why zn acetylides?

Catalytic, Enantioselective Carbonyl AdditionReactions of Metal Acetylides

An Evans Group Afternoon SeminarJake Janey

May 31st, 2002

I. Introduction II. Stoichiometric Zn, catalytic ligandIII. Catalytic Zn and ligand (Carreira)IV. Other metal acetylides

R HO

R'+

Catalytic

Metal/Ligand

OH

R'

R

Keywords: Acetylene, Metal Acetylide, Enantioselective, Carbonyl, Catalytic, Zinc, Copper, Iridium, Lithium, Ephedrine, Asymmetric, Addition, Imine, Nitrone, Aldehyde, Alkyne

01 Introduction 6/5/02 9:31 AM

A Versatile Synthetic Intermediate

OH

R'

RR''

• Propargylic alcohols are an important synthetic building block

• Subunit in Merck's HIV-1 reverse transcriptase inhibitor Efavirenz

OH

R'

RR''

OH

R'R''

R

OH

R'R''

R

orH2

XNH2OH

R'R''

R

NHX

[3+2] or[4+2]

ZY

XR'R''

OH

R ZY

XW

R'R''

R

OH

or

OH

R'R''

X

XY

R = H

R

BaseE+

OH

R'

ER''

Yhydrohalogenationhydrozirconationhydroborationcarboaluminationcarbocupration

Cu2Cl2OH

R'R''

R

Pd(0)

CuI

OH

R'R''

R

The Chemistry of Triple Bonded Functional Groups; Patai, S., Rappoport, Z., Eds.; Wiley: New York, 1983Preparative Acetylene Chemistry; Brandsma, L., Ed.; 2nd ed.; Elsevier: Amsterdam, 1988Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH: Weinheim, 1995

02 Synthetic Importance 6/5/02 9:32 AM

Common Methodology

R MO

R'+

OH

R'

RR'' R''

• Resolution or diastereoselective

M = Li, MgBr, Cs, K, Na, SnX3

O

R'

R

" H- "

Chiral Catalyst

OH

R'

R

O

R'

R

(R'')2Zn

Chiral Ligand

OH

R'

RR''

O

H

R

OM

R'+

Chiral CatalystOH

R

R'

O

O

R'R

HO

MeMe

Al(OR)3 or

Zr(Ot-Bu)4+

OH

R'

R

Maruoka, K. et. al. Tetrahedron, 2001, 867-873 (and ref. cited therein)

03 Alkynlation 5/31/02 11:24 AM

Alkyne Acidity

HR

pKaR=H 24 (H2O)R=Ph 23 (H2O) 28.8 (DMSO)

High kinetic acidity

HR

pKaR=H 50 (H2O)R=Ph 43 (H2O) 44 (DMSO)

HR

R

pKaR=H 48 (H2O) 56 (DMSO)R=Me 51 (H2O)

Typical Bases: n-BuLi or EtMgBr

t-BuO Me

O

pKa24.5 (H2O) 30.3 (DMSO)

A few known examples of catalytic base...

HRR' R''

O

R'

OH

RR''

+cat. base

THF or DMSO

KOH or NaOH: Shachat, N.; Bagnell, J. J. J. Org. Chem. 1962, 27, 1498-1504KOt-Bu: Babler, J. H.; Liptak, V. P.; Phan, N. J. Org. Chem. 1996, 61, 416-417CsOH: Tzalis, D.; Knochel, P. Angew. Chem. Int. Ed. 1999, 38, 1463-1465

04 Acidity 5/30/02 11:23 AM

Catalytic, Enantioselective Alkynylation

R H

X

R'XML*

R'

R

R''

R''

cat. ML*R ML*

chiral nucleophile

XH

R'

RR''

ML*

• Need either catalytic base to transfer proton, or a metal capable of oxidative addition

A Simple Analogy...

R MXChiral Ligand

(L*)R MXL*

X

R'XML*

R'

R

R''

R''chiral nucleophile

XM

R'

RR''

L*

• Stoichiometric formation of a metal acetylide with a catalytic amount of chiral ligand

Reviews of organozinc additions:Noyori, R.; Kitamura, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 49-69Pu, L.; Yu, H. -B. Chem. Rev. 2001, 101, 757-824Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833-856

05 Catalytic schemes 6/5/02 9:32 AM

Why Zn Acetylides?

Me2Zn + HRTHF/tol.

ZnR2

insoluble white ppt.

conditions: • 30% conversion in 17h at 0 °C without ligand• NMR shows no dialyknyl zinc formation when Me2Zn and alkyne mixed without ligand• Addition of chiral ligand gives 100% conversion in 3h at 0 °C

R'CHOR'

R

OH

Ligand Acceleration !

Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele, L.; Reider, P. J. Synthesis 1999, 1453-1458

R Zn R

Why?

sp hybridized

nonpolar

unreactive

RZn

Xδ+δ−

X = alkyl, N, O, Halogen, etc...

spn hybridizedpolar

reactive

OZn

R'2N

ZnO

NR'2

R

R

OZn

R'2N

R2

reactive

Noyori, R.; Kitamura, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 49-69

unreactive

06 Why Zn Acetylides 5/30/02 11:33 AM

R

Organozinc Catalytic Cycle

OZn

R'2N

ZnO

NR'2

R

ROZn

R'2N


OH

NR'2

+R2Zn-RH

1/2

+R2Zn

-R2ZnZn

R

RR

+ArCHO-ArCHO

OZn

R'2N O

R

Ar

OZn

R'2N+R2Zn

-R2ZnZn

R

RR

+ArCHO-ArCHO

OAr

Slow

OZn

R'2N

ZnO

R

Ar

R

ArCHO

1/4 A

R2Zn

Zn

O

O

O

ZnZn

Zn

O

R

R

Ar

R

ArR

ArR

R

A

1/4insoluble aggregate

drives reaction forward=> ligand turnover

R

07 Zn Catalytic Cycle 6/5/02 9:32 AM

Model for Asymmetric InductionGeneral for β-Amino Alcohols


OZn

R'2N

Ph

Me

OZnR2

R

α

β

(S)

(R)

OZn

R'2N

Ph

Me

RZnR2

O

α

βAr

(S)

(R)N-alkyl-ephedrine

N

OZn

ZnO

R

R'

R'Me

(S)α

β

α gears ZnR2

Disfavoredinteraction between Ar and ZnR2

Favored

or

General Features:• α stereocenter dictates observed product selectivity without exception• trans α,β chelate offset and show lower selectivity, α still dominates -->Cis best• Gearing effect --> direct sterics between aldehyde and ligand unimportant

H

ArR

R

N

OZn

ZnO

R

R'

R'Me

(R)α

β

Ar

HR

R

Evans, D. A. Science 1988, 240, 420-426.

Ar

08 Model for induction 6/5/02 9:32 AM

Origins of Non-Linear Effect


Large positive non-linear effect: 15% ee catalyst delivers 95% ee product for diethylzinc addition to benzaldehyde in presence of 3-exo-(dimethylamino)isoborneol [DAIB]

OZn

Me2N

ZnO

NMe2

R

R1/2

(2S, 2'S)

OZn

Me2N

ZnO

NMe2

R

R1/2

(2R, 2'R)

OZn

Me2N

R

OZn

Me2N

ZnO

NMe2

R

R

(2S, 2'R)

ZnO

NMe2

R+

(2S) (2R)

Heterochiral dimer very stableno activity

Homoochiral dimer not stableno activity

Chiral monomeractive

• Slight excess of one enantiomer is enhanced as all of the minor enantiomer is tied up as heterochiral dimer

09 Nonlinear 6/5/02 9:33 AM

Kinetic Chicanery...(Don't be fooled by rates)

Noyori, R.; Kitamura, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 49-69Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028-4036

Et2Zn + PhCHODAIB

tol. 0 °C Et Ph

OH

• Example: using 34 mM DAIB, 0.42M Et2Zn, and 0.42M PhCHO indicates that (-)-DAIB is merely 14-times faster than (±)-DAIB• 15% ee catalyst gives 95% ee product indicates that chiral is 171-times faster than racemic

The independant and competitive figures are not the same !

• Answer: The rate of (-)-DAIB catalysis is not as affected by [Et2Zn] or [PhCHO], whereas rate for (±)-DAIB is very dependent upon substrate concentration.

10 Kinetics 6/5/02 9:33 AM

Chelate Controlled Additions

R CHO

OBnMR1 + -78 °C

R

OR1

OH

R1

R

OR1

OH

R1

+

syn anti

Entry

1

2

3

4

5

6

7

8

9

10

11

12

R'

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

n-Hex

n-Hex

Aldehyde (R)

Me

Me

Me

Me

Me

Me

Me

Me

i-Pr

BnOCH2

Me

i-Pr

M

Li

MgBr

ZnCl

ZnBr

ZnBr

MgBr

ZnCl

ZnBr

ZnBr

ZnBr

ZnBr

ZnBr

Solvent

THF

THF

THF

THF

THF, 0 °C

Et2O

Et2O

Et2O

Et2O

Et2O

Et2O

Et2O

syn : anti

45:55

62:38

66:34

81:19

76:24

74:26

88:12

95:5

99:1

86:14

84:16

98:2

Yield (%)

-

-

-

75

70

82

65

95

92

76

79

78

• Zn acetylide formed by transmetalation of Li acetylide with ZnX2• 2 equiv. of Zn acetylide used, as 1 equiv. gave same selectivity, but lower yields.• Zn chelate is proposed to explain syn selection

Mead, K. T. Tetrahedron Lett. 1987, 28, 1019-1022

For chelate controlled Sn-acetylide additions, see: Evans, D. A.; Halstead, D. P.; Allison, B. D.Tetrahedron Lett. 1999, 40, 4461-4462

11 Chelate addition 6/5/02 9:33 AM

Early Example of Zn Acetylide Addition

R1CHO + ZnR2

2

5 mol%

Hex/THF, r.t.2 equiv.

OHn-Bu2N

Me PhH H

R1

OH

R2(R)

(R)(S)

Entry

1

2

3

4

5

6

7

8

R1

Ph

n-Octyl

PhCH=CH

Ph

Ph

Ph

n-Octyl

Ph

R2

Ph

Ph

Ph

n-Hex

Bu

Me3Si

Me3Si

c-Hex

Time (h)

14

5

14

44

52

168

48

48

Yield (%)

99

78

97

81

93

36

80

88

ee (%)

34

9

10

22

20

21

24

7

• Zn-acetylides formed by heating Et2Zn and the acetylene• Stereochemistry in accord with Noyori's model• Mixed alkylalkynyl zinc reagents (e.g. MeZn-≡C-Ph) gave only alkynylation with 40% ee

Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990, 937-943

12 Soai Zn-ephedrine 6/5/02 9:33 AM

Improved Zn Acetylide Addition

RCHO + ZnBrPh1 equiv.

toluene2 equiv.

