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Recent Advancements In The [2+2+2] Cycloaddition Brandon Dutcher January 17, 2007 Michigan State University

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Page 1: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Recent Advancements In The [2+2+2] Cycloaddition

Brandon DutcherJanuary 17, 2007

Michigan State University

Page 2: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity

RegioselectivityChemoselectivityEnantioselectivity

ConclusionsAcknowledgments

Page 3: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity

RegioselectivityChemoselectivityEnantioselectivity

ConclusionsAcknowledgments

Page 4: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

General Information

[2+2+2] cycloaddition first reported by Bertholet in 1866First transition metal catalyzed [2+2+2] cycloaddition by Reppe et. al. in 1948.A multitude of metals have been employed on the catalysis of the [2+2+2]

Ni, Co, Pd, Cr, Rh, Zr, Nb, Ir, Ta, and Ti

The [2+2+2] cycloaddition has been found to have a wide range in synthesis

Page 5: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Important [2+2+2] Cycloadditions

Used the Nickel complex Ni(PPh3)2(CO)2Between 25°C and 80°C

2CO2R (PPh3)2Ni(CO)2

benzene

R=Bu

CO2R

HO3

(PPh3)2Ni(CO)2

HO

OHOH

OH

HO

OHbenzene65%

Reppe

BertholetFirst [2+2+2] cycloadditionThermally induced reaction

Kotha, S.; Brachmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767Reppe, V.W.; Schweckendeik, W.J. Justus Leibigs Ann. Chem. 1948, 560, 104-116

Page 6: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

General [2+2+2] Cycloaddition

Tolerant of many functional groupsApplicable to many π-bond containing systemsExcellent for building aromatic systems –benzene and pyridine moietiesSymmetry favored – exothermic (∆H= -594 kJ/mol)High temperature or catalyst required due to entropic factors

X∆

X

R

RR

RR

RR

RR

RR

Ror

catalyst

Kotha, S.; Brachmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767

Page 7: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity

RegioselectivityChemoselectivityEnantioselectivity

ConclusionsAcknowledgments

Page 8: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

π-bond System Approach To The MetalThree possibilities for alignmentTwo possibilities give the 1,2,4 trisubstituted ringOne gives 1,3,5 trisubstituted ringStatistically slightly greater than a 2 to 1 mixture of

1,2,4- to 1,3,5-trisubstituted rings

MR

RM

R

R R

R

R

MM

R

R

R

R RR

R

M

R

R MR

RR R

R

R

RR

Kotha, S.; Brachmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767

Page 9: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Metal-Carbon Insertion Mechanism

M

R

R

M

R

RM

RR

R

RR

R

RR -M

MR

R

R

MR

R

MR

R

M

RR

R

M

R

R

R R

R R

R

R RR

R

-M

-M

Kotha, S.; Brachmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767

Page 10: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Diels-Alder Type Mechanism

M

RR

RR

R

R

M-M

R

RM MR

RRR

R

R

R R

R

M

R

-M

R

R

R

M MR

R R

Kotha, S.; Brachmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767

Page 11: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity

RegioselectivitySubstrate controlReagent control

ChemoselectivityEnantioselectivity

ConclusionsAcknowledgments

Page 12: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Statistical Regioselectivity of [2+2+2] cycloaddition

MR

RM

R

R R

R

R

MM

R

R

R

R RR

R

M

R

R MR

RR R

R

R

RR

Statistically a slightly greater than a 2 to 1 1,2,4- to 1,3,5-trisubstitution ratio

1,2,4 tri-substituted only

1,2,4 tri-substituted only

Mixture of Both

Page 13: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

“Tethered” Alkynes

Force regiochemistry of alkyne reactionSpeed up reaction – intramolecular reactionIncrease yield

XR1

R2

X= O, S, C(CO2Me)2 etc.

