jakob schneider 1 – planar-chiral hydrogen-bond donor catalysts – synthesis, application and...

Jakob Schneider

1

– Planar-Chiral Hydrogen-Bond Donor Catalysts – Synthesis, Application and Structural Analysis

Literature Seminar Montréal, 11.04.2011

3

Hydrogen-Bond Catalysis

[2.2]Paracyclophane Chemistry

Synthesis of planar-chiral H-bond donor catalysts

Organocatalytic applications

Experimental and computational structural analysis

Synthesis and Application of amino acid-based organocatalysts

Outlook:

– Planar-Chiral Hydrogen-Bond Donor Catalysts – Synthesis, Application and Structural Analysis

4 4

Organocatalysis: Structural motivs

Takemoto, 2003Rawal, 2002

Jacobsen, 2004Fu, 2002

MacMillan, 2003

Akiyama, 2004Wang, 2005

L-proline-mediated

enamine-catalysis;

1970

Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743; Dalko, P. I.; Moisan, L. Angew. Chem. 2004, 116, 5248-5286; Angew. Chem., Int. Ed. 2004, 43, 5138–5175; Fu, G. C. Acc. Chem. Res. 2000, 33, 412–420.

NH

NMe2

NH

S

F3C

CF3

NMe2

NH

S

NH

NH

N

NH

S

Me PhO

N

iBu

iBu

tBu

NFe

Me

Me

Me

MeMe

N

NH

NMe

O

Ph

O

O

Ar

Ar

PO

OH

O

OMe

Me OH

OH

Ph

PhPh

Ph

NH

CO2HO

O

Me

O Me

OMe

OHO

(quant)ee = 99%

5 5

Hydrogen-Bond catalysis

Strong Moderate Weak

Type of bonding Mostly covalent Mostly electrostatic Electrostatic

Length of H-Bond (Å) 1.2-1.5 1.5-2.2 2.2-3.2

Bond angles (°) 175-180 130-180 90-150

Bond energy (kcal/mol) 14-40 4-15 <4

+O

R

O

R

O

R

OH

R Nu

proton transfer

HX

H

X

cat. H-X

Brønsted acid catalysis

Hydrogen-bond catalysis

NuH

Nu = Nucleophile

ion-pair

H-bondcomplex

Properties of hydrogen bonds

Pihko, P. M. Hydrogen Bonding in Organic Synthesis, 2009, Wiley-VCH, Weinheim.

Hydrogen-bond vs. Brønsted acid catalysis

6 6

Broensted acid catalysis

N

Ph

HO

+OTMS

OTMScat. (30 mol%)

toluene, 78 °CHN

Ph

HO

CO2Me

Ar

Ar

O

OP

O

OHcat.

Ar = 4-NO2C6H4, 96% yield, 87% ee

Broensted basic site

Broensted acidic site

defining chiral pocket

Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566-1568; Angew. Chem. 2004, 116, 1592-1594. Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. Adv. Synth. Catal. 2005, 347, 1523-1526.

BINOL-derived phosphoric acid-catalyzed addition of silyl ketene acetales to aldimines.

7 7

Hydrogen Bond catalysis – Chiral Diols

OH

OH O

H

Ph

TADDOL-catalyzed hetero-Diels Alder reaction

Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146. Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 1336-1337.

H-Bond-promoted H-Bond

O

O

Ar

ArAr

Ar

OHOH

TMSO

NMe2

O

R H+ O

RTMSO

NMe2

O

O Rcat. (20 mol%)

toluene, 78 °C

AcCl

CH2Cl2/toluene 78 °C

up to 99% ee

cat. Ar = 1-naphthyl

8 8

O

PhN

+cat. (1 mol%)

CDCl3, r.t.

Ph

O

Nkrel = 8.2

F3C

CF3

NH

S

NH

CF3

CF3

cat.

NO2 NO2

O OH H

OO

Ph

NO2 NO2

O OH H

O

C3H7C3H7

H

Hine, J.; Ahn, K.; Gallucci, J. C.; Linden, S.-M. J. Am. Chem. Soc. 1984, 106, 7980-7981; Hine, J.; Ahn, K. J. Org. Chem. 1987, 52, 2083-2086; Etter, M. C.; Panunto, T. W. J. Am. Chem. Soc. 1988, 110, 5896-5897 ; Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217-220.

