A general approach to enantiomeric γ-aminophosphonic acids using chiral sulfinimine methodology

Article abstract of DOI:10.1002/hc.20710

A new approach to asymmetric synthesis of γ-aminophosphonic acids is described. It involves the diastereoselective addition of various carbon and phosphorus nucleophiles to enantiopure (+)-(S)-N-[(3-diethoxyphosphoryl) propylidene]-p-toluenesulfinamide an

Full text of DOI:10.1002/hc.20710

Heteroatom Chemistry
Volume 22, Number 3/4, 2011
A General Approach to Enantiomeric
γ-Aminophosphonic Acids Using Chiral
Sulfinimine Methodology
Piotr Łyz˙wa and Marian Mikołajczyk
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department
of Heteroorganic Chemistry, Sienkiewicza 112, 90-363 Ło´dz˙, Poland
Received 9 November 2010
enzymes (e.g., HIV protease, serine protease). Many
ABSTRACT: A new approach to asymmetric syn-
natural and synthetic aminophosphonic acids and
thesis of γ-aminophosphonic acids is described. It
their conjugates with peptides exhibit antibacterial,
involves the diastereoselective addition of various
anticancer, and antiviral properties. Some of them
carbon and phosphorus nucleophiles to enantiopure
are important in agriculture since they show pesti-
(+)-(S)-N-[(3-diethoxyphosphoryl)propylidene]-p-
cidal, insecticidal, and herbicidal activity. In spite
toluenesulfinamide and subsequent acid hydrol-
of the fact that a lot of experimental material has
ysis of the adducts formed. The utility of the
been accumulated in this field [1–5], there is a con-
method is illustrated by the synthesis of (+)-(S)-2-
tinued interest in aminophosphonic acids focused
amino-4-phosphonobutanoic acid (AP4), and
especially on the synthesis of optically active com-
both enantiomerically enriched (–)-(R)- and (+)-
pounds. For instance, Beletskaya and her cowork-
ꢀ
C
(S)-1-amino-propane-1,3-diphosphonic acid.
2011
ers [6] and, independently, the group of Onys´ko [7]
elaborated recently a new and straightforward ap-
proach to optically active α-aminophosphonic acids
via the enantioselective catalytic reduction of C-
phosphorylated imines. As in the case of other
classes of chiral bioactive compounds, the enan-
tiomeric forms of aminophosphonic acids show dis-
tinct differences in bioactivity. Therefore, the devel-
opment of suitable and simple methodologies for
their preparation has been a challenging task.
As a part of our program aimed at the devel-
opment of a new methodology for the synthesis
of racemic and optically active aminophosphonic
acids, we devised a new and general asymmetric
synthesis of α and β-aminophosphonic acids using
as the first the enantiopure p-toluenesulfinimines
1 as chiral reagents [8–10]. A key step here was a
highly diastereoselective addition of phosphite an-
ions and α-phosphonate carbanions to sulfinimines
1 (Scheme 1).
Wiley Periodicals, Inc. Heteroatom Chem 22:594–598,
2011; View this article online at wileyonlinelibrary.com.
DOI 10.1002/hc.20710
INTRODUCTION
Aminophosphonic acids are amino acid isosteres
in which the planar carboxylic group has been
replaced by a tetrahedral phosphonic acid moiety.
Owing to this structural steric change, aminophos-
phonic acids mimic the unstable tetrahedral inter-
mediates formed in enzyme-mediated peptide bond
cleavage and usually act as inhibitors of proteolytic
Dedicated to Professor Kin-ya Akiba on the occasion of his 75th
birthday.
Correspondence to: Marian Mikołajczyk; e-mail: marmikol
@bilbo.cbmm.lodz.pl.
Contract grant sponsor: Ministry of Science and Higher
Education.
Our approach has been applied by other re-
search groups for the synthesis of structurally
Contract grant number: PBZ-KBN-126/T09/2004.
2011 Wiley Periodicals, Inc.
c
ꢀ
594

