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Synthesis, Structure and Properties of Some Chiral-at-Metal Transition Metal

Organometallics

by

o

Yongfei ¥u

B.Sc.(Hons.),Anhui Nanna! University,Anhui,China. 1984 M.Sc.,AnhuiNanna!University,Anhui,China, 1987

A thesissubmitted to the Schoolof GraduateStudies

inpartialfulfilment of the requirementsforthe degreeof

Doctor of Philosop hy

Departmentof Chemistry MemorialUniversity ofNewfo undland

April 1998

St.John's Newfoundland

Abstnct

Although chirality can ariseinvarious guisesinorganometallic systems. metal centered chiralityhasbecome an ever growing concern due to its potential high efficiencyinasymmetric synthesis. Thisthesisfocuses on the synthesis, structure and properties of some chiral-et-metal transition metal organometallics.

Reactions ofCpCo(X)(Y)(I) (X=(srPh)PNHCH(Me)Ph, Y=I,CFJ;XY=PhCH(Me}- N=CH-C~HlN)withE~NP(OMehtoward diastereoselective synthesis of novelCo- and P-chinJ amidophosphonatc Co(llI) complexes were studied by a combination of IH.lJC,'''F,JlpNMR.proton NOED,CO spectroscopy and single crystal X-ray diffractioninorder to rationalize the Co· - P chiral induction and to establish the solid-state structure, configuration and solid-state/solutionconformations.The results show that chemical outcome varies from one system to another.

Study on reaction of a series of resolved crural eminophosphine Co(DI) complexes (CpC o(I)(P(O)(RXOMe»)(Ph:)NHCH(Me)Ph») with gaseous HCI shows that the reaction affords regicselective P·N bond cleavage products with retention of configuration at Co· and establishes a convenient method to obtain homochiral transition meta! complexes.The regioselectivity was discussed based on EHMO

calculations.IIINMR evidence for the formation of isobutene,resulting from P-C bond activation via j>-eliminationinadiestereoselctive, Arbuzov dealkylationreaction involving dimethylt-butylphosphite,wasfound.

A series of new chiral-at-metaJand non-chiral titanocene derivatives with general fonnula Cp(c,R.,)Ti(X)(Ar) (R=Me, X=C1,~F,.o-FC,H.;R=H, X=CI,Ar=C,F,.

o-FC,H~;R=H, X=Ar=Ci",.o-FC,HJwassynthesized and characterized.The barrier of aI)'1 rotation around Ti-C1po<I and the possibility of coordination ofortho-F to Ti were examinedby variable temperature NMR, MMX and ERMO methods.as well as solid state single crystal X-ray diffraction.

iii

Acknowledgements

I would like to express my appreciation to my supervisor,Professor Chet R.

Jablonski, for his outstanding supervision. encouragement, and financial support throughout the course of thesis studies.His great assistance and patienceinthe preparation of this thesis are also gratefully acknowledged.

I am greatly indebted toDr.John. N.Bridson andMr.David Miller for the X- ray single crystal structural determination, to Ms.Nathalie Brunet andMr.David Miller for numerous NMR spectroscopic measurements, to Dr. Dan Drummond (University of New Brunswick) for FAS mass spectrometry,to Dr.Kelvin E.Gilbert (Serena Software) for providing PCMODEL for Windows 6.0andtoDr.Carlo Mealli (Italy) for providing the CACAO package for EHMO analysis.

I amverygrateful toDrs.John.N. Bridscn and Graham J.Bodwell for their patience in reviewing this thesis. and helpful comments and suggestions in shaping this thesis.

Many thanks arc extended to the CRJ group and other members of the Chemistry Department for providing a pleasant working atmosphere and making the years at MUN enjoyable.

I wish to thank Memorial University of Newfoundland for the award of a

iv

graduate fellowship.

Special thanksare extended to my wife.Fang Liu, forher steadfast encouragementand understanding and for herdedicatedcare of ourSOD.

To My Wife, Fang Liu and Our Parents

Abstract... ..

Acknowledgements Tableof Contents .. Listof Tables List of Figures List of Schemes Listof Abbreviations

Table or Contents

... ....Ii

iv

. vii

...xvii

xix xxiv

Chapter 1. Tr.nsition Metal-MediatedAsymmetric Synthesis... ... . ..1 1.1. Introduction .. . . ... . ... . . ..1

1.1.1.Whyasynunetricsynthesis? 1

1.1.2.Approachesto obtain enantiopurematerials 4 1.1.2.1.Resolutionof racemetes. ._.5

1.1.2.2.Asymmetric synthesis 8

1.2.Transition-metal-mediated (TMM) asymmetricsynthesis II 1.2.1.TMM asymmetricsynthesiswith chiralligand auxiliaries .13 1.2.2.TMM asymmetricsynthesiswith chiral-et-metal auxiliaries22 1.2.2.1.Chiral-et-metalorganometallics.. . ..22

vii

1.2.2.1.1.Absoluteconfiguration. . . . .. . 24 1.2.2.1.2.Cbiroptica1 properti es.. 26 1.2.2.1.3.Stereochemis try ... ..27 1.2.2.2.TMM asymmetricsynthesisoCC·-materiais .. .•30 1.2.2.3.TMM asymmetric synthesisoCP-ehiral material svia

Arbuzoy·li)'e deallcylationreactions. .. . .. .33 1.2.2.3.1.ClassicalArbuzav reaction. ...33 1.2.2.3.2.TMM Arbuzov reaction. ...39 1.2.2.3.3.Synthesis ofP-ehiralmaterialsviaTMM

Arbuzov reaction 42

Chapter2.Synt hesis.St r uctureandConfor mal iona l Anal ysisof NovelCo- and P·Ch ir al.' midophosphona te Co(IlI) Complexes . ... ..•.47

2.1.Introduction... .... • . . . ..47

2.2.Results and discussion .49

2.2.1.Reaction oflawithE~NP(OMeh.. .49

2.2.1. 1.Characterizatio n of the amidophos phonate sJa and pbcspbone tes4a. ... . . ... .... ...50 2.2.1.2.Solid-state structure,chiropticaJproperties,and

\'iii

absoluteconfiguration.. . 2.2.1.3.Conformationalanalysis 2.2.1.4.Co·...p Chira! induction

....61 ._.71 .76 2.2.2.Reaction ofIbwithEtzN}'(OMehandcharacterizationofthe

products .. 78

2.2.2.1.Relativeconfiguration of3b _80 2.2.3.Reaction of lcwithE~NP(OMehand characterizationof the

products ._81

2.2.3.1.Mechanismofreaction of lcwithE~NP(OMeb .84

2.3.Summary.. . 8S

2.4.Experimental _. . 87

2.4.1.Reagents and methods 87

2.4.2.Crystal structure determination 89

2.4.3.Preparation of dimethyl diethylamidophosphiteE~NP(OMe)2

....91

2.4.4.Reaction of(S)-('1'..c p)CoI2(pNH) (pNH⁼(S}{-)- PPh1NH CH(Me)Ph»(la) with Et2NP(OMeb.Preparation of (R,S~;R.S.;Sol-(~'-Cp)Col(pPh,NHCH(Mc)Ph)­

(P(O)(NEt,)(OMc»(3.)end(R,S~;ScJ-(~'-

Ox

Cp)Col(pPh,NHCH(Mc)Ph)(P(O)(OMc ),) (' a) ..91 2.4.5.NMR reaction of Ie withE~NP(OMeh ..92 2.4.6.Variable temperature NMR of3.-2 ..93 2.4.7.Reactionof(R,Sc..:SJ-(tt '·Cp)Co{CF,)(PNH){I.)(l b,PNH⁼

(S)-{-)-PPh,NHCH (Mc) Ph) withE~NP(OMc),.. .. 93 2.4.8.Reaction of(R,Seo:SJ-{Tl'· Cp)Co(N-N -)(l)(I c,N·N· ""(Sc)-

Phl(Me)C·H-N=CH-C~H,N·.C4H,N "::::pyrrelyf)with

E~NP(OMc), ..94

Cha pter 3. Inorganometallic. Phosphorus Chemistry: Regieselective Phosphorus·N itrogenBond Cleavageof Some Co(III) Complexesand Evidenc.e(or Phosphorus-Carbon Bond Ac.tivation .

3.1.Introd uction .. 3.2 .Results and Discussion

...95 ..95

" 97 3.2 .1.Regiospecific P-Nbond cleavageof chiral aminophosphine

c:obalt(Ill )complexesviareac tionwithHelgas . ..97 3.2 .1.1.Reaction of CpCo(1)(pPh_1NHCH(Mc:)Ph}-

(P(O)(O Mc)(R))(R=OMc,Sc':;c',la,l,~':;c"Ia-2; R=Ph.Sc.,R,sc·.Ib-I.~,sc-,1b-2;S..,s,s.-.1b-3.

RcJl,s~.I b-4)withHC1(g)... ... ..99 3.2.1.2.Stereoc hemistryduring the transfonnation of 1to 3.