XR3R3

R3

R3

R1

R2

Page 14: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Macrocycles by [2+2+2] Cycloaddition

1:755

3:449

1:157

1:142

Meta:ParaYield %α,ω-diynes

OO

(CH2)6

(CH2)7EtO2CEtO2C

N

pTol

N

pTol

15 mol% CpCo(CO)2

o-xylene140 oC, 100 h

meta para

N

pTol

O

OOO

Maryanoff, B.E.; et. al. J. Am. Chem. Soc. 2006, 128, 3473-3485

Page 15: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Macrocycle Regioselectivity

N

MO

OOO

N

p-Tol

Tol-

OO

OO

N

p-Tol

O

O

O

O

MN

p-TolO

O

O

O

N

p-Tol

XMO

O O

O

Page 16: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity

RegioselectivitySubstrate controlReagent control

ChemoselectivityEnantioselectivity

ConclusionsAcknowledgments

Page 17: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Ortho/meta Selectivity Of “Tethered”Alkynes

MeMe

Me

RMe Me2 mol%

[Ir(cod)Cl]2

4 mole % ligandargon

Me

Me

Me

MeR

RO M

84/1668Benzene reflux 2 hDPPF(CH2)3OH686/1483Benzene reflux 1 hDPPFn-Oct588/1284Benzene reflux 1 hDPPFn-Bu418/8275Benzene r.t 12 hDPPE(CH2)3OH319/8180Benzene r.t 1 hDPPEn-Oct220/8092Benzene r.t 0.5 hDPPEn-Bu1

Ratio O/M Yield%ConditionsLigandREntry

Ph2PPPh2

DPPE

Fe

Ph2P

PPh2

DPPF

Takeuchi, R.; et. al. J. Org. Chem. 2006, 71, 543-552

Page 18: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Regioselective Pathways

Me

MeIr

Me

PP

Cl

R

Ir

Me

Me

R

PP Me

Me

Me

R

Me

MeIr

Me

PB

PA

Cl Me

MeIr

Me

PBCl PA

R

Ir

Me

Me

Me R

ClPA

PB

Me

Me

MeR

Meta Pathway

Ortho Pathway

Takeuchi, R.; et. al. J. Org. Chem. 2006, 71, 543-552

Page 19: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Substrate Directed Regioselectivity

C2H2 (1atm)THF

-40oC to rt, 4 h

B

R

OO

(Pin)B RB(Pin)R

CoCpR R

B(Pin)(Pin)B

CoCp

A B

CpCo

-tBu1

4A/4B 1:9 (84)CH2OMe45A/5B 1:20 (92)Ph5

3A/3B 1.5:1 (93)C6H1332A/2B 1:0 (18)iPr2

A/B (yield%)REntry

R B(Pin)

R(Pin)BCoCp

R=tBu 59%

Aubert, C.; Vollhardt, K.P.C.; Malacria, M.; et. al. Angew. Chem. Int. Ed. 2005, 44, 7114-7118

Page 20: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

1,2,4 –Trisubstitution Using Titanium-Calixarene Complexes

RCatalyst

Na, toluene

R

RR R

RR

A B

O

O

Ti

ClCl But

But

ButBut

O

O

SiMeMe

>97<3Ph3

100--N,N’-dimethylamine4

973p-Tol2

982TMS1

B(Yield%)A(Yield%)REntry

Lapido, F.T.; Ozerov, O.V.; Patrick, B.O. J. Am. Chem. Soc. 1999, 121, 7941-7942

Page 21: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

1,3,5 –Trisubstitution Using Titanium-Calixarene Complexes

S SSO OO

O

ButBut

ButBut

S

Ti

ClCl

Ti

ClCl

1: 65% yield� ratio A:B 77:23

OS

SSS

O

Ti

ClCl But

But

ButBut

O

O

TiClCl

2: 95% yield� ratio A:B 85:15

PhCatalyst

Na, toluener.t., 20 h

Ph

PhPh Ph

PhPh

A B

Morohashi, N.;Yokomakura, K., Hattori, T, Miyanao, S. Tet. Lett. 2006, 47, 1157-1161

Page 22: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

1,3,5 –Trisubstitution Using Titanium-Calixarene Complexes (continued)

XX

XHO OO

OH

ButBut

ButBut

SiSi Pri

Pri

Pri

PriO

X

3: X=S: 93% yield � ratio A:B 83:174: X=CH2: 94% yield ratio A:B 1:99

XOHOH

ButBut

5: X=S: 95% yield� ratio A:B 32:686: X=CH2: 85% yield � ratio A:B 33:67

PhCatalyst

Na, toluener.t., 20 h

Ph

PhPh Ph

PhPh

A B

Morohashi, N.;Yokomakura, K., Hattori, T, Miyanao, S. Tet. Lett. 2006, 47, 1157-1161

Page 23: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

1,3,5 –Trisubstitution Using Titanium-Calixarene Complexes (continued)

