Click Chemistry: Diverse Chemical Function from a Few Good Reactions

REVIEWS

Hartmuth C. Kolb, M. G. Finn, and K. Barry Sharpless*

Dedicated to Professor Daniel S. Kemp

Examination of natureꢀs favorite mol-

ecules reveals a striking preference for

making carbon ± heteroatom bonds

over carbon ± carbon bondsÐsurely

no surprise given that carbon dioxide

is natureꢀs starting material and that

most reactions are performed in water.

Nucleic acids, proteins, and polysac-

charides are condensation polymers of

small subunits stitched together by

carbon ± heteroatom bonds. Even the

35 or so building blocks from which

these crucial molecules are made each

contain, at most, six contiguous C C

bonds, except for the three aromatic

amino acids. Taking our cue from

natureꢀs approach, we address here

the development of a set of powerful,

highly reliable, and selective reactions

for the rapid synthesis of useful new

compounds and combinatorial libra-

defined, enabled, and constrained by a

handful of nearly perfect ªspring-load-

edº reactions. The stringent criteria for

a process to earn click chemistry status

are described along with examples of

the molecular frameworks that are

easily made using this spartan, but

powerful, synthetic strategy.

ries

through

heteroatom

links

Keywords: combinatorial chemistry ´

drug research ´ synthesis design ´

water chemistry

(C X C), an approach we call ªclick

chemistryº. Click chemistry is at once

catalysts which prevent natureꢀs carbonyl chemistry based

syntheses from collapsing into chaos. Since many biosynthetic

pathways require a unique enzyme for each step, the enzyme-

control strategy required a heavy investment of time and

resources for catalyst development. With a few billion years

and a planet at her disposal, nature has had both time and

resources to spare, but we, as chemists on a human timescale,

do not.

Nevertheless, carbonyl-based reactions have always been

profoundly appealing to students and practitioners of organic

chemistry. It is our contention that organic synthesis con-

ducted, as it has been, in imitation of natureꢀs carbonyl

chemistry is ill-suited for the rapid discovery of new molecules

with desired properties.

1. Introduction:

Beyond the Paradigm of Carbonyl Chemistry

Life on Earth requires the construction of carbon ± carbon

bonds in an aqueous environment. Carbonyl (aldol) chemistry

is natureꢀs primary engine of C C bond formation. Not only

do the requisite carbon electrophiles (carbonyls) and nucleo-

philes coexist in water, but water provides the perfect

environment for proton shuttling among reactants, which is

required for reversible carbonyl chemistry.

With CO₂as the carbon source and a few good carbonyl

chemistry based reaction themes, nature achieves astonishing

structural and functional diversity. Carbonyl chemistry is used

to make a modest collection of approximately 35 simple

building blocks, which are then assembled into biopolymers.

The enzymatic polymers serve, in concert with increments of

energy provided by adenosine triphosphate, as selective

Many transformations that form ªnewº carbon ± carbon

bonds are endowed with only a modest thermodynamic

driving force. In particular, equilibrium ªaldolº reactions are

1 [1]

often energetically favorable by less than 3 kcalmol . For

[*] Prof. K. B. Sharpless, Prof. M. G. Finn

Department of Chemistry

these processes to reach completion in the laboratory, an

additional ªpushº must be provided, often by application of

Le Chatelierꢀs principle (for example, azeotropic removal of

water), by coupling the desired process to an exothermic co-

reaction (for example, a strong ªbaseº a strong ªacidº), or

by virtue of favorable entropic considerations (such as

intramolecular ring closure) without enthalpic penalties (such

as formation of strained rings). Thus, due in effect to the loss

of one ªequivalentº of ester, resonance stabilization, the first

The Scripps Research Institute

10550 North Torrey Pines Road

La Jolla, CA 92037 (USA)

Fax : (1)858-784-7562

E-mail: sharples@scripps.edu

Dr. H. C. Kolb

Vice President of Chemistry

Coelacanth Corporation

East Windsor, NJ 08520 (USA)

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001

1433-7851/01/4011-2005 $ 17.50+.50/0

2005

K. B. Sharpless et al.

REVIEWS

step of the intermolecular Claisen condensation (for example,

ªThe most fundamental and lasting objective of

synthesis is not production of new compounds,

but production of properties.º

George S. Hammond, Norris Award Lecture,

1968

two molecules of ethyl acetate !ethyl acetoacetate-

1

ethanol), is endothermic by approximately 11 kcalmol ,

but the next stepÐdeprotonation of the b-ketoester to its

enolateÐis highly exothermic and drives the process to

completion when a stoichiometric amount of the alkoxide

base is provided. Approximately 30 years ago the develop-

ment of kinetically controlled enolate chemistry, enabled by

even stronger bases like lithium diisopropylamide, provided

the ultimate form of this type of reaction control. Natural

products of bewildering complexity are synthesized almost

routinely in this manner by the elite practitioners of the art, so

it is obviously a powerful strategy, and the best work in this

area is fascinating to study as a rich source of new insights into

factors which affect chemical reactivity. However, as dis-

cussed below, we believe that this approach ultimately pulls

organic synthesis in troubling directions, the most insidious

problem being the complexity engendered by the need for

global protection and deprotection of protic functional groups.

If useful properties are our goalÐfor example, better

pharmaceuticalsÐthen the use of complicated synthetic

strategies is justified only if they provide the best way to

achieve those properties. The bioactive natural products that

have most intrigued synthetic organic chemists have frame-

works which are difficult to construct largely because there

are too many contiguous carbon ± carbon bonds. However,

these are not the only kinds of molecules that can have useful

biological effects. The long and admirable history of natural

products synthesis, culminating as it has in the protection-

laden schemes of kinetic carbonyl chemistry, perhaps blinds us

to the possibility of developing synthetic strategies that enable

much more rapid discovery and production of molecules with

a desired profile of properties.

K. Barry Sharpless and his co-

workers have discovered and devel-

oped many widely used catalytic

oxidation processes, including the

first general methods for stereose-

lective oxidationÐthe Sharpless re-

actions for asymmetric epoxidation,

dihydroxylation, and aminohydrox-

ylation of olefins. His mentors at

Dartmouth College (BA in 1963),

Stanford University (PhD in 1968

and postdoctoral research), and

Harvard University (further post-

K. B. Sharpless

M. G. Finn

H. C. Kolb

doctoral research) were Prof. T. A. Spencer, Prof. E. E. van Tamelen, Prof. J. P. Collman, and Prof. K. Bloch, respectively.

Before 1990, when he became W. M. Keck Professor of Chemistry at The Scripps Research Institute, Prof. Sharpless was a

member of faculty at the Massachusetts Institute of Technology (1970 ± 77, 1980 ± 90) and Stanford University (1977 ± 80).

Prof. Sharplessꢀs honors include the Chemical Sciences Award of the National Academy of Sciences (of which he is a

member), the Roger Adams and Arthur C. Cope Awards from the American Chemical Society, the Tetrahedron Award, the

King Faisal Prize, the Prelog Medal, the Wolf Prize, and honorary doctorates from five American and European

universities. The Sharpless research group continues to search for new homogeneous oxidation catalysts and for transition

metal catalyzed asymmetric processes.

M. G. Finn received his PhD degree from the Massachusetts Institute of Technology, working with Prof. K. B. Sharpless.

This was followed by an NIH postdoctoral fellowship with Prof. J. P. Collman at Stanford University. He joined the faculty

of the University of Virginia in 1988, and moved to his present position on the faculty of the Department of Chemistry and

The Skaggs Institute for Chemical Biology at The Scripps Research Institute in 1998. His group has studied the reactivity of

Fischer carbene complexes, metal-substituted phosphorus ylides, and a variety of transition metal catalyzed processes. His

current interests include methods for combinatorial catalyst discovery and the use of viruses as molecular building blocks.

Hartmuth Kolb received his PhD in synthetic organic chemistry under the supervision of Prof. S. V. Ley at Imperial College

in London. After two years of postdoctoral study with Prof. K. B. Sharpless at The Scripps Research Institute, he joined the

Central Research Laboratories of Ciba ± Geigy in Basel. Four years later, he moved to Princeton, New Jersey, to join the

Coelacanth Corporation, a high-performance chemistry company founded by K. B. Sharpless and A. Bader. Currently, he

is Vice President of Chemistry at the Coelacanth Corporation. His research interests include natural product and

carbohydrate synthesis, investigation of reaction mechanisms, molecular modeling, medicinal chemistry, process chemistry,

and combinatorial chemistry.

2006

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

Click Chemistry

REVIEWS

2. A ªProcess Chemistryº Point of View

OH

H

OH

H

N

H

N

S

O

S

NH₂

The molecules produced by living systems have always

fascinated and inspired synthetic organic chemists. As our

skills and tools have advanced, the compounds chosen for

synthesis have become ever more challenging. So it is no

surprise that todayꢀs favorite targets are found among the

most diabolically complex natural substances ever discov-

eredÐthe various secondary metabolites produced by plants

and microorganisms for self-defense. No expense or effort is

spared to synthesize even minute quantities of these extra-

ordinary molecules.^{[2, 3]}

O

CO₂H

N

H

NMe₂

CO₂H

Thienamycin

Meropenem

OH

O

N

NHtBu

N

H

Ph

OH

N

Indinavir

The pharmaceutical industry, a direct scion of natural

products chemistry,^[4]has not been put off by difficult

syntheses and many compounds being explored today as drug

candidates represent substantial synthetic challenges.^[5]While

it sharpens the skill and fraternal esteem of the research team,

implicit in the decision to pursue a complex drug target is the

acceptance of enormous constraints on the scope of the

structure space to be explored. When natural products are the

models, it usually takes so long to synthesize analogues in a

given series that even the most ambitious exploratory efforts,

viewed objectively, are often superficial. The process of

probing structure ± activity relationships (SAR) in these

situations has a perverse tendency to discover the ªbestº

candidates in difficult synthetic territory, near the outer limits

of ªaccessibility.º Difficult syntheses also tend to arise when

trying to reach patentable structural territory after original

discoveries have been made by a competitor.

The time required for SAR probing and then synthesis of

enough of the better compounds for pharmacokinetic and

toxicity profiling is staggering, and goes a long way toward

explaining why this phase of pharmaceutical research takes so

long. And yet, buoyed by the eventual success in obtaining

complex target structures, discovery chemists and top exec-

utives alike display little concern for issues of synthetic

accessibility. Ignored is the fact that any lead or development

series that has supply problems risks inadequate SAR

conclusions and development decisions. The story of the

carbapenem antibiotic thienamycin^[6±8]is illustrative: it re-

quired six years of superb effort by several research groups in

both industry and academia to develop the final therapeutic

agent (meropenem,^[9]a derivative of thienamycin) after the

initial synthesis of thienamycin was published.^[10a]The AIDS

protease inhibitor Crixivan (indinavir) provides a more recent

exampleÐa very difficult synthesis at nearly commodity-

chemical scale.^[10b]

manufacture. If a more modular, faster style of synthesis were

to prove effective, lower manufacturing costs should be the

least of its benefits. Lead structures should not be syntheti-

cally ªpreciousº, and one should be able to jump easily from

one series to another. As it is now, most discovery endeavors

suffer from being too invested in structure, when function is

what is sought.

