10.1002/anie.201900442
Angewandte Chemie International Edition
COMMUNICATION
[5] (a) Albrecht, H.; Bonnet, G.; Enders, D.; Zimmermann, G. Tetrahedron
Lett. 1980, 21, 3175. (b) Fang, J.-M.; Chang, C.-J. J. Chem. Soc. Chem.
Commun. 1989, 1787. (c) Chang, C.-J.; Fang, J.-M.; Liao, L.-F. J. Org.
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mixture of fluxional allylic anions, wherein the E-isomer
preferentially reacts with the chiral nonracemic rhodium-allyl
intermediate to furnish (E)-3a (Scheme 3B). Furthermore, the p-
facial alkylation of the two geometrical isomers is a critical
component to controlling enantioselectivity, which is not
immediately evident from the one-pot process, thereby making
the isolation of the cyanomenamines 3 an important feature for
the development of this process.
[6] For a review on (–)-sparteine lithium carbanion pairs, see: Hoppe, D.;
Hense, T. Angew. Chem. Int. Ed. 1997, 36, 2282.
[7] For selected examples of asymmetric (–)-sparteine mediated
deprotonations of allylic BOC-amines, see: (a) Weisenburger, G. A.; Beak,
P. J. Am. Chem. Soc. 1996, 118, 12218. (b) Weisenburger, G. A.; Faibish,
N. C.; Pippel, D. J.; Beak, P. J. Am. Chem. Soc. 2001, 121, 9522. (c)
Whisler, M.; Beak, P. J. Org. Chem. 2003, 68, 1207. For O-allyl
carbamates, see: (d) Hoppe, D.; Krämer, T Angew. Chem. Int. Ed. 1986,
25, 160. (e) Seppi, M.; Kalkofen, R.; Reupohl, J.; Fröhlich, R.; Hoppe, D.
Angew. Chem. Int. Ed. 2004, 43, 1423.
In conclusion, we have developed a direct and highly
enantioselective rhodium-catalyzed allylic alkylation of b,g-
unsaturated α-amino nitriles, which serve as synthetic
homoenolate equivalents. A critical aspect to the development of
this methodology is the ability to control the geometrical outcome
of the transformation, given that the rhodium-catalyzed allylation
of discrete allylic anion isomers does not proceed with uniform
enantiocontrol in the formation of E- and Z-alkylation products.
Overall, the ability to govern a highly regio- and enantioselective
reaction provides efficient access to g-stereogenic α-
cyanoenamines, which represent potentially interesting synthetic
intermediates that will be the subject of future studies. For
example, the cyanoenamine adducts are readily hydrolyzed in
situ to provide a convenient approach to the carboxylic acids that
can be readily converted to b-substituted carbonyl derivatives.
Finally, in light of the paucity of methods that employ homoenolate
nucleophiles in asymmetric transition metal-mediated cross-
coupling reactions, we anticipate that this approach will promote
the examination of related pronucleophiles.
[8] For a review on the use of chiral homoenolate equivalents, see: Ahlbrecht,
H.; Beyer, U. Synthesis 1999, 365.
[9] For examples, see: Pd: (a) Zhang, P.; Brozek, L. A.; Morken, J. P. J. Am.
Chem. Soc. 2010, 132, 10686. (b) Brozek L. A.; Ardolino, M. J; Morken, J.
P. J. Am. Chem. Soc. 2011, 133, 16778. (c) Le, H.; Kyne, R. E.; Brozek,
L. A.; Morken, J. P. Org. Lett. 2013, 15, 1432. Cu: (d) Hornillos, V.; Pérez,
M.; Fañanás-Mastral, M.; Feringa, B. L. J. Am. Chem. Soc. 2013, 135,
2140. (e) Yasuda, Y.; Ohmiya, H.; Sawamura, M. Angew. Chem. Int. Ed.
2016, 55, 10816. Ir: (f) Hamilton, Y. J.; Hauser, N.; Sarlah, D.; Carreira,
E. M. Angew. Chem. Int. Ed. 2014, 53, 10759.
[10] For reviews on the rhodium-catalyzed allylic substitution reaction, see: (a)
Evans, P. A.; Leahy, D. K. in Modern Rhodium-Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VHC: Weinheim,, Germany, 2005; Ch.
10, p. 191-214. (b) Turnbull, B. W. H.; Evans, P. A. J. Org. Chem. 2018,
83, 11463.
[11] For mechanistic studies, see: Evans, P. A.; Nelson, J. D. J. Am. Chem.
Soc. 1998, 120, 5581.
