Asymmetric synthesis of structurally diverse aminophosphonic acids by using enantiopure N-(p-Tolylsulfinyl)cinnamaldimines as reagents

Article abstract of DOI:10.1002/ejoc.201201589

We have developed new approaches to diverse enantiopure aminophosphonic acids by using enantiomeric (S)-N-(p-tolylsulfinyl)cinnamaldimine (1) as a single starting material. The synthetic strategy is based on a highly diastereoselective addition reaction of phosphite anion or α-phosphonate carbanion to a sulfinimine followed by isolation of the major diastereoisomeric α-amino- or β-amino adducts and their further conversion to the desired targets through proper transformation of the cinnamylidene moiety. Both diastereoisomerically pure (S_S,R_C)- and (S _S,S_C)-α-amino adducts 2 and 4 obtained were converted under acidic conditions into the unknown enantiomerically pure (R)- and (S)-α-amino-β,γ-propenylphosphonic acids 3. In the same way, the enantiopure (R)- and (S)-β-amino-γ,δ-butenylphosphonic acids were synthesized from the corresponding (S_S,R_C)- and (S_S,S_C)-β-amino adducts. Starting from the (S_S,R_C)-β-amino adduct a new stereoselective synthesis of (R)-2-amino-3-phosphonopropanoic acid (9) has been accomplished in three simple steps (tandem ozonolysis/reduction reaction, oxidation reaction and acidic hydrolysis) in an overall 40 % yield. The 3-amino regioisomer of 9 has been prepared from the (S_S,R_C)-α-amino adduct 2 through a two-reaction sequence involving a tandem ozonolysis/reduction reaction and a Mitsunobu cyanation/acidic hydrolysis. The overall yield of this conversion to 11 was 52.5 %. According to our strategy, we have been able to complete the first synthesis of the enantiopure (R)-phosphoemeriamine 15, which is an unknown phosphonic analogue of emeriamine (aminocarnitine). The conversion of the (S_S,R_C)-β-amino adduct 5 into (R)-phosphoemeriamine has been accomplished in five simple synthetic steps (ozonolysis/reduction reaction, mesylation reaction, amination reaction, methylation reaction and acidic hydrolysis) in 24 % overall yield. The stereochemistry of the addition of P^III-nucleophiles and α-phosphonate carbanion to a chiral sulfinimine is also discussed. Starting from sulfinimine (+)-(S)-1, as a single reagent, the synthesis of diverse enantiopure aminophosphonic acids was accomplished. In addition to the synthesis of unsaturated α- and β-aminophosphonic acids, the first synthesis of (-)-(R)-phosphoemeriamine and new approaches to (+)-(R)-2-amino-3-phosphonopropanoicacid (8) and its 3-amino regioisomer 11 are reported. Copyright

Full text of DOI:10.1002/ejoc.201201589

Job/Unit: O21589
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Date: 04-03-13 11:16:22
Pages: 11
FULL PAPER
DOI: 10.1002/ejoc.201201589
Asymmetric Synthesis of Structurally Diverse Aminophosphonic Acids by
Using Enantiopure N-(p-Tolylsulfinyl)cinnamaldimines as Reagents
Piotr Łyzwa,*[a] Jarosław Błaszczyk,[a] Lesław Sieron´,[b] and Marian Mikołajczyk*[a]
˙
Keywords: Synthetic methods / Asymmetric synthesis / Diastereoselectivity / Aminophosphonic acids
We have developed new approaches to diverse enantiopure
(tandem ozonolysis/reduction reaction, oxidation reaction
aminophosphonic acids by using enantiomeric (S)-N-(p-tolyl- and acidic hydrolysis) in an overall 40% yield. The 3-amino
sulfinyl)cinnamaldimine (1) as a single starting material. The
synthetic strategy is based on a highly diastereoselective ad-
dition reaction of phosphite anion or α-phosphonate carb-
anion to a sulfinimine followed by isolation of the major dia-
stereoisomeric α-amino- or β-amino adducts and their further
regioisomer of 9 has been prepared from the (SS,RC)-α-amino
adduct 2 through a two-reaction sequence involving a tan-
dem ozonolysis/reduction reaction and a Mitsunobu cyan-
ation/acidic hydrolysis. The overall yield of this conversion
to 11 was 52.5%. According to our strategy, we have been
conversion to the desired targets through proper transforma- able to complete the first synthesis of the enantiopure (R)-
tion of the cinnamylidene moiety. Both diastereoisomerically
pure (SS,RC)- and (SS,SC)-α-amino adducts 2 and 4 obtained
were converted under acidic conditions into the unknown
phosphoemeriamine 15, which is an unknown phosphonic
analogue of emeriamine (aminocarnitine). The conversion of
the (SS,RC)-β-amino adduct 5 into (R)-phosphoemeriamine
enantiomerically pure (R)- and (S)-α-amino-β,γ-propenyl- has been accomplished in five simple synthetic steps (ozon-
phosphonic acids 3. In the same way, the enantiopure (R)-
and (S)-β-amino-γ,δ-butenylphosphonic acids were synthe-
sized from the corresponding (SS,RC)- and (SS,SC)-β-amino
adducts. Starting from the (SS,RC)-β-amino adduct a new
olysis/reduction reaction, mesylation reaction, amination re-
action, methylation reaction and acidic hydrolysis) in 24%
overall yield. The stereochemistry of the addition of PIII-nu-
cleophiles and α-phosphonate carbanion to a chiral sulfinim-
stereoselective synthesis of (R)-2-amino-3-phosphonopropa- ine is also discussed.
