10.1002/adsc.201900247
Advanced Synthesis & Catalysis
been developed using as starting point Wennemers
tripeptides. These dipeptides were able to catalyze
asymmetric 1,4-additions of aldehydes to β-
nitrostyrenes. Such catalysts combine two highly-
modular building blocks: amino acids and
carbohydrates. The carbohydrate motif is embedded in
the -aminoacids, which are coupled with a proline to
obtain the dipeptide. The bifunctional nature of these
organocatalysts and the significance of the
tetrahydropyran unit in their reactivity and
stereoselectivity were also demonstrated. The present
work also emphasizes the modular nature of the
carbohydrate unit that facilitates tuning of the
dipeptide catalytic properties. By simple structural
changes, such as the elimination of the methoxy group
at the C4 position of the tetrahydropyran ring, a
significant improvement in the catalytic performance
was achieved. We also benefit from two
complementary catalysts that allow accessing both
enantiomers of the -nitroaldehydes, with similar
yields, and diastereo- and enantioselectivity, using
catalytic loads even below 1 mol%. It should be noted
that these catalysts work in a single solvent system, at
room temperature and without the use of additives.
Additionally, using competition experiments between
catalysts that provide opposite enantiomers, we were
able to quantify the improvement of the catalytic
efficiency. The structural design of these
organocatalysts offers enormous possibilities of
[1] a) C. R. Jones, G. D. Pantoş, A. J. Morrison, M. D.
Smith, Angew. Chem. 2009, 121, 7527-7530; Angew.
Chem., Int. Ed., 2009, 48, 7391-7394; b)A. J. Neuvonen,
T. Fꢀldes, ꢁ. Madarász, I. Pápai, P. M. Pihko, ACS
Catal. 2017, 7, 3284-3294; c) D. Bꢂcart, V. Diemer, A.
Salaꢃn, M. Oiarbide, Y. R. Nelli, B. Kauffmann, L.
Fischer, C. Palomo, G. Guichard, J. Am. Chem. Soc.
2017, 139, 12524-12532; d) C. Rigling, J. K. Kisunzu, J.
Duschmalꢂ, D. Hꢄussinger, M. Wiesner, M.-O. Ebert, H.
Wennemers, J. Am. Chem. Soc. 2018, 140, 10829-10838.
[2] a) S. J. Miller, G. T. Copeland, N. Papaioannou, T. E.
Horstmann, E. M. Ruel, J. Am. Chem. Soc. 1998, 120,
1629-1630; b) E. R. Jarvo, G. T. Copeland, N.
Papaioannou, P. J., Jr. Bonitatebus, S. J. Miller, J. Am.
Chem. Soc. 1999, 121, 11638-11643; c) J. S. Alford, N.
C. Abascal, C. R. Shugrue, S. M. Colvin, D. K. Romney,
S. J. Miller, ACS Central Science 2016, 2, 733-739; d)
N. C. Abascal, S. J. Miller, Org. Lett. 2016, 18, 4646-
4649; e) A. J. Metrano, N. C. Abascal, B. Q. Mercado,
E. K. Paulson, A. E. Hurtley, S. J. Miller, J. Am. Chem.
Soc. 2017, 139, 492-516; f) C. R. Shugrue, A. L.
Featherston, R. M. Lackner, A. Lin, S. J. Miller, J. Org.
Chem. 2018, 83, 4491-4504.
[3] D. Lehnherr, D. D. Ford, A. J. Bendelsmith, C. R.
Kennedy, E. N. Jacobsen, Org. Lett, 2016, 18, 3214-
3217.
[4] T. Schnitzer, H. Wennemers, J. Am. Chem. Soc. 2017,
139, 15356-15362.
[5] a) E. G. von Roedern, H. Kessler, Angew. Chem. 1994,
106, 684–686; Angew. Chem. Int. Ed. 1994, 33, 687-689;
b) T. K. Chakraborty, S. Jayaprakash, P. V. Diwan, R.
Nagaraj, S. R. B. Jampani, A. C. Kunwar, A. C. J. Am.
Chem. Soc. 1998, 120, 12962-12963.
[6] a) R. Carrillo, M. López-Rodríguez, V. S. Martín, T.
Martín, Angew. Chem. 2009, 121, 7943-7948; Angew.
Chem. Int. Ed. 2009, 48, 7803-7808; b) R. Carrillo, M.
López-Rodríguez, V. S. Martín, T. Martín, Cryst
EngComm, 2010, 12, 3676-3683; c) R. Carrillo, A.
Feher-Voelger, T. Martín, Angew. Chem. 2011, 123,
10804-10808; Angew. Chem. Int. Ed. 2011, 50, 10616-
10620; d) R. Carrillo, E. Q. Morales, V. S. Martín, T.
Martín, Chem. Eur. J. 2013, 19, 7042-7048; e) R.
Carrillo, E. Q. Morales, V. S. Martín, T. Martín, J. Org.
Chem. 2013, 78, 7785-7795.
modulation
by
changing
substituents
or
stereochemistry in the carbohydrate unit. In this way,
they could be adapted and extended to different types
of reactions. Current work is ongoing in this direction
and our progress will be published in due time.
Experimental Section
For detailed experimental information and the
characterization of compounds, see the supporting
information.
General Procedure
The β-nitrostyrene (1.0 equiv) and the aldehyde (3.0 equiv)
were added to a solution of dipeptide (0.01 equiv) and N-
methylmorpholine (0.01 equiv) in dichloromethane at room
temperature. The reaction mixture was stirred until TLC
showed the end of the reaction. The solvents were removed
[7] A. Feher-Voelger, J. Borges-González, R. Carrillo, E. Q.
Morales, J. González-Platas, T. Martín, Chem. Eur. J.
2014, 20, 4007-4022.
[8] J. Borges-González, A. Feher-Voelger, F. P. Crisóstomo,
E. Q. Morales, T. Martín, Adv. Synth. Catal. 2017, 359,
576-583.
under vacuum and the crude was purified by
a
chromatography column with silica gel using mixtures of
hexanes and ethyl acetate as eluent.
[9] J. L. Vicario, D. Badía, L. Carrillo, E. Reyes,
Organocatalytic enantioselective conjugate addition
reactions: a powerful tool for the stereocontrolled
synthesis of complex molecules, Royal Society of
Chemistry, Cambridge, 2010.
[10]For selected examples with pyrrolidine-type catalysts,
see: a) J. M. Betancort, C. F. III Barbas, Org. Lett. 2001,
3, 3737-3740; b) A. Alexakis, O. Andrey, Org. Lett.
2002, 4, 3611-3614; c) O. Andrey, A. Alexakis, A.
Tomassini, G. Bernardinelli, Adv. Synth. Catal. 2004,
346, 1147-1168; d) W. Wang, J. Wang, H. Li, Angew.
Chem. 2005, 117, 1393-1395; Angew. Chem. Int. Ed.
Acknowledgements
This research was supported by the Spanish MINECO (CTQ2014-
59649-P), cofinanced by the European Regional Development
Fund (ERDF) and the Canary Islands Government
(ProID2017010019, ACIISI/FEDER, UE). The authors thank
technician Ms. Estefanía Gámez García for her experimental
assistance. J. B-G. thanks the Spanish MEC for an FPU fellowship.
References
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