R E S E A R C H I

Chemists Take Different Routes to Chlorophyll α Harvard group's synthesis goes all the way from monocyclic pyrroles; Germans fill last remaining gaps in route proposed by chlorophyll pioneer Hans Fischer

The synthesis of chlorophyll α, re­corded in two independent and sparsely worded communications to the Journal of the American Chemical Society and Angewandte Chemie (and in C&EN, July 11, page 20) , is a tri­umph that has resisted chemists' ef­forts for a generation. The two com­munications, which show different routes to the compound, describe the work of Harvard's Dr. Robert B. Woodward and Munich's Dr. Martin Strell and their co-workers.

Total synthesis completely confirms the structure of chlorophyll proposed by Dr. Hans Fischer of Munich's Technische Hochschule in 1940. Per­haps more important, it adds a fund of knowledge to the chemistry of chlorophyll and its intermediates. And it provides a number of new tech­niques which should advance the art of organic synthesis.

Biochemically, the syntheses are un­doubtedly a major step toward under­standing the complicated life processes of plants. But, both Dr. Woodward and Dr. Strell emphasize, photosyn­

thesis is not a single process; it is a whole branch of biochemistry. And while chlorophyll does play a central role in photosynthesis, biochemists still do not know for sure whether chlorophyll is involved chemically.

The Harvard Route. Dr. Woodward and his group use more than 30 reac­tion steps in their synthesis (JACS, July 20) . Many of these steps and methods used to carry them out are novel, Dr. Woodward says.

The synthesis starts with four rela­tively simple building blocks, each a monocyclic pyrrole synthesized from 2,4-dimethyl-3,5-dicarbethoxy pyrrole. These form the cornerstones of the chlorophyll molecule. The synthesis goes through a porphyrin, several pur­purins, and finally to chlorin efi. From there, only three more steps, pre­viously studied by other workers, are needed to reach chlorophyll a.

This synthesis took four years to work out, Dr. Woodward says. It follows a general plan developed in advance, but it also includes several discoveries that could not be antici­pated. The first part is aimed at pro­ducing a key porphyrin intermediate. The two halves of this molecule, each a dipyrrylmethane, were synthesized from pyrroles.

Fitting the dipyrrylmethanes to­gether so that they join at the proper spots took a bit of doing. Dr. Wood­ward and co-workers directed this re­action by inserting a thioformyl group at the 5-position of the right-hand di­pyrrylmethane. This was reacted with the aminoethyl group on the left-hand intermediate to form a bridge between the two molecules. This bridge served to hold the molecules in place while they were condensed to the porphyrin. Dr. Woodward

HARVARD'S WOODWARD. Dr. Robert B. Woodward of Harvard and 17 co­workers synthesized chlorophyll a from monocyclic pyrroles

comments that this is the first directed porphyrin synthesis and emphasizes the mild conditions under which it proceeds. Yield is about 507c

Next the porphyrin is oxidized by air in warm acetic acid. This removes two hydrogens from one of the carbo-methoxyethyl side chains. From here, the group sought to convert the por­phyrin to a purpurin. They found that the two compounds could be equilibrated in acetic acid under ni­trogen and the desired purpurin sep­arated. Dr. Woodward calls this the most remarkable synthesis step.

Chance Discovery. After adding a vinyl group within the molecule, the Harvard chemists oxidize the first purpurin to 7-methoxalylpurpurin 5. Air in the presence of visible light does the job. This particular reac­tion was discovered by chance. One Saturday morning, Dr. Woodward came in to the lab and noticed a reaction mixture containing the pur­purin and hydrazine which had been left to stand overnight on a window sill. There apparently had been no reaction. (The compounds in the synthesis are highly colored, and re­actions often can be followed by color change. )

A couple of hours later, Dr. Wood­ward saw that the solution had changed color. The factor that did it, he suspected, was visible light, since nothing had occurred during the night. Later he found that hydrazine was not needed for the reaction.

