Principles of Asymmetric Synthesis

560 Pages·2012·19.481 MB·English

by  Robert E. Gawley, Jeffrey Aube

Principles of Asymmetric Synthesis
Principles of
Asymmetric Synthesis
Second Edition
Robert E. Gawley
Department ofChemistry and Biochemistry
Universityof Arkansas
Fayetteville, AR
USA
and
Jeffrey Aube´
DepartmentofMedicinal Chemistry
Universityof Kansas
Lawrence, KS
USA
AMSTERDAM(cid:129)BOSTON(cid:129)HEIDELBERG(cid:129)LONDON(cid:129)NEWYORK(cid:129)OXFORD
PARIS(cid:129)SANDIEGO(cid:129)SANFRANCISCO(cid:129)SINGAPORE(cid:129)SYDNEY(cid:129)TOKYO
Elsevier
TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UK
Radarweg29,POBox211,1000AEAmsterdam,TheNetherlands
Firstedition1996
Secondedition2012
Copyrightr2012,ProfessorRobertE.GawleyandProfessorJeffreyAube´.ElsevierLtd.
Allrightsreserved
Nopartofthispublicationmaybereproduced,storedinaretrievalsystemortransmitted
inanyformorbyanymeanselectronic,mechanical,photocopying,recordingorotherwise
withoutthepriorwrittenpermissionofthepublisher
PermissionsmaybesoughtdirectlyfromElsevier’sScience&TechnologyRights
DepartmentinOxford,UK:phone[phone];fax[phone];
email:[e-mail]tyourrequestonlineby
visitingtheElsevierwebsiteathttp://elsevier.com/locate/permissions,andselecting
ObtainingpermissiontouseElseviermaterial
Notice
Noresponsibilityisassumedbythepublisherforanyinjuryand/ordamagetopersonsor
propertyasamatterofproductsliability,negligenceorotherwise,orfromanyuseor
operationofanymethods,products,instructionsorideascontainedinthematerialherein.
Becauseofrapidadvancesinthemedicalsciences,inparticular,independentverificationof
diagnosesanddrugdosagesshouldbemade
BritishLibraryCataloguinginPublicationData
AcataloguerecordforthisbookisavailablefromtheBritishLibrary
LibraryofCongressCataloging-in-PublicationData
AcatalogrecordforthisbookisavailablefromtheLibraryofCongress
ISBN:978-0-08-044860-2
ForinformationonallElsevierpublications
visitourwebsiteatwww.store.elsevier.com
PrintedandboundinUK
121311 1098765432
Dedicated to Lorraine Gawley and Janet Perkins,
in appreciation for their love and patience.
Foreword
Chirality in chemistry and asymmetric synthesis (chemical reac-
tions, in which elements of chirality are generated) have deve-
loped from a specialty pursued by outsiders (“chiromaniacs”) to
an art cultured bysome learnedones,and noware partof essen-
tially every chemist’s daily life. We should, however, not forget
thatinamultistepsynthesisthetransitionfromachiralintermedi-
ates or from racemic mixtures to enantiopure intermediates is
unique.Inalloftheothersteps,itisfunctional-groupselectivity,
regio-anddiastereoselectivitythatareatstake.
The development of asymmetric synthesis has taken place
exponentially in the last three decades, triggered by a number of
circumstances. Many more chemists are intrigued and attracted
bythephenomenonofchiralityandbytheoriginofhomochirality
of the molecules of life. Practitioners of organic synthesis and
synthetic methodology have annexed transition-metal chemistry (with chiral ligands on the
metals) and biological(cid:1)chemical transformations to achieve enantioselective catalysis.
Concomitantly, new chromatographic and spectroscopic methods for determining enantiomer
ratios have facilitated the ease and accuracy of analyses of products of enantioselective reac-
tions. Perhaps the strongest driving force for the development was the necessity of producing
pharmaceuticals,diagnostics,vitamins,andagrochemicalsinenantiopureform(theirbiological
targetsarechiral,afterall!).
As I stated in the foreword of the first edition in 1996, the authors of Principles of
Asymmetric Synthesis have managed to cover the subject in a condensed and masterly way;
theyhavechosenwell-definedtopicsfortheeightchaptersofthebook;theyhaveusedclear-
cutconceptsandconcisechemicallanguageforthepresentations;theyhavediscussedmecha-
nistic considerations with due care; they have included a glossary of stereochemical terms
(thosetouseandthosenottouse!);theyhaveprovidedextensivereferencing.Allofthisisstill
trueforthesecondedition,whichhasgrownfrom372to556pages,withanalmostdoubling
ofreferencesfromca.1300to2400.Thisisnotduetojustaddingmoreofthesamebutmostly
duetoincludingthedramaticnewdevelopmentsthathaveoccurredinthepast15years.
