conformationally tailored peptidic catalysts enable new … · 2020. 9. 14. · laboratory of...
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Synthesis of small molecules is a major task in the chemical industry. Small molecules serve as precursors for e.g. pharmaceuticals, agrochemicals and organic materials and their efficient and preferably catalytic
synthesis is essential for our society. Thus, the development of new and superior catalysts providing small molecules in excellent yields and stereoselectivities is important. An attractive class of catalysts are
secondary amine organocatalysts: These provide products under mild reaction conditions, are often cheap and non-toxic and can be combined with other modern organic methods such as photo- or electrochemical
processes. Yet, these catalysts typically require high loadings of 10–30 mol%, which hamper their use in industrial settings. Hence, general concepts to improve secondary amine catalysts are necessary.
Conformationally Tailored Peptidic Catalysts
Enable New Asymmetric Transformations
Tobias Schnitzer, Jasper S. Möhler, A. Budinská and Helma Wennemers
Laboratory of Organic Chemistry, ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland.
Reactivity?
Enantioselectivity?
Diastereoselectivity?
1. Peptidic Catalysts of the H-Pro-Pro-Xaa Type – Substrate Scope, Reaction Mechanism & Conformational Analysis
Peptides are among the most reactive and stereoselective 2° amine catalysts…
R2 NO2
NO2
R2 NO2
R3
R2 NO2
COOEt
H
ONO2
R1
R2
HONO2
R1
H
ONO2
R1
R2
H
ONO2
R1
R2
2) BH3 THF.
R3
COOEt
H
O
R1
HNO O
NHO
O
O
O
R
OH78 - 82% ee
66 - 99% yieldH R
O
H
O
R1
1)
1 mol% Cat I
≤ 1 mol% Cat II
1mol% Cat II
5 mol% Cat III
10 mol% Cat IV
5 mol% Cat V
88 - 98% eed.r. 4:1 - >99:1
84% - 99% yield
92 - 98% eed.r. 5:1 - 19:1
80% - 99% yield
94 - 99% eed.r. 2:1 - 5:1
59% - 98% yield
89 - 97% eed.r. 3:1 - 10:1
72% - 90% yield
95 - 99% ee67% - 90% yield
N
ONH
HN
O
CONH2
CO2HCat I
N
ONH
HN
O
CONH2
Cat II CO2H
N
ONH
HN
O
CO2H
Cat III CONH2
N
ONH
HN
O
Ph
p-Me-C6H4Cat IV
N
ONH
HN
O
CONH2
CONH2Cat V
a) P. Krattinger, R. Kovasy, J. D. Revell, S. Ivan, H. Wennemers, Org. Lett. 2005, 7, 1101. b) M. Wiesner, M.Neuenburger, H. Wennemers, Chem. Eur. J. 2009, 15, 10103. c) M. Wiesner, J. D. Revell, S. Tonazzi, H.Wennemers, J. Am. Chem. Soc. 2008, 130, 5610. d) J. Duschmale, H. Wennemers, Chem. Eur. J. 2012, 18,1111. e) R. Kastl, H. Wennemers, Angew. Chem. Int. Ed. 2013, 52, 7228. f) C. Grünenfelder, J. Kisunzu, H.Wennemers, Angew. Chem. Int. Ed. 2016, 55, 8571.
Reaction Mechanism and peptide conformation studied in depth…
H
O
R1
+ H
O
R1
R2
NO2R2 NO21 mol% PeptideCHCl3/iPrOH 9:1
NH*
N
R2
R1N OO
**
*CO2H H
R1H
O
H2O
N*
R1
R2 NO2CO2H
H
O R2
NO2
R1
O
O
H2O
rate- and enantioselectivity determining step
no productinhibition intramolecular
protonation
H-Pro-Pro-Xaa type catalysts are excellent model systems
to derive design principles to improve peptidic & 2° amine catalysts
Ground state Enamine
more flexiblerigid
a) M. Wiesner, G. Upert, G. Angelici, H. Wennemers, J. Am. Chem. Soc.
2010, 132, 6. b) J. Duschmale, J. Wiest, M. Wiesner, H. Wennemers, Chem.
Sci. 2013, 4, 1312. c) F. Bächle, J. Duschmale, C. Ebner, A. Pfaltz, H.Wennemers, Angew. Chem. Int. Ed. 2013, 52, 12619. d) C. Rigling, J. K.Kisunzu, J. Duschmale, D. Häussinger, M. Wiesner, M. O. Ebert, H.Wennemers, J. Am. Chem. Soc. 2018, 140, 10829. e) T. Schnitzer, H.Wennemers, Helv. Chim. Acta 2019, 102, e1900070.
2. Optimization of Peptidic Catalysts 3. Optimization of 2° Amine Catalysts
a) T. Schnitzer, H. Wennemers J. Am. Chem. Soc. 2017, 139, 15356. b) T. Schnitzer, H. Wennemers Synthesis 2018, 22, 4377.c) T. Schnitzer, H. Wennemers J. Org. Chem. 2020, 85, 7633.
