master thesis defence - magnus 20-10-2015

20. OKTOBER 2015MASTER THESIS DEFENCEMAGNUS EMIL JENSENAARHUS UNIVERSITETAU

EXPLORATION AND INVESTIGATIONS OF ENANTIOSELECTIVE AMINOCATALYTIC CYCLOADDITIONS


OUTLINE

Introduction Norcamphor scaffolds Preliminary work on higher order cycloadditions Inclusion tubular cavitaries

2


CHIRALITY“I call any geometrical figure, or group of points, chiral, and say that it has chirality, if its image in a plane mirror, ideally realized, cannot be brought to coincide with itself” Lord Kelvin

3


EFFECTS OF CHIRALITYLimonene

(R)-Limonene (S)-LimoneneCitrus Terpentine

Carvone

(R)-Carvone (S)-Carvone Caraway Spearmint

O O

4


EFFECTS OF CHIRALITY Thalidomide

Drug for reducing morning sickness

Developed in the 1950’s on marked in 1960’s

(R) reduced morning sickness

(S)had a teratogenic effect

N

O

O

NHO

O N

O

O

NHO

O

(R)-Thalidomide (S)-Thalidomide

5


NORCAMPHOR SCAFFOLDS Norcamphor scaffold overview Norcamphor in natural and bioactive compounds Screening Scope Mechanistic considerations Transformations Conclusion

6


NORCAMPHOR - BIOACTIVITY

O

D-Camphor

HN

N

HN

NH2

US 5731337 A compound 3


CO2H

OR

H

H

OHC

Sordarins

NH2

NH2

PtCl

Cl

ClCl

1,2-diamine ligands

NHSO2R

COOH

PGD2 Inhibitor

NH

S

N

O

AMG 221

NHN

O

O

SO2Ar

ALR1/ALR2 inhibitor

7

R1

EWG

O R1

EWG

ONHCatalyst

aminocatalyticactivation

[4+2]-cycloadditionand hydrolysis

N

N

MeOH2N R2

R2

EWG = NO2, CN, (C=O)R, (C=O)NHR, or CO2R


NORCAMPHOR - BIOACTIVITY

O

D-Camphor

HN

N

HN

NH2



CO2H

OR

H

H

OHC

Sordarins

NH2

NH2

PtCl

Cl

ClCl

1,2-diamine ligands

NHSO2R

COOH

PGD2 Inhibitor

NH

S

N

O

AMG 221

NHN

O

O

SO2Ar

ALR1/ALR2 inhibitor

8


NORCAMPHOR SCAFFOLDS

O

Ph O

OPh

Ph

NO2

OPh O

NO2

Ph O

OF3C

O

OMeO

Ph O

OEtO

Ph O

OBnHN

PhO2S O

O

Ph

CN

O

O

MeO

NC

NC

CN

NC

Ph

SO2PhOMe

O

MeO

OPh

Ph

O

Ph

F3C O

PhO2S

SO2Ph

NC

CNPh

Ph

NCCN

Ph

CN

O

EtO

PhCN

O

NHBn

Ph

O2N

Ph

NO2

Ph OO

O

Ph

O

O

9


NORCAMPHOR – PREVIOUS EXAMPLES

Ph

NO2O Ph

NO2

O

THF, rt

1f (30 mol%)2,4 dinitrobenzoic acid (30 mol%) Cordova et al. 2007

66% yield32% ee

CN

O

O

CN CN

Ph

toluene, 35 oC NC

Phsalicylic acid (40 mol%) Xu et al. 2012

94% yield75% ee

1d (20 mol%)

Ph

O O2N O1a (20 mol%)PhCOOH

PPG600, rt

NO2

Ph

Chen et al. 201276% yield85% ee

10

NH

N 1f

N

NH2

N

OMe

1d

NH

S

N

@PPG1000

1a


NORCAMPHOR - SCREENINGPh

NO2O Ph

NO2

O

PhCOOH (20 mol%)solvent, 40 °C

NH2

2a 3a aEntry Solvent Time(h) Conversion(%)b Yield(%)b

1 CDCl3 60 30 19

2 H2O 19 0 0

3 Toluene 19 4 7

4 Toluene 70 11 10

5 THF 19 25 5

6 THF 70 39 10aReactions were performed with 2a (0.2 mmol), 3a (0.1 mmol), catalyst (0.02

mmol), additive (0.02 mmol) in solvent (0.1 mL). bYield and conversion were

determined by 1H-NMR spectroscopy of the crude reaction mixture with 1,3,5-

tris(trifluoromethyl)benzeneastheinternalstandard.

