Catalyst Directed Asymmetric Hydrogenation of Carbonyls
Mike Brochu
MacMillan Group Meeting
March 31, 2004
! Homogeneous Hydrogenation
! Hydride Transfer
! Bifunctional Catalysis
Reduction of Carbonyls
Introduction
! Oxazaborolidine structure based catalysts
H Ph
N
O
H3B
Ph
B
H
Ph
O
Me
OH
Ph
(S/C = 5-10)
Me
97% ee
Corey JACS 1987 (109) 5551
Corey JACS 1987 (109) 7925
1
Reduction of Carbonyls
Introduction
! Oxazaborolidine structure based catalysts
H Ph
N
O
B
H
H3B
Ph
Ph
O
OH
Me
Ph
(S/C = 5-10)
Me
97% ee
Corey JACS 1987 (109) 5551
Corey JACS 1987 (109) 7925
! Homogeneous hydrogenation - bifunctional catalysis
O
OH
RuCl2((+)-binap)
X
Me
H2
X= OH, NR2
X
Me
>95% ee
Noyori ACIEE 2001 (40) 40
(S/C = 10,000)
! Transfer hydrogenation - bifunctional catalysis
H
O
Ph
N
Ru
Ph
Me
N
Ts
OH
Ph
Ph
i-PrOH
Me
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
H2 (1 atm)
quant. yield
Wilkinson J. Chem Soc. (A) 1966, 1711
! First report of asymmetric hydrogenation came from William Knowles
CO2H
*
Pr(Ph)(Me)P
*
Pr(Ph)(Me)P
*
P(Me)(Ph)Pr
Rh
CO2H
Cl
Me
H2 (1 atm)
15% ee
Knowles Chem. Commun. 1968, 1445
! Monsanto Chemical Company produces L-DOPA
Ph
Rh
CO2H
Ar
NHAc
AcO
OMe
Ar
P
CO2H
P
Ph
i-PrOH, H2 (1 atm), rt
>99% yield
Ar= o-(OCH3)C6H4
NHAc
AcO
OMe
93% ee
CO2H
H3O+
NH2
AcO
OMe
L-DOPA
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)
Rh
P
Me
Me
P
CO2H
CO2H
NHAc
NHAc
i-PrOH, H2 (1 atm), rt
>95% ee
Me
Me
HO2C
P
P
NH
Rh
O
CO2H
HN
Me
Rh
Me
Ph
Ph
minor diastereomer (not detectable by NMR)
P
P
O
Me
Me
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
Ru
P
Ph2
O
! Noyori develops BINAP-Ru complex
MeO
AcO
MeO
0.5-1.0 mol%
catalyst
OMe
EtOH:DCM,
H2 (4 atm), r.t.
O
Me
NAc
OAc
O
NAc
AcO
OAc
morphine
92% yield
95% ee
OMe
Noyori JACS 1986 (108) 7117
! BINAP-Ru shows improved substrate scope
Me
CO2H
0.5-1 mol%
Me
MeOH, H2, 15-30 C
CO2H
0.5-1 mol%
Ph
MeOH, H2, 15-30 C
CO2H
Me
Me
CO2H
Me
Ph
H2 (4 atm): 91% ee
H2 (101 atm): 50% ee
H2 (4 atm): 48% ee
H2 (101 atm): 92% ee
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
Olefin reductions
Me
O
Ar2
P
Ru
P
Ar2
O
! Hydrogenation of allylic and homoallylic alcohols
O
O
Me
(S)-Ru-Binap
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
Me
O
Me
Me
N
OH
(R)-Ru-Binap
OEt
OEt
OH
(R)-Ru-Binap
Me
O
Me
Me
Me
N
Me
41% yield
4% ee
72% yield
96% ee
! 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
X
P
P Ru
H
O
RO
X
P
P Ru O
O
X
H2
R
O O
O
Diastereomeric T.S.
H+
protonation
H
X
P
P Ru
O
R
O
O
H
O
HX
pi-complex
sigma-complex
Me
X
P
P Ru
X
P
P Ru O
O
H
H
H
O
R
O
O
RuX2[(R)-binap](solv)2
solv, H+
X
P
P Ru
H2
O
X
P
P Ru
O
O
R
O O
O
H
O
RO
OH
solv.
intramolecular
hydride delivery
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.
X
P
P Ru
H
H
O
R
O
O
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
Ph Ph
P
P
O
R
Ph
O
OR'
H2
OH
RuCl2Ln
O
R
OR'
>100
Ph
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
NMe2
amino ketones
100% conv.
