Chris Borths

MacMillan Group Meeting

October 3, 2001

I. Definition

II. Oxidations

III. Reductions

IV. Alkylations

V. Lewis base catalysis

Reviews:LAC: Berrisford, D.J.; Bolm, C.; Sharpless, K.B. Ang. Chem. Int. Ed. Engl. 1995, 34, 1059.Non-Linear Effects: Girard, C.; Kagan, H.B. Angew. Chem. Int. Ed. Engl. 1998, 37, 2922. Blackmond, D.G. J. Am. Chem. Soc. 1997, 119, 12934.Asymmetric Activation: Mikami, K.; Terada, M.; Korenaga, T.; Matsumoto, Y.; Ueki, M.; Angelaud, R. Angew. Chem. Int. Ed. Engl. 2000, 112, 3532.

Ligand Accelerated Catalysis (LAC)

Berrisford, D.J.; Bolm, C.; Sharpless, K.B. Angew. Cem. Int. Ed. Engl. 1995, 34, 1059.

! Ligand accelerated catalysis can be most simply defined as any reaction where

! Ligand acceleration effect (LAE) is defined by

! Useful levels of selectivity can be achieved when the LAE is 20 or higher.

! If ligand exchange occurs faster than or on the same time scale as the transormation,

asymmetric catalysis becomes viable at high levels of LAE.

A Definition of LAC

A + Bcatalyst

catalyst + ligand

P

A + B P

!ML

!M> 1

k0

k1

k1Keq[ligand]

k0

E

Titanium-Catalyzed Asymmetric Epoxidation

Metal-ligand species detected in solution: Ti(OiPr)4 (M) and diisopropyl tartrate (L)

M1L0, M2L0, M2L1, M3L1, M2L2, M3L2, M3L3, M4L4

(evidence for existence based on NMR, MS, or XRD)

! Multiple metal-ligand species are active epoxidation catalysts

OR

TiRO

OROR

Ti

RO

OOR

ORO

ORO

Ti

OR

OR

ORE

Ti

RO

OO

ORO

ORO

Ti ORO

E

O OR

OR

M1L0

~ 10%

1.4

none

M2L1

~ 10%

1.0

low

M2L2

~ 80%

3.6

high

Berrisford, D.J.; Bolm, C.; Sharpless, K.B. Angew. Cem. Int. Ed. Engl. 1995, 34, 1059.

! Titanium exhibits complex metal ligand association in solution.

O

solution fraction (1:1 M:L)

relative epoxidation rate

enantioselectivity

! The standard SAE receipe calls for a 20% excess of tartrate, practically removing the unwanted epoxidation

catalysts from solution.

OH OH

Titanium-Catalyzed Asymmetric Epoxidation

Ti

O

O

O

O

O

O

TiRO

O

OR

O

Gao, Y.; Hanson, R.M.; Klunder, J.M.; Ko, S.Y.; Masamune, H.; Sharpless, K.B. J. Am. Chem. Soc. 1987, 109, 5765.McKee, B.H.; Kalantar, T.H.; Sharpless, K.B. J. Org. Chem. 1991, 56, 6966.

O

E

RO

E

E

R

OHR

ee ! 94

! Sharpless system shows excellent enatioselectivity. (Ligand DET or DIPT)

OH

R

ee ! 80

OH

R

ee ! 95

OHR

R

ee ! 91

OP

ee ! 90

OP

R

ee ! 92

OPR

ee ! 90

OP

R

ee ! 86

R

OH OH

Osmium-Catalyzed Dihydroxylation

! This is the first reaction to show ligand acceleration by chincona alkaloids.

! The ligand acceleration effect has been demostrated to be greater than 15 and as high as 100 for stilbene at 0 °C.

