Asymmetric cyanation of a-ketiminophosphonates catalyzed by cinchona alkaloids: Enantioselective synthesis of tetrasubstituted a-aminophosphonic acid derivatives from trisubstituted a-aminophosphonates

Article abstract of DOI:10.1002/adsc.201200516

An enantioselective synthesis of tetrasubstituted a-phosphono-a-amino nitriles through asymmetric cyanation of a-ketiminophosphonates catalyzed by Cinchona alkaloids is reported. a-Ket- ACHTUNGTRENUNGiminophosphonates are generated, in a very efficient sy

Full text of DOI:10.1002/adsc.201200516

COMMUNICATIONS
DOI: 10.1002/adsc.201200516
Asymmetric Cyanation of a-Ketiminophosphonates Catalyzed
by Cinchona Alkaloids: Enantioselective Synthesis of
Tetrasubstituted a-Aminophosphonic Acid Derivatives from
Trisubstituted a-Aminophosphonates
Javier Vicario,a Josꢀ Marꢁa Ezpeleta,b and Francisco Palaciosa,*
a
Departamento de Quꢁmica Orgꢂnica I, Centro de Investigaciꢃn y Estudios Avanzados “Lucio Lascaray” – Facultad de
Farmacia, Universidad del Paꢁs Vasco, UPV/EHU, Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain
Fax : (+34)-945-013103; phone: (+34)-945-010756; e-mail: francisco.palacios@ehu.es
Departamento de Fꢁsica Aplicada, Facultad de Farmacia. Universidad del Paꢁs Vasco, UPV/EHU, Paseo de la
b
Universidad 7, 01006 Vitoria-Gasteiz, Spain
Received: June 12, 2012; Published online: September 28, 2012
This paper is dedicated in honour to Professor Henri-Jean Cristau on the occasion of his 70th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200516.
Abstract: An enantioselective synthesis of tetrasub-
stituted a-phosphono-a-amino nitriles through
asymmetric cyanation of a-ketiminophosphonates
catalyzed by Cinchona alkaloids is reported. a-Ket-
ACHTUNGTRENNUNGiminophosphonates are generated, in a very effi-
cient synthetic protocol, by oxidation of trisubstitut-
All-substituted stereogenic carbon centers are ubiq-
uitous motifs in natural products and pharmaceutical
agents and the efficient formation of tetrasubstituted
centers is a crucial challenge in chemical synthesis.[9]
However, the formation of tetrasubstituted centers
from ketones and ketimines was unachievable for
a long time, due to the poor electrophilic character of
the carbonyl or the ketimine groups and to the addi-
tional steric hindrance on the substrate, and the enan-
tiotopic faces of ketimines are not as easily discrimi-
nated as those of aldimines when asymmetric synthe-
sis is sought.[10]
ed a-aminophosphonates.
Keywords:
aminonitriles;
aminophosphonates;
asymmetric catalysis; cyanation; imines
Only a few diastereoselective preparations of a-
aminophosphonic acid derivatives can be applied to
a-Aminophosphonates are structural analogues of a- tetrasubstituted a-aminophosphonates,[11] and the
amino acids, where the planar carboxylic acid has asymmetric synthesis of tetrasubstituted a-amino-
been substituted by a bulkier tetrahedral phosphonate phosphonates is limited to the Cinchona alkaloids-cat-
group,[1] which have numerous applications[2] in me- alyzed hydrophosphonylation of sulfonylimines
dicinal and pharmaceutical sciences as haptens of cat- (Scheme 1, a),[12] Pd- or Zn-catalyzed enantioselective
alytic antibodies,[3a] peptide mimetics,[3b] enzyme in- amination of b-ketophosphonates, using dialkyl azo-
hibitors,[3c] antibacterial agents[3d] as well as agrochem- carboxylate (Scheme 1, b).[13] and Pd-catalyzed allyla-
icals.[4] The biological activity of a-aminophosphonic tion of b-keto-a-aminophosphonates (Scheme 1, c)[14a]
acids is strongly dependent on their absolute configu- or Brønsted acid-catalyzed addition of a-nitrophosph-
ration[5] and the stereoselective synthesis of a-amino- onates to electrophiles (Scheme 1, d).[14b,c]
phosphonic acid derivatives[6] is an imperative task in
Our group has been involved in the preparation of
organic chemistry. The synthesis of optically active a- simple[15] and vinylic[16] a-aminophosphonates as well
aminophosphonic acids was reported for the first time as of phosphadepsipeptides derived from a-amino-
in 1972.[7] Based on the chiral auxiliary approach, phosphonates.[17] Continuing with our concern in ami-
some syntheses of optically active a-aminophosphonic nophosphorus chemistry,[18] we believed that an enan-
acid derivatives have been reported[6] and, likewise, tioselective addition of nucleophiles to a-ketimino-
catalytic asymmetric methodologies[8] have also been phosphonates would be a convenient pathway to
À
À
reported, where the key step involves C P, C N and access optically active tetrasubstituted a-amino-
À
C C bond formation.