Hydrogen-Bond catalysis – Development of (thio)urea compounds

Activation of epoxides and unsaturated ketones

Schreiner´s electron-deficient N,N`-diphenyl thiourea

9 9

Hydrogen-Bond catalysis

PhNO2

PhNO2

EtO2C CO2Et

F3C

CF3

NH

NH

S

N

EtO2C CO2Et+cat. (10 mol%)

toluene, r.t., 24 h

cat.

86%, 93% ee

Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2000, 39, 1279-1281; Angew. Chem. 2000, 112, 1336-1338.; Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672-12673.

Strecker reaction of N-alkyl imines, catalyzed by Jacobsen´s Schiff-base thiourea

Takemoto´s thiourea catalyst: asymmetric Michael reaction

Bifunctional mode of action

Ph

N Ph

H+ HCN

Ph

N Ph

CN

F3COC1) cat. (1 mol%) toluene, -78 °C2) TFAA

HO

tBu OCOtBu

N

NH

S

NH

N

O

tBu

cat.

91% ee

10 10


O

+O

H

O OHcat. (20 mol%)

r.t., CH3CN, 0 °C

63%, 94% ee

N

NH

S

NH

CF3

CF3

cat.

Wang, J.; Li, H.; Duan, W.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293-4296.; Sibi, M. P.; Itoh, K. J. Am. Chem. Soc. 2007, 129, 8064-8065.

Wang, 2005: Asymmetric MBH reaction.

NN

O

NN

O NH OBn

CF3

F3C NH

S

NH OH

cat.

cat. (100 mol%)

BnONH2, CF3C6H5, MS 4 Å r.t., 72 h

82%, 87% ee

Asymmetric Michael reaction

11 11


Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187-1198.

Mono- and bidentate interaction of thiourea derivatives with anionic substrates

Role of the thiourea: - preorganizing the arrangement of substrates - activating substrates through polarization - stabilizing charges, transition states or intermediates

H H

O O

N

R

H H

O O

S

H H

O O

C

R

H H

O O

N

H H

O O

S

H H

O O

P2+

R RR

2+

OO RO OR

H H

XH H

O

H H

X

R RR R

R R

X = Hal, CN X = O, NH

12 12

Proposed mechanisms

N

S

N

N

CF3

F3C

HO

NO

Ph

H H

O O

EtO OEt

N

S

N

N

CF3

F3C

H

H H

O ON O O

EtO OEt

a) b)

Ph

Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672-12673; Hamza A; Schubert, G.; Soo´ s, T.; Papai, I. J. Am. Chem. Soc. 2006, 128, 13151-13160.

Mechanistic controversies

Ternary complexes in the thiourea-catalyzed Michael reaction : a) Takemoto’s proposal and b) results calculated by Pápai et al

13 13

[2.2]Paracyclophane

C2

C1

C9

C10

C3

C4

C11

Winberg, H. E.; Fawcett, F. S.; Mochel, W. E.; Theobald, C. W. J. Am. Chem. Soc. 1960, 82, 1428-1435; Reich, H.; Cram, D. J. J. Am. Chem. Soc. 1967, 89, 3078-3080.

NMe3

OH

toluenephenothiazine,

reflux, 3 h

B

A

pseudo-geminal pseudo-ortho

a) b)A

B

X250 °C,

p-diisopropyl-benzene

X

X

X

SP

rac

X = CO2Merotation

Ar-ring distance: 3.08–3.09 Å

14 14

[2.2]Paracyclophane

Chen, H.-Y.; Hirtz, M.; Deng, X.; Laue, T.; Fuchs, H.; Lahann, J. J. Am. Chem. Soc. 2010, 132, 18023–18025.; http://www.parylene.com/applications/parylene-applications.html

„Light-weight Parylene functions under rugged vacuum conditions and extreme temperatures, and has been proven in multiple spaceflight applications”

“Parylene meets MIL-I-46058C, Army Regulation 70-71, NAV.INST. 3400.2, and USAF-80-30 regs”

Applications of [2.2]Paracyclophane-based polymers:

15 15

[2.2]Paracyclophane

Reich, H.; Cram, D. J. J. Am. Chem. Soc. 1967, 89, 3078-3080; Reich, H. J.; Yelm, K. E. J. Org. Chem. 1991, 56, 5672-5679.

