organic synthesis in a changing world - durham university · the lecture, “organic synthesis in a...

377© 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.

Organic Synthesis in a Changing World

STEVEN V. LEY, IAN R. BAXENDALEDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW,United Kingdom

Received 2 May 2002; Accepted 23 May 2002

ABSTRACT: This article is based on a lecture presented to the Chemical Society of Japan at WasadaUniversity on March 27, 2002, by Professor Steven V. Ley. The lecture, “Organic Synthesis in aChanging World,” was a comprehensive account of the ongoing research efforts of professor Ley’sgroup in the development and application of solid-supported reagents and scavengers for use inorganic synthesis. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. ChemRec 2: 377–388, 2002: Published online in Wiley InterScience (www.interscience.wiley.com) DOI10.1002/tcr.10033

Key words: organic synthesis, reagents, seavengers

Introduction

The title of this article suggests we are in a rapidly changingworld, which is undoubtedly true. It would also be fair to saythat organic synthesis has played a vital role in changing theworld and will undoubtedly continue to do so into the future.The benefits afforded by synthesis already considerably enrichour lives: from the development of drugs in the ongoing fightagainst disease to the more aesthetic aspects of society withpreparation of perfumes and cosmetics. Furthermore, thequality and quantity of our food supply relies heavily uponsynthesized products, as do almost all aspects of our modernsociety ranging from paints, pigments, and dyestuffs to plastic,polymers, and materials of all kinds. However, the demandsmade on science are changing at an unprecedented pace, andsynthesis, or molecular assembly, must continue to evolve inresponse to the new challenges and opportunities that arise.

Regulatory requirements necessitate cleaner and more effi-cient chemical processes, including better catalysts with lowerenvironmental impact. There is an urgent need for new, strate-gically important reactions that change the way we plan andthink about our synthesis today. We the chemists are underconsiderable pressure to speed up the discovery process by

The Chemical Record, Vol. 2, 377–388 (2002)

T H EC H E M I C A L

R E C O R D

� Correspondence to: S. Ley; e-mail: [email protected]

delivering more and better designed compounds that haveimportant function. Recent interest in combinatorial chem-istry and associated automation, computational, analytical,and IT tools are beginning to have a significant impact on syn-thesis programs. Nevertheless, we still have a long way to go.

One popular approach to making large numbers of com-pounds in a parallel sense has been to assemble molecules onimmobilized supports following the pioneering work firstintroduced by Merrifield,1 Letsinger,2 Patchornik,3 Leznoff,4

Rappaport,5 Camps,6 Koster7, and others. This has been a verysuccessful approach and has led to a vast amount of publishedwork. However, the difficulty encountered in optimising and following reactions on solid-supports, together with many other drawbacks, has caused people to reevaluate thisapproach. There is therefore a need for alternative protocolsthat can rapidly deliver compounds cleanly, in parallel, andpreferably by convergent rather than linear routes. Our viewwas that multistep organic synthesis programmes would be

© 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.

T H E C H E M I C A L R E C O R D

378

better conducted in solution by using an orchestrated suite ofsupported reagents to effect all the chemical transformations(Fig. 1).8 We saw several practical advantages to this approach.However, before commenting on these, it is pertinent to statethat though the use of supported reagents, scavengers, andquenching agents to achieve individual reactions was wellestablished,9 longer multistep syntheses (i.e. in excess of threesteps), had not been achieved—especially not with the idea ofbuilding combinatorial libraries or even complex natural products.

By combining the power of supported reagents with othertechniques such as immobilized scavengers and quenchingagents, or catch and release methods, tremendous opportuni-ties present themselves for general organic synthesis programs.Obviously these methods are well suited to parallel synthesis

because simple work-up is affected by the filtration of spentreagents and products are isolated by evaporation of solvents.These processes are readily automated, but moreover, can befollowed in real-time using LC-MS (and other solution phaseanalytical techniques) and the information fed back to affectthe synthesis and optimisation of the reactions. Much morehowever is possible. For example, if toxic, obnoxious, orvolatile compounds are used, then by immobilisation theybecome benign and much easier to handle. Furthermore, whenby-products co-run with the required materials then conven-tional chromatography is ineffective, scavenging or catch andrelease techniques become particularly valuable. Also, manyreagents are catalytic or at least the spent reagent can be readilyrecovered by filtration and recycled to minimise costs. Scale-up of the process is usually straightforward, and in the future

