Enantioselective synthesis of functionalized αα-aminophosphonic acid derivatives

Article abstract of DOI:10.1080/10426507.2018.1528258

An umpolung process for the enantioselective functionalization of α-aminophosphonates with nucleophiles has been developed. This consists in a formal oxidation of tetrasubstituted α-aminophosphonates to α-iminophosphonates followed by an organocatalyzed nucleophilic addition reaction to the imine bond. The optimal enantioselectivity has been reached by studying the effect of the size of the substituent at the phosphonate. Applications for the preparation of tetrasubstituted α-amino α-cyanophosphonates and α-amino β-nitrophosphonates enantiomerically enriched are reported.

Full text of DOI:10.1080/10426507.2018.1528258

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Enantioselective synthesis of functionalized αα-
aminophosphonic acid derivatives
Aitor Maestro, Xabier del Corte, Edorta Martinez de Marigorta, Francisco
Palacios & Javier Vicario
To cite this article: Aitor Maestro, Xabier del Corte, Edorta Martinez de Marigorta,
Francisco Palacios & Javier Vicario (2019): Enantioselective synthesis of functionalized αα-
aminophosphonic acid derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2018.1528258
To link to this article: https://doi.org/10.1080/10426507.2018.1528258
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2018.1528258
SHORT COMMUNICATION
Enantioselective synthesis of functionalized a-aminophosphonic acid derivatives
Aitor Maestro, Xabier del Corte, Edorta Martinez de Marigorta, Francisco Palacios, and Javier Vicario
ꢀ
ꢀ
Departamento de Quımica Organica I, Facultad de Farmacia, University of the Basque Country, Vitoria-Gasteiz, Spain
ABSTRACT
ARTICLE HISTORY
Received 27 July 2018
Accepted 14 September 2018
An umpolung process for the enantioselective functionalization of a-aminophosphonates
with nucleophiles has been developed. This consists in a formal oxidation of tetrasubstituted
a-aminophosphonates to a-iminophosphonates followed by an organocatalyzed nucleophilic
addition reaction to the imine bond. The optimal enantioselectivity has been reached by
studying the effect of the size of the substituent at the phosphonate. Applications for the
preparation of tetrasubstituted a-amino a-cyanophosphonates and a-amino b-nitrophospho-
nates enantiomerically enriched are reported.
KEYWORDS
a-Aminophosphonates;
organocatalysis; nucleophilic
addition; ketimines;
cyanation; aza-Henry
GRAPHICAL ABSTRACT
Introduction
antibiotic activity.[4b] In consequence, the enantioselective
synthesis of tetrasubstituted a-aminophosphonic acid deriva-
tives has acquired great relevance in organic chemistry dur-
ing the last few years.[5] a-Aminophosphonic acids are
normally prepared from the hydrolysis of their phosphonate
esters and, for this reason, a strong effort has been made
during the last decades in order to develop efficient
synthetic protocols for the enantioselective synthesis of
quaternary a-aminophosphonates. From all the available
synthetic protocols for the synthesis of enantioenriched
a-aminophosphonates, the addition of nucleophile reagents
to a-iminophosphonates is the less explored and most chal-
lenging route, due to the difficulty for the preparation of
a-phosphorated ketimine substrates, that additionally suffer
from an extreme instability. In addition, the formation of
tetrasubstituted centers from ketimines is complicated by
the poor electrophilic character of ketimine group and the
additional steric hindrance present on the substrate.
Moreover, the enantiotopic faces of ketimine derivatives are
not as easily discriminated as those of aldimine derivatives
a-Aminophosphonic acids are the structural isosters of
a-aminoacids, where the flat carboxylic group has been
replaced by a phosphonic acid group, which is tetrahedral
and more bulky. Due to this tetrahedral configuration of
the phosphorus atom, a-aminophosphonic acid functional-
ity is able to mimic in a stable manner the transition state
for the hydrolysis of peptides, and, molecules owing this
moiety are able to inhibit enzymes involved in peptide
metabolism (Figure 1).[1] Consequently, a-aminophosphonic
acid derivatives show important biological activities and,
they have found numerous applications in medicine and
agrochemistry.[2]
Moreover, the biological activity of drugs in general is
known to be strongly dependent on their absolute configur-
ation.[3] This is also true in the case of biologically active
a-aminophosphonic acid derivatives. For instance, the R
enantiomer of phospholeucine is a more potent inhibitor of
leucine-peptidase than its S isomer[4a] and, from the four
possible isomers of the phosphapeptide alaphosphaline, the
one with S, R configuration, shows the more potent when asymmetric synthesis is sought.[6]
ꢀ
ꢀ
Departamento de Quımica Organica I, Facultad de Farmacia, University of the Basque Country, UPV/EHU
CONTACT Javier Vicario
javier.vicario@ehu.es
Paseo de la Universidad 7, Vitoria-Gasteiz, 01006, Spain.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
ß 2019 Taylor & Francis Group, LLC