phosphonates (Scheme 2) and that the generation of
Adv. Synth. Catal. 2012, 354, 2641 – 2647
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2641

Javier Vicario et al.
COMMUNICATIONS
Scheme 3. Synthesis of starting a-aminophosphonates 3.
drawing group at the nitrogen. These synthons would
favor nucleophilic addition to the C=N double bond
and at the same time would allow an easy deprotec-
tion of the nitrogen in an ultimate synthetic step.
Construction of a carbon-nitrogen double bond
from a-aminophosphonates I would imply the intro-
duction of a good leaving group at the aminophosph-
onate to promote then its elimination with a base.
Then, selective N-chlorination can be achieved by
treatment of a-aminophosphonates 1 with trichloro-
Scheme 1. Enantioselective synthesis of tetrasubstituted a-
aminophosphonates.
AHCTUNGTREGUNiNN socyanuric acid (TCCA) in dichloromethane at 08C
(Scheme 3). A large excess of inexpensive TCCA is
normally required in order to decrease the reaction
times, since higher reaction temperatures result not
only in a faster reaction but also in the obtention of
a mixture of N- and C-chlorinated aminophospho-
nates. In the case of a-aminophosphonates 1 holding
large phosphonate groups (R1 =R2 =i-Pr), due to the
higher steric hindrance present in the a-carbon, selec-
Scheme 2. Strategy for the enantioselective synthesis of tet-
rasubstituted a-aminophosphonates.
a-ketiminophosphonates might be feasible by oxida- tive N-chlorination can be completed in a few hours
tion of the parent a-aminophosphonates. Consequent- at room temperature using an excess of TCCA. N-
ly, this synthetic approach could be considered global- Chloroaminophosphonates 2 are unstable species and,
ly as a new route for the generation of tetrasubstitut- in order to prevent the dechlorination reaction, they
ed a-aminophosphonates by the substitution of hydro- are readily used without purification after elimination
gen in a trisubstituted a-aminophosphonate by a nu- of the solid residue by filtration. Nonetheless, their
1
cleophilic reagent and the complementary process formation can be confirmed by H NMR of the crude
(“umpolung reaction”) of the electrophilic substitu- mixture, where a simplification (double doublet to
tion of trisubstituted a-aminophosphonate (Scheme 1, doublet) coincident with a downfield shift of 1 ppm of
c, d). We report herein an efficient synthesis of a-imi- the signal, corresponding to the methyne group at-
nophosphonates derived from ketones (II, Scheme 2) tached to the phosphorus, as well as the disappear-
as well as their synthetic applications as precursors of ence of the broad doublet in the range 6–7 ppm, cor-
optically active tetrasubstituted a-aminophosphonates responding to the NH, are observed. 31P NMR also
(III, Scheme 2) through a Cinchona alkaloid-catalyzed shows an upfield shift of aproximate 3 ppm of the
enantioselective Strecker reaction, using cheap and signal of the N-chloro a-aminophosphonates 2 rela-
non-toxic pyruvonitrile.
tive to a-aminophosphonates 1.
