10.1002/anie.201903090
Angewandte Chemie International Edition
COMMUNICATION
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upon addition of a strong nuclephile has been shown to serve as
precursors for Brook rearrangements.[20] Moreover, the
morpholine amide products can also be smoothly reduced to
yield amines with a stereocenter at γ-position (8, Scheme 6).[21]
Following a procedure described by the Helmchen group,[6] we
synthesized known compound 9 via a Grignard addition and
subsequent ring closing metathesis in 45% overall yield and
98% ee. Notably, no erosion of enantiomeric excess was
observed in any transformation, with the exception of compound
7.
a) K. Zhang, Q. Peng, X. L. Hou, Y. D. Wu, Angew. Chem. Int. Ed.
2008, 47, 1741; For examples of other similar nucleophiles such as
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For different examples developed recently in our group see: a) T.
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D. H. R. Barton, G. Hewitt, P. G. Sammes, J Chem Soc C 1969, 16.
[10] S. N. Gradl, J. J. Kennedy-Smith, J. Kim, D. Trauner, Synlett 2002, 411.
[11] H. Baganz, L. Domaschke, Chemische Berichte 1962, 95, 2095.
[12] For more details, see Supporting Information.
Scheme 6. Elaboration of morpholine amide products. [a]Absolute
stereochemistry determined by comparison with literature [measured: (c = 0.42,
CHCl3): –278, reported: (c = 0.51, CHCl3, 97% ee): –284].[6b] GC-II = Grubb´s
catalyst 2nd generation.
[13] H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988, 18, 249. For
calculated s-factors see Supporting Information.
[14] Absolute configuration of recovered starting materials determined by
comparison with literature known compounds: J. Štambaský, A. V.
Malkov, P. Kočovský, J. Org. Chem. 2008, 73, 9148; and ref. 8f.
[15] Compound I-3 has been detected in the crude 1H-NMR of different
samples. But our attempts to purify it were never successful due to its
prompt hydrolysis to the corresponding amide product.
In summary, we have disclosed an asymmetric allylic
alkylation that enables the preparation of β-substituted γ,δ-
unsaturated amides. Morpholine ketene aminal was shown to be
competent nucleophile for the allylic alkylation reaction in both a
kinetic resolution and stereospecific substitution. This method
presents a new approach to the challenging iridium catalyzed
allylic alkylation of amide enolates. We have demonstrated that
the morpholine amide products can be further transformed to the
corresponding ketones, acyl silanes or amines in high
enantiomeric excess.
[16] A. Armati, P. De Ruggieri, E. Rossi, R. Stradi, Synthesis 1986, 573.
[17] For a detailed mechanism study involving chiral phosphoramidite ligand
L1, see: S. L. Rössler, S. Krautwald, E. M. Carreira, J. Am. Chem. Soc.
2017, 139, 3603.
[18] S. Nahm, S. M. Weinreb, Tetrahedron Letters 1981, 22, 3815.
[19] For some examples of Grignards additions to morpholine amides, see:
a) Z. Yu, R. J. Ely, J. P. Morken, Angew. Chem. Int. Ed. 2014, 53,
9632; b) S. R. Borkar, N. Bokolia, I. S. Aidhen, I. A. Khan, Tetrahedron
Asymmetry 2017, 28, 186; c) Y.-H. Chen, M. Ellwart, G. Toupalas, Y.
Ebe, P. Knochel, Angew. Chem. Int. Ed. 2017, 56, 4612.
Acknowledgements
ETH Zürich and the Swiss National Science Foundation
(200020_152898) are gratefully acknowledged for financial
support. We thank Dr. M.-O. Ebert, R. Arnold, R. Frankenstein
and S. Burkhardt of the NMR service and Dr. N. Trapp and M.
Solar of the X-ray crystallography service for their assistance.
[20] C. T. Clark, B. C. Milgram, K. A. Scheidt, Org. Lett. 2004, 6, 3977.
[21] N. Assimomytis, Y. Sariyannis, G. Stavropoulos, P. G. Tsoungas, G.
Varvounis, P. Cordopatis, Synlett 2009, 2777.
Keywords: Iridium • amide • allylation • enantioselective •
synthesis
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