Catalyst Directed Asymmetric Hydrogenation of Carbonyls

Home , Asymmetric hydrogenation

Mike Brochu MacMillan Group Meeting March 31, 2004

! Homogeneous Hydrogenation ! Hydride Transfer ! Bifunctional Catalysis

Reduction of Carbonyls Introduction

! Oxazaborolidine structure based catalysts

H Ph Ph

O N O OH B H3B H Ph Me Ph Me (S/C = 5-10) 97% ee Corey JACS 1987 (109) 5551 Corey JACS 1987 (109) 7925

1 Reduction of Carbonyls Introduction

! Oxazaborolidine structure based catalysts

H Ph Ph

O N O OH B H3B H Ph Me Ph Me (S/C = 5-10) 97% ee Corey JACS 1987 (109) 5551 Corey JACS 1987 (109) 7925 ! Homogeneous hydrogenation - bifunctional catalysis

O OH

X RuCl2((+)-binap) X Me Me

H2 >95% ee X= OH, NR2 Noyori ACIEE 2001 (40) 40 (S/C = 10,000)

! Transfer hydrogenation - bifunctional catalysis

Ru H N N Ts O OH

Ph Me Ph Ph Ph Me i-PrOH Noyori JOC 2001 (66) 7931 >93% ee

History of Asymmetric Hydrogenation I Olefin reductions ! Wilkinson's catalyst capable of achiral olefin hydrogenations

Ph3P PPh3 Rh Ph3P Cl

H (1 atm) Wilkinson J. Chem Soc. (A) 1966, 1711 2 quant. yield ! First report of asymmetric hydrogenation came from William Knowles * Pr(Ph)(Me)P* P(Me)(Ph)Pr CO2H Rh CO2H Pr(Ph)(Me)P* Cl

Me H2 (1 atm) Knowles Chem. Commun. 1968, 1445 15% ee ! Monsanto Chemical Company produces L-DOPA

Ph Ar P Rh CO H CO2H P 2 CO2H + Ar Ph H3O NHAc NHAc NH2 AcO AcO AcO i-PrOH, H2 (1 atm), rt OMe >99% yield OMe OMe L-DOPA Ar= o-(OCH3)C6H4 93% ee Knowles JACS 1975 (97) 2567 ! First demonstration of a chiral metal complex transfering chirality to a non-chiral substrate with high ee ! Limited substrate scope

2 History of Asymmetric Hydrogenation II Origin of asymmetric induction in Knowles' system ! Chelation of carbonyl from acylamino group energetically stabilizes one diastereomeric transition state

(R, R-CHIRAPHOS) P Rh Me Me P

CO2H CO2H

NHAc NHAc i-PrOH, H2 (1 atm), rt >95% ee

Me HO2C NH HN CO2H P P Rh Rh Me Me Me Me P O O P Me Ph Ph

minor diastereomer (not detectable by NMR) major diastereomer (detected by NMR and x-ray crystallography)

! Minor diastereomer is 580 fold more reactive towards H2 oxidative addition - leads to 60:1 product ratio

Halpern Science 1982 (217) 401

History of Asymmetric Hydrogenation III Olefin reductions Me O Ph2 P O ! Noyori develops BINAP-Ru complex Ru P O Ph2 O MeO MeO Me

NAc NAc AcO 0.5-1.0 mol% AcO OAc catalyst OAc morphine EtOH:DCM, OMe 92% yield OMe H2 (4 atm), r.t. 95% ee Noyori JACS 1986 (108) 7117 ! BINAP-Ru shows improved substrate scope

CO2H 0.5-1 mol% CO2H H2 (4 atm): 91% ee Me Me MeOH, H2, 15-30 C Me Me H2 (101 atm): 50% ee

CO2H 0.5-1 mol% CO2H H2 (4 atm): 48% ee Me H2 (101 atm): 92% ee Ph MeOH, H2, 15-30 C Ph

Noyori JOC 1987 (52) 3174 ! First demonstration of high asymmetric induction of substrates lacking an acylamino group

! No trend observed between H2 pressure and enantioselectivity and no rationale given

3 History of Asymmetric Hydrogenation IV Me Olefin reductions O Ar2 P O Ru P O ! Hydrogenation of allylic and homoallylic alcohols Ar2 O (S)-Ru-Binap Me

OH OH 96% ee >97% yield bis-homoallylic and higher analogues are not hydrogenated Noyori JACS 1987 (109) 1596

! Can Ru-Binap catalysts be applied to ketone hydrogenations?

