asymmetric lewis base strategies for heterocycle synthesis · 2020. 6. 24. · asymmetric lewis...

Asymmetric Lewis Base Strategiesfor Heterocycle Synthesis

Dr Andrew Smith

EaStCHEM, School of Chemistry, University of St Andrews

1st Scottish-Japanese Symposium of Organic Chemistry, University of Glasgow

Friday 9th September 2011

Thursday, 8 September 2011

N NN

PhTBSO Ph

N

N

S

N NPhPh

N NN

Ph

N

N

SPh

Ph

ADS group research

Organocatalysis

Organocatalysis

Probe new reactivity

N-heterocycliccarbenes

Isothioureas

Catalytic enolate chemistry

Catalystdevelopment


R

ArO

NN

N PhPh Ph

TBSO

azolium enolate

O

N

N

SPh

ammonium enolate

Ar

ADS group research

Organocatalysis

Catalystdevelopment

Organocatalysis



Isothioureas


N NN

PhTBSO Ph

N

N

S

N NPhPh

N NN

Ph

N

N

SPh

Ph


O

ClR1

O

NR3Y/H

X

O

RO Cl

Ar R1

O

O O

FeN

NRO H

NN

R RR R

R

ormono-substitutedin-situ generated "ketene enolates"

di-substituted enolatesfrom isolable ketenes

For reviews 1. "ketene enolate" chemistry

Lectka et al. Tetrahedron, 2009, 65, 6771

2. For ammonium enolates Gaunt and Johansson,

Chem. Rev., 2007, 107, 5596

up to 94% eeFu et al.

Angew. Chem. Int. Ed.,2007, 46, 977

ON

O

ArR1

Ar

ammonium enolateR1

O

RO F

R1

OAr

R1


Angew. Chem. Int. Ed.,2009, 48, 2391

NN

O

ArR1

CO2Me

CO2Me


Angew. Chem. Int. Ed.,2008, 47, 7048

up to 99% eeLectka et al.

J. Am. Chem. Soc.,2008, 130, 17260

J. Org. Chem. 2010,75, 969

up to 99% eeLectka et al.

J. Am. Chem. Soc.,2006, 128, 1810

OO

Cl3C

99% eeWynberg et al.

J. Am. Chem. Soc.,1982, 104, 166

Lewis base catalysis: ammonium enolate chemistry


N NN

PhTBSO PhN N

PhPh

N NN

Ph

Ph

R

ArO

NN

N PhPh Ph

TBSO

azolium enolate

ADS group research

Organocatalysis

Organocatalysis



Isothioureas


Catalystdevelopment


Typical organocatalytic NHC reactivity

• Generation of enolate equivalents

Organocatalytic NHC reactivity

Chem. Commun, 2011, 47, 373-375

H

O

N NR R

OH

N

NR

R

azolium enolate

Bode, Rovis (halide)Scheidt (aryloxy)

Cl

R1Cl

R1

O

N

NR

R

OAr

R1base - HCl

O

N

NR

RR1

Ar

azolium enolate

ADS / Ye

H

OO

R1

unstable

Ar O

OH

N

NR

R

O

R1

OAr

benchstable

O

N

NR

R

base

azolium enolate

ADS

asymmetriccatalysis

R1 R1


Applications of NHC-generated enolates from ketenes

ArOH

OAr

OAr

RH

OC6Cl5

OAr

ClR

OCl

ClCl

Cl

ClCl

up to 60% eeEur. J. Org. Chem.,

2010, 5863

up to 84% eeAdv. Synth. Cat., 2009, 351, 3001

NN

O

ArR CO2Et

CO2Et

up to 91% eeYe et al, J. Org. Chem.,

2009, 74, 7585

NN

OO

COPh

Ph

RAr

up to 97% eeYe et al, Angew. Chem. Int. Ed,

2009, 48, 192

NNR'

R'

O

N

NR'

R'R

Ar

azolium enolate

NTs

Ar H

NTsO

Ph ArPh H

up to 90% eeOrg. Biomol. Chem.,

2008, 6, 1108

ONTsAr

O

NTsO

ArR

ArH

up to 95% eeYe et al, Angew. Chem. Int. Ed,

2010, 49, 8412

R' = CO2Et

R' = COPh

Generally - 2-aryl substitutedarylalkyl ketenes show

moderate reactivity


ADS group research

Organocatalysis

Organocatalysis



Isothioureas

New Asymmetric Transformations

Catalystdevelopment

Catalytic generation of ammonium enolates from acids

One-pot domino Lewisbase catalysis

LB*

RO

OHR

O

N N

S

Ph

RO

N N

S

PhE

RO

EX

enolate

acyl donor

E-X

X


O

OH

Me

NMe

BrOTf

+

Mukaiyamareagent (1.5 eq)

