 7.84 (lH,q) (vinyl CH), 9.19, 9.52, 9.60, 10.28 (each lH,s) (meso-H), 11.06 (lH.s) (aldehyde H). Mass Spectrum (%) 592 (100)(parent), 519 (57) (loss of CH 2C0 2CH 3), 446 (18) (loss of CH2C02CH3 twice). Monp-acrylic acid-mono-vinyl-deuteroporphyrin IX DMEs (37) A solution of the mixed isomers of porphyrin 33 (65mg) was dissolved / in pyridine (50ml) and malonic acid (2g) in pyridine (10ml) was added. The mixture was heated to 50* , with s t i r r i n g , and piperidine (0.75ml) added. The temperature of the reaction mixture was then raised to 80* and maintained there for five hours. After cooling the reaction mixture to room temperature f i t was poured into dilute hydrochloric acid (100ml, 5% v/v). The porphyrin was extracted into chloroform and the organic layer washed with water, dried over sodium sulphate and the solvent removed in vacuo. The residue was chromatographed on a s i l i c a gel preparative layer plate with chloroform-methanol 20:1 v/v as eluent. The slow moving band was removed from the s i l i c a gel with a chloroform-methanol solution and the solvent removed in vacuo. The residue was crystallised from dichloromethane-methanol in a yield of 72%. Absorption Spectrum A 418 512 552 581 637 r r max L i t . 1 * 0 X 419 512 552 580 637 max -48-3.26 (4H,m) (propionate gCH 2), 3.52-3.66 (18H,m), ( r i n g methyls, methyl e s t e r CH 3), 4.38 (4H,m) (propionate aCH 2), 6.24 (2H,m) ( v i n y l CH 2), 6.88 (lH.m) ( a c r y l i c a c i d BCH), 8.16 (lH,m) ( v i n y l CH), 9.18 (lH.m) ( a c r y l i c a c i d aCH), 9.84 (4H) (meso-H). Phot o - o x i d a t i o n of mono-acrylic acid-mono-vinyl-deuteroporphyrin IX DME (37) A s o l u t i o n of porphyrin (37) (20mg) i n dichloromethane c o n t a i n i n g 10% p y r i d i n e i n a 100ml measuring c y l i n d e r was exposed to d i r e c t s u n l i g h t . A c o l o u r change from red to green was observed a f t e r a day. The r e a c t i o n was monitored by TLC u s i n g dichloromethane-ether 20:1 v/v. The completion of the r e a c t i o n was gauged by the disappearance of the s t a r t i n g m a t e r i a l on TLC. The r e a c t i o n mixture was s u c c e s s i v e l y washed with IN h y d r o c h l o r i c a c i d , 5% sodium bicarbonate s o l u t i o n and f i n a l l y w i t h water. The organic phase was d r i e d over sodium sulphate and the solv e n t removed i n vacuo. The t h i n - l a y e r chromatogram of the r e a c t i o n mixture revealed two p a i r s of bands which could not be separated by TLC. Mono-formyl-mono-(l-hydroxyethyl)-deuteroporphyrin IX DME (38) The p o r p h y r i n (38) was prepared from (33) according to the method of Clezy.* 4 1 The r e a c t i o n time was fo u r hours. The y i e l d of the r e a c t i o n was 40%. -49-Absorption Spectrum X_ peak ratios max 415 516 556 583 642 13.7 4.9 6.4 4.0 1.0 Mass Spectrum (%) 610 (11) (parent), 592 (100) (loss of H20), 519 (55) (loss of H20,-CH2C02CH3). Mono-formyl-mono-(2,2-dimethoxyethyl)-deuteroporphyrins (39a) and (39b) The porphyrins (39a) and (39b) were prepared from (33a) and (33b) respectively, according to the method of Kenner et.al.* 4 2 with slight modifications. The modifications are; i) The reaction mixture was stirred at room temperature for 45 minutes, i i ) Porphyrins (39a) and (39b) were purified by column chromatography using dichloromethane-ether 20:1 v/v as eluent and crystallised from dichloromethane-pet.ether, in an average yield of 90%. 