Crystal structure of3.·l. . 104

3.2.1.3.Why regiosetective P-N bondcleavage? 114 3.2.2.Reactionof(S)-('ls-Cp)CoI~(pPhlNHC·H{Me)Ph)(4)with t-

BuP(OMe),... . ..116

3.2.2.1.Formation of7-land 7-2and evidence for P·Cbond

activationof S ..119

...124 ... .124 . ...123 ... ... .. 123 3.3.Summary•..

3.4. Experimental.. 3.4.1.General

3.4.2.X-rayCrystallography...

3.4.3.Preparation ofS~-(~'-Cp)Col(PPh,OH)(P(O)(OMe),).(30-1) ...126 3.4.4.Preparation ofRc..-(TJ'-Cp)CoI(p Ph10 H)(P (O)(O Me)J,(3.-2)

... . . .127 3.4.5.PreparationofSo.R,-(~'-Cp)Col(pPh,OH)(p(O)(phXOMe»

~D

.. m

3.4.6.Preparation ofRc.S,-(~'-Cp)Col(pPh,OH)(P(O)(phXOMe»

(Jb-2) .. 127 3.4.7.PreparationofS.,.s,-(~'-Cp)CoI(pPh,oH)(P(O)(pbXOMc))

(J b-J) . 128

3.4.8.Preparation of Rc..R,..(TJ'·Cp}CoI(pPhzOH)(p(O)(ph)(OMc»

(Jb-4) . ... .128

3.4.9.Reactionof(Tl'-Cp)ColPNH)(4)witht-BuP(OMeb Preparationof(TJ'·Cp)Col(PNH)(P(OXt-BuXOMe »(ScfirSc.

6-1;R.,.s,s~6-2) and(~'-Cp)Co[(pNH)(p(OXOMc ),) (S.,.s~7-1;R.,.s~7-2) ....128 3.4.10.NMR reactionof(''l'·Cp)Co I2(PNH) (4)with,. BuP( OMch

.129

Cbepter4.Synthesis.Str uctu reand Rea ctivity of('l5-Cydopentadienyl)(11'·

Pentamethykydopentadie nyl)Pentan uo rophenylChiaroTitanium Complexes..

4.1.Introduction. 4.2.Resultsand discussion

....130 ....130 .._.133 4.2.1.Synthesisand characterizationof(R.StJ-CpCp· TiCICC, F,), S

.. . .133

4.2.2.X-raystructure ofS .136 4.2.3.Molecular mechanics(MMX)andEHMO Analysis. 147 4.2.3.1.MolecularMecbanics(MMX)calculations 148 4.2.3.2.Molecular Orbital Calculations.. ...153 4.2.4 .Attempted resolutionofS.. . ..165 4.2.4.1Chemical resolution. ...165

4.2.4.2.NMR.resolution.. . __ 166

4.2.5.Arbuzovreactivity .166

4.2.5.1.ReactionofSwithP(OMe1 ...168 4.2.5.2.Reaction ofCPlTiCI(C,F,)withP(OMe)J. .168 4.2.5.3.ReactionsofCPlTiCllwithP(OMe) ] 168 4.2.5.4.ReactionsofCPlTiBrlwithP(OMe)J _ 169

4.3.Summary. . . 170

4.4.Experimental 171

4.4.1.General procedure. . 171

4.4.2.X.raycrystallography _..172

4.4.3.MolecularMechanicsModeUing 173

4.4.4.Molecularorbital calculations. ..174 4.4.5.PreparationofCpCp·TiCl(C,F,)(Cp·=C,Me,)(S) ...175

xiii

4.4.6.Reaction of 5withthesodi um salt of(-}-Menthol 176 4.4.7.Reactionof 5 with(srPPh~C·H(Me)Ph.

4.4.8.AttemptedNMRresolution 0£5... 4.4.9.Reactionof 5 with P(OMeh

4.4.10.Reaction ofCP2TiCI(C,F,)withP(OMeh.. 4.4.11.Reaction of CPzTiCI~withp(OMe1. 4.4.12.Reaction ofCP2TiBrl with P(OMe») .

..116 .177 ...117

. 177

. 177

. 178

196 .5.2.4 .I~NMR observations on(C,H')lTi CI(C,F,)(3) 5.2.5.NMRobservationson (C,H,hTiC1(o-fC,H.) (4) Chapter5.RotationalBarrie randConformatio na lPrerer~n«:of . Fluo ri ne

Substit ute dArylGrou pinTItanoceneDerivatives:Experimenta land TheoreticalAppro aches .. ... . . . ... ..179

.5.1.Introduction. _ _ 179

.5.2.Resultsand discussion.. . 181

.5.2.1.Synthesis of complexes . . 181

.5.2.2.NMR observations on (C,H,)(C,Me,)TiCI(o-Fc;H.)(2)..182 .5.2.3.Solid state confonnation of (C,H ,)(C,Me,)TiCI(o-FC,H..)(1)

.... 182 ..190

5.2.6.ltpNMR observationson(C,H'hTi(C, F,)z(5) .196 5.2.7.Solidstateconfonnation of(C,H'hTi (C,F, :h(5) 200 5.2.8.NMR observations on(C, H,hTi(o-FC,H,:h(6) 208

5.2.9.Molecular mechanics (MMX) study 208

5.2.10.Extended Hackel molecular orbital (ERMO)calculations .212

5.3.Summary .. 231

5.4.Experiments. . 23 1

5.4.1.General Procedur e 231

5.4.2.X-rayCrystallogra phy. 232

5.4.3.MolecularMechanics Modelling. .234 5.4.4.Molecular orbitalcalc ulatio ns . .234 5.4.5.Preparatio nofCpCp·Ti. CI(o-FC, H.)(Cp·=C,Me,)(2) _.235

Refe ren ces ..

Appendix:1.Sourcecode ofCHANGEprogram

. ..236 ...259 Appendix:2.CACAO input filefor rota tionalstudy ofCpCp · TiCI(C,F,) 282 Appendix:3.CACAO inputfile forFMO study of CpCp·TiCl(C, F,) 283 Appendb: 4. 300.1MHzIHNMR ofRc..StSc-CpCo(I)(E t,NP(OXOMe»-

(pPbJiliCH(Me)Ph) (3a-1inChapter 2)inCDCl}at room temperature .... ...• .. ...•... .•.. . . ... 284 AppendiJ: 5.75.5 MHzllCNMRof.Rc...SPScCpCo(I)(E~NP(OXOMe»­

(PPh1NHCH(Me)Ph) (3a-2inChapter 2)inCDCl} at room temperature

... . . . ... . . 285

Appendix 6. 121.5MHz"PNMR of Rc..S.ScCpCo(I)(Ei:zNP(O)(OMe»- (pP~NHCH(Me)Ph)(3a-2inChapter2)inCDCl}at room temperature

... ... ... ... ... . 286

Appendix 7.300.1MHzIH NMR ofRc...cpCo(I}(P(O)(OMe)J(PP~OH}(3.·1in Chapter 3)inCDCI] at room temperature ._ .. 287 Appendix 8. 300.1MHz'H NMR of(Rc.S,}-CpCo(I)(PhP(OXOMe»)(pPh,OH)

(3 b-2inChapter 3)inCDC1}at room temperature 288 Appendix 9.300.1MHz lHNMR of(R.Sr,}-CpCp·TiCl(C~F,)(5inChapter 4)in

CDCl}at room temperature: . ... . ... .289 Appendix 10.282.4 MHzI"FNMR of(R.Sr-,)-CpCp·TiCI(C~F])(5inChapter 4)

inCDCl)at room temperature 290

Appendix 11. 300.1MHzIH NlvtRofCpCp·TiCI(o.Fc.H~)(2inChapter 5)in CDCI]at room temperature .. . . ... .... . ... . .291

xvi

List ofT.bles

Table 1-1. Potential benefits of therapeutic use ala single enantiomer ... 3

Table 2-1.Physical and IRdata... 52

Table 2-2.IH,lip and 1'F NMR data S3

Table 2-3.IlC NMRdata. S6

Table 24. Summary ofcrystaIlographic data for 38·2. ..6S Table 2-5.Atomic coordinates (xlet) and isotropic temperature factors (pm' xlO-')

for 38-2 ... ..66

Table 2-6.Selected bond distance (.4.)and bond angles (deg) for 38-2 67

Table 3-1. Physical and IR deta. . 100

Table 3-2 . IH andlipNMR data Table3-3.llC NMR data..

Table3-4.Summary of crystallographic data for 3a-l..

..101 ..102 ..106 Table 3-5.Atomiccoordinates("lO~)and isotropicthennal parameters (pm' KI(rI)

forJa-l . .

Table 3-6.Selected bond distances (A) {or Ja-l Table 3-7.Selected bond angles for 3a-l...