noic acid (9) has been accomplished in three simple steps
growth regulators. Therefore, selected APs and their deriva-
Introduction
tives have found commercial applications in medicine and
agriculture. This class of phosphorus compounds still has
remarkable potential in medicinal chemistry.[1]
Aminophosphonic acids (AP) are important analogues
of protein and nonprotein amino acids in which the planar
carboxylic group is replaced by a tetrahedral phosphonic
acid moiety. As a consequence of this structural change APs
mimic the tetrahedral transition state (or intermediate)
formed in enzyme-mediated peptide bond cleavage and act
as inhibitors of proteolytic enzymes. (e.g. HIV protease, ser-
ine protease). The spectrum of biological activities ex-
pressed by APs and their conjugates with peptides is very
wide. They exhibit antibacterial, anticancer, antiviral and
neuroactive properties. Some of them show pesticidal, in-
secticidal and herbicidal activity and function as plant
Although a lot of experimental material has been ac-
[2,3]
cumulated in the field of chemistry and biology of APs
there is continued interest in this class of phosphorus com-
pounds focused particularly on the synthesis and bioactivity
studies of optically active, enantiopure compounds. The
biological activity of APs depends markedly on the absolute
configuration of the stereogenic carbon atom connected
with the amino group. Therefore, the development of gene-
ral synthetic methods for the preparation of enantiomer-
ically pure APs has been a challenging task. Currently, the
synthetic chemistry of optically active APs encompasses
three main directions. The first aims to discover new, origi-
nal synthetic methodologies. The second is connected with
the improvement of existing methods to increase their
scope, efficiency and applicability. The final direction is de-
voted to the synthesis of new structures of aminophos-
phonic acids, including conformationally constrained ones,
and new phosphorus analogues of natural and unnatural
amino acids, which, after determination of their bioactivity,
may be selected as potential drugs (Scheme 1).
[a] Department of Heteroorganic Chemistry, Centre of Molecular
and Macromolecular Studies, Polisch Academy of Sciences,
Sienkiewicza Str. 112, 90-363 Łódz´, Poland
Fax: +48-42-680-32-60
E-mail: HHplyzwa@cbmm.lodz.pl; marmikol@cbmm.lodz.pl
Homepage: www.cbmm.lodz.pl
[b] Institute of General and Ecological Chemistry, Technical
University of Łódz´,
˙
Zeromskiego 116, 90-924 Łódz´, Poland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201589.
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tains, in addition to a very powerful stereodirecting p-tolyl-
sulfinyl group, the cinnamylidene moiety that can be easily
transformed into diverse functional groups. In this paper
we report the first synthesis of enantiopure unsaturated α-
amino- and β-aminophosphonic acids, a new synthesis of
enantiopure 2-amino-3-phosphonopropanoic acid (9) and
its 3-amino regioisomer 11 as well as the first synthesis of (–
)-(R)-phosphoemeriamine 15. All these structurally diverse
APs were efficiently obtained by using the enantiomers of
sulfinimine 1 as reagents.
Scheme 1. General structure of amino acids and their correspond-
ing aminophosphonic acids.