2-formyl-4-(2,2-dimethoxyethyl)-deuteroporphyrin IX DME (39a) Melting Point Analysis Absorption Spectrum 167-169 calculated found Xmax loge C 67.87 67.76 H 6.47 6.27 N 8.56 8.34 413 515 555 578 640 5.40 4.04 4.28 4.07 3.31 NMR 3.24 (4H,t) (propionate BCH2), 3.42 (6H,s) (acetal CH3), 3.48,3.53,3.56, 3.59 (each 3H,s) (ring methyls), 3.66 (6H,d) (methyl ester CH3), 4.24 (4H,m)(propionate -50-aCH2),4.38 (2H,t) (acetal CH2), 5.05 (lH.t) (acetal CH), 9.62, 9.85, 10.59 (4H,s) (meso-H), 11.22 (lH,s) (aldehyde H). Mass Spectrum (%) 654 (44) (parent), 622 (100) (loss of CH30H), 549 (44) (loss of CH3OH, -CH2C02CH3). 2-(2,2-dimethoxyethyl)-4-formyl-deuteroporphyrin IX DME (39b) Melting Point 174-176 Analysis C37Hi4 2N 40 7 calc. found C 67.87 68.17 H 6.47 6.00 N 8.56 8.14 Absorption Spectrum max loge 413 515 555 578 639 5.27 3.93 4.14 3.94 3.15 NMR 3.22 (4H,t) (propionate BCH2), 3.36 (6H,s) (acetal CH2), 3.48, 3.52, 3.58, 3.61 (each 3H,s) (ring methyls), 3.64, 3.68 (each 3H,s) (methyl ester CH3), 4.06 (2H,d) (acetal CH2), 4.24, 4.32 (each 2H,two t) (propionate ctCH2), 4.9 (lH,t) (acetal CH ), 9.60 (lH,s) 9.74 (2H,s) 10.6 (lH,s) (meso-H), 11.24 (lH,s) (aldehyde H) . Mass Spectrum (%) 654 (15) (parent), 622 (100) (loss of CH30H), 549 (44) (loss CH30H, -CH2C02CH3). - 5 1 -Mono-methylacrylate-mono-(2,2-diroethoxyethyl)-deuteroporphyrin IX DMEs  (40a) and (40b) The method used was based on the procedure of Hamilton.**0 The porphyrins (40a) and (40b) were prepared from (39a) and (39b) respectively. Porphyrin (40b) was not characterised, but converted into porphyrin (41b). A solution of (39a) or (39b) (lOOmg) and malonic acid (3g) in pyridine (100ml) was heated to 50 . To this solution piperidine (0.2ml) was added and the temperature raised to 80 . The progress of the reaction was monitored by TLC using dichloromethane-methanol 20:1 v/v, Rf-starting material 0.88, product 0.12. After five hours the reaction mixture was cooled and poured into IN hydrochloric acid (400ml) and extracted into chloroform (200ml). The cnloroform layer was washed with 5% sodium bicarbonate solution and repeatedly with water. The organic phase was dried over sodium sulphate and the solvent evaporated under reduced pressure. The porphyrin residue was treated with 5% sulphuric acid in methanol (100ml) overnight in the cold (refrigerator). The porphyrin ester was extracted into chloroform and the organic phase washed first with 5% sodium bicarbonate solution and then with water; i t was dried over sodium sulphate and the solvent removed in vacuo. The residue was chromatographed on lOOg silica gel using chloroform-acetone 30:1 v/v as eluent. The desired porphyrin was eluted second. The eluate collected was evaporated and the residue crystallised from dichloromethane-pet.ether (30-60) in a yield of 78mg or 72%. 