O O (R)-Ru-Binap OH O 41% yield 4% ee Me OEt Me OEt

O Me (R)-Ru-Binap OH Me 72% yield N N 96% ee Me Me Me Me

! Ru-hydride of Binap dicarboxylate catalysts are not hydridic enough in character

4 Substrate-Directed Ketone Hydrogenation Mechanism ! Functional group chelation stabilizes one diastereomeric transition state ! Heteroatom coordinational also affords rate enhancement Diastereomeric T.S. + H X R H X R P P O P Ru O O P Ru O O protonation O H H O O sigma-complex pi-complex RO Me

H X X X P R P P O O P Ru O P Ru O P Ru O O O X H H H2 HX

RuX2[(R)-binap](solv)2

+ solv, H X X P P R P Ru O P Ru O O H2 O O O intramolecular H hydride delivery O OH solv.

RO Me ! Small amount of acid dramatically improves reaction efficiency ! Protonation of keto-oxygen increases electrophilicity of carbonyl carbon and facilitates hydride delivery Noyori ACIEE 2001 (40) 40

5 Diastereomeric T.S. H X R P O P Ru O O H

pi-complex

Ru-BINAP Catalyzed Asymmetric Hydrogenation Enantiodetermining Transition States

! Diastereomeric chelate rings are present in stereodetermining hydride-transfer step

In TSR the R group occupies an open space of the chiral template

PhPh OH O P RuCl2Ln P R OR' Ph Ph >100 O O

R OR' H2 non-bonding repulsion OH O

R OR' 1

In TSS the R group undergoes unfavorable steric interactions

! Enantio-discrimination driven by non-bonding interactions between equatorial phenyl rings and R group

Noyori ACIEE 2001 (40) 40

6 Ru-BINAP Catalyzed Asymmetric Hydrogenation Reaction scope and application

! Variety of functional groups are tolerable

O O O O OH O O NMe2 O S P(OMe)2 Me Me Me O Me

amino ketones diketones keto sulfonates keto phospohnates 100% conv. 100% conv. 100% conv. 100% conv. 95% ee 100% ee 97% ee 98% ee 99:1 anti:syn

! Synthetic Applications of asymmetric hydrogenations

O OH O R S OH

O OH O O HO OH R S S R S R HO OH OH OH OH OH OH OH OH OH OH OH OH OH

(+)-mycoticin roflamycoin

! Stereocenters set by asymmetric hydrogenation are marked Schreiber JACS 1993 (115) 3360 Rychnovsky JACS 1997 (119) 2058

Can Simple Ketones be Asymmetrically Hydrogentated? Chelation traditionally required for rate enhancement and selectivity

Ruthenium Catalyzed Hydrogenation of Simple Ketones Noyori has breakthrough result

! Ruthenium is traditionally a poor metal for carbonyl hydrogenation

O OH RuCl2[P(C6H5)3]2

Me 2-propanol, H2 Me

Ethylene diamine and KOH enormously accelerated hydrogenation N,N,N',N'-tetramethylethylenediamine is totally ineffective NH proton was postulated to act as a hydrogen bond donor

H H2 Ph3P N R Ph3P N X H2 Possible reducing species

! Diamine ligand and inorganic base increase reactivity of Ru-catalyzed carbonyl hydrogenation

7 Asymmetric Hydrogenation of Ketones in the Diamine-BINAP System Catalytic cycle

! Hydrogenation occurs through direct hydride and proton transfer ... Ru-H Hax-N distances are at the outer limit of protonic-hydridic or dihydrogen bonding. (2.4 A)

Ru-H bond weakened by high trans influence of hydride which explains the reactivity of hydridic hydride toward ketones.