95% ee
OH
O
O
Me
S
Me
Me
diketones
100% conv.
100% ee
99:1 anti:syn
O
O
O
keto sulfonates
100% conv.
97% ee
O
P(OMe)2
Me
keto phospohnates
100% conv.
98% ee
! Synthetic Applications of asymmetric hydrogenations
O
O
HO
OH
S
S
R
OH
OH
OH
OH
O
OH
HO
R
R
O
OH
OH
OH
S
OH
O
OH
(+)-mycoticin
OH
OH
OH
S
R
OH
OH
OH
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
RuCl2[P(C6H5)3]2
Me
2-propanol, H2
OH
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
Ph3P
Ph3P
H H2
N
R
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.
H
H
N
H
N
H
H
O
Me
N
P
H
Ar2
P
R
H
Ar2
H
P
Ru
R
Me
Me
Me
trans-dihydride
H
P
Ru
P
H
Proposed mechanism involves
concerted transfer of hydridic RuH and protic N-H to the ketone via
a 6-membered pericyclic TS.
O
C
Hax
H
N
Heq
Ru
N
H2
P
H
-H2
H2
N
Me
N
H2
Me
Me
Me
(R - binap)(H)Ru
H
N
H
Trans effect: labilization of
ligands trans to other ligands,
typically those with a strong
sigma-bonding character.
R
HO
hydroamido complex
*H
R
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
H2N
NH2
(S,S)
O
Ar
OH
[RuCl2((S)-BINAP)(dmf)]2
Me
Ar
2-propanol, KOH
H2 (4 atm), r.t. 6h
Running reaction with diamine antipode affords product with 14% ee
99% yield
97% ee
Me
Noyori JACS 1995 (117) 2675
! Diamine-BINAP catalyst selective for carbonyls over olefins
O
Ph
Ph2
Cl
P
Ru
H
N
P
Cl
Ph2
N
H
Ar
2-propanol, KOH
H2 (8 atm), r.t. 3h
Ar
i-Pr
OH
>99% yield
90% ee
99% chemoselectivity
Ph
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
Reduction
>96% conv.
99.6% ee
O
N
Me
24 h.; 30 C; 8 atm H2
(S/C)= 2,000
Enone Reduction
100% conv.
97% ee
O
Ph
Me
43 h.; 30 C; 80 atm H2
(S/C)= 100,000
Ar2
Cl
P
Ru
H
N
P
Cl
Ar2
N
H
R
R
bis-Aryl ketone Reduction
100% conv.
99% ee
O
OMe
i-Pr
Ar = 3,5-(CH3)2C6H5
R= 4 - CH3OC6H4
15 h.; 30 C; 8 atm H2
(S/C)= 13,000
Cyclopropyl Reduction
96% conv.
95% ee
Aryl Ketone Reduction
>99.7% conv.
>99% ee
O
O
Me
R
12 h.; 30 C; 10 atm H2
(S/C)= 11,000
Me
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
O
M
L
O
L
RL
RS
H
Me
Me
L
L
M
M
H
L
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
Meerwein-Ponndorf-Verley Reduction
L
O
RL
RS
! Evans develops a chiral samarium catalyst for MPV reaction
Bn
Ph
Cl
O
Sm
Cl
O
OH
R
I
R
H
L
O
Me
Me
Ph
N
O
M
2-propanol, 2 h
r.t.