Consider how nature synthesizes her most important

molecules, the primary metabolites. While the aforementioned

secondary metabolites have extensive networks of contiguous

carbon ± carbon bonds, and have claimed the lionꢀs share of

synthetic organic chemistsꢀ attention, it is reversible conden-

sation processes involving carbon ± heteroatom connections

that are used to assemble polynucleotides, polypeptides, and

polysaccharidesÐthe three families of macromolecules

that are central to life processes. By embracing the strategy

of making large oligomers from small building blocks,

Only at the end are issues of process development

considered, and synthesis on production scale is often

expensive. Nevertheless, the prospect of a blockbuster drug

is such a powerful motivator for a synthesis team that the job

nearly always gets done. The crucial point is that the cost

which complex synthesis adds to the final drug, while

substantial, is insignificant compared to all the ªhiddenº costs

imposed on the speed and quality of the discovery/develop-

ment phase by this same complex style of synthesis. In other

words, the way organic synthesis is done has pervasive effects

on the entire process of drug discovery, development, and

nature is also a consummate combinatorial chemist^[11]and

achieves astonishing diversity from less than 40 monomers.

These building blocks contain at most six contiguous C C

bonds, with the exception of the three aromatic amino acids.

Thus, nature is a promiscuous creator of carbon ± heteroatom

connections, choosing this method to encode and express

information.

Natureꢀs ability to create and control biomolecular diversity

is largely dependent on the exquisitely selective catalysts she

deploys. Our devices for managing reactivity and selectivity

are much less sophisticated, particularly with respect to C C

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

2007

K. B. Sharpless et al.

REVIEWS

bond formation. Therefore, the chemist who plans a synthesis

that requires the construction of C C bonds that are not

most common examples, including the following classes of

chemical transformations:

*

present or latent (for example, CH CXbase !C C) in the

cycloadditions of unsaturated species, especially 1,3-dipo-

lar cycloaddition reactions, but also the Diels ± Alder

family of transformations;

nucleophilic substitution chemistry, particularly ring-open-

ing reactions of strained heterocyclic electrophiles such as

epoxides, aziridines, aziridinium ions, and episulfonium ions;

carbonyl chemistry of the ªnon-aldolº type, such as

formation of ureas, thioureas, aromatic heterocycles, oxime

ethers, hydrazones, and amides; and

available starting materials is asking for trouble, particularly if

such a synthesis must be reliable for a number of substrates

(as for combinatorial searches or SAR studies) or applicable

to practical, large-scale production. Problems are less likely if

one only needs to unite, functionalize, and/or reorganize

starting materials and intermediates in ways which do not

require de novo C C bond construction. If such ªnewº C C

bonds are required, it is best to make them intramolecular-

ly,^[12]but it is better still to leave the really tough C C bond

synthesis to nature.^[13]

*

additions to carbon ± carbon multiple bonds, especially

oxidative cases such as epoxidation, dihydroxylation,

aziridination, and sulfenyl halide addition, but also Michael

additions of Nu H reactants.

There is, however, still plenty of room for discovery: Guida

and co-workers have estimated the pool of ªreasonableº drug

candidates (ꢀ30 non-hydrogen atoms; ꢀ500 daltons; con-

sisting of only H, C, N, O, P, S, F, Cl, and Br; likely to be stable

at ambient temperature in the presence of water and oxygen)

at between 10⁶²and 10⁶³discrete molecules.^[14]With this kind

of structure space available,^[15]we contend that it makes little

sense to search in hard-to-reach places for a desired function.

Instead, we present here synthetic methods for drug discovery

that adhere to one rule: all searches must be restricted to

molecules that are easy to make. We hope to convince the

reader that a wide diversity of interesting molecules can be

easily made, and that the chances for achieving desirable

biological activity are at least as good with such compounds as

with the traditional target structures now favored by medic-

inal chemists.

2.2. Olefin-Based Organic Synthesis

Consider, as a counterpoint to the pharmaceutical industry,

the world of petrochemicals and the materials it has spawned

(textiles, resins, plastics, etc.). The petrochemistꢀs starting

materials are ªgiftsº prepared by the carbonyl-based synthe-

ses of ancient organisms; in fossil oils are stored the energy of

CO₂-based photosynthesis, and, more importantly, countless

carbon ± carbon bonds. However, natural petroleum, being

almost completely saturated, is useless for most organic

synthesis needs. The petroleum industry is therefore based

upon the manipulation of C C bond ªcurrencyº, which entails

exchanging C C s bonds for new C C p bonds by ªcrackingº,

and creating new C C p bonds at the expense of C H bonds

by ªreformingº. The products of these processes are a small

number of reactive monomers, which are then assembled,

with a battery of selective catalysts, into myriad useful

materials. Thus, the manufacture of petrochemical products,

based as it is on a modular, and supremely efficient, synthetic

strategy, makes the energy expended on ªupgradingº satu-

rated hydrocarbons to olefins seem insignificant.

In a general sense, life chemistry and petrochemistry have

evolved identical strategies for the synthesis of substances

with diverse functions/properties: modular assembly of spe-

cially synthesized monomers under the control of selective

catalysts. That one depends on reversible carbonyl chemistry

and the other on irreversible olefin chemistry should not

obscure the striking similarity at the heart of the two

approaches. We are denied the ability to realistically imitate

natureꢀs modular carbonyl-based synthesis style (see above),

so the modular olefin-based style given to us by the petroleum

chemist is the model we choose to follow.^[16]

2.1. ªClick Chemistryº

Following natureꢀs lead, we endeavor to generate substan-

ces by joining small units together with heteroatom links

(C X C). The goal is to develop an expanding set of

powerful, selective, and modular ªblocksº that work reliably

in both small- and large-scale applications. We have termed

the foundation of this approach ªclick chemistry,º and have

defined a set of stringent criteria that a process must meet to

be useful in this context. The reaction must be modular, wide

in scope, give very high yields, generate only inoffensive

byproducts that can be removed by nonchromatographic

methods, and be stereospecific (but not necessarily enantio-

selective). The required process characteristics include simple

reaction conditions (ideally, the process should be insensitive

to oxygen and water), readily available starting materials and

reagents, the use of no solvent or a solvent that is benign (such

as water) or easily removed, and simple product isolation.

PurificationÐif requiredÐmust be by nonchromatographic

methods, such as crystallization or distillation, and the

product must be stable under physiological conditions.

The concept of the C C bond as a unit of ªcurrencyº is

central to an appreciation of the value of click chemistry in

organic synthesis. Scheme 1 depicts examples of how the

currency can be exchanged. The bookkeeping device to keep

track of the ªtotal C C bond countº is often, but not

necessarily, connected to demonstrable interconversions.

Starting with n-octane, the total C C bond count remains

constant at seven regardless of the number of transformations

It is important to recognize that click reactions achieve

their required characteristics by having a high thermodynamic

driving force, usually greater than 20 kcalmol . Such pro-

cesses proceed rapidly to completion and also tend to be

highly selective for a single product: we think of these

reactions as being ªspring-loadedº for a single trajectory.

Carbon ± heteroatom bond forming reactions comprise the

1

of a saturated C C bond into a C C p bond, for example,

C¹C²C³H !C¹HC C . Such a transformation is of

2

3

2008

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

Click Chemistry

REVIEWS

to cyclooctadiene and cyclododecatriene are perfect examples

of processes that further expand the core olefin structures

available to us at modest cost.^[19]The p bonds of butadiene are

reorganized effortlessly by the catalyst, to regio- and stereo-

selectively create sophisticated new carbon skeletons while

leaving behind one olefinic linkage per butadiene monomer

for the ªdecorationº steps to follow. Thus, between natural

olefin sources (terpenes, fatty acids,^[20]etc.) and ªreworkedº

natural hydrocarbons (olefins derived from petroleum) we

have been richly endowed by living systems with a diverse

olefinic starting material platform. It would be fitting if we

could devise short sequences for assembling these ªgiftº

olefins into new substances with beneficial biological functions.

The importance of olefins is dramatically enhanced by their

role as progenitors of still higher energy intermediates, such as

epoxides, aziridines, episulfonium ions, and aziridinium ionsÐ

all nearly perfect for click chemistry transformations

(Scheme 3). This sequence of oxidative creation/nucleophilic

Scheme 1. The C C bond as a unit of ªcurrencyº (DH⁰in kcalmol ¹; the

value given for hydroformylation compares olefin and aldehyde only). No

new C C bonds are formed in these processes.

course endothermic, but becomes favorable at high temper-

atures, thanks to a substantial positive entropy term. The

petrochemical industry practices ªsteam crackingº (a gas-

phase process at approximately 8508C) on enormous scales, to

make available a family of inexpensive olefins. The newly

created C C p bonds are highly reactive, having about 22 ±

1

25 kcalmol greater free energy content^[17]than a C C s

bond; in effect, the energy expended in ªcrackingº is partly

captured/stored in the C C linkage. This becomes apparent in

processes such as the Diels ± Alder reaction and hydroform-

ylation, which gain s links by reorganizing p C C links, again

without altering the total C C bond count. Olefin metathesis

Scheme 3. Examples of the genesis and relative energetics of click

chemistry components. New bonds made with click reactions are in bold.

Nu nucleophile.

provides an extraordinarily facile way to redistribute C C

links for further manipulation. (Acetylene links (counting as

3C C bonds), with two unstable p bonds, are even better than

olefins for driving a host of useful p !s carbon ± carbon bond

reorganizations.) Many such processes are highly reliable

precisely because no ªnewº C C bonds are created; all are

nascent in the reactantꢀs p bonds.

quenching of reactive electrophiles is what most enables the

crucial block ligation steps at the heart of click chemistry.

Thus, the chemistry of olefins provides for the creation of

diverse scaffolds and the attachment and display of myriad

functionality through oxidative addition of heteroatoms to

specifically placed olefinic sites.^[21]The robust nature of these

reactions is predicated on the irreversible progression from

systems of high energy to systems of lower energy in a stepwise

fashion. Each step has a high driving force, the sine qua non

condition of click chemistry, which enables reliable intermo-

lecular connections to be established.

Carbonyl compounds, by contrast, are quite stable thermo-

dynamically relative to olefins and even relative to their

hydrocarbon progenitors. Hence, their repertoire of click

chemistry transformations is limited. Among the few general

and highly reliable reactions starting from aldehydes and

ketones are their imine-forming condensations to give oximes

and hydrazones, and particularly to generate aromatic hetero-

cycles (see below). Also noteworthy, are the few intermolec-

ular carbonyl-based new C C bond forming reactions which

approach perfection (Scheme 4): 1) hydroxymethylation and

Olefins are the most attractive starting materials available

to the synthetic chemist, readily accessible in large quantities

and in many varieties, especially if one includes the naturally

abundant terpenes. The simplest are the handful of C₁± C₈

blocks shown in Scheme 2. Produced by the petrochemical

H

C

H₂C CH₂

CH₄

CH₃

H₂C

(butenes and

butadiene)

CH₃

H₃C

(isomeric xylenes)

Scheme 2. Small carbon building blocks from petroleum.

industry on a massive scale, they are the ultimate starting

materials for 90% by weight of all useful man-made organic

compounds.^[18]The Wilke cyclooligomerizations of butadiene

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

2009

K. B. Sharpless et al.

REVIEWS

1) Click reactions often proceed readily in hot water, to give a

single product, even when one or more of the reactants, as

well as the product, appear to be insoluble in this medium.

The fact that reactions between organic species in aqueous

solution can have higher apparent rate constants than the

same processes in organic media has been observed and

exploited by a number of laboratories.^[24]Among the many

explanations offered for such phenomena, we call partic-

ular attention to the notion that the free energies of

organic molecules are substantially greater when poorly

solvated in water, and often impart increased reactivity,

which compensates for the low concentration of the

participants.^[25]

2) Nucleophile additions to epoxide^[26](ªhomocarbonylº)

and aziridine (ªhomoimineº) electrophiles (as well as

aziridinium and episulfonium ions) are favored by solvents

best able to respond continuously to the demanding range

of hydrogen-bonding situations that arise during these

processes. In this respect, water is unique, and for the same

reasons, it is the perfect milieu for reversible carbonyl

chemistry.