Thiscanbeseenasarealizationoftwodreams,expressedin1990byanorganicchemist[1]:
(i)“Theprimarycenterofattentionforallsyntheticmethodswillcontinuetoshifttowardscata-
lyticandenantioselectivevariants;indeed,itwillnotbelongbeforesuchmodificationswillbe
available with every standard reaction for converting achiral educts into chiral products, ...
leadingtoundreamedofefficiencyandselectivity”and(ii)“Thediscoveryoftrulynewreactions
is likely to be limited to the realm of transition-metal organic chemistry, which will almost
certainlyprovideuswithadditionalmiraclereagentsintheyearstocome.”
ix
x Foreword
As far as the first dream is concerned, there has been a revival of what was called, in
1935, organocatalysis [2], i.e. catalysis of the classical, main-group organic transformations
without involvement of metals or metal ions, using chiral amino compounds, carbenes,
Brønsted acids, counter ions, ureas, or HMPA derivatives as catalysts for essentially all the
well-known workhorse reactions of organic synthesis, such as aldol, Michael, Diels(cid:1)Alder,
1,3-dipolar additions, hydride transfer from Hantzsch ester, Mannich, Strecker, Stetter,
Baylis(cid:1)Hillman reactions, α-alkylation and -functionalization of carbonyl compounds,
Friedel(cid:1)Crafts-typereactions,epoxidations,andaziridinations,tonameonlyafew.
The second dream concerns new types of miraclereactions catalyzed by transition metals
that enable the synthetic chemist to perform often incredibly complex transformations in one
step, which were undreamed of by experts of classical organic reactions; three Nobel prizes
have beenawardedinthis fieldin the pastdecade (2001,2005, and2010).A plethora of chi-
ralligandshasbecomeavailableforenantioselectiveversionsofmostofthesereactions.
Indeed, inclusion of sections covering organocatalysis (in Chapters 3(cid:1)8), and new transi-
tion-metal catalyzed reactions (in Chapters 4(cid:1)8) have mainly contributed to the increase of
the volume of this second edition. But there are also other important additions and changes:
there is a scholarly written highlight box in each chapter; the presentations of the formulae,
with some red color for emphasizing steric interactions, is much better; remarkable additions
are found in Chapter 1 (entropy, iso-inversion principle, kinetic and dynamic resolution, non-
linear effects), in Chapter 2 (enantiomer enrichment during chromatography on achiral col-
umn material), in Chapter 4 (sulfinimines and phosphinoyl imines), in Chapter 5 (reductive
aldol additions, N-, O-, and S-nucleophiles in Michael additions), in Chapter 6 (reshuffled to
emphasize importance of [412]- and [312]-cycloadditions), in Chapter 7 (“desymmetriza-
tions”),andinChapter8(dioxiranes,sulfoxidations,Baeyer(cid:1)VilligerandBeckman(cid:1)Schmidt
typereactions).
The second edition of Principles of Asymmetric Synthesis is up-to-date in all aspects of
this important part of organic synthesis. Of special note, the first two chapters on
“Introduction, General Principles, and Glossary of Stereochemical Terms” and “Practical
Aspects of Asymmetric Synthesis” are unique among all the books I have seen on stereo-
chemistry.Thisbookcanserveasatextbookforclasses,asamonographonenantio-anddia-
stereoselective synthesis, and as a reference work to find seminal publications, even for the
expertinthefield.
DieterSeebach
REFERENCES
[1] Seebach,D.Angew.Chem.1990,102,1363Int.Ed.Engl.1990,29,1320.
[2] Langenbeck, W.DieOrganischenKatalysatorenundihre Beziehungzu denFermenten;SpringerVerlag:
Berlin,1935.
Preface
The field of asymmetric synthesis continues to grow at an exponential rate. To even address
thetopicinasignificantwayisaformidabletask.Intheend,wehavecontinuedtheformatof
thefirsteditionbyselectingseveralreactioncategoriesthatcomprisemanyofthemostuseful
syntheticreactiontypes.Asthetitleimplies,thefocusisontheprinciplesthatgovernrelative
andabsoluteconfigurationsintransitionstateassemblies.Thereareonlyafewprinciples,but
they recur constantly. For example, organization around a metal atom, A1,3 strain, van der
Waalsinteractions,dipolarinteractions,etc.,arefactorsaffectingtransitionstateenergies,and
whichinturndictatestereoselectivityviatransitionstatetheory.Onemightcalltheseanalyses
molecularrecognitionatasaddlepoint.