Ta ble 4-1. Summary of crystallographic data for S Ta ble 4-2.Positional parametersforS. and!b

xvii

" 107 ... ...108 108 ..140 ...141

Table4-3.Selected bond distances for Sa and Sb._ _.143 Table 44.Selected bond angles for Sa and Sb ... ..145 Tabie4-5.Comparison of selected crystallographic and MMX data for S_...149 Table4--6.Mulliken overlap populations for selected bonds as a function ofTi-

C rotation .

Table5-1. Summary ofcrystaJlographicdata for 2

. .. .IS6 ._185 Table5-2.Atomic coordinates(x1O~)and isotropic thermal parameters (pm1x10-¹)

~2 1~

Table 5-3.Bond distances (A) for 2. . 186

Table 54.Bond angles for 2. . 187

Table5-5.Summery of crystallographicdata for S.. .202 Table5-6.Atomic coordin ates (x1O~)and isotropicthennal parameters(pm:x10-¹⁾

for 5

Table5-7.Bond distances(A)for5 .. Table5-8.bond angles for5.. ..

.. .203 ..204 ..20S Table5-9.Some structural parameters from MMX calculations and X-rayanalysis

...211

xviii

List of Figures

Figure2- 1.Time dependencefor reaction ofCpCoI1(PNH)(Ia)with Et:NP(OMehinCDC),indry condition at 25o~

Figure 2-2.ORTEP representation for(1')'-

Cp)CoI(p Ph,NHCH(Me) Ph)(P(O)(NEt,)(OMe» , 3. - 2 Figure 2-3.Conformational representations of 3a-2

.. . 62

...64 .. .. ..70 Figure 2-4.Circular dichroism spec traof(A) 3.-1 (_ ) ,3.-2(- --};(B) 3.-3

(...),3.-4( -"-).

Figure2-5.Proton NOED spectraof3.-1 .

..12 74 Figure 2-6.ProtonNOEDspectraof 3. -2.

Figure2-7.CD spectrum of3b-2.

..•..•.75

.81 Figure 2-8.CDspectrum of3e-l&3e-2(ca.60:40). . 84 Figure 2·9.Time dependentIHNMR for reaction of IcwithEt:NP(OMe}l 85 Figure3- 1.Moleculargeometry and absolute configur ationofSCo-3. -1 105 Figure3-2.Circular dichroism(CD) spectra of3a- l(- ) and la-I (...) (left);3.-1

(- ) and 3.-2( -)(right) Figure3-3.Newman projectionof3.-1.

..110

. III

Figure3-4.IHNOED spectraof 3a-1 . . .. .112

Figure3-5.CD spectra of3b-l(- ) , 3b-2(---),3b-3 ( ) and3b-4(- ._.. ) xix

..113 Figure 3-6.'H NMR ofreaction mixture of 4 and t-BuP(OMehinCD2CI2(top)

and authentic sample ofisobutene(bottom, solvent:CD2CIJ.. _...122 Figure441. Solid state structure ofCpCp·TiCI(CtFs) ,(Sa) •.

Figure 4-2.Solid state structure ofCpCp·TiCI(CtF,), (Sb)_..

....138 .139 Figure443.Projection(from thecrystal structure,Sa)on Cl-Ti-C.,....showing the

staggered conformationofCp and Cp· rings _146

Figure 4-4.Projection(fro m thecrystal structure,Sb)on Cl4Ti4C_showing nearly eclipsed conformation ofep and Cp' rings 147 Figure 4-5.(A)Lowest energyconformer from PCMODEL (MMX);(8)view of

the conformer down the Ti-Cy- bond;(C)stick drawing of (D). .IS1 Figure 4-6.Lowest energy(MMX)confonnerof S with dihedral drivenatoms

labelled (top);conformatio nal energy profile for perfluorophenylrotationin

S (bottom) .152

Figure4-7.EHMO scheme showing theinteraction between CpCp'TiCI andC6F,

W~S •. ._... .157

Figure4-8.Energy profile with respect to the C,F,group rotation around Ti-C_ forS...

Figure4-9.LUMO(MO 61.62) and HOMO (MO 63,64)for S, top(top );

....158

side(bottom)view 159 Figure 4-10.Compositio nofLUMO (MO 61)intmnsof FMO. top(top );side

(bottom) view.. . • . • . ... . .. . .•.• ... ... .. ..•160 Figure 4-11.Compositionof LUMO(MO 62)intermsofFMO,top(top); side

(bottom) view .. . . ... .... . . .• • .. .••. • .. . ... . . ...161 Figure4-12.Compositionof HOMO (MO63)intermsofFMO,top(top);side

(bottom) view ... •...•.. ... . . ... ... ...•... .... .. .. ... .162 Figure4-13.Composition of HOMO (MO64)intermsofFMO. top(top);side

(bottom) view... . . 163

Figure 4-14.Low-lyingLUMOsinthe fragmentCpCp· TiCI, view down z axis (top);view downY axis(bottom)... .. . . ... .•... ...164 Figure5-1. Structure(A)and proposedLUMO (B)Of Cp2TiX2 182

Figure5-2.Twotypes ofTl¹. acylorientations 183

Figure 5-3.ORTEP represen tationofthe molecularstructureofCpCp·TiCI(o--

FC,H.)(2) 184

Figure 5-4.Ball-Stickdrawing(fromX-raycrystaldata)of Cp and Cp· prcjeetice on CI-Ti-C_ plane.... ... . ... . .. . . . ...• .• . .189 Figure 5-5.Variable temperaturelt fNMRofCplTiCl(~F,)(3)in d'.toluene 193 Figure5-6.Calculated VTItFNMR OfCP1TiC1(C.F , h (3).. . ... 194

xxi

Figure5~7.Eyringplotsfor3(.6.)and5(.). . 195 Figure 5-8.Variable temperatureI'FNMR ofCPlTi(C,F,)z(5)ind'-toluene . 198 Figure 5-9.Calculatedvr"F NMR spectta ofCp1Ti(C.F ,)z(5) 199 Figure 5-10.ORTEPdrawing of X-ray crystal structure ofCPlTi(C,F,)z(5)..201 Figure5-11.Ball-stick drawing(from Xeay crystaldata)of two Cp rings

projected onC_-Ti-C_'plane. _..207

Figure 5·12 .Lowest energy conformer found by PCMODEL (MMX force field) forla

Figure 5-13.Partialinteraction diagram for l ("out"isomer).

209 ...214 Figure 5-14. Energy profile of rigid rotationofo-FC.H~around Ti-C"....bond for l

.. . ..215 Figure 5-15.LUMOs (FMO 47 and 48) ofCpCp·TiCl\Top view (top).side view

(bottom) _. ..216

Figure 5-16.HOMOs (FMO 108 and 109) ofo-FC,H;.Top view (top). side view

(bottom) 217

Figure5-17.Partial interaction diagram for 3 223

Figure5-18.Energy profile of rigid rotation ofC,F,around Ti-C_ bond for 3 224 Figure5-19.Partialinteraction diagram for 4. with F "in". ..225

xxii

Figure 5·20. Energy profile of rigid rotation ofo.FC6~around Ti-C bond for 4,

~F~ l l i

Figure 5-21.Partial interaction diagram for 5. ..227 Figure 5-22.Energyprofile of rigid rotation of C,F,around Ti-C...bond for 5,

geared. . . . ... . .

Figure 5-23.Partial interaction diagram for 6, with both F "ouf'

_..228

...229 Figure 5-24.Energy profile of rigid rotation ofo-FC, H, around

n·c_

bond for 6,

geared with both F"our" .. . ..230

xxiii

ListofSchemes

Scheme 1-1. Contrasting biological behavior exhibited by enantiomeric pairs... 2

Scheme 1·2. Example of deraccmization process ..6

Scheme 1·3.Example of kinetic resolution 8

Scheme 1-4.Approaches to optically pure isomers 10

Scheme 1-5.Glycidol ..11

Scheme 1-6.Two types of chiral auxiliaries ._.. 13

Scheme 1·7.Two-layer dendrizyme .. 13

Scheme 1-8.Frequently used chiral diphosphine Ligands 16 Scheme 1·9.Selected hydrogenation with Rh-P" system. . 17 Scheme 1-10. Industrial process with Rh-P'" system. . 18

Scheme 1-11. Olefin requirement.. . 18

Scheme 1-12.Successful substrates with Rh-P'" system 19 Scheme 1-13.BINAP-Ru dicarboxylate catalyst .._.19 Scheme 1·14.Applications ofRu-BtNAP catalytic hydrogenation .21

