Enantioselective Catalysis

Oliver Reiser University of Regensburg Importance of Chiral Compounds

Market Value for chiral ﬁne chemicals (2000)

Total 6600 Mill US$ Pharmaceutics 5400 Mill US$ Other (Agro, Flavors etc) 1200 Mill US$

Any new drug that’s chiral is likely to be developed and marketed as a single enantiomer. You win more than you lose with single enantiomers.

Chem. Eng. News 2003 Important Factors when Deciding the Application of Catalysis

• Product - availability of competitive alternative routes time frame for development cost vs added value • Catalytic reaction maturity - known scope / limitations catalyst availability development time IP situation required equipment / techniques cost • Chemist & education, acceptance of novel methods Company catalytic know how and facilities

Adapted from H.U-Blaser, Solvias Top Catalysis Reactions in Industry

Adapted from H.U-Blaser, Solvias Principles of Enantioselective Catalysis Principles of Enantioselective Catalysis Synthesis of (L)-Dopa (Monsanto)

CO2H CO2H CO2H

NHAc H2, Rh-DiPAMP NHAc NH2 H3O

AcO OMe AcO OMe HO OH

95% ee, TON 10000, TOF 1000/h Enantiomerically pure product crystallizes Separation from catalyst and MeO undesired racemate

Ph P P Ph OMe Knowles et al. DiPAMP Principles of Enantioselective Catalysis

Catalyst design: Metal–chiral ligand combination

• more than 2000 chiral ligands to choose from

• enhancement of selectivity • regio- / chemoselectivity • diastereoselectivity • enantioselectivity

• enhancement of reactivity • LAC - Ligand Accelerated Catalysis

Give me reactivity, and I will give you selectivity later B. Sharpless, nobel laureate 2001 Ligand Accelerated Catalysis

• change of the electronic properties donor / acceptor ( and )

Complex pKa (MeCN) 8.4 H—Co(CO)4 Increasing ability of the ligands to stabilize H—Co(CO)3[P(OPh)3] 11.4 the conjugate base by back bonding

H—Co(CO)3[PPh3] 15.4

–1 CO (cm ) 1908 (CO)5WOEt2 CO Bindung becomes stronger, since back bond to CO becomes weaker (CO)5WPMe3 1947 back bonding to other ligand (not CO) (CO)5WP(OPh)3 1965 becomes stronger

CH2 (CO)5W 1973 CH2 Ligand Accelerated Catalysis

• change of reagent geometry

180• R H Et Zn Et x no reaction

Me2N OH O

R H HO H Me2N O Zn R Et Et Et 100• Privileged Ligand Classes

Binaphthyls Bis(oxazolines) Salen X = OH

X = PPh2 X = OPPh2 O X O X X = P(O)Ph2 N N X N N X = NH2 R1 R1 OH HO X = NHPPh2 X = N CHAr R R

X = AsPh2 Noyori Evans, Pfaltz, Masamune Jacobsen, Katsuki

Oxabor DUPHOS PNNP

H Ph Ph R R O O P N O NH HN P B R R R PPh2 Ph2P

Burk Corey Trost L-Menthol (Takasago)

NEt2 Rh(I)-BINAP NEt2 HO

>1000t/year 97.6% ee, TON 40000, TOF 1300/h

blocked quadrants H

P Ru P H

(S)-BINAP (R)-BINAP (R)-BINAP

Review: T. Wabnitz, O. Reiser Organic Synthesis Highlights IV (Eds. H. G. Schmalz, H. Waldmann), VCH Weinheim, 2000, 155-165 Epoxidation of Allyl Alcohol

Ti(OiPr) 4 O OH OH HO OH 88-90% ee i i PrO2 C CO2 Pr TON >40; TOF < 1/h

• Arco–GGP-Sipsy, multi ton scale (discontinued)

• good selectivity

• low TON and TOF Oxazoline-Ligands for Catalysis

NO2 R R R O O O N O O O But N N N N N PPh2 N OH 1 1 1 R R R R1 R1 R1

Box Azabox P,N-Oxazolines O,N-Oxazolines Evans, Pfaltz, Masamune Reiser Pfaltz, Helmchen, Williams Bolm