OLin-Bu2N

H HMe Ph

R

OH

Ph

(R) (S)

(S)

Entry

1

2

3

4

R

Ph

t-Bu

n-Pent

T (°C)

-30

-30

-30

0-5

Time (h)

19

24

20

20

Yield (%)

70

50

90

80

ee (%)

80

67

19

88O

F

Cl

Cl

O

MeMe

Ph

O

F

H

OInsecticide

ZnEtPh

delivers product in42% ee

Tombo, G. M. R.; Didier, E.; Loubinoux, B. Synlett. 1990, 547-548

• Catalytic reaction with 10 mol% isolated Zn acetylide amino alcoholcomplex gives product in only 35% ee

13 Amino alkoxide cat 5/30/02 1:03 PM

Tridentate Chiral Ligand

R1CHO + ZnEtR2 10 mol%

THF R1

OH

R2(R)

Entry

1

2

3

4

5

6

7

8

9

R1

Ph

n-Octyl

c-Hex

t-Bu

Ph

n-Octyl

c-Hex

t-Bu

c-Hex

R2

Ph

Ph

Ph

Ph

n-Hex

n-Hex

n-Hex

n-Hex

Ph3Si

Time (h)

15

4

10

10

2

1

3

3

5

Yield (%)*

64

65

88

61

41(52)

62(22)

79(18)

67

55

ee (%)

90

83

91

95

78

73

82

87

91

Temp. (°C)

0

0

0

0

r.t.

r.t.

r.t.

r.t.

r.t.

* Values in parenthesis are yields of ethylated product

N

O

HO

ArAr(S)

Ar = α-naphthyl

• Opposite facial selectivity as Noyori's bidentate ligand model• Zn acetylide formed by diethylzinc and acetylene heated at reflux

Ishizaki, M.; Hoshino, O. Tetrahedron: Asymm. 1994, 5, 1901-1904

14 Tridentate ligand 6/5/02 9:34 AM

Merck's Ephedrine Derivative

OHN

H HMe Ph(R) (S)

1. ZnMe2

2. ROH Ph

Me

N

ZnO

ORM

Ph

Me

N

ZnORO

M+

+

ClCF3

O

NH2

ClOH

NH2

F3CClO

NH

F3C

O

Efavirenz: HIV reversetranscriptase inhibitor

1 equiv.

M

Li

MgCl

MgBr

MgI

ee (%)

83.0

87.0

53.6

50.6

ROH

MeOH

EtOH

(CH3)3CCH2OH

CH2=CHCH2OH

BnOH

CF3CH2OH

CF3CO2H

(CH3)3CCO2H

p-NO2PhOH

ee (%)

87.0

55.0

95.6

90.0

89.0

95.7

89.4

71.6

89.0

M = MgCl

ClOH

NH2

F3CCl

OH

NH2

F3C

OH

F3C

Cl

O CF3

95.2% ee 97.0% ee

97.0% ee

NH2

Tan, L.; Chen, C.; Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J. Angew. Che,. Int. Ed. 1999, 38, 711-713

15 Merck Zn 6/5/02 9:34 AM

Merck's Catalytic Process

Ar

O+ Ph H

ZnMe2, toluene/THF

10mol% ligand, -30 °C Ar

OH

Ph

OHN

H HPh Ph(R) (S)

OHN

Ph PhH H(S) (R)

A B

Entry

1

2

3

4

5

6

7

8

9

Ar

Ph

o-F-Ph

m,o-di-F-Ph

o-Cl-Ph

o-Br-Ph

o-NO2-Ph

o-MeO-Ph

o-Me-Ph

2-naphthyl

Ligand

A

B

B

A

A

A

A

A

B

Yield (%)

70

90

94

77

77

81

74

65

87

ee (%)

68(-)(S)

82(-)

81(+)

80(+)

80(+)

76(+)

82(+)

62(+)

75(-)

• Use of toluene/THF eliminate methyl addition• Small non-linear effect observed• Stereochemistry in accord with Noyori's model• Zn-acetylide only forms upon addition of ligand (by NMR)

Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele, L.; Reider, P. J. Synthesis 1999, 1453-1458

16 Merck's catalytic Zn 6/5/02 9:34 AM

BINAP Derived Amino Alcohol

Ar

O+ Ph H

ZnMe2 (2 equiv.), tol.

10mol% ligand, 0 °C Ar

OH

Ph

OHN

H HPh Ph

(R)(S)

Entry

1

2

3

4

5

6

7

Ar

o-F-Ph

o-Br-Ph

o-NO2-Ph

o-MeO-Ph

o-Me-Ph

2-naphthyl

Ph

Conv. (%)

>95

>95

>95

>95

>95

>95

>95

ee (%)

87(+)

90(+)

87(+)

71(+)

71(+)

61(+)

70(-)(S)

• Other diasteromers of ligand give low ee• Stereochemistry in accord with Noyori model• OH bearing stereocenter on ligand determines facial selectivity

Lu, G.; Li, X.; Zhou, Z.; Chan, W. L.; Chan, A. S. C. Tetrahedron: Asymm. 2001, 12, 2147-2152

(R)

(1R, 2S, 3R)

2 equiv.

Time (h)

12

12

24

6

24

24

24

(S)

17 BINAP derived ligand 6/5/02 9:35 AM

Titanium H8-BINOL Catalyzed

R

O+ Ph H

ZnMe2, Ti(Oi-Pr)4 (1.5 equiv.)