HO O

Br+

Br

H BrOH

BrO

fast slow

H+

OROH OH

OO

R = H R = CONEt2

(CH2O)n

SnCl4NBu3

1) s-BuLi, TMEDA2) DMF3) HCl

for R = H for R = CONEt2

Transannular substitution: Pseudo-geminally directing effect of: acetyl, carbomethoxy, carboxy, nitro and sulfone substitutents

Selective ortho-functionalization of 4-hydroxy[2.2]paracyclophane derivatives via Friedel-Crafts acylation or directed metalation

16 16

[2.2]Paracyclophanes - Applications

Masterson, D. S.; Hobbs, T. L.; Glatzhofer, D. T. J. Mol. Cat. A: Chem. 1999, 145, 75-81; Danilova, T. I.; Rozenberg, V. I.; Vorontsov, E. V.; Starikova, Z. A.; Hopf, H. Tetrahedron: Asymmetry 2003, 14, 1375-1383; Danilova, T. I.; Rozenberg, V. I.; Sergeeva, E. V.; Starikova, Z. A.; Bräse, S. Tetrahedron: Asymmetry 2003, 14, 2013-2019.

+Cu(II)/ligand (0.1 mol%)

benzene, , 5.5 h

CO2tBu

1.5 equiv.

ligand

N

HO

N2CHCO2tBu

cis/ trans: 1:6, 40 % ee

Catalytic enantioselective cyclopropanation of styrenes

Enantioselective diethylzinc addition to benzaldehyde

O OHZnEt2 (2 equiv)ligand (10 mol%)toluene, r.t.

OH

N

tBu

ligand

quant, 93% ee

17 17


O1) Et2Zn (2 equiv) ligand (2 mol%) hexane, 0 °C, 14 h

2) Ac2O, r.t., 24 h

ligand RP,S

quant, 96% ee

OO

OH

N

O O OH

Et

Et

*

Et2Zn (2 equiv)2 mol% ligandtoluene-25 °C, 1.5 d

+

1,4-product 1,2-product

90% brsm, 99% ee <1%

a)

b)

Hermanns, N.; Dahmen, S.; Bolm, C.; Bräse, S. Angew. Chem., Int. Ed. 2002, 41, 3692-3694; Angew. Chem. 2002, 114, 3844-3846; Ay, S.; Ziegert, R.; Zhang, H.; Nieger, M.; Rissanen, K.; Fink, K.; Kubas, A.; Gschwind, R. M.; Bräse, S.J. Am. Chem. Soc. 2010, 132, 12899-12905

a) 1,2-addition of diethylzinc to isobutyraldehyde

b) 1,4-addition of diethylzinc to cinnamylaldehyde

18 18


OMe

O O

OMe

OOH

Ph2P

Ph2P

[(SP-Phanephos)Ru(CO2CF3)2](0.4-0.8 mol%) Bu4NI (5 mol%)H2 (3.5 bar)

MeOH/H2O, -5 °C, 18 h

SP-Phanephosquant, 96% ee

Pye, P. J.; Rossen, K.; Reamer, R. A.; Volante, R. P.; Reider, P. J. Tetrahedron Letters, 1998, 39, 4441-4444; Focken, T.; Rudolph, J.; Bolm, C. Synthesis, 2005, 3, 429-436; Fürstner, A.; Alcarazo, M.; Krause, H.; Lehmann, C. W. J. Am. Chem. Soc. 2007, 129, 12676-12677.

Application of the Phanephos ligand in the enantioselective hydrogenation of β-ketoesters

NN

MeI

Fürstner´s [2.2]Pyridinophane- -based NHC ligand

OH

OH

O

HN

+

OH

Ncat. (10 mol%)r.t., 66 h

66% yield

O

Hcat. (10 mol%)

r.t., 15 h

CHO+

endo/exo: 3.8/1

cat.

a)

b)

Epoxide ring-opening and Diels-Alder reaction (essentially racemic), catalyzed by RP-PHANOL

19 19

Bifunctional thiourea-catalyst

H-bond donor

Planar chirality

Defined distance between the functionalities

Flexible catalyst design

Development of planar-chiral catalysts

OH

NH

S

NH

CF3

CF3

NH

S

NH

ArNH

S

NH

Ar

RP SP

NH

S

NH

Arpseudo-geminal

substitutionFG

H-bond-donor

2.9-3.3 Å

substrate activation

20 20

Synthesis

Schneider, J. F.; Falk, F. C.; Fröhlich, R.; Paradies, J. Eur. J. Org. Chem. 2010, 2265–2269.

