Asymmetric Hydrocyanation of N-Phosphinoyl Aldimines with Acetone Cyanohydrin by Cooperative Lewis Acid/Onium Salt/Br?nsted Base Catalysis

Article abstract of DOI:10.1002/cctc.202001921

α-Amino acids are of fundamental importance for life. Both natural and artificial α-amino acids also play a crucial role for pharmaceutical purposes. The catalytic asymmetric Strecker reaction still provides one of the most attractive strategies to prepare scalemic α-amino acids. Here we disclose a new concept for Strecker reactions, in which an achiral Br?nsted base cooperates with a Lewis acid and an aprotic ammonium salt, which are both arranged in the same chiral catalyst entity. The described method could successfully address various long-standing practical issues of this reaction type. The major practical advantages are that (1) the N-protecting group is readily removable, (2) acetone cyanohydrin is attractive as cyanation reagent in terms of atom economy and cost efficiency, (3) an excess of the cyanation reagent is not necessary, (4) the new method does not require additives and (5) is performed at ambient temperature.

Full text of DOI:10.1002/cctc.202001921

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ChemCatChem
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Asymmetric Hydrocyanation of N-Phosphinoyl Aldimines
with Acetone Cyanohydrin by Cooperative Lewis
Acid/Onium Salt/Brønsted Base Catalysis
Thorsten Junge,[a] Marvin Titze,[a] Wolfgang Frey,[a] and René Peters*[a]
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proton source, is considered as more attractive cyanation agent
in this reaction type, because in the optimal case the only side
product that is formed is one equivalent of acetone. In addition,
acetone cyanohydrin is relatively inexpensive, because it is
technically widely used, for instance for the synthesis of
methacrylic acid and thus acrylic glass.[5] Nevertheless, to our
knowledge, acetone cyanohydrin has to date not been reported
in highly enantioselective hydrocyanations of aldimines.[6–8]
Another practical issue is the circumstance that a number of
asymmetric Strecker reactions are limited to the use of imines
equipped with N-protective groups that require relatively harsh
reaction conditions to be removed from follow-up products.[3]
In this regard, phosphinoyl protecting groups are attractive,
because they are removable under mild conditions. Compared
to N-Boc protected imines, N-phosphinoyl aldimines have a
higher storage stability, whereas the former usually need to be
stored in the form of α-aminosulfones.[9] Still, there is only one
method reported by Yamamoto et al. for the highly enantiose-
lective cyanation of N-phosphinoyl aldimines, which favored
ethyl cyanoformate (1.5 equiv.) as cyanation agent.[10,11]
Here, we report the first asymmetric hydrocyanation of N-
phosphinoyl aldimines with acetone cyanohydrin. This method
provides a rapid and practical access towards enantioenriched
α-amino acids. It does neither require additives nor an access of
cyanation reagent. The presented method is enabled by the
combination of a catalytic achiral Brønsted base and our
concept of cooperative asymmetric bifunctional Lewis acid/
onium salt catalysis.[12–15]
The Lewis acidic metal center is supposed to activate the
imine electrophile, whereas the onium moiety should stabilize
the cyanide anion – in situ released by the catalytic base – and
spatially control its trajectory for an imine attack to attain
effective enantioface differentiation (Figure 1).
α-Amino acids are of fundamental importance for life. Both
natural and artificial α-amino acids also play a crucial role for
pharmaceutical purposes. The catalytic asymmetric Strecker
reaction still provides one of the most attractive strategies to
prepare scalemic α-amino acids. Here we disclose a new
concept for Strecker reactions, in which an achiral Brønsted
base cooperates with a Lewis acid and an aprotic ammonium
salt, which are both arranged in the same chiral catalyst entity.
The described method could successfully address various long-
standing practical issues of this reaction type. The major
practical advantages are that (1) the N-protecting group is
readily removable, (2) acetone cyanohydrin is attractive as
cyanation reagent in terms of atom economy and cost
efficiency, (3) an excess of the cyanation reagent is not
necessary, (4) the new method does not require additives and
(5) is performed at ambient temperature.