THF, 20mol% H8-BINOL, 0 °C Ar

OH

Ph(S)

OHOH

(R)-H8-BINOL

Entry

1

2

3

4

5

6

7

8

9

10

11

12

13

14

R

Ph

o-Cl-Ph

m-Cl-Ph

p-Cl-Ph

p-Me-Ph

p-F-Ph

p-Br-Ph

p-NO2-Ph

m-NO2-Ph

2-naphthyl

p-CF3-Ph

i-Pr

c-Hex

n-Pr

Yield (%)

85

90

87

91

84

82

89

89

88

75

89

84

86

87

ee (%)

92 (S)

76

95

94

86

87

94

95

96

80

93

82

74

77

• BINOL gave slightly reduced yieldsand selectivity

Lu, G.; Chan, W. L.; Chan, A. S. C. Chem. Commun. 2002, 172-173

18 TiBINOL catalyzed 6/5/02 9:35 AM

Titanium BINOL Catalyzed

R

O+Ph ZnEt

50 mol%Ti(Oi-Pr)4

20 mol% (S)-BINOL, r.t. Ar

OH

Ph(R)

Entry

1

2

3

4

5

6

7

8

9

10

11

R

Ph

m-Cl-Ph

p-Cl-Ph

o-Me-Ph

m-Me-Ph

o-MeO-Ph

m-MeO-Ph

p-F-Ph

p-NO2-Ph

2-naphthyl

1-naphthyl

Yield (%)

77

79

81

81

77

73

78

74

79

77

71

ee (%)

96

92

92

96

94

93

93

96

97

98

92

Ph HEt2Zn

tol. reflux2 equiv. CH2Cl2/toluene

i-Pr3Si H + PhCHOgives 75% yield and 92% ee

Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855-1857

19 TiBINOL catalyzed II 5/28/02 7:05 PM

"Soft" Metal Acetylide Formation

R HCuX or

AgXR H

M(I)X

:NR3

HNR3X

R M

Advanced Inorganic Chemistry; Cotton, F. A., Wilkinson, G.; 5th ed.; Wiley: New York, 1988, p.765, 945

R

M

R

M

n

sp-C-H activation:R H

MLn

R MLn

H

R H

+

Ox. Add.

Insertion

MLn

HR

R or

MLn

H

R

R

Red. Elim.

RR R

Ror

Metals: Ru(II), Ir(I), Ti(IV), Pd(0), Rh(I), others?

Ru(II): Naota, T.; Takaya, H.; Murahashi, S.-I. Chem Rev. 1998, 98, 2599-2660

Unreactive to electrophiles

20 Metal Acetylide 6/5/02 9:35 AM

Early Examples of Catalytic Metal

Ph H + CH2O HNR2+

5-8h, 100 °Cdioxane

or cat. Cu(X) or ZnX2

-30 °C to r.t.

R2N

Ph

Thermal: Mannich, C.; Chang, F. T. Ber. 1933, 418-420Catalytic ZnX2 or CuX: for an example, see: Stutz, A.; Granitzer, W.; Roth, S. Tetrahedron 1985, 41, 5685-5696.

H + CH2O HNR2+ R2N

HO

Cu(SO4)2

H2O (pH 9)+ Cu(0)

• A copper acetylide is proposed• Extensive screening found basic medium is best, as acidic conditions cannot form Cu-acetylide

Salvador, R. L.; Simon, D. Can. J. Chem. 1966, 44, 2570-2575

Ph H +cat.

0.5-3h, 135 °CHC(OEt)3 Ph

OEt

OEt

H H +cat.

0.5-3h, 135 °CHC(OEt)3 H

OEt

OEt+

OEt

OEt

EtO

EtO

EtO

OEt

OEt

OEt+

indicates ionic mechanism

cat. = ZnCl2, ZnI2, Zn(NO3)2, CdI2

Howk, B. W.; Sauer, J. C. J. Am. Chem. Soc. 1958, 80, 4607-4609

OH

21 Precedent 6/5/02 9:35 AM

Sn Acetylide Formation

R H R'CHO+

Sn(OTf)2 or SnCl4(1-3 equiv.)

R3N (1-3 equiv.)R

R'

OH

• Propose formation of Sn-acetylide• Also reacts with acetals and adds 1,4 to enones

Yamaguchi, M.; Hayashi, A.; Minami, T. J. Org. Chem. 1991, 56, 4091-4092Yamaguchi, M.; Hayashi, A.; Hirama, M. Chem. Lett. 1992, 2479-2482

"...copper or palladium acetylides have been generated with amine bases, although these species are not reactive enough to add to aldehydes. It seemed to us that the proper slection of a metal salt in combination with an amine base might allow generation of metal acetylides that are reactive enough to add to C=O bonds."

22 More early examples 6/5/02 9:35 AM

Zn(OTf)2 Catalyzed Additions to Nitrones

R1 H + NO

R2

Bn10 mol% Zn(OTf)225 mol% i-Pr2NEt

"In this context, we have been interested in developing methods that lead to the generation of metal alkynilides directly from terminal acetylenes under conditions that parallel those involving Ag(I) or Cu(I) in simplicity and mildness but that can be utilized in catalytic nucleophilic C=O and C=N addition reactions."