Jacobsen, E.N.; Markó, I.; Mungall, W.S.; Schröder, G.; Sharpless, K.B. J. Am. Chem. Soc. 1988, 110, 1968.Jacobsen, E.N.; Markó, I.; France, M.B.; Svendsen, J.S.; Sharpless, K.B. J. Am. Chem. Soc. 1989, 111, 737.Sharpless, K.B.; Amberg, W.; Beller, M.; Chen, H.; Hartung, J.; Kawanami, Y.; Lübben, D.; Manoury, E.; Ogino, Y.; Shibata, T.; Ukita, T. J. Org. Chem. 1991, 56, 4585.Kolb, H.C.; Van Nieuwenhze, M.S.; Sharpless, K.B. Chem. Rev. 1994, 94, 2483.

N

HRO

Et

N

MeO

DHQD

N

HOR

N

OMe

Et

DHQ

R = PHAL PYR

THE CATALYSTS

RS RM

HRL

DHQ

DHQD

PYRPHAL

ee 30 - 97 %

PHALee 70 - 97 %

PHALee 90 - 99.8 %

PHALee 90 - 99 %

NN

N N

R'O OR'

Ph

Ph

OR'R'O

INDee 20 - 80 %

IND

N

CO2R'

PYRPHAL

20 - 97 %

OHOH

Multiple Catalytic Cycles Operate in the Osmium Dihydroxylation

O OsO

O

O

L

O

OsO

O

OL

! Slow addition of olefin substrate in presence of acetate can select against the second catalytic cycle.

! Use of K3Fe(CN)6 as the oxidant can eliminate the second catalytic cycle.

Wai, J.S.M.; Markó, I.; Svendsen, J.S.; Finn, M.G.; Jacobsen, E.N.; Sharpless, K.B. J. Am . Chem. Soc. 1989, 111, 1123.Kwong, H.L.; Sarato, C.; Ogino, Y.; Chen, H.; Sharpless, K.B. Tetrahedron Letters 1990, 31, 2999.

OsO

O O

O

O

L

[O]

OsO

O O

O

O

[O]

OsO

O O

O

O

O

H2O

HO OH

H2O, LHO OH

L

Ligand-Accelerated Cycle

High ee

Second CycleLow ee

81% ee in first cycle -7% ee in second cycle

Mechanism of Osmium Dihydroxylation

O

OsO O

OO Os

O

O

O

L

O

OsO

O

OL

[ 3 + 2 ]

Norrby, P.O.; Becker, H.; Sharpless, K.B. J. Am. Chem. Soc. 1996, 118, 35.Nelson, D.W.; Gypser, A.; Ho, P.T.; Kolb, H.C.; Kondo, T.; Kwong, H.L.; McGrath, D.V.; Rubin, A.E.; Norrby, P.O.; Gable, K.P.; Sharpless, K.B. J. Am. Chem. Soc. 1997, 119, 1840.DelMonte, A.J.; Haller, J.; Houk, K.N.; Sharpless, K.B.; Singleton, D.A.; Strassner, T.; Thomas, A.A. J. Am. Chem. Soc. 1997, 119, 9907.Norrby P.O.; Rasmussen, T.; Haller. J.; Strassner, T.; Houk, K.N. J. Am. Chem. Soc. 1999, 121, 10186.

+L

-L

! Hammett studies favor the existence of a concerted mechanism

! Frontier molecular orbital calculations favor a concerted [ 3 + 2 ] mechanism.

! Transition state models with chiral chelating dinitrogen ligands are inconclusive.

! Kinetic isotope effects match the predicted [ 3 + 2 ] calculations and do not match the predicted

[ 2 + 2 ] calculations.

! Quantum mechanical modelling based on the [ 3 + 2 ] mechanism (using MM3* calculations)

can predict the experimental enantioselectivities to within a few percentage points.

O

OsO

O

OL

O OsO

O

O

Os

OO

L

O

O

[ 2 + 2 ]

+L

-L

A concerted [ 3 + 2 ] mechanism is beleived to be correct

Palladum-Catalyzed Oxidations

Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. Tetrahedron Letters 1998, 39, 6011.Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64, 6750.