Scheme 1·15.Hydrogenation of simple olefins 22

Scheme 1-16. The 1" resolved octahedral (A) and tetrahedral(8)chiral-et-metal

compoonds. ...23

Scheme1-17.Resolution of the I· chiral-at-metal organometallics 24

><Xiv

Scheme 1- 18. Application of modified CIP rule .. . 25 Scheme 1-19.CD spectra of two ehiral-et-metal,M-epimeric diastereomers...26 Scheme 1-20.Retention of configuration at metal. 28 Scheme 1·21. Inversion of configuration at metal '" 28 Scheme1~22_Example of racemization reaction. .. 29 Scheme1~23_Alkylation reaction mediated by a chiraJiron auxiliary ..32 Scheme 1-24.Synthesisof(-)-actinonin via chiral iron auxiliary 32 Scheme1-25.Classica.l Arbuzovreaction .. . .... . . . .33 Scheme1-26.Widely accepted Arbuzov reaction mechanism 35 Scheme 1-21.Lossofconfiguration at P via rapidBerty pseudorotation 36 Scheme 1-28.Retentionof chirality at P with Arbuzovreaction . . 36 Scheme 1-29.Arbuzov reactionvsPerkowreaction .38 Scheme 1-3 0.Synthetic applicati ons of traditionalArbuzov reaction s. _39

Scheme 1-31. Cp-like, tripod KJiui ligand.. . 40

Scheme 1-32.Transitionmetal mediatedArbuzov reaction ... . . ... .40 Scheme 1·33.lome mechanism for a TMM Arbuzovreaction 41

Scheme 1-34.Attempted substitution atp. . 43

Scheme 1-35.Diastereoselective synthesisofP~hiralstereoisome rs 43 Scheme 2-1. Nucleophilic substitutionoforganophos phinates 41

Scheme 2-2.Successful nucleophilic displacement at P of metallophospbonate 48

Scheme 2-3.Numbering scheme 49

Scheme 2-4.Reaction of 1a with El2NP(OMeh. . SO

Scheme 2-5.Proposed mechanism for the formation of 4 S9 Scheme 2-6.Suggested mechanism for chiral induction Ccv- P . . 77 Scheme 2·7.TWDreaction channels for Ib with EtzNP(OMe}z. .._79

Scheme 2-8.Reaction te with EtzNP(OMe:h. . 83

Scheme 2-9.Numbering scheme of3c_ 83

Scheme3-1. Evidence showing phosphoryl oxygen is basic .. .97 Scheme3· 2.Aminophosphine P-N bond c:leavage.. . . 98 Scheme 3-3.Calculated net charges on heteroatomsinla-IandI~I 114 Scheme3-4.Proposedenergy profile for the reaction of

CpCo(\ )(P(O)(R)(OMe) (ph, PNHC' H(Me)Ph)with2 equiv. ofHCI(g) 116 Scheme 3-5.Proposed Co"-P c:biralinduction model. . 117

Scheme 3·6.Reaction of 4with,-BuP(OMeh 118

Scheme 3·7.Proposed P-C bond activation... ...121 Scheme 4-1. Examples of two typesofc:hiral titanium complexes. . 132

Scheme 4-2.Synthesis ofCpCp·TiCI(C,F,)(S) 134

Scheme4-3.Proposed procedure for resolutionof(R,5;-')-S 165

Scheme4-4.Classical Arbuzov reaction _....166 Scheme 4-S.Attemptedtitanium mediated Arbuzov reaction.. ..167 SchemeS-l.Selected fluorine substituted phenyl titenocene derivatives ..._.181

SchemeS-2.Synthetic route for complex:: ...181

Scheme5-3.Flow chart for obtaining activation parameters.. ..192

xxvii

BICIlEP BDPP BINAP Bn BPPFA

BPPM

CAMPHOS CD CffiRAPHOS CIP Cp Cpo CSA CT CYCPHOS de

Listof AbbrevatioDs

2,2'-bis(dicyclohexylphosphino)-6,6'-dimethyl-t ,I'-biphenyl 2,4-bis(diphenylphosphino)pentane

2,2'-bis(diphcnylpbosphino)-l.l'-binapbthyl benzyl

N,N-dimcthyl-l-[ I'.2-bis(diphcnylphosphin o) fcIJocenyl]- ethylamine

N·t-butoxycarbonyl-4-diphcnylphosphino-diphcnylphosphino- methyl-pyrrolidinc

1,2,2-bimcthyl-l ,3-bis(diphcnylphosphino )cyclopcntane circulardichroism

2,3-bis(diphenylphosphino)butane Cahn-lngold-Prelog l1'-cyclopentadienyl ,,'-pentamethylcyciopentadienyl (+)-camphor- l()..sulphonic acid

centroidof cyciopentadienyVpentamethyl cyclopentadicnyl l,2-bis(diphcnylphosphinoj-f-cyclohexylethene diastereomericexcess

xxviii

deg

DIOP DIPAMP opep Eu(D PM), EAC

EHMO HOMO FAB FMO

Ind IR isodiCp L-Dopa LUMO MAC

MelEt-DuPHOS MO

deg:rees( O)

4.S-bis(diphenylpbosphinomethyl}-2,2-dimethyl-l .3-dioxolane 1.2·bis[a.methoxyphenyl)phenylphospbino]ethane l,2-bis(diphenylphosphino)cyclopentanc tris(dipivalomethanato)europium(Ill) cthyl-2-acctamidocinnamatc enantiomericexcess extendedHackelmolecularorbital highestoccupiedmolecularorbital fastatombombardment

fragmentmolecular orbital indcnyl

infrared isodicyclopentadienyl (S}3,4--dihydroxyphcnylaJanine lowest unoccupied molecularorbital methyl (Z)-c- (acctamido)cinnamatc l,2-bis[{I,5-dimethyllcthyl}-phospholano[benzene molecularorbital

xxix

mp NMR N-N' NOBA

NQED NORPHOS PNH ProNOP

PYRPHOS TIIF TLC VT

melting point nuclear magnetic resonance

(oSrPhC' H(M e)-N=CH.c.HlN·(C.H3N·=pyrrolyl) 3.nitrobenzylalcohol

nuclear Overbauser effect difference 2,3-bis(diphenylphosphino)bicyclo[2.2 .1]hept-S-ene (S)-diphenyl-« I-phenylethyl)amino)phosphin e N-di phcny lphosphino- l -di pheny lphosphinoo xym ethy l- pyrrolidine

3.4-bis (diphenylphosphino)-pyrrolidine tetrahydrofuran

thinlayerchromatography variabletemperance

Ch apter 1

Transition Metal-Medi ated Asym met ric Synthesis

1.1.Introd uction

1.1.1.Whyasym metricsynth~is?Ingeneral. a cbinlcompound which contains one srereogen iccenter exists as a pair ofenantiomer s,whereanenantiomer isdefined as

"one of apair of molecularspeciesthat are mirrorimagesof each other and not superirnposable,"!However,although thedifferenceinphysicalproperti es between two enantiomersissmall,¹their chemical propertiesincludingbiologicalactivitymay vary dramatically."The thalidomide tragedy"offers a notewo rthy example.Inthe early I%0'$ thedrugthalidomidewasusedtherapeutically as a sedativeand bypnotic.

However,it was marketedinits racemicConn and caused ahigh incidenceof fetal deaths,neonatal deaths,andcongenital malfonnationswhentakenbypregnant women.'Subsequently,it was foundthat the teratogenic itywasattributed(0the(S)-

<+enantiomer.'This differentbiologicactivityarisesfrom theinheren t chirality of theenzym esinbiological systemswhic h can differentiate two enantiomersof a specificmolecule.Someexamplesincluding(R••S} thal idomide whichdemonstrate stereospecificity throughprecise molecularrecognition are given in Scheme1_1.'·10 Potentialbenefitsofthera peuticuse of a sing leenentiomer,based on properties of

~o 0 ;rP

.o;

oM ~ ~

(R)·Thalidomide (S}-Thalidomide

Sedative: Teratogc:n

a

H....NJlN...CHJ

Hlc...N~N

^....H

~o aX?

(R) (5)

NarCOl:ic Antieoovulsant

a a

HO~NH'

^{H ' N doH}

H , H, H

(R)-Asparaginc: (S)-Asparaginc:

s....^"CCt Bitter

~ ~

H<Y '00

H H

(+)-Meu boliteofBc nzo[AJpyrenc (-)-Metabolite ofBenz.o[Alpyrene

Carcinogen Innocuous

S(:h~me1-1.Contrastin gbiologica'behniorexhibitedbycnant iomcric pain',la

Table1-1. Potentialbenefits ofthenpeulicuseofa singleen. ntiomc....

Propertjer qfRaqmqte Potentiqllkru:fily qfEnquUomer Oneenantioll1Cf has exclusive activity RcdUl:Cdose andload on metabolism Other enantiomer is toxic Increased latitudeindose and broader usage Enantio mersba~"Cdifferent phannokinctics Better coouoloflcinetics and dose EnMltiomers rnetaboliud at different ratc$(in Widerlatitudeindose setting; less variabilityin

oneperson) patient response

Enantiomers metabolized at different rates Reductioninvariability of patient responses;

(different people) large confidence in dose selection

Oneeeanuomerpl"onetointeraetionwithkey Reduced interactionswithother common drugs detoxificationpathways

One enantiomeris agonist,otherantagoni st Enhanced activityand reductionofdose EnantiOf11er'S vII")'in spectra ofpharmaeologiea l Increased specificity and reducedsideeffects action andtiss ue specificity for one enantiomer, usc of other enantiomcr for

differentindie.tion

racemat es,are summarized in Table 1-1.¹ Theincreasing awareness of the importance of enanriomericpurity in the study of biological activities and their applications in pharmaceutical,agrochemical, flavour and fragrance industries provides incentivefordevisingnew methodology for the synthesis of pure enantiomers.Regulatorypressurefrom guidelines issued recentlyby the Food and Drug Administration(FDA)ll in the United States are an added incentive.

