Oliver Reiser University of Regensburg · 2008. 4. 22. · Synthesis of bicyclo[2.2.1]heptanones...

Thermal Cycloadditions Reactions Nature never intended…but should have

Oliver ReiserUniversity of Regensburg

Thermal [4+2] Cycloadditions

The Diels-Alder Reaction

The Protagonists

Otto Diels Kurt Alder R. B. Woodward

Roald

Hoffmann Kenichi Fukui

NP 1950

NP 1981

NP 1965

The general process -

1

HOMO

LUMO

4π

HOMO

LUMO

2π

E


2

LUMO

HOMO

D A C

Donor (D): OR, NR2Acceptor (A): CN, CORConjugated (C): aryl, vinyl


3

Y

Y

H HH

X HX

Y

Y

HHX

X

Y

YX

X

Y

Y

H HX

H XH

Y

YX

X

HH

Y

Y

XXH

H

HH

exo

endo

Stereospecifity


4

X

X

X

100

76

60

100

0

24

40

0

CO2Me

CN

CH2Br

+

endo exo

CHO

X

Exo - Endo Selectivity

Lewis Acid catalysts enhance endo selectivity

Y

Y

HH

XH X

H


5

Regioselectivity - The ortho / para Rule

NEt2

+EtO2C

δ– δ+

CO2EtNEt2

20°C

94%

NEt2

CO2Et

100:0

D

+A

DA

"ortho"


6


δ–EtO+

MeO2C

δ+

CO2Et160°C

EtO50% EtO CO2Me

100:0

+D

A

D

A"para"


7


A

+A

AA

"ortho"

+A

A

A

A"para"

CO2H

+HO2C

δ+ δ+

CO2HCO2H

75°C

CO2H

CO2H

8.8:1


8

δ–EtO+

RO OR160°C

EtO50% EtO OR

50:50

δ–

D

+

D

D D"meta"

+D DD D

"meta"


9

E

HOMO

LUMO

+

O OLA

NRR

LUMO3

HOMO3

LUMO2

LUMO1

ΔE (LUMO3-HOMO) < ΔE (LUMO2-HOMO) < ΔE (LUMO1-HOMO)

Rate Acceleration

Lewis acids catalysts / organo

catalysts

Natural product synthesis -

the beginning -

1

We explicitly reserve for ourselves the application of the reaction developed by us - Diels, O.; Alder, K. Lieb. Ann., 1928, 460, 98.

CH3

O

OO

O

CH3

Cantharidin

OCO2Me

CO2Me CO2Me

O

CO2Me

Stork, G.; Van Tamalen, E. E.; Friedman, L. J.; Burgstahler, A. W. J. Am. Chem. Soc. 1951, 73, 4501.

Natural product synthesis -

the beginning -

2

O

OH

HO

MeN

Morphine

OHO

OMeMeO

OO

OMeMeO

CH2CN

Cl

Cl

CNδ+

δ–

17%85°C, 4.5 d

6

Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1956, 78, 1380.