OHH

O5 mol % Pd(OAc)210 mol % ligand

Ligand

nonepyridine

2,6-lutidinetriethylamine2,2'-bipyridine

pyridine with 3ÅMS

Conversion (2h)

5 %86 %82 %78 %5 %

quantitative

OH

R R

O

R R

! Reaction rate shows a marked dependence on ligand concentration; efficient oxidations at 4 eq ligand / Pd

5 mol % Pd(OAc)220 mol % pyr

3ÅMS

O2

O2

yields ! 63 %most ! 80 %

R = alkyl, aryl, alkenyl, H, keto, cyclic

! Reaction rate accelerated by nitrogen ligands

Palladum-Catalyzed Oxidations: Kinetic Resolution

Jensen, D.R.; Pugsley, J.S.; Sigman, M.S. J. Am. Chem. Soc. 2001, 123, 7475.Ferreira, E.M.; Stoltz, B.M. J. Am. Chem. Soc. 2001, 123, 7725.

OH

R R

O

R R

! (-)-Sparteine is most selective ligand.

5 mol % Pd(II)20 mol % (-)-sparteine

O2

NN

(-)-sparteine

Me

OH

Me

OH

Me

OH

Et

OH

Me

OH

F

MeO

krel = 17.5 / 23.1 krel = 11.6 / 14.8 krel = 15.1 / 12.3

krel = 12.2 / 14.4 krel = 10.1 / 47.1

(Note: first krel is from Sigman paper, second krel is from Stoltz paper)

Zirconium-Catalyzed !"Cyanohydrin Synthesis

Yamasaki, S.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 1256.

! Mono-, di-, and tri-substituted olefins are good substrates for this reaction.

+ +

(BTSP)

TMS

OO

TMS

TMSCN

1) 20 mol % Zr catalyst ClCH2CH2Cl

2) KF, MeOH

Zr catalyst

Zr(OnBu)4

Zr(OiPr)4

Zr(OtBu)4

time

84 h

63 h

38 h

yield (%)

62

63

63

O

Zr(OtBu)2

O

PhPh

PhPh+ Ph3PO

15 h

1.5 h

68

94

alone

OH

CN

R R

R

R

R

R CN

OH

yields ! 53

! Reaction shows significant ligand acceleration.

Zirconium-Catalyzed !"Cyanohydrin Mechanism

Yamasaki, S.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 1256.

! Mechanism proposal based on Ti-catalyzed epoxidation and Yb-catalyzed epoxide opening

Zr(OtBu)4 + TMSCN + Ph3PO +OH

OH

ZrO

O CN

CN

OPh3P

ZrO

O CN

O

OPh3P

O

TMS

ZrO

O CN

O

OPh3P

O

TMS

ZrO

O CN

OTMS

OPh3P

ZrO

O O

O

OPh3P

CN

TMS

TMS

Zr O

O

CN

ZrO

O O

O

OPh3P TMS

TMS

Zr OH

O

CN

O

ZrO

O O

O

OPh3P

NC

TMS

Zr O

O

CN

OTMS

NC

O

BTSP

TMSCN

TMSOTMS

TMSCN

TMSCN

OTMS

CN

Enantioselective Zr-Catalyzed !"Cyanohydrin Synthesis

Yamasaki, S.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 1256.

! An enantioselective variant has been proposed and is under development.

+ BTSP + TMSCN

1) Zr(OtBu)4 : ligand : H2O (1:1:1) ClCH2CH2Cl

2) KF, MeOH

OH

CN

OH

OH

Ph Ph

Ph Ph

O

O

Et

Et

LIGAND

85% yield62% ee

Pt

PtPt

Platinum-Catalyzed Hydrogenation of Ethyl Pyruvate

! Chincona alkaloids have been shown to adsorb to Pt surfaces in an ordered pattern with uniformly shaped pores.

! Relative reaction rates from kinetic data suggest a ligand acceleration effect of !13.

Blaser, H.U.; Jalett, H.P.; Lottenbach, W.; Studer, M. J. Am. Chem. Soc. 2000, 122, 12675.Thomas, J.M. Angew. Chem. Int. Ed. Engl. Adv. Mater. 1989, 28, 1079.Garland, M.; Blaser, H.U. J. Am. Chem. Soc. 1990, 112, 7048.