In the course of our work in this area we devised a new
and general asymmetric synthesis of α- and β-aminophos-
phonic acids starting from enantiopure p-toluenesulfin-
imines as chiral reagents.[4–7] Recently, we extended this ap-
proach to the asymmetric synthesis of γ-aminophosphonic
acids. In this case, (+)-(S)-N-(p-tolylsulfinyl)-3-(diethoxy-
phosphoryl)propanalimine was used for highly diastereo-
selective generation of the new stereogenic carbon atom
bearing the amino group.[8] As a result, a short and efficient
synthesis of (+)-(S)-2-amino-4-phosphonobutanoic acid
was developed. The latter is a phosphonic analogue of glut-
amic acid and acts as a modulator for the N-methyl-d-
aspartate receptor site.
Results and Discussion
Synthesis of Enantiopure Unsaturated α-Amino- and β-
Aminophosphonic Acids
From the outset of this work it was obvious that the ad-
dition of phosphite anions and α-phosphonate carbanions
to the enantiomers of 1 should produce the corresponding
phosphonate adducts that, in turn, could be converted into
enantiomerically enriched or pure unsaturated α-amino-
and β-aminophosphonic acids. To the best of our knowl-
edge, this group of optically active and enantiopure APs
has not been obtained and reported nor their biological
properties investigated. It is interesting to note that their
precursors i.e. unsaturated aminophosphonates have been
obtained by enantioselective hydrophosphonylation of
imines but only in an enantiomerically enriched state.[10,11]
Therefore, in an extension of our program on the use of
chiral sulfinimines in the asymmetric synthesis of APs, and
stimulated by a recently published enantioselective multi-
As part of our efforts to develop further the synthesis of step synthesis of unsaturated α-aminophosphonates,[12] we
enantiopure APs by using the sulfinimine methodology we disclose our two-step approach to both enantiomers of APs.
turned our attention to chiral N-(p-tolylsulfinyl)cinnamald-
The starting (+)-(S)- and (–)-(R)-sulfinimines 1 with [α]D
imine (1). It was obtained by the Davis group[9] but so far = +389 (c = 1.43, CHCl3) and [α]D = –393 (c = 1.38,
has not been exploited as the asymmetric synthesis. An im- CHCl3), respectively, were prepared according to a de-
portant structural feature of this sulfinimine is that it con- scribed procedure[9] from the corresponding commercially
Scheme 2. Synthesis of enantiopure (1-amino-3-phenylpropen-2-yl)phosphonic acid (3).
2
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Asymmetric Synthesis of Diverse Aminophosphonic Acids
Scheme 3. Synthesis of enantiopure (2-amino-4-phenyl-buten-3-yl)phosphonic acid (6).
available (+)-(S)- and (–)-(R)-p-toluenesulfinamides with state model for the addition reaction of α-phosphonate
[α]D = +85 and –85. The details of the synthesis of both carbanion to chiral sulfinimines.[4,7] Acidic hydrolysis of (–)-
enantiomers of 1-amino-3-phenylpropen-2-ylphosphonic (SS,RC)-5 gave corresponding β-aminophosphonic acid (+)-
acid (3) are outlined in Scheme 2.
(R)-6 in 63% yield. Starting from (–)-(R)-sulfinimine 1 the
In the first step, lithium diethyl phosphite was added at opposite enantiomer of acid 6 was similarly prepared. Inter-
–78 °C to a tetrahydrofuran (THF) solution of (+)-(S)-sulf- estingly, the addition reaction of α-phosphonate carbanion
inimine 1. The addition product formed in this reaction was to (–)-(R)-1 was highly diastereoselective leading to the for-
found to be a 16:1 mixture of two diastereoisomeric phos- mation of a mixture of diastereoisomers in a 38:1 ratio. The
phonates 2 as determined by 31P NMR spectroscopy [δP overall yield of (–)-(S)-6 from (–)-(R)-1 was 53 %.
