1

Applications of a Novel Nickel-Catalyzed Reductive Coupling Reaction Towards the Total Synthesis of

Amphidinolide T1

Julie FarandApril 1st, 2004

O

CH2

Me

O

OMe

Me

HO

O

Me

Jamison et al, J. Am. Chem. Soc., 2004, 126, 998Jamison, T.F. et al, Org. Lett., 2000, 26, 4221

2

Introduction

• Methods of generating allylic alcohols

• Nickel-catalyzed coupling between• alkynes and aldehydes• alkynes and epoxides• alkynes and imines

• Jamison’s methodology applied towards the total synthesis of amphidinolide T1

O

CH2

Me

O

O

Me

Me

HO

O

Me

3

Preparation of Allylic Alcohols

• Reductions, organomagnesium and organolithium reagents

H

O

R

OH

RMgBrLi

R

O

H

R

O

NaBH4

• Reactive allylic sulfoxides via a [2,3]-sigmatropic rearrangement

R

SOPh

R

PhS

O P(OMe)3

R

OS

Ph

P(OMe)3

MeOH

R

OH

4

Preparation of Allylic and Homoallylic Alcohols

• Allylic oxidation with selenium dioxide

• Homoallylic alcohols via chiral or achiral crotyl and allyl metals

H R1

OM

R1

OHR2

R2

M = B, Al, Sn, Si ... + auxiliaries

(L.A.)

R

H

O Se O

R

SeOHO

[2,3]

R

OSe

OH

R

OH

[2+4]

5

Preparation of Allylic Alcohols : The Nozaki-Hiyama-Kishi Reaction

Nozaki et al, J. Am. Chem. Soc., 1986, 108, 6048

R1 OTf+ R2CHO

CrCl2, catalytic NiCl2

DMF, 25 °C R1R2

OH

Entry Alkenyl triflate Aldehyde Product Yield

1

2

3

4

5

Bu OTf

Ph

OTf

Ph OTf

Ph

OTf

OTf

Bu

OH

OH

Oct

Ph

PhHO

Ph

PhHO

OctCHO

PhCHO

PhCHO

87%

83%

92% (from trans)

46% (from cis)

85%

OHC

O

7

O

7

6

Nozaki-Hiyama-Kishi Mechanism

• In 1983, anhydrous CrCl2 from ROC/RIC Corp (New Jersey) proved to contain ca. 0.5 mol% of Ni on the basis of Cr • Aldrich Co. (90% purity) and Rare Metallic Co. (99.99% purity) offers anhydrous CrCl2 free from Ni salts

The success of this reaction heavily depended on thenature of the CrCl2!

Hiyama, T.; Nozaki, H. et al, Tetrahedron Letters, 1983, 24, 5281Kishi Y. et al, J. Am. Chem. Soc, 1986, 108, 5644

Nozaki, H. et al, J. Am. Chem. Soc, 1986, 108, 6048

X

X = I, Br, OTf

NiX Cr(III)

RCHO

R

OH

Cr(III)

Ni(II)

2 Cr(II)2 Cr(III)

Ni(0)

7

Synthesis of Enantioselective (E)-Allylic Alcohols

R1

HB

2

1)

2) Et2Zn

R1

ZnEt

H R2

O

Me2N

HO

(+)DAIB

Me2N

O

Zn

Et

OZn

R1Et

L

R2

HC=O Re-face attack

NH4Cl (aq)

R1 R2

OH

(79-98% ee)

67-94%

Oppolzer, W.; Radinov, N. J. Am. Chem. Soc., 1993, 115, 1593

8Oppolzer et al, J. Org. Chem., 2001, 66, 4766

Synthesis of Macrocyclic (E)-Allylic Alcohols

O

1) (c-hexyl)2BH2) Dilute rxn (0.05M)

3) (+)-DAIB/Et2Zn4) NH4Cl (aq)

HO

n n

HO

n

+

Entry n ring size Yield (%) ee (%) A B of A

13

14

15

18

21

901

2

3

4

5

20

35

60

61

43

91

88

91

88

1

2

3

6

9

9

7

3

7

8

Me2N

HO

(+)-DAIB

Limitation: -Disubstituted allylic alcohols only! -Procedure is not effective with internal alkynes

A B

9

R1 Cp2ZrHCl

R1 R2

OH

63-99% ee

R1ZrCp2Cl

CH2Cl2, 22°C

Me2Zn

toluene, -65°C R1ZnMe

R2CHO, NMe2

SH

*

EWG on aromatic R2CHOincrease ee

Not catalytic!