Increas ingenvironmentalpressureserves asanother impetus for enanticselective synthesis since unneeded by-productsare reducedbyupto 50%,thusminimizi ng

ecologicimpacton the euvironmea t.PIJSingle enantiomersare alsousefulprobes inthe elucidationof chemical reactionsand reaction mechani sms."Inaddition.

enanti omeri callypure compoundshavegrowingapplicationsinareas of molecular ele ctronics, optical data storage and specialitypolymerssuch as high strength lightwe ightmaterialsandliqui d crystals.U

Lastly, asynunetric synthesisaffects syntheticefficiency.It is wellknown that uncontrolledsynthesisof nsterecgeniccentresproduces2- stereoisomers.Clearly, withoutstereochemicalcontrol,the construction of a moderatelysized molecule would behopelesslyinefficient Withoutrepeated separationof stereciscm ers,chaos would occur.Anon-st ereo selectivesynthesisofa compo und with64 asymmetric carbons and7doublebond s ofaparticularconfigurati onwouldafford only one molecule with thecorrectstereoch emistryoutofeach moleof substance - one in every1()Dmolecules!" Areal examplethat hasbeenachieved" is thetotalsynthesis of aprotectedpalytcxin carbo xylic acid, which contains65 asymmetriccarbons and 6double bonds!

1.1.2.Approachestoobtainenantiopul'"e matel'"ials.Themethod stoachieve enanti omeri eallypureorenriched material scan generally begrouped intotwo

categories,although . variety of epproeches'...1"' 11."havebeendeveloped.

1.1.2 .1. Resolutionof eaeemetes, Resolution,whichincludesseparationof enantiomeric c:rystals (c:onglomerates),H conversion to and separation of diastcreomers.1l.:lDemploymentof bioche:mica1andc:hemical lci.netictec:hniques.^ll.ll -::J

selectiveextractio n'andc:hiralpreparative c:hroma.tography,'·IIetc,served as the primary methodto obtainenantiopurec:ompounds untiltheearly1970's.1~ The techn ique of resolution via manual separation of enantiomeric: crystals (conglomerates) wasrustemployedby Louis Pasteurin1848.:UHeobtained two types of crystal s with different asymme tric:facesbypartialevaporationofaqueous solutions ofammonium-sodiumdouble salts of racemic tartaricac:id.Inthis regard, preferential c:rystallization ccupted with spontaneousin situracemization,knownas

secondorderasymmetrictransformation, isa particularlyattractivemethod for

industri al synthesissince the theoreticalyield is IOOOAo. Anelegant example²¹¹is shownin Scheme1-2. A c:atalytic:amount(3 mor'Ao)of an aldehyde fac:ilitates racemizatio ninsolutionatambienttemperature viathe imineand thedesired(5)- amine continuouslyc:rystallizesas its(+)-camphor-lo-sulphonic acid(CSA) saltin 910/0yieldand>98%ee.Itisimponantto addless thanafull equivalent of (+}-CSA inorder tomaintainaconcentration of freeaminewhich ensurestheracemization of

+ArCHOcat.

-ArCHO

~ ^:

Me

^k~=CHM

B N

"'"

I.."

unwanted (R)-amine

1 1

~JS

^O,H

. . 0

Crystallization

92mol% (+)..cSA (S)-amine'(+)-CSA B

+ArCHOcat.

-AcCHO

HD CI

Ar --q

CI Schem e 1-2.Exampleordencemiza tionprocess:'

the imine. This efficient, one-poiresolution-racemiza tion process,designated as

"deracemizaticn",has beensuccessfully usedbyMerck"on a 6 kg scale 10produce an intermediatefor a possib lecholecystok inin antagonist.

The technique of resolution via theseparation of diastereomersgenerally involvestwo steps . Theracemate isconvertedinto diastereomers by treatmentwithan optically activereagent (resolving agent)and theresulting diasterecmers,which have distinct phy sical properties,are separatedby distillatioc.chromatographic separation or fractionalcrystallization.Thecorresponding enantiomers are recover edby removing theresolvingagent.Sincetheresolving agent for thismethod is crucial,it must be carefully chosen. A good resolvingagentshould beinexpensive,react easilyand in goodyieldwith theracemat eto be resolved and beeasily remov edafter separation.

Biochemicaland chemicalkineticresolutiondependon differentreaction ratesof eachenanrio merwith anenzyme and a chemical reagent,respe ctively .Recently, Jacobsenat Harvard University developeda direct and efficient routetoenantiopure Lz-amino alcoholsfrom readilyavailableepoxidesbyusing catalytickinetic resolution." Enantiopur e 1,2-amino alcoholsare difficulttosynthesize,butvery usefulfor generating importantsynthetic intermediat es. Jacobsen' sapproachis sho wninScheme1-3.The catalystdeliversan azide group to a particular carbon atomof oneof twoenantiomers of the epoxide.Removal of thetrimethylsilyl group andreducti onof the azidegroupin the generated l-azido-2-trim ethylsiloxyalkane leadsto1,2-arnino alcohol. The actual form(RorS)dependson thechiralityof the

catalyst used.

(R.RHSalcn)CJ(III)complex

Scheme 1-3. Eumpleofkineticresolut io n¹¹

All theseresolution methods,except the second orderasymmetrictransformation, generallygive,at the verybest, a50''/0 yieldofthe desiredenantiomers.U The situationworsensand makes resolutionimpractical,ifnot impossible,when a moleculecontainsmore chiral centres sincethenumber of stereoisomersis dramatically increased.

1.1.2.2.Asymmetricsynthesis.This method is a solution tothe aforementioned problem.Asymmetric synthesis is characterized by its generality,efficacyand

flexibility.These versatilitieshavebeen fully acknowledgedby chemists in synthetic organic chemistry,medicalchemistry,agricultural chemistry,natural products chemistry.plwmaceutical industries,andagricultural industries and clearlyreflected by a huge number of publications dealing withasymmetric syntheses of enantiomerically pure or enriched compounds over the last two decades.

Srereoselectivesynthesis, one of themostcovetedand long-sought after goals of chemis ts, has nowreachedthelevel whichallows organic compoundsof virtually everytypetobeobtainedincompleteenantioselective or diastereoselectivefonn.^1a Theprominenceof asymmetricsynthesisislargelydueto the explosive development ofnumerousnewand efficient catalytic andstoichi ometricmethods during the last decade.

However, regardlessof the method anditsinheren tefficiency,asymmetricsynthesis requires thechemistto"pay the price."Achiral molecule,eitherinthesubstrate,the reagents, thecatalyst,or thesolventmustbeincorporated.Without a chiral agentthe isolatedproduct(s)will beracemicandrequireresolution.Schematicrepresentation"

ofthiscentralidea onasymme tricsynthesis isgiveninScheme1-4.Scheme 1-4 clearlydemonstratesthatchiralitydoesnot occur spontane ouslyand itmustbe imposed duringtheresolution(eq.1)and theasymmetri c synthesis(eq.2-6in

~~

^nsolutian

~

^(I)