Recently, we reported the synthesis of a-imino-
b-Elimination of HCl in N-chloro a-aminophospho-
phosphonates derived from ketones through an aza- nates 2 can be performed using pyridine as a base.
Wittig methodology.[16a,19] One of the drawbacks of Unfortunately, the resulting unstable a-iminophosph-
this methodology[20] is that only N-aryl- or N-alkyl- onates 3 cannot be separated from pyridine hydro-
phosphazenes can be used for the generation of the chloride avoiding the hydrolysis of the imine bond.
imine bond. Taking into account the moderate elec- The use of an insoluble base in organic solvents as the
trophilic character and the additional steric hindrance promoter of the b-elimination reaction would allow
present in ketimine groups, we were mostly interested the elimination of both the hydrochloride and the
in ketimines II (Scheme 2) bearing an electron-with- excess of base from the reaction solution. Finally, re-
2642
asc.wiley-vch.de
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2641 – 2647

Asymmetric Cyanation of a-Ketiminophosphonates Catalyzed by Cinchona Alkaloids
fluxing overnight the resulting clear solution of N- addition of TMS-CN to N-tosylimines,[23] and metal
chloroaminophosphonate 2 with an excess of poly(4- catalysis such as Ti-catalyzed addition of TMS-CN or
vinylpyridine) affords pure a-ketiminophosphonates 5 EtO2C-CN to N-tosylimines[24] or Gd-catalyzed addi-
in very good yields (Scheme 3, 77–85% overall, See tion of TMS-CN to N-diphenylphosphinylimines.[25]
also the Supporting Information), after filtration and
crystallization from diethyl ether.
Cyanation of a-iminophosphonate 3 can be per-
formed in a few hours by treatment with 2 equivalents
With an efficient protocol in hand for the genera- of pyruvonitrile in the presence of a nucleophilic
tion of a-ketiminophosphonates 3, next we studied amine such as triethylamine 4 or 1,4-diazabicyclo-
the organocatalytic asymmetric addition of nucleo-
ACHTUNGTRENNUNG
philes to imines 3. In this context, the Strecker reac-
tion[21] is one of the most efficient methods for the presence of a catalytic quantity of Cinchona alkaloid
preparation of a-aminonitriles, useful precursors of a- derivatives (10%). Although bifunctional thiourea 6
amino acids. A few catalytic systems have been devel- catalyzed very efficiently the nucleophilic addition of
oped for the enantioselective cyanation of ketimines cyanide, no significant enantiomeric excess was ob-
to generate tetrasubstituted centers. This embraces or- served (Table 1, entry 3). Dihydroquinine (7) and di-
ganocatalysis, like thiourea-catalyzed addition of hydroquinidine (8) showed a modest enantioselectivi-
HCN to N-benzylimines[22] or N-N-dioxide-catalyzed ty (Table 1, entries 4 and 5) as did other Cinchona al-
kaloids tested such as cinchonidine (9a), quinine (9b),
cinchonine (10a) or quinidine (10b) (Table 1, en-
tries 6–9). Given that a maximum enantiomeric excess
of 36% was observed for quinidine (10b), several
sources of cyanide were analyzed using 10b as cata-
lyst. While practically the same results were obtained
using methyl cyanoformate (Table 1, entry 10), the
use of tosyl cyanide or diethyl cyanophosphonate re-
sulted in a drop in the conversions and enantioselec-
tivities (Table 1, entries 11 and 12) and no trace of
cyanated product was observed when trimethylsilyl
cyanide was used (Table 1, entry 13). A strong de-
pendence of the conversion and enantioselectivity
with the electron-withdrawing character of cyanide
substituent is concluded in this experiment. These re-
sults suggest that a source of cyanide with a strong
electron-withdrawing group is needed in this reaction,
Figure 1. Catalysts tested in the asymmetric cyanation reac-
tion of a-iminophosphonates 3.
Table 1. Screening of catalysts and cyanide sources.
