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
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� 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.
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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. �
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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-
© 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.
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.
© 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.
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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.
381© 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.
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.
© 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
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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.
383© 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.
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.
© 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
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.
T h e C h e m i c a l R e c o r d L e c t u r e
385© 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.
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.
T h e C h e m i c a l R e c o r d L e c t u r e
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.).
REFERENCES
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© 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.
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.
© 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
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