CH2Cl2, r.t.R2

NHO Bn

R1

Entry

1

2

3

4

5

6

7

8

9

10

11

12

13

R1

TMS

TMS

TMS

TMSCH2

TMSCH2

TMS

n-Bu

Ph(CH2)2

TBSOCH2

Ph

t-Bu

BrCH2

R2

c-Hex

Ph

n-Pent

n-Pent

t-Bu

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

Time (h)

12

24

12

12

12

12

3

3

6

1

1

3

3

Yield (%)

95

43

62

90

67

99

95

96

85

94

93

68

85

• Zn-acetylide detected by 13C NMR• Also adds to ketones, aldehydes, N-Ts imines• ZnCl2 and ZnO also catalyze reaction (unpub.)

Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999, 121, 11245-11246

23 Nitrone add. 6/5/02 9:35 AM

ZnI2 Catalyzed 5-endo Dig Cyclization

R2

NHO Bn

R1

10 mol% ZnI210 mol% DMAP

CH2Cl2, r.t. 1-28h

N OR1

R2

Bn

R2

NHO Bn

R1Zn(II)

-H+N O

R1

R2

Bn

Zn(II)

+H+

• DMAP is vital, as Et3N gives no product• Other Zn(II) salts work, but ZnI2 is fastest• Other Lewis acids and protic acids gave no product• Crossover experiments preclude retro-addition followed by [3+2]

Aschwanden, P.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2000, 2, 2331-2333

24 5-endo dig 6/5/02 9:36 AM

Enantioselective Addition (Stoichiometric)

R1 H +O

R2

Zn(OTf)2 (1 equiv.)

i-Pr2NEt (1 equiv.)toluene, r.t.

R2

OH

R1

OHMe2N

Me PhH H (R)(S)

(R)

Entry

1

2

3

4

5

6

7

8

9

1 equiv.

R1

Ph

Ph(CH2)2

Ph(CH2)2

Ph

Ph(CH2)2

Ph(CH2)2

Ph

Ph(CH2)2

Ph

R2

c-Hex

c-Hex

i-Pr

i-Pr

PhCH=CH

t-Bu

t-Bu

Ph

Ph

Yield (%)

99

98

90

95

39

84

99

52

53

ee (%)

96

99

99

90

80

99

95

96

94

Entry

10

11

12

13

14

15

16

17

R1

TMS

Ph(CH2)2

Ph

TMSCH2

TBDMSOCH2

(EtO)2CH

R2

c-Hex

Me3CCH2

Me3CCH2

c-Hex

c-Hex

c-Hex

c-Hex

i-Pr

Yield (%)

93

72

90

84

83

90

94

97

ee (%)

98

99

97

98

98

98

98

98

HO

• Alipahtic aldehydes more reactive than aromatic• Unbranched alipahtic aldehydes give good ee, but poor yield from self-aldol condensation• Facial selectivity of (2R ) ephedrine in accord with Noyori model• Slight non-linear (20% ee ephedrine gives 39% ee product)• Insensitive to moisture and oxygen

Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806-1807Epothilone Synthesis: Bode, J. W.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 3611-3612

25 Enantioselective Addition 6/5/02 9:36 AM

Acetylene as a Nucleophile

H H +O

R

Zn(OTf)2 (1 equiv.)

i-Pr2NEt (1 equiv.)toluene, r.t.

R

OH

OHMe2N

Me PhH H (R)(S)

1 equiv.

(R)excess

sat. tol. at -40 °C

Entry

1

2

3

4

5

6

7

R

n-Pent

i-Pr

c-Hex

t-Bu

Ph

PhCH=CH

Ph

Me

Yield (%)

30

76

70

92

35

34

28

ee (%)

97

98

98

98

97

92

91

• Reactions were sluggish, 7-14 days• Mass balance was recovered s.m.

Sasaki, H.; Boyall, D.; Carreira, E. M. Helv. Chim. Acta 2001, 84, 964-971

26 Acetylene 6/5/02 9:36 AM

An Acetylene Equivalent

H +O

R

Zn(OTf)2 (1 equiv.)

NEt3 (1 equiv.)toluene, r.t.

R

OH

OHMe2N

H HMe Ph(R) (S)

1 equiv.

OH

OH(S)1. BzCl

2. cat. 18-C-6, K2CO3toluene, reflux

R

OBz

(S)H

$3/kg70-91% yield

Entry

1

2

3

4

5

6

7

8

R

i-Pr

c-Hexyl

t-Bu

n-Pentyl

n-Propyl

Ph

PhCH=CH

TIPSO(CH2)2

Yield (%)

97

89

82

81

77

96

99

82

ee (%)

98

99

98

98

99

98

88

97

• Protection of alcohol needed for good yields in fragmentation reaction• Protection performed in same pot as Zn reaction• Many aldehydes required 2-3 equivalents of Zn(OTf)2 and ephedrine

Boyall, D.; Lopez, F.; Sasaki, H.; Frantz, D.; Carreira, E. M. Org. Lett. 2000, 2, 4233-4236

27 Terminal alkyne equiv. 6/5/02 9:36 AM

Propargyl Alcohol Functionalization

H +O

R

Zn(OTf)2 (1 equiv.)

NEt3 (1 equiv.)toluene, r.t.

R

OH

OHMe2N

Me PhH H (R)(S)

1 equiv.

AcOOAc(R)

1. TBDPSCl, Im., DMF

R

OTBDPS

25-72% overall Yield

2. 2 mol% Pd2(dba)3•CHCl3 23 mol% Ph3P, HOAc toluene, reflux3. Et3N, MeOH

54-95% Yield88-97% ee

Me

O

OTBS

H +AcO

MeMe

HO NMe2

OH

OAc

Me

OTBS

OH

OAc

Me

OTBS

OHMe2N

Me PhH H (R)(S)

OHMe2N

H HMe Ph(R) (S)

syn

anti

d.r. (syn:anti)

96:4

80:20

9:91

CHO

Catalyst Control...