The synthesis of α-amino acids by 1,2-addition of HCN to imines
followed by hydrolysis of the formed α-amino nitriles – well-
known as Strecker reaction – has a very long history initiated by
the original report in 1850.[1] A number of enantioselective
catalytic methods giving access to highly enantioenriched
amino acids were described since the first report by Lipton
et al. in 1996.[2,3] Since gaseous, highly toxic HCN is laborious
and costly to handle in a safe manner, liquid synthetic
equivalents of it have been utilized in the majority of
applications.[3] As such, trimethylsilyl cyanide and alkyl cyano-
formates are the most commonly employed cyanide transfer
reagents. Whereas silyl protecting groups are undesired in
production processes for technical reasons,[4] with cyanofor-
mates, for which usually a significant excess is required for
useful results, carbonate side products are formed that need to
be removed.[3] From a practical point of view, a stoichiometric
amount of acetone cyanohydrin, acting as both cyanide and
The investigation started with complex C1-I (Table 1,
entry 1, 5 mol%) carrying a diethylmethyl ammonium iodide
[a] T. Junge, M. Titze, Dr. W. Frey, Prof. R. Peters
Universität Stuttgart
Institut für Organische Chemie
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
E-mail: rene.peters@oc.uni-stuttgart.de
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cctc.202001921
© 2021 The Authors. ChemCatChem published by Wiley-VCH GmbH. This is
an open access article under the terms of the Creative Commons Attribution
Non-Commercial License, which permits use, distribution and reproduction
in any medium, provided the original work is properly cited and is not used
for commercial purposes.
Figure 1. Cooperative intramolecular Lewis acid/onium salt catalysis con-
cept.
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Table 1. Development of the asymmetric hydrocyanation of N-phosphino-
yl aldimine 1a with acetone cyanohydrin 2 by Lewis acid/onium salt
catalysis.
Table 2. Investigation of the reaction scope.
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Entry
1/3
R
Yield 3
er 3[b]
[%][a]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Ph-
95
90
97
74
83
66
92
97
71
63
95
39
81
83
94:6
85:15
95:5
89:11
91:9
95:5
95:5
87:13
92:8
90:10
Entry
C
NR3
YÀ
Base
NEt3
X
Yield er[b]
[%][a]
2-ClÀ C6H4-
4-ClÀ C6H4-
4-FÀ C6H4-
1
2
3
4
5
6
7
8
9
C1-I
C1-I
C1-I
NEt2Me
NEt2Me
NEt2Me
IÀ
IÀ
IÀ
2.0 68
79:21
89:11
90:10
88:12
88.5:11.5
93.5:6.5
90:10
87.5:12.5
94:6
4-BrÀ C6H4-
4-IÀ C6H4-
iPr2NEt 2.0 90
DMAP
2.0 81
4-MeÀ C6H4-
4-MeOÀ C6H4-
1-naphthyl-
2-naphthyl-
2-furyl-
C1-Br NEt2Me
BrÀ iPr2NEt 2.0 99
ClÀ iPr2NEt 2.0 99
C1-Cl
C2-I
C3-I
C4-I
C2-I
NEt2Me
NMe2Bn
pyridine
9
IÀ
IÀ
iPr2NEt 2.0 94
iPr2NEt 2.0 95
iPr2NEt 2.0 91
iPr2NEt 1.1 90
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14
93:7
quinuclidine IÀ
2-pyrrolyl-
(E)-MeÀ CH=CH-
(E)-PhÀ CH=CH-
88:12
83:17
85:15
NMe2Bn
IÀ
[a] Yield of isolated product 3a. [b] Enantiomeric ratio (er) determined by
HPLC. DMAP=4-dimethylaminopyridine.
[a] Yield of isolated product 3. [b] Enantiomeric ratio (er) determined by
HPLC.
moiety. Triethylamine was used as catalytic base to release a
cyanide anion from acetone cyanohydrin. In chloroform at
room temperature the product was formed with moderate
yield, but promising enantioselectivity. Different bases were
then screened and improvements were achieved with ethyl-
diisopropylamine (entry 2) and 4-dimethylaminopyridine
(DMAP, entry 3). Weaker bases like pyridine did not allow for
product formation. Investigation of different ammonium coun-
terions revealed only small differences between the different
halide ions (entries 4 & 5). Various ammonium moieties were
also examined and an improvement was achieved by a
benzyldimethylammonium group (entry 6). Most other onium
salt moieties resulted in lower enantioselectivity (see e.g.
entries 7 & 8). Finally, for the sake of practicality the quantity of
acetone cyanohydrin was decreased to a nearly equimolar
amount (entry 9).[16] This change had almost no effect on the
yield of 3a (90%), which was formed with an enantiomeric ratio
of 94:6 (i.e. 88% ee).[17]
The optimized conditions of Table 1, entry 9 were then
employed for the investigation of the substrate scope
(Table 2).[18] On preparative scale the model reaction gave a
similar yield with unchanged enantioselectivity (entry 1) com-
pared to the initial screening. Notably, catalyst C2-I could also
be readily recycled and reused by an extraction protocol taking
advantage of its polar ionic nature (for details see the
Supporting Information).