= 20.8 ppm (major), δP = 21.4 ppm (minor)]. After flash
To conclude this part of the present work we wish to
chromatography and crystallization pure, major dia- provide a complete explanation of the stereochemical out-
stereoisomer (+)-2 was obtained in 62% yield. In accord- comes and very high diastereoselectivities observed in the
ance with our previous results[5,7] and rationalization given addition reactions discussed above. Our rationale is based
below the absolute configuration (R) was assigned to the on the consideration of the ground state and reactive struc-
newly generated stereogenic α-carbon atom in (+)-2. In the tures of both reacting components, i.e. sulfinimine 1 and P-
next step, phosphonate (+)-2 was converted efficiently (71% and C-nucleophiles, as well as steric and chelation effects
yield) into the corresponding enantiopure α-aminophos- operating there. First, it is necessary to point out that sulf-
phonic acid [(+)-(R)-3] by heating for 5 h in hydrochloric inimine (+)-(S)-1 exists in equilibrium between two most
acid heated to reflux.
stable conformations s-cis-1 and s-trans-1 (see Scheme 4).
To synthesize the (–)-(S)-enantiomer of 3 the addition of According to recent DFT calculations the difference in en-
lithium bis(diethylamino)phosphido–borane complex to the ergy between such conformers of a sulfinimine is about
same (+)-(S)-sulfinimine 1 was performed. Analytically 4 kcal/mol.[13] Therefore, conformer s-cis-1 is more stable
pure addition product (+)-4 was obtained in 72% yield. The than s-trans-1.
latter upon similar acidic treatment as described above af-
forded (–)-(S)-3 with the same value of optical rotation as
that of (+)-(R)-3 indicating that it is enantiomerically pure.
Hence, the addition of the lithiated diaminophosphane bor-
ane complex to (+)-(S)-1 occurred with complete diastereo-
selectivity but with opposite stereochemical course to that
observed for lithium diethyl phosphite.
Scheme 4. Conformations of (+)-(S)-sulfinimine 1.
In a similar way, enantiomerically pure (2-amino-4-phen-
ylbuten-3-yl)phosphonic acids (6) were synthesized (see
In the case of the addition reactions of lithium dialkyl
Scheme 3). In this case, however, both enantiomers of sulf- phosphites, which exist in trivalent phosphorus form with
inimine 1 were used for the addition reaction with α-phos- the lithium cation coordinated to the phosphoryl oxygen,
phonate carbanion.
the nucleophilic phosphorus atom approaches the confor-
Reaction of (+)-(S)-1 with the lithium salt of diethyl mation s-trans-1 from the diastereotopic π-face occupied by
methanephosphonate afforded a mixture of diastereoiso- the sulfinyl oxygen atom to allow chelation of the lithium
meric adducts in a 9:1 ratio [δP = 28.3 ppm (major), δP
=
cation by the sulfinyl oxygen atom (Scheme 5, Path A) and
27.5 ppm (minor)] from which pure major diastereoisomer stabilization of the cyclic seven-membered transition state
(–)-5 was isolated in 65% yield. The absolute (R)-configura- formed in this way.[14] This chelation-controlled addition re-
tion was ascribed to the newly formed stereogenic β-carbon action results in the formation of adduct 2 with the (RC)-
atom in (–)-5 on the basis of an earlier proposed transition- configuration as a major diastereoisomer.
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ordination of lithium by the sulfinyl and phosphoryl oxygen
atoms.
Synthesis of Enantiopure 2-Amino-3-phosphonopropanoic
Acid (9) and Its 3-Amino Regioisomer 11
To demonstrate the wide applicability of chiral sulfin-
imine 1 for the synthesis of various Aps, and encouraged
by our efficient asymmetric synthesis of (+)-(S)-2-amino-4-
phosphonobutanoic acid mentioned above,[8] we decided to
develop a new synthesis of 2-amino-3-phosphonopropanoic
acid (9), which is a phosphonic analogue of aspartic acid.
This phosphonic acid is a selective, potent modulator of the
metabotropic excitatory amino acids receptor subtype.[16] In
accordance with our desire to prepare 9[17] in a more simple
and efficient way, diastereoisomerically pure adduct (–)-5
was selected for conversion into 9. As shown in Scheme 6,
this conversion was easily accomplished in three steps.
Scheme 5. The proposed transition-state models for the preferred
addition of P- and C-nucleophiles to (+)-(S)-sulfinimine 1.
The switchover of diastereoselectivity in the addition re-
action of lithium bis(diethylamino)phosphido–borane,
[(Et2N)2P(BH3)Li], to (+)-(S)-1 is undoubtedly as result of
the peculiar structure of this reagent. Although its exact
structure is not known, recent elegant studies by a French-
Italian research group showed unequivocally that in the
closely
related
lithium
diphenylphosphido–borane,
[Ph2P(BH3)Li], the lithium cation is bound to the hydrides
on the boron.[15] Most probably in our bis(diethylamino)
analogue the site of coordination of lithium is the same.