Scheme 4. Strongly driven intermolecular C C bond forming reactions.

aminomethylation reactions using formaldehyde, the least

stable carbonyl representative, and 2) HCN additions to

carbonyl compounds, driven by the great stability of the

resulting cyanohydrin unit (primarily due to the nitrile groupꢀs

attachment through an sp-hybridized bond, made even

stronger by a substantial dipolar contribution). Another

excellent carbonyl-based process for intermolecular C C

bond formation is the Michael reaction, an exception which

proves the rule, since no new C C bond is created. Its

1

>20 kcalmol driving force is provided by the C C bond

which is consumed in the H Nu addition step.

3) Two important subsets of olefin and acetylene click

reactions are oxidations by electrophilic reagents and

cycloaddition reactions. These processes are either con-

certed or involve polarizable nucleophiles/electrophiles, so

that water is not an interfering medium.^[27]More generally,

it should be appreciated that the use of water offers the

greatest leverage for differentiating the reactivities of

competing ªhardº (nonpolarizable) and ªsoftº (polariz-

able) species.

4) A highly favorable reaction of two solutes (say at 0.1m

concentration) is usually much faster than a low driving

force side-reaction of one of the solutes with solvent water

(55m).^[28]The Schotten ± Baumann method for making

amides from acyl or sulfonyl halides in water is a well-

known example [Eq. (1)].^[29]

Since click chemistry is intended to provide a foundation

for the rapid assembly of new and pure molecular entities,

stereochemistry is important. The ideal click reactions are

based on stereospecific processes, but absolute stereochemis-

try need not be so stringently controlled. In any case, when

only one stereogenic element is involved, generation of the

racemate for initial biological screening will be preferred.

Even when two stereogenic elements are united or created in

a ligation step, it should be advantageous to test the racemic

mixtures of two or three diastereomers in the first pass at a

biological target.^[22]With the accelerating development of

improved analytical and separation techniques for deconvo-

lution of complicated mixtures,^[23]even greater relaxation of

stereochemical restrictions on assembly reactions will be

feasible in the near future.

Nature achieves highly specific syntheses of complex

substances by the uniquely selective action of enzyme

catalysts. However, the success of a desired click chemistry

sequence requires that virtually all of the control elements

and the enabling ªenergy packetsº be present in the reactive

components. At first, this plan may sound fancifulÐhow could

any but the most trivial set of reactive components be ªself-

containedº regarding the instructions and potential energy

needed to direct a reaction cascade to a unique synthetic

endpoint? Happily, we are finding that this goal is not so

difficult, provided one plans carefully and, above all, uses only

the handful of ªperfectº reactions for the crucial intermolec-

ular block ligation steps.

O

H

N

H₂O

R³

+

R¹

N

R²

(1)

R¹

Cl

R²

R³

NaOH

5) Water is a superb heat sink, due to its high heat capacity,

and has a convenient boiling temperature; both are useful

for large-scale processes.

Water is usually regarded as an ideal solvent in terms of its

environmental impact and low cost. A benefit which is little

appreciated but has enormous consequences is that most

hydroxy O H and amide N H groups will not interfere with

click reactions performed in water. As a consequence, the

installation and removal of protecting groups is avoidedÐ

probably the best single reason for adopting this style of

synthesis. Indeed, we view many of the best reactions for

installing ªprotecting groupsº as good click reactions in their

own right (see Section 3.3).

2.3. Click Chemistry in Water

Over the past two years, we have found that many of the

reactions that meet click chemistry standards often proceed

better in water than in an organic solvent. This is a natural

outcome of one or more of the following five factors.

These considerations highlight the fact that, although click

reaction components are necessarily highly reactive, their

chemoselectivity profiles are quite narrowly defined, that is,

ªorthogonalº to an unusually broad range of reagents,

2010

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

Click Chemistry

REVIEWS

solvents, and other functional groups. This attribute allows for

reliable and clean sequential transformations of broad

scope.^[30]For example, opening epoxide or aziridine rings by

ªHN₃º installs a highly reactive ªsticky spotº for [32]

cycloaddition with alkynes, but one that is ªinvisibleº to most

other functional groups.

combinatorial approaches to the discovery of biologically

active compounds ignore most of the issues that constrain

practical organic syntheses, the most likely outcome is a trend

toward drugs that are even harder to manufacture.

The types of reactions, and especially reaction conditions,

that fall into the click chemistry category were more common

in the organic literature of 50 to 100 years ago.^[31]Few solvents

were used then, and heat was the preferred way to speed up

reactions. The dearth of available purification techniques

meant that processes were chosen for their reliability in giving

a single isolable product. Without seeking to collect an

exhaustive list of click or click-like reactions,^[31]an attempt is

made here to illustrate the scope of this approach with a

number of representative examples taken both from the

literature and from our own work. We focus on nucleophilic

openings of the reactive small-ring species readily made by

oxidative addition of heteroatoms to olefins, and on concerted

cycloadditions and carbonyl/imine condensation reactions to

aromatic heterocycles.

2.5. Creation of Modules by Oxidative Addition of

Heteroatoms to Olefins

The potential of olefins for generating diversity is unlocked

by their oxidative functionalization. Much of our effort for the

past three decades has centered on this goal, and a useful set

of reliable transformations has emerged from a number of

laboratories including our own. The broad scope and high

yields of many olefin oxidation processes, and the fact that

olefins are the primary organic starting materials, render these

reactions the most fundamental enablers of click chemistry.

The oxidation step generates highly reactive, yet stable

intermediates such as epoxides and aziridines. Both the

oxidations to the intermediates and their subsequent fusion

with nucleophiles are stereospecific, and thus very predict-

able; Table 1^[33±39]shows the processes we use most often.

Most of the oxidation steps depend on transition metal

catalysis for which efficient enantioselective versions are well

established.

2.4. Comments on ªSolid-Phaseº Synthesis

A nearly ideal case is our recent discovery of a class of

olefins that exhibits unique reactivity in osmium-catalyzed

aminohydroxylation and dihydroxylation reactions per-

formed in water or water/organic mixtures. Unlike most

olefins, these special substrate classes undergo rapid and

nearly quantitative aminohydroxylation, with very low cata-

lyst loading, in the absence of cinchona alkaloid ligands, and

with only one equivalent of the haloamine salt. Moreover, the

reactions can be conducted at molar concentrations in

substrate, whereas the standard asymmetric aminohydroxy-

lation process is best performed at ꢀ0.1 molar concentration.

Among the substrates that exhibit this type of enhanced

reactivity are a,b-unsaturated acids and amides; Scheme 5

gives five examples.^[40]

We are proposing here the use of click reactions in

combinatorial style to generate molecules of highly diverse

structure and function. Much of the enormous effort in library

synthesis currently pursued in academic and industrial

laboratories makes use of polymeric supports for the stepwise

construction of products.^[32]In our view, solid-phase organic

synthesis is popular precisely because it allows reactions that

fall short of ªclickº status to be employed as click reactionsÐ

that is, in situations where extremely high yields and simple

purification procedures are required. These attributes are

achieved by using a large excess of the reactants in the mobile

phase. While this approach has been very effective for the

synthesis of large libraries, the final products tend to be too

lipophilic to probe the full range of biological interactions.

The hydrophobic character of these collections may, in part,

be due to the absence of ªbystanderº protic functional groups,

which tend to be omitted, intentionally or otherwise, to avoid

extra protection/deprotection steps.

3. Click Chemistry Reaction Types

Most importantly, the solid-phase approach is ill-suited to

ªprocess-drivenº discovery: it is very expensive and highly

wasteful of reagents and sol-

Below appears a description of the three most useful click

reactions presently in use in our laboratory. The best are pure

Table 1. Processes used to create oxidized electrophiles or their precursors from olefins.^[33±39]

vents; it is difficult to make

large amounts of products, and

when such large-scale syntheses

are attempted, the yield per

unit volume is poor; intermedi-

ates bound to polymeric sup-

ports are difficult to analyze

directly by standard spectro-

metric methods; and another

layer of chemical technologyÐ

the installation and cleavage of

a ªlinkerºÐis required. In oth-

er words, since solid-phase

racemic

TsNNaCl,^[a]

PhNMe₃Br₃

cat. MeReO₃,

H₂O₂, pyridine

cat. OsO₄,

cooxidant

RN(Cl)Na,

cat. OsO₄

asymmetric

allylic alcohols:

Ti(OiPr)₄, Me₃COOH,

dialkyl tartrate;

unfunctionalized olefins:

[(salen)Mn^III],^[b]

oxidant

cat. OsO₄,

cooxidant,

cinchona alkaloid

RN(Cl)Na,

cat. OsO₄,

cinchona alkaloid

[a] Ts tosyl toluene-4-sulfonyl. [b] H₂salen N,N'-bis(salicylidene)ethylenediamine.

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

2011

K. B. Sharpless et al.

REVIEWS

Scheme 5. Examples of unusually efficient osmium-catalyzed aminohydroxylation and dihydroxylation of olefins. Bn benzyl.

fusion processes, which means that the combined formulae of

the reactants equals the formula of the product.^[41]They can

be divided into two classes: those in which protons must be

shuffled about (epoxide ring opening, for example) and those

in which no s-bond connections are severed (cycloaddition

reactions, the most useful and reliable being the Huisgen

dipolar cycloadditions). The former tend to benefit dramat-

ically from an aqueous environment, while the latter reveal

little solvent dependence and are better overall in their

adherence to click chemistry ideals. Indeed, the azide acet-

ylene ! triazole version of Huisgenꢀs [2 3] cycloaddition

family of processes is about as good as a reaction can get. Never-

theless, it is the ªless idealº epoxide and aziridine opening pro-

cesses which are the workhorses for installing, often in the pen-

ultimate step of a block synthesis, the azide or alkyne moieties.

useful (Scheme 6). We focus here on the chemistry of three-

membered ring heterocyclic electrophiles.

The paramount advantage of nucleophilic openings of

three-membered rings is that competing elimination processes

are stereoelectronically disfavored,^[42]which results in high

yields and easy product isolation. All of the ring opening

reactions shown in Scheme 6 are fusion events, and most can

be performed in the absence of solvents^[43]or in water,

alcohol, or water/alcohol mixtures. In a number of cases, the

regioselectivity can be controlled by the choice of solvent, a

perfect example being the reaction of cis-cyclohexadiene

diepoxide 1^[44]with amines^[45](Scheme 7). In the absence of

solvents, the bis-epoxide reacts with amines to give the amino

alcohol 2, in which the entering nucleophiles are 1,3-related.

When protic solvents are added, the same reactants give

regioisomer 3, with the entering nucleophiles in the 1,4-

relationship.^{[46, 47]}In both cases, the diamino diol products are

isolated in pure form by direct crystallization from the crude

reaction solution, which enables reactions at any scale.

Regioselectivity is similarly well-controlled for the ring

opening of the trans diepoxide 4; the example in Scheme 7

shows the one-pot stitching of three diepoxide units with two

equivalents of ammonia to give 5 (85% yield) as a mixture of

its three possible racemic diastereomers.

