In Case You Get Bored: Propose Reasonable MechanismsIn Case You Get Bored: Propose Reasonable Mechanisms

NHP(O)Ph2 NHP(O)Ph2

+

35% 32%

Br Cp2ZrBu2 ZrCp2Br

NPPh2

H

O

Me2Zn, tolueneTHF

Ph

NHP(O)Ph2

RN

H

PPh2

O

+ ClCp2ZrR

Ph

Me2Zn;

Zn(CH2I)2

Hydrozirconation/ZrHydrozirconation/Zr→→Zn Transmetalation/Aldimine Addition:Zn Transmetalation/Aldimine Addition:One-pot Synthesis of Allylic, One-pot Synthesis of Allylic, CC-Cyclopropyl-Cyclopropyl

and Homoallylic Amines from Alkynes.and Homoallylic Amines from Alkynes.

R1Schwartz Reagent

ZrCl

R1

N

H

quantitative

R2

R3

Me2Zn

R1MeZnNHR3

R2 R1(chiral ligand)

Christopher Kendall and Prof. Peter WipfDept. of Chemistry, University of Pittsburgh

Pittsburgh, PA 15260

“The time is apt for synthetic chemists to fully enter the world of organozirconium … chemistry.”V. Snieckus in Titanium and Zirconium in Organic Synthesis, I. Marek, Ed., Wiley-VCH, Germany, 2002.

Chiral Allylic AminesChiral Allylic AminesJohannsen + Jorgensen 1998 CR 1689

HN O

NH

O

CO2H

HN O

MeN

ONHO

HO2C

OMe

NHO

O

HN

O

OH

HN

O

HN

O

N

NHAc

ONH

NH

H2N

motuporin

cyclotheonamide B

O

O

NNs

1. i-BuCu(CN)Li, THF, -78 °C

2. TFA, CH2Cl23. TMS-Cl, MeOH

(68%)

NsHN

Wipf + Henninger 1997 JOC 1586

NH

Cl3C

O

Ph NH

Cl3C

ORuCl3, NaIO4

CCl4/MeCN/H2O(92%)

Walsh 2002 JACS 12225

• Schreiber 1992 JACS 6570• Nicolaou 1995 JACS 1225• Ottenheijm 1997 JOC 3880

• Wipf 1993 JOC 5592• Shioiri 1994 ACIE 1729• Wasserman 2002 Tet 6277

• Schreiber 1995 JACS 9069• Armstrong 1999 JACS 6255

• Toogood 1999 JOC 2711• Panek 2002 JACS 11368

N

H

TBSO

5% mol Ni(cod)2, 5 mol% L*,Et3B, AcOMe/MeOH, rt

(85%)

HN

TBSO

89% eePatel + Jamison 2004 ACIE 3941

OMe

O

O

OH

4-octyne

ZrZr→→Zn Transmetalation, Aldimine Addition: OptimizationZn Transmetalation, Aldimine Addition: Optimization

Enabling Methodology: EtEnabling Methodology: Et22Zn Addition to BenzaldiminesZn Addition to BenzaldiminesSoai 1992 JCS CC 1097

Enabling Methodology: ZrEnabling Methodology: Zr→→Zn Transmetalation, Aldehyde AdditionZn Transmetalation, Aldehyde AdditionWipf + Ribe 1998 JOC 6454; Wipf + Xu 1994 TL 5197

Et2Zn

1 equiv L*,toluene, 0 °C

(89%)

NHP(O)Ph2N

H

PPh2

O

90% ee

OH

Ph

N

O L*

O

H

ClCp2Zr

Me2Zn, 10 mol% L*,toluene, -30 °C

(80%)

OH

95% ee

NMe2

SH

EtL*

N

H

PPh2

O

ClCp2Zr

1.5 equiv Me2Zn

1.5 equivNHP(O)Ph2

Solvent Temperature Time Yield

CH2Cl2 reflux 16 h 59%

THF rt 36 h 54%

toluene rt 2 h 76%

ZrZr→→Zn Transmetalation, Aldimine Addition:Zn Transmetalation, Aldimine Addition:Racemic ScopeRacemic Scope

