The essence of total synthesisK. C. Nicolaou* and Scott A. SnyderDepartment of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; and Department ofChemistry and Biochemistry, University of California, 9500 Gilman Drive, La Jolla, CA 92093

Edited by Jack Halpern, University of Chicago, Chicago, IL, and approved July 1, 2004 (received for review May 27, 2004)

For the past century, the total synthesis of natural products has served as the flagship of chemical synthesis and the principal drivingforce for discovering new chemical reactivity, evaluating physical organic theories, testing the power of existing synthetic methods,and enabling biology and medicine. This perspective article seeks to examine this time-honored and highly demanding art, distillingits essence in an effort to ascertain its power and future potential.

Essence (es’ns) n. the most signifi-cant part of a thing’s nature; the sumof the intrinsic properties withoutwhich a thing would cease to be whatit is, and which are not affected byaccidental modifications. (The NewLexicon Webster’s Dictionary)

Although the practice of totalsynthesis and the rationale be-hind its pursuit have changedthroughout the course of its

history, its most fundamental propertyhas not. At its core, in its most essentialform, natural product total synthesis is avehicle for discovery, one that is per-haps unparalleled by any other endeavorin the realm of chemical synthesis (1–3).The reason follows: every natural prod-uct type isolated from the seeminglylimitless chemical diversity in natureprovides a unique set of research oppor-tunities deriving from its distinctivethree-dimensional architecture and bio-logical properties. For instance, in theearly part of the 20th century, effortsdirected toward the synthesis of the an-timalarial agent quinine (1) (Fig. 1) ledto a sizeable body of knowledge regard-ing the construction of heteroaromaticsystems and the unique physical proper-ties of quinoline and piperidine rings. Inmore recent times, its structure hasserved as the basis for the design of sev-eral new classes of antimalarial drugsthat have saved thousands of lives (4).Similarly, attempts to construct steroidssuch as progesterone (2) before WorldWar II provided insights into how car-bon–carbon bonds could both be forgedand cleaved, with their partial or totalsynthesis ultimately rendering themavailable in quantities that are sufficientto propel them into useful drugs, suchas the birth control pill, which is nowused by millions of women around theworld (5). In the 1950s, the highly sensi-tive �-lactam ring of penicillin (3)served as the impetus for John Sheehan(6) to develop carbodiimide-based re-agents for the formation of peptidebonds. This discovery capped the firstpractical synthesis of this essential me-dicinal agent, enabled the synthesis of

designed penicillins with activity profilessuperior to the parent natural product,and revolutionized the entire peptide-synthesis field. In the 1960s and 1970s,members of the eicosanoid family ofnatural products, such as prostaglandinF2a (4), served as the artistic canvas onwhich E. J. Corey was inspired to createthe first catalysts capable of orchestrat-ing asymmetric Diels–Alder reactions. Italso was the arena in which he and hisgroup developed the now ubiquitousfamily of silyl-based protecting groups,one of the most general and powerfulmethods for the catalytic asymmetricreduction of ketones (Corey–Bakshi–Shibata reduction), and a series ofprostaglandin analogs used for variouspurposes (7). During the same era, theunique structures possessed by mole-cules like vitamin B12 and cobyric acid(5) served as the testing ground for newreactions and fundamental physical or-ganic principles, such as the Eschen-moser corrin synthesis (8) and theWoodward–Hoffman rules (9).

This brief synopsis drawing from justfive examples barely scratches the sur-face of the rich history of scientificbreakthroughs in this field and the po-tential for making fundamental ad-vances. Here, we offer several additionalexamples from our own experiences inthe hope that they will illustrate the truewealth of discoveries that can emanatefrom more contemporary endeavors intotal synthesis.

Selected Total Synthesis EndeavorsIf the past few decades have taught usanything about the power of our syn-thetic tools, it is that we have yet toreach a level of efficiency and deftnesscommensurate to that possessed by na-ture. Yet, although we cannot exactlyemulate the master chemical artisan,

This paper was submitted directly (Track II) to the PNASoffice.

*To whom correspondence should be addressed. E-mail:kcn@scripps.edu.

© 2004 by The National Academy of Sciences of the USA

Fig. 1. Structures of quinine (1), progesterone (2), penicillin (3), prostaglandin F2� (4), and cobyric acid(5), natural products whose total synthesis inspired and resulted in the development of manifold advancesin chemistry, biology, and medicine.