O

Me CO2Et

OH

Me CO2Et

Pt/Al2O3, H2

modifier

N

HOMe

N

Et

ee 93%

N

HOH

N

Et

ee 20%

HON

ee 75%

NH2

ee 82%

N

N

RO H

Me

OEtO

Pt

MeO

H

! Author's rendition of proposed transition states

PtPt

N

RO HO

EtO

R

H

O

Me

Pt Surface Modifiers

Ruthenium-Catalyzed Transfer Hydrogenation

! Only aryl ketones are reduced enantioselectively.

20 mol % RuCl2(PPh3)3

26 mol % ligand

iPrOH / iPrOK Me

OH

Me

O

Ligand

none

time

20 h

6 h

conversion

5 %

93 %(94% ee)

Fe O

NPh

PPh3

R

Me

Et

iPr

20 mol % RuCl2(PPh3)3

26 mol % A

iPrOH / iPrOK Ar R

OH

Ar R

O

A

yields ! 75 %

Sammakia, T.; Strangeland, E.L. J. Org. Chem. 1997, 62, 6104.

ee (%)

! 84

96 (Ar = Ph)

88 (Ar = Ph)

Copper-Catalyzed Enolsilane Amination

! Amination reaction allows access to chiral building blocks: protected chiral hydrazines, hydrazino alcohols,

and oxazolidones.

Evans, D.A.; Johnson, D.S. Org. Lett. 1999, 1, 595.

XR

OTMS

ONNN

Troc

O O

N

O

N

O

Me Me

tBu tBu

Cu

2+

2 OTf-

ONNH

NTroc

O OR

X

O

1-10 mol %

CF3CH2OH

X = Ar, pyrrole, StBuR = Me, Et, iPr, tBu, Ph, Bn

+

yield ! 64ee ! 96

NN

O

L2CuO

N

O

Ph OTMS

R

Troc NN

O

Ph OTMS

R

Troc ON

O

proposed intermediates

! Evidence for LAC: Use of excess Cu(OTf)2 (50 mol %) relative to ligand (2 & 10 mol %) shows no significant

decrease in enantioselectivity (99 % vs. 96 % ee).

ROH

ROTMS

Conjugate Additions of Dialkylzinc Reagents

O

R HEt2Zn+

2 mol % catalyst

! Diamines and amino-alcohols accelerate the reaction of dialklzinc reagents with aldehydes.

Et

OH

98 % ee

Me

NMe2

OH

CatalystO

Me

OH

99 % ee(using (C5H11)2Zn)

OH

Me

OH

Me

96 % ee

90 % ee

Me

OH

Me

61 % ee

Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.; Oguni, N.; Hayashi, M.; Kaneko, T.; Matsuda, Y. J. Organomet. Chem. 1990, 382, 19.Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley and Sons, Inc.: New York, 1994.

! Without catalyst, no product is generated under reaction conditions.

Me2N

OZn

MeMe

ZnR

R

O

R

Ph

H

proposed T.S.

Titanium-Catalyzed Enantioselective Alkylation of Aldehydes

Et2Zn+20 mol% B

1.2 equiv Ti(OiPr)4

O

O

Ti(OiPr)2

O

O

Me

Me

PhPh

Ph Ph

Ph Et

OH

96% yield98% ee

Weber, B.; Seebach, D. Tetrahedron 1994, 50, 7473.Rozema, M.J.; Sidduri, A.; Knochel, P.; J. Org. Chem.; 1992; 57; 1956.Rozema, M.J.; Eisenberg, C.; Lütjens, H.; Ostwald, R.; Belyk, K.; Knochel, P.; Tet. Lett.; 1993; 34; 3115.

R1 H

O R2Zn, Ti(OiPr)4

8 mol% cat R1 R

OH TfN

NTf

Ti(OiPr)2

56-95% yield68-98 %eeR1 = alkyl, !,"-unsat, aryl

O

Ph H

! Catalytic ligand loading can be used with stiochiometric titanium

! Taddol prevents titanium oligomerization.

! Diamine ligand increases titanium's Lewis acidity.

Lewis Base-Catalyzed Aldol Reactions

Denmark, S.E.; Stavenger, R.A. Acc. Chem. Res. 2000, 33, 432.