Limitation....intermolecular rxn only!RCHO hydrozirconation is faster than alkyne hydrozirconation

H

O

n

ZrH

H

O

n

HZr

Addition to RCHO by Zirconocene-Zinc Transmetallation

Wipf, P.; Ribe, S. J. Org. Chem., 1998, 63, 6454

10

Intramolecular Ni-Catalyzed Alkylative Cyclizations

HX

O R1 Ni(COD)2

ZnR22

X

HO

R2

R1

Alkylative Cyclization

Entry X R1 R2 Yield(%)

H

H

H

CH3

CH3

701

2

3

4

5

Ph

n-Bu

Ph

n-Bu

72

62

64

76

CH2

CH2

CH2

CH2

CH2

6 NCOPh H

CH3

CH3 72

Terminal and internal alkynes .... tri- and tetrasubstituted allylic alcohols

Montgomery, J.; Oblinger, E. J. Am. Chem. Soc., 1997, 119, 9065

HX

O R1 Ni(COD)2 : PBu3

ZnR22

X

HO

H

R1

Reductive Cyclization

Terminal and internal alkynes .... tri- and tetrasubstituted allylic alcohols

Terminal and internal alkynes .... di- and trisubstituted allylic alcoholswith PBu3!

20 mol% Ni(COD)2 is required to avoid 1,2-addition of the organozinc to RCHO

11Montgomery, J.; Oblinger, E.; J. Am. Chem. Soc, 1997, 119, 9065

Nickel-Catalyzed Alkylative and Reductive Coupling

R3R2

H R1

ONi0 Ni

LL

R3

R2

R1H

O

Small Substituent

(or tether chain)

Large Substituent

O

NiIIR3

R2R1

H

LL

ZnEt2

R1 R3

EtZnO

R2

Ni

H

L

L

Et

R1 R3

OH

R2

Et

OxidativeCyclization+

L = (n-Bu)3P

R1 R3

EtZnO

R2

Ni

H

L H

L = THF

R1 R3

OH

R2

H

Alkylative Coupling Reductive Coupling

12

Choice of Ligand

Phosphine Ligands with EDG

• Soft neutral 2e-donor ligand

• σ-donor ability : (t-Bu)3P > Cy3P > (n-Bu)3P > Et3P > Ph3P

CO

NiR3P

CO

CO

PR3 , cm-1

(t-Bu)3P

Cy3P

(n-Bu)3P

Et3P

Ph3P

2056.1

2056.4

2060.3

2061.7

2068.9

-donor ability

CO

P M

R

R

R

Tolman, C. Chem. Rev. 1977, 77, 313

13

• π-acidic ligands (aldehyde) accelerate reductive elimination• In the absence of (n-Bu)3P, unreacted RCHO can coordinate to Ni

• Direct reductive elimination is accompanied by a 2e- reduction of Ni• Process disfavored by the coordination of good σ-donor (n-Bu)3P

Reductive vs β-Hydride Elimination : Additive Effect?

R1 R3

EtZnO

R2

Ni

H

L

L

Et

R1 R3

OH

R2

Et

L = (n-Bu)3P

R1 R3

EtZnO

R2

Ni

H

L H

L = THF

R1 R3

OH

R2

H

Alkylative Coupling Reductive Coupling

R3R2

H R1

O

Ni0

+

Intramolecular Rxn Only!

