Asymmetric Lewis Base Strategies for Heterocycle Synthesis · 2020. 6. 24. · Asymmetric Lewis...

transcript

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

PhTBSO Ph

N NPhPh

ADS group research

Organocatalysis

Probe new reactivity

N-heterocycliccarbenes

Isothioureas

Catalytic enolate chemistry

Catalystdevelopment

N PhPh Ph

azolium enolate

ammonium enolate

ADS group research

Organocatalysis

Catalystdevelopment

Organocatalysis

Isothioureas

PhTBSO Ph

N NPhPh

NR3Y/H

R RR 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

ammonium enolateR1

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

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

99% eeWynberg et al.

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

Lewis base catalysis: ammonium enolate chemistry

PhTBSO PhN N

N PhPh Ph

azolium enolate

ADS group research

Organocatalysis

Isothioureas

Catalystdevelopment

Typical organocatalytic NHC reactivity

• Generation of enolate equivalents

Organocatalytic NHC reactivity

Chem. Commun, 2011, 47, 373-375

N NR R

azolium enolate

Bode, Rovis (halide)Scheidt (aryloxy)

R1base - HCl

azolium enolate

ADS / Ye

unstable

benchstable

azolium enolate

asymmetriccatalysis

Chem. Commun, 2011, 47, 373-375

N NR R

azolium enolate

R1base - HCl

azolium enolate

ADS / Ye

unstable

benchstable

azolium enolate

asymmetriccatalysis

Chem. Commun, 2011, 47, 373-375

N NR R

azolium enolate

R1base - HCl

azolium enolate

ADS / Ye

unstable

benchstable

azolium enolate

asymmetriccatalysis

Chem. Commun, 2011, 47, 373-375

N NR R

azolium enolate

R1base - HCl

azolium enolate

ADS / Ye

unstable

benchstable

azolium enolate

asymmetriccatalysis

Applications of NHC-generated enolates from ketenes

OC6Cl5

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

2010, 5863

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

ArR CO2Et

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

2009, 74, 7585

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

2009, 48, 192

azolium enolate

Ph ArPh H

up to 90% eeOrg. Biomol. Chem.,

2008, 6, 1108

ONTsAr

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

Isothioureas

New Asymmetric Transformations

Catalystdevelopment

Catalytic generation of ammonium enolates from acids

One-pot domino Lewisbase catalysis

enolate

acyl donor

Mukaiyamareagent (1.5 eq)

Lewis base

aldoland

lactonisation

R = H or Me

Lewis base (LB)derived enolate

i-Pr2NEt,CH2Cl2, rt

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.

Hactivating agent (1.2 eq)

isothiourea

i-Pr2NEt (3.5 eq),CH2Cl2, rt

activating agent

isothiourea

87%, dr 99:1

53%, dr 99:1

73%, dr 99:1ee 97%

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

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

isothiourea

activating agent

isothiourea

87%, dr 99:1

53%, dr 99:1

73%, dr 99:1ee 97%

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

61%, dr 99:1ee 97%

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

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

isothiourea

activating agent

isothiourea

87%, dr 99:1

53%, dr 99:1

73%, dr 99:1ee 97%

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

61%, dr 99:1ee 97%

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

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

isothiourea

activating agent

isothiourea

87%, dr 99:1

53%, dr 99:1

73%, dr 99:1ee 97%

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

61%, dr 99:1ee 97%

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

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

(i) pivaloyl chloride, NEt3

Michael addition

lactonisation mixed anhydride

ammonium enolate

CO2COt-Bu

COPhHO Ph

acyl ammonium

COPh acyl ammonium

deprotonation

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

.HClR1 R1

61%, dr 99:1ee 97%

81%, dr 99:1ee 94%

94%, dr 99:1

ee 91%

99%, dr 99:1

ee 99%

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

(5-20 mol%)

O CO2H

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

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

HO2N Me

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

(5-20 mol%)

O CO2H

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

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

HO2N Me

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

(5-20 mol%)