Aromatic imines with both electron withdrawing and
donating substituents (entries 2–6 & 7–8) were also well toler-
ated. The absolute configuration was determined to be (R) for
3c.
Experiments on gram scale were performed with 1b
(Scheme 1) and provided similar results as on smaller scale (see
Table 2/entry 2). It was also shown that N-deprotection and
nitrile hydrolysis of 3b is possible under mild conditions with
nearly no racemization.[19] Product 4 is a precursor towards
Clopidogrel, a drug that prevents platelet activation and
aggregation and is commonly used for secondary prevention of
ischemic events like stroke and myocardial infarction.[20]
Also polycyclic aromatic residues were well accommodated
(Table 2, entries 9–10), as well as heteroaromatic rings (en-
tries 11–12). Moderate enantioselectivities yet good yields were
Scheme 1. Gram scale synthesis of 3b and further transformation to (2-
chlorophenyl)glycine methyl ester (4), a precursor towards Clopidogrel.
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attained from α,β-unsaturated imines (entries 13–14). In con-
trast, aldimines that are aliphatic, those bearing additional π-
acceptors and ketimines[21] did not provide useful data so far.
Several investigations were performed to learn more about
the reaction mechanism. Continuous reaction monitoring by 1H-
NMR spectroscopy showed no induction period. The enantio-
meric ratios were found to be stable during the course of the
reaction showing that partial racemization is not an issue.
Moreover, NMR studies revealed a cyanide release by
deprotonation of acetone cyanohydrin by Hünig’s base (see
Supporting Information). The cyanide ion is expected to be
picked up by the ammonium moiety of the catalyst in a
reversible anion exchange. Using catalytic NaH (5 mol%)
instead of Hünig’s base resulted in significantly lower con-
version (44%), yield (41%) and enantioselectivity (er=67:33). If
the role of the non-nucleophilic base was just to generate a
catalytic amount of cyanide, similar reaction outcomes would
be expected for both bases. It thus appears likely that the
generated conjugated acid of Hünig’s base – and not 2 – is
acting as the main proton source to release the product. It was
also found that the rate of imine and acetone cyanohydrin
conversion is nearly identical.
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Figure 3. Working model.
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catalyst molecule was confirmed by a control experiment in
which catalyst C5[3g] lacking an ammonium moiety was
employed (Scheme 2). In this case the enantioselectivity was
significantly diminished and the opposite (R) configured
enantiomer was formed in slight excess.
In addition, kinetic studies were performed (Figure 2). It was
found that the reaction rate got higher by a larger amount of
the cyanation reagent 2 (compare curves 1 & 3). These experi-
ments also showed that the reaction rate is not increased by a
higher catalyst amount without simultaneously increasing the
amount of base (compare curves 1, 2 & 4). In contrast, simulta-
neously increasing the amount of base and catalyst consid-
erably accelerated the reaction (curve 5). Unfortunately, an
excess of base relative to catalyst slowed the reaction (maybe
due to blocking the Lewis acid by coordination) and catalyst
decomposition was found. The results of Figure 2 suggest that
the release of cyanide by deprotonation of 2 is the rate limiting
factor and the catalyst in not involved in that step.
To explain the enantioselectivity, Figure 3 depicts our work-
ing hypothesis, which is in agreement with the absolute
configuration of products 3. According to this model, the imine
coordinates by its electron rich phosphinoyl oxygen atom to
the hard Al center. The imino moiety points away from the
cyclohexane backbone thus allowing for a cyanide direction by
the ammonium moiety to facilitate the 1,2-addition step.
In conclusion, we developed the first asymmetric hydro-
cyanation of storable N-phosphinoyl aldimines with acetone
cyanohydrin. This method provides a rapid access towards
enantioenriched α-amino acids. The major practical advantages
are that (1) the N-protecting group is readily removable, (2)
acetone cyanohydrin is attractive in terms of atom economy
and cost efficiency, (3) an excess of the cyanation reagent is not
necessary, (4) the new method does not require additives and
(5) is performed at ambient temperature. These features were
enabled by the combination of a catalytic achiral Brønsted base
and our concept of cooperative asymmetric bifunctional Lewis
acid/onium salt catalysis.