N

HR2

ClCp2ZrR1

R2 R1

R3NHR3

Me2Zn, toluene, rt

NHP(O)Ph2

76%2.5 mmol scale: 72%

0.2 equiv Me2Zn: 72%

NHP(O)Ph2

72%

NHP(O)Ph2

TMS

< 10%

NHP(O)Ph2

OBDPS

73%

NHP(O)Ph2

NTs

OEt

O

59%

NHP(O)Ph2

OTIPS

O

65%

NHP(O)Ph2

MeO

O84%

NHP(O)Ph2

MeO35%

NHP(O)Ph2

85%

NHTs

90%

NHBoc

81%

NHAc

44%

NHS(O)Tol

< 10%

HN

OMe

0%

NHOPh

0%

NHTMS

0%

ZrZr→→Zn Transmetalation, Enantioselective Aldimine AdditionZn Transmetalation, Enantioselective Aldimine Addition

H

NR

ClCp2Zr

Me2Zn, toluene, L*

NHR

*

REquivMe2Zn

L* (Equiv) Temperature Yield eeEntry

12

34

56

78

910

1112

13

P(O)Ph2

CO2Me

1.2 I (0.1) rt 65% < 5%1.2 I (0.5) rt 70% < 5%

1.0 I (1.0) rt 0% ---1.5 II (0.1) 0 °C 69% < 5%

1.5 II (0.1) -20 °C 39% 10%3.0 I (1.0) 10 °C 75% 23%

3.0 II (1.0) 10 °C 56% 34%3.0 I (1.0) 0 °C 27% 29%

0.2 II (0.5) 50 °C 56% 18%1.5 II (0.1) -30 °C 78% 9%

1.5 II (0.5) -30 °C 77% 25%1.5 II (1.0) -30 °C 48% 33%

1.5 II (1.5) -30 °C 26% 23%

NMe OH

PhPh

I

SH

NMe2

II

OHN

O

HO NHP(OMe)2

Ph

HO

Ph

N

N

N

HH

HH

O

NHP(O)Ph2

Ph

(-)-sparteine

(-)-MIB

OH

OH

(+)-BINOL[with/out Ti(Oi-Pr)4]

Ph

HO N

O

Ph

NOH

N

H

quinine

Other Ligands Tested (all < 30% ee)

ZrZr→→Zn Transmetalation, Aldiminium AdditionZn Transmetalation, Aldiminium Addition

Carreira 2004 OL 1497

N

H

OMeO

Cl

ClCp2Zr

CH2Cl2

N

OMeO

N

OMeO

+

I II

Conditions Yield I Yield II

no other metal --- ---

1 equiv Me2Zn, rt 51% 32%

0.02 equiv ZnCl2, 0 °C 82% ---

0.1 equiv CuBr, 0 °C 86% ---

0.08 equiv CuCl, 0.1 equiv (R,R)-DIOP, rt

71% (3% ee) ---

NN

Bn Bn

O O

Ph Ph

PPh2N

O

P

P

(R,R)-Me-DuPHOS

O

O

PPh2

PPh2

PPh2

PPh2

(R,R)-DIOP

(S)-BINAP

FePPh2

P(t-Bu)2

Other Ligands Tested (all < 10% ee)

ZrZr→→Zn Transmetalation, Diastereoselective Aldimine AdditionZn Transmetalation, Diastereoselective Aldimine Addition

PO

N

H

Me

Br

1. BuLi, THF; B(OMe)3; H+

2. 1,2-C6H4Br2, cat. Pd(PPh3)4, K2CO3, DME/H2O (1:2)

Me

Br

1. Mg, THF; ClP(OEt)2

2. 0.1 N HCl, THF

3. Ph-I, cat. Pd(OAc)2, cat. dppf, Et3N, MeCN

P

O

OEtPh

Me

1. TMS-Br, CH2Cl2; MeOH

2. (COCl)2, cat. DMF, CH2Cl23. liq. NH3, CH2Cl2

(90%)(69%) (54%)

P

O

NH2Ph

Me

PhCHO

0.5 equiv TiCl4,i-Pr2NEt, CH2Cl2

(88%)

P

O

NPh

Me

H

Ph

ClCp2Zr

Me2Zn, toluene, 40 °C(87%)