R H H Ar2 Me O P H N R Ru Me P H N Me Ar H Me 2 H Proposed mechanism involves concerted transfer of hydridic Ru- trans-dihydride O H H H C H and protic N-H to the ketone via P N Hax H a 6-membered pericyclic TS. Ru P H N eq P H N Ru H2 P H N

Trans effect: labilization of H ligands trans to other ligands, -H Me 2 N typically those with a strong H2 (R - binap)(H)Ru Me R sigma-bonding character. H N Me HO R H2 Me * H hydroamido complex

Morris JACS 2001 (123) 7473 Hydroamido complex rapidly splits H2 under normal reaction conditions

Asymmetric Hydrogenation Ligands can impart chirality

! Chiral diamine ligands influence reaction selectivity

Ph Ph (S,S)

H2N NH2 O OH [RuCl2((S)-BINAP)(dmf)]2 Ar Me Ar Me 99% yield 2-propanol, KOH 97% ee H2 (4 atm), r.t. 6h

Noyori JACS 1995 (117) 2675 Running reaction with diamine antipode affords product with 14% ee

! Diamine-BINAP catalyst selective for carbonyls over olefins

Ar Ph2 H P Cl N Ar Ru P Cl N Ph H i-Pr O 2 OH >99% yield 90% ee Ph Ph 2-propanol, KOH 99% chemoselectivity H (8 atm), r.t. 3h 2 Noyori JACS 1995 (117) 10417

Presence of diamine and inorganic base essential for excellent chemoselectivity

8 Asymmetric Hydrogenation Diamine-BINAP system tolerates broad substrate scope

! Change of chiral diphosphine increases enantioselectivities for many substrates

Heteroaromatic Ketone bis-Aryl ketone Reduction Reduction R 100% conv. >96% conv. Ar2 H P Cl N R 99% ee 99.6% ee O O OMe Ru P N N Me Cl Ar2 H i-Pr

Ar = 3,5-(CH3)2C6H5 15 h.; 30 C; 8 atm H2 24 h.; 30 C; 8 atm H2 R= 4 - CH3OC6H4 (S/C)= 2,000 (S/C)= 13,000

Enone Reduction Cyclopropyl Reduction Aryl Ketone Reduction 100% conv. 96% conv. >99.7% conv. 97% ee 95% ee >99% ee O O O

Ph Me Me Me R

43 h.; 30 C; 80 atm H2 12 h.; 30 C; 10 atm H2 (S/C)= 100,000 (S/C)= 11,000 4-10 h.; 30 C; 8-10 atm H2 R=F, Cl, Br, I, CF3, C(O)OR,

NO2, NH2 in m-, p-, o- positions

! New ligands also show wider scope for aryl ketones Noyori JACS 1998 (120) 13529 Noyori ACIEE 2001 (40) 40

9 Asymmetric Hydrogen Transfer Reactions Introduction ! The reduction of multiple bonds by a metal catalyst with the aid of a hydrogen donor is known as hydrogen transfer

! Hydrogen transfer is advantageous on account of increased safety and chemical flexibility

! Two mechanistic pathways exhist in hydrogen transfer reactions

Hydridic (Stepwise Route)

OH O

Direct Hydrogen Transfer

L L M O O L L L M RL H Me M RS Me L H Favored by main group elements

OH O

R' R" R' R"

Favored by transition metal complexes

Review of H-Transfer: Chem. Rev. 1992, 92, 1051

Asymmetric Hydrogen Transfer Reactions L L Meerwein-Ponndorf-Verley Reduction M O O

RL H Me ! Evans develops a chiral samarium catalyst for MPV reaction RS Me

Bn Ph Ph N Cl O Cl OH R= Me R= Et O Sm O 97% ee 68% ee R R I 100% conv 95% conv 2-propanol, 2 h r.t. Substrate Scope limited to aryl ketones Evans JACS 1993 (115) 9800

! Maruoka develops a bidentate aluminum system

(PhMeCHO)2Al Al(OCHMePh)2 O O Me Me

Ph Ph Ph Me Ph Me Cl Cl DCM, 5 h O OH O OH 0° C 82% yield 54% ee Requires enantiopure alcohols Maruoka ACIEE 1998 (37) 2347 ! Also reports of Lanthanide catalyzed system

10 Asymmetric Hydrogen Transfer Reactions "Classical" Mechanism ! Hydridic route favored by transition metal complexes thought to proceed via stepwise T.S.