1) SOCl2

2) NaN3

65%

3) toluene

4) 50%-aq. KOH

CO2H NH2 NH

S

NH

CF3

CF3ArF-NCS

82%28%, 3 steps; >99% ee; SP

ArF = 3,5-(CF3)2-C6H3

5 steps, 15%

21 21

Synthesis


1) SOCl2

2) MeOH

74%, 2 steps 67%

2) B(OMe)3;

H2O2/NaOH TFA, 40 °C

63% 68%

1) Br2, kat. Fe, 81%

2) KOH, MeOH

99%

1) SOCl2

2) NaN3,

1) nBuLi

3) , tBuOH

CO2H

CO2Me CO2H

Br

NH-Boc

Br

NH-Boc

OH

NH2

OH

NH

S

NH

CF3

CF3OHArF-NCS

80%

28%, 3 steps; >99% ee; SP

12 steps, 4.6%

22 22

[2.2]Paracyclophanes – Synthetic Approaches

Fe, Br2, CCl4

25 °C, 24 h

Br

Br

Br

Br

Br

Br

Br

Br

pseudo-para

40%

RP + SP pseudo-ortho

14%

RP + SP pseudo-meta

36%

RP + SP para5%

Br

OHn-BuLi, B(OMe)3

THF,-78 °C - rt

KOH, H2O2

69%Br

Br

Br

BrTriglyme

reflux (216 °C)4 cycles

71%

pseudo-para pseudo-ortho

23 23

[2.2]Paracyclophanes – Synthetic Approaches

Br

O

O

O O

O OO

O

Br

Br

OH

O

OCl

O

pyridine, 2 h, rt,

resolution

Br

HO

Br

OH

KOH, MeOH,2 h, rt

(RP) 47%

(RP,S) 49%

(SP,S) 44%

rac

(SP) 42%

24 24

Synthesis

Br

OMEM

Br

OH MEMClNaH

THF69%

1.) t-BuLi, THF-78 °C - rt

SO

O N3

NH2

OMEM

65%

HCl MeOH

OH

NH2

CF3

CF3

NC

S

THF, rtO

NH

NH

S

F3C

CF3

52%

O

O

50°C, 8 h,79%

2.) LiAlH4

OH

NH

NH

S

F3C

CF3

75%

CF3

CF3

NC

S

THF, rt

25 25

Synthesis

N O

Br

N

Br

Versatile precursor synthesis

racNO2

HNO3 (10 equiv.)AcOH

60 °C, 1 min

48% 80%

Br2, kat. Fe Br

NO2

Br

NH2

Fe, HCl,

91%

(RP,1S); 45%

(SP,1S); 42%1S-CA-Cl;pyridine

+

1S-CA-Cl =

O

NH

Br

O

O

O

NH

Br

O

O

O

OO

Cl

NH2

Br

RP

HBr-HOAc,propionic acid,

MW (120 °C), 3 h

95%

26 26

Synthesis

Schneider, J. F.; Fröhlich, R.; Paradies, J. Synthesis 2010, 20, 3486–3492.

SNH

R

NH2

SP, 54%

NH2

Br

RP

F

F

FF

F

NH2

SP, 81%

NH2

SP, 62%

NH

NH2

SP, 95%

NMe2

Suzuki-coupling:Ar-B(OH)2K3PO4Pd(dppf)Cl2H2O, 1,4-dioxane95 °C

ArF-NCS

THF, 40 °C

ArF = 3,5-(CF3)2-C6H3

R = C6F5: 90%, R = 4-indolyl: 77%,R = 1-naphthyl: 84%, R = 3-NMe2-C6H4: 88%, R = Br: 90%

NH

CF3

CF3

27 27

Synthesis

Schneider, J. F.; Fröhlich, R.; Paradies, J. Synthesis 2010, 20, 3486–3492.

NH289%

N N

pyrazol, CuI, cyclohexyldiamineK3PO41,4-dioxane95 °C, 48 h

NH2

Br

93%

RP

THF, 40 °CArF-NCS

SNH N

H

CF3

CF3N N

SNH

R

NH2

SP, 54%

NH2

Br

RP

F

F

FF

F

NH2

SP, 81%

NH2

SP, 62%

NH

NH2

SP, 95%

NMe2

Suzuki-coupling:Ar-B(OH)2K3PO4Pd(dppf)Cl2H2O, 1,4-dioxane95 °C

ArF-NCS

THF, 40 °C

ArF = 3,5-(CF3)2-C6H3

R = C6F5: 90%, R = 4-indolyl: 77%,R = 1-naphthyl: 84%, R = 3-NMe2-C6H4: 88%, R = Br: 90%