P

O

NHPh

Me

Ph

dr = 63:37

dr = 69:31

dr = 69:31

PN Ph

HO

Ph

ClCp2Zr

Me2Zn, toluene, rt(76%)

PNH

PhO

Ph

dr = 72:28

PNH

PhO

Ph

PNH

PhO

Ph

dr = 51:49

TMS

PNH

PhO

Ph

dr = 59:41 (40 °C)

PNH

PhO

Ph

dr = 57:43 (rt, 51% yld)dr = 54:46 (40 °C, 68% yld)

PNH

PhO

Ph

dr = 65:35 (40 °C)

Ph

PNH

PhO

Ph

NHP(O)Ph2 NHP(O)Ph2

+

35% 32%

NHP(O)Ph2NHP(O)Ph2

+

DD

Br Cp2ZrBu2 ZrCp2Br

NPPh2

H

O

Me2Zn, toluene

NPPh2

H

O 1. BrCp2Zr

Me2Zn, toluene

2. CD3OD3. H2O

THF

Takahashi 1995 JACS 11039

Ph

NHP(O)Ph2

RN

H

PPh2

O

+ ClCp2ZrR

Ph

Me2Zn; Zn(CH2I)2

Ph

NHP(O)Ph2

RN

H

PPh2

O

+ ClCp2ZrR

Ph

Me2Zn; Zn(CH2I)2

Mechanism HintsMechanism Hints

Three-Component Aldimine Vinylation/Cyclopropanation:Three-Component Aldimine Vinylation/Cyclopropanation:DiscoveryDiscovery

N

H

PPh2

O

ClCp2Zr

Me2Zn, CH2Cl2, reflux

NHP(O)Ph2

I

+

NHP(O)Ph2

Equiv Zr, Zn Time Yield I Yield II

1.5 16 h 59% ---

3 1 h 43% 29%

3 16 h 11% 58%

IIdr > 95:5

N

H

PPh2

O

ClCp2Zr

Me2Zn, CD2Cl2, reflux(34%)

Ph2(O)PHN

dr > 95:5

DD

N

H

PPh2

O

ClCp2Zr

Me2Zn, CH2I2,CH2Cl2, reflux

N

H

PPh2

O i. ClCp2Zr

Me2Zn, CH2Cl2, refluxnot cyclopropane

NHP(O)Ph2

dr = 97:3

ii. CH2I2, CH2Cl2, reflux

(74%)

Three-Component Aldimine Vinylation/Cyclopropanation:Three-Component Aldimine Vinylation/Cyclopropanation:ScopeScope

N

R2 H

R3 ClCp2ZrR1

Me2Zn,CH2Cl2, reflux

allylicamideimine

SM

Rxn

CH2I2

CH2Cl2, reflux

NHR3

R2 R1

NHP(O)Ph2

74%, dr = 97:31 equiv BnOH: 91% yld

NHP(O)Ph2

OBDPS

NHP(O)Ph2

OTIPS

O

NHP(O)Ph2

NTs

OEt

O

68%, dr = 98:271%, dr > 95:5

45%, dr > 95:5

NHTs

NHP(O)Ph2

NHTs

66%, dr > 95:5 60%, dr > 95:5 67%, dr = 87:13

NHP(O)Ph2 NHP(O)Ph2

MeH

Ph2(O)PHN

46%, dr = 96:4(3-hexyne)

52%, dr > 95:5(CH3CHI2)

47%, dr = 90:10(methylalumination)

Three-Component Aldimine Vinylation/Cyclopropanation:Three-Component Aldimine Vinylation/Cyclopropanation:Relative StereochemistryRelative Stereochemistry

NHP(O)Ph21. HCl, MeOH

2. (PhCO)2O, i-Pr2NEt, cat. DMAP, CH2Cl2

(99%)

NHCOPh(R)

(R)(R)

H

O 1. PhSO2Na, TsNH2, HCO2H/H2O

2. NaHCO3, H2O/CH2Cl2

(71%)

H

NTs i. ClCp2Zr

Me2Zn, CH2Cl2, reflux

ii. CH2I2, CH2Cl2, reflux

NHTs

(67%, dr = 87:13)

ClCp2Zr

Me2Zn, CH2Cl2(84%)

OH

CH2Cl2(90%, dr = 86:14)