! Hydride delivered to substrate by reactive metal hydride species

Hydridic (Stepwise Route)

coordinatively unsaturated M-H first conversion to metal alkoxide 1 forms a C=O complex O R

2 R1 R2 O R M H L L 1 M R H H O R2 "metal hydride" M

OH O Me Me H Me Me Me Me O Me O Me OH M H M

1 2 insertion/elimination R R 2-propanoxide exchanges with substrate ! Nature of base should effect reaction rate by increasing concentration of alkoxide in solution ! Chiral H-donors have only a marginal effect on enantioselectivity in these processes

Ruthenium and Rhodium mediated Asymmetric Hydrogen Transfer Reactions Phosphine ligands

O ! Ruthenium PPh2 PPh O 2 (-)-DIOP O H Ru (CO) [(-)-DIOP) ] OH 4 4 8 2 9.8% ee Ph i-Pr 2-propanol Ph i-Pr 120 C J. Organomet. Chem. 1980 73

Most transfer hydrogenations require temperatures above 150 C with ee's below 50%

Me PPh2 ! Rhodium

Me PPh2 (-)-CHIRAPHOS O [Rh(nbd)((-)-Chiraphos)] OH 59% yield Ph Et Ph Et 34% ee

J. Organomet. Chem. 1986 292 Typical ketone hydrogenations afford 10% ee or less

11 Asymmetric Hydrogen Transfer Reactions Nitrogen-ligand systems

! Phenanthroline ligands afford moderate selectivities N O Ph N Rh H Me Me N N O OH N N t-Bu 89% yield Ph Me Ph Me 63% ee Rh(cod)Cl2 2-propanol Tet. Asymmetry 1990 (1) 635

! Pfaltz's bioxazole ligands can achieve high selectivities

O O

O N N OH i-Pr i-Pr 70% yield Ph i-Pr Ph i-Pr 91% ee [Ir(cod)Cl]2 2-propanol Pfaltz Helc. Chim. Acta 1991 (74) 232

Typical substrates have ee's below 60% ! Iridinium systems may undergo MVP type mechanism

Asymmetric Transfer Hydrogenations Noyori has breakthrough result

! Structurally similar salen-derived catalysts provide drastically different results

O OH OH chiral O Ru catalyst Me + Me +

diphosphine/diamine diphosphine/diimine

H H N Cl N N Cl N Ru Ru P Cl P P Cl P Ph2 Ph2 Ph2 Ph2

1 2 93% yield 3% yield 93% ee 18% ee r.t. 5 h r.t. 48 h

! Lack of amine N-H in 2 makes catalyst much less effective

12 Asymmetric Transfer Hydrogenations Effect of ligand on reactivity ! Amine ligand has a marked effect on reactivity and extent of enantioselectivity

Ethylenediamine (TOF=1) less reactive than no ligand (TOF=3)

N-Tosylated ethylenediamine second fastest catalyst (TOF=86)

Amino alcohol has the fastest reaction rate (TOF=227)

Presence of a primary or secondary amine end is crucial for catalytic activity: dimethylamino analogues are totally unreactive

Noyori JOC 2001 (66) 7931

! Move away from phosphine ligands: Arene ligands are electronically desirable

Spectator ligands automatically occupy three adjacent coordination sites of Ru in an octohedral environment; thereby leaving three sites with a fac relationship for other functions

Ru H L L fac relationship

Ts Ph N Ru Ph N Cl H2

13 Asymmetric Transfer Hydrogenation Away from BINAP Ts Ph N Ru ! Chiral amine ligand affords sufficient enantiofacial discrimination Ph N Cl H2

O Chiral Ru catalyst OH 95% yield Ph Me 2-propanol, KOH Ph Me 97% ee H2 (4 atm) Noyori JACS 1995 (117) 7562

! Methodology extendable to acetylinic ketones

O OH Chiral Ru catalyst >99% yield Me Me 97% ee Ph 2-propanol, KOH Ph H2 (4 atm) Noyori JACS 1995 (119) 8738