Entry
Catalyst
R-CN
Time [h]
Conversion [%]
ee [%]
1
2
3
4
5
6
7
8
4
5
6
7
CH3CO-CN
CH3CO-CN
CH3CO-CN
CH3CO-CN
CH3CO-CN
CH3CO-CN
CH3CO-CN
CH3CO-CN
CH3CO-CN
MeO2C-CN
Ts-CN
12
12
3
100
100
95
–
–
15
17
48
48
48
48
48
48
48
72
72
48
100
100
100
100
100
100
100
55
8
À30
9a
9b
10a
10b
10b
10b
10b
10b
24
20
À14
À36
À35
À11
À6
–
9
10
11
12
13
A
50
0
Adv. Synth. Catal. 2012, 354, 2641 – 2647
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2643

Javier Vicario et al.
COMMUNICATIONS
Table 2. Influence of the phosphorus substituent.
(Table 2, entries 15 and 16). This result may be due to
the planarity of the phenyl ring which allows a confor-
mation with less steric crowding at the iminic carbon.
Surprisingly, almost no enantioselectivity was ob-
served in the cyanation of neopentylene phosphonate
3f (Table 2, entries 17–20), where the free rotation of
phosphonate substituents has been restricted by the
presence of a cyclic structure (Table 2, entries 17–20).
Finally, the best enantioselectivity (ee=80%) was ob-
served when the cyanation reaction of diisopropyl
phosphonate was performed using cinchonidine (9a)
as organocatalyst (Table 2, entry 11).
It is well known that a drop in the reaction temper-
ature results normally in an increase in the enantiose-
lectivity and, therefore, we studied the cinchonidine-
catalyzed cyanation of diisopropyl phosphonate 3d
with pyruvonitrile at different temperatures. The
enantiomeric excess is increased from 80% to 84%
and 92% if the reaction temperature is lowered to
08C or À458C but, as a consequence, the reaction
times are substantially increased. Further decrease of
the temperature to À558C results in very low rates of
conversion. Increasing the catalyst loading reduces
significantly the reaction times but, unfortunately, still
raising the catalyst loading to 25%, very low conver-
sion rates are obtained at À558C. Finally, a decrease
on the catalyst quantity to 5% results in lower conver-
sions and a considerable decrease in the enantioselec-
tivity.
Entry Compound Catalyst R1
R2
ee [%]
1
2
3
4
5
6
7
8
9a
9b
10a
10b
9a
13b
14b
13a
14a
13b
14b
13a
14a
13b
14b
13b
14b
13a
14a
13b
14b
13b
14b
13a
14a
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Et
16
10
À20
À22
24
9b
14
10a
10b
9b
10b
9a
À20
À36
30
9
Et
Et
10
11
12
13
14
15
16
17
18
19
20
Et
À38
i-Pr
i-Pr
i-Pr
i-Pr
Ph
i-Pr
i-Pr
i-Pr
i-Pr
Ph
80
9b
58
10a
10b
9b
10b
9a
9b
10a
10b
À58
À60
6
À7
Ph
Ph
H2C-C
H2C-C
H2C-C
H2C-C
(CH3)2-CH2 À1
(CH3)2-CH2
0
(CH3)2-CH2 À5
AHCTNURTGEG(NNNU CH3)2-CH2
1
which may confer a high nucleophilic character to the
cyanide carbon.
Now, in order to examine the influence of the po-
larity of the solvent on the enantioselectivity of the
Taking advantage of our new protocol for the prep- process, the cinchonidine (9a)-catalyzed asymmetric
aration of a-ketiminophosphonates 3, we implement- cyanation of iminophosphonate 3d was studied in dif-
ed an analysis of the influence of the phosphorus sub- ferent solvents. The dielectric constant (Ke)[27] and the
stituent on the enantioselectivity of the cyanation re-
action using cinchonidine (9a), quinine (9b), cincho-
nine (10a) and quinidine (10b) as organocatalysts
(Table 2).
Table 3. Influence of the polarity of the solvent.