OH DPPA

DEAD, PPh3, THF(85%, dr = 78:22)

1. H2 (1 atm), 10% Pd-C, THF2. TsCl, Et3N, cat. DMAP, CH2Cl2

(85%)

Upper Route: 41% overall, 1 column

Lower Route: 37% overall, 4 columns

Zn(CH2I)2N3

NH

O

H

H

(S)

(S)

(S)

Three-Component Aldimine Vinylation/Cyclopropanation:Three-Component Aldimine Vinylation/Cyclopropanation:MechanismMechanism

ClCp2ZrR1

Me2ZnMeZn

R1

N

HR2

R3

N

R2 R1

R3 ZnMe H2O NHR3

R2 R1

(CH2X2)

N

R2 R1

R3 ZnCH2XN

R2 R1

R3 ZnXH2ONHR3

R2 R1

H2C

R2

N

H R3H

Zn

X

Cl

synclinal

H

R1

H2C

H

N

H R3

R2

Zn

X

Cl

allylicA1,3-strain

H

R1

ZrCp2Me

ZrCp2Me

NHR3

R2 R1

NHR3

R2 R1

syn anti

mechanistic precedent: Charette 1999 Tet 8845

Three-Component Aldimine Vinylation/Cyclopropanation:Three-Component Aldimine Vinylation/Cyclopropanation:Wipf Group Synthetic ApplicationsWipf Group Synthetic Applications

Ph

H2N OH

O

Me2Zn; CH2I2

N

Ph H

PPh2

O

+ClCp2Zr

OPG

Ph

H2NOH

O

Me2Zn; Zn(CH2I)2

N

Ph H

PPh2

O

+ ClCp2Zr OPG

N

S

OEt

O

O

O

Ph

NHP(O)Ph2

R

N

H

PPh2

O

+ ClCp2ZrR

Ph

Me2Zn; Zn(CH2I)2

Wipf + Xiao2005 OL 103

Wipf + Stephensonmanuscript in preparation

17-estradiol (E2)-induced transcriptionantagonist (i.e. antiestrogen)

Janjic, Wipf, Day et al.2005 BMC 157

Wipf, Stephenson + Okumura2003 JACS 14694

Wipf, Stephenson + Walczak2004 OL 3009

HNP

O

NH

HN

O

pregnane X receptor (PXR) agonistMu et al.

manuscript in preparation

O

O

NHP(O)Ph2

R1 R3

R2

Me2Zn; CH2I2

N

R1 H

PPh2

O

+ClCp2Zr

R2

R3

Wipf, Coleman et al.JCC; accepted

NHCOR4

R1 R3

R2

NHSO2R5

R1 R3

R2 NHCO2R6

R1 R3

R2

Tandem Zirconocene Homologation/Aldimine Allylation:Tandem Zirconocene Homologation/Aldimine Allylation:Discovery and ScopeDiscovery and Scope

N

H

PPh2

O

ClCp2Zr

Me2Zn, CH2I2, CH2Cl2(71%)

NHP(O)Ph2

dr = 85:15

NHP(O)Ph2

OBDPSMeO

O

69%, dr = 85:15

NHP(O)Ph2

MeO

79%, dr = 83:17

Ph2(O)PHN

49%, dr = 75:25

NHP(O)Ph2

48%, dr = 62:38

CO2TIPS

NHTs

OBDPS

81%, dr = 60:40

NHTs

OBDPS

87%, dr > 95:5

N

H

PPh2

O

ClCp2Zr

Me2Zn, CH2I2,CH2Cl2, reflux

N

H

PPh2

O i. ClCp2Zr

Me2Zn, CH2Cl2, refluxnot cyclopropane

NHP(O)Ph2

dr = 97:3

ii. CH2I2, CH2Cl2, reflux

(74%)

Tandem Zirconocene Homologation/Aldimine Allylation:Tandem Zirconocene Homologation/Aldimine Allylation:Relative Stereochemistry and MechanismRelative Stereochemistry and Mechanism

NH

O

H

H

(S)

(R)

1. HCl, MeOH

2. DEPC, Et3N CH2Cl2

(56%)

NHP(O)Ph2

CO2TIPS

1. HCl, MeOH

2. DEPC, Et3N CH2Cl2

(69%)