About 75% of all peptidic catalysts contain at least one proline residue…
cis trans
Design principle:
High population of trans amide: high reactivity, chemo- & stereoselectivity
Tools:
H
O R2
R1
NO2R2 NO2+H
O
R1 CHCl3/iPrOH 9:1
ONH
NHN
O
CONH2
CO2H
Low catalyst loading
500 ppm
Solvent-free conditions
Ring-size analoguesof Pro
g-substitutedPro derivatives
Applications:
High stereoselectivity
a) T. Schnitzer,* J. S. Möhler,* H. Wennemers Chem. Sci. 2020, 11, 1943. b) J. S. Möhler,* T. Schnitzer,* H. Wennemers Chem. Eur. J.
2020, DOI: 10.1002/chem.202002966.
The enamine intermediate is involved in the rate- and stereodetermining step…
Design principle:
High population of endo pyramidalized enamine: high reactivity & stereoselectivity
Tools:
Access to g-nitroaldehydes bearing N-heterocycles
Bicyclic Pro derivatives
Application:
4. Reversal of the Diastereoselectivity
a) T. Schnitzer, A. Budinská, H. Wennemers Nat. Catal. 2020, 3, 143.
Design principle:
s-cis enamine leads to anti-configured product
Tool:
d,d-disubstituted Pro derivatives
5. Conclusion
s-ciss-transsyn antiR1
N CO2H* N CO2H*
R2
H
O R2
R1
NO2H
O R2
R1
NO2
RR
RR
Application:
N
ONH
HN
O
X
R
N
OHN
HN
O
X
R
Ktrans/cis
NN
O O
N3
OONN
O O
N3
OO
H
O R2
R1
NO2R2 NO2+H
O
R1 CHCl3/iPrOH 9:1
ONH
NHN
O
CONH2
CO2H
sovent-free
0.1–0.3 mol%
H
O
R1
+ H
O
R1
R2
NO2R2 NO2 dioxane/MeCN 1:15 mol% Peptide
NH O
NH O
NHN
O
CO2H
ONH CONH2
NH
MeMe
O
Access to anti-configured g-nitroaldehydes
NH O
NH O
NHN
O
X
RON
R1
2° Amine catalysts:
N
endo / exo
Peptidic catalysts:
trans / cis
N
OO
s-cis / s-trans
N R
H
Conformational tuning of organocatalysts enables both, improved catalytic performance and emergence of new reactivity.
The Wennemers GroupThanks!
88% yield5.5:1 d.r., 98% ee
H
O
iPr
NO2
57% yield>20:1 d.r., 98% ee
H
O
Et
NO2
98% yield3.5:1 d.r., 98% ee
H
O
Et
NO2
CF3O
98% yield4.0:1 d.r., 96% ee
H
ONO2
6
H
O
Et
NO2
94% yield2.0:1 d.r., 96% ee
96% yield6.5:1 d.r., 98% ee
H
O
Et
NO2
97% yield4.0:1 d.r., 97% ee
H
O
Et
NO2
OMe
92% yield4.5:1 d.r., 96% ee
H
ONO2
OMe2
O
99% yield14:1 d.r., 98% ee
H
O
Me
NO2
98% yield26:1 d.r., 97% ee
H
O
Et
NO2
80% yield>100:1 d.r., 97% ee
H
O
Et
NO2
98% yield39:1 d.r., 97% ee
H
O
nBu
NO2 H
O
Me
NO2
93% yield6:1 d.r., 99% ee
99% yield45:1 d.r., 99% ee
H
O
Et
NO2
92% yield28:1 d.r., 97% ee
H
O
Et
NO2
OMe
94% yield>100:1 d.r., 97% ee
H
O
iPr
NO2
F
O O
H
O
R1+ Het NO2
0.5 mol% Peptide
CHCl3/iPrOH 9:1
O
R1
NO2
Het
HN
HN
OO
NH
CONH2
CO2H
91% yield27:1 d.r., 98% ee
92% yield9:1 d.r., 92% ee
87% yield>50:1 d.r., 96% ee
53% yield13:1 d.r., 89% ee
95% yield>50:1 d.r., 98% ee
81% yield12:1 d.r., 99% ee
71% yield,18:1 d.r., 90% ee
84% yield13:1 d.r., 96% ee
O
nPr
NO2
N
H
O
Bn
NO2
N
H
O
Et
NO2
NN
H
O
Pent
NO2H
NNMe
O
Oct
NO2H
NN
Trt
ONO2H
2
N
CO2Me
Boc O
iPr
NO2H
HNO
NO2H
NH
3
Et
rate- andenantioselectivitydetermining step
E+
endo
fast
RN
R1HE
R1
OE+
exoslow
N R1
R
HE
R1
O
More than 100 organocatalysts are known that form syn-configured g-nitroaldehydes but no general access to anti-configured products is known…
2° Amine catalysts:
N
endo / exo
Peptidic catalysts:
trans / cis
N
OO
s-cis / s-trans
N R
H
2° Amine catalysts:
N
endo / exo
Peptidic catalysts:
trans / cis
N
OO
s-cis / s-trans
N R
H