~

,nms!ormat1on

• ~

⁽²⁾

~

l"rrru"oI«ular

~

clliraJirytraflS(er

•

⁽³⁾

~

/rfl(!ntfokc.Jor

r

clliraI;ryl1'Dns(er

•

⁽⁴⁾

~

chirality multiplication

• rrrrrrr r (S )

~~~

chirolity omp/ificotion

• rrrrrrr r

⁽⁶⁾

Scheme 1-4.Approachesto optica llypu~uomrnl'

Scheme1-4). Transfonnation (eq.2) as an approachis often referred to as the "chiral pool"method. which is onlyvalid for thepreparation of derivatives of inexpensive.

readily available,natural optically pure compounds suchas aminoacids,~"~'}Otartaric and lactic acids,"terpenes"and cerbcbydrates."A limitation of thismeth odology results from the fact thatnot allmaterials isolatedfrom natural sources are enantiopure.For example,many terpenes are obtainedin"sc:a1emic..:I-lforminwhich oneenantiomer predominates over the other. However the chiral pool is not a

\0

stagnant pond. As enzymesand reagentsarediscoveredand developed, they can be appliedto producelarge quantitiesofuseful chiral

starting material. A timely exampleisthe use of Sharplessepcxidation of prochiral allylicalcohols to

fonn homochiral glycidols(Scheme1.5)by ARCO.^JS Sc h e me 1-5. Glyci do l Glycido lscan thenbe convertedinto enantiomerically purederivatives via conventional organic reactionsinvolvingretentionor inversionof configuration or chirality transfer.

Other approachessuchas intra- or inter- molecularchirality transfer (eq.3,4) aswell aschirality multiplicationoramplification (eq.S,6)involve the use of chiral auxiliaries tocreatenew stereogeniccentres, either stoichiometrically or catalyticall y.

A great deal of effort devotedtotheseapproacheshas resultedin exponentialgrowth of asymmetricsynthesisinlast decade.Amongvariouspossibilities ,the use of chiral transition metal complexes,i.e.,transitionmetal-mediated(TM:M.)asymmetric synthesisI.17

, II, ''''ll-«lpromises tobeone of the most general andflexible methods and

willcontinue to grow.

1.2.Transition-meta l-mediated(TMM) asymmet ricsynt hesis

II

Organicmolecules can be bonded to transition metalsina greatvariety of ways due totheflexibl ebonding patterns. variableoxidation statesand coordination numbers of transitionmetals.The reactivitie sof the organic compoundsare oftenalteredI regulated' ?'-.u as a consequ enceof bonding to thecentral metal.Inthecontext of organicsyn thes is. thischange offers exciting and unconventionalopportunities throughtheprovisionof newtypes of reactionsto be harnessedforthe construction oftargetmolecules.Furthermore,geometric restrictionsto theorientation of bonding ligand sinmanytransitionmetal complexes determine sthealignment ofreactin g species broughttogetherbythemetalandintumprovide scontrolofstereoselecdvity as wellaschemicalselectivity.Theuse oftransirion metalscontinuestoprovidea plethora of asynunetricreaction s,and this trendwill, nodoub t, contin ue as organometal licchemistryseesfurtherdevelopments.'

Basedon the positionof thesrereogen iccentre in thetransitionmetalcbiral auxiliary, trans ition metal-mediated asymme tric synthesis can nonnallybe dividedinto two groups (Scheme 1--6).Thestereogenlccentreis inthe chiralligand in thefirst group whilethesecondgroup involves a chiral-at-metal organometallicspecies.Inthefirst casethechiralsource is"distal" totheprochiraltarget-ToInthesecondcase the chiral sour ceis "proximal" tothe prochiraltarget. Inprinciple, a proximalchiral

12

~M-~ ~

^,

4-5

A

' - - -- "Distal"

Scheme1-6.Two typesorc:hiral aUJ.i1ia ri es

"proxima l"

centre would be expectedto havelarger influence(cbiral induction)on the target molecule than the distalone.Thisis easy to be understoodsince the former chiral centre isrelativelyfar fromthe targetmolecule. ~

..(p_

Howeve ra great deal ofeffort isbeingspentto~p~p~

extend the chirality of ligands into theactive siteof

~ ~~

atarget moleculevia phenyltransmitter groupsin (Ji f

d 1~; et\)~"'U

Sche me 1-7.Two-lay er expanded "de ndrizymc"ligands. For instance,a dendrizyme two-layerdendrizyme as showninScheme 1-7 hasrecently been synthesizedand examined byBrunner."

1.2.1.TM l\fasymmet ricsynthesiswithchir al ligand auxilial'"its.Thistechn ique

13

isusually catalytic and represents one of the most promising methods for synthesis of optically active compounds,since a small amount of chiral material (catalyst) can producenaturally occurring and nonnaturally occurring chiral productsinlarge quantiti es...·I"1.1. ]'.:l<l.'" Generallyspeaking,especiallywith respect to chiral induction. homogeneous catalystsare more selective than heterogeneous catalysts.^o06 This argument isbasedon the proposal that only onecatalytical ly active species is present in solutionfor anideal homogeneouscatalystwhile a heterogen ouscatalyst ismorelikelyto contain differentcatalytically activesites.Inthe latter case.overall low selectivity would be observedas.each sitehas its own selectivity.Inaddition,it ismoreconvenienttostudy catalyticmechanisms with a homogeneoussystem.

However. itis easierto isolate desiredproducts from a heterogeneoussystem .Recent advancesinthe areaof catalytic TMM asymmetricsynthesis havebecomeindustrial rea1ity.'·~··'"·'"Special attentionin thisregardhas been given to reduction."11.1U !l. n.

"'-'''''~oxida tion"17. 0'11.'O. O~!1and carbon-carbon bond fonnation...17.l l••g.:IO. '10-7J

"Hetercgen izedhomogeneouscatalysts"represent a bridge between homogeneous and heterog eneouscatalystsand are known as the thirdgeneration catalysts .These th ird generationcatalystscombine advantagesof homogeneous and heterogeneou s catalysts.However.a problemassociated with thirdgenerationcatalystsisthe loss

14

of activityand selectivitydue to metal leaching;"

Thesetopics have been extensively coveredby literature, hence only homogeneous catalytic hydrogenation promotedbytransition metal complexes bearing chiralligand auxiliarieswill be highlighted since it providesexceptionallyclear insight into the natureof ThfM chiral synrhesis.

The first homogeneous asymmetric hydrogenation, achieved via replacing triphenylphosphin einUteWilkinsoncatalyst"byachiral tertiary phosphine, was reportedindependentlybyHorner" and Knowles"in 1968.However, the initial opticalyield was very low (8- 15% ee). Since then, significant improvementsin opticalyieldhavebeenachieved.Morrison"firstrecognizedthat phosphinesachiral at phosphorus but bearinga chiralsubstituentmay also serve as ligandsfor ena ntios elective hydrogenation. A further breakthroughin this area camewhen Kaganl'll , lOdiscoveredthat the optical yield could be greatly enhanced bythe useof bidentatephosphines,whichreduced the number ofpossibleconformations and hence transition states,Some frequentlyused diphosphinesareshown in Scheme1-8."

Most haveaC2symmetryaxis which servesthe importantfunctionof reducingthe numberof competing, diastereornerictransition states." Soonafter, it wasfound that

IS

X*PP~

^PP~

~ ^Ph ~~PP~

>EO

~ &O~

^{RaMe:~PROPHOS}

(R.R)-D1PAMP

I

^R-Ph:(S}-PHE NPHOS

(R,R)-DJOP R-e·C6Hll: (S}-CYCPHOS

Ph;>--Z:~ ^crxP~

^P~

^~

(S.s>-CHIRA PHOS (R,R).NORPHOS (R,R}-BDPP

O:: PPh2

^{,/j_PP~ P~P~PPIn}

PP~

R - \.-l.PP~ 'COR

(S,.s)-D'CP (SS)-PYRPHOS R"'f-BuO: (S,5).BP' M K-R'NH:(S,5)-R'·CAPP

~;

R'-Q;HJ-3,4-01:

gs:

^Q'j:H4-4-Br

F. 'PhI

~Ph

~

I

; / PPh1

~PP"'

R-Nj\.II:2:(R,S)-BPPFA 'PhI

R-OK:(R.S)-BP'FOH

R'-N(Mc)CHICH~ (RrBINA' CAMPHOS

~P~' ^{U R D K} ~

...'Rl

)j

^[

ProND' RaMe:Me--DuPHOS R-Ph:(R}-BIPH£MP

R-Et:E(-DuPROS R"'CoQiHll :(R)-BICHE' Scheme1-8.Frequentlyusedch in ldiphosphin eligands"

16

thebestsubstrates for rhodium-catalyzedenantioselectivehydrogenations were2- acyl-amin ocinnamic acids. Nowadays,a series of naturally and non-naturally occurrin g amino acids can be prepared routinelyingreater thangoo/oee using phosphine-Rh catalysts. Some examples" are showninScheme1-9.

R~COR'

COOH

PhosphineLigand + Ih

R

Chiralphosphine-Rh ^COOH

R~COR'

%eeofproduct

(S)-BlNAP Ph Ph lOO(R)

(S)-BlNAP H Ph 98(R)

(S.S)-BPPM Ph Me 91(R)