OSiCl3

MeO

O

H tBu MeO tBu

O OSiCl3CD2Cl2, -80 °C+

Additive

none

10 mol % HMPA

time

2 h

<3 min

Conversion

50 %

100 %

! Phosphoramide ligands greatly increase the reactivity of silicon as a Lewis acid.

OSiCl3

R1

O

H R2 R1 R2

O OH

CH2Cl2, -78 °C+

R1

nBu

nBu

nBu

Me

tBu

Ph

R2

(E)-CH=CHPh

c-C6H11

tBu

Ph

Ph

Ph

ee (%)

84

89

92

87

52

49

N

P

N

Me

Me

O

N

5-10 mol % catalyst

CATALYST

yields ! 79%

! Enantioselective methyl ketone aldol reactions:

Lewis Base-Catalyzed Aldol Reactions

Denmark, S.E.; Stavenger, R.A.; Wong, K.T.; Su, X. J. Am. Chem. Soc. 1999, 121, 4982.Denmark, S.E.; Stavenger, R.A. Acc. Chem. Res. 2000, 33, 432.

OSiCl3 O

H R R

O OH

+

! Geometry of enolate controls stereochemical outcome of reaction.

OSiCl3

Ph

O

H R Ph R

O OH

+

ee (%)!84929110*

N

P

N

Me

Me

O

N

15 mol % catalyst

CATALYST

yields ! 89%

Raryl

CH=CHPhCMe=CHPh

C!CPh

syn/anti1 / !61<1 / 99<1 / 991 / 5.3

ee (%)!93889282

yields !90

10 mol % catalyst

Me

Me

Raryl

CH=CHPhCH=CHMe

C!CPh

syn / anti!3 / 19.4 / 17.0 / 11 / 3.5

* anti ee

Silicon-Catalyzed Allylation and Propargylation of Aldehydes

Denmark, S.E.; Wynn, T. J. Am. Chem. Soc. 2001, 123, 6199.

CATALYST

N

N

P

Me

Me

O

N

Me

(CH2)5

2

O

R HSnBu3

5 mol % catalyst

110 mol % SiCl4

+ R

OH

Raryl

cinnamylC!CPh

furyl

ee (%)!83652262

yields ! 65%

O

R H

5 mol % catalyst

110 mol % SiCl4

+R

OH

H

H SnBu3

H H

RPh

cinnamyl2-naphthyl

ee (%)978793

yield (%)819095

! Variation in catalyst linker length affects reaction efficiency and selectivity. This supports a mechanism involving 2

phosphoramides in the transition state.

Lewis Base-Catalyzed Aldol Mechanism

Denmark, S.E.; Stavenger, R.A. Acc. Chem. Res. 2000, 33, 432.

! Kinetics and a demonstrated non-linear relationship between catalyst ee and product ee

suggest two phosphoramide molecules involved in the transition state.

! Exerimental evidence suggests chloride dissociation is involved in the reaction.

! Kinetics of a more sterically encumbered catalyst suggest an alternate mechanism involving

only one phosphoramide molecule.

N

P

N

Me

Me

O

N

CATALYST

OSiCl3

2 (R2N)3PO

(R2N)3PO

O SiCl

O

O

Cl

P(NR2)3

P(NR2)3

Cl-

SiO

O OPR3

Cl

OPR3

Cl

Ph

H

PhCHO

Cl-

O

Ph

OSiCl3

-2 (R2N)3PO

Chair-like T.S.high selectivity

O

SiO Cl

Cl

P(NR2)3Cl-

anti

PhCHOSi

O

O OPR3

Cl

ClPh

H

Boat-like T.S.low selectivity

Cl-

-(R2N)3PO

O

Ph

OSiCl3

syn

! Most ligand accelerated processes exhibit non-linear effects (rate and ee).

! LAC allows for highly selective transformations by selecting against an undesired pathway.

! LAC lends itself well to the development of asymmetric transformations.

! The discovery of more ligand-accelerated transformations will be a fruitful field in asymmetric catalysis.

This is my Summary Slide