2-methylacrylate-4-(2,2-dimethoxyethyl)-deuteroporphyrin IX DME (40a) Melting Point 192-194* Analysis C H N CitoHi l6Ni,'08 calc. 67.59 6.52 7.88 found 67.26 6.25 7.75 -52-Absorption Spectrum A 412 509 549 574 635 r max loge 5.34 4.16 4.32 4.09 3.55 NMR 3.26 (4H,t) (propionate gCH2), 3.43 (6H,s) (acetal CH 3), 3.56 (6H,s) (methyl ester CH 3), 3.56,3.63, 3.68 (12H,s) (ring methyls), 4.08 (3H,s) (acrylic ester CH 3), 4.34 (6H,m) (propionate aCH 2, acetal aCH), 5.06 (lH,t) (acetal BCH), 6.99 (lH,d) (acrylic acid BCH), 9.22 (lH,d,J=17Hz), (acrylic acid aCH), 9.87, 9.94, 9.98 (4H,s) (meso-H). Mass Spectrum (%) 710 (44) (parent), 678 (100) (loss of CH3OH), 605 (44) (loss of CH30H, -Cr^CC^CHg). 2-methylacrylate-4-(2-hydroxyethyl)-deuteroporphyrin IX DME (41a)  2-(2-hydroxyethyl)-4-methylacrylate-deuteroporphyrin IX DME (41b) The porphyrins (41a) and (41b) were prepared from (40a) and (40b) respectively. A solution of (40a) or (40b) (53mg) in tetrahydrofuran (30ml) containing water (0.6ml) was refluxed with cone, hydrochloric acid (0.2ml) for five minutes. The reaction mixture was cooled and the porphyrin extracted into dichloromethane (30ml) containing pyridine (10ml). The organic phase was washed with water, dried over sodium sulphate and the solvent removed in vacuo. The residue in dichloromethane (30ml) at 0 was treated with a cold (0 ), solution of borohydride (250mg) in methanol (10ml). While s t i r r i n g , the reaction mixture was allowed to attain room temperature. The excess sodium borohydride was then destroyed by the dropwise addition of acetic acid. The organic phase was washed with water, dried over sodium sulphate and the solvent evaporated under reduced pressure. The residue was re-esterified_with 5%_.sulphuric acid in methanol and chromatographed usingdichloromethane-ether 20:1 v/v as eluent. The major band was collected, -53-the solvent evaporated and the residue c r y s t a l l i s e d from dichloromethane methanol i n a y i e l d of 70%. 2-methylacrylate-A-(2-hydroxyethyl)-deuteroporphyrin IX DME (Ala) A n a l y s i s C H N C 3 8 H 4 2 N 4 ° 7 c.alc. 68.A5 6.35 8.AO found 68.08 6.72 8.16 Absorption Spectrum A A12 508 5A8 57A 636 max loge 5.AA A.30 A.A2 A.22 3.70 NMR 3.28 (6H,m) (propionate BCH 2, hydroxyethyl 6CH 2), / . 3.50, 3.95, A.60 (18H,m) ( r i n g methyls, propionate e s t e r CH 3), A.08 (3H,s) ( a c r y l i c e s t e r CH 3), A.A2 (6H,m) (propionate aCH 2, hydroxyethyl aCH 2), 7.07, (lH,d,J=17Hz) ( a c r y l i c gCH), 9.35 (lH.d,J=17Hz), ( a c r y l i c aCH), 10.OA (2H,s) 10.10 (lH,s) 10.14 (IH (meso-H). Mass Spectrum (%) 666 (100) ( p a r e n t ) , 635 (26) ( l o s s of -0CH 3), 607 (10) ( l o s s of -C0 2CH 3), 593 (21) ( l o s s of -CH 2C0 2CH 3). 2-(2-hydroxyethyl)-A-methylacrylate-deuteroporphyrin IX DME (Alb) A n a l y s i s C H N c 3 8 H 4 2 Nt4°7" l2 H2 0 c a l c - 6 7 - 5 3 6.A2 8.29 found 67.66 6.83 7.79 Absorption Spectrum \ 410 507 548 573 635 max l o g e 4.86 3.79 3.88 3.71 3.22 2-methylacrylate-4-(2-bromoethyl)-deuteroporphyrin IX DME (42a) Porphyrin (42a) was prepared from (41a) by two methods. Method 1 This compound (42a) was prepared from (41a) according to the method of Kenner e t . a l . 