El-Sayed, E.; Anand, N. K.; Carreira, E.M. Org. Lett. 2001, 3, 3017-3020

28 Propargyl alcohol Pd 6/5/02 9:37 AM

Enantioselective Nitrone Addition

Ph H + NO

cat. Zn(OTf)2cat. i-Pr2NEt

NHO

Ph

Me

Me

Ph

BuMe

Me

Bu

Ph

10:1 diastereoselection

H + NO Bn

cat. Zn(OTf)2cat. i-Pr2NEt

NHO Bn

Me

Me

Me

Me88% ee

85% Yield

Ph

PhO

N N

OMeMe

Ph Phcat.

Frantz, D. E.; Fassler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Rec. 2000, 33, 373-381

29 Enantio. nitrone addition 6/5/02 9:37 AM

Catalytic, Enantioselective Acetylene Addition

R1 H +O

R2

20 mol% Zn(OTf)250 mol% NEt3toluene, 60 °C

R2

OH

R1

OHMe2N

Me PhH H (R)(S)

(R)

22 mol%

Entry

1

2

3

4

5

6

7

8

R1

Bn2NCH2

Ph(CH2)2

Ph

Ph(CH2)2

Ph(CH2)2

TBSOCH2

(EtO)2CH

TMSO

R2

c-Hex

c-Hex

c-Hex

i-Pr

n-Heptyl

t-Bu

t-Bu

c-Hex

Yield (%)

91

89

94

77

45

77

81

88

ee (%)

97

94

86

98

92

93

93

94

Entry

9

10

11

12

13

14

15

16

R1

n-Bu

TES

Bn2NCH2

TBSOCH2

Bn2NCH2

Ph(CH2)2

Bn2NCH2

TMSO

R2

c-Hex

c-Hex

c-Hex

c-Hex

n-Heptyl

Yield (%)

81

80

85

80

88

81

80

55

ee (%)

93

99

96

95

90

94

93

91

TIPSO

NBn

• Racemic reaction proceeds in CH3CN w/o ephedrine• ArCHO yields are low due to Canizzaro reaction• Reactions proceed neat• Some self-aldol condensation observed

Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687-9688

O

Ar CF3

also works75% ee (unpub.)

30 Catalytic in Zn and ligand 6/5/02 9:37 AM

Catalytic Nitrone Addition

R1 H + NO

R2

R320 mol% ZnEt2

toluene, r.t. R2

NHO R3

R1

Entry

1

2

3

4

5

6

7

8

9

10

R1

n-Bu

n-Decyl

p-Pent-Ph

Cl(CH2)3

TMS

NC(CH2)3

MeCO2CH2

(EtO)2CH

t-BuOCH2

R2

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

R3

Bn

Bn

Bn

Bn

Bn

Bn

Bn

Bn

Bn

Bn

Yield (%)

92

82

88

92

96

90

78

62

90

82

Entry

11

12

13

14

15

16

17

18

19

R1

t-BuO2C

n-Bu

p-Pent-Ph

Cl(CH2)3

MeCO2CH2

n-Bu

TMS

MeCO2CH2

R2

Ph

p-MeO-Ph

p-MeO-Ph

p-MeO-Ph

Ph

Ph(Me)CH

Ph(Me)CH

Ph(Me)CH

Ph(Me)CH

R3

Bn

Ph

Ph

Ph

t-Bu

Me

Me

Me

Me

Yield (%)

<42

72

56

61

>99*

94

97

87

91

d.r.

-

-

-

-

-

78:22

74:26

76:24

77:23

ON

AcO

Ph

t-Bu

* isolated only

Pinet, S.; Pandya, S. U.; Chavant, P. Y.; Ayling, A.; Vallee, Y. Org. Lett. 2002, 4, 1463-1466

31 Another nitrone add. 6/5/02 9:37 AM

Enantioselective Li-Acetylide AdditionsEarly Examples

R1 H + R2CHO

n-BuLi (6.7 equiv.)Ligand (4 equiv.)

DME, -123 °C2.7 equiv.

R2

R1

OH

NN

Me

Ligand

Mukaiyama, T.; Suzuki, K.; Soai, K.; Sato, T. Chem. Lett. 1979, 447-448Mukaiyama, T.; Suzuki, K. Chem. Lett. 1980, 255-256

Entry

1

2

3

4

5

6

R1

H

TMS

TES

TBS

Ph2MeSi

TPS

R2

Ph

Ph

Ph

Ph

Ph

Ph

Yield (%)

76

87

93

67

88

83

ee (%)

54

92

80

72

80

76

Entry

7

8

9

10

11

12

13

R1

TMS

TMS

TMS

TMS

TMS

TMS

TMS

R2

Et

n-Pent

n-Octyl

n-C11H23

n-C13H27

(CH3)2CHCH2

CH3(CH2)2CH=CH

Yield (%)

77

87

83

82

76

54

74

ee (%)

68

76

80

70

73

65

40

• Aromatic aldehydes gave (S) alcohol, whereas aliphatic gave (R)

HO

32 Early Li-acetylide 6/5/02 9:38 AM

Enantioselective Li-Acetylide AdditionsEarly Merck Examples

R2 Li

quinine-Li (1.5 equiv.)

