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Journal of the Franklin Institute 347 (2010) 664–671

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The 2006 Benjamin Franklin Medal in Chemistrypresented to Samuel J. Danishefsky, Ph.D.

William F. Michne

Department of Medicinal Chemistry, AstraZeneca Pharmaceuticals, Wilmington, DE 19850, USA

Abstract

Organic synthesis of natural products began in 1828 with Wohler’s synthesis of urea, the first time

a substance derived from a living organism had been produced by combining inorganic materials.

Progress in the field was slow at first, due to the limited purification and analytical methods.

Advances in those areas gave rise to rapid progress in synthesis, as chemists could now focus their

energies on devising new approaches to the preparation of increasingly complex molecules. While it is

possible to prepare many molecules by using known chemistry in new combinations, real progress

has been the result of keen insight and creativity on the part of only a few individuals.

Professor Samuel J. Danishefsky established himself early on as a leader in this field when he

recognized that a well-known ring forming reaction could be greatly extended by adding chemical

functionality to one of the components. He then found that these new reactive components could

react with heretofore unreactive components to produce new rings containing oxygen atoms both in

the ring and as attachments to the ring. These products were very similar to naturally occurring

sugars. Danishefsky realized that he could develop this chemistry further to produce precisely defined

polysaccharides as well. Some of these polysaccharides occur on the surface of cancer cells. Using the

chemistry he developed, he was able to prepare these cancer cell markers, and after combining them

with certain proteins, showed that the resulting molecules behaved as cancer vaccines. Several have

entered clinical trial.

Danishefsky has synthesized many other natural products, but he is particularly interested in those

that may be useful in treating cancer. His syntheses allow for the modification of the final product in

ways that improve both safety and efficacy. Several of these compounds have also entered clinical

trials. Thus his work has not only advanced the art and science of organic synthesis, but stands to

make dramatic advances in the treatment of cancer as well.

r 2008 The Franklin Institute. Published by Elsevier Ltd. All rights reserved.

2.00 r 2008 The Franklin Institute. Published by Elsevier Ltd. All rights reserved.

.jfranklin.2008.04.013

dress: wmichne@pinelink.org

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1. Chemical synthesis

Chemical synthesis is the production of a new molecule from an available one byexposure to conditions of temperature, solvent, catalyst, reagent, and other physicalconditions, for a period of time, so as to effect the desired chemical transformation. Untilwell into the nineteenth century, only simple changes in inorganic molecules had beenachieved. Indeed, it was believed that the organic, or carbon-based molecules found inliving plants and animals, could not be synthesized, because they were the result ofprocesses that were initiated and maintained by a ‘‘vital force.’’ This myth was shattered in1828 when Wohler allowed an aqueous solution of ammonium cyanate to evaporate,leaving behind a residue of urea, thereby achieving the first synthesis of a natural product,and marking the beginning of the science and art of synthetic organic chemistry. Whileprogress in the field was rather slow through the early twentieth century, advances in thetechnologies for the purification and identification of new compounds allowed thesynthetic organic chemists to focus their efforts on devising new strategies for the synthesisof increasingly complex molecules.

There are several reasons to pursue synthetic organic chemistry. It is an importantmethod to determine or confirm the proposed structure of newly discovered naturalcompounds. It is used to modify existing compounds to produce new molecules withenhanced properties for many applications in medicine and materials science. New andmore efficient methods continue to be developed, in many cases resulting in production ofsizeable quantities of rare and useful compounds for further studies and actualapplications. R.B. Woodward, one of the greatest practitioners in the history of synthesis,recognized its impact in 1956 when he wrote [1], ‘‘ythe whole face and manner of societyhas been altered by its productsythe dramatic advances in synthetic medicinal chemistrycomfort and maintain usythe evidence is overwhelming that the creative function oforganic chemistry will continue to augment Nature, with great rewards, for mankindy’’.The record of synthetic organic chemistry confirms the veracity of Woodward’s vision tothe present day.