N O O O X X N N R O n OH N n Fe N N Ph N N N Ph R1 R1 R1 O O n Y Y n

Ferrocene-ox N,N-Oxazolines Pybox (NX2)-box Bolm Brunner Nishiyama Reiser

Reviews: P. Guiry, Chem. Rev. 2004, 104, 4151 M. Glos, O. Reiser in Organic Synthesis Highlights IV VCH Weinheim, 2000, 17 Oxazolines as Chiral Auxiliaries

HO Ph Ph R O 1) LDA R CN + 2) R1X H2N N OH OMe

Ph Ph HCl R O R O R CO H 2 N 1 N 1 R 45-85% H R R1 Li O OMe X Me

75-85% ee

A. I. Meyers, G. Knaus, K. Kamata, M. E. Ford, J. Am. Chem. Soc. 1976, 98, 567 Review: T. G. Grant, A. I. Meyers, Tetrahedron 1994, 50, 2297 Synthesis of bis(oxazoline) ligands

R2 R2

NC CN R2 R2 R ZnCl2 R' O O R' R' R' R' N N R' H2N OH R2 R2 R R 1) ClOC COCl

2) Activation / Cyclization

Activation / Cyclization: ZnCl2; NEt3 /TsCl; SOCl2/NaOH; Burgess-Reagent… Synthesis of bis(oxazoline) ligands

NHCbz BnOCONClNa OH 4% K2OsO2(OH)4

(DHQD)2PHAL

H2, Pd/C

NH2 O O 1) ClOC COCl OH N N 2) SOCl2, 2-Naph 2-Naph 3) NaOH,

G. Desimoni et al., Tetrahedron, 1998, 54, 15721 Synthesis of azabis(oxazoline) ligands

R H R O N O BrCN TsOH, PhCHO NO N N H2N OH MeOH Toluol, , 58-59% 89 % NH2 R R R=iPr,tBu R = t-Bu, i-Pr

30-75% NO

OEt

H O N O O N O n-BuLi N N N N R1 R1 R R Br

1 R, R = t-Bu, i-Pr, Ph, CO2Et MeOPEG; Polystyrene, Tentagel, Dendrimers

M. Glos, O. Reiser, Org. Lett. 2000, 2, 2045 H. Werner, A. Gißibl, R. Vicha, O. Reiser, J. Org. Chem. 2003, 68, 10166 Virus bound Azabis(oxazolines)

N R N N N M * N R x Collaboration with M. G. Finn, Scripps Polymer-supported Bis(oxazoline) ligands

n O O O n O n n

O H3 C H3 C 4 O N O O O O O O O NN NN NN NN R R R R R R R R

1a : R = i-Pr 2a: R = Ph 3 4 1b: R = t-B u 2b: R = t-Bu

Reiser et al. Fraile, Mayoral et al. Cozzi et al. Salvadori et al. Org. Lett. 2000, 2, 2048 Org. Lett. 2000, 2, 3905 J. O rg.Chem. 2001, 66, 3160 Angew. Ch em. 2001, 40, No 13

Review: Le Maire et al., Chem. Rev. 2002, 102, 3467 Oxazoline Ligands in Catalysis - The Beginning

1) Ph2SiH2 H C H C 3 RhCl3 •L* (1 mol%) 3 + O 2) H OH

86% ee

L* = N O N R

H. Brunner, U. Obermann, Chem. Ber. 1989, 122, 499 Semicorrins in Catalysis – Pd(0)-catalyzed Allylations

CH3 N OAc [Pd(C3H5)Cl]2 (1 mol%) CH(CO2Me)2 N N Ph Ph Ligand (2.5 mol%) Ph Ph

95% ee OR RO

t R = SiMe2 Bu H. Fritschi, U. Leutenegger, A. Pfaltz, Angew. Chem. 1986, 98, 1005

Nu Bn a O a Ph Ph Ph N + Pd Nu b N Nu O Ph b X-rayBn structure Ph Ph

A. Pfaltz et al., Helv. Chim. Acta 1995, 78, 265 Pd(0)-catalyzed allylations

OAc [Pd(C3H5)Cl]2 CH(CO2Me)2

Ph Ph A Ph Ph

28-70% 94-95% ee

O O O O m n O

Multiple runs, high O O enantiosele NN ctivity, variable yields Ph Ph A C. Moberg, Tetrahedron: Asymmetry 2001, 12, 1475 P, N-oxazolines – Pd(0)-catalyzed Allylations