NH

CF3

CF3

28 28

Synthesis

NHNMe2

OCF3

NH

O

CF3

OH

NH

O

CF3

NH

N

OOBr

HCF3

CF3

Variation of the steric environment

Variation of the H-bond donor functionality

NH

S

HN

CF3

CF3

NH

S

HN

CF3

CF3

NH

S

HN

CF3

CF3

29 29


Asymmetric transfer hydrogenation of nitro olefins


OH

N

S

N

F3C

CF3

H H

N

O O

NH R

R

HH

Ph

R = CO2Et

possible catalyst-substrate

complex

cat. (20 mol%)

NH

CO2EtEtO2C

*N N

O

O

O

O

1,2-dichloroethane, 40 °C, 72 h

H H

30 30


Asymmetric transfer hydrogenation of nitro olefins


OH

N

S

N

F3C

CF3

H H

N

O O

NH R

R

HH

Ph

R = CO2Et

possible catalyst-substrate

complex

30%; 24% ee 29%; 21% ee 42%; <5% ee

cat. (20 mol%)

NH

CO2EtEtO2C

*N N

O

O

O

O


H H

NH

S

NH

CF3

CF3

cat. 1

NH

S

NH

CF3

CF3

OH

cat. 2 cat. 3

NH

OH

O

CF3

2.67 Å

2.54 Å

31 31

Structural analysis

NH

S

NH

CF3

CF3

X-Ray structure of the racemic [2.2]Paracyclophane-thiourea H-bond-mediated association of the dimer

32

1. Simple Force Field Approach – Rough classification

2. „Best of“ – Energy Optimization – simple method (e.g. B3LYP, B98)

> +130 kJ

N N

S

N N

S

H H H

HN N

S

H H

N N

S

H HN N

SH H

N N

S

N N

S

H H H

HN N

S

H H

N N

S

H H

3. Single Point Energy calculation (various methods and basis sets)

mPW1K, MP2, MP2(FC), QCISD, …

Comparison of relative energies

Structural analysis - Conformational Analysis

A quick introduction:

33

N N

S

H H

N N

S

H

H

N N

S

H H

- „Ranking“ dependent on applied method

Structural analysis - Comparison of relative energies

34 34

Computational analysis of conformers

NH

S

NH

CF3

CF3

1. Force-field conformational analysis

2. Energy optimization with DFT (B98/6-31G(d))

3. Single-point energy calculation with HF (MP2(FC)/6-31+G(2d,p))

4. Comparison of all obtained structures

0.0 +26.76 kJ/mol

+26.01 kJ/mol +38.41 kJ/mol

PhNO2

CDCl3r.t.

1 equiv.

+

N

S

N

F3C

CF3

H H

N

O O

Ph

NH

S

NH

F3C

CF3

0 3 equiv.

NH-x

35 35

Structural analysis – NMR-titration

Observing the complexation of substrates

8.1208.135

8.142

ppm (t1)6.507.007.508.00

8.146

Addition (equiv)of the substrate

0

1

2

3 Determination of the catalyst/substrate stoichiometry

36 36

Structural analysis – anion-complexation

2.41 Å

2.49 Å

NMe4+

Cl–

co-crystal structure of a thiourea–NMe4Cl complex

double hydrogen bonding

S

N

CF3

CF3N

HH

ClNMe

MeMeMe

S

NH

CF3

CF3NH

NMe4Cl, 1.0 equiv.

CDCl3

37 37

Structural analysis – anion-complexation

Complexation of DMSO

2.6102.606

2.5992.581

ppm (t1)0.01.02.03.04.05.06.07.08.09.0

2.466

DMSO

NH

S

HN

CF3

CF3

NH

S

HN

CF3

CF3

H

NH

S

HN

CF3

CF3

NH

S

HN

CF3

CF3

δ (DMSO) = 2.610 ppm

δ = 2.606 ppm

δ = 2.599 ppm

δ = 2.466 ppm

δ = 2.581 ppm

Δδ = 0.144 ppm

S

NH

CF3

CF3NH

Ar

SO

N

S

NH H

DMSO, 1.0 equiv.