Hence, the addition reaction is not controlled by chelation
Scheme 6. Synthesis of enantiopure (+)-(R)-9.
First, ozonolysis of (–)-5 and subsequent reduction with
and the phosphido–borane reagent reacts with another con- sodium borohydride gave corresponding alcohol (+)-7.
formation of 1. Among four diastereotopic π-faces formed Then, the latter was subjected to oxidation with sodium me-
by s-trans-1 and s-cis-1, that occupied by the sulfur lone taperiodate in the presence of ruthenium chloride to afford
electron pair in the more stable s-cis-1 is the least hindered carboxylic acid (+)-8 containing a N-p-tolylsulfonyl moiety.
one. So, approach of lithium aminophosphido–borane In the final step, both the amino and phosphonate func-
takes place from this π-face of s-cis-1 (Scheme 5, Path B). tions were deprotected under acidic conditions to give de-
Such a steric course generates the (SC)-configuration on the sired (+)-9. The overall yield of the conversion of (–)-5 into
α-carbon atom in adduct 4 that is preferentially or exclu- (+)-9 was 40 %.
sively formed.
Taking into account the fact that the bonds around the
Finally, the stereochemical course of the addition reac- stereogenic β-carbon atom are not broken and no racemiza-
tion of a larger α-phosphonate carbanion to (+)-(S)-1 is tion occurred during the conversion of (–)-5 into (+)-9, the
controlled primarily by steric factors (steric approach con- (R)-configuration was assigned to the resulting product.
trol). Hence, nucleophilic attack of the α-phosphonate carb- This is in accordance with the literature assignment.[17f]
anion occurs from the least hindered π-face of s-cis-1 that
Having diastereoisomerically pure adduct (+)-2 with the
is occupied by the sulfur lone electron pair (Scheme 5, amino function at the α-carbon atom in hand we were able
Path C) and major adduct 5 is produced with the (R)-con- to convert it into 3-amino-3-phosphonopropanoic acid (11),
figuration at the β-carbon atom bearing the amino moiety. which is a regioisomer of 9 with regard to the position of
As in the case of phosphite anions, stabilization of the the amino group. To the best of our knowledge there are
eight-membered cyclic transition state may be through co- only two reports of the asymmetric synthesis of this amino-
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Asymmetric Synthesis of Diverse Aminophosphonic Acids
phosphonic acid.[18] Scheme 7 shows the transformation in-
volving a two-step reaction sequence. The synthesis starts
with the tandem ozonolysis/sodium borohydride reduction
reaction of (+)-(SS,RC)-2 producing corresponding alcohol
(+)-(SS,RC)-10 in almost quantitative yield. In the next step,
it was converted under Mitsunobu reaction conditions into
the corresponding cyanide that, without isolation, was hy-
drolysed to target acid (–)-(R)-11. The overall yield for the
above conversion was 52.5%.
Therefore, in an extension of our work on phosphocarni-
tine,[20] we decided to synthesize the enantiomers of phos-
phoemeriamine to study their structure-activity relation-
ships. According to our strategy devised for the synthesis
of phosphoemeriamine mediated by sulfinimine (S)-1 and
outlined retrosynthetically in Scheme 8, the precursor of
(R)-phosphoemeriamine would be the corresponding (R)-β-
amino-γ-hydroxypropanephosphonate. This, in turn, could
be obtained from the adduct formed in the addition reac-
tion of α-phosphonate carbanion to (S)-1.
Scheme 7. Synthesis of enantiopure (–)-(R)-3-amino-3-phosphono-
propanoic acid (11).
The First Synthesis of (R)-Phosphoemeriamine 15
In the course of searching for new phosphonic analogues
of biologically active amino acids, we found that, in con-
trast to carnitine, the phosphonic analogue of emeriamine
is unknown. Emeriamine, also called aminocarnitine, which
is derived from carnitine, exhibits interesting pharmacologi-
Scheme 8. Retrosynthetic analysis for the synthesis of (R)-phospho-
emeriamine.
To our satisfaction, phosphoemeriamine precursor (+)-
cal properties. Emeriamine itself and a few other related (SS,RC)-7 was obtained during the synthesis of (+)-(R)-
compounds inhibit fatty-acid oxidation and reduce hyper- aminophosphonic acid (9). So, the real synthetic task was
glycemia and ketosis.[19]
its conversion into the desired phosphoemeriamine. We
Scheme 9. Synthesis of enantiopure (–)-(R)-phosphoemeriamine 15.