N

N

R1

O

Cl+

N

NH

R1

O

Cl

R2

NH

NH

O

Cl

N

HIV reverse transcriptaseinhibitor

N

N

HOLi

HOMe

1.5 equiv.THF, -25 C

Entry

1

2

3

4

5

6

7

R1

PMB

Bn

p-Cl-Bn

Me

2,4,6-Me3Bn

2,6-Cl2Bn

9-anthrylmethyl

R2

2-pyridyl

2-pyridyl

2-pyridyl

2-pyridyl

2-pyridyl

2-pyridyl

2-pyridyl

best ee (%)

64

56

37

70

74

80

97

Entry

8

9

10

11

12

13

14

15

R1

9-anthrylmethyl

9-anthrylmethyl

9-anthrylmethyl

9-anthrylmethyl

9-anthrylmethyl

9-anthrylmethyl

9-anthrylmethyl

9-anthrylmethyl

R2

2-pyridyl

3-pyridyl

4-pyridyl

p-MeOPh

Ph

p-Cl-Ph

Bu

TMS

ee (%)

94

22

6

86

65

58

77

82

Huffman, M. A.; Yasuda, N.; DeCamp, A.E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590-1594

33 Li-acetylide/Merck 6/5/02 9:38 AM

THF

Enantioselective Li-Acetylide AdditionsEphedrine Mediated

Li

NH

CF3

PMB

Cl

+

2 equiv.

O OLiN

H HMe Ph(R) (S)

2 equiv.

THF, -50 °CNH

OH

PMB

ClF3C

• 2 equiv. of ligand and acetylide required for complete conversion• Low ee if ephedrine and Li-acetylide not warmed above -40 °C prior to addition at -50 °C

Li

O

O

C

LiLi

Li

CN

N

Me

Ph

Me

Ph

O

CF3Ar

reactive 2:2 tetramer

THF

Li

O

O

C

LiLi

Li

ON

N

Me

Ph

Me

Ph

THF

CF3Ar

unreactive

Based on calculations, extensive NMR (1H, 13C, 6Li), and X-ray of various aggregates

Thompson, A. S.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 8937-8940Thompson, A. S.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J.; Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1998, 120, 2028-2038Pierce, M. E.; Chen, C.; Tillyer, R. D. et. al. J. Org.Chem. 1998, 63, 8536-8543 (Efavirenz Synthesis)Xu, F.; Reamer, R. A.; Collum, D. B.; Huffman, J. C.; et. al. J. Am. Chem. Soc. 2000, 122, 11212-11218 (X-Ray)

C2-Symmetric

>97% Yield98% ee

34 Merck's Li/Ephedrine 6/5/02 9:38 AM

R2

Enantioselective B-Acetylide Additions

R1 SnBu3 R2

R12. R2CHO

OHMe2BBr

-78 °Ctoluene

1.NH

BR

O

Ph

Ph

R1 BMe2

Entry

1

2

3

4

5

6

7

8

9

10

11

12

13

R1

Ph

n-Pent

Ph

n-Pent

Ph

n-Pent

Ph

Ph

Ph

Ph

Ph

Ph

Ph

R2

c-Hex

c-Hex

Ph

Ph

n-Pent

n-Pent

c-Hex

t-Bu

n-Pent

Ph

c-Hex

p-MeO2C-Ph

p-NO2-Ph

R (equiv.)

Bu (1)

Bu (1)

Bu (1)

Bu (1)

Bu (1)

Bu (1)

Me (1)

Bu (1)

Ph (0.25)

Ph (0.25)

Ph (0.25)

Me (1)

Ph (1)

Yield (%)

96

82

78

28

90

80

95

71

77

72

80

80

86

ee (%)

90

95

96

94

96

96

90

97

93

97

85

96

96

O

NHB

BMe

R

O R1

H

MeCorey's model(also similar to his modelfor R2Zn additions with

amino alcohols)

• Comments that R = Ph on B is catalyticbecause bulk of Ph promotes dissociationfrom the formed alkoxide

Corey, E. J.; Cimprich, K. A. J. Am. Chem. Soc. 1994, 116, 3151-3152

35 Corey's Boron 6/5/02 9:38 AM

Cu/Ru Catalyzed Addition to Imines

Ph HR

NHAr

Ph

+ ArNH2 RCHO+

3 mol% RuCl320 mol% CuBr

H2O or neat40 °C, 20 hpreheated

60 °C, 2h

Entry

1

2

3

4

5

6

7

8

9

10

11

12

13

14

R

Ph

p-Cl-Ph

m-Cl-Ph

p-Br-Ph

m-Br-Ph

p-Me-Ph

p-tBu-Ph

p-CF3-Ph

t-Bu

p-Ph-Ph

1-naphthyl

Ph

Ph

Ph

Ar

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

p-Cl-Ph

p-Br-Ph

p-Me-Ph

Yield (%)

91

90

89

95

93

87

86

87

64

85*

96*

82*

88*

77*

* Conducted neat

Ph HRu(III)

1.2 equiv.