2
A. MAESTRO ET AL.
Figure 1. Phosphonopeptides are able to mimic the transition state for peptide cleavage.
Scheme 2. Synthesis of starting a-aminophosphonates 3.
then promote its elimination with the proper base.
According to this, the selective N-chlorination reaction can
be achieved by treatment of trisubstituted a-aminophospho-
nates 1 with trichloroisocyanuric acid (TCCA) in dichloro-
Scheme 1. Global approach for the enantioselective synthesis of tetrasubsti-
tuted a-aminophosphonates.
Following with the interest of our research group in the methane (Scheme 2). N-Cloro a-aminophosphonates 2 are
unstable species and, in order to prevent the dechlorination
reaction, they are readily used without purification after
elimination of the solid residue by filtration.
development of new strategies for the preparation of amino-
phosphorus compounds[7] and, in particular, in the synthesis
of enantioenriched a-aminophosphonates,[8] we believed that
an enantioselective addition of nucleophiles to a-ketimino-
phosphonates III would be a convenient pathway to access
optically active tetrasubstituted a-amino phosphonates II.
The preparation of a-ketiminophosphonate substrates III
might be feasible by oxidation of the parent a-amino-
phosphonates I and, consequently, this synthetic approach
could be considered globally as an alternative route for the
synthesis of tetrasubstituted a-aminophosphonates IV by the
substitution of hydrogen in a trisubstituted a-aminophosph-
onate I by a nucleophilic reagent. This approach would be
the complementary process (“umpolung reaction”)[9] to the
electrophilic substitution of trisubstituted a-aminophospho-
nates[10] (Scheme 1).
b-Elimination of HCl in N-chloro a-aminophosphonates 2
can be performed using pyridine as a base but, unfortunately,
the resulting unstable a-iminophosphonates 3 cannot be sepa-
rated from pyridine hydrocloride avoiding the hydrolysis of
the imine bond. The use of an insoluble base in organic sol-
vents as the promoter of the b-elimination reaction allows
the elimination of both the hydrochloride and the excess of
base from the reaction solution. Therefore, refluxing over-
night the resulting clear solution of N-chloro a-aminophosph-
onate 2 with an excess of poly(4-vinylpyridine) affords pure
a-ketiminophosphonates 3 in very good yields after filtration
and crystallization from diethyl ether (Scheme 2).
With an efficient protocol in hands for the preparation of
a-ketiminophosphonates 3, next we studied the organocata-
lytic asymmetric addition of nucleophiles to imines 3. First we
tested the cyanation reaction of a-iminophosphonic acid
dimethyl ester 3a in the presence of 2 equivalents of pyruvoni-
trile and 1,4-diazabicyclo[2.2.2]octane 5 (DABCO) (Table 1,
Results and discussion
We reported an efficient synthesis of b,c-unsaturated a-imi-
noesters and a-iminophosphonates through an aza-Wittig
approach.[11] These imines showed a very assorted reactivity
and proved to be very useful intermediates for the synthesis of
several a-aminophosphonic acid derivatives.[12] Although quite
general, one of the drawbacks of the aza-Wittig methodology
is that only N-aryl and/or N-alkyl phosphazenes can be used
for the preparation of N-aryl- and/or N-alkyl-a-iminophospho-
nates. Considering the moderate electrophilic character and the
additional steric hindrance present in ketimine groups, we
were interested in ketimine substrates bearing an electron with-
drawing group at the nitrogen. This kind of protecting group
would both favor nucleophilic addition to the C ¼ N double
bond and allow an easy deprotection of the nitrogen in an
ultimate synthetic step.
Table 1. Screening of catalysts.
Entry
Cat.
Time (h)
%Conv.
%ee
1
2
3
4
5
6
7
8
DABCO
I
II
III
IV
V
VI
X
12
48
48
48
48
48
48
48
100
100
100
100
100
100
100
95
–
17
24
20
30
14
36
15
Construction of a carbon-nitrogen double bond from
a-aminophosphonates 1 would imply the introduction of a
good leaving group at the a-aminophosphonate skeleton to