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synthetic chemists can come close whenthey develop synthetic strategies towardnatural products based on biogeneticconsiderations because what often re-sults is a concise and elegant construc-tion of molecular complexity. As anadded benefit, such approaches also af-ford insights into how reactions can becombined productively into novel cas-cade events. Historical examples of suchsuccesses include W. S. Johnson’s syn-thesis of progesterone by means of aseries of cation-� cyclizations and ourown construction of several members ofthe endiandric acid family of naturalproducts by means of a cascade se-quence that combined electrocycliza-tions and Diels–Alder reactions (10).

A more recent entry comes from ourresearch program directed toward se-lected members of the bisorbicillinoidfamily of natural products (11). For in-stance, although the cage-like naturalproduct trichodimerol (12) (Scheme 1)seemed hopelessly complex on initialinspection based on its dense array ofchiral centers and unusual ring frame-work, closer analysis suggested that itsentire architecture could arise in a sin-gle step from a far simpler, but highlyreactive, intermediate: quinol 7 and itstautomer 8. The operations required tobring about this tantalizing proposal,however, were relatively complex be-cause they involved a dimerization-baseddomino sequence comprised of two Mi-chael reactions and two ketalizations.After careful experimentation, we wereable to accomplish this ambitious seriesof events in the laboratory by carefullycleaving the acetate group within 6 un-der basic conditions to generate the re-active monomers and then quenchingthe reaction with NaH2PO4�H2O. A sim-ilar strategy protocol was employed byBarnes-Seeman and Corey in their suc-cessful synthesis of trichodimerol (12).Amazingly, if this protocol was alteredjust slightly, we could also convert 7 and8 into two other members of the family,bisorbicillinol (13) and bisorbibutenolide(14), by coaxing them to participate inan intermolecular Diels–Alder unioninstead (11). Whether or not nature cre-ates these natural products in the sameway is unknown, but it is difficult toconceive that nature would employ apathway that is any less expedient. Inany case, these sequences point to oneof the key directions for the future ofchemical synthesis as pressure increasesto generate molecular complexity rap-idly through efficient and atom-econom-ical processes that produce minimalchemical waste.

Similar levels of beauty, challenge,and opportunity for discovery also existin multistep total synthesis, especially

when targeting a complex natural prod-uct with a unique conglomeration ofstructural motifs. Indeed, rare and chal-lenging molecular features within sec-ondary metabolites have long presentedsynthetic chemists with golden opportu-nities for invention, whether simply byinspiring creative strategies and tactics,or serving as a stringent testing groundthat reveals weaknesses in the power ofexisting methodology to fashion suchcomplexity effectively. The brevetoxins(15, 16) (Scheme 2), the toxic agentsresponsible for the ‘‘Red Tide’’ phenom-ena, certainly fit this bill with their ex-quisite array of trans-fused ether ringsof various sizes (13). Of particular chal-lenge were their medium-sized cyclicethers because the technology that wasavailable when we undertook their totalsynthesis in the 1980s did not possess

the power to forge such strained struc-tural domains in highly functionalizedsettings. By using this gap in methodol-ogy as an opportunity for discovery, wedeveloped a series of synthetic reactionsbased on the power of heteroatoms (i.e.,sulfur and phosphorous) to drive theseentropically disfavored ring closures;four of these methods are shown inScheme 2. Apart from finding wide-spread applicability to a range of othersynthetic problems, these unique ap-proaches were critical to the completionof both of these formidable targets, ac-complishments that have more recentlyinspired a host of researchers to attemptthe total synthesis of other cyclic poly-ethers, some of even greater size andcomplexity (14–20).

In addition to new science emanatingfrom well planned endeavors, discover-

Scheme 1. Insights into the synthetic efficiency of nature: total synthesis of trichodimerol (12) througha dimerization event based on a double Michael�ketalization sequence. A different pathway from 6 ledto bisorbicillinol (13) and bisorbibutenolide (14).

