J. Org. Chem., 69 (9), 2917 -2919, 2004.

Impossible Dreams
E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, M
assachusetts 02138
corey@chemistry.harvard.edu
Received January 12, 2004
You will understand the title at one level by knowing that I have been a fan o
f the Boston Red Sox for about seventy years. This loyalty was partially rewar
ded about seventeen years ago when by chance I had the pleasure of spending an
hour with my boyhood hero, Ted Williams. At about the time that I started to
follow the Red Sox games by radio, I acquired the notion that I would like som
eday to know in detail how to build from scratch radios, planes, skyscrapers,
bridges, and all the other objects of modern life. I sometimes wonder, in retr
ospect, whether this impossible dream somehow had an influence on the course o
f my life.
I had no idea that I would choose chemistry as a profession when I entered MIT
as a 16-year-old freshman in June of 1945. In fact, until my senior year in h
igh school, the only science that I had ever taken in school was mathematics.
I enjoyed math more than any other subject, although I liked all of my studies
. My preference for math led to my being handed a two-page application form fo
r MIT which I completed in less than an hour and returned to my high school ad
visor, Mr. O'Brien. A few weeks later, I learned that I had been admitted into
MIT. Mr. O'Brien's advice was that I should consider majoring in electrical o
r chemical engineering at MIT because the chances of finding good employment i
n math were low. I eventually found my way into chemistry in my sophomore year
at MIT because it was more interesting to me than the engineering options. My
hope was that I might find work as a scientist with a large corporation after
graduation from college. I never dreamed that in the short space of about fiv
e years I would have a Ph.D. degree in chemistry and a faculty position at the
University of Illinois. My undergraduate years flew by-partly because MIT was
then still on an accelerated wartime academic schedule. I usually took three
extra courses each semester since that was permitted then. As a result, I was
able to take all of the available MIT chemistry courses, the other requirement
s, and a few engineering courses as well. At the invitation of Professor John
C. Sheehan I stayed on for graduate research at MIT as a member of his pioneer
ing project on the chemical synthesis of penicillins. Early on in my third yea
r of graduate work, I received word that Roger Adams, then Head of the Departm
ent of Chemistry and Chemical Engineering at the University of Illinois, was v
isiting Cambridge and wanted to see me. I well remember that very cordial meet
ing on the campus at Harvard where Adams served as an Overseer. A week later I
was offered an Instructorship at Illinois provided that I could report for wo
rk within six weeks, at the start of 1951. It was astounding that somehow I ha
d been chosen from so many other young chemists for what was clearly one of th
e premier academic positions that year. Professor Sheehan readily agreed that
I could accept the offer despite such short notice. For years it remained a my
stery to me that I could be so lucky. Just a few years ago I learned from Nels
on Leonard, a faculty colleague of Adams, that it was a group of my former fel
low MIT students, then at Illinois as graduate and postdoctoral fellows, who r
ecommended that I be considered for the Illinois opening and that Nelson had r
elayed their suggestion to Roger Adams. I remained at the University of Illino
is until mid-1959 when I assumed my present faculty position at Harvard. It ha
s been a privilege to work for this period of over fifty years at these two gr
eat institutions with wonderful students and faculty colleagues.
At Illinois, I was especially close to Roger Adams, C. S. Marvel, Nelson Leona
rd, John C. Bailar, I. C. Gunsalus, David Y. Curtin, and Douglas E. Applequist
-all great chemists for whom I have enormous respect. I am grateful to John Ba
ilar for a very stimulating collaboration that produced the first conformation
al analysis of metal chelates and led to what are now known as the  and  stere
ochemical descriptors. A collaboration with "Gunny" Gunsalus on the microbial
hydroxylation of camphor led to his pioneering and historic biochemical progra
m over the next four decades on cam P-450, the first and now the best understo
od member of the P-450 class of biochemical oxidants. There were a number of o
ther research discoveries at Illinois that brought great pleasure to me. I sha
ll mention just a few: the recognition that stereocontrol in a reaction could
arise from a preference for a three-dimensional transition state involving the
maximum overlap of the perturbed molecular orbitals (which I called stereoele
ctronic control); the determination of the structures of the natural products
friedelin and limonin; the first functionalization of unactivated methyl group
s, such as those in steroids; syntheses of natural products, including the pen
tacyclic triterpenes - and -amyrin, and the steroid alkaloid conessine; and de
velopment of general methods for prediction of the stereochemistry and absolut
e configuration of -haloketones.