A
non-linear effect (NLE)[22] was not found (see ESI)
supporting a scenario in which only one catalyst molecule is
involved. An intramolecular cooperation between the Lewis
acidic Al center and the aprotic ammonium residue within this
Scheme 2. Control experiment with catalyst C5 lacking an ammonium
moiety.
Acknowledgements
This work was financially supported by the Deutsche Forschungs-
gemeinschaft (DFG, PE 818/8-1, project 404194277). Open access
funding enabled and organized by Projekt DEAL.
Figure 2. Reaction monitoring showing the amount of imine 1a during the
course of reaction for different amounts of catalyst, base and acetone
cyanohydrin (DIPEA=iPr2NEt).
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J. 2010, 16, 9132–9139; c) P. Meier, F. Broghammer, K. Latendorf, G.
Conflict of Interest
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3
4
5
Rauhut, R. Peters, Molecules 2012, 17, 7121–7150; d) F. Broghammer, D.
Brodbeck, T. Junge, R. Peters, Chem. Commun. 2017, 53, 1156–1159;
e) M. Titze, J. Heitkämper, T. Junge, J. Kästner, R. Peters, Angew. Chem.
Int. Ed. 2020, 59, DOI: 10.1002/anie.202001725; f) for other applications,
see e.g.: K. Ohmatsu, S. Kawai, N. Imagawa, T. Ooi, ACS Catal. 2014, 4,
4304–4306; g) this concept is also very useful in macromolecular
chemistry see, e.g.: M. Winnacker, S. Vagin, B. Rieger, in: Cooperative
Catalysis – Designing Efficient Catalysts for Synthesis, R. Peters (Ed.),
Wiley-VCH, Weinheim, 2015.
The authors declare no conflict of interest.
Keywords: 1,2-addition · aluminum · amino acid · amino
nitrile · cooperative catalysis
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[13] Selected related catalyst systems developed by our group: a) M.
Mechler, R. Peters, Angew. Chem. Int. Ed. 2015, 54, 10303–10307; Angew.
Chem. 2015, 127, 10442–10446; b) F. Willig, J. Lang, A. C. Hans, M. R.
Ringenberg, D. Pfeffer, W. Frey, R. Peters, J. Am. Chem. Soc. 2019, 141,
12029–12043; c) J. Schmid, T. Junge, J. Lang, W. Frey, R. Peters, Angew.
Chem. Int. Ed. 2019, 58, 5447–5451; d) V. Miskov-Pajic, F. Willig, D. M.
Wanner, W. Frey, R. Peters, Angew. Chem. Int. Ed. 2020, 59, 19873–
19877.
[14] Cyanation of aldehydes: a) D. Brodbeck, F. Broghammer, J. Meisner, J.
Klepp, D. Garnier, W. Frey, J. Kästner, R. Peters, Angew. Chem. Int. Ed.
2017, 56, 4056–4060; Angew. Chem. 2017, 129, 4115–4119; b) D.
Brodbeck, S. Álvarez-Barcia, J. Meisner, F. Broghammer, J. Klepp, D.
Garnier, W. Frey, J. Kästner, R. Peters, Chem. Eur. J. 2019, 25, 1515–1524.
[15] R. Peters (Ed.), Cooperative Catalysis – Designing Efficient Catalysts for
Synthesis, Wiley-VCH, Weinheim, 2015.
[16] With the less stable N-Boc imines, almost racemic products were
obtained.
[17] Temperature, concentration and solvent screening did not provide
further improvements.
[18] CDCl3 was used for practical reasons, because it was available with
higher purity without the need for further purification. However, in
CHCl3 and CDCl3, identical results were obtained.
[19] For a hydrolysis of an N-phosphinoyl cyanohydrin to the free amino
acid, see: N. Kato, M. Suzuki, M. Kanai, M. Shibasaki, Tetrahedron Lett.
2004, 45, 3147–3151.
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9
[1] A. Strecker, Ann. Chem. Pharm. 1850, 75, 27.
[2] M. S. Iyer, K. M. Gigstad, N. D. Namdev, M. Lipton, J. Am. Chem. Soc.
1996, 118, 4910–4911.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
[3] Reviews: a) N. Kurono, T. Ohkuma, ACS Catal. 2016, 6, 989–1023; b) M.
Shibasaki, M. Kanai, K. Mita, Org. React. 2008, 70, 1–119; c) J. Wang, X.
Liu, X. Feng, Chem. Rev. 2011, 111, 6947–6983; d) L. Yet, Angew. Chem.