OAc [Pd(C3H5)Cl]2 (1 mol%) CH(CO2Me)2 O Ph Ph Ligand (2.5 mol%) Ph Ph N PPh2 99% ee Ph

b Ph Ph a Ph Ph Ph Ph P + P Pd Pd Ph N R b 1:8 N R a O Ph O

Attack via a is observed but stereoelectronics should favor attack via b

Original report: A. Pfaltz et al., Angew. Chem. Int. Ed. Engl. 1993, 32, 566; b) J. G. Helmchen et al., Tetrahedron Lett. 1993, 34, 1769-1772; c) J. M. J. Williams et al., Tetrahedron Lett. 1993, 34, 3149 Mechanistic discussion: O. Reiser, Angew. Chem. Int. Engl. Ed., 1993, 32, 547-549 Mechanism: G. Helmchen, Angew. Chem. Int. Ed. Engl. 1996, 34, 2687 Cu(I)-catalyzed Cyclopropanation (Sumitomo)

CO2Et O Cu(I)–L + N 2 OEt

Bn 92% ee R 100-200 TON N R Cu O O 2

Intermediate for cilastatin (dehydropeptidase); small scale

Critical issue: preparation and handling of diazoester Cu(I)-box catalyzed cyclopropanation

good enantiocontrol O N 2 N R CO2R CO2Et Cu Ph N R O Ph CO Et Cu(I)•L" CO2Et 2 Ph Helv. Chim. Acta low enantiocontrol 2-3 : 1 1988, 71, 1533

Me H3C CH3 Me N O O O O O N O N N NH N N N N N t t t t t t PhMe2SiO OSiMe2Ph Bu Bu Bu Bu Bu Bu

95% ee 98% ee 99% ee 92% ee

Tetrahedron Tetrahedron Lett. J. Am. Chem. Soc. Org. Lett. 1992, 48, 2143 1990, 31, 6005 1991, 113, 726 2000, 2, 2045 Copper(I)-Catalyzed Cyclopropanation

O + Cu(OTf)2 / PhNHNH2 CO Me Ph Ph 2 N2 OMe

O N O NN But tBu 1 mol%

% 100 90 yield 80 ee 15 70 60 50 40 30 20 PEG-bound aza(box) 10 0 1234567891011 cycles Org. Lett. 2000, 2, 2045 J. Mater. Sci. 2002, 14, 1 Immobilization on naﬁon by anion exchange

+ + Bn O N O O O N N N N Cu Cu tBu tBu tBu tBu

No leaching of ligand Leaching of ligand

Multiple cycles possible

In collaboration with J. Mayoral, Chem. Eur. J. 2004, 10, 2997 Cu(I)-catalyzed cyclopropanations – Applications

Cl CuClO (CH CN) Cl 4 3 4 Cl + N2 CO R CO R Cl 2 2 L* Cl CO2R Cl

L O O R = Menthyl 88 12 92% ee 85% ee Ph N N Ph 99 Ph Ph R = (Dicyclohexylmethyl) 1 92% ee

S. Masamune et al., Tetrahedron Lett. 1991, 32, 7373

CHO Cu(OTf) /L* (1 mol%) O 2 O H 2 steps MeO2C PhNHNH2 MeO2C O O Nu CO2Et N2 CO2Et H

45% yield (large scale, 77% based on conversion) 85-90 % ee >99 % ee (32%) O O single recrystallization NN Eur. J. Org. Chem. 2000, 2955–2965 Pri Pri Org. Lett. 2001, 3, 1315–1318 Chemistry2003 , 9, 260–270 Org. Lett.2003 , 5, 914 Cu(II) or Mg(II)-catalyzed Diels-Alder reactions (1)

O O

N O COX COX t H3C CH3 MgI2• Box-Bu > 95 < 5 O O Cu(OTf)2• Box-Ph < 2 > 98 N N R R Box-R H O O O H N Ph O Mg N But O N N O Ph O Cu N O N t O H O Bu H