N

N

OAc

HOMe

Lewis base

aldoland

lactonisation

R = H or Me

CO2H

O

LB

O

R

R

O

Lewis base (LB)derived enolate

i-Pr2NEt,CH2Cl2, rt

N

N

PPY

O

OH

H

aldoland

lactonisation

48% yield>19:1 dr82% yield

>19:1 dr92% ee

Catalytic generation of enolates from acids: literature - Romo

J. Am. Chem. Soc., 2001,123, 7945.Org. Lett., 2006, 8, 4363.J. Am. Chem. Soc., 2008,130, 10478.Angew. Chem. Int. Ed., 2010, 49, 9479.


NEt

BrOTf

CO2H

Ph

O

O

Ph

OH

Hactivating agent (1.2 eq)

isothiourea

i-Pr2NEt (3.5 eq),CH2Cl2, rt

activating agent

N

N

S

N

N

SPh

isothiourea

1.0

0.2

yield

87%, dr 99:1

53%, dr 99:1

eq

0.5

0.2

73%, dr 99:1ee 97%

43%, dr 99:1ee 97%.HCl

O

Cl

N

N

SPh

.HCl

N

N

SPh

0.2

0.2

61%, dr 99:1ee 97%

72%, dr 80:20ee 70% (ent)

Catalytic generation of enolates from acids: Michael-lactonisation

J. Am. Chem. Soc., 2011,133, 2714


(i) pivaloyl chloride, NEt3

Michael addition

lactonisation mixed anhydride

ammonium enolate

N

N

SPh

O

Ph

OH

H

CO2COt-Bu

Ph

O

O

N

COPhHO Ph

H

O

NN

acyl ammonium

O

N N

COPh acyl ammonium

deprotonation

CO2H

Ph

O

N

S

Ph

S

Ph

S

Ph

O

N N

Ph

S

HH

O

R

Catalytic generation of enolates from acids: mechanism?

J. Am. Chem. Soc., 2011,133, 2714


Catalytic generation of enolates from acids: Generality

J. Am. Chem. Soc., 2011,133, 2714

(CH3)3CCOCl (1.2 eq)tetramisole.HCl

(20 mol%)

i-Pr2NEt (3.5eq),CH2Cl2, rt

1 hourCO2H

R2

O

O

R2

OH

H

N

N

SPh

.HClR1 R1

61%, dr 99:1ee 97%

O

Ph

OH

H

81%, dr 99:1ee 94%

O

Me

OH

H

94%, dr 99:1

ee 91%

O

Ph

OH

HO

Ph

OH

H

99%, dr 99:1

ee 99%

MeO



J. Am. Chem. Soc., 2011,133, 2714

(CH3)3CCOCl (1.2 eq)tetramisole.HCl

(5-20 mol%)

O CO2H

R

O

O

O

R

OH

H

i-Pr2NEt (3.5 eq),CH2Cl2, rt

15 minutes

98%, dr 99:1

ee 94%87%, dr 96:4

ee 95%Ar = 4-MeC6H495%, dr 96:4

ee 94%

Ar = 4-ClC6H463%, dr 97:3

ee 84%

OCO2MeO

R

H

HMeOH

OCO2MeO

Ph

H

H

OCO2MeO

Me

H

H

OCO2MeO

Ar

H

H

OCO2MeO

Ar

H

H

1 hourR' R' R'

73%, dr 99:1

ee 92%62%, dr 99:1

ee 94%79%, dr 96:4

ee 96%75%, dr 98:2

ee 95%

OCO2MeO

Me

H

H

OCO2MeO

Me

H

H

OCO2MeO

Me

H

H

OCO2MeO

Me

H

HO2N Me

MeMe


Catalytic generation of enolates from acids: intermolecular reaction

J. Am. Chem. Soc., 2011,133, 2714

Ph OH

O isothioureapivaloyl chloride (1.2 eq)

i-Pr2NEt (3.5 eq),CH2Cl2

Ph CO2Me

OOPh

Ph

O

CO2Me

N

N

SPh

.HClN

N

SPh

20 mol%, rt 61%, dr 95:5ee 82% (ent)