11


NORCAMPHOR - SCREENING

PhPh

NH2

NH2

conv: 67% yield: 26%ee : 28%

NH

SN

NH

Ph

OTMSPh

conv: 43% yield: 8%ee : 40%

N

NH2

N

conv: 79% yield: 49%ee : -83%

OMe

NH2N

N

MeO

conv: 95% yield: 51%ee : 80%

OHPh

NH2

conv: 58% yield: 17%ee : 24%

conv: 48% yield: 8%ee : 14%

Reactionswereperformedwith2a(0.2mmol),3a(0.1mmol),cat(0.02mmol),additive(0.02mmol).Yieldandconversionwasdetermined by 1H-NMR spectroscopy of the crude reaction mixture with 1,3,5-tris(trifluoromethyl)benzene as the internalstandard.

Ph

NO2O Ph

NO2

O

EtCOOH (20 mol%)toluene, 40 °C

Catalyst (20 mol%)

2a 3a

12


NORCAMPHOR - SCREENINGPh

NO2O Ph

NO2

O

additive (20 mol%)CDCl3, 40 °C

2a 3a

1d (20 mol%)

Entrya Additive Time(h) Conversion(%)b Yield(%)b ee(%)

1 EtCOOH 19 91 52 90

2 AcOH 18 85 48 89

3 PhCOOH 18 100 51 90

4 PhCOONa 18 68 20 91

5 p-NO2(C6H4)COOH 18 90 34 87

6 Salicylicacid 18 90 44 91

7 TFA 18 62 14 90

8 Bu4N+-BF4 18 23 13 n.d.aReactionswereperformedwith2a (0.2mmol),3a (0.1mmol),1d (0.02mmol),additive (0.02mmol) in solvent(0.1mL). bYield and conversion were determined by 1H-NMR spectroscopy of the crude reactionmixture with1,3,5-tris(trifluoromethyl)benzeneastheinternalstandard.

13

N

NH2

N

OMe

1d


NORCAMPHOR - SCOPE

R

NO2O

Yield: 62% ee: 90% dr: >20:1

Yield: 56% ee: 89%dr: >20:1

Yield: 56% ee: 92%dr: >20:1

Yield: 50% ee: 90%dr: >20:1

Ph

NO2

O

NO2

O

NO2

O

F Br

NO2

O

Me

R

NO2

OEtCOOH (20 mol%)

toluene, 40 °C

1d (20 mol%)

Yield: 81% ee: 95%dr: >20:1

NO2

O

Cl

14

N

NH2

N

OMe

1d


NORCAMPHOR - SCOPE

R

NO2O R

NO2

OEtCOOH (20 mol%)

toluene, 40 °C

1d (20 mol%)

Yield: 79% ee: 95%dr: >20:1

Yield: 49% ee: 90%dr: >20:1

Yield: 48% ee: 86%dr: >20:1

NO2

O

OMe

NO2

O

OMe

NO2

O

MeO

Yield: 59% ee: 84%dr: >20:1

Yield: 41% ee: 87%dr: 9:1

NO2

O

Ph

NO2

OO

Yield: 49% ee: 89% dr: >20:1

NO2

O

Yield: 37% ee: 86%dr: >20:1

NO2

OS

15

N

NH2

N

OMe

1d


NORCAMPHOR - SCOPE

R

NO2O R

NO2

OEtCOOH (20 mol%)

toluene, 40 °C

1d (20 mol%)

Yield: 79% ee: 95%dr: >20:1

Yield: 49% ee: 90%dr: >20:1

Yield: 48% ee: 86%dr: >20:1

NO2

O

OMe

NO2

O

OMe

NO2

O

MeO

Yield: 59% ee: 84%dr: >20:1

Yield: 41% ee: 87%dr: 9:1

NO2

O

Ph

NO2

OO

Yield: 49% ee: 89% dr: >20:1

NO2

O

Yield: 37% ee: 86%dr: >20:1

NO2

OS

16

N

NH2

N

OMe

1d


NORCAMPHOR - SCOPE

Yield: 79% ee: 93%dr: >20:1

Temp: 60 oC

Yield: 52% ee: 99% dr: >20:1

Temp: 40 oC

Yield: 63% ee: 96%dr: >20:1

Temp: 40 oC

Yield: 66% ee: 96%dr: >20:1

Temp: 60 oC

R1

O R1 OEtCOOH (20 mol%)

