JACS AT 125
PEPTIDES ON DEMAND
Merrifield's m e t h o d rapidly transformed the synthesis of polypeptides and oligonucleotides, and its importance was acknowledged in 1984 when he received the Nobel Prize in Chemistry. 'Vet a case could easily be made that the real impact of solid-phase synthesis on chemistry came later, when the techF BRUCE M E R R I F I E L D H A D BEEN A B E T the solid support. At each step, he purified nique began to be applied far beyond the ter chemist at the start of his career the product simply by washing away side synthesis of biopolymers. Stepwise solin the late 1950s, chemistry might be products and excess reactants, all of which id-phase synthesis on resin supports is at quite different today. Merrifield, a remained in solution. The method practhe heart of combinatorial chemistry. biochemist working at what would tically eliminated the tedious purification It's also become a valuable tool become Rockefeller Universiin the synthesis of many comty in New York City, needed to NOo BUILDING PEPTIDES plex natural products. synthesize the small peptide Merrifield's original synthesis growth factors he was studypolystyrene "One of the big revolutions ing. Using the standard methin chemistry in the 1990s has ods of the day, he recalls, "I been small-molecule synthesis N0 2 R1 0 found that I could make them, in combinatorial libraries, or I II but it took a long time, yields - • C b z o - •NHCHCOhigh-throughput parallel synpolystyrene were low, and a lot of things thesis, using resin beads," notes went wrong along the way. Of Kim D. Janda, professor of HBr — HOAc NOo course, I was a rank amateur, chemistry at Scripps Research R1 0 and a real expert could have Institute. 'A lot of this work is I II Repeat many polystyrene NH2CHCO •CH. really grounded in Merrifield's done it faster. But it seemed to times initial paper." me that there ought to be a betDiimide ter way to do the synthesis." "Today, complex organic R20 R1 0 N0 2 As Merrifield was soon to molecules, including some of I II I III /*\ polystyrene show, there was, indeed, a betnature's most intriguing sec-Cbzo —NHCHC HCHC —NHCHCO — C H 2 ^ f j } > — ter way In his classic 1963 paper ondary metabolites, are being NaOH in the Journal of the American synthesized by solid-phase n 2 1 Chemical Society {85, 2149 chemistry techniques that have R 0 R 0 R 0 Cbzo = carbobenzoxy their origins in the pioneering (1963)], he demonstrated that I II I II I II protecting group work Bruce Merrifield demonby covalently attaching the first NHoCHC-NH2CHC—NHCHCOH Ac = acetyl strated 40 years ago with pepamino acid of a desired peptide tides," says K. C. Nicolaou, also a profesto a solid resin support, he could build the and repeated recrystallization steps of classor of chemistry at Scripps. Synthetic product peptide in a stepwise fashion on sic peptide synthesis. Perhaps more imstrategies using solid-phase synthesis have portant, Merrifield's approach made it the added advantage that they can propossible to get almost quantitative yields duce a valuable library of analogs in addifor each amino acid addition, greatly extion to the target molecule, he notes. panding the range of polypeptides and proteins accessible by chemical synthesis. A new twist that chemists are exploring now is to attach catalysts for making Conceptually, it's a small jump from small molecules onto resin beads. As in Merrifield's stepwise high-yield synthesis Merrifield's original application, attachof polypeptides to an automated procement to a solid support greatly simplifies dure. In practice, it took Merrifield and his purification and, in this case, recovery of colleague, John Stewart, less than a year to the catalyst. design and build a peptide-synthesizing apparatus. Others soon applied the gen"It's really the general principle, rather eral approach to develop automated synthan the exact procedure, that's lasted," thesis for nucleic acid polymers, as well. Merrifield notes. "Usually a methodology paper is good for two or three years; Merrifield noted the possibility of authen someone comes up with a better tomating his synthesis in his JACS paper, method, and people forget about the though not quite as explicitly as he had first one. I've been lucky in that way."— originally intended. One of the reviewers REBECCA RAWLS of the manuscript found mention of automation " 'regrettable,' meaning, he didC&ENis celebrating the 125th volume ofthe n't believe a word of it," Merrifield recalls. A U T O M A T E D Merrifield adjusts an "So I had to tone that down a little to get Journal of the American Chemical Society £)/ early version of his peptide the paper published. I did mention it, but featuring selected papersfrom among its 125 most cited. This paper was ranked fifth synthesizer in this 1969 photo. in a milder way."
Bruce Merrifield's 1963 paper paved the way for automated synthesis of peptides and proteins
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