R2.5 mol% 2

Na, toluene

R

RR R

RR

A B

100:0141550TMS595:5711523Oct4

75:25731523Pr3~100:0303.5234-CF3C6H42

95:5953.5234-Tol1

Ratio A:BYield%Time (h)Temp (oC)REntry

OS

SSS

O

Ti

ClCl But

But

ButBut

O

O

TiClCl

2

Morohashi, N.;Yokomakura, K., Hattori, T, Miyanao, S. Tet. Lett. 2006, 47, 1157-1161

Page 24: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

OS

SSS

O

Ti

ClCl But

But

ButBut

O

O

TiClCl

O

O

Ti

ClCl But

But

ButBut

O

O

SiMeMe

Lapido catalyst vs. Morohashi catalyst

Page 25: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Lapido catalyst vs. Morohashi catalyst

OS

SSS

O

Ti

ClCl But

But

ButBut

O

O

TiClCl

O

O

Ti

ClCl But

But

ButBut

O

O

SiMeMe

Page 26: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

1,2,4 regioselectivity

Morohashi, N.;Yokomakura, K., Hattori, T, Miyanao, S. Tet. Lett. 2006, 47, 1157-1161

O

O

TiClCl But

But

ButBut

O

O

SiMeMe

ButBut

O O

Si

MeMeButBut

O O

Ti

R RButBut

O O

Si

MeMeButBut

O O

Ti RR

Page 27: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

1,2,4 regioselectivity (continued)

ButBut

O O

Si

MeMeButBut

O O

TiButBut

O O

Si

MeMeButBut

O O

Ti

R

RR

R

R

R R

R

Page 28: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

1,3,5 Regioselectivity

O

But

O

But

O

Ti

O

But But

RR

S

O

But

O

But

O

Ti

O

But But

S

R

R

O

But

O

But

O

Ti

O

But But

S

RR

O

But

O

But

O

Ti

OS

But But

R

R

Page 29: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

1,3,5 Regioselectivity (continued)

O

But

O

But

O

Ti

O

But But

S

O

But

O

But

O

Ti

O

But But

S

R

R

O

But

O

But

O

Ti

O

But But

S

RR

O

But

O

But

O

Ti

OS

But But

R

R

RR

Page 30: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Explanation of Regioselectivity

O

But

O

But

O

Ti

OS

But But

R

R

R

O

But

O

But

O

Ti

OS

But But

R

RR

R

RR

Page 31: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity

RegioselectivityChemoselectivity

Nitriles, olefins and alkynesIsocyanates, isothiocyanates and carbondisulfide

Enantioselectivity ConclusionsAcknowledgments

Page 32: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Olefin vs. Nitrile

OCN

2 mol %Wilkinson's

catalyst

tBuOH82oC, 6 h

XCN

59%

Grigg, R.; Scott, R.; Stevenson, P. J. Chem. Soc. Perkin Trans I, 1988, 1365-1369

X NX

3 mol% [Rh(cod)2]BF4/

BINAP

CH2Cl2, rt-40 oC

X=C(CO2Me)2

CN

59%

Tanaka, K.; Suzuki, N.; Nishida, G. Eur. J. Org. Chem., 2006, 3917-3922

PPh2PPh2

BINAP

Page 33: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity

RegioselectivityChemoselectivity

Nitriles, olefins and alkynesIsocyanates, isothiocyanates and carbondisulfide

Enantioselectivity ConclusionsAcknowledgments

Page 34: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Alkenyl Isocyanates and Alkynes

Trace56(CH2)2OTBS71270n-Bu6

trace60n-Pr536313-furanyl438342-thiophenyl372--p-OMeC6H4263--p-Tol1

Yield% 4Yield% 3REntry

NC

OR

R

N

OR

R

NR

R

O

[Rh(ethylene)2Cl]2(5 mol%)

P(4-OMe-C6H4)310 mol%

toluene, 110 oC

1 2 3 4

Rovis, T.; Yu, R.T. J. Am. Chem. Soc. 2006, 128, 2782-2783

Page 35: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Mechanistic Pathways

NC

OR

R

NRh

O

Pathway A

NRhO

1 21

Rh NRh

O

R

R

NRhR

R O

Rh

NR

R O

N

OR

R

NR

R

O

Rh

Pathway B

Rh

Rh

3 4

Rovis, T.; Yu, R.T. J. Am. Chem. Soc. 2006, 128, 2782-2783

Page 36: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

(+)-Lasubine II

N

OMeMeO

HOH

Page 37: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

NC

OR2

R1

N

OR2

R1

NR1

R2

O

[Rh(ethylene)2Cl]2(5 mol%)