During my tenure at Illinois, I became fascinated by the deeper thought proces
ses involved in planning pathways for the chemical synthesis of complex molecu
les such as natural products, a topic that had intrigued me even as an undergr
aduate at MIT. Because my research group at Illinois was small and spread out
over many research areas, including reaction mechanisms and stereochemistry, n
ew synthetic methodology, and structure determination, it was not feasible to
undertake complex synthetic projects. Nonetheless, I spent considerable time t
hinking about the design of syntheses at an abstract level. A flood of novel a
nd unusual natural product structures that came along during the 1950s provide
d much food for thought, especially because many of the these structures lacke
d features which might suggest either starting materials or building blocks fo
r synthesis. Thus began a thirty-year involvement with the logic of chemical s
ynthesis.
At Harvard, I continued my research along a broad scientific front and conduct
ed my own experiments in a small laboratory that was connected to my office, a
s at Illinois. I thoroughly enjoyed teaching both undergraduate and graduate s
tudents. My initial ideas on logical procedures for analyzing synthetic proble
ms led to an entirely new and systematic way of thinking about synthetic plann
ing that had a dramatic impact on both my research and teaching in synthesis.
By the mid-1960s, several quite novel syntheses of challenging molecular targe
ts were designed in this way and demonstrated experimentally. In addition, I w
as able to teach students in just 3-4 months how to design complicated synthes
es on their own. Another exciting advance was the development of the first gra
phical input and output of organic structures to and from a computer and the e
volution of a computer program that effectively generated possible syntheses b
y retrosynthetic analysis. That computational research proved the validity of
the logic that I had developed and made available the computerized organic for
mula graphics that are omnipresent today. On May 4, 1964, I suggested to my co
lleague R. B. Woodward a simple explanation involving the symmetry of the pert
urbed (HOMO) molecular orbitals for the stereoselective cyclobutene  1,3-butad
iene and 1,3,5-hexatriene  cyclohexadiene conversions that provided the basis
for the further development of these ideas into what became known as the Woodw
ard-Hoffmann rules. During the 1960s, my group also developed many new synthet
ic reagents and reactions that are now standard tools of the synthetic chemist
. In addition, this period saw our experimental demonstration of 2,3-oxidosqua
lene as a key intermediate in the remarkable biosynthesis of cholesterol. Even
tually we were able to clone the gene for the cyclizing enzyme (yeast and huma
n), purify the protein, and characterize the fine mechanistic details of this
remarkable reaction that generates the steroid ring system in a single step.
Between the mid 1960s and 1990 my group carried out research on the superfamil
y of natural compounds that I named the "eicosanoids" which includes prostagla
ndins and leukotrienes. This effort led to the first general synthesis of the
natural prostaglandins from a common intermediate and many further refinements
. We surmised the correct structures of the immune mediators now known as the
leukotrienes A, B, and C and synthesized these unambiguously even before they
were isolated and characterized. It has been noted in the medical literature t
hat there is no field of medicine that has not been impacted by fundamental re
search on these eicosanoids. This work was summarized in my Japan Prize lectur
e of 1989.
For almost five decades, a constant theme of our research has been the develop
ment of new tools for synthetic chemistry including enantioselective methodolo
gy. We have also been continuously engaged in the multistep synthesis of compl
icated target molecules and have accomplished a large number of such total syn
theses. A good fraction of this work and the essentials of retrosynthetic thin
king are summarized in my 1989 book, "The Logic of Chemical Synthesis". Becaus
e it is so challenging to do, total synthesis is often compared metaphorically
with climbing mountains. However, I prefer to think of our syntheses using a
musical metaphor, as our sonatas and string quartets, because I see in them a
clear and lasting beauty.