CDCl3

CF3

CF3

Ar = phenyl 1-naphthyl 1-pyrenyl

38 38

Structural analysis

Binding mode of the thiourea catalyst:

weak H-bond- interactions

strong H-bond- interactions

S

N

CF3

CF3N

S

N

CF3

CF3N

HH

H

H

R R

R = substrate

39 39

Synthesis of amino acid-based catalysts

easily accessible library of catalysts:

CF3

F3C NH

S

NH

OH

R´R´

R

H2N

OH

R´R´

R

H2N

O

R

O

Me

commercially available amino acid esters as starting materials

tertiary alcohols:

secondary alcohols:

primary alcohols:

NH

NH

S

ArFPh

OHNH

NH

S

ArF OH

Ph R2

R1

R1 = H, R2 = Ph

R1 = Me, R2 = Ph

NH

NH

S

ArFR

OH

Ph Ph

OHNH

R

Ph Ph

HO

R

PhPhNH

S

R = iPr Bn CH2(3-indolyl)

R = iPr Bn CH2(3-indolyl)

NH

NH

S

ArFPh

OHNH

NH

S

ArF

NH

NH

S

ArFR

OHPh

OH

R = Me iPr Bn

(S)-sBu tBu

Schneider, J. F.; Lauber, M. B.; Muhr, V.; Kratzer, D.; Paradies, J. Org. Biomol. Chem. 2011, asap.

40 40

Application of amino acid-based catalysts

Asymmetric transfer hydrogenation of nitro olefins and nitro acrylates

catalyst-screening:

tertiary alcohols:

26 – 81%, <5 – 16% ee

secondary alcohols:

70 – 90%, 20 – 62% ee

primary alcohols:

78 – 99%, 50 – 70% ee

99%, 70% ee

optimized conditions

NH

NH

S

OH

CF3

F3C

cat. (20 mol%)

NH

CO2tButBuO2C

*N N

O

O

O

O


NO2

MeNO2

Me

NO2

Me

Cl

NO2

Me

F

NO2

Me

NC

NO2

Et

NO2

tBu

NO2

Me

NO2

CO2Me

NO2

CO2Et

NO2

CO2iPr

41 41


Asymmetric transfer hydrogenation of nitro olefins and nitro acrylates

scope:

99%, 70% ee 99%, 50% ee 97%, 67% ee 95%, 63% ee 88%, 56% ee

95%, 68% ee 76%, 87% ee 84%, 40% ee

95%, 60% ee 99%, 58% ee 93%, 54% ee

(20 mol%) *R1

R2

NR1

N

O

O

O

O


R2

NH

NH

S

ArF OH

Hantzsch ester(1.1 equiv.)

42 42


mechanistic considerations

Schneider, J. F.; Lauber, M. B.; Muhr, V.; Kratzer, D.; Paradies, J. Org. Biomol. Chem. 2011, asap.

ArF

NS

NtBu

H

OH

HHO

ONH

PhMe

NH

H

H

E

E

Me

Me

Re-attack(disfavored)

ArF

NS

NtBu

H

OH

HHO

ON

NH

H

H

E

E

Me

Me

Si-attack(favored)

HPh

Me(20 mol%)Ph

Me

NO2Ph

NO2

DCE, 0 °C, 72 h

MeNH

NH

S

ArF OSiMe3

NH

tBuO2C CO2tBu

52% yield, (51% ee)

(20 mol%)Ph

Me

NO2Ph

NO2

DCE, 0 °C, 72 h

MeNH

NH

S

ArF

NH

tBuO2C CO2tBu

41% yield, (rac)

(20 mol%)Ph

Me

NO2Ph

NO2

DCE, 0 °C, 72 h

MeNH

NH

S

ArF OH

N

tBuO2C CO2tBu

30% yield, (rac)Me

(20 mol%)Ph

Me

NO2Ph

NO2

DCE, 0 °C, 72 h

MeNH

NH

S

ArF OH

NH

tBuO2C CO2tBu

90% yield, (50% ee)1.0 equiv. EtOH

1.0 equiv. EtOH

43 43

Conclusion

Organocatalytic applications: transfer hydrogenation

OH

NH

S

NH

CF3

CF3

Development of planar-chiral organocatalystsNH

S

HN

CF3

CF3NHNMe2

OCF3

Conformational / substrate-binding analysis

Synthesis and application of amino acid- based catalysts

cat. (20 mol%) *N N

O

O

O

OHantzsch ester

44

Acknowledgements

Montréal, 11.04.2011

German Chemical Industry Association

Landesgraduiertenförderung Baden-Württemberg

Dr. Jan Paradies Prof. Stefan Bräse

http://fonds.vci.de/

http://mwk.baden-wuerttemberg.de/

jakob schneider 1 – planar-chiral hydrogen-bond donor catalysts – synthesis, application and...

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