! Resident stereogencity has little impact on reaction selectivity

OH O OH (S,S)-Ru-cat (R,R)-Ru-cat

2 h 5 h Ph NHCbz Ph NHCbz Ph NHCbz >99% ee >99% ee >97% yield >97% yield

Asymmetric Transfer Hydrogenation Solution for reversibility problem

! Structural similarity of product and 2-propanol frequently deteriorates enantiomeric purity

Ts Ph 1 N Ru N O OH Ph Cl OH O H2 95% yield + + Ph Me Me Me Ph Me Me Me 97% ee KOH

! Azeotropic mixture of formic acid and triethyl amine makes reaction irreversible

1 OH O >99% yield + CO2 98% ee Ph Me Ph Me HCO2H-TEA

Noyori JACS 1996 (118) 2521

New conditions allow for higher yields, higher substrate concentrations (2-10 M vs. <0.1 M) and wider substrate scope

O O O

MeO S S

>99% yield >99% yield 95% yield 97% ee 99% ee 99% ee

14 Asymmetric Transfer Hydrogenations Mechanism "Revisited"

! Prior results on the effects of primary and secondary amine ligands cause mechanistic questioning.

Classical Hydridic Mechanism Bifunctional Pericyclic Mechanism

OH O 1 O R

2 R1 R2 O R M H L L 1 M R H H H H 2 M N H O R M N H R "metal hydride" M R R2 OH O Me Me R1 O O H OH Me Me H H 1 2 Me Me O Me O Me 1 2 R R R R M N H OH M H M R R1 R2

Theoretical Study on Catalytic Cycle of Asymmetric Transfer Hydrogenations Energy Diagrams of pericyclic and elimination/insertion mechanisms ! MO and DFT calculations show pericyclic mechanism to be more energetically favorable

H Ph CH Ru O O N H H Ph H Ru O Ph O N Ru O H H H H N O H Ru O H H N H Ru O H PhHCO N Ru O H DFT H HN MO

H Ru O Ph H Ru O N H O N H H Ru O H H PhCH2OH Ru N N O PhHC O H H H Ru O PhCH2O N H H

! Neither carbonyl oxygen nor alcoholic oxygen interact with metal center during pericyclic mechanism

Noyori JACS 2000 (122) 1466

15 Asymmetric Transfer Hydrogenation Proposed Catalytic cycle ! Theoretical calculations indicate novel catalytic pathway All pathways are reversible Ru O (CH3)2C H O H N H (CH3)2CHOH Ru Ru O N O H H N (H3C)2C O H H O Base required for "true catalyst" formation not for improving alkoxide OH ion concentration

O Ru O Ru Ru O H N N Cl HN H H2 base HCl-base H "true catalyst" "loaded catalyst"

Preformed complexes of "true catalyst" do not exhibit rate depreciation in the absence of base PhCH2OH Ru Ru O N O H H PhHC O H N Ph H H H Ru O O H N H Hydride delivery occurs through a pericyclic mechanism via a 6-membered T. S. ! Ruthenium and amine ligand simultaneously participate in forward and reverse steps Noyori JACS 2000 (122) 1466

16 Asymmetric Transfer Hydrogenation Synthetic Applications ! Jacobsen's synthesis of Fostriecin

Ts Ph N Ru N H OPMB OH OPMB O Ph H2 Fostriecin O O iPrOH Me OTES TMS TMS 93% conv. >95:5 d.r.

Control of relative stereochemistry of 1,3 diol unit through choice of catalyst enantiomer Jacobsen ACIEE 2001 (113) 3779

! Methodology useful in synthesis of biologically active compounds

CO2H

N O S H3CO2C F C O OMe 3 N S Cl N R NHCH3

96% yield, 91% ee 68% yield, 92% ee MA-20565 L-699,392 (herbal fungacide) (LTD4 antagonist)

Conclusions

! Asymmetric hydrogenation of prochiral ketones is a highly efficient method for obtaining a range of optically pure alcohols in high ee and yield.

! Bifunctional catalytic systems have been developed to overcome reactivity limitations of transition metals for the hydrogenation of simple ketones.

! Transfer hydrogenation is a desirable alternative for the asymmetric reduction of simple ketones due to increased safety and high selectivities.