R= Me
R= Et
97% ee
100% conv
68% ee
95% conv
Evans JACS 1993 (115) 9800
Substrate Scope limited to aryl ketones
! Maruoka develops a bidentate aluminum system
(PhMeCHO)2Al
O
O
Ph
Cl
O
Ph
Al(OCHMePh)2
Me
Me
Ph
Me
OH
DCM, 5 h
0° C
Requires enantiopure alcohols
Cl
OH
Ph
Me
O
82% yield
54% ee
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
forms a C=O complex
O
R1
conversion to metal alkoxide
R1
M
L
R2
O
R2
M
H
L
R1
H
"metal hydride"
O
Me
M
Me
Me
O
M
H
R2
O
Me
Me
H
O
OH
H
Me
Me
Me
OH
M
R1
insertion/elimination
R2
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
PPh2
O
O
Ph
OH
H4Ru4(CO)8[(-)-DIOP)2]
i-Pr
2-propanol
120 C
(-)-DIOP
Ph
9.8% ee
i-Pr
J. Organomet. Chem. 1980 73
Most transfer hydrogenations require temperatures above 150 C with ee's below 50%
Me
PPh2
Me
PPh2
! Rhodium
(-)-CHIRAPHOS
O
Ph
OH
[Rh(nbd)((-)-Chiraphos)]
Et
Ph
Et
59% yield
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
Me
OH
O
Ph
N
N
N
Me
Ph
Ph
Me
N
89% yield
63% ee
t-Bu
Rh(cod)Cl2
2-propanol
NO
Rh H
Me
Tet. Asymmetry 1990 (1) 635
! Pfaltz's bioxazole ligands can achieve high selectivities
O
Ph
i-Pr
i-Pr
O
O
N
N
OH
i-Pr
Ph
[Ir(cod)Cl]2
2-propanol
70% yield
91% ee
i-Pr
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
Me
+
chiral
Ru catalyst
OH
O
Me
diphosphine/diamine
diphosphine/diimine
H
N Cl N
Ru
P Cl P
Ph2 Ph2
N Cl N
Ru
P Cl P
Ph2 Ph2
H
1
2
93% yield
93% ee
r.t. 5 h
3% yield
18% ee
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
H
Ru
L
L
fac relationship
Ph
Ph
Ts
N
Ru
N
Cl
H2
13
Asymmetric Transfer Hydrogenation
Away from BINAP
Ph
! Chiral amine ligand affords sufficient enantiofacial discrimination
Chiral Ru catalyst
O
Ph
Me
Ph
OH
Ph
2-propanol, KOH
H2 (4 atm)
Ts
N
Ru
N
Cl
H2
95% yield
97% ee
Me
Noyori JACS 1995 (117) 7562
! Methodology extendable to acetylinic ketones
OH
O
Chiral Ru catalyst
>99% yield
97% ee
Me
Me
2-propanol, KOH
H2 (4 atm)
Ph
Ph
Noyori JACS 1995 (119) 8738
! Resident stereogencity has little impact on reaction selectivity
OH
Ph
O
(S,S)-Ru-cat
2h
NHCbz
Ph
OH
(R,R)-Ru-cat
5h
NHCbz
Ph
>99% ee
>97% yield
NHCbz
>99% ee
>97% yield
Asymmetric Transfer Hydrogenation
Solution for reversibility problem
! Structural similarity of product and 2-propanol frequently deteriorates enantiomeric purity
1
O
Ph
OH
Me
+
Me
Ph
Ph
Me
Ts
N
Ru
N
Cl
H2
OH
O
+
Ph
KOH
Me
Me
Me
95% yield
97% ee
! Azeotropic mixture of formic acid and triethyl amine makes reaction irreversible
1
O
Ph
Me
OH
Ph
HCO2H-TEA
Me
+
>99% yield
98% ee
CO2
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
Me
MeO
S
>99% yield
97% ee
>99% yield
99% ee
S
95% yield
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
M
L
R2
O
R2
M
H
L
R1
H
O
M
N
O
M
O
H
Me
1
R
R
H
N
2
H
O
O
H
Me
OH
M
R1
OH
H
Me
H
M
R
R2
OH
Me
Me
H
R
M
Me
Me
H
R2
O
"metal hydride"
Me
O
OH
R1
O
R1
Bifunctional Pericyclic Mechanism
H
M
N
H
R1
R2
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
Ph
O
H
Ph
Ph
H
H
H
H
O H
Ru O
Ru O
O
H
Ru O
N
CH
H
H
Ru O
N
H
N
H
H
N
PhHCO
H
Ru O
HN
H
Ru O
N
DFT
H
MO
H
Ph
H
PhHC O H
Ru O
N
H
Ru O
O
H
PhCH2OH
H
N
Ru
N
H
H
Ru O
N
H
H
O
PhCH2O
H
Ru O
N
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
(CH3)2CHOH
H
Base required for "true catalyst"
formation not for improving alkoxide
ion concentration
(CH3)2C H Ru O
O H N
H
N
Ru
O
H Ru O
(H3C)2C O H N
H
O
Ru
N
Cl
H2
base HCl-base
H Ru O
H N
H
Ru O
HN
"true catalyst"
Preformed complexes of "true
catalyst" do not exhibit rate
depreciation in the absence of base
O
OH
"loaded catalyst"
PhCH2OH
H
N
Ru
O
H
Ph
H Ru O
O H N
H
H Ru O
PhHC 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
Ph
OPMB O
O
Ph
O
Me
Ts
N
Ru
H
N
H2
OPMB OH
Fostriecin
iPrOH
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
O
N
S
O
F3C
S
N
H3CO2C
OMe
Cl
NHCH3
N
R
68% yield, 92% ee
L-699,392
(LTD4 antagonist)
96% yield, 91% ee
MA-20565
(herbal fungacide)
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.
17