COX COX

D. A. Evans et al., J. Am. E. J. Corey et al., Chem. Soc. 1993, 115, 6460 Tetrahedron Lett. 1992, 33, 6807 Cu(II)-catalyzed Diels-Alder reaction (2)

t O O CuX2• Box-Bu (10 mol%) R R N O 25°C, 8h COX

counterion endo ee yield H3C CH3 O O X = TfO– 94% ee 95% R = Me – N N X = SbF6 96% ee 98% R R Box-R X = TfO– 90% ee 85% R = Ph – X = SbF6 96% ee 95%

X = TfO– 53% ee – R = Cl – X = SbF6 94% ee 95%

J. S. Johnson, D. A. Evans, Acc. Chem. Res. 2000, 33, 325 Cu(II)-box catalyzed Diels-Alder reaction

O O CuX2• Si-Box (10 mol%) N O r.t. COX

Silica R endo / exo % ee

OR Si OR Si OR H 85:15 65 (CH2)3 (H2C)3 OH 86:14 81 (92 at –78°C) NH HN

O O O O

O O NN

Si-Box: R = H, SiMe3

M. Lemaire, Org. Lett. 2001, 3, 2493-2496 Cu(II)-box catalyzed reactions

J. S. Johnson, D. A. Evans, Acc. Chem. Res. 2000, 33, 325 Cu(II)-box-catalyzed Michael reactions

H3C CH3 O O – More reactive 2 SbF6 N N Cu R R 1 Direct reduction to aldehyde possible

J. S. Johnson, D. A. Evans, Acc. Chem.` Res. 2000, 33, 325 Cu(II)-box catalyzed electrohilic amination

H3C CH3 O O – 2 SbF6 N N Cu R R 1

J. S. Johnson, D. A. Evans, Acc. Chem. Res. 2000, 33, 325 Cu(II)-box catalyzed Mukaiyama syn-aldol reactions

OTMS O Me OH O MeO + t 1-10 mol% B MeO Me S- Bu S-tBu O R O R

i Me, Ph R=H: 99%ee (96%) alkyl Butyl R=Me: 96%ee 94:6 syn:anti H, Me, Et, iPr, iBu

2+ O O

NN =B Cu PM3

2SbF6

D. A. Evans et al. J. Am. Chem. Soc., 1999, 121, 685 Cu(II)-box catalyzed Mukaiyama aldol reaction

HO Me O OTMS MeO O S-tBu A MeO + S-tBu O Me R = H R O Me3SiO Me O MeO S-tBu O

8 runs: 52-97% yield (GLC), 88-95% ee

4 CH3 O O NN Cu tBuTfO OTf tBu P. Salvadori et al., Angew. Chem. Int. Ed. Engl. 2001, 40, 2519-2521. Cu(II)-pybox catalyzed Mukaiyama syn-aldol reactions

OH O OTMS O 0.5-10 mol% A BnO t BnO + SEt S- Bu H R R R=H: 98%ee (95%) R=Me: 97%ee 97:3 syn:anti

Limited scope

O O N Cu N =A Nu (Si face) Ph Ph X-ray

2OTf

D. A. Evans et al., J. Am. Chem. Soc., 1999, 121, 669 Sn(II)-pybox catalyzed Mukaiyama anti-aldol reactions

OTMS O HO Me O MeO + t 1-10 mol% C MeO Me S- Bu S-tBu O R O R R = Me, Et, iBu 97% ee, 98:2 anti/syn 2+

O O N Sn N =C

Ph Ph

2OTf

D. A. Evans et al., J. Am. Chem. Soc. 1997, 119, 10859 Ni(II)-box catalyzed aldol reaction

S O D (10 mol%), S O OH + RCHO S N S N R 2,6-lutidine, TMSOTf (1 equiv) Me Me

R = Aryl, Vinyl, enolizable(!) Alkyl syn:anti 88:12, 90% ee

D. A. Evans et al., J. Am. Chem. Soc. 2003, 125, 8706 Cu(II)-catalyzed Baeyer-Villager Oxidation

O O O

Ph t Ph O2 / BuCHO O + Ph CuL2

69% ee

t Bu tBu O

O2N O N CuL = 2 Cu N O NO2 O tBu tBu

C. Bolm et al., Angew. Chem. 1994, 106, 1944 Cu(I)-box catalyzed heteroatom transfer

Ts N CO Ph A Ph H Ph 2 H CO2Ph 97% ee + PhI NTs O O N N D. A. Evans et al., J. Am. Chem. Soc. 1993, 115, 5328 Cu tBu tBu OTf