� Steve Ley is currently the BP (1702) Professor of Organic Chemistry at the University ofCambridge, and Fellow of Trinity College, Cambridge, England. He studied for his PhD atLoughborough University working with Harry Heaney and then carried out postdoctoral workin the United States with Leo Paquette at Ohio State University. In 1974 he returned to theUnited Kingdom to continue postdoctoral studies with Sir Derek Barton at Imperial College.He was appointed to the staff at Imperial College in 1975 and was appointed to Professor in1983 and Head of Department in 1989. In 1990 he was elected to the Royal Society (London)and moved to Cambridge in 1992. Ley’s work involves the discovery and development of newsynthetic methods and their application to biologically active systems. The group has publishedextensively on the use of iron carbonyl complexes, organoselenium chemistry, and biotransfor-mations for the synthesis of natural products. So far over 85 major natural products have beensynthesised by the group. The group is also developing new methods and strategies for oligosac-charide assembly and combinatorial chemistry. Ley’s published work of over 470 papers has beenrecognised by many awards, including the Hickinbottom Research Fellowship, the CordayMorgan Medal and Prize, the Pfizer Academic Award, the Royal Society of Chemistry Synthe-sis Award for 1989, the Tilden Lectureship and Medal, the Pedler Medal and Prize, the Simon-sen Lectureship and Medal and the Aldolf Windaus Medal of the German Chemical Societyand Göttingen University, the Royal Society of Chemistry Natural Products Award, the FlintoffMedal, the Paul Janssen Prize for Creativity in Organic Synthesis, the Rhône-Poulenc Lecture-ship and Medal of the Royal Society of Chemistry, and the Glaxo-Wellcome Award for Out-standing Achievement in Organic Chemistry. Recently he was awarded the Royal Society ofChemistry Haworth Memorial Lectureship, Medal, and Prize and The Royal Society DavyMedal, and the German Chemical Society August-Wilhelm-von Hofmann Medal together withthe Pfizer Award for Innovative Science. He was awarded the CBE in 2002.

Ley sits on many national and international boards, among which is the Chemicals Inno-vation and Growth Team. He is also chairman of the EPSRC International Review of Chem-istry Steering Group. He is presently the chairman of the Novartis Foundation ExecutiveCommittee and immediate president of the Royal Society of Chemistry. �

T h e C h e m i c a l R e c o r d L e c t u r e

379

one can envisage much more use being made of flow reactors.Another aspect that makes these systems attractive in synthe-sis is the potential to pilot new reaction schemes on smallquantities. The ability to investigate sequentially a number ofnew steps in a synthetic pathway by simply removing the con-taminating spent reagents and by-products rather than havingto use the standard protocols of water-quenching, solventextraction, drying, evaporation, and chromatography at eachstage generates substantial time savings. Even more excitingopportunities arise when one considers combining severalreagents in a single pot to effect multiple transformations. Thisis possible of course because of the site isolation of reagents byimmobilization, so that even mutually incompatible reagentsin solution (e.g., oxidants and reductants) do not reacttogether.

Using these concepts one can imagine how they could beharnessed to discover new chemistry, but without doubt theydo minimise long-winded conventional procedures and sim-plify the tasks to create time for more profitable planning,thinking, and innovation in synthesis. What is also important

to recognise is that not only are one-pot linear synthesis routespossible but that one can perform convergent synthesis orbatch splitting to maximise product variation (Fig. 2). All theseare attractive components of modern synthetic design.

In a short article such as this it is not possible to cite allthe relevant literature, nor can all the work that we have donein the area be covered properly. What follows constitutes aselection of topics to give a flavour of what can be achievedusing these systems.

Some years ago we recognised the importance of developing a catalytic oxidant for alcohols because the products of these reactions constitute useful building blocksfor synthesis. Following our previous studies on tetra-N-propyl ammonium perruthenate (TPAP)10 we prepared a polymer-supported version of this reagent (PSP) by ionexchange of an Amberlyst 27 resin with potassium per-ruthenate (Scheme 1).11

This has proven to be a very effective oxidant that is nowcommercially available.12 Oxidation of alcohols with catalyticPSP can be best achieved using toluene as a solvent in the pres-


Reagent

Reagent

Scavenger

Scavenged

Capture

Captured

a) The simplest case - No by-products

Substrate clean productSolution phase

b) The more complex case - Excess coupling component or by-product formed

(excess) Solution phase (excess)

Clean product

+ +

Clean product

Release

Filter and wash to purify

Remove by filtration

Use of Scavenging agents

Use of the catchand release protocol

Spent reagent removed

by filtration

Fig. 1. Solid-supported reagents in synthesis. (a) The simple case—no by-products generated. (b) A more complexcase—the use of excess coupling components or by-product removal.