(S.S)·BPPM H Me 98.5(R)

(S.S)-ClURAPHOS Ph Me 9S(R)

(S,S)-CIllRAP HOS H M, 9l(R)

(R.R~DlPAMP Ph M, 96( S)

(S,S)-DlPAMP H M, 94(S)

(S,S)-Et.D uPHOS Ph Me 99(R)

(S,S)-NORPHOS Ph Me 9S(R)

Scheme 1·9. Selectedhydrogen.tionwith Rh-P" system

Catalytic asymmetrichydrogenationwith Rh-phosphin ecatalystshasbeen highly successful andhas resultedinseveral commercialapplications.' · 12,1J Examples of industriallyrelevant targets are giveninScheme 1-10.'Unfortunately,however,the

17

(YL"OOH !J

HO"Y

^n..,

_~-(:H'

(5)- DOPA (S-S}-Aspanamc

Scheme 1-10.Industrialprocesswith Rh-P"system'

scope of'the Rh-eatalyzedsystemis very narrow.An extensive. systematic survey of thesereaction sindicates that an a-amide

functionalgroupmustbepresentforefficient enantiofaceselection(Scheme 1-11).Some useful generalizations have emerged:(i) amideor related groupsare necessary; if theyareabsent, high ee cannot be obtained

position3 position4

H

i

^COOH

-_.-or~~~~~; ..

position2 ! position1 Scheme1·11 .Olefin requirement withany catalyst system:"(ii)the phenylgroupinposition 2 may be replacedby any other arylgroup,alkylgroup,and evenhydrogen;(iii)thehydrogeninposition 3 is usuallynecessary;(iv)thecarboxyl groupinposition4can bereplaced by other electron-withdrawinggroups.Generally.the most successful substratesincatalytic asymme tric hydrogenationare N-acylaminoacry lic acidderivatives, carboxylicacids, enamides,enolderivatives,allylicalcohols,and (l,p-un saturat ed esters, amidesand

18

ketones,as showninScheme1·12.

H Co,R'"

R.>===\.mCOR"

'\ lo,Et

R';===='\OCOR"

H COOEt

rcs

^OMC

Sche me 1· 12. Successfu lsubsl rateswith Rh-p·system

Thelimitations of therhodium systemstimulateddevelopment of a catalyticsystem whichapplies to a wider range of olefinic substrates. The BINAP-Ru(II) dicarboxylatecomplexes showninScheme1-13are excellentexamples.Thissecond generationsystem, developedbyNoyori,can catalyze the hydrogenation of a variety

(R) (S)

Scheme 1-13.BINAP- Rudicarbokylatecatalyst

19

of functionalized prochical olefinsandketones:u.J,I which isnot possiblewith conventional Rh(I) systems.Thehighefficiencyof the system is believed to bea resultofthe structure of the chiral diphosphineBINAP althoughthe exact mechanism isunknown.u.25'.u.!t.I' BINAP is anaxiallydissymmetric, C2chical diphosphine (Sc heme1-13). TheC2synunetry dramaticallyreducesthe number of possible diast ereomericreactive intermediates and transition states." The fullyaromatic substitutionexertsa strong steric influence and provides high potarizability.Dueto its confonn ationat flexibility,BINAP can accommodat ea varietyof transitionmetals byrotating around itsC,-C\.pivot and<;-P or~P'bondswithoutserious increase of torsionalstrain.After coordinationwith transition metals the resulting seven- memberedchelatering is confonnarionaHy and skel etallyunambiguou s."Some examplcs24. n...of BINAP-Ru(U)catalystsarc showninScheme 1-14.The drawback of the ruthenium-based catalysts is that they requirehigh pressure and sometimes elevatedtem perature. Therefore,their bestfieldof applicationiswhererhodium catalysts do notexcel,for example.in carbonyl reductions (Scheme1-14).

20

V]l RllBr2{(R}-BINAPI.IOO"C,Sh PhCH10,...."u",_AOEt 100 attn H2; C!HSOH

~OOH

Ru(OCOCH3)2[(S}BINAP j

~COOH

CH)~

^- I3SalmH2.CH]OH

CHl~

NaproXCD 100% yield

srwee

CH~'I ^{COR CH'%COR}

CH -,-'-:'-':"'--':-_ CH,

OCH) ClHSO HCH2Cl2 OCH)

I

23'"C liS-16Gb

!

OCH) c.t·"Ru(OCOCH31[CR}-BINAPI OCR)

R"H,CH);yield-IOO'%;ee>99.S%(R)

Ru(O COCH ])2 [(R} BIN AP ] 4aimH2; C:zHSOH-CH2C12

PhCI-hO~OEI

)icl d : 99%

%ee:98 Scheme 1-14. Applicationsof Ru-BINAP catalytic hydrogen.li,)n¹"17

""

WithbothRh(l) and Ru(ll)systems.asymmetric hydrogenationof"simplc" olefins that lackfunctional !secondarybinding usuallygiveslowee.Howeve r,recently developedchiralcomplexes ofgrouplVBmetal sandlanthanideshave paveda road for asymmetrichydrogenationofsimpleolefins(Scheme I-IS ).

21

.i..

Cat'

CI'T;~),+

M"S~mCH(1MSh

~(-)MenthYt

70130(SY (R) '

-7S

-78

Ph~

%ee

95(5)

96(5)

#(5)and(R)indicatesthechiralityof epgroup Scheme1·15.H)'drogenationorsimpleoldins

1.2.2.TMM asymmetricsynthesis with c:hiral-at-metatauIiliarie.s.

1.2.2.1. Chiral-at-metalorganometallics.Althoughthe first chiral-at-carbcn compound,tartaric acid,wasresolv edbyLouisPasteurin1845,itwas 66 years bef ore the first optically active octahedra l transitionmetal compoundcis- [Co(enMNHJ)CI)~'(Scheme 1.16,A) wasfinallyresolvedvia crystallization of the

22

3-bromocampbor-9-sulfonates by Werner after fifteenyearsof effortand failure.I.

Seheme 1-16.The I"resolvedoctah~dn.l(A) and tetrahedrat (B) chiral-at-melal compounds Another 58 years passed

beforethefirst opticallyactive pseudotetrahedral chiral-et- metal transition metal organometallic compound [(C, H,)Mn(CO)(NO)(pph,)r

(A)

[

^ON

~I.~

Ph)^CO

^]+PF'-

(B)

PF~'(Scheme 1-16,B) was resolvedbyBrunnerin1969.⁹⁰Theresolutionof chiral- at-metalcomplexesis generally achievedintwo steps.Initialreaction of a racemic mixturewith anoptically activeresolvingagent affords a pairof diastereomerswhich arethen separatedbycrystallization or chromatography.Individual enantiomerscan then berecovered bychemicalremoval of theresolvingagent fromseparated diasrereomers.Scheme1-17shows theprocedurefor resolutionof the first optically acti veorganometallic complexwith four differentligands surroundingthemetal, [(C,Hs)Mn(CO)(NO)(PPh^3)]PF,. Treatment of theR.S"",-Tacemate with the sodium salt of thenatural opticallyactivealcohol {1R,3R,4S)-mentholgave twodiastereom ers withelimination ofNaPF,.The two diastereomerswereseparatedon thebasisof theirsolubility difference.The(+),19-diastereomer is solubleinpetroleum etherwhile the(-),~-diastereomerisinsoluble." The menthoxide resolvinghandle was then

23

-li)"O

-0 ii)PF,

(+)-Rldn

- li)HO

-0 ii)PF,

Scheme1-17.Resolu t io n orahe .- chiral-al - metalarganomel.llia

removedfrom the separateddiastereomersbypassing a streamof gaseousHel

The resulting salts(+}'751-and (-)' 751-[(C,H,)Mn(CO)(NO)(pPhJWCl",which are insolubleintoluene,werethen dissolvedinwater and treated with NH4PF6"toafford the cnantiomericaUy pure(+)'751-and(-)'7'.l-[(C,H,)Mn(CO)(NO)(Ppb)rPF,".

1.2.2.1.1.Absoluteconfiguration. Absolute configuration can be unequivocall y determined by single crystal X-raydiffraction study using Rogers'Tlmethod" or by

24

comparing the difference of R factorsafterindepend entrefinementof both enanriomers.Infavourablecases absoluteconfigurations can also be assignedbased on chircpticalproperties suchasCD spectra."

The descriptors(R, S)developedfor chiral carbon atoms"can also be applied to describetheabsolute configurationof a metal atom afterextension'U'" totreat polyhaptoligands.Polyhaptoligandsaretreatedas pseudo-atomswith atomicweight equal tothe sumof the atomicweights of allatomsbonded to the metal atom. Using thisextension, thefrequently usedpolyhaptoligandssuch asl1~-C~~,l1'- C,H,and 112-C2H~canbe consideredas pseudo-atoms of atomicweight72,60 and24(or atomicnumber 36,30and 12),respectively.9-I·9' Basedon

Wojcic ki's suggestion,9liif a complex containsmorechiral centers,the metal designationprecedes that ofcarbon.

According totheseproposals- andconventional Cahn - Ingold-Prelogrules,"the ligandpriority seriesinthe

shown inScheme 1-18,areC~H6>CI>0>NforRu"and RR~C Scheme1-18.

Application or modifiedCIP rule

N>Ph>Me >H forC·,whichspecifiestheabsoluteconfigurationof thecomplex

25

1.2.2 .1.2 .Chiropticalproperties. Unlike opticallyactive organiccompounds, optically activeorganotransitionmetal complexe sexhibit extremelylargespecific rotations.often largerthan those oforganic compounds by afactor of one ortwo pow ersof ten."These larger rotationsare due tothefact that the optically active organotransilionmetal complexesare coloredand thusshow strong Cotton effec tsin thevisiblepartof the spectrum.

610 510

/\ - Se>.RpoSc·CpCoI(PPhzN(H}C· H(Me)PhXJlhP(O)(OMe»