3 9 The reaction was carried out at room temperature and the yield of the reaction was 55%. Method 2 ^ A solution of carbon tetrabromide (lOOmg) and triphenyl phosphine (80mg) in dry dichloromethane (2ml) was added to a stirred solution of (41a) (30mg) in dry dichloromethane (10ml) and refluxed for twenty minutes. The cooled reaction mixture was diluted with dichloromethane (20ml) and washed with water. The organic phase was dried over sodium sulphate and the solvent removed i n vacuo. The residue was chromatographed using dichloro-me thane-ether 20:1 v/v. The major band eluted f i r s t was collected and taken to dryness. The residue was crystallised from dichloromethane-pet.ether to give compound (42a) in a yi e l d of 72%. The two Isomers of (42) (42a and 42b) were also separated on a preparative scale using dichloromethane-ether 30:1 v/v as eluent. The isomer eluted f i r s t was identified with 2-methylacrylate-4-(2-bromoethyl)-deutero-porphyrin IX DME. The yield for each isomer was 15%. Melting Point 196-200* Analysis C H N Br C 3 8 H 4 1 N 4 ° 6 B r c a l c - 62.55 5.66 7.68 10.95 found 62.50 5.54 7.44 10.68 -55-Absorption Spectrum \ 413 508 548 576 635 max l o g E 4.67 3.52 3.62 3.40 2.96 NMR 3.24 (4H,m) (propionate 6CH 2), 3.50 (12H,m) (ring methyls), 3.64 (3H,s) 3.66 (3H,s) (propionate ester CH 3), 4.08 (5H,m) ( a c r y l i c ester CH3, bromoethyl 6CH2), 4.34 (6H,m) (propionate otCH2» bromoethyl <*CH2) , 6.93 (lH,d,J=17Hz) ( a c r y l i c BCH), 9.12 (lH,d,J=17Hz) ( a c r y l i c aCH), 9.74 (2H,s) 9.80 (lH,s) 9.92 (lH.s) (meso-H). Mass -Spectrum (%) 728/730 (50/50) (parent, 655/657 (21/21) (loss of -CH 2C0 2CH 3), 648 (46) (loss of HBr), 675 (37) (loss of HBr, -CH 2C0 2CH 3). 2-methylacrylate-4-(2-cyanoethyl)-deuteroporphyrin IX DME (43) To a solution of (42) (lOmg) i n N-methylpyrrolidone (10ml) was added , with s t i r r i n g , a solution of sodium cyanide (lOmg) i n N-methylpyrrolidone (5ml). The reaction mixture was s t i r r e d at room temperature and the progress of the reaction was monitored by TLC using dichloromethane-ether 20:1 v/v; R f - s t a r t i n g material 0.58, product 0.29, On completion of the reaction, the reaction mixture was diluted with dichloromethane. The organic phase was repeatedly washed with water, dried over sodium sulphate and taken to dryness. The residue was chromatographed on s i l i c a gel using dichloromethane-ether 20:1 v/v as eluent. The major band was collected, the solvent evaporated and the residue c r y s t a l l i s e d from dichloromethane-pet.ether i n a y i e l d of 70%. -56-M e l t i n g P o i n t 242-244' Absorption Spectrum A 412 507 547 576 634 max loge 4.59 3.52 3.57 3.38 2.97 NMR 3.26 (6H,m) (propionate BCH 2, cyanoethyl 6CH 2), 3.60 (9H) 3.67 (9H) ( r i n g methyls, propionate e s t e r CH 3), 4.09 (3H,s) ( a c r y l i c e s t e r CH 3), 4.36 (6H,m) (propionate aCH, cyanoethyl aCH 2), 7.04 (lH,d,J=17Hz) ( a c r y l i c a c i d BCH), 9.28 (lH,d,J=17Hz) ( a c r y l i c e s t e r aCH), 9.81 (IH) 9.98 (IH) 10.02 (2H) (meso-H). Mass Spectrum (%) 675 (100) ( p a r e n t ) , 602 (30) ( l o s s of CH 2C0 2CH 3), 635 (50) ( l o s s of CH2CN) . Porphyrin S 4 l l Compound (43) (lOmg) was d i s s o l v e d i n methanol (10ml) saturat e d w i t h hydrogen c h l o r i d e and l e f t overnight i n the r e f r i g e r a t o r . The porphyrin was ext r a c t e d i n t o dichloromethane and the organic l a y e r washed w i t h 5% sodium bicarbonate s o l u t i o n and water. A f t e r the solvent was removed i n vacuo the residue was chromatographed w i t h dichloromethane-ether 20:1 v/v as e l u e n t . The f i r s t e l u t e d compound was c o l l e c t e d , the solv e n t removed i n vacuo and the r e s i d u e c r y s t a l l i s e d from dichloromethane pet.ether, i n almost q u a n t i t a t i v e y i e l d s . M e l t i n g P o i n t 237-239 - from dichloromethane-pet.ether L i t . 