Over the years, I have had the pleasure of working one-on-one with almost seve
n hundred young chemists. I am very proud of them not only because of their ou
tstanding contributions to my research program but because of their impressive
achievements in subsequent years, from Nobel Prizes to Presidencies to Profes
sorships. I am absolutely convinced that the synergy between research and educ
ation is one of the great aspects of modern science and one of the best invest
ments a society can make in its future. Unfortunately, this happy relationship
is still not widely appreciated. For about fifty years I have been an advisor
to Pfizer, Inc. This part of my career has also been gratifying. In the early
days, Pfizer was just establishing itself in the pharmaceutical business and
the research effort was tiny. Today, Pfizer is a global leader in the field wi
th a research budget of $7 billion and a market capitalization approaching $30
0 billion.
From my long involvement with biologically active substances such as the eicos
anoids and from much study on my own and years of advising pharmaceutical rese
archers, I have received a great medical education. I would like to share some
of my current thoughts with you on the linkages between chemistry, progress i
n medicine, health care, and the future of humankind on this planet. I believe
that chemistry, including chemical synthesis, will be a key driver of progres
s in medicine and human health during the rest of the 21st century. Not long a
go, I gave a short talk at the dedication of a major new Pfizer research compl
ex in which I speculated that a hundred years from that day there might well b
e a celebration at the same site of that facility's centennial. I expressed my
opinion that the celebration might be especially appropriate because the disc
overies made by health care companies and academia had resulted in the cure or
control of the vast majority of metabolic, organ, circulatory, malignant, and
infectious diseases. Although a massive effort by academic, industrial, and m
edical scientists will be required, such an accomplishment seems to me to be v
ery possible. Enlightened, wise, and fair investment in fundamental research b
y government and the private sector will play a crucial role. Government suppo
rt of high-quality, fundamental research therefore needs to continue with emph
asis on quality and minimization of political issues.
I believe even more strongly that the 21st century will see the general availa
bility of up-to-date, good-quality basic health care and education in all coun
tries of the earth because this will be seen by the more advanced countries no
t only as achievable but also as a prerequisite to world stability and the wel
l being of peoples everywhere. I hope that it is not an impossible dream becau
se the economic and social benefits will be great, especially as medicine adva
nces. I believe that scientists, medical professionals, economists, the media,
those skilled in governance, and especially the young and altruistic should s
tart to champion this cause and make clear plans for how it might be accomplis
hed. I should stress the young because it will be a very complex and lengthy u
ndertaking. To them and to those starting careers in chemistry, I would offer
the following advice: Never underestimate what you can accomplish if you prepa
re yourself well, continue to learn, work hard and optimistically, and value y
our integrity.
I am often asked about my vision for the future of chemistry, especially synth
etic chemistry. As just stated, I believe that chemical synthesis will make en
ormous contributions to human progress in the next century especially when cou
pled to biology and medicine. However, those developments will not be fully re
alized without great and continuing advances in the central disciplines of che
mistry. There is so much that remains to be discovered, in my opinion, that to
day's chemistry will seem archaic to a 22nd century chemist. I envy the young
people in chemistry who will experience the excitement and pleasure of making
the many discoveries of the next century of chemical research. Yet, at the sam
e time, I worry about whether the younger generations of this country and the
world will aspire to high creativity and persevere to achieve their impossible
dreams.
If I may, I would like to close on a personal note by thanking my family, espe
cially my wife, Claire, and children David, Bethany, John, and Susan for the c
ompanionship, love, and support that have guided me along the path to the pres
ent.
Acknowledgment
Cover image courtesy of NASA/ JPL-Caltech.
* In papers with more than one author, the asterisk indicates the name of the
author to whom inquiries about the paper should be addressed.
--
FROM 162.105.22.*