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Entry 1) and a-cyano a-aminophosphonate 4a was obtained in when the cyanation reaction of di-iso-propyl phosphonate
full conversion.[13a]
3d was performed using cinchonidine (II) as organocatalyst.
Then, we obviously tested the asymmetric cyanation reac-
tion in the presence of a catalytic quantity of cinchona alkal-
(Table 2, Entry 6) and this result could be improved to a
92% ee by performing the reaction at lower temperature
(Table 2, Entry 9). It should be noted that this reaction can
be extended to other aromatic a-iminophosphonates bearing
electron donating or electron withdrawing groups with
almost equal enantioselectivities.[13a]
In our pursuit of new synthesis of enantioenriched tetrasub-
stituted a-aminophosphonic acid derivatives, next we studied
the enantioselective aza-Henry reaction of a-iminophosphonate
substrates 3. Initially, the treatment of a-iminophosphonate 3a
with nitromethane, without solvent, in the presence of a catalytic
amount of a Cinchona alkaloids I-V led to a fast formation of
a-amino b-nitrophosphonates 5a but, unfortunately, with poor
enantioselectivity (Table 3, Entries 1–5).[13b]
However, the use of bifunctional thioureas VII-X (Figure 2,
vide supra) as organocatalysts in the aza-Henry reaction of
a-iminophosphonate 3a a-amino b-nitrophosphonate 5a with
increased enantioselectivities (Table 3, Entries 7–10).[13b]
Encouraged by these results, we again implemented the
analysis of the influence of the phosphorus substituent in
a-iminophosphonate substrates 3 on the enantioselectivity of
the aza-Henry reaction using thiourea IX (Figure 2). In this
reaction an increased enantiomeric excess was observed
towards dimethyl phosphonate 3a when diethyphosphonate 3c
(Table 4, Entry 2) or di-iso-propylphosphonate 3d (Table 4,
Entry 3) were used.[13b]
oid derivatives. Dihydroquinine (I) showed
a modest
enantioselectivity (Table 1, Entry 1) as well as other cin-
chona alkaloids tested such as cinchonidine (II) quinine
(III), dihydroquinidine (IV), cinchonine (V) or quinidine
(VI) (Table 1, Entries 4–7). Moreover, although bifunctional
thiourea X catalyzed very efficiently the nucleophilic add-
ition of cyanide, no significant enantiomeric excess was
observed (Table 1, Entry 8).
Taking the advantage of our new protocol for the prepar-
ation of a-ketiminophosphonates 3, we implemented the
analysis of the influence of the phosphorus substituent on
the enantioselectivity of the cyanation reaction using cin-
chona alkaloids II and VI as organocatalysts (Table 2).[13a]
A significant dependence of the enantioselectivity of the
reaction was observed for acyclic aliphatic substituents at
the phosphonate moiety. The lowest enantiomeric excesses
were obtained for dibenzyl phosphonates 3b (Table 2,
Entries 1–2), while slightly higher enantioselectivity was
obtained for dimethyl or diethyl phosphonates 3a and 3c
(Table 2, Entries 3–5). The best results were observed for
di-iso-propyl phosphonate 3d (Table 2, Entries 6–7). A spe-
cial case is the use of diphenyl phosphonates. Curiously,
very low asymmetric induction is observed in the cyanation
reaction of diphenyl phosphonate 3e (Table 2, Entry 8).
This result may be due to the ability of phenyl ring to adopt
a parallel conformation, decreasing the steric crowding at
the iminic carbon. The best enantioselectivity was obtained
Bearing these results in mind, we thought that better
results could be obtained if the aza-Henry reaction was per-
Table 3. Screening of the catalyst for the aza-Henry reaction of a-imino-
phosphonate 3a.
Table 2. Influence of the phosphorus substituent in the cyanation reaction of
a-iminophosphonates 3.
Temp (ꢀC)
%ee
Entry
Cat.
t (h)
%Conv.
%ee
Entry
Comp.
Cat.
R
1
2
3
4
5
6
7
8
I
II
22
3
3
3
3
3
6
6
6
60
95
95
100
75
95
100
95
12
10
13
6
10
29
22
27
23
1
2
3
4
5
6
7
8
9
4b
4b
4a
4a
4c
4d
4d
4e
4d
II
VI
II
VI
VI
II
VI
II
Bn
Bn
Me
Me
Et
25
25
25
25
25
25
25
25
ꢁ30
16
22
24
36
38
80
60
6
III
IV
V
VII
VIII
IX
X
iPr
iPr
Ph
iPr
90
95
II
92
Figure 2. Organocatalysts tested in this study.

4
A. MAESTRO ET AL.
Table 4. Screening of the phosphorus substituent for the aza-Henry reaction of a-iminophosphonates 3.
Entry
Comp
R
Solvent
t (h)
%Conv.
%ee
1
2
3
4
5
6
5a
5c
5d
5d
5d
5d
Me
Et
No
No
No
CH2Cl2
CHCl3
Toluene
24
6
24
24
36
36
95
100
95
90
95
27
30
45
68
67
80
iPr
iPr
iPr
iPr
100
b) Macchiarulo, A. R.; Pellicciari. Exploring the Other Side of
Biologically Relevant Chemical Space: Insights into Carboxylic,
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formed under solvation conditions. An inverse dependence
of the enantioselectivity into the polarity of the solvent is
observed if non coordinating solvents are used (Table 4,
Entries 4-5). This dependence probably arises from a dimin-
ishing in the difference of the energy of activation for the
formation of the two enantiomers due to a stabilization of
both possible diastereomeric transition states in a polar solv-
ent, rational for reactions with ionic transition states. An
optimal enantiomeric excess of 80% was obtained when the
reaction was performed at room temperature in toluene. As
in the case of the cyanation reaction this process can be
extended to other aromatic a-iminophosphonates bearing
electron donating or electron withdrawing groups with
almost equal enantioselectivities.[13b]
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Conclusions
The enantioselective functionalization of a-aminophospho-
nates with nucleophiles has been achieved through an
umpolung process consisting in the oxidation of tetrasubsti-
tuted a-aminophosphonates to a-iminophosphonates fol-
lowed by the organocatalyzed addition of nucleophile
reagents such as cyanide and nitromethane.
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Financial support by Ministerio de Economıa, Industria
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(GV, IT 992-16) is gratefully acknowledged.
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