380

ence of molecular oxygen as the co-oxidant. In favourable casesthe spent reagent can be recovered and reused. The aldehydeproducts can then be directed to many other synthesis pro-grammes by batch splitting (Scheme 2).13

Hypervalent iodine reagents are also similarly useful in awide range of synthetic applications. Accordingly we have pre-pared a number of these systems on an immobilised formatand used these for oxidation.14 What is attractive is that thespent solid supported aryliodide by-product can be readilyrecovered by filtration and recycled by oxidation with peracids(Scheme 3).

Some other solid supported reagents we have developedto solve problems when the products or the by-products areparticularly obnoxious or hazardous are shown in Scheme 4.15

In many of these reactions we have also found the use offocused microwaves to be particularly beneficial in driving thereactions to completion.16 The combined use of toluene and anionic liquid to achieve both a rapid heating cycle and ease of work-up is also advantageous in parallel solid-supported synthesis projects.17 In the two examples above, the odorousproducts of the reaction, thioamides or isocyanides, were used immediately as starting points for other syntheses and

Reagent

Reagent

Reagent

Reagent

Reagent Reagent

Reagent

Reagent

Reagent

Reagent

Linear routes

Convergent routes Split routes

+ ++

+

one

pot

Fig. 2. The opportunities for solid-supported reagents in synthesis.

NMe3+ Cl– NMe3

+ RuO4–

ROH

RO

— KCl

+

Amberlyst A-27

H2OKRuO4

Scheme 1.


X

OH

X

O

X

NH

R

NMe3 CNBH3

R NH2. HCl

NMe3 RuO4

H3C N

H

OH

NMe3 AcOX

NO

CH3

OMeO

X

NO

CH3

MeO

O

NMe3+ RuO4

–

NMe3 F1.TMS-CF3

X

O

CF3

R1

R1 R1

R1

R1R1 +

X = CH, N X = CH

X = N

> 95%> 95% 89%

X = CH 87%

R = CH3, R = BnR = CH3

2.

70 - 99 %

X

R2

R3

R1

P

R3

R2Ph

Ph

X = CH R1 = H, R2 = Ph 80-100%

R1, R2 = Me 70-95%

R1 = H, R2 = Me 77-90%

R1 = H, R2 = H 83-99%

R1 = CN, R2 = H 80%

R1 = H, R2 = I ~69%

+ _

+

+

+

_

_

_

_

+

Scheme 2.

I (OAc)2

R1

OHR1

HO

R

COOH

O

R1

OOH

CHO

R1

O

OO

R

I (OAc)2

I (OAc)2

D

ROH

OH

RO

O

I (OAc)2

AcOOH AcOH

I

R1= H, 2'-MeO, 4'-F, 4'-C.CH2Cl2, MeCN, TFA , >95%

CH2Cl2, MeCN, >95%

CH2Cl2, MeCN, 75-95%

R1= H, 2'-MeO, 4'-F, 4'-Cl.

R= H, NHAc, NHBoc, NHZ, NHFmoc

60oC 2h

yields >95%

R=H, COOMe, SPh, CH2OH, NHAc

4h RT

12h 40oC

RT

Scheme 3.



382

consequently did not require complex isolation and thereforeworker exposure was minimised. The availability of appropriatestarting materials is always an issue in the preparation of chem-ical libraries, and many of these compounds that contain desir-able features are often not commercially available and need tobe synthesised. There is a demand therefore to produce com-pounds with other common functional groups from readilyavailable species. We have therefore developed a number of thesepro-cesses, which can be illustrated by two examples, namely theconversion of aldehydes to nitriles18 and the direct transforma-tion of alcohols to acids19 (Scheme 5). Both examples lead toclean products and are therefore suitable for automation.

The last example in this scheme is interesting in that while theconversion of alcohol to acid is straightforward using conven-tional reagents, the isolation and work-up of the product is oftenlaborious. In the immobilised reagent version all the compoundsare added together at the start of the process and the product acidis isolated by simple filtration through a silica cartridge.

Most of our work however has focused on multistep syn-theses using solid-supported reagents and scavengers.8 The aimof this approach has been to develop enhanced efficient syn-thetic sequences to the more complex species that are found inbiologically active systems—either pharmaceutical drugs, agro-chemicals, or natural products. Implicit in this methodologyis the desire to avoid conventional methods of product isola-tion such as chromatography, distillation, or crystallisation, asthese are often consuming, expensive, and are tasks not easilyperformed in parallel using automated methods.