Regiocontrol

by tethering diene

+ dienophile

O

O

OMeBnO

CH2OH

benzene80°C, 30 h

O

O

MeO

R

HOH2C

ROMe

O

OHOH2C

H

R91%

OMe

OO

ClH

160°C, 45h

O

Me

benzeneOMe

OO

HCl

OHCO2H

H

O

O

HMe

HO

Gibberellic acid

H

Corey, E. J. and co-workers, JACS 1978, 100, 8031, 8034

55%

Notable Dienes

OMe

TMSO

EWG OREWG RO

EWGDanishefsky's Diene

SO

O=~

O

EWG

OMe

OMe

R1R1

R R

BrBr

=~

ortho-quinodimethane

Notable Dienophiles

PPh3CNCl~=

O

~=SO2Ph

~= or

R

SO2Ph

H Na/Hg

H

H

Base

CNCl

OH

CNOH

PPh3

H

1) Base2) RCHO

H

R

Danishefsky’s

Diene

Cyclohexenones

/ δ-Lactones

Me3SiO

OMe

MeO2C

+

OMe

Me3SiO

CO2Me

HO

CO2Me

H O O O

O

H

OHH

H

Vernolepin

Danishefsky, S. J. Acc. Chem. Res. 1981, 14, 400

Synthesis of bicyclo[2.2.1]heptanones

OMe

CNCl+

Cu(BF4)2 0°C

90% Cl

CN O

KOHOMe

NC Cl

OMe OMe

Diene: functionalized cyclopentadieneDienophile: ketene equivalent

Synthesis of 7-aza-[2.2.1]-bicycloheptanes

Shen, T. Y. Tetrahedron Lett. 1993, 4477

N CO2Me

NMeO2C

N

Cl

SO2Ph

+

NMeO2C

N

Cl

HN N Cl

H

Epibatidine

NSO2PhCl

85°C, 24 h

Synthesis of Combiasin

A

Nicolaou, K. C. et al. Angew. Chem. Int. Ed. 2001, 40, 2482

O

OOMe

Me

Me

HO

SO2Me

MeH

toluene180°C, 20 min

– SO2O

OOMe

Me

Me

HO

Me

MeH

O

OOMe

Me

Me

HOH

MeH

Me

O

OOH

Me

Me

H

MeH

Me

(–)-combiasin A

89%

ortho-quinodimethanes

Me OTMS

TMS

TMS

TMS

Me O

Δ

>70%

TMS

TMS

Me O

H

H

HHO

Me O

H

H

H

Estrone

Vollhardt, K. P. C. et al.; J. Am. Chem. Soc. 1980, 102, 5253.

EDG

EWG

EDG

EWG

Torquoselectivity

Outward

Torquoselectivity

Inward

Houk, K. N. et al. Acc. Chem. Res. 1996, 29, 471.

A “photochemical”

[4+2]-cycloaddition

OMeMe

MeOOMe

Me

CHO hν

OMeMe

MeOOMe

OH OMeMe

MeOOMe

OH OMeMe

MeOOMe

OH Me

CO2Me

82%

CO2MeMe

exo

O

OH

OHHO

MeOH

Me

OHOH

O

O O

O

OH

Et Et

HO

Hybocarpone

OMeMe

MeOOMe

O

H

H

hνMeO

Me

MeOMeO

endo

OH

MeO2C Et

H

Nicolaou, K. C.; Gray, D. Angew. Chem. Int. Ed. 2001, 40, 761.

Lewis Acids –

1

Activation

Houk, K. N.; Strozier, R. W. J. Am. Chem. Soc. 1973, 95, 4094.

LUMO

HOMO

O

2.5

–14.5

–7.5

–23.2

OH

eV

Garcia, J. I.; Martinez-Merino, V.; Mayoral, J. A.; Salvatella, L. J. Am. Chem. Soc. 1998, 120, 2415.

LUMO

O

OLA

kcal/mol

ΔE = 10 kcal/mol

Rate acceleration = 105

Lewis Acid –

2

O

O

Me

MeO+ Me

O

OMeO

O

OMeO

Me MeMe

MeH H

thermal (100°C)BF3•OEt2 (–16°C, 1 equiv.)SnCl4 (–16°C, 1 equiv.)

1 4<1

1 120

:::

δ- 80-85%

Selectivity

O

O

Me

MeO

F3B

δ+

O

O

Me

MeO

δ+

Cl4Sn2 Tou, J. S.; Reusch, W. J. Org. Chem. 1980, 45, 5013

Lewis-Acid –

3

O

OOH

RO

MeO

Me+

O

OOH

ROH

H

O

OOH

ROH

H

+

BF3•OEt1 (0.4 equiv)MgI2 (0.5 equiv)

95 5

595

::

OMe

OMeMe

Me

Selectivity

O

OOH

ROO

OHO

RO

F3B

MgI2

δ+

δ+

O

OOH

ROO

OOH

RO

BF3 F3B

Kelly et al., Tetrahedron Lett. 1978, 4311

Lewis -

Acids

R1

O

R1

O

R1

O

R1

O

R1

O

R1

OLA

LALA LA LA LA

η1-complex η2-complex diastereomeric complexes s-cis s-trans

hard soft ground stateelectronicpreference

often reactiveconformation

steric

bias

Chiral

Auxiliaries / Lewis Acids

Me

Me

O

O

Ph

Me Me

OBn

AlCl3–55°C Me O

Me

O

OR*O

BnO

R*

94% de

89%

Cl3Al

Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908.