P(4-OMe-C6H4)310 mol%

toluene, 110 oC

R1 = H OMe

OMe

R2=

N

OMeMeO

HOH

Rovis, T.; Yu, R.T. J. Am. Chem. Soc. 2006, 128, 2782-2783

(+)-Lasubine II

Page 38: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Total Synthesis of (+)-Lasubine II

OMeOMe

O C N

N

OMeMeO

OH

N

OMeMeO

HOH

OP

OO

O

Ph Ph

Ph Ph

N

5 mol% Rh(C2H2)2Cl]210 mol% L

Toluene, 110oC

62% yield98% ee

N

OMeMeO

HOH

Pd/C, H2

80% yieldd.r.>20:1

1) PPh3, DEAD p-nitrobenzoic acid

2) K2CO3, MeOH 64% yield

MeOHL=

Rovis, T.; Yu, R.T. J. Am. Chem. Soc. 2006, 128, 12370-12371

Page 39: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Isocyanate Selectivity

X OCNR

5 mol% Cp*RuCl(cod)

DCE, 90oCArgon

XN

O

R

87654321Entry

SO

C(CO2Me)2

C(CO2Me)2

C(CO2Me)2

C(CO2Me)2

C(CO2Me)2

C(CO2Me)2

X

PhPhCyPrBn

2-furyl1-napthyl

PhR

6058858993877987

Yield%

Yamamoto, Y.; Takagishi, H. J. Am. Chem. Soc. 2005, 127, 605-613

Page 40: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Isothiocyanate And Carbon Disulfide Selectivity

54321Entry

SNCOPhNCO2Et

NCyNPh

X

5476715088

Yield%

SCXS

X

MeO2C

MeO2C

MeO2C

MeO2C

10 mol% Cp*RuCl(cod)dichloroethane,

90oC Argon

Yamamoto, Y.; Takagishi, H. J. Am. Chem. Soc. 2005, 127, 605-613

Page 41: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Isothiocyanate And Carbon Disulfide Selectivity (continued)

X CY

S

[Rh(cod)Cl]2/2BINAP(5 mol% Rh)

dichloroethane80 oC, 12-20 h

SX

Y

75SC(CH2OMe)2787NPhC(CH2OMe)2674SC(C=OMe)2581NPhC(C=OMe)2485SC(CO2Me)2389N(4-ClC6H4)C(CO2Me)2288NPhC(CO2Me)21

Yield%YXentry

Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2006, 8, 907-909

Page 42: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity

RegioselectivityChemoselectivityEnantioselectivity

ConclusionsAcknowledgments

Page 43: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Total Chirality Transfer

PhPPh2

O

Ph

OH

(S) (S)

>95%ee >95%ee

CpCo(CO)2

THF, ∆hν

H

CpCo

P OPh

Ph

Ph

quant.>95%ee

Malacria, M.; Aubert, C.; Buisine, O. Synthesis, 2000, 7, 985-989

Page 44: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Chirality Transfer Mechanism

Ph

PhCo

H

PhP

Co

H

PCp Cp

Co

H

Cp

approachsyn to Ph

approachanti to Ph

H

CpCo

P

Ph

P

P = PO

PhPh

Malacria, M.; Aubert, C.; Buisine, O. Synthesis, 2000, 7, 985-989

Page 45: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Ortho-diarylbenzenesO

O

Ar

ArOO

ArAr10 mol%[IrCl(cod)]2 + 2(S,S)-MeDUPHOS

xylene

90

95

90

87

90

%ee

5

4

3

2

1

Entry

E

D

C

B

A

Ar

60

60

60

r.t.

60

Temp. (°C)

0.5

0.3

0.3

18

0.5

Time (hours)

95

>99

86

68

82

Yield%

12:1

2:1

14:1

>20:1

5:1

dl:meso

Cl

NO2

Me

OMe

OMe

A

B

C

D

E

Shibata, T.;Tsuchikama, K.; Otsuka, M Tetrahedron: Asym, 2006, 17, 614-619

P

P

Me

Me

Me

Me

(S,S)-MeDUPHOS

Page 46: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

dl Ortho-dinaphthylbenzene

Structure: ChemDraw 3D

Page 47: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Chiral Intermediate

IrO P

PMe

O

Me

O

O

Ir

P

PMe

Me

OO

Page 48: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Enantioselective Isothiocyanate Addition