The effect of acyclic aliphatic substituents at the
phosphonate on the enantioselectivity of the reaction
correlates with their Winstein–Holness A values.[26]
For example, while an enantiomeric excess of 22%
was observed for the dibenzylphosphonate 11a with
N
quinidine (10b) (Table 2 entry 4,
ABn =1.68 kcal
Entry Solvent
ET
Ke
Conversion ee
[%] [%]
[kcalmolÀ1]
molÀ1), this value is increased to 36% and 38%, re-
spectively, in the case of dimethyl and diethyl phos-
phonates 11b and 11c (Table 2, entries 8 and 10), with
similar A values for their substituents (AMe =1.74 kcal
molÀ1, AEt =1.79 kcalmolÀ1). Then, as expected, the
enantiomeric excess was increased to 60% for diiso-
1
CCl4
0.052
0.099
0.117
0.231
0.207
0.259
0.309
2.24 65
2.39 85
4.34 79
7.20 83
7.58 95
4.81 100
8.93 100
10.6 100
37.5 100
19.9 100
24.6 100
32.7 100
10
52
23
35
65
92
86
63
46
0
2
3
toluene
Et2O
4
5
DME
THF
6
7
CHCl3
CH2Cl2
propylphosphonate 3d (Table 2, entry 13, Ai-Pr
=
2.21 kcalmolÀ1). A special case is the use of diphenyl-
phosphonate 3e. In view of the high A value for the
phenyl group (APh =2.80 kcalmolÀ1), the highest
enantiomeric excess would be expected. Nevertheless,
very low asymmetric induction is observed in the cy-
anation with quinine (9b) and quinidine (10b)
8
ClACHTNGUTERNUN(G CH2)2Cl 0.327
9
AcN
0.460
0.546
0.654
0.762
10
11
12
i-PrOH
EtOH
MeOH
0
0
2644
asc.wiley-vch.de
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2641 – 2647

Asymmetric Cyanation of a-Ketiminophosphonates Catalyzed by Cinchona Alkaloids
Figure 2. Possible transition state for asymmetric cyanation
of a-iminophosphonates 3.
normalized molar electronic translation energies
N
[28]
(ET
)
are used as indicators of the polarity of the
solvent (Table 3). Low conversions with modest enan-
tiomeric excesses were observed when the reaction
was performed in the least polar solvents, which may
be attributable to the low solubility of the substrates
and/or catalyst in those solvents at low temperature
(Table 3, entries 1–5). A faster reaction with very
good conversions was observed for more polar sol-
vents (Table 3, entries 6–12). Within the good solubi-
lizing solvents, the less polar one, chloroform, showed
the best enantioselectivities (Table 3, entry 6). This in-
verse dependence of the enantioselectivity on the po-
larity of the solvent is probably due to a diminution
in the difference of the energy of activation for the
formation of the two enantiomers due to a stabiliza-
tion of both possible diastereomeric transition states
in a polar solvent, rational for reactions with ionic
transition states.
It is noteworthy that a very fast reaction (12–24 h)
with complete loss of the enantioselectivity is ob-
served if alcohols are used as solvents (Table 3, en-
tries 10–12). This might indicate a crucial role for the
hydroxy group of Cinchona alkaloids in the transition
state which may activate the substrate via hydrogen
bonding with the iminic nitrogen as shown in
Figure 2. This necessary catalyst-substrate coordina-
tion may be replaced by a solvent-substrate coordina-
tion in the presence of protic solvents, speeding up
the reaction with a concomitant collapse of the enan-
tioselectivity.
Figure 3. X-ray structure of (S)-11d.
Table 4. Generalization of asymmetric cyanation reaction.
Entry Compound Ar
Yield[a] [%] ee [%]
1
2
3
4
5
11d
11g
11h
11i
Ph
80[b]
78[b]
92, >99[d]
p-CF3-C6H4
89, 95[d]
73, 82[d]
88, 95[d]
90, 98[d]
p-NO2-C6H4 75[b]
p-MeO-C6H4 78[c]
11j
p-Cl-C6H4
77[c]
[a]
[b]
[c]
[d]
Isolated yield after crystallization.
