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A tribute to pioneer in reactive polymers: R. Bruce Merrifield, 1984 nobel prize in chemistry
Reactive Polymers, 3 (1985) 2 4 9 - 2 5 0
249
Elsevier Science Publishers B.V., A m s t e r d a m - Printed in T h e N e t h e r l a n d s
A TRIBUTE TO A PIONEER IN REACTIVE POLYMERS: R. BRUCE MERRIFIELD, 1984 NOBEL PRIZE IN CHEMISTRY May 26, 1959. After several years of work on the synthesis of peptides, R.B. Merrifield consigns to his notebook a new and seemingly far-fetched idea for a better and faster synthetic approach to large peptides. His notebook entry entitled "'A new approach to the continuous stepwise synthesis of peptides'" asserts that "'there is a need for a rapid, quantitative, automatic method for the synthesis of long chain peptides" and goes on to develop the concept of p o l y m e r - s u p p o r t e d synthesis:"A possible approach may be the use of chromatographic columns where the peptide is attached to the polymeric packing and added to by an activated amino-acid, followed by removal of the protecting group & with repetition of the process until the desired peptide is built up. Finally, the peptide must be removed from the supporting medium". October, 17, 1984. On the way to his office at Rockefeller University in New York, Dr. Merrifield is met by one of his coworkers who informs him that he has been awarded the 1984 Nobel prize in chemistry for his development of the solid phase method of synthesis. In the twenty-five years which separate these two events, there have been some very significant advances not only in Merrifield's own research area of peptide and protein chemistry, but also in a number of related areas of organic synthesis where Merrifield's vision of polymer-supported chemistry and his report of the first solid-phase synthesis have sparked a number of efforts in several directions. In the early years, Merrifield's pioneering work was complemented by that of other such notable innovators as R.L. Letsinger and E. Katchalski, with many other
research groups joining in as the field matured and its scope broadened. Merrifield's solid-phase synthesis concept is remarkable in its simplicity and in its broad applicability: to achieve the multistep synthesis of a large or complex molecule, the initial fragment, or precursor molecule, is attached to an insoluble reactive polymer. This initial attachment confers insolubility to the bound moiety while not affecting its chemical reactivity; thus it allows for the sequential modification of the bound moiety in a series of successive reactions (such as the removal of protecting groups and the formation of peptide bonds in Merrifield's original scheme). The main advantage of the technique is that after each reaction, the polymer-bound species can be "purified" by simple washings as all soluble impurities are not retained by the polymer; indeed this "purification advantage" is at the heart of Merrifield's discovery. Because of this, reactions can be pushed towards completion through the use of excess soluble reagents which will not cause problems during product isolation and may even be recycled by a simple filtration process; and last but not least, the process can be automated readily as was so brilliantly demonstrated by Merrifield. Once the desired synthetic sequence has been completed by man or machine, the bond between the polymer support and the completed product is cleaved, selectively liberating the product in solution, while the by-product of the cleavage reaction (the polymer) remains insoluble and may even be recycled in some instances if warranted. Obviously the implementation of the solid phase method for the synthesis of large
250
peptides or proteins requires much more than "just" the design of a revolutionary concept (!). It also requires the development of new reactions and techniques which span several areas of chemistry. It is no accident that the resin most commonly used in solidphase syntheses nowadays is still Merrifield's original chloromethylated polystyrene, while Merrifield's contributions to the chemistry of peptide bond formation, the selective protection and deprotection of amino-acids, the development of new techniques for the purification of peptides, and the refinement of the automated technology, are all receiving the recognition which they warrant. The impact of the solid phase method of synthesis on several fields of biochemistry, pharmacology, physiology, medicine, etc., is well known and is widely recognized. Lesser known perhaps is Merrifield's impact on several areas of more classical organic synthesis in non-peptidic areas. While Merrifield himself did not experiment in these areas, his
work has inspired many other scientists in their own creative activities involving the use of polymer-supported species. Thus, significant advances have been made in the development of polymeric reagents, polymeric protecting groups, polymer-bound catalysts and photosensitizers, polymer-based separation media, and other related areas where the general concept of immobilization has contributed to the rapid advancement of science. It is impossible to conclude without a word about R. Bruce Merrifield's outstanding human qualities. Those of us who have had the pleasure of meeting him and his most gracious wife Elizabeth will certainly agree that the 1984 Nobel prize, which he so richly deserves for his outstanding contributions to science, could not possibly have been bestowed upon a nicer human being. JEAN M.J. F R E C H E T