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ies can also arise by serendipity when anattempt to construct a certain structuralmotif does not proceed as expected. Ouradventures related to the total synthesisof the CP molecules (31 and 32)(Scheme 3) underscore this mode ofdiscovery as forging its complex polycy-clic architecture not only demanded thedevelopment of many planned sequencesand new methods but also afforded sev-eral examples of unexpected chemicalreactivity that led to the opportunisticdevelopment of new chemistry (21–24).For example, as shown in Scheme 3,treatment of intermediate 33 with Dess–Martin periodinane (DMP) at elevatedtemperatures was expected to provide34. Instead, the sole product of this ex-periment was the polycyclic adduct 36, acompound of little use for the prosecu-tion of our strategy to access the targetmolecules. Yet, its occurrence unlocked

a new field of chemistry, as the deter-mined pursuit of the mechanistic under-pinnings of this reaction led to the ratio-nal design of several new reactions.Some of the most important of theseprocesses include the synthesis of het-erocycles from intermediate o-quinodimethanes generated from com-pounds such as 37, the formation of�,�-unsaturated compounds from satu-rated precursors (40341), the deprotec-tion of dithianes (42343), the oxidationof heterocyclic systems (44345), andthe generation of p-quinones from ani-lides (46347). These studies have alsoled to the design and synthesis of anumber of new and highly selectiveclasses of hypervalent iodine reagents(ref. 25 and references therein). Had theexperiment seeking to convert 33 into34 not been performed and had the ra-tionale for its outcome never been ex-

plored, this field of study might haveremained latent for many years to come,if ever uncovered at all.

As a final set of examples related tothe theme of how challenging molecularconnectivities of natural products canlead to new methodology, we mentionour recent forays toward diazonamideA, a natural product whose originallyproposed structure (48) has recently(26) been revised to 49 (Scheme 4).Both of these architectures offeredunique chances to make discoveries ofthe designed and unexpected varieties.For instance, early efforts directed to-ward the generation of the quaternarycenter linking the two major macro-cycles of 48 were based on effecting a5-exo-tet cyclization on a precursor, suchas 50, leading to 54 (Scheme 4). Thistransformation would, indeed, be real-ized eventually, opening a new entry forthe formation of such benzofuranoneadducts (27). At first, however, initialexperiments led to the observation of anunintended cyclofragmentation cascadeleading to the highly desirable 3-aryl-benzofuran nucleus (53), a privilegedstructural motif found in numerous clin-ically used pharmaceuticals. This insightinto chemical reactivity inspired us toextend this finding into the realm ofsplit-and-pool combinatorial synthesis,ultimately providing technology for thefacile and traceless preparation of di-verse members of this important familyof compounds (28).

The opportunity to design and de-velop another cascade sequence withinthe context of the diazonamide A pro-gram came with roadblocks confrontedin forming a carbon–carbon bond toclose the right macrocycle of the revisedstructure (49) (29) with enough func-tionality to assemble all its disparateheteroaromatic rings. Inspired by a se-ries of seemingly unconnected literatureprecedents, we anticipated that we couldaccomplish this objective by combiningthree known reactions into a new singlesequence. As shown in the conversion of55 to 60, those operations were a het-eropinacol reaction initiated by thepower of SmI2 complexed to N,N-dimethylacetamide, in situ N–O bondcleavage to generate an amino alcohol,and subsequent peptide coupling. Notonly did the successful realization of thiscascade sequence represents the firstmacrocyclization using a heteropinacolreaction, it also fueled the completionof the revised structure of diazonamideA (49), an endeavor that finally provedits long-questioned structural disposition(30, 31). Reflecting on this program, aswell as the other programs describedthus far from a broader perspective,these endeavors illustrate that virtually

Scheme 2. The brevetoxins: ornate architectures whose unique ring systems demanded the develop-ment of several novel synthetic technologies before yielding to total synthesis.

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all complex architectures are destined tolead to some form of discovery. Key tothis state of affairs is the fact that totalsynthesis is uncompromising, i.e., noatom or functional group within thestructure of a natural product can bealtered or subtracted to make the taskof synthesizing it any easier. Conse-quently, every failure along the way(and there are usually many failures insuch research programs) forces the prac-titioner to be creative if progress is tobe made toward the final destination.

It is also important to recognize that,no matter how unique they may be, nat-ural products are not merely compoundsmeant to show off the synthetic skills ofnature. Secondary metabolites almostalways have a specific biochemical pur-pose, and more often than not, theirpresence has conferred some form ofevolutionary advantage to the producingorganism. This concept has importantramifications because if we can deter-mine both how and why nature hasevolved these molecules to achieve cer-

tain objectives, then we can likely un-ravel many of the mysteries of biologyand gain the insights needed to impartfunction to molecules of our own imag-ining. Over the course of the past 15years, one of the most important fami-lies of natural products that has helpedto guide scientists in such directions isthe enediyne antitumor antibiotics, theflagship of which is calicheamicin �1

I

(61, Scheme 5) (32). These compoundsexhibit their potency by cleaving single-and double-stranded DNA through adiradical species generated upon Berg-man cycloaromatization of theirenediyne motif. What is especially inter-esting, however, is the way that naturehas loaded a uniquely engineered trig-gering system within each enediynemolecule to set this critical event intomotion at just the right moment. Forinstance, in the case of calicheamicin�1

I, this process is initiated by the cleav-age of its trisulfide moiety to reveal athiol species followed by the attack ofthis newly unveiled motif onto its neigh-boring enone functionality through anintramolecular conjugate-additionreaction.