toluene, 18 h

1d (20 mol%)O

R2

OR2

Ph O

OPh

Ph O

O

Br

O

OPh

O

OPh

O2N

O2N

Yield: 91% ee: 99%dr: >20:1

Temp: 40 oC

Yield: 85% ee: 96%dr: >20:1

Temp: 60 oC

O

O

Ph O

O

O2N

Br

O2N

17

N

NH2

N

OMe

1d


NORCAMPHOR - SCOPE

Yield: 79% ee: 93%dr: >20:1

Temp: 60 oC

Yield: 52% ee: 99% dr: >20:1

Temp: 40 oC

Yield: 63% ee: 96%dr: >20:1

Temp: 40 oC

Yield: 66% ee: 96%dr: >20:1

Temp: 60 oC

R1


toluene, 18 h

1d (20 mol%)O

R2

OR2

Ph O

OPh

Ph O

O

Br

O

OPh

O

OPh

O2N

O2N

Yield: 91% ee: 99%dr: >20:1

Temp: 40 oC

Yield: 85% ee: 96%dr: >20:1

Temp: 60 oC

O

O

Ph O

O

O2N

Br

O2N

18

N

NH2

N

OMe

1d


NORCAMPHOR - SCOPE

Yield: 79% ee: 93%dr: >20:1

Temp: 60 oC

Yield: 52% ee: 99% dr: >20:1

Temp: 40 oC

Yield: 63% ee: 96%dr: >20:1

Temp: 40 oC

Yield: 66% ee: 96%dr: >20:1

Temp: 60 oC

R1


toluene, 18 h

1d (20 mol%)O

R2

OR2

Ph O

OPh

Ph O

O

Br

O

OPh

O

OPh

O2N

O2N

Yield: 91% ee: 99%dr: >20:1

Temp: 40 oC

Yield: 85% ee: 96%dr: >20:1

Temp: 60 oC

O

O

Ph O

O

O2N

Br

O2N

19

N

NH2

N

OMe

1d


NORCAMPHOR - SCOPE

R1


toluene, 18 h

1d (20 mol%)O

R2

OR2

Yield: 52% ee: 96%dr: >20:1

Temp: 80 oC

Yield: 38% ee: 87%dr: >20:1

Temp: 100 oC

Yield: 75% ee: 99%dr: >20:1

Temp: 60 oC

Ph O

O

Ph O

O

Ph O

O

OMeMeO

MeO

Yield: 37% ee: 92%dr: >20:1

Temp: 100 oC

Ph O

OO

O

20

N

NH2

N

OMe

1d


NORCAMPHOR - SCOPE

R1


toluene, 18 h

1d (20 mol%)O

R2

OR2

Yield: 62% ee: 87%dr: >20:1

Temp: 80 oC

O

OPh

O

Yield: 58% ee: 91%dr: >20:1

Temp: 80 oC

O

OPh

S

Yield: 47% ee: 91%dr: >20:1

Temp: 80 oC

O

OPh

Yield: 32% ee: 91%dr: >20:1

Temp: 40 oC

Me O

OPh

Yield: 19% ee: 92%dr: >20:1

Temp: 60 oC

Ph O

OMe

21

N

NH2

N

OMe

1d


NORCAMPHOR - SCOPE

R1

R3 R1

R3

O1d (20 mol%)

EtCOOH (20 mol%)

toluene

R2R2

O

Ph

CN

ONC

53% yield>20:1 dr, 42% ee

CN

ONC

62% yield19:1 dr, 83% ee

PhPh

COCF3

O

71% yield>20:1 dr, 98% ee

MeO2C

CO2Me

O

74% yield>20:1 dr, 65% ee

Ph

CO2Et

ONC

79% yield>20:1 dr, 80% ee

Ph

CONHBn

ONC

84% yield>20:1 dr, 87% ee

Ph O

27% yield>20:1 dr, 90% ee

O

O

22

N

NH2

N

OMe

1d


ABSOLUTE CONFIGURATION

O

O

NO2

Br

23


NORCAMPHOR – MECHANISTICS

HN

N H O

R

RAr

R

O R ONAr

H2NO

R

ORH+ H2O

Our proposed mechanism

24



NH

R

EWGNH

EWGR

O R

EWG

Mechanism proposed by Chen et al.[1]

[1] X. Feng, Z. Zhou, R. Zhou, Q.-Q. Zhou, L. Dong, Y.-C. Chen, J. Am. Chem. Soc. 2012, 134, 19942.

HN

N H O

R

RAr

R

O R ONAr

H2NO

R

ORH+ H2O

Our proposed mechanism

25



O

Ph

NO2 O

Ph

NO2

9 % yield79% ee>19:1 dr

O

NO2

Traces

Ph

114h

1d (20 mol%)Salicylic acid (40 mol%)