We have reported many multistep sequences to poten-tially useful targets that use combinations of solid-supportedreagents, scavengers, catch and release, and other phase-switching processes.20 Shown below are three Schemes 6, 7,and 8, which demonstrate the versatility of these conceptsleading to a pyrrole library21 (Scheme 6), a collection of matrixmetalloproteinases (MMP) inhibitors22 (Scheme 7), and thesynthesis of sildenafil (ViagraTM)23 (Scheme 8).

Though these examples illustrate routes to molecules ofinterest to the pharmaceutical industry and point the way inwhich these multistep syntheses can be accomplished in futurediscovery programs, we have also used these procedures toprepare natural products. Needless to say, if natural systemscan be prepared simply and in quantity, then it follows that

N NHP

S OEt

R1 N

O

R3

R2R1 N

S

R3

R2Toluene, ionic liquid 4x15 min mW

R1

mW 1h 140˚C, MeCNNCS R1 N C

N

OPPh

Scheme 4.

R1 OHNMe3 RuO4+ -

R1 O

NNH2

1.

2. mCPBA

3.N

R1-CN

R1 OH

NMe3 ClO2+ -

NMe3 H2PO4+ -

O-

N O

R1 O

OH

a)

b)

Scheme 5.


X

OHR1

X

CHO

R1

XR1

NO2

R2

HONMe3

+RuO4-

R2 NO2

NMe3+OH-

XR1

NO2

R2

NH

R2X

R1

O

O

N

N

N

O

ONC

SO3H

N

R2X

R1

O

O

Ar

ArCH2Br

NH2

N

R2X

R1

Ar

TFA

PPh2

ArCH2OH

N NP

N N

R1= H, NO2, MeO, 4-F, 2-F.

or 3-pyridyl 1. TFAA2. Et3N

3.

X = CH or N

1.

2.

CBr4, CH2Cl2

NEt3

Scheme 6.

NP

N

N

NEt2

PPh2

R1

H3NO

Cl

R1

NH O

OSR2

R1

N

O

OSR2

R3

R3 Br

CH2Cl2

N

R1

N

O

OHSR2

R3

R1

N

O

HNS

R2

R3

R1

N

O

HNS

R2

R3

O

O PhOH

EtOAc/iPrOH

TFACH2Cl2

CBr4, Et3N, H2NOBn

CH2Cl2

NH2

SO3H

+-1. R2SO2Cl, py

2.

92-98%96-99%

44-92%quant.96-98%

Pd/C, H21.

2.

OO O OO O

O OO O

Scheme 7.



384

H2N

NN

Me

Pr

H2N

O

H2N

NN

Me

Pr

EtO

O

NP

N

N

MeN

NH3 / MeOH

NCN

NMe

Pr

EtO

O

NCNH

NMe

Pr

EtO

O

NN

Me

Pr

EtO

O

NHN

Me

Pr

NCO

CHOPrMeNHNH2 EtO

OBr

NH2

NMe3+CN-

NP

N

N

MeN

100%

1. MnO2

2.

90%

MgSO4

100%

1.

2.

95%

EtOH, AcOH cat

92%

100%

OH

SO2Cl

O

OH

EtO

O2SN

NMe

O

OH

HN N Me

iPr2NEt

Et2SO4

1.

2.

EtO

O2SN

NMe

O

N

NN

Me

PrH

OH2N

H2N

NN

Me

Pr

OH2N

NN

N

OH

O

NN

H

NN

N

O

OH

NCO

92%

PyBrOP

1.

2.

3.

EtO

SO2

N

HNN

NMe

Pr

O

N

N

Me

Sildenafil (Viagra TM )

NaOEt (cat), EtOH mW 120 ˚C, 10 min

100%

Scheme 8.



O OH

O

O O

O

O O

O O

O O

H

H

O OH

O

O OH

O

N

N

P

N

N

Br

NN PF6-

PPh2

PPh2

Ir(H)2(THP)2+ –PF6

O O

O

CoN

O

N

O

O2

NEt3(CO32-)0.5

HN

N NH2

NH2Carpanone

MeCN / DMF

98%

+

mw 220 o

3 x 15 min 97%

quant.78%

Toluene

1.

2.

+

Sesamol

Scheme 9.

novel natural product-like analogs can be made to probe cellular mechanisms and signal transduction pathways usingrelated approaches.