A General Approach to Enantiomeric γ-Aminophosphonic Acids Using Chiral Sulfinimine Methodology 595
diverse α and β-aminophosphonic acids [4,5].
However, in contrast to these widely investigated
subclasses of aminophosphonic acids, a few meth-
ods exist for the synthesis of enantiomeric γ-
aminophosphonic acids. The most representative
members of this subclass of aminophosphonic acids
are 2-amino-4-phosphonobutanoic acid 2 (AP4) and
phosphinothricin 3. The first of them is a phospho-
nic analogue of glutamic acid and acts as a modu-
lator for the N-methyl-D-aspartate (NMDA) receptor
site, whereas the latter is a potent inhibitor of glu-
tamine synthetase and shows antibacterial and her-
bicidal activity. Interestingly, the (S)-enantiomer of
2 is 40 times more active than the (R)-form in sup-
pression of glutamate-mediated neurotransmission,
thus illustrating that bioactivity depends essentially
on the absolute configuration of the stereogenic
carbon atom [11]. Although syntheses of individ-
ual structures of enantiomeric γ-aminophosphonic
acids are reported, they are not general in scope
and are of limited applicability. This prompted us
to elaborate a general approach to enantiomeric γ-
aminophosphonic acids based on our chiral sulfin-
imine methodology. Herein we disclose the first
asymmetric synthesis of γ-aminophosphonic acids
from the enantiopure (+)-(S)-sulfinimine 4. In this
reagent, the imino-nitrogen atom of the stereodirect-
ing sulfinyl group is bonded to the γ-carbon atom
of the phosphonate moiety, securing in this way γ-
aminophosphonic acid framework.
SCHEME
1
Synthesis of enantiopure
aminophosphonic acids.
α
and β-
O
O
P
CH3
OH
H2N
P(OH)2
H2N
SCHEME 2 Synthesis of sulfinimine (+)-(S)-4.
CO2H
CO2H
(S) -2 (AP4)
(S)-3
toluenesulfinamide 6 in the presence of Ti(OEt)4 that
was used in a half molar amount (Scheme 2). At this
reagents ratio (1:1:0.5), the formation of side prod-
ucts was the lowest. The product was isolated in 80%
yield. However, it was found to contain ca. 5% of
double-bond isomers (δp = 31.8 ppm) and unreacted
aldehyde. As we were not able to remove the above
impurities from 4 by column chromatography, it was
used as such for addition reactions.
O
S
(EtO)2P
O
N
Tol- p
(S)-4
Synthesis of sulfinimine (+)-(S)-4: Under a ni-
trogen atmosphere, a solution of aldehyde 5 (1,94 g,
o.01 mol), sulfinamide (+)-(S)-6 (1,55 g, 0.01 mol),
and titanum(IV) ethoxide (1.14 g, 0,005 mol) in
CH2Cl2 (50 mL) was stirred at room temperature
for 12 h. The reaction mixture was then quenched
at 0◦C by addition of H2O (50 mL). The turbid solu-
tion was filtered through Celite, and the filter cake
RESULTS AND DISCUSSION
The sulfinimine 4 devised for the synthesis of γ-
aminophosphonic acids was obtained according to
the procedure described by Davis et al. [12], in
the condensation reaction of equimolar amounts of
3-(diethoxyphosphoryl)propanal 5 and (+)-(S) − p-
Heteroatom Chemistry DOI 10.1002/hc

596 Łyz˙wa and Mikołajczyk
SCHEME 3 Asymmetric addition of carbon and phosphorus nucleophiles to sulfinimine (+)-(S)-4.
was washed with CH2Cl2 (2 × 50 mL). After separa-
tion, the aqueous phase was washed with CH2Cl2
(10 mL) and combined organic layers were dried
over MgSO4 and concentrated to give 2.8 g (80%
yield) of sulfinimine (+)-(S)-4 contaminated with 5%
of unreacted aldehyde and double-bond isomers; its
TABLE 1 Results of Addition of Nucleophiles to (S)-sulfinimine 4
Heteroatom Chemistry DOI 10.1002/hc