14

Catalytic Intermolecular Reductive Coupling of Alkynes and Aldehydes

Jamison, T.F. et al, Org. Lett., 2000, 26, 4221

CH3Ph +H

O

R

Ni(COD)2 (10 mol%)phosphine (20 mol%)

Et3B (200 mol%)

Solvent, 23 °C, 18 hPh R

OH

CH3

Entry Aldehyde Phosphine Solvent Product Yield Regioselectivity

1a Cy3P

(n-Bu)3P

(n-Bu)3P

(n-Bu)3P

(n-Bu)3P

Et3P

THF

THF

THF

THF

Toluene

Toluene (40 °C)

100 mol% 100 mol%

1a R = Ph1b R = n-Pr

2a-2b

2a

2b

76%

46%

77%

86%

85%

88%

77:23

91:9

92:8

90:10

92:8

92:8

1

2

3

CH3Ph +H

O

R

Ni(COD)2 (10 mol%)phosphine (20 mol%)

Et3B (200 mol%)

Solvent, 23 °C, 18 hPh R

OH

CH3

Entry Aldehyde Phosphine Solvent Product Yield Regioselectivity

1a Cy3P

1b

(n-Bu)3P

(n-Bu)3P

(n-Bu)3P

(n-Bu)3P

Et3P

THF

THF

THF

THF

Toluene

Toluene (40 °C)

100 mol% 100 mol%

1a R = Ph1b R = n-Pr

2a-2b

2a 76%

46%

77%

86%

85%

88%

77:23

91:9

92:8

90:10

92:8

92:8

1

2

3

4

5

6

15

Proposed Mechanism via an Oxametallacyle

R3R2

H R1

ONi0(COD)2 Ni

LL

R1H

O

(n-Bu)3P

O

NiIIR3

R2R1

H

LL

Et3B

R1 R3

Et2BO

R2

Ni

H

Et

L

L

R1 R3

Et2BO

R2

Ni

H

H L

R1 R3

OH

R2

H

OxidativeCyclization

-H Elimination

Reductive Elimination

+R3

R2

Small Substituent

Large SubstituentPh

SiMe3

Stabilized cation

16

Choosing the Reducing Agent

Montgomery, J.; Tang, X-Q. J. Am. Chem. Soc., 1999, 121, 6098

R3R2

H R1

O

+ZnR2

H R1

OZnR

R

1,2-addition onto the aldehydein complex systems20 mol% Ni

O

NiIIR3

R2R1

H

LL

Et3SiH

R1 R3

Et3SiO

R2

Ni

H

H

L

LO

NiIIR3

R2R1

H

LL

Et3Si

H

intermolecular

Et3B

R1 R3

Et2BO

R2

Ni

H

Et

L

L

R1 R3

Et2BO

R2

Ni

H

H L-H Elimination

R1 R3

OH

R2

HReductive Elimination

Jamison, T.F. et al, Org. Lett., 2000, 26, 4221

17

Catalytic Intermolecular Reductive Coupling of Alkynes and Aldehydes

Entry Aldehyde Product Solvent, T °C Yield Regioselectivity

58%

83%

89%

93:7

1

2

3

4

5

PhCHO

PhCHO

n-HeptCHO

n-HeptCHO

o-TolCHO

Ph Ph

OH

CH3

n-Hex Ph

OH

Ph n-Hept

OH

SiMe3

n-Bu n-Hept

OH

SiMe3

Ph

OH

CH3

CH3

77% 92:8

76% 96:4

>98:2

>98:2

THF, RT

THF, RT

Toluene, RT

Toluene, RT

Toluene, RT

R2R1

+H

O

R3

Ni(COD)2 (10 mol%)(n-Bu)3P (20 mol%)

Et3B (200 mol%)

Solvent, 18 hR1 R3

OH

R2

18

Asymmetric Reductive Coupling with NMDPP

R3R2

H R1

O

+

Ni(COD)2 (10 mol%)(+)-NMDPP (20 mol%)

Et3B (200 mol%)EtOAc:DMI (1:1)

R1 R3

OH

R2

H CH3

PPh2

H3C

CH3

(+)-(neomenthyl)diphenylphophine

Jamison, T.F. J. Am. Chem. Soc., 2003, 125, 3442

Entry R1 R2 R3 Yield (%) ee (%)

Regioselectively

i-Pr Ph

i-Pr

i-Pr

i-Pr

n-Pr

Ph

(p-Cl)Ph

Ph

Ph

Me

Me

CH2OTBS

CH2NHBoc

SiMe3

95 (>95:5)

75 (>95:5)

59 (>95:5)

60 (>95:5)