O

Ph

NO2

32 % yield76% ee>19:1 dr

O

NO2

Ph114h


26

N

NH2

N

OMe

1d




O

Ph

NO2 O

Ph

NO2

9 % yield79% ee>19:1 dr

O

NO2

Traces

Ph

114h


O

Ph

NO2

32 % yield76% ee>19:1 dr

O

NO2

Ph114h


27

N

NH2

N

OMe

1d




O

Ph

NO2 O

Ph

NO2

9 % yield79% ee>19:1 dr

O

NO2

Traces

Ph

114h


O

Ph

NO2

32 % yield76% ee>19:1 dr

O

NO2

Ph114h


HN

NO2

Ph

O

Ph

NO2

28

N

NH2

N

OMe

1d


NORCAMPHOR – TRANSFORMATIONS

O

Ph

NO2O

CO2Me

Ph

NO2

3% 12M HCl

MeOH

82% yield

HO

mCPBANaHCO3

CH2Cl2, rt, 6 hNO2

Ph

O

70% yield9:1 regioisomers

29



O

Ph

NO2O

CO2Me

Ph

NO2

3% 12M HCl

MeOH

82% yield

HO

mCPBANaHCO3

CH2Cl2, rt, 6 hNO2

Ph

O


30



CO2Et

EtO2C

EtO2C

CO2Et

O

CHO

TBDPSO

O

O

TBDPSO

MeO OMe

OHO

HOO

O

OAc

31



O

Ph

NO2O

CO2Me

Ph

NO2

3% 12M HCl

MeOH

82% yield

HO

mCPBANaHCO3

CH2Cl2, rt, 6 hNO2

Ph

O


32


NORCAMPHOR – TRANSFORMATIONSO

Ph

NO2O

CO2Me

Ph

NO2

3% 12M HCl

MeOH

82% yield

HO

mCPBANaHCO3

CH2Cl2, rt, 6 hNO2

Ph

O


59% yield20:1 dr

NHBnNO2

Ph

NO2

Ph

O

BnNH2NaBH(OAc)3

THF, rt, 24 h

33



34


NORCAMPHOR – CONCLUSION

We have developed a method with high Versatile Efficiency Potential for future development

R1

EWGO R1

EWG

ONHCatalyst

aminocatalyticactivation

[4+2]-cycloadditionand hydrolysis

N

N

MeOH2N R2

R2

EWG = NO2, CN, (C=O)R, (C=O)NHR, or CO2R

yields up to 91%ee up to 99%dr up to >20:1

35


HIGHER-ORDER CYCLOADDITIONO

O

O

OEtCOOH (20 mol%)

toluene, 40 °C, 18 h

isolated yield 50% ee 70%dr >20:1

1d (20 mol%)

O

O

36

N

NH2

N

OMe

1d


HIGHER-ORDER CYCLOADDITION

O

HOHOHO CH2OH

H

Ingenol

OO

OH

OO

OO

Goyazensolide

OO

OO

OHO

H

Eremantholide C

O

OHOHO CH2OH

H

Picato (synthetic)

O

37


HIGHER-ORDER CYCLOADDITIONO

X

X

O(-)-CSA (40 mol%)

solvent60 °C, 16 h

1k (20 mol%)

R RR2R2

O

O

conversion 73% isolated yield 51%

ee 96%dr >20:1

O

conversion 95% yield 51% ee 40%dr >20:1

NCCN

O

O


ee 83%dr >20:1

CO2Et

O


ee 70%

Me

NCCN

O

O


ee 77%dr >20:1

Me

38

N

NH2

N

1k



O

O

O(-)-CSA (40 mol%)

toluene60 °C, 8 d

1k (20 mol%)OH

Ph

O

PhO

O

Ph

yield 12% ee 19%dr >20:1

yield 6% ee 87%dr >20:1

[4+2] and [6+4] cycloaddition products

OO

OO(-)-CSA (40 mol%)

1,4-dioxane, 60 °C, 16 h

1k (20 mol%)conversion 76%

yield 69% ee 70%dr >20:1

39

N

NH2

N

1k



O

EtCOOH (20 mol%)

toluene, 60 °C

1d (20 mol%)conversion 100%

yield 62% ee 98%dr 85:15

CN

CO2Et

O

CO2EtCN

O(-)-CSA (40 mol%)

1,4-dioxane, 60 °C, 16 h

1k (20 mol%)

OO

O

[8+2] cycloaddition

Future work

40

N

NH2

N

OMe

1d

N

NH2

N

1k


HIGHER-ORDER – CONCLUSION

In the process of developing a method for producing multibridged polycyclic compounds

First time these are made enantioselectively Exploration of mechanisms

O

X

X

O(-)-CSA (40 mol%)

solvent60 °C, 16 h

1k (20 mol%)

R RR2R2

41

N

NH2

N

1k


TUBULAR INCLUSION CAVITIES

42



43



Hexagonal Orthorhombic

44



Hexagonal Orthorhombic

45



46


ACKNOWLEDGEMENTSKarl Anker JørgensenRasmus Mose, Gert PreegelLydia Klier and Christian SibbersenJacob Overgaard and the crystallographersGroup 109 and Lise Ravn PetersenUNF and AAKMads Mørk Jensen, friends and my family for all the supportYou!

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AARHUS UNIVERSITETAU

4 8

master thesis defence - magnus 20-10-2015

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