20 mol%, rt 68%, dr 95:5

ee 91%

5 mol%, -30˚C

67%, dr 95:5ee 96%

+



J. Am. Chem. Soc., 2011,133, 2714

N

N

SPh

Ar OH

O(CH3)3CCOCl (1.2 eq)isothiourea (10 mol%)

i-Pr2NEt (3.5 eq),CH2Cl2, -30˚CPh CO2Me

OOAr

Ph

O

CO2Me

+

O

Ph

O

CO2Me67%, dr 95:5

ee 97%81%, dr 95:5

ee 99%67%, dr 95:5

ee 97%66%, dr 95:5

ee 87%

O

Ph

O

CO2Me

Me

O

Ph

O

CO2Me

O

Ph

O

CO2Me

O

Ph

O

CO2Me62%, dr 90:10

ee 93%76%, dr 95:5

ee 98%72%, dr 96:4

ee 86%73%, dr 93:7

ee 97%

O

Ph

O

CO2Me

O

Ph

O

CO2Me

O

Ph

O

CO2Me

Br MeO

Me

Me



J. Am. Chem. Soc., 2011,133, 2714

N

N

SPh

Ph OH

O(CH3)3CCOCl (1.2 eq)isothiourea (10 mol%)

i-Pr2NEt (3.5 eq),CH2Cl2, -30˚CR1 CO2R2

OOPh

R1

O

CO2R2

+

OPh

Ph

O

CO2Me

67%, dr 95:5

ee 97%67%, dr 87:13

ee 99%87%, dr 94:6

ee 97%82%, dr 95:5

ee 99%

OPh

Ph

O

CO2i-Pr

OPhO

CO2Me

OPhO

CO2Me

OPhO

CO2Me

71%, dr 96:4

ee 98%66%, dr 92:8

ee 99%82%, dr 95:5

ee 99%80%, dr 88:12

ee 96%

OPhO

CO2Me

OPhO

CO2Me

OPh

Me

O

CO2Me

Br Me

O

N


ADS group research

Catalytic generation of ammonium enolates from acids

Intramolecularand

Intermolecular

One-pot domino Lewisbase catalysis

LB*

Catalystvariation

Electrophilevariation

Product derivatisationand mechanistic

studies

RO

OHR

O

N N

S

Ph

RO

N N

S

PhE

RO

EX

enolate

acyl donor

E-X

X

"activation"

catalyst


Ar

R O

NH

O

Ar R

then NH4Cl (aq)

N O

NOH

Boc

O

NOH

Boc

+

ADS group research

Organocatalysis

Organocatalysis



Isothioureas

New asymmetric transformations

Catalystdevelopment


Ph

N OPh

H Ph Et

O

NH

O

Ph Et

83% yield

THF, 30 minsthen

0.1M HCl (aq)

Serendipity

Ph

N OPh

H Ph Et

O N NN

Ph ON OPh

Ph Et Ph[3+2]


Ph

N OPh

H Ph Et

O

NH

O

Ph Et

83% yield

THF, 30 minsthen

0.1M HCl (aq)

Serendipity

• Anticipated [3+2]-cycloaddition gave consistent by-product

•Reaction occurs in the absence of NHC “catalyst”

Ph

N OPh

H Ph Et

O N NN

Ph ON OPh

Ph Et Ph[3+2]


NO

OPh

Ph [3,3]

sigmatropicrearrangement

N

OPh

O

HPh

Ph

Ph ON ON

O

Ph Ph

N

OHPh

O

Ph Ph

Ph O

PhO

O

Ph

Ph"2:1 adduct""1:1 adduct"

HH

1 eq 1 eq

Literature precedent

Staudinger and Miescher, Helv. Chim Acta., 1919, 2, 554Hafiz and Taylor., J. Chem. Soc., Perkin Trans. 1, 1980, 8, 1700

No examples of asymmetric reactions


Ar

R ON O

NH

O

Ar R

+

asymmetric induction?

then NH4Cl (aq)R1

R2R2

O

HR1

chiral auxiliary

cleaved and regenerated on

work-up

N O

NO

Boc

H

O

NO

Boc

H

(R,Z)

NH

OH

MgSO4

CH2Cl287%

H

Asymmetric Hetero-Claisen Reactions

Org. Lett., 2009, 11, 3858


Asymmetric Hetero-Claisen Reactions: Generality

Org. Lett., 2009, 11, 3858

R2

O

NH

O

R2R1

R1

NH

O

Me

NH

ONH

O

NH

O

Me

NH

O

F

NH

O

Me

85%, 87% ee 80%, 81% ee 82%, 78% ee

78%, 80% ee 91%, 86% ee 84%, 87% ee

NH

O

Me

91%, 90% ee

MeO

N

HN

O

Boc

O

THF, -78˚C 3 hours thenNH4Cl (aq)

HN

O

Boc

O

+

78-91% yield

Me

NH

O

88%, 90% ee

MeO


Ar

R O

N O

NO

R

NH

O

RAr

N O

NO

R

OAr

R

[3,3]-sigmatropic

rearrangement

nucleophilicaddition

hydrolysisand

cyclizationN

O

HCO2

Ar R

N

NO

R

CO2H

Ar R

imino acidN

O

R

H

O+

R

N

HH

H

H

Asymmetric Hetero-Claisen Reactions: mechanism?