A General Approach to Enantiomeric γ-Aminophosphonic Acids Using Chiral Sulfinimine Methodology 597
SCHEME 4 Synthesis of enantiomeric forms of 2-amino-propane-1,3-diphosphonic acid.
optical rotation was [α]2D0 = +102.8 (c, 0.1, CHCl3).
Spectroscopic data for (+)-4: 1H NMR (CDCl3): δ 1.2
(t, J= 7 Hz, 6H, CH3CH2O), 1.88–2.05 (m, 2H, CH2P),
2.31 (s, 3H, CH3), 2.6–2.78 (m, 2H, CH2CH2P), 3.9–
4.1 (m, 4H, CH2O), 7.71–7.54 (AB system, 4H, J =
8.1 Hz, arom), 8.2 (s, 1H, CH N); 13C NMR (CDCl3):
δ 16.1, 21.0, 20.7 (d, JCP = 144.5 Hz, CH2P), 61.45,
124.2, 125.7, 129.45, 141.2, 164.6 (d, J = 16.8 Hz,
C N); 31P NMR (CDCl3): δ 30.3. MS (FAB): m/z 332
(M + 1).
methylphosphonate and ethyl lithium acetate was
found to occur with the lower diastereoselectivity
(dr = 3:1).
In contrast to our previous results, it turned out
that the diastereomers of 7 could not be separated
by column chromatography. Therefore, the adduct
7 with dr 9:1 was converted under acidic conditions
directly to (+)-2-amino-4-phosphonobutanoic acid
2 (AP4) in 73% yield (Scheme 4). Its spectroscopic
and physicochemical properties were in very good
agreement with those reported in the literature [13].
The highest optical rotation, [α]2D0 = +13.2 (H2O), for
(+)-(S)-2 was reported by Acher et al. [13d]. Assum-
ing that it corresponds to enantiopure compound,
our product was isolated with 95% ee. This needs
further confirmation.
Having in mind the synthesis of enantiomeric
AP4 as an important goal of this work, the addi-
tion of the cyano group to the sulfinimine (+)-(S)-
4 was investigated in the first instance (Scheme 3;
Table 1). With Et2AlCN in the presence of BF3·Et2O,
the addition reaction gave the corresponding adduct
7 as a mixture of two diastereomers in a 3:1 ratio.
They showed two well-separated signals at δ 30.12
and 29.4 ppm in 31P NMR spectra, allowing easy
determination of the diastereoselectivity of the ad-
dition reaction. Using Me3SiCN/CsF as a source of
the cyanide anion, the diastereomeric ratio (dr) of 7
formed in addition was increased to 6:1. A further
increase in the dr to 9:1 was achieved when Et2AlCN
in the presence of isopropanol and (MeO)2C(Li)CN
were used for addition to (+)-(S)-4. Addition of
other carbon nucleophiles such as diethyl lithium
Since the dextrorotatory AP4 obtained has the
absolute configuration (S), the major diastereomer
of the starting adduct 7 should have the (S)-chirality
at the stereogenic carbon atom newly formed in
Heteroatom Chemistry DOI 10.1002/hc

598 Łyz˙wa and Mikołajczyk
the addition reaction. Our new synthesis of (+)-(S)-
2 compares favorably with other methods [13] in
terms of simplicity and brevity.
pylidene-p-tolulenesulfinamide]. The value of this
method has been demonstrated by a two-step
synthesis of (+)-(S)-2-amino-4-phosphonobutanoic
acid (AP4), and both enantiomerically enriched
forms (–)-(R)- and (+)-(S) of 1amino-propane-1,3-
diphosphonic acid. Further improvements (an in-
crease in dr, separation of diastereomers, and purifi-
cation of sulfinimine) and applications (synthesis of
phosphinotricin) are currently ongoing in our group.
In the second set of experiments, the addition
of phosphorus nucleophiles to (+)-(S)-4 was investi-
gated (Scheme 3). Thus, a THF solution of (+)-(S)-
sulfinimine 4 was added to the lithium salt of diethyl
phosphite in THF at −78◦C. After 5 h of stirring at
this temperature and usual work-up, the adduct 10
as a mixture of two diastereomers in a 2.9:1 ratio (31P
NMR assay) was obtained in 53% yield. Under simi-
lar conditions, the addition of the lithium salts of bis-
(dimethylamido) phosphite and bis-(diethylamido)
phosphite afforded the corresponding adducts 11
and 12 with the same dr (2.9:1). The lithiated di-
aminophosphine borane complex was found to give
the adduct 13 in 74% yield. It showed in 31P NMR
spectrum only one single resonance for P1 and a
broad signal for P2 bonded to borane. This precluded
determination of dr by 31P NMR in this case.
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drolyzed to dextrorotatory acid 14 with the (S )-
C
configuration. This result confirmed our earlier ob-
servation that the stereochemical outcome of the
addition of dialkyl phosphites and bis-amido phos-
phites is opposite [9]. The acid 14 with the highest
optical rotation ([α]D20 = +3.7) was obtained from the
adduct 13, indicating very high diastereoselectivity
in the addition reaction of the aminophosphine bo-
rane complex to (S)-4. It is interesting to point out
that it is the first synthesis of the optically active acid
14, which has been obtained earlier only in racemic
form [15].
CONCLUSION
A new and general asymmetric synthesis of γ-
aminophosphonic acids has been developed. The
key step included diastereoselective addition of car-
bon and phosphorus nucleophiles to a new chiral
sulfinimine [(+)-(S)-N-(3-diethoxyphosphoryl) pro-
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3, 1757–1760.
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Heteroatom Chemistry DOI 10.1002/hc