3.1. Nucleophilic Opening of Spring-Loaded Rings

The four types of primary olefin oxidation products shown

in Table 1 are themselves high-energy species or may be

readily converted into such intermediates. The S_N2 ring-

opening reactions of these moleculesÐepoxides, aziridines,

cyclic sulfates, cyclic sulfamidates, aziridinium ions, and

episulfonium ionsÐare reliable, stereospecific, often highly

regioselective, and nearly quantitativeÐall in all, surpassingly

Aziridines, the aza analogues of epoxides, are readily

prepared by direct aziridination of olefins,^[48]by manipulation

2012

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

Click Chemistry

REVIEWS

Scheme 6. Generation and opening of spring-loaded cyclic electrophiles (shown in red) from olefins or their oxidation products (blue).

aziridines have even more potential

than epoxides from the standpoint of

click chemistry applications.^[55]

While N H and N alkyl aziridines

are perfectly stable under basic con-

ditions, we and others have found that

they can be readily opened, particu-

larly by heteroatom nucleophiles, un-

der buffered conditions in various

solvents including water.^{[56, 57]}The

examples in Scheme 9 illustrate the

practicality of aziridine-based click

chemistry.^[58a]A solvent is often not

required,^[58b]so that the ring-opened

compounds 7 and 8 are obtained in

pure form by neat fusion of 6 with the

appropriate secondary amine at ap-

Scheme 7. Amine reactivity with cyclohexadiene diepoxides.

of epoxides^[49]or amino alcohols,^[50]and by haloazidation of

olefins followed by reductive cyclization.^[51]Through variation

of the substituent on the ring nitrogen, aziridines enable much

greater product diversity than epoxides. Their ring-opening

reactivities can be modulated over an enormous range,^[52]and,

most importantly, the nitrogen substituent and the nature of

the solvent can be used to control the regioselectivity of ring

opening in unsymmetrical cases.^[53]The example in Scheme 8

from Stamm and co-workers reveals just how dramatic the

effect of the nitrogen substituent can be.^[54]Effects deriving

from the tendency of sulfonamides to be pyramidal at

nitrogen and amides to be planar cause N-sulfonyl aziridines

usually to furnish the regioisomer derived from attack of the

nucleophile at the sterically least hindered center, while N-

acyl aziridines favor the opposite regioisomer.^[53]Thus,

Scheme 8. Influence of the nitrogen substituent (sulfonyl, acyl) on the

regioselectivity of aziridine opening.^[54]Tol tolyl.

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

2013

K. B. Sharpless et al.

REVIEWS

hydrazine (to give 12 at 258C). The

resulting intermediates are highly useful;

their cycloadditions and condensations

with alkynes and b-diketones, respective-

ly, are reliable click reactions in their own

right (see Section 3.2). Water is often the

solvent of choice, as illustrated by the

opening of a simple aziridine with 5-phe-

nyltetrazole to give heterocycle 13. Such a

modular approach allows for the forma-

tion of a large variety of useful organic

intermediates.

Highly activated aziridinium systems

are easily generated in situ in the course

of neighboring group assisted nucleophil-

ic substitution starting from amino alco-

hols,^[59]or b-halo amines^[60]and related

compounds^[61](Scheme 6). The reactions

of the analogous episulfonium systems^[62]

are even more facile.^[63]All these substi-

tutions are stereospecific and proceed

with double inversion, and hence net

retention of configuration in cases where

the nucleophilic attack on the aziridinium

or episulfonium ion occurs at the center

bearing the leaving group, or with inver-

sion of both centers in cases where the

amino or thioether group undergoes a 1,2-

shift. The broad scope of these reactions

Scheme 9. Use of activated and nonactivated aziridines as building blocks. Boc tert-butoxycar-

bonyl.

and the easy access to the starting materials from the

corresponding epoxides makes them perfectly suited for the

rapid generation of building blocks and combinatorial libra-

ries (Scheme 10).^[64]An example of the swift access provided

by aziridinium chemistry to ªdruglikeº molecules is shown by

proximately 1208C. Neat thermal fission then removes the N-

Boc group in 7 to provide the secondary amine 9, while the

primary amine in 10 is unmasked in excellent yield by heating

compound 8 at 1708C with two equivalents of p-TsOH ´ H₂O,

again in the absence of solvent. The high temperatures of

these solvent-free processes are presented to highlight the

reliability of the bond-forming events under any conditions.

Each of these reactions can also be done in standard solvents

at ꢀ708C.

the preparation of

(Scheme 11).

a

1,5-benzodiazepine derivative

Aziridinium and episulfonium chemistry is particularly

well-suited to the aqueous phase because the spring-loaded

three-membered ring intermediates bear a positive charge,

balanced by the anionic counterion which served as the

The opening of even unactivated aziridines proceeds read-

ily in water with buffered azide (to give 11 at 508C) and with

Scheme 10. Aziridinium intermediates in combinatorial assembly. Ms mesyl methane sulfonyl.

2014

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

Click Chemistry

REVIEWS

Scheme 11. Efficient assembly of a benzodiazepine via an aziridinium

intermediate.

leaving group. We have noted that, when this leaving group is

chloride or, particularly, sulfonate, the beneficial effects of

water are most apparent, whereas little or no improvement is

noted on changing the solvent from acetonitrile to water when

the leaving group is iodide or bromide.^[65]The greater

stabilization offered by strong protic solvation of the harder

anions in water is probably the dominant factor. Furthermore,

these ªhomocarbonylº electrophiles, like the acyl halides that

participate in Schotten ± Baumann reactions, are much more

reactive toward a range of heteroatom nucleophiles in water

than toward the solvent. An example of the beneficial effects

of performing these types of reactions in water is given in

Scheme 12, in which both yield and selectivity are shown to be

Scheme 13. Generation and reactions of activated sulfonium (thiiranium)

electrophile 14.

products. The dramatically different outcomes for reaction of

14 with saturated solutions of NH₃in CH₃OH or H₂O

underscore the crucial role played by solvation in these

substitutions and the unique properties of water as a solvent,

especially when solvent separation of ion pairs and/or

efficient proton shuttling through solvent hydrogen-bonding

networks are important.

3.2. Cycloaddition Reactions

Click chemistry ideals are beautifully represented among

cycloaddition reactions involving heteroatoms, such as het-

ero-Diels ± Alder^{[70, 71]}and, especially, 1,3-dipolar^[72±74]cyclo-

additions. These modular fusion reactions unite two unsatu-

rated reactants and provide fast access to an enormous variety

of interesting five- and six-membered heterocycles.^[75]

Scheme 12. Solvent dependence of aziridinium ring opening by azide.

improved as the water content of the reaction medium is

increased. For the last two sets of conditions shown, which

lead to the highest selectivities, neither the starting material

nor the products are soluble in the reaction solvent.

As already mentioned, in this powerful class of concerted

click reactions we have come to regard the Huisgen dipolar

cycloaddition of azides and alkynes^[76]as the ªcream of the

cropº. However, probably because of concerns about the

safety of the azide moiety,^[77]medicinal chemists have not

given these transformations the special attention they de-

serve.^[78]The actual cycloaddition step may be as reliable for

other types of [23] reactions, but the azide group is by far the

most convenient of the 1,3-dipolar components to introduce

and to ªcarryº until needed. Indeed, it may be the only one

which is stable toward dimerization and/or hydrolysis. While

azides are widely valued for their ease of introduction and

reduction to primary amino groups, the remarkable stability

(orthogonality) of aliphatic azides to a wide variety of other

standard organic synthesis conditions seems largely unappre-

ciated. With a few interesting exceptions, they remain

ªinvisibleº unless a good dipolarophile is present.

In this context, it should also be noted that the mustard-

type sulfur compounds are directly accessible from olefins in

very high yields by addition of sulfenyl halides (RSX)^[66]or the

inorganic parent SCl₂^[67](Scheme 13, top). The addition often

proceeds under thermodynamic control, allowing reliable

prediction of the products. The exceptional reactivity of the

resulting compounds such as 14 enables many additional click

chemistry transformations through neighboring-group partic-

ipation, which provides episulfonium intermediates such as

15.^[68]These pathways, and especially the required ejection of

anionic leaving groups (for example, the chloride in 14), are

uniquely assisted by an aqueous environment. In the cases

shown at the bottom of Scheme 13,^[69]the reactions proceed

cleanly and rapidly from solid-to-solid in aqueous suspension;

presumably, the episulfonium ion intermediates are the only

water-soluble species on the path from starting materials to

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

2015

K. B. Sharpless et al.

REVIEWS

Two typical examples of azide cycloadditions are shown in

Scheme 14.^[79]Bis(azide) 16 readily adds two molecules of

alkyne to give bis(triazole) 17. A wide variety of alkynes

3.3. ªProtecting Groupº Reactions

While hydroxy groups are nearly ªinvisibleº in aqueous

solution, in the absence of water a pair of neighboring hydroxy

groups often exhibit unique reactivity. Thus, acid-catalyzed

reactions with aldehydes and ketones provide cyclic 1,3-

dioxolane rings in high yields. Instead of their ubiquitous role

as diol protecting groups, should not acetals, ketals, and some

of their aza-analogues be better viewed as an attractive class

of heterocycles for medicinal chemistry applications? They

are generally stable at physiological pH,^[81a]have already

appeared as components in orally available drugs,^[81b]contrib-

ute several hydrogen bond acceptor sites and interesting

dipole effects, provide constrained scaffolds with well-defined

projections and spatial orientations of their substituents, are

assembled from modular and abundant components, and

represent one of the rare click chemistry modules based on

reversible carbonyl chemistry.

Scheme 14. Examples of azide cycloaddition reactions.

The five acetal-like derivatives (23 ± 26 and ent-26) were

easily prepared on multigram scales from the appropriate

diols or hydroxysulfonamides.^[82]As a consequence of their

engage in such reactions, with electron-deficient cases usually

being the most reactive. Azide 18 reacts with the cyanoacet-

ylene equivalent, 2-chloroacrylonitrile, to give only one

regioisomer of triazole 19, which retains its isolated olefins

for further decoration.

Other (that is, non-azide) 1,3-dipolar cycloaddition pro-

cesses provide interesting five-membered heterocycles, such

as the examples shown in Scheme 15, in good yields.^[80]The

heteroatom substituent inductive effects, they are resistant to

standard acidic hydrolysis conditions, all the more so if the

azide group is reduced to the amine. The saturated dioxolane

cores can be regarded as permanent elements of the blockꢀs

structure under most physiological and chemical conditions,

and if further transformations are desired the pendant azide

substituents offer many diverse and reliable options.

4. Examples of Click Chemistry SequencesÐ

Diversity with Ease

Complex structures can be rapidly assembled using short

sequences of simple click chemistry transformations. An

example is the formation of the tricyclic molecule 29 in just

three steps, conducted sequentially in one pot and starting

from bis-epoxide 4^{[34, 44]}(Scheme 16).^[83]The nucleophilic

opening of 4 with buffered azide is highly regioselective,

resulting in the formation of the crystalline azido alcohol 27 in

excellent yield. The bis-triazole 28, formed by 1,3-dipolar

addition of the bis-azide with diethylacetylene dicarboxylate,

can be collected from the reaction mixture by filtration. The

C₂-symmetry of the system is then broken during base-

catalyzed lactonization to furnish lactone 29, the three

rings of which resemble the B, C, and D rings found in

Scheme 15. Cycloaddition reactions based on the hydrazine-derived [23]

dipole 22.^[80a]

sequence starts with addition of hydrazine to the aziridinium

intermediate generated from 20. The resulting cyclic hydra-

zide 21 then undergoes condensation with aromatic aldehydes

to give azomethine ylides 22, which react with a variety of

unsaturated components to give [32] cycloadducts. The rich

array of functionality displayed by these products provides

opportunities for the creation of unique combinatorial

libraries.

2016

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

Click Chemistry

REVIEWS

Scheme 18. A click chemistry library sequence from olefinic acids.^[88]

Scheme 16. Steroid-like skeletons assembled from cyclohexadiene diep-

oxides.

Regioselective aziridine ring opening by a diverse set of

primary and secondary amines then yields the threo-3-amino-

2-sulfonamides 33. The aminohydroxylation was also per-

formed with the chloramine salt of p-nosyl sulfonamide (see

above), and the b-aminosulfonamide products 33 (R⁴ p-

NO₂C₆H₄(p-nosyl)) were freed of their sulfonamide group

through the Fukuyama deprotection method,^[86]to give 34.