OBz A R R

up to 84% ee t + PhCO3 Bu

A. Pfaltz, Tetrahedron Lett. 1995, 36, 1831 Cu(II)-catalyzed benzoylations

Ligand (5mol%) CuCl2 (5mol%) Ph Ph Ph Ph PhCOCl (0.5 eq) Ph Ph Ph Ph

HO OH HO OH DIPEA (1.0 eq) HO OBz HO OH CH2Cl2, 0°C

Me H R O O O N O O N O O N O N N N N N N N N

1 2 3 4: R = H 5: R = Bn-PEG5000

Ligand Time [h] Yield (%) ee (%) Configuration 124899 (R,R) 2 3 48 86 (R,R) 3 3 46 93 (S,S) 4 (0.5 mol%) 3 44 97 (S,S) 5 (5 cycles) 3 40-44 92-97 (R,R)

Y. Matsumura et. al., J. Am. Chem. Soc., 2003, 125, 2052-2053 A. Gissibl, M. G. Finn, O. Reiser Org. Lett. 2005, 7, 2325 Co(II)-catalyzed conjugate reduction

* CoCl2, L Me Me O O NaBH4 N O N O R OEt EtOH/diglyme R OEt N N N N 24h rt * Ph Ph

Me3SiO Me3SiO

R yield % ee % ee Konfiguration (E) 86 95 90 S (Z) 89 81 73 R (E) 86 93 94 R (Z) 86 97 94 S (E) 88 96 94 R (Z) 87 96 94 R TBDMSO 85 95 – S (E)

A. Pfaltz et al., Angew. Chem. 1989, 101, 61 C. Geiger, P. Kreitmeier, O. Reiser, Adv. Synth. Catal. 2005, 347, 249 Cu(II)-catalyzed benzoylations

Ligand (5mol%) O O O CuCl2 (5mol%) PhCOCl (0.5 eq) * + OH DIPEA (1.0 eq) OO OH CH2Cl2, 0°C

H H Me N O O O N O O N O N N N N N N

45%, –39%ee 32%, 77%ee 32%, 27%ee

H H N O O O N O N N N N

38%, 81% ee 36%, 10% ee

A. Gissibl, M. G. Finn, O. Reiser Org. Lett. 2005, 7, 2325 Dendrimers for immobilization of aza(bisoxazolines)

Cl CHO Cl OHC P Cl S Me Cl S N P Cl Cl HO CHO CHO N Cl N S Cl Cl N Cl O H2N P N P P P O N O Cl N K CO P P Cl 2 3 O S N N N N N N P OHC P Cl THF O Cl O K2CO3 O O reflux CHCl N 3 O P P O CHO -63°C N N P O CHO O Gc0 Gc'0 N N P N S Cl S N N P Cl CHO Cl OHC N S Cl OHC CHO P Cl O Cl O P OHC S CHO O S N Gc1 P O O N S N P O N N N

O O THF, rt N O P P O N N P O OHC ONa O

N N O P N S up to 8th generation with S N CHO O N P O 1536 aldehyde functions N OHC S O P O O

CHO CHO CHO

OHC

Gc'1 J.-P. Majoral, Acc. Chem. Res. 2004, 37, 341 Dendrimers for immobilization of aza(bisoxazolines)

OH O N N N

S S O Cl Cs2CO3 O Gc0-3 P + Gc0-3 P THF Cl O N O O T.A. N N O N N O N

Dendrimers with 6, 12, 24, 48 azabis(oxazolines)

F. Jaroschik, in collaboration with J.-P- Majoral Dendrimers for immobilization of aza(bisoxazolines)

O N N N O N O N O N N N N O O O O N P N O S N N O O O N S O N N P N N O O N N O P N N O N S O O N N O O P P O N N P O O O N Gc1-dendrimer N N N N O O P N S N O S N N P O N O O N N S O O P N N N O O O O O N N O N N N O N O N O N N

Chemical Formula: C294H398N51O42P9S6 Exact Mass: 5785.65 F. Jaroschik, in collaboration with J.-P- Majoral Dendrimers for immobilization of aza(bisoxazolines)