Ottawa, Canada June 1985
249
Elsevier Science Publishers B.V., A m s t e r d a m - Printed in T h e N e t h e r l a n d s
A TRIBUTE TO A PIONEER IN REACTIVE POLYMERS: R. BRUCE MERRIFIELD, 1984 NOBEL PRIZE IN CHEMISTRY May 26, 1959. After several years of work on the synthesis of peptides, R.B. Merrifield consigns to his notebook a new and seemingly far-fetched idea for a better and faster synthetic approach to large peptides. His notebook entry entitled "'A new approach to the continuous stepwise synthesis of peptides'" asserts that "'there is a need for a rapid, quantitative, automatic method for the synthesis of long chain peptides" and goes on to develop the concept of p o l y m e r - s u p p o r t e d synthesis:"A possible approach may be the use of chromatographic columns where the peptide is attached to the polymeric packing and added to by an activated amino-acid, followed by removal of the protecting group & with repetition of the process until the desired peptide is built up. Finally, the peptide must be removed from the supporting medium". October, 17, 1984. On the way to his office at Rockefeller University in New York, Dr. Merrifield is met by one of his coworkers who informs him that he has been awarded the 1984 Nobel prize in chemistry for his development of the solid phase method of synthesis. In the twenty-five years which separate these two events, there have been some very significant advances not only in Merrifield's own research area of peptide and protein chemistry, but also in a number of related areas of organic synthesis where Merrifield's vision of polymer-supported chemistry and his report of the first solid-phase synthesis have sparked a number of efforts in several directions. In the early years, Merrifield's pioneering work was complemented by that of other such notable innovators as R.L. Letsinger and E. Katchalski, with many other
research groups joining in as the field matured and its scope broadened. Merrifield's solid-phase synthesis concept is remarkable in its simplicity and in its broad applicability: to achieve the multistep synthesis of a large or complex molecule, the initial fragment, or precursor molecule, is attached to an insoluble reactive polymer. This initial attachment confers insolubility to the bound moiety while not affecting its chemical reactivity; thus it allows for the sequential modification of the bound moiety in a series of successive reactions (such as the removal of protecting groups and the formation of peptide bonds in Merrifield's original scheme). The main advantage of the technique is that after each reaction, the polymer-bound species can be "purified" by simple washings as all soluble impurities are not retained by the polymer; indeed this "purification advantage" is at the heart of Merrifield's discovery. Because of this, reactions can be pushed towards completion through the use of excess soluble reagents which will not cause problems during product isolation and may even be recycled by a simple filtration process; and last but not least, the process can be automated readily as was so brilliantly demonstrated by Merrifield. Once the desired synthetic sequence has been completed by man or machine, the bond between the polymer support and the completed product is cleaved, selectively liberating the product in solution, while the by-product of the cleavage reaction (the polymer) remains insoluble and may even be recycled in some instances if warranted. Obviously the implementation of the solid phase method for the synthesis of large
250
peptides or proteins requires much more than "just" the design of a revolutionary concept (!). It also requires the development of new reactions and techniques which span several areas of chemistry. It is no accident that the resin most commonly used in solidphase syntheses nowadays is still Merrifield's original chloromethylated polystyrene, while Merrifield's contributions to the chemistry of peptide bond formation, the selective protection and deprotection of amino-acids, the development of new techniques for the purification of peptides, and the refinement of the automated technology, are all receiving the recognition which they warrant. The impact of the solid phase method of synthesis on several fields of biochemistry, pharmacology, physiology, medicine, etc., is well known and is widely recognized. Lesser known perhaps is Merrifield's impact on several areas of more classical organic synthesis in non-peptidic areas. While Merrifield himself did not experiment in these areas, his
work has inspired many other scientists in their own creative activities involving the use of polymer-supported species. Thus, significant advances have been made in the development of polymeric reagents, polymeric protecting groups, polymer-bound catalysts and photosensitizers, polymer-based separation media, and other related areas where the general concept of immobilization has contributed to the rapid advancement of science. It is impossible to conclude without a word about R. Bruce Merrifield's outstanding human qualities. Those of us who have had the pleasure of meeting him and his most gracious wife Elizabeth will certainly agree that the 1984 Nobel prize, which he so richly deserves for his outstanding contributions to science, could not possibly have been bestowed upon a nicer human being. JEAN M.J. F R E C H E T
Ottawa, Canada June 1985