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Jakob Schneider
1
– Planar-Chiral Hydrogen-Bond Donor Catalysts – Synthesis, Application and Structural Analysis
Literature Seminar Montréal, 11.04.2011
2
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
Hydrogen-bond catalysis
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
Hydrogen-bond catalysis
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
[2.2]Paracyclophanes - Applications
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
[2.2]Paracyclophanes - Applications
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
Schneider, J. F.; Falk, F. C.; Fröhlich, R.; Paradies, J. Eur. J. Org. Chem. 2010, 2265–2269.
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
Organocatalytic applications
Asymmetric transfer hydrogenation of nitro olefins
Schneider, J. F.; Falk, F. C.; Fröhlich, R.; Paradies, J. Eur. J. Org. Chem. 2010, 2265–2269.
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
Organocatalytic applications
Asymmetric transfer hydrogenation of nitro olefins
Schneider, J. F.; Falk, F. C.; Fröhlich, R.; Paradies, J. Eur. J. Org. Chem. 2010, 2265–2269.
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
1,2-dichloroethane, 40 °C, 72 h
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
1,2-dichloroethane, 0 °C, 72 h
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
Application of amino acid-based catalysts
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
1,2-dichloroethane, 0 °C, 72 h
R2
NH
NH
S
ArF OH
Hantzsch ester(1.1 equiv.)
42 42
Application of amino acid-based catalysts
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