Reaction at À458C.
Reaction at 08C.
% ee after crystallization.
aromatic a-substituents (Table 4). Compared with the
The absolute configuration of a-cyano-a-amino- model a-ketiminophosphonates 3d, with a phenyl sub-
phosphonate 11d was determined by X-ray diffrac- stituent at the a-carbon, a slight drop on the enantio-
tion.[29] Key features of the crystal structure of 11d selectivity is observed for the most reactive a-ket-
are its S configuration and a unit cell formed by a di-
ACHTUGNTERNiNUNG minophosphonates 3g and 3h (R=p-CF3-C6H4, p-
meric structure, where two intermolecular hydrogen NO2-C6H4), bearing electron-withdrawing substituents
bonds are established between the amine hydrogens at the aromatic ring (Table 4, entries 2 and 3). In the
and the phosphoryl oxygens. In order to tolerate this case of a-ketiminophosphonates 3i and 3j (R=p-Cl-
dimeric structure, the sulfonyl groups of both mole- C6H4, p-MeO-C6H4), bearing electron-donating sub-
cules adopt the opposite conformation as showed in stituents at the aromatic ring (Table 4, entries 4 and
Figure 3.
5), the cyanation reaction did not proceed at À458C,
The generalization of the asymmetric cyanation of but raising the temperature to 08C afforded a-cyano-
diisopropyl a-ketiminophosphonates 3 catalyzed by a-aminophosphonates 11i and 11j with satisfactory
cinchonidine (9a) was put into effect using different enantiomeric excesses. It is remarkable that in all
Adv. Synth. Catal. 2012, 354, 2641 – 2647
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2645

Javier Vicario et al.
COMMUNICATIONS
Acknowledgements
The present work has been supported by the Direcciꢀn Gen-
eral de Investigaciꢀn del Ministerio de Ciencia e Innovaciꢀn
(CTQ2009-12156) and by Gobierno Vasco and Universidad
del Paꢁs Vasco (GV, IT 422-10; UPV, UFI-QOSYC 11/12). J.
Scheme 4. Hydrolysis of a-cyano-a-aminophosphonate (S)-
11d.
V. thanks the Ministerio de Ciencia
a “Ramꢀn y Cajal” contract.
e Innovaciꢀn for
cases purification by crystallization from methanol af-
fords of a-cyano-a-aminophosphonates 11 in very
good yields (75 to 80%) and enantioselecitivies (82 to
>99%).
Finally (S)-a-phosphonophenylglycine (S)-12 was
synthesized by simultaneous hydrolysis of nitrile,
phosphonate and sulfonyl groups by treatment with
10M hydrochloric acid (Scheme 4).
References
[1] Aminophosphonic and Aminophosphinic Acids.
Chemistry and Biological Activity, (Eds: V. P. Kukhar,
H. R. Hudson), Wiley, Chichester, 2000.
[2] a) K Van der Jeught, C. V. Stevens, Chem. Rev. 2009,
109, 2672–2702; b) L. Berlicki, P. Kafarski, Curr. Org.
Chem. 2005, 9, 1829–1850; c) P. Kafarski, B. Lejczak,
Curr. Med. Chem: Anti-Cancer Ag. 2001, 1, 301–312.
[3] a) R. Hirschmann, A. B. Smith III, C. M. Taylor, P. A.
Benkovic, S. D. Taylor, K. M. Yager, P. A. Sprengeler,
S. J. Venkovic, Science 1994, 265, 234–237; b) A. Mac-
chiarulo, R. Pellicciari, J. Mol. Graphics Modell. 2007,
In summary we present here a new and general
synthesis of a-iminophosphonates derived from ke-
tones and an efficient strategy for the enantioselective
synthesis of tetrasubstituted a-aminophosphonic acid
derivatives from trisubstituted a-aminophosphonates
through a global substitution of the hydrogen atom by
a nucleophilic reagent, where the key step is an asym-
metric cyanation of a-ketiminophosphonates cata-
lyzed by Cinchona alkaloids. The new approach for
the synthesis tetrasubstituted a-aminophosphonates
with the addition of a nucleophilic reagent in the a po-
sition, not easily available by alternative methods, in-
´
26, 728–739; c) M. Sienczyk, L. Winiarski, P. Kasperkie-
wicz, M. Psurski, J. Wietrzyk, J. Oleksyszyn, Bioorg.