4 236-238* -57-Absorption Spectrum L i t . * 4 NMR max max 413 413 509 549 510 548 576 577 635 635 Mass Spectrum (%) M e l t i n g P o i n t of 3.26 (6H,m) (propionate gCH 2), 3.48 (9H) 3.60 (3H) 3.64 (3H) 3.68 (6H) 4.08 (3H) ( r i n g methyls, propionate e s t e r CH 3), 4.38 (6H,m) (propionate ctCH 2), 7.04 (lH,d,J=17Hz) ( a c r y l i c BCH), 9.30 (lH,d,J=17Hz) ( a c r y l i c aCH), 9.96 (IH) 10.00 (2H) 10.04 (IH) (meso-H) 708 (100) ( p a r e n t ) , 677 (7) ( l o s s of -0CH 3), 649 (14) ( l o s s of -C0 2CH 3), 635 (34) ( l o s s of -CH 2C0 2CH 3). (of admixture) 235-240* 2-(2-acetoxyethyl)-4-methylacrylate-deuteroporphyrin IX DME (44) Compound (41b)(8mg) was d i s s o l v e d i n p y r i d i n e (10ml) c o n t a i n i n g a c e t i c anhydride (1ml) and l e f t o v e r n i g h t . The r e a c t i o n mixture was poured i n t o 1% h y d r o c h l o r i c a c i d (50ml) and the porphyrin e x t r a c t e d i n t o e t h e r . The organic laye.r was washed w i t h 5% sodium bicarbonate s o l u t i o n f o l l owed by water. A f t e r d r y i n g over sodium sulphate the s o l v e n t was removed i n vacuo. The r e s i d u e was p u r i f i e d by chromatography u s i n g dichloromethane-ether 20:1 v/v. The major band was c o l l e c t e d , the s o l v e n t removed and the residue c r y s t a l l i s e d from dichloromethane-pet.ether. i n a y i e l d o f 72%. Absorption Spectrum A max peak r a t i o s NMR 411 508 548 575 635 47.4 3.4 4.8 3.02 1.0 2.10 (3H,s) (acetoxy e t h y l CH 3), 3.16 (4H,m) (propionate 6CH 2), 3.56, 3.62. 3.64 (18H) ( r i n g methyls, propionate CH 3), 4.90 (2H,m) ( a c e t o x y e t h y l gCH 2), 4.02 (3H,s) ( a c r y l i c e s t e r CH 3), 4.34 (6H,m) (propionate aCH 2, -58-acetoxyethyl aCH2), 7.02 (lH.d,J=17Hz), (acrylic BCH) , 9.A3 (lH,d,J=17Hz) , (acrylic ctCH) , 10.12 (2H) , 10.20 (1H),10.2A (IH) (meso-H). 2-(2-acetoxyethyl)-A-(2-methoxycarbonylethyl)-deuteroporphyrin IX DME(A5) Compound (AA) (5mg) in tetrahydrofuran (5ml) was hydrogenated over 10% palladium-charcoal at room temperature until the solution turned colourless. The catalyst was fil t e r e d off and while s t i r r i n g air was bubbled through the solution until the visible spectrum indicated the complete oxidation of the porphyrinogen. The solvent was removed in vacuo and the residue chromatographed using dichloromethane-ether 20:1 v/v as eluent. The major band was collected, the solvent evaporated under reduced pressure and the residue crystallised from dichloromethane-pet.ether to give compound (45) in a yield of 65%. Absorption Spectrum X 399 500 531 567 621 wax L i t . 