Synthetic chemists are frequently asked how they know what chemicals to mix andunder what conditions in order to achieve the desired result. There are fundamentally threeways to proceed. First, many known reactions have been extensively studied, and theirscope and limitations are well understood. Thus, the synthetic chemist can draw on thislarge body of knowledge, using known reactions in new combinations to obtain a predictedresult. This approach is widely used in industrial research laboratories throughout theworld. A second approach is based on the serendipitous observation of an unexpectedtransformation, i.e., a new reaction. Studies of such new reactions often lead to efficientways of assembling molecules not otherwise readily attainable. Finally, steady advances inunderstanding why molecules behave the way they do has allowed the prediction of newreactions that can be used to advantage in synthesis. It is this approach, widely pursued inacademic laboratories, that has resulted in some of the greatest achievements in synthesis,and holds the greatest promise for continued advances in the field.

This article describes some of the work of Professor Samuel J. Danishefsky in the field ofsynthetic organic chemistry. It is noted at the outset that his contributions have beenprodigious, and a detailed treatment of his work is well beyond the scope of this article [2].Rather, the article will illustrate his deep understanding of chemical reactivity to discovernew transformations, and his vision for the application of this new chemistry to the

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solutions of current problems in cancer chemotherapy, by focusing on his approach tocarbohydrate synthesis, and the development of potential cancer vaccines. Other aspects ofhis work in the cancer area will also be noted.

2. The Diels–Alder reaction

Many natural products, drugs, and other theoretically and commercially importantcompounds contain atoms that are formed into rings of various sizes ranging from threemembers as the smallest up to 30 or more members. Among the most common sizes aresix-membered rings. Consequently, synthetic chemists have devoted much effort indevising methods for their construction. Among the most widely used of all ring formingreactions is the Diels–Alder reaction, illustrated in Fig. 1 [3]. In this reaction, a four atompiece, the diene, and a two atom piece, the dienophile, merge to form a six-membered ringdirectly.Notwithstanding the broad applicability of this reaction, most of its value derived from

the A and B portions of the dienophile for further elaboration. Danishefsky recognizedthat the reaction could be greatly extended if the diene fragment contained a function thatcould be elaborated, as shown in Fig. 2 [4].The results were so successful that these functionalized four atom fragments became

known as ‘‘Danishefsky dienes’’. He also recognized that another effect of these oxygenatoms would be to dramatically enhance the reactivity of the diene fragment, perhapsallowing it to react with heretofore inert dienophiles, such as aldehydes [5].The Lewis acid catalyzed diene–aldehyde cyclocondensation, or ‘‘LACDAC’’ reaction

(Fig. 3), allows for the simple synthesis of complex monosaccharides via glycals [6], andhas been widely applied in natural product total syntheses, such as vineomucinone,tunicaminyluracil, mevinolin, and many others.

3. Cancer vaccines

Now consider for a moment the current approaches to cancer therapy. Surgery is oftenbrutal and disfiguring. Radiation and chemotherapy are both non-selective, and killhealthy cells as well as cancer cells, a situation that leads to often debilitating side effects.On the other hand, cancer vaccines, by their very nature, would be highly selective withminimal side effects. Malignant cells are commonly characterized by large and unusualoligosaccharide motifs on their surface. Coupling of these purified oligosaccharides toimmunogenic proteins could form the basis of development of highly selective cancervaccines. Unfortunately, the required oligosaccharides, also known as carbohydrateantigens, are difficult to isolate in the required purity, often being contaminated with other

diene

A

B

A

Bdienophile

Fig. 1.

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Danishefsky diene

O

O

SiMe3

O

O

SiMe3

A

B

A

B

Fig. 2.

aldehyde

O

O

SiMe3

O

O

O

SiMe3

A

O

AH

O

AHO

“glycal”

Fig. 3.

disaccharide glycal

O

PO

PO

PO

O

PO

PO

OHO

PO

PO

O

PO

PO

PO

O

E

Fig. 4.

W.F. Michne / Journal of the Franklin Institute 347 (2010) 664–671 667

carbohydrates or unrelated foreign material. Furthermore, oligosaccharide synthesis wasso difficult that it was simply not practical. Danishefsky found that glycals from theLACDAC reaction could be oxidatively coupled to yield a disaccharide glycal, which canbe coupled again to yield a trisaccharide glycal, etc. It was now possible to preparecomplex oligosaccharides in pure form conveniently in the laboratory (Fig. 4).