NH

Ph O

HH

J = 4.9 Hz

(S) NH

H O

PhH

J = 9.3 Hz

(R)

NHP(O)Ph2

CO2TIPS

N

IZn

R3

R2

R1

H H2ONHR3

R1

R2

CH2I2Zn

R1I R1IZnClCp2Zr

R1

Me2ZnMeZn

R1

N

HR2

R3

N

IZn

R3

R2

R1

H

mechanistic precedent: Marek 2002 Tet 9463

ConclusionsConclusions

ee

Ph

H2N OH

O

Ph

H2NOH

O

NTs

OEt

ONHP(O)Ph2

NHP(O)Ph2

R1 R3

R2

NHP(O)Ph2

R1 R3

R2

+

J. Xiao

C. Stephenson

ZrCl

R1

N

HR2

R3

Me2Zn

NHR3

R2 R1

+

NHR3

R2 R1

Me2Zn;CH2I2

Me2Zn,CH2I2

NHR3

R2

R1

Wipf, Kendall + Stephenson2001 JACS 5122; 2003 JACS 761

Wipf + Kendall2001 OL 2773

17-estradiol (E2)-inducedtranscription antagonist

(IC50: 11 M)

N

H

R1

ClCp2ZrR2

Me2Zn, L*

NHR1

R2

Zr Zn40 30

zirconium zinc

+ = unique, synergisticreactivity characertistics

Wipf + Kendall 2002 CEJ 1778

AcknowledgementsAcknowledgements

Prof. Peter Wipf

Prof. Dennis Curran Prof. Scott Nelson Prof. Billy Day Prof. Paul Floreancig

NSF Aventis Pharmaceuticals

Dr. Steve Geib: X-rays Dr. Fu Tyan Lin: 2H NMR

2004 2002

Wipf Group Members Past and Present

The Rogue Homoallylic AmideThe Rogue Homoallylic Amide

NHP(O)Ph2 NHP(O)Ph2

+

35% 32%

NHP(O)Ph2NHP(O)Ph2

+

26% 46%D

D

Br Cp2ZrBu2 ZrCp2Br ZrCp2Bu - BuH

Cp2Zr

Me2Zn

ZnMe

NP(O)Ph2

HPh N

Ph

ZnMePh2P

O

N

Ph

ZnMePh2P

O

ZrCp2

NH

Ph

Ph2P

O

DD

Cp2ZrBu2

Br Cp2ZrBu2 ZrCp2Br

NPPh2

H

O

Me2Zn, toluene

(Me2Zn) (-MeH) 1. CD3OD

(ZrCp2Me)

NPPh2

H

O

2. H2O

1. BrCp2Zr

Me2Zn, toluene

2. CD3OD

mechanistic precedent: Takahashi 1997 Organometallics 2216

THF

Takahashi 1995 JACS 11039

Transition-Metal-Mediated Cascade Reactions: Transition-Metal-Mediated Cascade Reactions: CC,,CC-Dicyclopropylmethylamines-DicyclopropylmethylaminesBy Way of Double C,C-By Way of Double C,C--Bond Insertion into Bicyclobutanes-Bond Insertion into Bicyclobutanes

NHP(O)Ph2N

H

PPh2

O

N

H

PPh2

OClCp2Zr

R

Ph

Me2Zn

NP(O)Ph2

Ph

MeZn

R

Zn(CH2I)2N

P(O)Ph2

Ph

IZn

R

Zn(CH2I)2 NP(O)Ph2IZn

RPh

Zn(CH2I)2

NP(O)Ph2IZn

RPh

Zn(CH2I)2

PhN

R

Zn

P(O)Ph2

I

PhN

R

IZn

P(O)Ph2Ph

N

R

Zn(CH2I)2

1

1

1

2

2

22

2

3

3

3

3

44

4

4

5

5

mechanistic precedent: Jones Jr. 1985 Tetrahedron 1453

Wipf, P.; Stephenson, C. R. J.; Okumura, K. J. Am. Chem. Soc. 2003, 125, 14694

1. ClCp2Zr

Me2Zn, ClCH2CH2Cl, rt

2. Zn(CH2I)2, 0 °C

(68%)

IZn P(O)Ph2