[12] For general reviews on the transition metal-catalyzed allylic substitution
reaction, see: (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96,
395. (b) Lu, Z.; Ma, S. Angew. Chem. Int. Ed. 2008, 47, 258. (c) Crawley,
M. L. in Science of Synthesis: Stereoselective Synthesis 3; de Vries, J. G.;
Evans, P. A.; Molander, G. A., Eds.; Thieme: Stuggart, Germany, 2011, p.
403-422. For a review on the stereoselective construction of α- and b-
substituted carbonyl derivatives using allylic substitution, see: (d) Oliver,
S.; Evans, P. A. Synthesis, 2013, 45, 3179.
Acknowledgements
We sincerely thank the National Sciences and Engineering
Research Council (NSERC) for a Discovery Grant and Queen’s
University for financial support. NSERC is also thanked for
supporting a Tier 1 Canada Research Chair (PAE) and for a
[13] (a) Evans, P. A.; Clizbe, E. A.; Lawler, M. J.; Oliver, S. Chem. Sci. 2012,
3, 1835. (b) Turnbull, B. W. H.; Evans, P. A. J. Am. Chem. Soc. 2015, 137,
6156. (c) Wright, T. B.; Evans, P. A. J. Am. Chem. Soc. 2016, 138, 15303.
[14] For an enantioselective example involving an NHC-catalyzed b-allylation-
annulation reaction of enals with vinyl benzoxazinanones, see: (a) Guo,
C.; Fleige, M.; Janssen-Müller, D.; Daniliuc, C. G.; Glorius, F. J. Am.
Chem. Soc. 2016, 138, 7840. For mechanistic studies, see: (b) Guo, C.;
Janssen-Müller, D.; Fleige, M.; Lerchen, A.; Daniliuc, C. G.; Glorius, F. J.
Am. Chem. Soc. 2017, 139, 4443.
PGDS3 Scholarship (TBW).
Government of Ontario for an Ontario Graduate Scholarship
(TBW).
We also acknowledge the
Conflict of interest
The authors declare no competing financial interest.
[15] Wright,
T.
B.;
Evans,
P.
A.
e-EROS
(2018),
1-5.
Keywords: allylic substitution • a-amino nitrile • asymmetric
[16] The use of a secondary allylic acetate furnishes the b,g-stereogenic
carboxylic acid with excellent b/l selectivity and in good yield, albeit with
poor diastereocontrol.
catalysis • homoenolate • rhodium-catalyzed
[1] For an excellent review and tome on umpolung reactions, see: (a)
Seebach, D. Angew. Chem. Int. Ed. 1979, 18, 239. (b) Umpoled
Synthons: A Survey of Sources and Uses in Synthesis, Hase, T. A., Wiley,
New York, 1987.
cat. RhCl(PPh3)3
O
Ph
CN
(R)-BINOL-POMe
OAc
Ph
Ph
HO
N
Ph
LiHMDS, then
5 M HCl, RT
Ph
Et
[2] For select seminal examples, see: (a) Ahlbrecht, H.; Vonderheid, C.
Synthesis 1975, 512. (b) Lesur, B.; Toye, J.; Chantrenne, M.; Ghosez, L.
Tetrahedron Lett. 1979, 20, 2835. (c) Jacbosen, R. M.; Lahm G. P.;
Clader, J. W. J. Org. Chem. 1980, 45, 395.
84%, 2:1 dr, ≥19:1 b/l
[17] Alkyl-substituted allylic α-amino nitriles undergo alkylation with poor
regiocontrol. Studies on these systems are the subject of further
investigation in our laboratory.
[3] For reviews on the use of heteroatom-stabilized allylic anions, see: (a)
Katrizky, A. R.; Piffl, M.; Lang, H.; Anders E. Chem. Rev. 1999, 99, 665.
(b) Yorimistsu, H.; Oshima, K. in Comprehensive Organic Synthesis II;
Knochel, P., Molander, G. A., Eds.; Pergamon Press: Oxford, 2014, Vol.
2, Chapter 2.04; pp 192–207.
cat. RhCl(PPh3)3
CN
(R)-BINOL-POMe
CN
Ph
N
Ph
LiHMDS
N
Et
[4] For a related example where the alkylation of an allylic cyanohydrin anion
proceeds with complete a-selectivity (i.e. acyl anion), see: Turnbull, B. W.
H.; Oliver, S.; Evans, P. A. J. Am. Chem. Soc. 2015, 137, 15374.
CH2=CHCH2OAc (2)
Et
(γ :α ~1:2, ~90:10 E/Z)
81% ee (E-isomer)
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