Such ingenious reactivity has inspiredchemists to develop their own enediynesystems with equally sophisticated acti-vation devices. As part of our programthat culminated in the first total synthe-sis of calicheamicin �1 in 1992 (33–35),we designed several such compounds byusing information gathered from a seriesof physical organic studies that estab-lished the structural parameters re-quired for cyclic enediynes to undergoBergman cycloaromatization. As shownin Scheme 5, these molecules rangedfrom simple hydrocarbons (i.e., 62) acti-vated by exposure to heat to far moreornate systems like 65 (which is a com-pound patterned after the natural prod-uct dynemicin A), whose reactivity wasunleashed under basic conditions. Thelatter of these in vivo-activated designedenediynes exhibited cytotoxicity at pico-molar concentrations (36). As such, thisprogram illustrates how endeavors intotal synthesis not only can lead to abetter understanding of specific archi-tectural domains but also how the reac-tive features of a natural product canbe harnessed to deliver new classes oftherapeutic agents with real-worldapplicability.

Similar themes drove our programtoward the clinically used anticanceragent Taxol (69, Fig. 2) (37), in whichthe presence of two highly functional-ized six-membered rings led to thedesign of unique Diels–Alder-based syn-thetic strategies (38) for their construc-tion, and its novel activity inspired thedesign of several types of taxoid mole-

Scheme 3. The CP-molecules: a serendipitous discovery during their total synthesis, in what wasexpected to be a routine oxidation, served as the catalyst for the design and development of a series ofnew synthetic technologies.

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cules (39–43). Such rationales also pro-pelled our work with vancomycin (70,Scheme 6), the agent currently consid-ered to be the antibiotic of last resortagainst deadly methicillin-resistantstrains of Staphylococcus aureus (44).Here, our program sought to accomplishboth the total synthesis of the moleculeand, subsequently, the preparation of aseries of vancomycin analogs to counterbacterial resistance to the parent natural

product. Achieving the first of these ob-jectives required the development ofnew synthetic methodology because thetests provided by the unique conglomer-ation of vancomycin’s sensitive func-tional groups (including seven epimeriz-able arylglycines) and stereochemicalcomplexity (including 18 chiral centersand three axes of atropisomerism) wererather rigorous. Most noteworthy amongthese discoveries was a triazene-driven

aryl ether forming reaction catalyzed bycopper salts to generate the two 16-membered macrocyclic rings of the tar-get molecule, a transformation withbroad synthetic scope (45–49). The sec-ond task, preparing vancomycin analogswith improved activity, was accom-plished by means of an inventive use ofa process known as dynamic combinato-rial screening (also known as target-driven combinatorial synthesis). Drawinginsight from the fact that two moleculesof vancomycin can bind simultaneously,and reversibly, to its biological target(an L-Lys-D-Ala-D-Ala peptide subunit)through a number of hydrogen bonds,we hypothesized that we could createpotent vancomycin-like antibiotics bycreating a dimeric form of the naturalproduct. Our method was to expose acollection of monomeric analogs to thebiological target by using a reactive han-dle on these building blocks to trap thestrongest binders as a new heterodimer.As indicated in Scheme 6, this goal wasaccomplished under ambient conditionsthrough the power of olefin cross-metathesis by using catalytic amounts ofa ruthenium catalyst (50) and a phase-transfer reagent (51). In each round ofscreening, the predominant product wasalso the most potent (based on synthe-sizing and testing all dimers separately),with several compounds possessing en-hanced activity relative to vancomycin aswell as high potency against several van-comycin-resistant bacterial strains.Again, total synthesis provided an outletto develop not only new reactions andsynthetic strategies but also tools thatmight prove key in combating bacterialresistance.