Ligand (5mol%) CuCl (5mol%) OH 2 OBz OH PhCOCl (0.5 eq) + OH DIPEA (1.0 eq) OH OH (±) CH2Cl2, 0°C

Catalyst yield ee (R,R) Aza-BOX 45 % 71 % Aza-BOX- 32 % 74 % linker

Gc0 42 % 73 %

Gc1 34 % 78 %

Gc2 41 % 82 % 3 cycles possible

Gc3 40 % 72 % F. Jaroschik, in collaboration with J.-P- Majoral Pybox – Synthesis of the ligand

H. Nishiyama et al., Organometallics 1991, 10, 500 Review: Desimoni et al., Chem. Rev. 2003, 103, 3119 Pybox – Synthesis of the ligand

OH R1 NH R 2 O N O N N NC N CN 1 R ZnCl2, chlorobenzene, R R R1

G. Celucci et al., Tetrahedron: Asymmetry 1999, 10, 3803

Cl Cl MeO OMe N N O O NH NH O O O N O Ph OH N Ph Ph Ph Ph N N N N R NH2 1 R R1 R R inversion retention

P. Reider et al., J. Org. Chem. 1996, 61, 9629 Polymer bound pybox ligands

SnBu3 O O N O O N

N N Pd(PPh3)2Cl2 N N Pri iPr Pri iPr

styrne/DVB

AIBN

Ruthenium complexes were prepared and tested in cyclopropanation reactions O N O N N Pri iPr

A. J. Mayoral et al., Org. Lett. 2002, 4, 3927 Metal complexes of pybox ligands

RhCl3•pybox Re(CO)3Cl•pybox

Organometallics 1989, 8, 846 J. Chem. Soc., Dalton Trans. 1997, 1083

2+ [Cu(BnOCH2CHO)•pybox] La(OTf2)(H2O)4•pybox J. Am. Chem. Soc. 1999, 121, 669 Tetrahedron 2001, 57, 10203 La(III)-pybox catalyzed reaction

TMSO O O

La(OTf)3 • L* O + N O or Ce(OTf) •L* O O 4 H O O N O complete stereoselectivity

O N O N N Ph iPr

G. Desimoni et al., Tetrahedron 2001, 57, 10203 Rh(III)-catalyzed hydrosilylation

X X 1) Ph2SiH2 RhCl3 •L* (1 mol%) Alkyl Alkyl AgBF4 O 2) H+ OH

Alkyl = Me, Et up to 99% ee

L* = O N O N N R R

R = i-Pr > s-Bu > t-Bu > Et

H. Nishiyama et al., Organometallics 1989, 8, 846; Organometallics 1991, 10, 500; J. Org. Chem. 1992, 57, 4306 Metal-pybox catalyzed reactions (=X transfer)

• Ru(II)-catalyzed cyclopropanations (alkene + diazoacetates) • Cu(II)-catalyzed aziridinations (alkene + phenyliodonium ylides)

inferior or similar results compared to box

• Ru(II)-catalyzed epoxidations

O O Ru(II)•L* H Ph N Ph N N Ph + PhI(OAc)2 Ph O H Ru R toluene, 0°C R O O up to 74% ee N O O

H. Nishiyama et al., Chem. Commun. 1997, 1863 C2-chiral Bis(oxazolines) with Secondary Binding Sites

SPACER SPACER O O O O N N N N M X M R

X R

Secondary Interaction through Hydrogen Bond Donor or Acceptor Lewis-Acid or Lewis-Base Asymmetric Diethylzinc Addition to Enones

O O

Et2Zn / –30°C

CuOTf or Cu(OTf)2 Ligand

Ph Ph O O CH N O PN 3 P NMe2 O CH3 Me N N S Pri Pri

32 %ee 98 %ee 62 %ee

Alexakis, 1997 B. Feringa, 1997 B. Feringa, R. M. Kellog, 1997 Mechanism for the Copper Catalyzed 1,4-Addition of Diethylzinc?!

Et Et L + Et Cu H L

O Et O O Zn Zn Et Et

• Activation of the Enone by Zinc • Asymmetric Alkyl Transfer from Copper to the Enone Cu-Bis(oxazolines) in 1,4-conjugated Additions

O O

Et2Zn

O O 65% NN racemic! Cu But But TfO OTf 2-10 mol% M. Schinnerl, 2000

• similar unsuccessful results were reported by A. Pfaltz with semicorrines Tetrahedron 2000, 56, 2879 Bis(oxazoline) Ligands for Zn and Cu?

