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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