The resulting primary 2-amino group of compounds 34 have

been capped with more than sixty electrophiles to date,

including acid chlorides, sulfonyl chlorides, anhydrides, iso-

cyanates, and isothiocyanates, to give structures of the general

form 35.^[87]The biological activities discovered in various

screens of this library will be reported elsewhere.

steroids. The analogous cis-diepoxide 1, through the same

three-step sequence, gives the related lactone 30, which is

identical to 29 except that the two ªBº-ring substituents have

switched positions. All steps for both sequences proceed in

excellent yield. (See the frontispiece for large-scale sequences

in this series.)

The capabilities of such reaction sequences for library

synthesis are illustrated in Scheme 17. Epoxide ring opening

with hydrazine and subsequent condensation with a variety of

b-dicarbonyls or other bis-electrophiles provide entry to an

enormous range of heterocyclic structures. Library synthesis

using these protocols is highly efficient, and achieves excellent

diversity from the large, available pool of epoxides.^[84]

The facile osmium-catalyzed aminohydroxylation of a,b-

unsaturated amides is also an attractive starting point for the

synthesis of diverse molecules based on the previously rare

a,b-diamino acid motif (Scheme 18). In this sequence, the

hydroxysulfonamide regioisomers 31a and 31b produced in

the aminohydroxylation step conveniently provide the same

cis-N-sulfonylaziridine intermediates 32 upon cyclization.^[85]

5. Summary and Outlook

We have described here the basic elements of a new style of

organic synthesis, or, perhaps more accurately, the reinvigo-

ration of an old style of organic synthesis. Its purpose is to

accelerate the discovery of substances with useful properties,

new medicines being the example emphasized. The approach

derives from a keen awareness of natureꢀs preferred methods

of synthesis, but does not seek to emulate them too closely.

Nature is a matchless creator of C C linkages and

we propose leaving the tough job of C C bond

synthesis as much as possible to her. Instead, it is

sensible for us to specialize in quick and easy

chemistry that nature uses only sparely, by focusing

on the high driving force reactions that emanate

from the olefins that she has provided either directly

(for example, terpenes) or that are produced by the

petroleum industry.

It is no accident, given the high energy content of

the olefinic p bond, that the most reliable and most

useful organic reactions all involve olefins, their

unsaturated cousins, or their uniquely accessible

heteroatom oxidative addition products. The latter

compounds either are, or can easily be transformed

into, the reactive building blocks that are ideal for

the fast, irreversible assembly (for example, through

Scheme 17. Click chemistry sequences from epoxides and hydrazine.^[84]

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

2017

K. B. Sharpless et al.

REVIEWS

metabolites, see: D. P. Singh, A. K. Pant, R. K. Rai, Chem. Environ.

Res. 1993, 2, 3 ± 18.

click chemistry) of diverse molecules with druglike structural

features. Three-dimensional space is efficiently accessed by

the stereospecific nucleophilic openings of such spring-loaded

rings, and when these spring-loaded units are embedded in

cyclohexane frameworks, the level of regio- and stereochem-

ical control available for core creation/decoration sequences

reaches a zenith. Nature certainly uses heteroatom connec-

tions, but not in this fashion. Therefore, the structures

assembled by opening aziridines and epoxides are usually

novel, and almost invariably so when the assembly sequence

involves two or more such ligations.

Natureꢀs giant molecules are constructed from a small set of

building blocks using a few types of reactions for stitching

them together. If we are to build small molecules which

interact specifically with these large and diverse structures, we

will need more components than nature has developed. While

new building blocks will always be welcome, we expect that a

good set of 500 or so will prove effective for many targets.

Our thinking about C C bonds as gifts of nature has been a

constant source of inspiration during the framing and the

ongoing refinement of this minimalist synthetic strategy. In

any event, endeavoring to transform these matchless building

blocks into substances with diverse and useful functions seems

an appropriate way to honor the bestowal of such an

embarrassment of riches.

[4] For an eloquent account of the history of medicinal chemistry, see: W.

Sneader, Drug Prototypes and their Exploitation, Wiley, New York,

1996. Here Sneader traces the origins of modern medicines back to

approximately 200 natural product prototypes, the majority of which

are toxic secondary metabolites created by plants and microorganisms

for self-defense.

[5] Some delightful exceptions do exist, such as Celebrex (celecoxib):

T. D. Penning, J. J. Talley, S. R. Bertenshaw, J. S. Carter, P. W. Collins,

S. Docter, M. J. Graneto, L. F. Lee, J. W. Malecha, J. M. Miyashiro,

R. S. Rogers, D. J. Rogier, S. S. Yu, G. D. Anderson, E. G. Burton, J. N.

Cogburn, S. A. Gregory, C. M. Koboldt, W. E. Perkins, K. Seibert,

A. W. Veenhuizen, Y. Y. Zhang, P. C. Isakson, J. Med. Chem. 1997, 40,

1347 ± 1365.

[6] Structure elucidation: G. Albers-Schönberg, B. H. Arison, O. D.

Hensens, J. Hirshfield, K. Hoogsteen, E. A. Kaczka, R. E. Rhodes,

J. S. Kahan, F. M. Kahan, R. W. Ratcliffe, E. Walton, L. J. Ruswinkle,

R. B. Morin, B. G. Christensen, J. Am. Chem. Soc. 1978, 100, 6491 ±

6499.

[7] Antibacterial properties: F. P. Tally, N. V. Jacobus, S. L. Gorbach,

Antimicrob. Agents Chemother. 1978, 14, 436 ± 438; S. S. Weaver, G. P.

Bodey, B. M. LeBlanc, Antimicrob. Agents Chemother. 1979, 15, 518 ±

521; J. S. Kahan, F. M. Kahan, R. Goegelman, S. A. Currie, M.

Jackson, E. O. Stapley, T. W. Miller, A. K. Miller, D. Hendlin, S.

Mochales, S. Hernandez, H. B. Woodruff, J. Birnbaum, J. Antibiot.

1979, 32, 1 ± 12.

[8] Process optimization: D. G. Melillo, I. Shinkai, T. Liu, K. Ryan, M.

Sletzinger, Tetrahedron Lett. 1980, 21, 2783 ± 2786; I. Shinkai, T. Liu,

R. A. Reamer, M. Sletzinger, Tetrahedron Lett. 1982, 23, 4899 ± 4902;

see also: D. L. Hughes, R. A. Reamer, J. J. Bergan, E. J. J. Grabowski,

J. Am. Chem. Soc. 1988, 110, 6487 ± 6491.

This review is dedicated to Professor Daniel S. Kemp, master

teacher of carbonyl chemistry to a generation of MIT students

and at least one assistant professor. We are very grateful to the

following co-workers for their willingness to sail the click

chemistry waters, and especially to those who have waited as

long as several years to see their efforts reach the printed page:

Michael Bartsch, Kristina Burow, John Cappiello, Han-Ting

Chang, Bin Chao, Zhengming Chen, Jay P. Chiang, Tsung-

Huang Chuang, Antonella Converso, Zachary Demko,

Klaus R. Dress, Valery V. Fokin, Alexander V. Gontcharov,

Vincent Jeanneret, Jae-uk Jeong, Dongyeol Lim, Hong Liu,

Susan Maddock, Andreas Marzinzik, Dominique Michel,

David S. Nirschl, Janet Elizabeth Pease, Wallace C. Pringle,

K. Laxma Reddy, Paul Richardson, A. Erik Rubin, Zai-Cai

Shi, Erland Stevens, Beata Tao, Allen A. Thomas, Andrew R.

Vaino, Koenraad P. M. VanHessche, Martin A. Winter, An-

drei K. Yudin, and Zhi-Min Wang. We also thank Dr. Thomas

Archibald (Aerojet Fine Chemicals, Inc.) for educating us on

the safe handling of azides and other reactive compounds, Prof.

Joseph Gajewski (Indiana University) for insightful mecha-

nistic discussions, and Prof. Subhash Sinha (The Scripps

Research Institute) for performing the reactions highlighted in

the frontispiece.

[9] a) Meropenem synthesis: M. Sunagawa, H. Matsumura, T. Inoue, M.

Fukasawa, K. Masatomo, M. Kato, EU-A EP126587, 1984; A. S.

Prashad, N. Vlahos, P. Fabio, G. B. Feigelson, Tetrahedron Lett. 1998,

39, 7035 ± 7038; b) structure ± activity discussion: M. Sunagawa, H.

Matsumura, T. Inoue, M. Fukasawa, M. Kato, J. Antibiot. 1990, 43,

519 ± 532.

[10] a) Synthesis: D. B. R. Johnston, S. M. Schmitt, F. A. Bouffard, B. G.

Christensen, J. Am. Chem. Soc. 1978, 100, 313 ± 315; T. N. Salzmann,

R. W. Ratcliffe, B. G. Christensen, F. A. Bouffard, J. Am. Chem. Soc.

1980, 102, 6161 ± 6163; b) S. Redshaw, G. J. Thomas, Emerging Drugs

1997, 2, 127 ± 154.

[11] While nature was the first combinatorial chemist, Ivar Ugi may be

regarded as the second. His idea of using one-step solution-phase

processes, such as his four-component coupling reaction, in such

applications was a stroke of genius, and about 30 years ahead of its

time: ªSince four different starting materials take part in the four-

component condensation, the reaction is extremely versatile. If, for

example, 40 each of the different components are reacted with one

another, the result is 40⁴ 2560000 reaction products, which is quite a

high figure considering that it is of the same order of magnitude as the

total number of chemical compounds described to date.º (G. Gokel,

G. Lüdke, I. Ugi, in Isonitrile Chemistry (Ed.: I. Ugi), Academic Press,

New York, 1971, pp. 145 ± 199; see also: I. Ugi, R. Meyr, U. Fetzer, C.

Steinbrückner, Angew. Chem. 1959, 71, 386). When the pharmaceu-

tical industry ªdiscoveredº combinatorial chemistry about 20 years

later, the solid-phase approach, pioneered by Merrifield for multistep

synthesis of large biopolymers, was adapted for multistep syntheses

of druglike molecules. Only recently, following ArQuleꢀs lead, has

the drug-discovery community realized the power of Ugiꢀs vision

for quickly generating molecular diversity through robust, yet

simple, reaction cascades that assemble multiple components in

solution.

Received: August 28, 2000 [A427]

[1] For equilibrium constants in a series of simple aldol condensations,

see: J. P. Guthrie, Can. J. Chem. 1978, 56, 962 ± 973.

[2] E. J. Corey, X.-M. Cheng, The Logic of Chemical Synthesis, Wiley,

New York, 1989; K. C. Nicolaou, E. J. Sorensen, Classics in Total

Synthesis, VCH, Weinheim, 1996.

[3] For reviews, see: a) I. T. Baldwin, C. A. Preston, Planta 1999, 208,

137 ± 145; b) O. C. Yoder, Dev. Plant Pathol. 1998, 13, 3 ± 15; c) T.

Hartmann, Entomol. Exp. Appl. 1996, 80, 177 ± 188; d) E. Haslam,

Chemoecology 1995, 5/6, 89 ± 95; for a review of antifeedant secondary

[12] The venerable Robinson annelation sequence is an example. The

components are first connected intermolecularly by the Michael

reaction (no new C C bonds made, only the favorable exchange of a p

for a s bond; DH < 20 kcalmol ¹) and only then is the hard part (the

aldol step) accomplished intramolecularly. The Dieckman condensa-

tion has enormous scope because it is intramolecular, whereas the

intermolecular parent reaction (Claisen condensation) is only reliable

for the simplest case (R H in RCH₂COOR').