O CO2H

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

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

HO2N Me

Catalytic generation of enolates from acids: intermolecular reaction

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

O isothioureapivaloyl chloride (1.2 eq)

i-Pr2NEt (3.5 eq),CH2Cl2

Ph CO2Me

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

Ph CO2Me

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

Ph CO2Me

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

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

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

CO2Me67%, dr 95:5

ee 97%81%, dr 95:5

ee 99%67%, dr 95:5

ee 97%66%, dr 95:5

ee 87%

CO2Me62%, dr 90:10

ee 93%76%, dr 95:5

ee 98%72%, dr 96:4

ee 86%73%, dr 93:7

ee 97%

Br MeO

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

CO2Me67%, dr 95:5

ee 97%81%, dr 95:5

ee 99%67%, dr 95:5

ee 97%66%, dr 95:5

ee 87%

CO2Me62%, dr 90:10

ee 93%76%, dr 95:5

ee 98%72%, dr 96:4

ee 86%73%, dr 93:7

ee 97%

Br MeO

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

CO2Me67%, dr 95:5

ee 97%81%, dr 95:5

ee 99%67%, dr 95:5

ee 97%66%, dr 95:5

ee 87%

CO2Me62%, dr 90:10

ee 93%76%, dr 95:5

ee 98%72%, dr 96:4

ee 86%73%, dr 93:7

ee 97%

Br MeO

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

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

67%, dr 95:5

ee 97%67%, dr 87:13

ee 99%87%, dr 94:6

ee 97%82%, dr 95:5

ee 99%

CO2i-Pr

71%, dr 96:4

ee 98%66%, dr 92:8

ee 99%82%, dr 95:5

ee 99%80%, dr 88:12

ee 96%

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

67%, dr 95:5

ee 97%67%, dr 87:13

ee 99%87%, dr 94:6

ee 97%82%, dr 95:5

ee 99%

CO2i-Pr

71%, dr 96:4

ee 98%66%, dr 92:8

ee 99%82%, dr 95:5

ee 99%80%, dr 88:12

ee 96%

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

67%, dr 95:5

ee 97%67%, dr 87:13

ee 99%87%, dr 94:6

ee 97%82%, dr 95:5

ee 99%

CO2i-Pr

71%, dr 96:4

ee 98%66%, dr 92:8

ee 99%82%, dr 95:5

ee 99%80%, dr 88:12

ee 96%

ADS group research

Catalytic generation of ammonium enolates from acids

Intramolecularand

Intermolecular

One-pot domino Lewisbase catalysis

Catalystvariation

Electrophilevariation

Product derivatisationand mechanistic

studies

enolate

acyl donor

"activation"

catalyst

then NH4Cl (aq)

ADS group research

Organocatalysis

Isothioureas

New asymmetric transformations

Catalystdevelopment

H Ph Et

83% yield

THF, 30 minsthen

0.1M HCl (aq)

Serendipity

H Ph Et

O N NN

Ph ON OPh

Ph Et Ph[3+2]

H 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”

H Ph Et

O N NN

Ph ON OPh

Ph Et Ph[3+2]

Ph [3,3]

sigmatropicrearrangement

Ph ON ON

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

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

R ON O

asymmetric induction?

then NH4Cl (aq)R1

chiral auxiliary

cleaved and regenerated on

work-up

CH2Cl287%

Asymmetric Hetero-Claisen Reactions

Org. Lett., 2009, 11, 3858

R ON O

then NH4Cl (aq)R1

chiral auxiliary

work-up

CH2Cl287%

Org. Lett., 2009, 11, 3858

R ON O

then NH4Cl (aq)R1

chiral auxiliary

work-up

CH2Cl287%

Org. Lett., 2009, 11, 3858

Asymmetric Hetero-Claisen Reactions: Generality

Org. Lett., 2009, 11, 3858

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

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

91%, 90% ee

THF, -78˚C 3 hours thenNH4Cl (aq)

78-91% yield

88%, 90% ee

Org. Lett., 2009, 11, 3858

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

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

91%, 90% ee

78-91% yield

88%, 90% ee

Org. Lett., 2009, 11, 3858

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

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

91%, 90% ee

78-91% yield

88%, 90% ee

[3,3]-sigmatropic

rearrangement

nucleophilicaddition

hydrolysisand

cyclizationN

imino acidN

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

Rnucleophilicaddition

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

O ON O

Et PhR

[3+2]C=C

Reaction modelling

[3+2]C=O

O ON O

Et PhR

[3+2]C=C

Et [3,3]-sigmatropicrearrangement

ringopening

Reaction modelling

[3+2]C=O

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

hydrolysisand

cyclization

tautomerisationand

ring-opening

[3+2]C=O

OPh EtH

asymmetric step

hydrolysisand

cyclization

tautomerisationand

ring-opening

[3+2]C=O

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

Si face

Re faceMe Ph

OMe PhH

OPh MeH

observed

C-Nanti/Rinside

anti to Ph

favoured

PhTBSO Ph

N PhPh Ph

azolium enolate

ammonium enolate

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...

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