Lactic Esters as Auxiliaries

O

OEtO

O

Me

+

TiCl4 (0.7 equiv)

–63 °C CO2R*

86% de

endo > 98%

EtAlCl2 (2.5 equiv)O

OEtO

O

Me

Cl2EtAl

AlEtCl2

56% de

endo > 98%

CO2R*–63 °C

O

OTiO

MeH

OEt

ClCl

ClCl

Poll, T.; Helmchen, G.; Bauer, B, Tetrahedron Lett. 1984, 25, 2191

Carbohydrates as Auxiliaries

OOO

O

O

But

OPiv

OCH3

OPivOR

dihydro-L-rhamnalR = acryloyl

TiCl2(OiPr)2

92%

CO2R*

98:2 R/S

dihydroglucal

6:94 R/S with cyclopentadiene

Stähle, W.; Kunz, H. Synlett 1991, 260

Oxazolidinones

as Auxiliaries

Me N

O

O

O

iPrLewis-Acid

XVO

+

XVO

N

OAl

Cl

Et Et

Me N

O

O

O

iPr

AlEt EtMe2AlCl2

O

Pri

OMe

N

O

O

O

iPr

AlEt EtMe2AlCl2

N

OAl

Cl

Et Et

O

Pri

O

Me

XV

87 MeMe

Me

0.8 equiv. Et2AlCl @ 0°C 87 : 13 (Σ endo/exo 94:6)1.4 equiv. Et2AlCl @ 0°C 88 : 12 (Σ endo/exo 98:2)1.4 equiv. Et2AlCl @ –78°C 94 : 6 (Σ endo/exo > 99:1)

Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238

Towards Lepicidin-A

O

EtMe

OTES

OTIPS

O NO

OO

OTBS

Bn

Me2AlCl, 0°C

71% (10:1 ds)

R

R

ON

O

O

AlMe

MeTBSO

H

O

EtMe

OTES

OTIPS

O

HH

N

O

O

O

Bn

OTBS

H

H

H

H

O

EtMe

OTES

OTIPS

O NO

OO

OTBS

Me2AlCl, 0°C

74% (6:1 ds)

ON

O

O

AlMe

MeTBSO

H

R

HO

EtMe

OTES

OTIPS

O

H

N

O

O

O

OTBS

HH

H

H

Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497.

Asymmetric Catalysis -

Box ligands

(1)

O

N

O

OCOX

COX

Cu(OTf)2• Box-Ph

MgI2• Box-But > 95 < 5

< 2 > 98

N

O

N

OCH3H3C

R RBox-R

D. A. Evans et al., J. Am. Chem. Soc. 1993, 115, 6460

E. J. Corey et al., Tetrahedron Lett. 1992, 33, 6807

NO

NO

CuBut

But

H

H

OO N

O

COX

NO

NO

MgPh

Ph

H

H

O

ON

O

COX

Asymmetric Catalysis -

Box ligands

(2)

O

N

O

O

COX

CuX2• Box-But

(10 mol%)

N

O

N

OCH3H3C

R RBox-R

25�C, 8h

counterion endo ee yield

X = TfOŠ

X = SbF6Š

94% ee96% ee

95%98%R = Me

RR

X = TfOŠ

X = SbF6Š

90% ee96% ee

85%95%R = Ph

X = TfOŠ

X = SbF6Š

53% ee94% ee

Š95%R = Cl

J. S. Johnson, D. A. Evans, Acc. Chem. Res. 2000, 33, 325

Cycloadditions

-

Nature never intended?

HO

CuCl

O2 HO OH

90%

Pd/BaSO4

45-55%

OHHO

8š-conrotatory

OHHO

6š-disrotatory

H

OHHO

HH

H

OSit-BuPh2

HH

Ph110 °C

100%

H

HPh

HH

CO2HH

H

Endianric Acid B

K. C. Nicolaou

et al.

J. Am.Chem. Soc. 1982, 104, 5555, 5557, 5558, 5560

Oliver Reiser University of Regensburg · 2008. 4. 22. · Synthesis of bicyclo[2.2.1]heptanones...

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