2018

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

Click Chemistry

REVIEWS

[13] We do not consider here the many polymerization (Ziegler± Natta)

reactions of olefins and acetylenes and related processes, which

account for the vast majority of man-made materials based on

contiguous carbon ± carbon bond networks. Being strongly exothermic

and superbly efficient, these polymerizations are clearly based on click

reactions, but ones which are hard to control for the construction of

small molecules in the stepwise ªmodularº fashion of the reactions

discussed above.

[14] R. S. Bohacek, C. McMartin, W. C. Guida, Med. Res. Rev. 1996, 16, 3 ±

50. K.B.S. thanks Prof. Daniel Rich for calling this paper to his

attention during a visit to the University of Wisconsin in 1997.

[15] The portion of this drug candidate ªuniverseº that has been

synthesized to date is approximately one part in 10⁵⁷, or roughly the

ratio of the mass of one proton to the mass of the sun! The distance

from Earth to the edge of the visible universe is traversed in only 25

powers of ten (10⁰!10²⁵meters) or so: P. Morrison, P. Morrison,

Powers of Ten, Scientific American, New York, 1982.

[29] Note, however, that amide bond synthesis by this or other methods, in

spite of being strongly favorable thermodynamically, does not often

reach the level of yield, generality, simplicity, and ease of product

isolation that characterizes click reactions. For example, compare

amide synthesis with the synthesis of ureas from amines and

isocyanates. The latter process is a nearly perfect transformation,

and like all the best click reactions it is a pure fusion process requiring

no adjuvants of any kind. Amide bond formation, in contrast, usually

requires external reagents and generates nontrivial by-products,

factors contributing to uncertain outcomes in new circumstances.

Reactions such as these are good enough for making building blocks,

but not for the final assembly sequences.

[30] A similar theme may be found in the development of sequential

(ªdominoº) reaction schemes for the rapid synthesis of single

compounds or compound libraries. See, for example: L. F. Tietze, A.

Modi, Med. Res. Rev. 2000, 20, 304 ± 322; L. F. Tietze, M. E. Lieb, Curr.

Opin. Chem. Biol. 1998, 2, 363 ± 371; L. F. Tietze, Chem. Rev. 1996, 96,

115 ± 136; L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137 ± 170;

Angew. Chem. Int. Ed. Engl. 1993, 32, 131 ± 163; A. Orita, Y. Nagano,

K. Nakazawa, J. Otera, Synlett 2000, 599 ± 602.

[16] For further discussion of this approach, and its relation to process

chemistry, see: Foreword by K. B. Sharpless in Practical Process

Research & Development (Ed.: N. G. Anderson), Academic Press, San

Diego, 2000.

[31] The series Houben-Weyl: Methods of Organic Chemistry, Thieme

Verlag, Stuttgart remains unchallenged as the best source of informa-

tion of this type.

[17] The free energy of the hydrogenation of ethylene to ethane is

1

24.1 kcalmol ¹, and of acetylene to ethylene is 33.7 kcalmol

.

Other convenient comparisons, such as the ones shown in Scheme 1,

can be made with the aid of the Benson group-additivity method:

S. W. Benson, Thermochemical Kinetics, 2nd ed., Wiley, New York,

1976.

[32] a) J. I. Crowley, H. Rapoport, Acc. Chem. Res. 1976, 9, 135 ± 144;

b) J. S. Früchtel, G. Jung, Angew. Chem. 1996, 108, 19 ± 46; Angew.

Chem. Int. Ed. Engl. 1996, 35, 17 ± 42; c) P. H. H. Hermkens, H. C. J.

Ottenheijm, D. C. Rees, Tetrahedron 1996, 52, 4527 ± 4554; d) P. H. H.

Hermkens, H. C. J. Ottenheijm, D. C. Rees, Tetrahedron 1997, 53,

5643 ± 5678.

[18] H. A. Wittcoff, B. G. Reuben in Industrial Organic Chemicals, Wiley,

New York, 1996.

[19] G. Wilke, A. Eckerle, Appl. Homogeneous Catal. Organomet. Compd.

1996, 1, 358 ± 373; b) P. W. Jolly, G. Wilke, The Organic Chemistry of

Nickel, Vol. I and II, Academic Press, New York, 1975; c) G. W.

Parshall, W. A. Nugent, CHEMTECH 1988, 18, 314 ± 320.

[20] U. Biermann, W. Friedt, S. Lang, W. Lühs, G. Machmüller, J. O.

Metzger, M. Rüsch gen. Klaas, H. J. Schäfer, M. P. Schneider, Angew.

Chem. 2000, 112, 2292 ± 2310; Angew. Chem. Int. Ed. 2000, 39, 2206 ±

2224.

[21] It should be appreciated that nature does make sparing use of olefin-

based chemistries. In general, their high reactivity toward oxidation

and addition makes olefins a liability for biology, in that harmful,

irreversible reactions are possible. But occasionally, necessity seems to

have been the mother of spectacular invention, as in the cationic

cyclization of squalene epoxide to lanosterol. In this and related

polyene cyclizations, we see that nature discovered the unique

effectiveness of olefin oligomerization processes for turning unstable

[33] Aziridination: a) J. U. Jeong, B. Tao, I. Sagasser, H. Henniges, K. B.

Sharpless, J. Am. Chem. Soc. 1998, 120, 6844 ± 6845; b) A. V.

Gontcharov, H. Liu, K. B. Sharpless, Org. Lett. 1999, 1, 783 ± 786.

[34] Olefin epoxidation using methylrhenium trioxide as a catalyst in the

presence of amine additives: a) H. Adolfsson, A. Converso, K. B.

Sharpless, Tetrahedron Lett. 1999, 40, 3991 ± 3994; b) W. A. Herrmann,

R. W. Fischer, D. W. Marz, Angew. Chem. Int. Ed. Engl. 1991, 30,

1638 ± 1641; c) W. A. Herrmann, F. E. Kühn, Acc. Chem. Res. 1997, 30,

169 ± 180; d) J. Rudolph, K. L. Reddy, J. P. Chiang, K. B. Sharpless, J.

Am. Chem. Soc. 1997, 119, 6189 ± 6190.

[35] Reviews of the asymmetric epoxidation of allylic alcohols: a) T.

Katsuki, V. S. Martin, Org. React. 1996, 48, 1 ± 299; b) R. A. Johnson,

K. B. Sharpless in Catalytic Asymmetric Synthesis (Ed.: I. Ojima),

VCH, New York, 1993, pp. 101 ± 158.

[36] Reviews of the asymmetric epoxidation of unfunctionalized olefins:

a) T. Katsuki, J. Mol. Catal. A 1996, 113, 87 ± 107; b) E. N. Jacobsen, in

Catalytic Asymmetric Synthesis (Ed.: I. Ojima), VCH, New York,

1993, pp. 159 ± 202.

C C networks into stable (C C) ones some years before the

petroleum chemist.

[22] a) Tetrahedron 1998, 54(16) (special issue devoted to solution-phase

combinatorial chemistry); b) H. An, P. D. Cook, Chem. Rev. 2000, 100,

3311 ± 3340.

[37] Osmium-catalyzed dihydroxylation of olefins: a) H. C. Kolb, K. B.

Sharpless, Transition Met. Org. Synth. 1998, 2, 219 ± 242; b) H. C. Kolb,

M. VanNieuwenhze, K. B. Sharpless, Chem. Rev. 1994, 94, 2483 ±

2547.

[23] For example, see: R. H. Griffey, H. An, L. L. Cummins, H. J. Gaus, B.

Haly, R. Herrmann, P. D. Cook, Tetrahedron 1998, 54, 4067 ± 4076.

[24] a) C.-J. Li, T.-H. Chan, Organic Reactions in Aqueous Media, Wiley,

New York, 1997; b) Aqueous Phase Organometallic Catalysis (Eds.: B.

Cornils, W. A. Herrmann), Wiley-VCH, Weinheim, 1998; c) Organic

Synthesis in Water (Ed.: P. A. Grieco), Blackie, London, 1998; d) R.

Breslow, Acc. Chem. Res. 1991, 24, 159 ± 164; e) R. Breslow, Pure

Appl. Chem. 1998, 70, 1933 ± 1938.

[38] Review of the osmium-catalyzed aminohydroxylation of olefins:

a) H. C. Kolb, K. B. Sharpless, Transition Met. Org. Synth. 1998, 2,

243 ± 260; b) G. Schlingoff, K. B. Sharpless in Asymmetric Oxidations

Reactions: A Practical Approach (Ed.: T. Katsuki), Oxford University

Press, in press; c) use of amino-substituted heterocycles as nitrogen

source: L. J. Goossen, H. Liu, K. R. Dress, K. B. Sharpless, Angew.

Chem. 1999, 111, 1149 ± 1152; Angew. Chem. Int. Ed. Engl. 1999, 38,

1080 ± 1083; K. R. Dress, L. J. Goossen, H. Liu, D. M. Jerina, K. B.

Sharpless, Tetrahedron Lett. 1998, 39, 7669 ± 7672; d) Z. P. Demko, M.

Bartsch, K. B. Sharpless, Org. Lett. 2000, 2, 2221 ± 2223.

[25] J. J. Gajewski, Acc. Chem. Res. 1997, 30, 219 ± 225.

[26] See, for example: F. Fringuelli, O. Piermatti, F. Pizzo, L. Vaccaro, J.

Org. Chem. 1999, 64, 6094 ± 6096.

[27] For an example of the beneficial effects of aqueous solvent on 1,3-

dipolar cycloaddition reactions, see: D. van Mersbergen, J. W. Wijnen,

J. B. F. N. Engberts, J. Org. Chem. 1998, 63, 8801 ± 8805.

[39] For a recent review of the asymmetric synthesis of aziridines from

amino alcohols, epoxides, alkenes, and imines, see: H. M. I. Osborn, J.

Sweeney, Tetrahedron: Asymmetry 1997, 8, 1693 ± 1715.

[28] With the concentrations indicated and the assumption of simple

second-order kinetics, the click reaction has to have a rate constant

approximately 50000 times that of the competing reaction with water

in order for the side product to constitute less than one percent of the

total. At room temperature, this translates to a difference in activation

energy of approximately 6.4 kcalmol ¹. The situation is more compli-

cated when, as is often the case, either or both of the reaction

components are poorly soluble in water.

[40] a) A. E. Rubin, K. B. Sharpless, Angew. Chem. 1997, 109, 2751 ± 2754;

Angew. Chem. Int. Ed. Engl. 1997, 36, 2637 ± 2640; b) W. C. Pringle,

K. B. Sharpless, unpublished results; c) V. V. Fokin, K. B. Sharpless,

Angew. Chem., in press; Angew. Chem. Int. Ed., in press; d) see also:

W. Pringle, K. B. Sharpless, Tetrahedron Lett. 1999, 40, 5151 ± 5154.

[41] For an appreciation of the virtues of fusion processes from the

viewpoint of ªatom economyº, see: B. M. Trost, Science 1991, 254,

1471 ± 1477.

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

2019

K. B. Sharpless et al.

REVIEWS

[42] a) The fact that stereoelectronic factors disfavor eliminations in small

rings has allowed the stereoselective alkylation of the a-carbon of

carboxylic acids, with oxygen-containing functionality in the b-

position, through heterocyclic enolates with an exocyclic double bond

(D. Seebach, J. D. Aebi, M. Gander-Coquoz, R. Naef, Helv. Chim.

Acta 1987, 70, 1194 ± 1216). For other uses of oxiranyl anions, see: b) T.

Satoh, Chem. Rev. 1996, 96, 3303 ± 3325; c) Y. Mori, Rev. Heteroat.