Int. Ed. 2001, 40, 875–877; Angew. Chem. 2001, 113, 900–902; e) W.-B.
Wu, J.-S. Yu, J. Zhou, ACS Catal. 2020, 10, 7668–7690; f) H. Gröger, Chem.
Rev. 2003, 103, 2795–2828, g) selected example with an Al salen
catalyst:M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 5315–
5316
[4] a) Y. N. Belokon, A. J. Blacker, P. Carta, L. A. Clutterbuck, M. North,
Tetrahedron 2004, 60, 10433; b) T. Kull, R. Peters, Adv. Synth. Catal. 2007,
349, 1647.
[5] R. J. H. Gregory, Chem. Rev. 1999, 99, 3649–3682.
[6] In one organocatalytic study moderate enantioselectivity was accom-
plished: S. Saravanan, N.– u. H. Khan, R. I. Kureshy, S. H. R. Abdi, H. C.
Bajaj, ACS Catal. 2013, 3, 2873–2880.
[7] Moderate enantioselectivity was usually also attained for cyanation of
amidosulfones: R. P. Herrera, V. Sgarzani, L. Bernardi, F. Fini, D. Pettersen,
A. Ricci, J. Org. Chem. 2006, 71, 9869–9872.
[8] For catalytic asymmetric cyanations of other substrate classes with
acetone cyanohydrin, see e.g.: a) aldehydes and ketones: N. Yoneda, Y.
Fujii, A. Matsumoto, K. Asano, S. Matsubara, Nat. Commun. 2017, 8,
1397–1403; b) Michael-acceptors: B. A. Provencher, K. J. Bartelson, Y. Liu,
B. M. Foxman, L. Deng, Angew. Chem. Int. Ed. 2011, 50, 10565–10569;
Angew. Chem. 2011, 123, 10753–10757; c) allylic cyanation in combina-
tion with hydrocyanation: J. Long, R. Yu, J. Gao, X. Fang, Angew. Chem.
Int. Ed. 2020, 59, 6785–6789.
[20] a) G. Escolar, M. Heras, Drugs Today 2000, 36, 187–199; b) B. Jarvis, K.
Simpson, Drugs 2000, 60, 347–377; c) G. Chow, R. C. Ziegelstein, Am. J.
Cardiovasc. Drugs 2007, 7, 169–171; d) P. Ferraboschi, M. De Mieri, F.
Galimberti, Tetrahedron: Asymmetry 2010, 21, 2136–2141; e) V. R. Alla,
K. R. Vyakaranam, A. K. Sirigiri, S. R. Bodapati, R. R. Billa, S. R. Gudibandi,
R. Alla, US 2007/0191609 A1.
[21] With the acetophenone derived imine, <15% conversion were found.
[22] T. Satyanarayana, S. Abraham, H. B. Kagan, Angew. Chem. Int. Ed. 2009,
48, 456–494; Angew. Chem. 2009, 121, 464–503.
[9] J. Veselya, R. Rios, Chem. Soc. Rev. 2014, 43, 611–630.
[10] J. P. Abell, H. Yamamoto, J. Am. Chem. Soc. 2009, 131, 15118–15119.
[11] For ketimines, see e.g.: a) S. Masumoto, H. Usuda, M. Suzuki, M. Kanai,
M. Shibasaki, J. Am. Chem. Soc. 2003, 125, 5634–5635; b) N. Kato, M.
Suzuki, M. Kanai, M. Shibasaki, Tetrahedron Lett. 2004, 45, 3147–3151;
c) N. Kato, T. Mita, M. Kanai, B. Therrien, M. Kawano, K. Yamaguchi, H.
Danjo, Y. Sei, A. Sato, S. Furusho, M. Shibasaki, J. Am. Chem. Soc. 2006,
128, 6768–6769; d) J. Huang, X. Liu, Y. Wen, B. Qin, X. Feng, J. Org.
Chem. 2007, 72, 204–208; e) K. Shen, X. Liu, Y. Cai, L. Lin, X. Feng, Chem.
Eur. J. 2009, 15, 6008–6014.
Manuscript received: December 1, 2020
Revised manuscript received: December 27, 2020
Accepted manuscript online: January 5, 2021
Version of record online: February 2, 2021
[12] a) T. Kull, R. Peters, Angew. Chem. Int. Ed. 2008, 47, 5461–5464; Angew.
Chem. 2008, 120, 5541–5544; b) T. Kull, J. Cabrera, R. Peters, Chem. Eur.
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