Our final entry for this article takestotal synthesis one step further withanother set of bioactive molecules.This group of compounds are theepothilones (73–76, Scheme 7), afamily of natural products whose ex-ploration has not only provided an op-portunity to develop new synthetictechnology but also is at the brink ofproviding real medical dividends forthe treatment of disease (52). First iso-lated in the 1980s, these agents killtumor cells with extremely high effi-ciency, possessing IC50 values in thelow nanomolar range for most of thecell lines that constitute a typical first-round anticancer activity screen. Suchpotency rivals, and in some cases ex-ceeds, that possessed by agents likeTaxol and vinblastine, two compoundscurrently used in the clinic to managecancer. Therefore, numerous research-ers from academe as well as the phar-maceutical industry have been lured topursue research programs directedtoward their total synthesis in order to

Scheme 4. The diazonamide A studies: confirming structural assignments and discovering new chemicalreactivity.

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render them readily available and tocreate new, and potentially better, clin-ical candidates (53).

Some of our work toward these highlypromising molecules is shown inScheme 7. Unlike most synthetic plansin which the controlled installation ofstereochemical elements is deemed tobe of critical importance, we initiallychose to develop a strategy toward theepothilones in which we could access as

many structural isomers as possible withminimal effort. That goal was achievedby using the power of solid-phase syn-thesis along with reactions that couldlead to stereochemical mixtures. Thus,after the synthesis of 77, a compoundgenerated as a mixture of two diaste-reomers by a nonselective aldol reaction,we exploited the nonselective nature ofring-closing olefin metathesis to formboth E- and Z-macrocycles. Accordingly,from one common resin-bound interme-diate, we were able to access four struc-turally different epothilones (78–81),compounds that were separated byHPLC and independently elaborated tothe final targets. This combinatorial ap-proach, complemented by target-ori-ented synthesis of specifically designedanalogs, led to several hundred distinctcompounds whose biological screeningestablished a clear set of structure–ac-tivity relationships for the epothilones(54). These studies ultimately paved the

way for the intelligent design of novelepothilone-like structures possessingcomparable or even more potent andselective anticancer properties than theparent natural products. One of thesecompounds (82) is now in clinical trialssponsored by Novartis, our collaboratorfor its development. Accordingly, thiswork further reinforces the value of nat-ural product total synthesis in leading todrug candidates and eventually to usefulmedicines; in fact, approximately one-half of the top-selling pharmaceuticalson the market today either are naturalproducts or are based on structures ofnatural products (55). As an aside, theseinvestigations provided one of the firstexamples of a complex natural productbeing synthesized on solid-support. Theuse of the radiofrequency method ofencoding combinatorial libraries in thisstudy was also pioneering (56).

Fig. 2. Taxol: total synthesis met the challengethrough a convergent strategy using two Diels–Alder reactions.

Scheme 5. Calicheamicin �1I and the enediynes: an opportunity to make fundamental discoveries in

chemical synthesis, physical organic chemistry, molecular design, and chemical biology.

Scheme 6. Vancomycin: a synthetic target whosenovel architecture afforded the opportunity to de-velop new chemistry, such as a triazene-drivenmethod for bisaryl ether formation and a cross-metathesis reaction in water to form dimeric van-comycin analogs with activity greater than that ofthe natural product.

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ConclusionsNew reactions, cascade sequences andbiomimetic strategies, clinical drugcandidates, physical organic chemistryprinciples, structure elucidation, art,and excitement: the list of discoveriesand concepts that consistently emanatefrom programs in total synthesis is richin content and is increasing in length(57). We leave it for the rest of theinsightful Perspectives and researcharticles in this Special Feature dedi-cated to natural product total synthesisto reinforce these categories and con-

vey the richness of this art, and weclose instead with some words pennedin 2003 by E. J. Corey:

How many challenging and worthysynthetic targets remain to be discov-ered? How many truly powerful andgeneral new synthetic strategies andsynthetic reactions remain to be dis-covered? Is there a prospect for thedevelopment of entirely new ways ofplanning or executing synthesis? Inmy judgment the opportunities fornew developments and discoveriesare so vast that today’s synthesis is

best regarded as a youngster with abrilliant future (2).

We thank our collaborators whose names ap-pear in the references and whose contribu-tions made this work enjoyable and highlyrewarding. This work was supported by theNational Institutes of Health, the SkaggsInstitute for Chemical Biology, AmericanBioScience, Merck, Schering Plough,Hoffmann–La Roche, GlaxoWellcome,Amgen, Novartis, Bristol-Myers Squibb (fel-lowship to S.A.S.), Boehringer Ingelheim,Zeneca, CaPCURE, the George E. HewittFoundation, Pfizer (fellowship to S.A.S.), andthe National Science Foundation (fellowshipto S.A.S.).

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