Ru(II)

Ph Ru(IV)H

ArN

R

CuX

R

ArHN

Ph

CuX

Ru(II)

Ru(II) + CuX

+

R

NHAr

Ph

Ph H+

N

R

Ar

• CuX salts mediate reaction alone (30% yield with CuBr)• RuCl3 allowed for complete conversion• RuCl3 alone gives no product• Enolizable aldehydes give self-aldol Li, C. -J.; Wei, C. Chem. Commun. 2002, 268-269

36 Cu/Ru catalyzed 6/5/02 9:39 AM

Cu Catalyzed Asymmetric Addition to Imines

Ph HR

NHAr

Ph

+

10 mol% CuOTf10 mol% PhPyBox

toluene, r.t., 2-4 d

NAr

R

Entry

1

2

3

4

5

6

7

8

9

10

11

R

Ph

p-Me-Ph

p-Et-Ph

p-Cl-Ph

p-Br-Ph

p-Ph-Ph

2-naphthyl

p-CF3-Ph

Ph

Ph

Ph

Ar

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

p-Br-Ph

p-Cl-Ph

p-Me-Ph

Yield (%)

78

85

70

85

87

81

63

71

93

92

93

ee (%)

96

92

96

94

94

94

88

93

91

91

94

O

N

N

N

O

Ph Ph

• CuBr gave low ee and CuSbF6 (in H2O)gave good ee, but low yield• Other Box and PyBox gave low ee • All reactions conducted in H2O gaveslightly lower ee and yield

Wei, C.; Li, A. -J. J. Am. Chem. Soc. 2002, 124, 5638-5639

37 Cu Enantio. addition 6/5/02 9:39 AM

Catalytic Cu Acetylide Additions to Nitrones

R1 H + NO

R2

R310 mol% CuI, ligand

K2CO3/DMFN

O

R1R2

R3

+N

R2

R3

R1

• most ligands (PPh3, dppe, dppp, dppb, bpy, phen, pyr, etc...) give a mixture of products• Box ligands give β-lactam with low d.r. and 40% ee

R1 CuL3

NO

R2

R3

R1

NR3

OL3Cu

R2

Cu(OH)L3

NO

R2

R3

[3+2]O

NR3

R1

L3Cu

R2

HOHNR3

O

R2R1

L3Cu

OH

imine

Cu(OH)L3

β-lactam

Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995, 60, 4999-5004

Original Reaction: Kinugasa, M.; Hashimoto, S. J. Chem Commun. 1972, 466-467

H

CNHR3

R1R2

O

38 Cu-acetylide and nitrones 6/5/02 9:39 AM

Fe

Catalytic, Asymmetric Cu Acetylide Additions to Nitrones

R1 H + NO

R2

R31-2.5 mol% CuCl•ligand

Cy2NMe, MeCN, 0 °CN

O

R1R2

R3

Entry

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

R1

Ph

p-CF3-Ph

p-MeO-Ph

Bn

Ph

1-cyclohexenyl

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

R2

c-Hex

c-Hex

c-Hex

c-Hex

PhCO

PhCO

Ph

p-CF3-Ph

p-MeO-Ph

c-Hex

PhCO

Ph

Ph

Ph

Ph

R3

PMP

PMP

PMP

PMP

Ph

Ph

PMP

PMP

PMP

PMP

PMP

Ph

PMP

p-Br-Ph

p-EtO2C-Ph

cis:trans

>95:5

>95:5

92:8

71:29

90:10

90:10

95:5

93:7

93:7

93:7

91:9

95:5

95:5

94:6

94:6

ee (%)

92

93

91

73

90

91

85

90

83

89

72

77

85

72

67

Yield (%)

65

57

60

43

56

45

53

50

46

57

42

69

53

74

79

N

Me

Me

Me

MeMeMe

NMe

FeMeMe

MeMe

Me

Ligand

Lo, M. M. -C.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 4572-4573

39 Fu Cu Kinugasa reaction 6/5/02 9:39 AM

Ir(I) Catalyzed Acetylene Addition

O

n-Prn-Pr NH2

+ TMS+cat. [{Ir(cod)Cl}2]

60 °Cn-Pr N n-Pr

TMS

n-Pr NH

n-Pr

TMS

+

Desired(C-H activation

next to N)

Observed(spC-H activation)

Sakaguchi, S.; Kubo, T.; Ishii, Y. Angew. Chem. Int. Ed. 2001, 40, 2534-2536

• All other acetylenes give desired product

TMSH

Ir(I)Ln

TMSHIr(I)Ln

TMSLn(III)Ir

H

TMSLn(III)Ir

H

NR'R

NR'R

TMSNR'Ln(III)Ir

R

H

TMSR'HN

R

40 Ir(I) 6/5/02 9:40 AM

Ir(I) Catalyzed Acetylene Addition

NAr

RTMS+

5 mol% [IrCl(cod)]2

THF, r.t., 1 d R

TMS

NAr

Entry

1

2

3

4

5

6

R

Ph

t-Bu

n-Pr

i-Pr

p-Br-Ph

Ph

Ar

Bn

Bn

Bn

Bn

Bn

p-MeO-Ph

Yield (%)

76

84

69

65

54

85

• Reactions conducted neat gave better yields• Only effective for silyl acetylenes• Only (t-Bu)3P leads to rate acceleration• Employing 2 mol% MgI2 allows Ir(I) loading to drop to 0.5 mol% (unpub.)

Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319-4321

41 Ir(I) Carreira 6/5/02 9:40 AM

Conclusions

• Metal acetylide additions to carbonyls giveversatile and useful synthetic building blocks.

• There are a few examples of stoichiometric,enantioselective additions, the most useful beingZn acetylide additions with a chiral amino alcoholcatalyst.

• Carreira's system is catalytic in both metal andchiral ligand and works well for aliphatic aldehydes.

• Cu(I) and Ir(I) offer a more efficient means (C-Hactivation) of generating transient metal acetylides and show some promising results.

42 Conclusion 6/5/02 9:40 AM

why zn acetylides?

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