O Y O R R NN R1 R1 1 1 R OH HO R

O Y O O Y O R R R R NN NN 1 1 1 Cu 1 R Zn Zn R R R X 1 O 1 1 1 R Et O R R OH HO R

O Y O R R NN R1 Cu R1 X 1 R1 OZnX HO R Zn(II)-catalysis: Diethylzinc addition to aldehydes

O Et2Zn OH toluene / hexane / 0°C H Et 2 mol% Ligand

O O O O O O Ph Ph Ph Ph Ph Ph N N N N N N

OH HO OH HO OH HO no reaction 53%, 50 %ee 31%, 49 %ee

5%, racemic O O O O O N O Ar Ar Ph Ph N N N N N N R R OH HO R OH HO R OH HO Ar = Ph: 96%, 93%ee Ar = p-SMe-Ph: 56%, 83% ee no reaction 19%, racemic Org. Lett 2001, 3, 4259 Necessity of Hydroxymethylene Side Chains

O Et2Zn OH toluene / hexane / 0°C H Et

R R O O 60% NN 20% ee But But Enantioselective Catalytic Alkylations

O Et2Zn OH toluene / hexane / 0°C H Et

R O O R Ph Ph NN

(1 mol%) OH HO

R Yield [%] ee [%]

H 96 93 p-OMe 99 95

p-Cl 76 83 2 mol% n-BuLi 92%, 87%ee

p-F 74 88 84%, 87%ee

Org. Lett 2001, 3, 4259 Asymmetric Conjugated 1,4-Additions

O O

Et2Zn (1.4 eq)

Cu(OTf)2 (2.4 mol%)

O O Temperature [°C] Yield (%) % ee Ph Ph N N +20 82 77 HOH C CH2OH +10 83 89 2 (2.8 mol%) +5 81 92 O Y O 0 93 94 Toluol: 72 %ee R R –18 80 67 CH2Cl2: 63 %ee NN Cu THF: 27 %ee Et Solvent: CH CN CH2OH 3 O Additives: TMSCl: 79%, racemic Zn H2O: 81%, 32 %ee O

Org. Lett 2001, 3, 4259 Asymmetric Conjugated 1,4-Additions

O O

R2Zn (1.4 eq)

Cu(OTf)2 (2.4 mol%) n n R R1 R1 R1 R1 O O Ph Ph N N

HOH2C CH2OH

O O O O

Et Ph Et Et

Ph2Zn: no reaction Et2Zn: 93%, 94 %ee Et2Zn: 71%, 41 %ee Et2Zn: 42%, 8 %ee

Ph2Zn / Et2Zn: 53%, 69 %ee (41%, 79 %ee) Ph Zn / Me Zn: 73%, 74 %ee 2 2 Org. Lett 2001, 3, 4259 Helical-Chiral Transition Metal Complexes

CM(R/S)(/) Design of Pentacoordinating Bis(oxazoline) Ligands

O Spacer O O Spacer O R R NN R R NNFe n n X X XH HX n n YYYY Y O Y Y Y OH

R R N N H H O O X H O R NFeN N O N

X = O, OH A. Borovik et al., Science 2001 Second Generation Bis(oxazoline) Ligands for Iron

O N O N NN X X n n n n X X N N O O m Y Y m n Y Y n 1st generation

2nd generation Oxazolines as Modular Building Blocks

N N X X Y Y

N N O N N O O O Y X n Y n n X n

Nucleophile / Electrophile Nucleophile / Electrophile

N N N N X X Lg Lg X X Lg Lg

Lg Lg X X Lg Lg Y Y n n O O O n n O N N N N N N N N O O O O Y n Y Y n n Y n X X X X Pentadentate Bis(oxazolines)

NH DIBAH (3.0 eq) Ph OEt Ph O O NH Cl 91% (>97% ee) Ph 3 20h, 85˚C MeO OH N N OMe or 88% (crude) LiAlH (0.51 eq) O O 4 HO 64% (>97% ee)

Ph O MsCl , NEt3 N 96% N MsO K2CO3, CH3CN, reflux, 31 h N N

46% + N N O O Ph Ph MeHN NHMe N N(NN)2 Adv. Synth. & Catal. 2004, 346, 737 Pentadentate Bis(oxazolines)