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Danishefsky used this strategy to prepare pure and characterized tumor oligosaccharideantigens, and used them to prepare vaccines. Globo-H for prostate and breastcancer, Lewisy-KLH conjugate for ovarian cancer, and O-linked mucin for prostatecancer represent the most complex fully synthetically derived constructs ever to beclinically evaluated [7]. He has gone on to produce the next generation of syntheticcarbohydrate vaccines, ‘‘multiantigenic agents’’, so-called because they carry severalantigens on the same vaccine making them potentially broad spectrum agents for a varietyof cancers.

4. Molecular editing

Danishefsky has made innumerable contributions to the science and art of organicsynthesis [2]. His seminal synthesis achievements in the field of natural products includesuch complex molecules as indolizinomycin, coriolin, avermectin A, and spirotrypostatin.Most recently he has focused his attention on those natural products that havedemonstrated anticancer activity, how they might be synthesized by methods capable ofproducing useable quantities (often unavailable from the natural sources), and how theymight be improved through a process he refers to as ‘‘molecular editing.’’ For example,taxol is an anticancer agent whose action is due to microtubule stabilization, and is aclinically useful anticancer agent. However, it is subject to the development of multidrugresistance (MDR), limiting its usefulness. Epothilone B (Fig. 5) also has anticancer actionthrough microtubule stabilization, but is NOT subject to MDR. Unfortunately, it exhibitsnon-tumor selective toxicity. Danishefsky reasoned that the indicated epoxy function wasthe likely cause of the toxicity, and replaced it with a double bond (Fig. 6). This indeedproved to be the case. However, the compound was less potent than Epothilone B.He next speculated that potency could be restored by introduction of a trifluoromethyl

group in place of the original epoxy group, and an additional double bond in the ring toadd rigidity (Fig. 7). This again proved correct, as potency was restored, with theadditional benefit of having improved the safety profile further. This compound isdramatically effective against taxol-resistant tumors [8].

O O

O

S

N

O

OH

OH

Fig. 5. Epothilone B.

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O O

S

N

O

OH

OH

H3C

Fig. 6. De-epoxy Epothilone B.

O O

S

N

O

OH

OH

F3C

Fig. 7. Trifluoromethyl-dehydro-de-epoxy Epothilone B.

W.F. Michne / Journal of the Franklin Institute 347 (2010) 664–671 669

5. Summary

Carbohydrates, particularly simple sugars, were among the earliest of natural substancesto be studied. However, because of the difficulty of their isolation and complexity of theirstructures, progress in their synthesis and characterization had been slow. Danishefsky’sinsight to further develop and expand a ‘‘mature’’ Diels–Alder reaction, and apply it to thestereo-controlled synthesis of complex oligosaccharides, has resulted in rapid advances inthe field. His application of this chemistry to cell surface carbohydrates has resulted in anumber of exploratory cancer vaccines. Continuing work in this area is being done todevelop broad spectrum vaccines using multiple defined oligosaccharide antigens attachedto a single protein conjugate molecule. Simultaneously his work on the total synthesis ofnatural products continues to move forward. The goal here is to develop sufficiently robustsyntheses of these substances in order to apply ‘‘molecular editing’’ to discover newcompounds with improved properties.

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5.1. Laureate’s biography

Professor Samuel J. Danishefsky was born in 1936 in Bayonne, New Jersey. He received aBachelor of Science degree at Yeshiva University in 1956, and a Ph.D. at Harvard in 1962.Following an NIH Post-doctoral Fellowship at Columbia University he joined the Facultyof the University of Pittsburgh, obtaining the rank of full Professor in1971. In 1979 he moved to Yale University, was appointed to the Eugene Higgins Chairin 1983, and was honored with a Sterling Professorship in 1989. In 1991 he became Directorof the Laboratory for Bioorganic Chemistry, and Eugene W. Kettering Chair at MemorialSloan-Kettering Cancer Center. In 1993 he joined the faculty of Columbia University.Professor Danishefsky is a member of the National Academy of Sciences and the