Thebookhas8chapters,whichthepublisherwillalsobemakingavailableonlineonanindi-
vidualbasistoreadersinterestedinonlypartsofthebook.Thefirstchapterprovidesbackground,
introduces the topic of asymmetric synthesis, outlines principles of transition state theory as
appliedtostereoselectivereactions,andincludestheglossaryofstereochemicalterms.Thesec-
ondchapterbeginswithadiscussionofpracticalaspectsofobtaininganenantiopurecompound,
andthendetailsmethodsforanalysisofmixturesofstereoisomers.Thenfollowfourchapterson
carbon-carbon bond forming reactions, organized by reaction type and presented in order of
roughlyincreasingmechanisticcomplexity:Chapter3discussesenolateandorganolithiumalky-
lations, while Chapter 4 covers nucleophilic additions to CQO and CQN bonds; these two
chapters cover reactions in which one new stereocenter is formed. Chapter 5 covers aldol and
Michael additions thatgenerateatleast two new stereocenters,while Chapter6 coversselected
cycloadditionsandrearrangements.Thelasttwochapterscoverreductionsandoxidations.
Transition state analyses are presented to explain - to the current level of understanding -
the stereoselectivity of most of the reactions covered. Critical examination of these rationales
sometimes exposes the weaknesses of current theories, in that they cannot always explain the
experimental observations. These shortcomings provide a challenge for future mechanistic
investigations.
Much of the work on the first edition of this book was completed during a sabbatical
leave for REG, at the Swiss Federal Institute of Technology (ETH), Zu¨rich, which was
funded in part by a Fogarty Senior International Fellowship from the National Institutes of
Health, in part by a sabbatical leave from the University of Miami, and in part by the ETH.
This financial support is warmly acknowledged, with thanks. Special thanks are also due to
Professor Dieter Seebach for his generous hospitality during that sabbatical year, and to his
colleagues, Professors Arigoni, Diederich, Dunitz, Prelog, and Vasella, who jointly contrib-
utedtomakingtheyearinZu¨richbothenjoyableandmemorable.
Many of our friends and colleagues contributed to this work with helpful discussions, or
byreadingandcommentingonvariousportionsofthisbook.Amongthese,thelateProfessor
Vladimir Prelog deserves special thanks for his exhaustive critique of an early draft of the
glossary. Evidence of his contribution is contained in a highlight box that precedes the
xi
xii Preface
glossary in Chapter 1. We are also grateful to the Kansas Book Club, who generously gave
their time to assist in literature searching for this edition, discussions about content, and who
providednumerousdrawingsandschemes.TheywereThomasCoombs,ErikFenster,Brooks
Maki, Daljit Matharu, Thomas Painter, Digamber Rane, Steven Rogers, and Denise Simpson.
We are forever indebted to them for their efforts and for their unwavering good cheer as this
project progressed. We also received valuable help from Emily Scott and Jenny Wang in
reorganizing the crystal structure in Scheme 6.16. Finally, we thank Christopher Katz of
PequodBookDesignforprovidinguswithinspirationalcoverart.
We are alsoindebted toour wives, who put up withour numerous weekends inthe office
andeveningsspentstaringintoourcomputers.Itistothemthatthisworkisdedicated.
Finally,wehavebeenheartenedbyunsolicitedcommentsfromstudentsandteacherswho
used the first edition of this book in a graduate course at universities around the world, and
whofoundituseful.Wehopefuturereaderswillfeelthesame.Commentsarewelcome.
RobertE.Gawley
Fayetteville,Arkansas
JeffreyAube´
Lawrence,Kansas
December16,2011
Chapter 1
Introduction, General Principles,
and Glossary of Stereochemical
Terms
1.1 WHY WE DO ASYMMETRIC SYNTHESES
L’universestdissyme´trique
LouisPasteur(1874)
In modern terminology, Pasteur would say “The universe is chiral.”1 We are constantly
learning more about the implications of chirality, from weak bosons in nuclear physics to the
origins of life on earth and the double helix of DNA [1(cid:1)5]. Most organic compounds are
chiral. Chemists working with perfumes, cosmetics, nutrients, flavors, pesticides, vitamins,
and pharmaceuticals, to name a few examples [6(cid:1)11], require access to enantiomerically
purecompounds.Singleenantiomerformulationsnowaccountformostofthechiraldrugson
the market. One estimate suggests that approximately half of the worldwide revenues from
chiral products were the result of traditional synthesis from the chiral pool or resolution,
whereaslessthanhalfresultfromchemicalcatalysis[12].
As ourability toproduce enantiomerically purecompounds grows, so does our awareness
ofthedifferencesinpharmacologicalpropertiesthatachiralcompoundmayhavewhencom-
paredwithitsenantiomerorracemate[13(cid:1)19].Weeasilyrecognizethatallbiologicalrecep-
tors are chiral, and as such can distinguish between the two enantiomers of a ligand or a
substrate. Enantiomeric compounds often have different odors or tastes [20(cid:1)22].2 Thus, it is
obvious that two enantiomers should be considered different compounds when screened for
pharmacological activity [10,13,23]. The demand for enantiomerically pure compounds as
drugcandidatesisnotlikelytoletupintheforeseeablefuture.