Chem. 1997, 17, 183 ± 211; d) T. Satoh, S. Kobayashi, S. Nakanishi, K.

Horiguchi, S. Irisa, Tetrahedron 1999, 55, 2515 ± 2528; e) Y. Mori, K.

Yaegashi, H. Furukawa, J. Am. Chem. Soc. 1997, 119, 4557 ± 4558.

[43] Care must be exercised with these reactive electrophiles, since the

ring-opening reactions are exothermic and often autocatalytic when

performed neat with basic amines as the nucleophile. In large-scale

applications without solvent, it is essential to start at a temperature

where the reaction at hand has been shown to be self-sustaining and

the amines then added at a rate to maintain the desired temperature.

If water alone cannot be used as solvent, we often employ boiling n-

propanol or boiling toluene for large-scale applications (depending on

whether or not a protic or aprotic environment is desired (see

refs. [44b] and [45]); in the former case, the addition of water after

cooling often results in precipitation of the product.

[44] Synthesis of cis-1,4-cyclohexadiene epoxides: a) T. W. Craig, G. R.

Harvey, G. A. Berchtold, J. Org. Chem. 1967, 32, 3743 ± 3749; b) G.

Kavadias, S. Velkof, B. Belleau, Can. J. Chem. 1978, 56, 404 ± 409; c) T.

Suami, S. Ogawa, H. Uchino, Y. Funaki, J. Org. Chem. 1975, 40, 456 ±

461; for ring-opening reactions of six-membered ring di- and

triepoxides, see: d) R. Kuehlmeyer, R. Keller, R. Schwesinger, T.

Netscher, H. Fritz, H. Prinzbach, Chem. Ber. 1984, 117, 1765 ± 1800;

e) J. Schubert, R. Keller, R. Schwesinger, H. Prinzbach, Chem. Ber.

1983, 116, 2524 ± 2545; f) C. Rucker, H. Muller-Botticher, W. D.

Braschwitz, H. Prinzbach, U. Reifenstahl, H. Irngartinger, Liebigs

Ann. 1997, 967 ± 989; g) S. Kagabu, C. Kaiser, R. Keller, P. G. Becker,

K. H. Mueller, L. Knothe, G. Rihs, H. Prinzbach, Chem. Ber. 1988, 121,

741 ± 756.

[45] a) H. T. Chang, J. P. Chiang, K. L. Reddy, M. A. Winter, A. K. Yudin,

K. B. Sharpless, unpublished results; b) for previous studies on the

regioselectivity of the ring opening of cis- and trans-1,4-cyclohex-

adiene diepoxides, see: G. Kavadias, R. Droghini, Can. J. Chem. 1979,

57, 1870 ± 1876; F. Haviv, B. Belleau, Can. J. Chem. 1978, 56, 2677 ±

2680; T. Suami, S. Ogawa, H. Uchino, Y. Funaki, J. Org. Chem. 1975,

40, 456 ± 461.

[46] The 1,3-selectivity in the neat reaction (that is, 1 !2) probably stems

from the interplay of two effects: trans-diaxial epoxide opening and

intramolecular epoxide activation by the hydroxy group that is

released in the first step (see Scheme 19). The latter effect is much less

important in the presence of a protic solvent, and thereby allows the

intermediate hydroxy epoxide to react from the other, more stable

chair conformer, which gives rise to the diamine from 1,4-attack (that

is, 1 !3, Scheme 7).

Alonso, A. V. Bedekar, P. G. Andersson, Tetrahedron Lett. 1997, 38,

6897 ± 6900; asymmetric transition metal catalyzed aziridination of

olefins: D. A. Evans, M. M. Faul, M. T. Bilodeau, B. A. Anderson,

D. M. Barnes, J. Am. Chem. Soc. 1993, 115, 5328 ± 5329; R. E.

Rowenthal, S. Masamune, Tetrahedron Lett. 1991, 32, 7373 ± 7376; Z.

Li, K. B. Conser, E. N. Jacobson, J. Am. Chem. Soc. 1993, 115, 5326 ±

5327; H. Nishikori, T. Katsuki, Tetrahedron Lett. 1996, 37, 9245 ± 9248;

aziridination of olefins with PhI NTs: Y. Yamada, T. Yamamoto,

Chem. Lett. 1975, 361.

[49] a) D. Tanner, C. Birgersson, Tetrahedron Lett. 1991, 32, 2533 ± 2536;

b) D. Tanner, A. Almario, T. Högberg, Tetrahedron 1995, 51, 6061 ±

6070; c) Z. Wang, L. S. Jimenez, J. Org. Chem. 1996, 61, 816 ± 818; d) P.

Besse, H. Veschambre, R. Chenevert, M. Dickman, Tetrahedron:

Assymmetry 1994, 5, 1727 ± 1744; e) P. Wipf, P. C. Fritch, J. Org. Chem.

1994, 59, 4875 ± 4886; f) V. C. O. Njar, R. W. Hartmann, C. H.

Robinson, J. Chem. Soc. Perkin Trans. 1 1995, 985 ± 991; g) P. Crotti,

V. Di Bussolo, L. Favero, F. Macchia, M. Pineschi, Tetrahedron:

Asymmetry 1996, 7, 779 ± 786; h) N. A. J. M. Sommerdijk, P. J. J. A.

Buynsters, H. Akdemir, D. G. Geurts, R. J. M. Nolte, B. Zwanenburg,

J. Org. Chem. 1997, 62, 4955 ± 4960.

[50] a) H. Wenker, J. Am. Chem. Soc. 1935, 57, 2328; b) P. A. Leighton, W.

Perkins, M. L. Renquist, J. Am. Chem. Soc. 1947, 69, 1540; c) C. F. H.

Allen, F. W. Spangler, E. R. Webster, Org. Synth. Coll. Vol. 1963, 4,

433 ± 435; d) A. Galindo, L. Orea, D. Gnecco, R. G. Enríquez, R. A.

Toscano, W. F. Reynolds, Tetrahedron: Asymmetry 1997, 8, 2877 ±

2879.

[51] a) I.-C. Chiu, H. Kohn, J. Org. Chem. 1983, 48, 2857 ± 2866; b) D.

van Ende, A. Krief, Angew. Chem. 1974, 86, 311 ± 312; Angew. Chem.

Int. Ed. Engl. 1974, 13, 279 ± 280.

[52] For a study on the influence of Lewis acids on the nucleophilic

opening of N-acyl aziridines versus their rearrangement to oxazolines,

see: D. Ferraris, W. J. Drury III, C. Cox, T. Lectka, J. Org. Chem. 1998,

63, 4568 ± 4569.

[53] a) H. Stamm, J. Prakt. Chem. 1999, 341, 319 ± 331; b) K. Bellos, H.

Stamm, J. Org. Chem. 1995, 60, 5661 ± 5666.

[54] P.-Y. Lin, K. Bellos, H. Stamm, A. Onistschenko, Tetrahedron 1992, 48,

2359 ± 2372.

[55] See, for example: a) D. Tanner, Angew. Chem. 1994, 106, 625 ± 646;

Angew. Chem. Int. Ed. Engl. 1994, 33, 599 ± 619; b) Y. L. Bennani, G.-

D. Zhu, J. C. Freeman, Synlett 1998, 754 ± 756.

[56] H.-T. Chang, Z. Chen, H. C. Kolb, K. B. Sharpless, unpublished

results.

[57] Opening of aziridines with thiols, see:a) G. Meguerian, L. B. Clapp, J.

Am. Chem. Soc. 1951, 73, 2121 ± 2124; b) J. Legters, L. Thijs, B.

Zwanenburg, Recl. Trav. Chim. Pays-Bas 1992, 111, 1 ± 15; c) H. Shao,

Q. Zhu, M. Goodman, J. Org. Chem. 1995, 60, 790 ± 791.

[58] a) Z.-M. Wang, J. E. Pease, K. R. Dress, K. B. Sharpless, unpublished

results; b) WARNING: When the neat synthesis of 7 (Scheme 9) was

performed on a 3-gram scale, it took off with a ªpopº and most of the

white crystalline product ended up on the ceiling of the fume hood.

The autocatalysis mentioned in ref. [43] is especially dramatic in such

neat amine openings of N-sulfonylaziridines, since the newly created

sulfonamide N H bond, being almost 10⁶times more acidic than an

alcohol O H group, is especially good at assisting in the opening

process. Such cases need a solvent if the scale is greater than

approximately 5 mmol.

H

OH

HO

O

OH

NuH

O

Nu

O

Nu

e.g., 2

Nu

1

NuH

[59] For selected examples, see: a) S. E. De Sousa, P. O'Brien, P.

Poumellec, J. Chem. Soc. Perkin Trans. 1 1998, 1483 ± 1492; b) P. A.

Grieco, W. A. Carroll, Tetrahedron Lett. 1992, 33, 4401 ± 4404; c) S. V.

D'Andrea, E. T. Michalson, J. P. Freeman, C. G. Chidester, J. Szmusz-

kovicz, J. Org. Chem. 1991, 56, 3133 ± 3137; d) P. Gmeiner, Hetero-

cycles 1991, 32, 1499 ± 1504; e) R. K. Dieter, N. Deo, B. Lagu, J. W.

Dieter, J. Org. Chem. 1992, 57, 1663 ± 1671; f) S. Zhao, J. P. Freeman,

C. G. Chidester, P. F. von Voigtlander, S. A. Mizsak, J. Szmuszkovicz,

J. Org. Chem. 1993, 58, 4043 ± 4048; g) H. H. Wasserman, C. B. Vu,

Tetrahedron Lett. 1994, 35, 9779 ± 9782; h) S. Zhao, A. Ghosh, S. V.

D'Andrea, J. P. Freeman, P. F. von Voigtlander, D. B. Carter, M. W.

Smith, J. R. Blinn, J. Szmuszkovicz, Heterocycles 1994, 39, 163 ± 170;

i) D.-K. Kim, G. Kim, Y.-W. Kim, J. Chem. Soc. Perkin Trans. 1 1996,

803 ± 808; j) G. Miao, B. E. Rossiter, J. S. Bradshaw, J. Org. Chem.

1995, 60, 8424 ± 8427; k) C. Perrio-Huard, C. Ducandas, M. C. Lasne,

B. Moreau, J. Chem. Soc. Perkin Trans. 1 1996, 2925 ± 2932.

Scheme 19.

[47] For the nucleophilic opening of epoxides derived from tetrahydro-

naphthalene and hexahydroanthracene, see: a) E. Vogel, F. Kuebart,

J. A. Marco, R. Andree, J. Am. Chem. Soc. 1983, 105, 6982 ± 6983;

b) E. Vogel, W. Klug, A. Breuer, Org. Synth. Coll. Vol. 1988, 6, 862 ±

865; c) E. Vogel, M. Biskup, A. Vogel, H. Günther, Angew. Chem.

1966, 78, 755 ± 756; Angew. Chem. Int. Ed. Engl. 1966, 5, 734 ± 735;

d) A. K. Yudin, J. P. Chiang, K. B. Sharpless, unpublished results.

[48] See ref. [33a]; synthesis by transition metal catalyzed aziridination of

olefins, see: H. Kwart, A. A. Kahn, J. Am. Chem. Soc. 1967, 89, 1951 ±

1953; D. Mansury, J.-P. Mahy, D. Annie, B. Gustave, P. Battioni, J.

Chem. Soc. Chem. Commun. 1984, 1161 ± 1163; D. A. Evans, M. M.

Faul, M. T. Bilodeau, J. Org. Chem. 1991, 56, 6744 ± 6746; E. Vedejs, H.

Sano, Tetrahedron Lett. 1992, 33, 3261 ± 3264; M. J. Sodergren, D. A.