Potassium hydroxide in methanol converts 7-methoxalylpurpurin 5 to racemic isopurpurin 5 methylester. A corresponding optically active com­pound was made by Dr. Fischer dur­ing his chlorophyll work in the 1940's. Infrared and visible spectra of the iso-purpurin 5 made by Dr. Woodward's group showed that it was identical to material from natural sources.

The next task is to separate the ac-

HARVARD CHEMISTS

START FROM

MONOCYCLIC PYRROLES

A U G . 1, 1960 C & E Ν 37

GERMAN WORKERS START FROM PREVIOUSLY-SYNTHESIZED INTERMEDIATES

38 C & E N A U G . 1, 1960

MUNICH'S STRELL AND CO-WORKERS. Team of chemists at Munich Technische Hoch-schule—Dr. A. Kalojanoff, Dr. Martin Strell, H. Koller (standing, left to right) and Dr. A. Triebs—completed chlorophyll a synthesis outlined by their mentor, Dr. Hans Fischer

tive optical isomer from the racemic isopurpurin. It is converted to racemic chlorin 5, from which a qui­nine salt that yields active chlorin 5 can be removed. This is converted to active purpurin 5 dimethyl ester, and finally to chlorin e6 trimethyl ester. From here, it is just three steps to chlorophyll a. These steps have been previously detailed by earlier work­ers, so Woodward's group needed to go no further.

Assisting Dr. Woodward at one time or another during the synthesis were 17 co-workers from seven countries, a sort of biochemical United Nations: Canada—W. A. Ayer, Z. Valenta; Eng­land—R. Bonnett; Germany—F. Bick-elhaupt, G. Closs, W. Lwowski, J. Sauer, H. Volz; Japan—Sho Ito; Scot­land—J. M. Beaton, J. Hannah; Swit­zerland—P. Buchschacher, H. Dutler, A. Langermann, W. Leimgruber; United States-F. Hauck, E. LeGoff.

Synthesis of chlorophyll by no means is the end of Dr. Woodward's interest in this field. In fact, it's more like the start. One evening recently, he sat down with a piece of yellow scratch paper and in a few minutes listed 26 related projects that the syn­thesis suggests. He figures this might well keep him busy for another 10 years if he follows them all up.

The German Route. Dr. Strell and co-workers Dr. A. Kalojanoff and H. Koller reported the last phases of their synthesis in their latest publication [Ang. Chem., 72, 169-170 ( I960) ] . Their work is the culmination of more than two decades of effort at Mu­nich Technische Hochschule and is an

extension of the chlorophyll synthesis plan developed by Dr. Fischer prior to his death in 1945. Dr. Fischer's approach was to make chlorophyll by breaking down the natural material to simpler intermediates and building these back up chemically. Dr. Strell's communication completes the Fischer synthesis and is the latest in a series of publications on the German studies.

In their latest report, Dr. Strell and his group start with 2-desvinyl-2-acetyl isochlorin e4. They reduce the 2-acetyl group with sodium borohy-dride, complex this product with iron, and react the complex with ethyldi-chloromethyl ether. This builds a ring onto the third pyrrole group.

Next step is to oxidize the C—OH in this new ring to C = 0 . This the Germans do with P t 0 2 and oxygen in acetic acid. To check their results, they compared properties of these in­termediates against samples of them they had obtained by chemical break­down of natural chlorophyll. Find­ings: Comparison compounds were identical.

The Germans then partially saponify their carbonyl intermediate with acid. This is followed by hydrolysis of the hydroxyethyl group in the 2-position to give their final intermediate, phaeo-phorbid a. Introducing the phytyl group and magnesium into the phaeo-phorbid a molecule—accomplished by Fischer and Wilstaetter earlier—gives chlorophyll a. Hence, says Dr. Strell, this synthesis of phaeophorbid a, "dis­regarding the racemic separation, rep­resents total synthesis of chlorophyll «."

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