American Academy of Arts and Sciences. Among his many awards, he was honored withthe ACS Guenther Award (1980), an Arthur C. Cope Scholar Award (1986), the ACSAldrich Award for Creative Work in Synthetic Organic Chemistry (1986), the Wolf Prizein Chemistry (1996), the Tetrahedron Prize (1997), the ACS Claude S. Hudson Award inCarbohydrate Chemistry (1997), the ACS Cope Medal (1998), the Nagoya Gold Medal(1999), the ACS H.C. Brown Medal (2000), and the Cotton Medal (2001).The Benjamin Franklin Medal in Chemistry medal legacy

1911

J.S. Hepburn (Longstreth)

For the chemistry of sugars

1933

Paul Sabatier (Franklin)

For the catalytic activity of finely divided common metals, and methods for their use in

organic chemistry

1936

George O. Curme (Cresson)

For the development of synthetic aliphatic chemistry

1945

William E. Doering and R.B. Woodward (Scott)

For the total synthesis of quinine

1947

Robert Robinson (Franklin)

For contributions to the determination of the structures and syntheses of plant products

1978

Herbert C. Brown (Cresson)

For development of the synthesis of diborane and alkali metal hydrides, and their

applications to organic synthesis

1978

Elias J. Corey (Franklin)

For the development of methods and systems for organic synthesis

1982

Charles G. Overberger (Potts)

For contributions to organic synthesis

2000

Robert H. Grubbs (Benjamin Franklin)

For advances in the field of olefin metathesis, simplifying the synthesis of a broad range

of complex molecules

2001

K. Barry Sharpless (Benjamin Franklin)

For the development of catalytic oxidation chemistry to produce chemical compounds

with proper handedness

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References

[1] R.B. Woodward, Perspectives in Organic Chemistry, Interscience Publishers, New York, 1956.

[2] At the time of Danishefsky’s initial nomination for the Franklin Medal he had over 750 publications spanning

43 years.

[3] For a recent review see K.C. Nicolaou, S.A. Snyder, T. Montagnon, G. Vassilikogiannakis, The Diels–Alder

Reaction in Total Synthesis, Angew. Chem. Int. Ed. 41(2002) 1668–1698.

[4] S. Danishefsky, Siloxy dienes in total synthesis, Acc. Chem. Res. 14 (1981) 400–406.

[5] S. Danishefsky, J.F. Kerwin, S. Kobayashi, Lewis acid catalyzed cyclocondensations of functionalized dienes

with aldehydes, J. Am. Chem. Soc. 104 (1982) 358–360.

[6] S. Danishefsky, Cycloaddition and cyclocondensation reactions of highly functionalized dienes: applications

to organic synthesis, Chemtracts—Org. Chem. 2 (1989) 273–297.

[7] S.J. Danishefsky, J.R. Allen, From the laboratory to the clinic: a retrospective on fully synthetic carohydrate-

based anticancer vaccines, Angew. Chem. Int. Ed. 39 (2000) 836–863.

[8] T.C. Chou, H. Dong, A. Rivkin, F. Yoshimura, A.E. Gabarda, Y.S. Cho, W.P. Tong, S.J. Danishefsky,

Design and total synthesis of a superior family of epothilone analogues, which eliminate xenograft tumors to a

nonrelapsable state, Angew. Chem. Int. Ed. 42 (2003) 4762–4767.

William F. Michne received his B.S. degree in Chemistry from Siena College in 1964, and Ph.D. in Organic

Chemistry from Rensselaer Polytechnic Institute in 1968. He joined the Sterling-Winthrop Research Institute

where he rose to Associate Director of Medicinal Chemistry. In 1994 he joined AstraZeneca as Director of

Medicinal Chemistry. In 2000 he was awarded the position of AstraZeneca Senior Principal Scientist, and at the

end of 2004 he retired from active employment. His major research achievements were in the areas of synthetic

opiates and in the development of the Hit-to-Lead process in early drug discovery. In addition he was active in the

scientific community as teacher, writer, and conference organizer. He continues professional activity as a

consultant in the drug industry, and is a 2006 inductee in the American Chemical Society Division of Medicinal

Chemistry Hall of Fame.