4 X A00 502 532 567 621 max NMR 2.08 (3H,s) (acetoxyethyl CH 3), 3.20 (6H,m) (propionate BCH2), 3.67, 3.69 (21H,d) (ring methyls, methyl ester CH 3), A.2A (8H,m) (propionate aCH2, acetoxyethyl aCH2), A.88 (2H,t) (acetoxyethyl BCH2), 10.10, 10.12 (AH,d) (meso-H), -59-2-hydroxymethyl-4-vinyl-deuteroporphyrin IX DME (46a)  2-vinyl-4-hydroxymethyl-deuteroporphyrin IX DME (46b) A solution of sodium borohydride (50mg) in dry methanol (2ml) was added to a stirred solution of the mixed isomers of porphyrin (33) (50mg) in dry dichloromethane (25ml). The solution was stirred for one hour. The reaction was monitored by TLC using dichloromethane-ether 20:1 v/v, Rf-starting material 0.68, product 0.05. On completion of the reaction excess borohydride was destroyed by the dropwise addition of acetic acid. The organic phase was washed with water, dried over sodium sulphate and the solvent removed in vacuo. The residue, after chromatographic purification using dichloromethane-ether 20:1 v/v, was crystallised from dichloromethane-pet.e^her in a yield of 88%. The mixed isomers of (46) were separated by chromatography using dichloromethane-ether 10:1 v/v as eluent. The isomer eluted f i r s t was identified with 2-vinyl-4-hydroxymethyl-deuteroporphyrin IX DME (46b) . The yield for each pure isomer was 30%. Compound (46a) Analysis C 3 5 H 3 8 N 4 ° 5 calc. found C 70.69 70.78 H 6.44 6.55 N 9.42 9.10 Absorption Spectrum max log e 404 502 537 573 628 5.14 3.95 3.82 3.63 3.45 NMR 3.24 (4H,t) (propionate gCH2), 3.67 (6H,s) (methyl ester CH3), 3.53 (12H,t) (ring methyls), 4.32 (4H,t) (propionate &CH2), 6.24 (2H,m) (vinyl CH2)» 5.86 (2H,s)(hydroxymethyl CH2), 8.19 (lH,dd) (vinyl CH) , -60-9.95 (4H,s) (meso-H) Compound (46b) Analysis C 37^0^06 NMR c a l c . found Absorption Spectrum A max loge C 70.69 71.04 H 6.44 6.27 N 9.10 9.66 403 502 536 572 628 5.19 4.12 4.00 3.83 3.65 3.24 (4H,t) (propionate gCH 2), 3.50 (9H,s) ( r i n g methyls ), 3.66 (6H,s) (ester CH 3) , 4.30 (4H,t), (propionate BCH 2), 5.80 (2H,s) (hydroxymethyl CH 2), 6.24 (2H,m) ( v i n y l CH 2), 8.19 (lH.dd) ( v i n y l CH), 9.92 (4H,q) (meso-H). 2-acetoxymethyl-4-vinyl-deuteroporphyrin IX DME (47a)  2-vinyl-4-acetoxymethyl-deuteroporphyrin IX DME (47b) Compounds (47a) and (47b) were prepared from (46a) and (46b) r e s p e c t i v e l y , according to the method given i n reference 28. The y i e l d of the r e a c t i o n was 75%. Compound (47a) Melting Point Analysis C 3 7 H i 4 0 N 4 ° 6 205-207 c a l c . found C 69.79 69.27 H 6.33 6.21 N 8.80 8.49 -61-Absorption Spectrum \ NMR max loge 404 502 537 573 627 5.29 4.17 4.02 3.85 3.68 3.26 (4H,t) (propionate gCH 2), 3.56 (3H,s) (acetate CH 2), 3.60 (6H,s) 3.67 (12H,s) (rin g methyls, methyl ester CH 3), 4.38 (4H,m) (propionate aCH 2), 6.18 (2H,m) ( v i n y l CH 2), 6.48 (2H,s) (acetoxymethyl CH 2), 8.20 (lH.dd) ( v i n y l CH ), 9.98, 10.05, 10.08 (4H,s) (meso-H). Mass Spectrum (%) Comp-ound (47b) 636 (100) (parent ) Melting Point 165-168 Analysis C 3 7 H 4 0 N H ° 6 Absorption Spectrum NMR c a l c . found A max loge C 69.79 69.85 H 6.33 6.37 405 503 537 573 628 5.34 4.42 4.26 4.10 3.91 N 8.80 8.66 3.26 (4H,t) (propionate aCH 2), 3.58 (9H,m) 3.68 (12 H,s) (ring methyls.methyl ester CH3,acetate CH 3), 4.36 (4H,t) (propionate cxCH2), 6.28(2H,m) (vinyl CH 2), 6.44 (2H,s) (acetoxymethyl CH 2), 8.25 (lH,q) (vinyl CH), 10.00 (4H,q) (meso-H). Mass Spectrum (°A 636 (100) (parent). -62-BIBLIOGRAPHY 1. J .WALDENSTROM, Z.Physio.Chem., I I I , (1936). 2. J.M.FRENCH and E.THONGER, C l i n . S c i . , J31, 3 3 7 » (1966). 3. J.M.FRENCH, D.C.NICHOLSON and C.RIMMINGTON, Biochem.J., 120,393, (1970). 4. P.W.COUCH,D.E.GAMES and A.H.JACKSON, J.Chem.Soc.Perkin I , 2492, (1976). 5. 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