Dual-activation asymmetric strecker reaction of aldimines and ketimines catalyzed by a tethered bis(8-quinolinolato) aluminum complex

Article abstract of DOI:10.1021/ja907268g

(Chemical Equation Presented) An aluminum complex was found to be high yielding and enantioselective for the addition of cyanide to aldimines and ketimines. Although catalytic asymmetric addition of cyanide to imines to generate ?-amino-protected nitriles (the Strecker reaction) has been extensively studied in the past, alternative, easier-to-handle reagents for this process are required for modern organic synthesis. To date, there are a limited number of reports utilizing alternative sources of cyanide other than KCN/HCN or TMSCN for this important reaction. The present catalyst provides uniformly high enantioselectivity for aromatic, heteroaromatic, and aliphatic aldimines and ketimines using ethyl cyanoformate as the cyanide source.

Full text of DOI:10.1021/ja907268g

Published on Web 10/02/2009
Dual-Activation Asymmetric Strecker Reaction of Aldimines and Ketimines
Catalyzed by a Tethered Bis(8-quinolinolato) Aluminum Complex
Joshua P. Abell and Hisashi Yamamoto*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received August 27, 2009; E-mail: yamamoto@uchicago.edu
Table 1. Aldimine Scopec
The asymmetric catalytic synthesis of R-amino acids via hydro-
cyanation of imines, the Strecker reaction,1 has seen a large number
of reports since the first one slightly more than a decade ago.2 After
this initial report, several organocatalytic and metal-catalyzed
asymmetric Strecker syntheses have been reported that have focused
on the use of TMSCN or in situ generation of HCN (via TMSCN
and a protic additive) as the cyanide source, limiting their use in
organic syntheses (Scheme 1).3,4 Meanwhile, significant progress
has been made toward using alternative cyanide sources for carbonyl
compounds in asymmetric cyanohydrin synthesis,5 but the extension
to their imine counterparts remains limited.6,7 Because of their high
toxicity, volatility, expense, and difficulty to handle, alternatives
to these cyanide sources are required.
Scheme 1. Cyanide Sources
a Isolated yield after column chromatography. b Determined by HPLC
analysis. c Absolute stereochemistry confirmed by X-ray analysis of
entry 2. d Reaction was allowed to run for 14 h. e DMAP was used as a
nucleophilic catalyst (10 mol %).
The recent success of our aluminum catalyst has shown wide
applicability in various asymmetric reactions.8 Herein, we report
dual chiral Lewis acid/achiral Lewis base activation in the asym-
metric Strecker reaction of aldimines and ketimines with broad
substrate applicability using ethyl cyanoformate as the cyanide
source.
A variety of tethered bis(8-quinolinolato) aluminum complexes
were synthesized10 and screened with alternative cyanide sources.11
Gratifyingly, ethyl cyanoformate and ethyl cyanophosphorylate
provided the product in almost quantitative yield and excellent
enantioselectivity.12 In contrast, cyanide sources of type B or D
provided no R-amino-protected hydronitrile product. Since ethyl
cyanoformate provided the product in nearly quantitative yield and
high enantioselectivity, the use of this readily available cyanide
source was selected for further investigation.