43 (>95:5)

90

83

85

96

92

1

2

3

4

5

19

Proposed Steric and Electronic Control

O

Ni

Ph

Me

R

PR3

Me

Me Me

PNi

H

O

H

R

Me

Me Me

PNi

H

O

H

R

C DSterically favored,electronically disfavored

Sterically andelectronically favored

Me

Ph

Ph

Me

Me

Me Me

PNi

O

RH

H

Me

Me Me

PNi

O

RH

H

A BSterically Disfavored,electronically favored

Sterically andelectronically disfavored

Me

Ph

Ph

Me

20

Proposed Mechanism for Asymetric Reductive Coupling

O

Ni

Ph

Me

R

PR3

Et3B

Ph R

Me

OBEt2NiL

L

Et

Ph R

Me

OBEt2NiL H

Ph R

Me

OHH HydrideElimination

Reductive Elimination

Me

Me Me

PNi

H

O

H

R

D Sterically andelectronically favored

Ph

Me

21

Catalytic Three-Component Coupling Reaction:Allylic Amines

R1 R2

H

N

R3

R4

Ni(COD)2 (5 mol%)

Cyp3P (5 mol%)+RBX2 +

X = OH, R R1 = aryl, alkyl

R2 = alkyl, H

R3 = aryl, alkyl

-Organoborane reagents are used for alkylative coupling-Exclusive cis addition across alkyne ( ³ 97:3) -Compatible with ketones, esters, and protic solvents

Yield : 65-98% 1a:2a >90:10

Regioselectivity >90:10

Ph Ph

HNEt

Me

Me

Ph Ph

HNH

Me

Me

+

1aAlkylative Coupling

2aReductive coupling

22

Boronic Acids in Catalytic Three-Component Couplings

MePh

B(OH)2

B(OH)2

N

H Ph

Me

Ph Ph

Ph HNMe

Me

Ph Ph

HNMe

Me

Ph

+MeOH/MeOAc

50 °C

Ni(COD)2 (5 mol%)(c-C5H9)3P (5 mol%)

72% (92:8 regioselectivity)

68% (92:8 regioselectivity)

23

Enantioselectivities for Alkylative and Reductive Coupling Using (S)-(+)-NMDPP

Ph MeH

N

Ar

MeNi(COD)2 (10 mol%)

(S)-NMDPP (20 mol%)

Ph Ph

HNEt

Me

Me

+ Et3B (300 mol%)

MeOAc/MeOH0 °C, 20 h

Ph Ph

HNH

Me

Me

+

1Alkylative Coupling

2Reductive coupling

Entry Ar ee 1(%) ee 2 (%)

421

2

3

41

33

40

33

39

Ph

p-ClC6H4

(p-CF3)C6H4

CH3

PPh2

H3C

CH3(+)-(neomenthyl)

diphenylphophine

+minor regioisomer

+minor regioisomer

Same ratio!

24

Proposed Mechanism for the Ni-catalyzed Coupling ReactionBetween Alkynes and Imines

• Enantioselectivity and regioselectivity are determined in the same step and before the azametallacyclopentene• Highly selective for alkylative coupling in MeOH

Ar

NiH

NPR3

MeBEt2

Ar

H NMe BEt2

ReductiveElimination

-H Elimination

Reductive Coupling

Ar

NiEt

NOH

MeBEt2

PR3

Me

Ar

Et NMe BEt2

ReductiveElimination

MeOH

Alkylative Coupling

Ni

PR3

L

+N

H Ar

Me

N

Ni

Ar

PR3

BEt2

Me

Me

Ar

Ni

H

NPR3

MeBEt2

Isolated in identical ee

25

Intermolecular Reductive Coupling of Alkynes and Epoxides

Jamison, T.F.; Molinaro, C. J. Am. Chem. Soc, 2003, 125, 8076

R2R1+

Ni(COD)2 (10 mol%)Bu3P (20 mol%)

Et3B (200 mol%)Solvent, 23 °C, 24 h

R1

R2100 mol%

R3

O

R3

OH

Entry R1 R2 R3 Additive Solvent Yield (%) Regioselectivity

alkyne epoxide

Ph Me

Ph Me

Me

Me

>95:51

2

3

4

5 n-Pr n-Pr Et

Bu3P Ether

Bu3P Toluene

Bu3P EtOAc

Bu3P Neat

Bu3P Neat

36

25

34

71

35

>95:5

na

>95:5

>95:5

>95:5

200 mol%

"