How doeschiral auxiliary

imposeenantioselectivity?


StA to SF


Reaction modelling

• March

unpublished results


Reaction modelling

Your project is an excellent one for us to study computationally, and we will be happy to do so! .....!We look forward to collaborating with you and should have the answers to your questions, soon! !Ken Houk

• March

unpublished results


Reaction modelling


• March

• 6 months later....

unpublished results


Your [3,3]-sigmatropic rearrangement is rather more challenging than we expected.

Reaction modelling


• March


unpublished results


Your [3,3]-sigmatropic rearrangement is rather more challenging than we expected.

To put a long story short, we could locate a TS for the rearranged product, but its geometry does not resemble a [3,3]-sigmatropic rearrangement transition structure at all - that's something we don't understand, as yet. Colin Lam

Reaction modelling


• March


unpublished results


......we could not find the intermediate that results from the nucleophilic addition of the nitrone onto the ketene......Colin Lam

Reaction modelling

unpublished results


......we could not find the intermediate that results from the nucleophilic addition of the nitrone onto the ketene......Colin Lam

Ar

R O

N

R

O N

R

O

OAr

Rnucleophilicaddition

H H

Reaction modelling

unpublished results


In fact, we located two 3+2 TSs (one of them has the nitrone adding across the C=C bond of ketene, the other across the C=O bond of ketene), which have much lower enthalpies of activationColin Lam

Reaction modelling

Angew. Chem., accepted



Reaction modelling


N

RH

O

Et Ph

O ON O

Et PhR

[3+2]C=C



Reaction modelling


N

RH

O

O

[3+2]C=O

Et Ph

O

ON

R

Et

Ph

N

RH

O

Et Ph

O ON O

Et PhR

[3+2]C=C



N

R

O

OPh

Et [3,3]-sigmatropicrearrangement

H

ringopening

Reaction modelling


N

RH

O

O

[3+2]C=O

Et Ph

O

ON

R

Et

Ph

N

RH

O

Et Ph

O ON O

Et PhR

[3+2]C=C


2 weeks later: I have some exciting results about the pathway of the hetero-Claisen reaction!

We now find a low-energy TS involving N-O bond cleavage.! This results in a seven-membered ring that is a formal [3,3]-sigmatropic transformation.Colin Lam

Reaction modelling: a pericyclic cascade







NH

O

EtPh

hydrolysisand

cyclization

RH

O+

tautomerisationand

ring-opening

N

R

CO2H

Ph Et

H

N

RH

O

O

[3+2]C=O

Et Ph

OON

R

EtPh

[3,3]

NO

R

OPh EtH






asymmetric step

NH

O

EtPh

hydrolysisand

cyclization

RH

O+

tautomerisationand

ring-opening

N

R

CO2H

Ph Et

H

N

RH

O

O

[3+2]C=O

Et Ph

OON

R

EtPh

[3,3]

NO

R

OPh EtH


Reaction modelling: Asymmetric oxindole synthesis


Stereoselectivity a consequence of:• allylic strain controls facial selectivity of nitrone• addition of nitrone anti to Ph substituent of ketene

NOPh H

N OH

PG

O

Me

Ph

NOPh H

N OH

PG

O

Ph

Me

Ph Me

O O

N RH

Si face

Re faceMe Ph

O O

N RH

*

*

NO

R

OMe PhH

NH

O

Me Ph

NO

R

OPh MeH

NH

O

Ph Me

observed

C-Nanti/Rinside

*

*

anti to Ph

favoured


N NN

PhTBSO Ph

N

N

SPhPh

R

ArO

NN

N PhPh Ph

TBSO

azolium enolate

O

N

N

SPh

ammonium enolate

Ar

Conclusions

• NHCs and isothioureas are efficient Lewis base catalysts

• Future: further catalytic asymmetric applications of azolium and ammonium enolates

• One-pot synthesis of oxindoles from acids and the development of a catalytic variant?


Acknowledgements

The Carnegie TrustFor the Universities of Scotland

Dorine Belmessieri

Craig Campbell

Phil Woods

Caroline Joannesse

James Douglas

Kenneth Ling

Edward Richmond

Chris Collett

Eoin Gould

Siobhan Smith

Prof. Alex Slawin (X-ray)Dr David Fox (Warwick)Dr. AnnMarie OʼDonoghue (Durham)Prof. Douglas Philp

Stuart Leckie

Pei-Pei Ye

Carmen Simal

Louis Morrill

Craig Johnston


asymmetric lewis base strategies for heterocycle synthesis · 2020. 6. 24. · asymmetric lewis...

Documents