\

'-,

\

\

\

310 \

\

\

\ /

\ j 60

40

20

~x

;;:

-20

-40

-60

Scheme1-19. CD spuCraor Iwochiral-al-meta l,M-epimericdiaslereomers

26

Correlationof configuration of organotransitionmetal compoundswith chiroptica1 propertieshas shown that chiroptical properties are generallydominated by the central metalatom." Inother words. the chirality ofligands makes only a minor contribution to chiroptical propertiesof chiral-at-metalcompounds. Based on this empirical rule. the similarity between circular dichroism(CD) spectra of two species has been usedto assign the same relative configuration to the central metal atoms whilequasi-mirrormorphology of two CD spectra indicates the opposite relative configurationat the central metal atoms.For example.thevirtuallymirror image morphology of the CD spectra of two diastereomers, (Sc..R,..5c-}- CpC o l ( P h2PN( H ) C - H( M e) Ph) ( Ph P( O )( O Me » and (Rc. ,Sp,Sc-)- CpCol(p h1PN(l-I)C- H(Me)Ph)(PhP(O)(OMe». asshown in Scheme 1-19,suggests that thetwo diastereomershave oppositeconfigurationsat cobalt."

1.2.2.1.3. Stereochemistry. Although optically active organometal1ics are configurationallystable at the metalcenter in the solid state.stereochemical studies of theirsolution behaviour show that retention, inversion and racemization may be observed9l,9lIin variouschemical transfonnations.

A.Retentionofconfigurati onal metal.If reaction of an optically active chirel-at-

27

compound does not involve metal-ligand bonds,retention of configurationat metal will beachieved.,oo.lell Reaction of(+}-[(C, H,)Mn (NO)(CO)P(C,H,1 f PF,· with LiCJI,serves as an example (Scheme1.20). Due to attack of LiC;H ,on the Cp ring and the carbonyl group.two types of products arc obtained.In

[0: : 1 (0] +PF' + LiPh- - PPh)

(+)-R Mn (+)-R Mn

Scheme 1-20.Retenti onofconfiguntionat metal

B.Inversion ofconfigu ralion at metal.Asshownin Scheme1-21,reaction of the

+

LiCH3 __ liO'¢ ----

[a.h46as+72°

" .

[a.]~6-120

Sc.heme l-ll.lnnrsionof configuracion al melat 28

optically active iron complexCpFe(CO)(pPbJXCOOC,oH,~)with methyl lithium resul tsinthe elimination of lithium mentholate and formation of an acetyl complex CpFe(COXCOCH,)(pPbJ.Interestingly,the optical rotations of starting material and theacetyl product have opposite signsandtheir CD spectra are almost mirror images, i.e.,startingwith(+)~menthylester,the(-)~acetyl complex is obtained while(-)~

menthylester gives the_<+)~acetyl eomptex.t"?" These chiropticaldata suggested an inversion of configuration at Fe,whichwas unambiguously confirmedbya single crystal X-ray study ofbothstarting materialand product.ID6-11l'Theseresultsimply that attack ofmethyllithiwn does not occurat theester group of the starting material asexpected, but at thecarbonylgroUp.IDl,It»

C.Racemizationofconfigu ration01metal.Racemization was demonstratedby the confi gura tionally labile complexes, (+)-and <-)-CpMn(NO) (COPh)(PPh) ." D.III

(Sch eme1-22).The halflife(25°C,toluene) wasdetenninedtobe 21 minutesby polarimetrickinetics.Mechanisticstudy showsthat racemization dependson the concentra tion of triphenylphosphine.Half-lifeappreciablyincreaseswith the added

Scheme 1-12.Enmple or racemization ruction 29

amount ofPPbJo110.111nus observation suggested that configurational stability of the complexes increases on addition of PPhJand thus implied a dissociation mechanism (Scheme1-22).Itisbelieved that the first step,re.,the phosphine dissociation step, isthe rate-determining step and involves a chiral intermediate [CpMn(NO)(COPh)]

whichhas been trapped by CO giving an optically active CpMn(CO)(NO)(COPh)1I1 with the same but stable, relative configuration. The tripodchiralintermediate may either invert chirality atMnand then bind PPhl to fonn a Mn-epimer,or bind a PPhl with configuration change atMn.The former process accounts for the observed racemization .Since the latter process is favored with increasing concentration of PPhl>the slow racemization{longer half-liveswill be achieved on addition ofPPhl.

1.2.2.2.TMM asymmetric synthesis of C"'-materials. Many chiral-at-metal organometallic species"are potentialauxiliariesfor a wide rangeof asymmetric organic syntheses." Here,only representative work with the chiral-at iron auxiliary (T1'-CpFe (CO)(PPh l)]is highlighted to show how versatile the chiral-at-metal auxiliary is in stereochemical control in asymmetric synthetic transformations.

Theduraliron acetyl complex T\'-CpFe(CO)(PPhlXCOCHI ) ,which was first resolved byBrunner'"and later extensivelystudied byDavies^llJ. l l6and Liebeskind'P'" for

30

synthesis of organiccompo unds through carbon-carbo nbond formingreactions, exertspowerful stereochemicalcontrolover a variety ofreactio nsofattachedacyl ligandsincluding alkylations, aldolreactions,tandemMichae l additions,aIkylations and DielsAlder reactions.The parent ironacetyl complexis commer cially availabl e in homochiral,(R)or(S),form."Thisthree-legged,piano-stool.pseudo-octahedral complex and most ofitsderivatives are air stable and thuseasytobandle.Theyare also highly crystallineandcolouredso that purificationby crystal lizationor chromatographyis relatively easy.The preferredconfonn ation oftheacetyl ligand placesthe acyloxygen anti-periplanartothecarbon monoxideligand.¹ⁿ-m_Inorder tominimizestericinteractionsbetween theacetyl ligandandthe phenyl rings,oneof thethreephenylringsis face exposedunder the acetylligand.Therefore,attacking subs trates are blockedfromone faceofthe acetyl group andhigh stereose lectivity results.This face selectivity has beenwell demonstratedinalkylatio n andtandem Michaeladdition-alky lationreactions.

Treating theacetyl complex withn-butyllithium clean lygeneratesthe corresponding enolate,whichmaybe trappedby alkyl halides. Further treatment with n- butyllithiumleadsto the corresponding£-eno late.Subsequentalkylationfrom the unhinderedface generatesa newchiral centrewith completestereocontrol.One

31

Sc:herne 1-23.Alkylation rea ct io n media ted by a chi n l ironaUJ.i1ia ryUf

electron oxidation.,most commonlywithbromineinthe presence of water,oralcohols or amines. liberates the correspond ingcarboxylic acids. esters andamines respectively,withretentionat thenew chiral centre(Scheme 1-23). The chirality of thenewlygeneratedstereogenic centreinthe finalproduct depends on thechirality of the starting duraliron acetyl and on the order of thetwo alkylation reactions.This strategy has been used for drug syntheses of,for example,the antihypertensivedrug (-)captopril'Z'land thepotent collagenase inhibitor (_)-actinonin':M'(Scheme1~24).

0r.~g ^Col8ool.i

1

~~g ^Ci)B..u ~?"g

'-"'r"" ,-=-.-'-- ,

...,~~

_

~ ,~~

.,.

o (5:tI(io)~ 0 (f?J It) , , 0/(ffJ

(.f){. ) s

Itrt.H>U-JOOnI

0""'0 0',/0 0

~:rnU~~H ~ ~:fuU~:1~=V~O~::'Bo

N·""""'"

Scheme1-24.Synt hesisor (-)-a ctino ni nvia chinlironaUJ.i1iaryl:M' 32

1.2.2.3.TMM asymmet ricsynthesisofP-c:hiral materials via Arbuzov- Iike dealkylation rea ctions.Numerous studiesinasymmebic synthesis have established that Pcchiral ligands play a crucial role in obtaining a high degree of stere oselectivity. P'1%7,121Enantiomersof P-chira1 phosphoruscompounds usually exhibit a variety of uniquebiological activities and hence couldbe usedin chemotherapy,pest control. and bioorganic chemistry.:I4.)t.12lII. 1J(l Inaddition.p_

homochiral materials are targets for basic studies of their stereochemistryand are widelyusedinasymmetric synthesis and asymmetric catalysis.34.s..lJ(lSinceP-chira1 materialscannot be foundinlite natural chiral pool, their preparation poses a challengeto chemists and mustbe achievedvia synthesis. Thisthesisdescribes attemptsto synthesizeP-chiral materials via transition metalmediated Arbuzov reactions.

1.2.2.3.1.ClassicalArbuzov rea ction.The Arbuzov reaction.also knownasthe

A 0

BI''P~R' + R-X R,A,B...alkyl.aryl,,.,

R'=alkyl,acyl,..

X=CI.Br,I Sche me1-25. ClassicalAr b ulOvre.clion

3J