"

"

"

"

"

"

"

"

"

26

Reductive Cyclization via a Proposed Nickella(II)oxetane

R

O

H

R

ONi

PBu3

Ni(COD)2

Bu3PO

NiR

Bu3P PBu3

Et3B

R

Ni

OBEt2

Et

PBu3

PBu3

R

Ni

OBEt2

H PBu3

ROH

H

exo-digcyclization

27

Summary of Nickel-Catalyzed Reaction

• Racemic and enantioselective allylic alcohols

R2R1+

H

O

R3

Ni(COD)2 , (n-Bu)3PR1 R3

OH

R2

Ni(COD)2 , (+)-NMDPP

R3R1

OH

R2

Et3B

Et3B

• Allylic amines via three-component coupling

R1 R2

H

N

R3

R4

R1 R3

HNR

R2

R4

+

R3B / RB(OH)2

MeOH

Ni(COD)2, PR'3

• Homoallylic alcohols

+Ni(COD)2), Bu3P

R1

R2

R3

O

R3

OHEt3B

R1 R2

28

Synthesis of Amphidinolide T1

• The amphidinolides are a family of macrolides produced by marine dinoflagellates of the genus Amphidinium

• The marine algae live in symbiosis with the Okinawan flatworm

• Amphidinolide T1, a 19-membered macrolide, is cytotoxic against human epidermoid carcinoma KB and murine lymphoma L1210 cell lines

Amphidiniumcarterae

Amphidiniumlactum

O

CH2

Me

O

O

Me

Me

HO

O

Me

Total Synthesis of Amphidinolide T1

• Ghosh (2003)• Fürstner (2003)• Jamison (2004)

Kobayashi, J. et al, J. Org. Chem., 2001, 66, 134

29

Ghosh’s Enantioselective Synthesis of Amphidinolide T1 via Macrolactonization

Ghosh, A.K.; Liu, C. J. Am. Chem. Soc., 2003, 125, 2374

O

CH2

Me

O

OMe

Me

HO

O

Me

O

OH

OMe

O

Me

O

Me

OHMe

Br

O

Cl

Cl

Cl Cl

i-Pr2NEt, then DMAPToluene

O

O

O

Me

O

Me

O

Br

Me

Me

Zn, NH4Cl, EtOH, 80 °C

(+)-Amphidinolide T130 steps

71%

61%

30

Fürstner’s Synthesis of Amphidinolide T1 via RCM Macrocyclization

Fürstner, A. et al, J. Am. Chem. Soc., 2003, 125, 15512

O

CH2

Me

O

OMe

Me

HO

O

Me

(+)-Amphidinolide T130 steps

O

O

Me

O

OMe

Me

MOMO

TBDPSO

Me

O

O

Me

O

OMe

Me

MOMO

TBDPSO

Me

RuCl

ClPCy3

NN

Ph

MesMes

CH2Cl2, reflux86%

E/Z = 6:1

H2 , Pd/C

31

Jamison’s Approach : Ni-catalyzed reductive rxn• alkyne-epoxide

• alkyne-aldehyde

Ph

Ph

O

Me

O

O

Me

Me

HO

Me

CH2

O

O

Me

O

O

Me

Me

Me

O

Ph

Ph

OH

Jamison’s Approach to Amphidinolide T1

Jamison et al, J. Am. Chem. Soc., 2004, 126, 998

32

O N

O

Me

O

i-Pr

1) LDA, THF2) PhC CCH2Br

O N

O O

i-Pr

Me Ph

1) LiAlH4, THF2) TBSCl, imid, DMF

Me Ph

TBSO

Me

O

Ni(COD)2 (10 mol%)Bu3P (20 mol%)