The reaction with alternative sources of cyanide, such as those
of type A or C, did not proceed without a catalytic amount of amine
base. Additionally, the reaction did not proceed without the alu-
minum catalyst, realizing the dual activation nature of the electro-
phile and nucleophile.5,13 A survey of common nucleophilic amine
bases revealed DMAP and NEt3 to be the best in terms of yield
and enantioselectivity.11 Moreover, the inclusion of an equimolar
amount of i-PrOH was effective in the cleavage of the aluminum-
amide bond due to product inhibition in the rate-determining step
of the reaction, as well as a slight rate enhancement of the
reaction.4k,9
Under the optimized conditions, a variety of aldimines were
subjected to this protocol (Table 1). Functional groups around the
aromatic ring were well-tolerated, providing high enantiomeric
excess in all cases. Electron-deficient and larger aromatic aldimines
showed reduced reactivities and yields, requiring slightly prolonged
reaction times (entries 3, 4, 11, and 12). Typically problematic
substrates, such as heteroaromatic imines, also provide R-amino-
protected hydronitrile products without deleterious effects on the
enantioselectivity (entries 5 and 6). Furthermore, unsaturated and
aliphatic aldimines also demonstrated high enantiomeric excess
under the optimized conditions, although a more nucleophilic base,
4-dimethylaminopyridine (DMAP), was required (entries 13 and
14).14
We further extended this optimized methodology to ketimines,
which provide access to enantiomerically enriched quaternary
stereocenters.15 Ketimines are inherently less reactive and more
challenging substrates than their aldimine counterparts because
of the steric demands during formation of the carbon-carbon
bond and discrimination of the prochiral faces. Although several
notable and highly selective metal-catalyzed and organocatalyzed
variants of this reaction have been accomplished using TMSCN
as the cyanide source, applications with alternative sources have
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15118 J. AM. CHEM. SOC. 2009, 131, 15118–15119
10.1021/ja907268g CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
yet to be investigated.3,4,16 Typical complications arise when
changing substrates, such as the need to retune or reoptimize
the reaction conditions, but we found that the same catalyst that
was found to be optimal for aldimines was equally effective for
ketimines (Table 2).
(3) Reviews of enantioselective Strecker reactions of imines: (a) Groger, H.
Chem. ReV. 2003, 103, 2795. (b) Khan, N. U. H.; Kureshy, R. I.; Abdi,
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Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875. (d) Spino, C. Angew Chem.,
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(f) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520.
(g) Shibasaki, M.; Kanai, M.; Mita, T. Org. React. 2008, 70, 1.
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Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012. (b) Wen,
Y.; Xiong, Y.; Chang, L.; Huang, J.; Liu, X.; Feng, X. J. Org. Chem. 2007,
72, 7715. (c) Ooi, T.; Uematsu, Y.; Maruoka, K. J. Am. Chem. Soc. 2006,
128, 2548. (d) Huang, J.; Corey, E. J. Org. Lett. 2004, 6, 5027. (e) Sigman,
M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901. (f) Sigman,
M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279.
(g) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867. (h) Wenzel, M. P.;
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Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157. (k) Krueger, C. A.;
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M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2000, 39, 1650. (m) Nakamura, S.; Sato, N.; Sugimoto, M.; Toru,
T. Tetrahedron: Asymmetry 2004, 15, 1513. (n) Banphavichit, V.; Man-
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(o) Berkessel, A.; Mukherjee, S.; Lex, J. Synlett 2006, 41. (p) Kato, N.;
Mita, T.; Kanai, M.; Therrien, B.; Kawano, M.; Yamaguchi, K.; Danjo,
H.; Sei, Y.; Sato, A.; Furusho, S.; Shibasaki, M. J. Am. Chem. Soc. 2006,
128, 6768. (q) Wung, J.; Hu, X.; Jiang, J.; Gou, S.; Huang, X.; Liu, X.;
Feng, X. Angew. Chem., Int. Ed. 2007, 46, 8468. (r) Byrne, J. J.; Chavarot,
M.; Chavant, P.-Y.; Valle´e, Y. Tetrahedron Lett. 2000, 41, 873. (s) Karimi,
B.; Maleki, A. Chem. Commun. 2009, 5180. (t) Hatano, M.; Hattori, Y.;
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6008. (w) Hou, Z.; Wang, J.; Liu, X.; Feng, X. Chem.sEur. J. 2008, 14,
4484. (x) Chen, Y.-J.; Chen, C. Tetrahedron: Asymmetry 2008, 19, 2201.