Med. Chem. Lett. 2011, 21, 7224–7227; d) F. R. Athe-
rton, C. H. Hassall, R. W. Lambert, J. Med. Chem.
1986, 29, 29–40.
´
[4] D. Bonarska, H. Kleszczynska, J. Sarapuk, Cell Mol.
Biol. Lett. 2002, 7, 929–935.
[5] a) A. Mucha, P. Kafarski, L. Berlicki, J. Med. Chem.
2011, 54, 5955–5980; b) F. Orsini, G. Sello, M. Sisti,
Curr. Med. Chem. 2010, 17, 264–289.
À
volves a C C bond formation through addition of
a carbon nucleophile, to phosphorylated iminic sys-
tems. This represents also a useful entry for asymmet-
ric cyanation of ketimines and for the first time of in-
expensive and non-toxic pyruvonitrile being used as
cyanide source for the asymmetric synthesis of tetra-
substituted a-amino nitriles. As far as we know, enan-
tiopure phosphorated tetrasubstituted a-amino ni-
triles and a-amino acids 11 and 12 have not been re-
ported so far.
[6] M. OrdꢃÇez, H. Rojas-Cabrera, C. Cativiela, Tetrahe-
dron 2009, 65, 17–49.
[7] W. F. Gilmore, H. A. McBride, J. Am. Chem. Soc. 1972,
94, 4361.
[8] P. Merino, E. Marques-Lopez, R. P. Herrera, Adv.
Synth. Catal. 2008, 350, 1195–1208.
[9] a) Quaternary Stereocentres: Challenges and Solutions
for Organic Synthesis, (Eds: A. Baro, J. Christoffers),
Wiley-VCH, Weinhein, 2006; b) M. Shimizu, Angew.
Chem. Int. Ed. 2011, 50, 5988–6000.
[10] O. Riant, J. Hannedouche, Org. Biomol. Chem. 2007, 5,
873–888.
Experimental Section
[11] a) A. Studer, D. Seebach, Heterocycles 1995, 40, 357–
378; b) M. Mikołajczyk, P. Łyz˙wa, J. Drabowicz, Tetra-
hedron: Asymmetry 1997, 8, 3991–3994; c) F. A. Davis,
S. Lee, H. Yan, D. D. Titus, Org. Lett. 2001, 3, 1757–
1760; d) Q. Chen, J. Li, C. Yuan, Synthesis 2008, 2986–
2990; e) E. Kuliszewska, M. Hanbauer, F. Hammersch-
midt, Chem. Eur. J. 2008, 14, 8603–8614.
[12] S. Nakamura, M. Hayashi, Y. Hiramatsu, N. Shibata, Y.
Funahashi T. Toru, J. Am. Chem. Soc. 2009, 131,
18240–18241.
[13] a) S. M. Kim, H. R. Kim, D. Y. Kim, Org. Lett. 2005, 7,
2309–2311; b) L. Bernardi, W. Zhuang, K. A. Jørgen-
sen, J. Am. Chem. Soc. 2005, 127, 5772–5773.
[14] a) R. Kuwano, R. Nishio, Y. Ito, Org. Lett. 1999, 1,
837–839; b) J. C. Wilt, M. Pink, J. N. Johnston, Chem.
Commun. 2008, 4177–4179; c) K. Bera I. N. N. Nam-
boothiri, Org. Lett. 2012, 14, 980–983.