Et3B

Me

TBSO

Ph

Me

OH

70% over 3 steps

>99% ee

81%, >99% dr

Synthesis of Amphidinolide T1O

CH2Me

O

OMe

Me

HO

O

Me

33

Mechanism Revisited

Ni(COD)2

Bu3P

Et3B

Me

O

TBSO

PhMe

Ni

Ph

R

PBu3

O

Me

NiO

Ph

MeR

Bu3P PBu3

NiOBEt2

Ph

MeR

EtL

L

NiOBEt2

Ph

MeR

H

L

HOH

Ph

MeR

+

O

CH2Me

O

OMe

Me

HO

O

Me

34Brown, H.C.; Bhat, K. J. Am. Chem. Soc.,1986, 108, 5919

Enantioselective Brown (Z)-Crotyl AdditionO

CH2Me

O

OMe

Me

HO

O

Me

CH3

B

CH3

RCHO

2

BO

H

R

CH3

H3C

H

CH3

BO

CH3

R

HS

S

L

L

M

M

RB

H3C

H OTBS

O

CH3(+)-Ipc2BOTBS

OH

CH3

Both methyl groups of thecampheyl moiety are on the

opposite side of the allyl group

2

93% ee

35

Synthesis of Amphidinolide T1O

CH2Me

O

OMe

Me

HO

O

Me

BH3.THF;

H2O2, NaOH

O (CH2)4OTBS

Me

HO

31% over 4 steps

OTBS

OH

Me

DIBAL-H

OTBS

OH

Me

HO

TPAP, NMO O (CH2)4OTBS

Me

O

O (CH2)4OTBS

Me

HO

36

Synthesis of Amphidinolide T1O

CH2Me

O

OMe

Me

HO

O

Me

Me3Si

Ph

Et2O.BF3, CH2Cl2-78 °C; then warm to23 °C (-TBS)

O (CH2)4OH

Me

>95:5 dr

Ph

40% overall

I2, PPh3, imid

1) LDA, LiCl,

PhN

O

Me

MeOH

MeO

Me

Ph

CO2H

Me

2) NaOH, t-BuOH, CH3OH

65% over 3 steps

O (CH2)4OTBS

Me

HO

O (CH2)4I

Me

Ph

>95:5 dr

37

Synthesis of Amphidinolide T1O

CH2Me

O

OMe

Me

HO

O

Me

N

N

4-PPY

Me

TBSO

Ph

Me

OH

1)

DCC, 4-PPY

2) TBAF3) Dess-Martin

O

MePh

Me

O

O

Me

Ph

O

H

Me

59% over 3 steps

O

Me

Ph

CO2H

Me

O

Me

O

OMe

Me

HO

Me

Ph

Ph

44%, >10:1 dr

Ni(COD)2 (20 mol%)Bu3P (40 mol%)

Et3B, toluene, 60 °CX = 0.05 M

* **

*

38

O

Me

O

OMe

Me

HO

Me

Ph

Ph

1) TBSOTf, 2,6-lutidine

O

O

Me

O

OMe

Me

TBSO

O

Me

2) HF.py

O

CH2

Me

O

OMe

Me

HO

O

Me

25% over 4 steps

2) O3; Me2S

1) CH2I2, Zn, ZrCl4, PbCl2

Synthesis of Amphidinolide T1O

CH2Me

O

OMe

Me

HO

O

Me

39

Conclusion

• Two nickel-catalyzed carbon-carbon bond forming reactions were utilized during the synthesis of Amphidinolide T1:

• catalytic intermolecular alkyne-epoxide reductive coupling• catalytic intramolecular alkyne-aldehyde reductive coupling

• This is the most direct synthesis of Amphidinolide T1 with 20 synthetic operations.

O

CH2

Me

O

O

Me

Me

HO

O

Me

40

Aknowledgements

Prof Louis BarriaultIrina DenissovaSteve ArnsEffie SauerJeff WarringtonRoxanne ClémentPatrick AngLouis MorencyRachel BeingessnerGerardo UlibarriDanny Gauvreau*Ross MacLean*Jermaine Thomas*Roch LavigneNathalie GouletChristiane Grisé

Financial SupportUniversity of OttawaNSERCOGS

Canada Foundation for InnovationOntario Innovation TrustPremier’s Research Excellence Award

Merck Frosst CanadaAstra ZenecaBristol Myers SquibbBoerhinger Ingelheim