MeO2C

Ph RhS

NPhRh

A

Ph CO2Me

B

Rh

2

2

3

Low%ee

High%ee

Ph

MeO2C

1

Ph

MeO2CCN

S

Ph [Rh(cod)Cl]2/2(R)-BINAP(10 mol% Rh)

dichloroethane60 oC, 12 h

S

NPhPh

MeO2C

21 (R)-(+)-3 98%, 61% ee

Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2006, 8, 907-909

Page 49: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Chiral Anilides

9662PhPhEtO49869BnOMeMeNSO2(4-BrC6H4)39779PhPhMeC(CO2Me)229729BnPhMeC(CO2Me)21

%eeYield%R3R2R1Xentry

XR1

R1SiMe3

NR2

O10%

[Rh(cod)2]BF4/(S)-xyl-BINAP

CH2Cl2, rt15-42 h

XR1

R1

NR2

O

SiMe3

R3

R3

Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006, 128, 4586-4587

Page 50: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Chiral Anilide - Selectivity

Ar

RhX

R1

R1

P P

Ar

Ar

Ar

Me3Si

N

R3

R2

O

Ar

Rh

X

R1R1

P P ArAr

ArMe3Si N

R3

R2

O

Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006, 128, 4586-4587

XR1

R1SiMe3

NR2

O10%

[Rh(cod)2]BF4/(S)-xyl-BINAP

CH2Cl2, rt15-42 h

XR1

R1

NR2

O

SiMe3

R3

R3

Page 51: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Enantioselective 1,4-Diene-Ynes to Bridged Cyclohexenes

X

R2

R1[Rh(cod)2]BF4/

tolBINAP10 mol%

X

R1R2

*

*DCE, 60oC

21

924024PhO4937648HC(CO2Bn)2393836HNTs2

>994648BuNTs1%eeYield%Time (h)R1XEntry

Shibata, T.; Tahara, Y. J. Am. Chem. Soc. 2006, 128, 11766-11767

P(p-Tol)2

P(p-Tol)2

tolBINAP

Page 52: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Enantioselective 1,4-Diene-Ynes to Cyclohexadienes

XR1

DCE, 60oC X

Me

*Me

1 3

[Rh(cod)2]BF4/tolBINAP10 mol%

945548PhO3

90806HC(CO2Bn)22

999112MeNTs1%eeYield%Time (h)R1XEntry

Shibata, T.; Tahara, Y. J. Am. Chem. Soc. 2006, 128, 11766-11767

P(p-Tol)2

P(p-Tol)2

tolBINAP

Page 53: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

1,4-diene-yne cyclization mechanism

Shibata, T.; Tahara, Y. J. Am. Chem. Soc. 2006, 128, 11766-11767

X

R1R2

*

*

2

XR1 M

MX

R2

R1

R2

olefininsertion

MX

R1 R2

*

*

MX

R1 R2

H

-MR2 = H

MX

R1

H

X

Me

*Me

3

Page 54: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Chiral Spyrocycles From Diynes and Exo-Methylene Compounds

X

X=C(CO2Bn)2

Me

Me

[Rh(cod){(S)-xylyl-binap}]BF4(5 mol%)

dichloroethane, 80oC, 30 minX

Y

Me

Me O

n

P(3,5-Xylyl)2

P(3,5-Xylyl)2

(S)-xylyl-binap97883

81624

98932

99941

%eeYield%Exo-methyleneEntry

OO

O

OO

OO

Shibata, T.; Kuwata, Y.; Tsuchikama, K. J. Am. Chem. Soc. 2006, 128, 13686-13687

Page 55: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Chiral Intermediate

RhRhXPH

P

3,5-xylyl

OO

3,5-xylyl3,5-xylyl

3,5-xylyl

X

O

O

PP

lylyx-5,3

lylyx-5,33,5-xylyl

3,5-xylyl

XO

Me

Me OX=C(CO2Bn)2

Page 56: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity

RegioselectivityChemoselectivityEnantioselectivity

ConclusionsAcknowledgments

Page 57: Recent Advancements In The [2+2+2] Cycloaddition...General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition

Conclusions

[2+2+2] cycloaddition is a useful synthetic toolWide scope of reaction – highly functional group tolerantExcellent multi-component reactionEnantioselective and regioselective advancements increase synthetic value of [2+2+2] cycloaddition