Procedure for the Asymmetric Cyanation of a-
Ketiminophosphonates 3
A solution of a-ketiminophosphonate 3 (0.5 mmol) and cin-
chonidine (9a) (10%) in CHCl3 under an N2 atmosphere
was cooled to À458C or 08C (see Table 4). Pyruvonitrile
(71 mL, 1 mmol) was added and the mixture was stirred for
72 h at À458C or 08C. The resulting solution was concen-
trated under reduced pressure and the residue was purified
by crystallization from EtOH to afford pure a-phosphono-
a-amino nitriles 11.
2646
asc.wiley-vch.de
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2641 – 2647

Asymmetric Cyanation of a-Ketiminophosphonates Catalyzed by Cinchona Alkaloids
[15] a) F. Palacios, A. M. Ochoa de Retana, J. I. Gil, J. M.
Alonso, Tetrahedron 2004, 60, 8937–8947; b) J. Vicario,
C. Alonso, J. M. de Los Santos, F. Palacios, Curr. Org.
Synth. 2010, 7, 628–649.
[16] a) F. Palacios, J. Vicario, A. Maliszewska, D. Aparicio,
J. Org. Chem. 2007, 72, 2682–2685; b) F. Palacios, A. M.
Ochoa de Retana, A. Velez del Burgo, J. Org. Chem.
2011, 76, 9472–9477.
[17] a) F. Palacios, D. Aparicio, Y. Lopez, J. M. de Los
Santos, Tetrahedron 2005, 61, 2815–2830; b) J. M.
de Los Santos, R. Ignacio, D. Aparicio, F. Palacios, J.
Org. Chem. 2007, 72, 5202–5206.
Wang, X. H. Liu, X. M. Feng, Chem. Eur. J. 2008, 14,
4484–4486.
[24] a) J. Wang, X. L. Hu, J. Jiang, S. H. Gou, X. Huang,
X. H. Liu, X. M. Feng, Angew. Chem. 2007, 119, 8468–
8470; b) J. Wang, W. Wang, W. Li, X. Hu, K. Shen, C.
Tan, X. Liu, X. Feng, Chem. Eur. J. 2009, 15, 11642–
11659.
[25] a) S. Masumoto, H. Usuda, M. Suzuki, M. Kanai, M.
Shibasaki, J. Am. Chem. Soc. 2003, 125, 5634–5635;
b) 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.
[26] Stereochemistry of Organic Compounds, (Eds.: E. L.
Eliel, S. H. Wilen, L. N. Mander), Wiley, New York,
1994.
[27] Perryꢂs Standard Tables and Formulas for Chemical En-
gineers, (Ed.: J. G. Speight), McGraw-Hill, New York,
2003.
[28] a) C. Reichardt, E. Harbusch-Gçrnert, Liebigs Ann.
Chem. 1983, 57–61; b) C. Reichardt, Chem. Rev. 1994,
94, 2319–2358.
[29] CCDC 871788 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[18] F F. Palacios, C. Alonso, J. M. de Los Santos, Chem.
Rev. 2005, 105, 899–931.
[19] J. Vicario, D. Aparicio, F. Palacios, Phosphorus Sulfur
Silicon Relat. Elem. 2011, 186, 638–643.
[20] a) F. Palacios, C. Alonso, D. Aparicio, G. Rubiales,
J. M. De Los Santos, Tetrahedron 2007, 63, 523–575;
b) F. Palacios, C. Alonso, D. Aparicio, G. Rubiales,
J. M. De Los Santos, in: Organic Azides. Synthesis and
Applications, (Eds.: S. Brꢅse, K Banert), Wiley, & Sons,
Chichester, U.K., 2010, pp 437–468.
[21] A. Strecker, Justus Liebigs Ann. Chem. 1850, 75, 27–45.
[22] a) P. Vachal, E. N. Jacobsen, Org. Lett. 2000, 2, 867–
870; b) P. Vachal, E. N. Jacobsen, J. Am. Chem. Soc.
2002, 124, 10012–11014.
[23] a) X. Huang, J. L. Huang, Y. H. Wen, X. M. Feng, Adv.
Synth. Catal. 2006, 348, 2579–2584; b) Z. R. Hou, J.
Adv. Synth. Catal. 2012, 354, 2641 – 2647
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2647