How might we obtain enantiomerically pure compounds? Historically, the best answer to
thatquestionhasbeentoisolatethemfromnaturalsources.Derivatizationofnaturalproducts
ortheiruseassyntheticstartingmaterialshaslongbeenausefultoolinthehandsofthesyn-
thetic chemist, but it has now been raised toan art form by some practitioners, wherein com-
plexmoleculesaredissectedintochiralfragmentsthatmaybeobtainedfromnaturalproducts
[24(cid:1)34]. Even today, there is no way of obtaining enantiomerically pure compounds without
ultimatelyresortingtoNature,whetherforabuildingblock,anauxiliary,oracatalyst.
1.Readersmayfindtheglossaryattheendofthischapterusefulforthedefinitionsofunfamiliarterms.
2.Forexample,theenantiomersoflimonenesmellandtastelikeorangesorlemons,theenantiomersofphenyl-
alaninetastebitterorsweet,theenantiomersofcarvonetastelikespearmintorcaraway.
PrinciplesofAsymmetricSynthesis.
©2012,ProfessorRobertE.GawleyandProfessorJeffreyAube´.ElsevierLtd.Allrightsreserved. 1
2 PrinciplesofAsymmetricSynthesis
So if the objective is to obtain an enantiomerically pure compound, one has a choice to
make:synthesizethemoleculeinracemicformandresolveit[35],findaplantorabacterium
thatwillmakeitforyou,startwithanaturalproductsuchasacarbohydrate,terpene,oralka-
loid (but beware of racemic or partly racemic natural products), or plan an asymmetric syn-
thesis. Among the factors to consider in weighing the alternatives are the amount of material
required, the cost of the starting materials, length of synthetic plan, etc., factors that have
longbeenimportanttosyntheticdesign[36(cid:1)41].Forthepurposesofbiologicalevaluation,it
may be desirable to include a resolution so that one synthesis will provide both enantiomers.
But for the production of a single enantiomer, a classical resolution will have a maximum
theoretical yield of 50% unless the unwanted enantiomer can be recovered and recycled, or
the process is stereoconvergent via an asymmetric transformation or a dynamic resolution.
In most cases, starting with a natural product will be restricted to the production of only one
enantiomerbyagivenroute,notwithstandingthetalentofsomeinvestigatorstoproduceboth
enantiomers of a target from the same chiral starting material. Such practical aspects are
discussedmorefullyinChapter2.
1.2 WHAT IS AN ASYMMETRIC SYNTHESIS?
The most quoted definition of an asymmetric synthesis is that published by Marckwald in
1904[42]:
“Asymmetrische”Synthesensind solche,welcheaus symmetrisch constituirtenVerbindungen
unterintermedia¨rerBenutzungoptisch-activerStoffe,aberunterVermeidungjedesanalytischen
Vorganges,optisch-activSubstanzenerzeugen.3
Inmodernterminology,thecoreofMarckwald’sdefinitionistheconversionofanachiral
substance into a chiral, nonracemic one by the action of a chiral reagent. Marckwald’s point
of reference, of course, was biochemical processes, so it follows that enzymatic processes
[43(cid:1)45] are included by this definition. Marckwald also asserted that the nature of the reac-
tion was irrelevant, so a self-immolative reaction or sequence4 such as an intermolecular
chiralitytransferinaMeerwein(cid:1)Pondorf(cid:1)Verleyreactionwouldalsobeincluded:
OH O O OH
+ +
R R R R R R R R
1 2 3 4 1 2 3 4
Interestingly, the Marckwald definition is taken from a paper that was rebutting a
criticism [46] of Marckwald’s claim to have achieved an asymmetric synthesis by a group-
selectivedecarboxylationofthebrucinesaltof2-ethyl-2-methylmalonicacid[47,48]:
HO2C CO2H HO2C H
brucine
Me Me
heat
Me achiral Me optically active
Thus, from the very beginning, the definition of what an asymmetric synthesis might
encompass, or even if one was possible, has been a matter of discussion. On the latter point,
3. “Asymmetric” syntheses are those that produce optically active substances from symmetrically constituted
compoundswiththeintermediateuseofopticallyactivematerials,butwiththeavoidanceofanyseparations.
4.Self-immolativeprocessesarethosethatgenerateanewstereocenterattheexpenseofanexistingone,eitherina
singlereactionorinasequencewherebythecontrollingstereocenterisdeliberatelydestroyedinasubsequentstep.