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(5) (a) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2002, 41, 3636. (b) Tian, J.; Yamagiwa, N.; Matsunaga, S.;
Shibasaki, M. Org. Lett. 2003, 5, 3021. (c) Yamagiwa, N.; Tian, J.;
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Table 2. Ketimine Scoped
a Isolated yield after column chromatography. b Determined by HPLC
analysis. c Values in parentheses are for recrystallized crystals. d Absolute
stereochemistry confirmed by X-ray analysis of entry 2. e PG ) di-
(o-tolyl)phosphinoyl
Various R-amino-protected hydronitriles bearing enantiomerically
enriched quaternary stereocenters were produced in good to high yields
and good to excellent enantioselectivities. Particularly noteworthy is
the enantioselective addition of cyanide to substrates other than
acetophenone-derived ones. In this regard, propiophenone-, butyrophe-
none-, tetralone-, and furyl-derived N-diarylphosphinoyl ketimines
provided the desired products in synthetically useful yields and
excellent ee’s (entries 3-6). Moreover, aliphatic substrates such as
that derived from pinacolone proved to be suitable for our catalyst
system (entry 7). X-ray analysis of the product revealed that the same
facial selection was observed for both aldimines and ketimines. This
observed facial selectivity is the same as in our hydrophosphonylation
of imines8b and agrees with the proposed model for stereocontrol
already reported with this catalyst.8a
In summary, we have developed an efficient protocol for dual
Lewis acid/Lewis base activation in a highly enantioselective
Strecker synthesis utilizing ethyl cyanoformate as a cyanide source
for both aldimines and ketimines at room temperature. This system
provides an environmentally benign protocol for the asymmetric
Strecker reaction that does not require the use of toxic stoichiometric
or superstoichiometric amounts of TMSCN or HCN. Investigations
into other complexes that display the cis-ꢀ configuration are
currently underway.
(6) (a) Pan, S. C.; List, B. Org. Lett. 2007, 9, 1149. (b) Pan, S. C.; Zhou, J.;
List, B. Angew. Chem., Int. Ed. 2007, 46, 612.
(7) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Fini, F.; Pettersen, D.; Ricci, A.
J. Org. Chem. 2006, 71, 9869.
(8) (a) Takenaka, N.; Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc. 2007,
129, 742. (b) Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130,
10521.
(9) Studies of the effects of protic additives in enantioselective Strecker
reactions: (a) Kato, N.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron
Lett. 2004, 45, 3147–3151. (b) Reference 4k, l. (c) Du, Y.; Xu, L.-W.;
Shimizu, Y.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2008,
130, 16146.
(10) Synthesis of TBOxH and related complexes: (a) Takenaka, N.; Xia,
G. Y.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 13198. (b) Xia, G. Y.;
Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 2554. (c) Xia, G. Y.;
Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 496. (d) Yamamoto, H.;
Xia, G. Y. Chem. Lett. 2007, 36, 1082. (e) Naodovic, M.; Xia, G.;
Yamamoto, H. Org. Lett. 2008, 10, 4053.
(11) See the Supporting Information for detailed information about the ligand,
imine protecting group, and Lewis base screening.
(12) North and Moberg independently reported a mechanistically related reaction
with aldehydes for asymmetric cyanohydrin synthesis using a titanium
SALEN dimer catalyst with alternative cyanide sources (see ref 5f, g).
(13) NMR analysis of the reaction mixture (Table 1, entry 8) revealed the
appearance of new ethoxy peaks [(q, 3.91) and (t, 0.97)] immediately after
the addition of the catalyst to the mixture without i-PrOH. This should
indicate the presence of the expected carbamate, given its mechanistic
relation to ref 5f, g. Also, GC-MS analysis of the reaction mixture indicated
the presence of a product with a mass corresponding to carbamate (474.8)
that, after aqueous workup and column purification, was hydrolyzed to the
secondary amine product in Table 1. See the Supporting Information for
NMR and GC-MS charts.
Acknowledgment. Support of this research was provided by
the National Science Foundation (CHE-0717618). Dr. Ian M. Steele
is also acknowledged for the X-ray structure determination.
(14) Triethylamine provided the products in entries 13 and 14 in 56 and 68%
yield, respectively.
Supporting Information Available: Complete experimental pro-
cedures, full spectral data for all new compounds, and crystallographic
data (CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Reviews of the enantioselective construction of quaternary stereocenters: (a)
Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (b)
Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591. (c) Fuji,
K. Chem. ReV. 1993, 93, 2037.
(16) Connon, S. Angew. Chem., Int. Ed. 2008, 47, 1176.
References
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