NaH (2.1 equiv.) N O Ph S S + N N DMF, 0°C to rt, 18 h HS SH 72% N N MsO O O (2.1 equiv) (1.0 equiv.) Ph Ph

N(SN)2

Adv. Synth. & Catal. 2004, 346, 737 Pentadentate Bis(oxazolines)

NaH (2.1 equiv.) N O Ph O O + N N DMF, 0°C to rt, 15 h Cl Cl 73% N N HO O O (2.1 equiv) (1.0 equiv.) Ph Ph

N(ON)2

Adv. Synth. & Catal. 2004, 346, 737 Complex Preparation

N N X X X X M N N N N O O Ph Ph O O Ph Ph X = O, S +

M(ClO4)n N(XN)2-Perchlorates - Rainbow Chemistry

II M -N(ON)2

Mn Fe Ni Cu Zn

II M -N(SN)2

Mn Fe Ni Cu Zn What did we get?

Possible Configurations with Linear Pentadentate Ligands A-B-C-B-A:

achiral 2 2

each as pair of enantiomers [Ru(N(SN)2)Cl]Cl and [Co(N(SN)2)(THF)](OTf)2

Front View (Ru) Front View (Co)

2 N(SN)2-Complexes in Solution

M Fe Co 2

2configuration also in solution? N(SN)2-Complexes in Solution

CD-spectroscopy of M(II)-N(SN)2-Perchlorates

2configuration for all complexes (?) N(ON)2-Complexes in Solution

CD-spectroscopy of M(II)-N(ON)2-Perchlorates

2configuration for Cu and Ni, 2 for Zn? Cu(II)-complexes

CD-spectroscopy of Cu(II)-N(XN)2-Perchlorates

2configuration, analogous complexation Zn(II)-complexes

CD-spectroscopy of Zn(II)-N(XN) -Perchlorates Zn(N(SN)2 2

–––– Zn-N(SN)2 •••••• Zn-N(ON)2 2

Zn(N(ON)2

2 -configuration for N(SN)2, 2 for N(ON)2 ! Ligand dependant helical conformation

2 for [Zn(II)-N(SN)2](ClO4)2 2 for [Zn(II)-N(ON)2](ClO4)2

Angew. Chem. Int. Ed. 2005, 44, 2422 Fe(II), Cd(II) and Mg(II) complexes

N O O

N N O O II II Fe (ClO4)2 * 6 H2O Ph Ph [Fe (L)(H2O)2](ClO4)2 * THF II II Cd (ClO4)2 * 6 H2O [Cd (L)(H2O)2](ClO4)2 * x solv. II II Mg (ClO4)2 * x H2O THF [Mg (L)(H2O)2](ClO4)2 * x solv.

CdCl2 CdBr2

Inorg. Chem. 2005, 44, 4630 Inorganic-Organic Hybrid Polymers

N O O

N N O O Ph Ph

CdX2 (1.0 equiv.)

MeOH, reflux

J. Am. Chem. Soc. 2004, 126, 11426 Coordination Chemistry of N(XN)2 Bis(oxazolines) Deutsche Forschungsgemeinschaft DAAD / BMBF (IQN) BACATEC Fonds der Chemischen Industrie S tudienstiftung des Deutschen V . Materia C-Tri Degussa Novartis S electide

Kooperationspartner J. W oon Boo F. Gnad M. Haque A. Kaiser A. Roithmeier Prof. A. Beck-Sickinger, Leipzig C. Boehm S. De Pol A. Schall A. Gißibl K. Döhring Prof. H. Waldmann, Dortmund R. B . C hhor R. Patil M. Seitz C. Geiger G. A dolin Dr. O. Zerbe, Zürich E. Jezek G. Heimgärtner S. Soergel R. W eisser R. Tomahagh Prof. Mayoral, Zaragossa B. Nosse Z. C hang Y. Shinde S . Eib auer Y. Rotermund Prof. Majoral, Tolouse A. Gheorghe Dr. A. Matsuno H. Ohli Prof. M. G. Finn, Scripps Dr. P. Kreitmeier Dr. C . Hirtreiter (IQN) Dr. M. Zab el (Xray)