2020

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

Click Chemistry

REVIEWS

[60] For selected examples, see: a) T. R. Webb, C. Eigenbrot, J. Org. Chem.

1991, 56, 3009 ± 3016; b) M. Shrimali, R. Kalsi, S. S. Parmar, J. P.

Barthwal, Arzneim. Forsch. 1991, 41, 101 ± 103; c) S. Corsano, G.

Strappaghetti, A. Codagnone, R. Scapicchi, G. Marucci, Eur. J. Med.

Chem. 1992, 27, 545 ± 549; d) M. A. Williams, H. Rapoport, J. Org.

Chem. 1994, 59, 3616 ± 3625; e) T. Morie, S. Kato, H. Harada, I.

Fujiwara, K. Watanabe, J. Matsumoto, J. Chem. Soc. Perkin Trans. 1

1994, 2565 ± 2569; f) S. Corsano, G. Strappaghetti, R. Scapicchi, G.

Marucci, Arch. Pharm. 1996, 329, 468 ± 470; g) E. J. Corey, R. Naef,

F. J. Hannon, J. Am. Chem. Soc. 1986, 108, 7114 ± 7116; h) L. F.

Lindoy, B. W. Skelton, S. V. Smith, A. H. White, Aust. J. Chem. 1993,

46, 363 ± 375.

Padwa), Wiley, New York, 1984, Chap. 5; d) J. Bastide, J. Hamelin, F.

Texier, V. Q. Ven, Bull. Soc. Chim. Fr. 1973, 2555 ± 2579; J. Bastide, J.

Hamelin, F. Texier, V. Q. Ven, Bull. Soc. Chim. Fr. 1973, 2871 ± 2887.

[77] ªAzidophobiaº seems to be largely based on the fact that a number of

metallic azides are shock sensitive. However, certain organic azides,

especially small ones, are also explosive. The following points are

noteworthy. Sodium azide is relatively safe, especially in aqueous

solution, unless acidified to form HN₃, which is volatile and highly

toxic. For organic azides, the ªrule of sixº is very useful: six carbons (or

other atoms of about the same size) per energetic functional group

(azide, diazo, nitro, etc.) provides sufficient dilution to render the

compound relatively safe. Note that the presence of acetylenic groups

or other energy producers with an azide makes for increased hazard.

Decomposition of organic azides can be catalyzed by certain transition

metal species (especially those from the Fe and Co triads) and by

strong acids (that is, the same catalysts that are most effective for

decomposition of organic peroxides). Azide groups attached directly

to olefinic, aromatic, or carbonyl moieties are much less stable and,

other things being equal, more dangerous than aliphatic azides (the

approximate activation energies for unimolecular loss of N₂being 29

and 49 kcalmol ¹, respectively). For these reasons, azides should not

be distilled or treated in a careless fashion. However, when common

sense is employed, they can be prepared, stored, and used without risk

in the standard organic chemistry laboratory: We have never

experienced a safety problem with these materials. See: M. Peer,

Spec. Chem. 1998, 18, 256 ± 263.

[61] P. F. Richardson, L. T. J. Nelson, K. B. Sharpless, Tetrahedron Lett.

1995, 36, 9241 ± 9244.

[62] a) J. A. J. M. Vincent, P. Schipper, A. deGroot, H. M. Buck, Tetrahe-

dron Lett. 1975, 1989 ± 1992; b) W. H. Mueller, Angew. Chem. 1969,

81, 475 ± 484; Angew. Chem. Int. Ed. Engl. 1969, 8, 482 ± 492.

[63] K. Burow, B. Tao, A. Converso, M. G. Finn, K. B. Sharpless,

unpublished results.

[64] T.-H. Chuang, K. B. Sharpless, Org. Lett. 1999, 1, 1435 ± 1437.

[65] T.-H. Chuang, A. Converso, K. Burow, K. L. Reddy, A. Marzinzik,

K. B. Sharpless, unpublished results.

[66] For a review, see: E. Kühle, Synthesis 1971, 563 ± 586.

[67] a) For a review, see: M. Mühlstädt, D. Martinetz, Z. Chem. 1974, 14,

297 ± 304; b) formation of macrocycles by reaction of nonconjugated

dienes with SCl₂: M. Mühlstädt, M. Ecke, K. Hollmann, M. Möder,

DE-B 288 603 A5, 1983; c) addition of SCl₂to cycloheptadienones:

P. H. McCabe, W. Routledge, Tetrahedron Lett. 1976, 85 ± 86; d) re-

action with aryl allyl ethers: M. Mühlstädt, K. Hollmann, R. Widera,

Tetrahedron Lett. 1983, 24, 3203 ± 3204; reaction with acyclic non-

conjugated dienes: F. Lautenschlaeger, J. Org. Chem. 1968, 33, 2620 ±

2627; e) reaction with cyclic polyolefins: F. Lautenschlaeger, J. Org.

Chem. 1968, 33, 2627 ± 2633; F. Lautenschlaeger, Chemistry in Sulfides

Conference (Ed.: A. V. Tobolsky), Interscience, New York, 1968,

pp. 73 ± 81; E. D. Weil, K. J. Smith, R. J. Gruber, J. Org. Chem. 1966,

31, 1669 ± 1679; F. Lautenschlaeger, J. Org. Chem. 1966, 31, 1679; E. J.

Corey, E. Block, J. Org. Chem. 1966, 31, 1663 ± 1668; F. Lauten-

schlaeger, Can. J. Chem. 1966, 44, 2813 ± 2817; f) reaction with vinyl

cyclohexenes: G. A. Tolstikov, B. M. Lerman, N. G. Komissarova,

L. M. Zelenova, Zh. Org. Khim. 1983, 19, 321 ± 332; G. A. Tolstikov,

B. M. Lerman, N. G. Komissarova, Zh. Org. Khim. 1983, 19, 299 ± 310.

[68] A. Converso, A. Marzinzik, A. R. Vaino, K. Burow, K. P. M.

VanHessche, H. C. Kolb, M. G. Finn, K. B. Sharpless, unpublished

results.

[69] A. Converso, K. Burow, A. Marzinzik, K. B. Sharpless, M. G. Finn, J.

Org. Chem., in press.

[70] For a review of the use of the hetero-Diels ± Alder reaction in organic

chemistry, see: L. F. Tietze, G. Kettschau, Top. Curr. Chem. 1997, 189,

1 ± 120.

[71] For a review of the asymmetric hetero-Diels ± Alder reaction, see: H.

Waldmann, Synthesis 1994, 535 ± 551.

[72] a) R. Huisgen in 1,3-Dipolar Cycloaddition Chemistry (Ed.: A.

Padwa), Wiley, New York, 1984, pp. 1 ± 176; b) A. Padwa in Compre-

hensive Organic Synthesis, Vol. 4 (Ed.: B. M. Trost), Pergamon,

Oxford, 1991, pp. 1069 ± 1109.

[78] Recent examples of the use of this process include: a) M. Yamashita,

K. Suzuki, Y. Kato, A. Iida, K. Ikai, P. M. Reddy, T. Oshikawa, J.

Carbohydr. Chem. 1999, 18, 915 ± 935; b) M. Moore, P. Norris,

Tetrahedron Lett. 1998, 39, 7027 ± 7030; c) D. J. Hlasta, J. H. Acker-

man, J. Org. Chem. 1994, 59, 6184 ± 6189; d) F. Palacios, A. M.

Ochoa de Retana, J. Pagalday, Heterocycles 1994, 38, 95± 102; e) W. H.

Pearson, S. C. Bergmeier, J. A. Chytra, Synthesis 1990, 156 ± 159.

[79] a) A. Marzinzik, A. V. Gontcharov, K. B. Sharpless, unpublished

results; b) R. Portmann (Novartis AG), WO-A 9802423, 1998 [Chem.

Abstr. 1998, 128, 140707].

[80] a) T.-H. Chuang, K. B. Sharpless, Helv. Chim. Acta 2000, 83, 1734 ±

1743; b) J. Svete, A. Preseren, B. Stanovnik, L. Golic, S. Golic-

Gradadolnik, J. Heterocycl. Chem. 1997, 34, 1323 ± 1328.

[81] a) P. Deslongchamps, Y. L. Dory, S. Li, Tetrahedron 2000, 56, 3533 ±

3537, and references cited therein; b) orally available drugs must be

stable to the acidic environment of the stomach. For acetal and ketal

examples, see: M. Jung, S. Lee, Bioorg. Med. Chem. Lett. 1998, 8,

1003 ± 1006; for ketoconazole, itraconazole, and derivatives, see: J.

Heeres, L. J. J. Backx, J. H. Mostmans, J. Van Cutsem, J. Med. Chem.

1979, 22, 1003 ± 1005; T. Bergan, Antiinfect. Drugs Chemother. 1995,

13, 149 ± 150; N. Sonino, F. Fallo, M. Boscaro, Med. Sci. Res. 1989, 17,

131 ± 134; J. Bolos, S. Gubert, L. Anglada, A. Sacristan, J. A. Ortiz, J.

Heterocycl. Chem. 1997, 34, 1709 ± 1713; L.-F. Huang, J.-W. Kim, L.

Bauer, G. Doss, J. Heterocycl. Chem. 1997, 34, 469 ± 476.

[82] Z. Demko, D. Michel, B. Chao, K. B. Sharpless, unpublished results.

[83] M. A. Winter, K. B. Sharpless, unpublished results.

[84] E. Stevens, A. V. Gontcharov, K. B. Sharpless, unpublished results.

[85] See ref. [40a] for 10- to 100-gram preparations of these crystalline

aziridines.

[73] For a review of asymmetric 1,3-dipolar cycloaddition reactions, see:

K. V. Gothelf, K. A. Jorgensen, Chem. Rev. 1998, 98, 863 ± 909.

[74] For a review of synthetic applications, see: J. Mulzer, Org. Synth.

Highlights 1991, 77 ± 95.

[75] a) W.-Q. Fan, A. R. Katritzky in Comprehensive Heterocyclic Chem-

istry II, Vol. 4 (Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven),

Pergamon, Oxford, 1996, pp. 101 ± 126; b) R. N. Butler in Compre-

hensive Heterocyclic Chemistry II, Vol. 4 (Eds.: A. R. Katritzky, C. W.

Rees, E. F. V. Scriven), Pergamon, Oxford, 1996, pp. 621 ± 678; c) K.

Banert, Chem. Ber. 1989, 122, 911 ± 918.

[86] T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36,

6373 ± 6374.

[87] It should be noted that the simple 1,2-diamine motif is almost

completely absent from that part of the ꢀ500-dalton drug candidate

ªuniverseº to have been explored so far, due to a woeful under-

utilization of the aziridine group as an intermediate in exploratory

medicinal chemistry. For us, this omission highlights the vast regions of

structural and functional ªspaceºÐthe 10⁶³candidates of Guida and

co-workers in ref. [14]Ðthat remain unexplored for the discovery of

biologically active molecules.

[76] a) R. Huisgen, Pure Appl. Chem. 1989, 61, 613 ± 628; b) R. Huisgen, G.

Szeimies, L. Moebius, Chem. Ber. 1967, 100, 2494 ± 2507; c) W.

Lwowski in 1,3-Dipolar Cycloaddition Chemistry, Vol. 1 (Ed.: A.

[88] a) A. E. Rubin, PhD thesis, The Scripps Research Institute (USA),

1999; b) D. S. Nirschl, PhD thesis, The Scripps Research Institute

(USA), 2000.

Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021

2021

Article Doi

Click Chemistry: Diverse Chemical Function from a Few Good Reactions

DOI: 10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5

Source and publish data:

Authors:

Article abstract of DOI:10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5

Full text of DOI:10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5

Products guided by the article

R&D Labs maybe for 177186-23-1

Relevant to this article

Hot Product