The synthesis of the natural product carpanone (Scheme9) is based on an early synthesis by Chapman24 but uses sup-ported reagents, some of which were new and designed for thisparticular synthesis. It also reports the use of microwaves and ionic liquids to enhance the Claisen rearrangement stepand makes use of scavengers to give a final clean, crystallineproduct.25 Likewise the route to epimaritidine (Scheme 10)utilises no less than six solid-supported reagents in an orches-trated sequential fashion. The route is based on a solutionphase conventional multistep process nicely developed byKita26 that required chromatography to give a clean product.The new route requires no chromatography and can delivergrams of product in less than one week.27

Similarly, the route to epibatidine is attractive and uses 10 solid-supported reagents including a scavenger, catch andrelease, and microwaves to enhance one of the synthetic steps(Scheme 11).28

Finally, we describe the synthesis of a newly isolatedalkoloid plicamine29 utilizing no less than 12 immobilisedsystems (Scheme 12).30 This route constitutes the first synthe-sis of this molecule but was achieved rapidly using the newmethods. Both enantiomeric forms have been prepared, andintermediates can be diverted into other unnatural productsynthesis programs. The complexity of plicamine as a targetmolecule nicely confirms the power and effectiveness of thesenew approaches and these new tools for organic synthesis.

As to the future we can expect many exciting develop-ments. We will see many new reagents being developed—reagents that have been designed for immobilisation ratherthan being first developed for traditional solution phase chem-istry. Many more catalytic and fully recyclable systems arerequired along with more effective and or selective scavengingagents. These systems will be developed as plug-in reagent cartridges or stacked/parallel flow reactors. The idea of usingreagent stirrer bars is already a reality. The ability to link theproduct formation with real-time feedback of informationshould lead to rapid and even self-optimising systems. It is also

© 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.386

MeOMeO

OH

MeO

CHO

MeO MeOMeO

NMe3RuO4

CH2Cl2NH

HO

H2N

HO

NEt3(CO32-)0.5

MeOH

MeOMeO

N

HO

O CF3

MeO

MeO

N

O

OCF3

MeO

MeO

N

O

N N

(CF3CO)2O

I(OCOCF3)2

NMe3 BH4

HNiCl2, MeOH

MeO

MeO

N

OH

H

NMe3 BH4

Oxomaritidine

quant.

70%

98%

99%

90%

+

-+

-

+

Epimaritidine88%

-+

Scheme 10.

NCl

COCl

NCl NCl

CHO

NCl

NO2

OH

OHNMe3BH4 NMe3RuO4

NMe3OH

MeNO2

NCl

NO2

NCl

O

NO2NCl

NO2

NClNO2

OH

OMs

NMe2 MeSO2ClTBDMSO

NMe3BH4

MeSO2ClN N

NClNH2

OMs N

H

N Cl

CH2Cl2 / MeOH

NMe3BH4

NiCl2.6H2O

N

NP

N

N

NH2

SO3H

110 oC

3. KOtBu mw

Epibatidine

+ - + +

+

- -

-

95% 96%

87% over 2 steps

1.

2. TFA

90%89%

90%

95%

+ -

1.

2.

4.

5. NH3 / MeOH85%

Scheme 11.


387

exciting to think how to use designed one-pot multi-solid-supported reagent sequences for synthesis and the possibleinvention of new reactions. Given that informatics and auto-mation will play an ever-increasing role in synthesis, the oppor-tunities are limited only by our imagination.

We gratefully acknowledge the financial support from PfizerGlobal Research and Development for a postdoctoralfellowship (to I.R.B.), the BP endowment, and the NovartisResearch Fellowship (to S.V.L.).

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OH

H2N CONHMeH

OH

CONHMeH

N

I(OAc)2

OH

H2N CO2H

OO

O EtOAc

Toluene

N

O

O CF3

O

CONHMe

O

N

O

OO

O

NMe

OCF3

H

H

NEt2NEt3 BH4

N

N

(F3CCO)2O

N

O

OO

MeO

NMe

OCF3

H

H

N

O

OO

MeO

NMe

H

H

O

OH

NEt3 BH4

SO3H

TMSCHN

86% 70%

2

CF2SO3H

NEt3 (CO3)0.5

NMe3 OH

OHBr

NH

CF3CH2OH

1. MeOH / TMSCl

2.

3. H2NMe

1.

2.

3.

99 %

+ -

91 %

78 %

Plicamine

1.+ -

2.

85 %

2.

1.+

3.

Quant

COCF3

O

O

-

+

SHN

O

OO

MeO

NMe

H

H

OH

2.

1.

3.

SO3H

NN

CrO3

Mixed Clay frit

Scheme 12.



388

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