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achieved this goal in four simple steps as shown in
Scheme 9.
The hydroxy group in (+)-7 was mesylated with mesyl
chloride in the presence of triethylamine to give mesylate
(+)-12 in 90% yield. Then, the mesyloxy group in the latter
was replaced with a dimethylamino group. Upon treatment
with methyl iodide, β,γ-diaminopropanephosphonate (+)-
13, which was formed in 65% yield, gave corresponding
phosphonopropyltrimethylammonium iodide 14 isolated
after column chromatography in 73% yield. This hygro-
1
scopic iodide exhibited correct H, 13C and 31P NMR and
mass spectra; however, attempts to purify it resulted in slow
decomposition, most probably owing to a deethylation reac-
tion taking place at phosphorus. Therefore, iodide 14 was
immediately hydrolysed under standard acidic conditions
(concd. HCl·aq, AcOH, 5 h reflux temperatures) to afford
desired phosphoemeriamine (–)-15 as white crystals in 75%
yield. The overall yield of (–)-15 from (+)-7 was 32%. The
crystalline product exhibited a sharp melting point and was
spectroscopically pure. The presence of a molecular ion
[M+] relating to C6H18N2PO3 was confirmed by HRMS.
Surprisingly, however, elemental analysis revealed substan-
tial differences between the calculated values for
C6H18N2PO3Cl and those found.
To clear this discrepancy, we selected a suitable crystal
of (–)-15 for X-ray diffraction analysis and determined the
crystal and molecular structure of phosphoemeriamine.[21]
A three-dimensional view of a molecule of (–)-15 and the
atom numbering are shown in Figure 1.
The X-ray diffraction analysis revealed that the absolute
configuration at the β-carbon atom C(2) is (R) confirming
our configurational assignments for the starting material
and intermediate products. The trimethylammonium group
at C(3) was found to exist in the solid state in two confor-
Figure 1. Molecular view of the asymmetric unit of phosphoemeri-
amine (–)-15 (two conformations), showing the atom-numbering
scheme. The displacement ellipsoids are drawn at the 50% prob-
ability level and H atoms are depicted as spheres of arbitrary radii.
mations A (major) and B (minor), the disorder ratio is 9:1. moiety was clearly visible in the difference Fourier map by
The elements that show disorder are three methyl groups the presence of three residual peaks near N(1). The unit cell
that rotate around the C(3)–N(2) bond by 60 degrees. Pro- contains four phosphoemeriamine cations and six chloride
tonation of nitrogen atom N(1) by the phosphonic acid ions (Figure 2) from which two chloride ions (labelled as
Figure 2. Molecular packing of compound (–)-15 in the crystal lattice. Only the phosphonic acid fragments and chloride anions are
shown for clarity. The phosphonic groups from neighboring molecules are in close contact, marked by the pink dashed lines. Chloride
ion CL2 lies in a special position.
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Asymmetric Synthesis of Diverse Aminophosphonic Acids
amide (LiHMDS; 1.2 g, 7.5 mmol) in THF (10 mL) was added.
The reaction mixture was stirred at this temperature for 1 h. Then,
(+)-(S)-sulfinimine 1 (1.345 g, 5 mmol) in THF (25 mL) was added
dropwise and stirring was continued for 5 h at –78 °C. The reaction
was quenched with an aqueous solution of NH4Cl (10 mL), ex-
tracted with CH2Cl2 (3ϫ 10 mL) and, after separation, the organic
layer was dried with MgSO4 and the solvents evaporated. The
crude mixture of diastereoisomeric adducts 2 obtained in a 16:1
ratio (31P NMR assay) was purified with flash chromatography (sil-
ica gel, CH2Cl2/MeOH, 20:1). After crystallization from diethyl
CL2) additionally incorporated from the reaction medium
occupy a special position in the crystal lattice.
Most probably the chloride ions also stabilize the supra-
molecular structure formed by the strongly hydrogen-
bonded phosphonic acid residues of phosphoemeriamine. It
is interesting to point out that the macrocyclic ring con-
sisting of six molecules of 15 is a repeating unit in this struc-
ture (Figure 2). With regard to the elemental analysis prob-
lem, we learned from the X-ray diffraction data that in one
molecule of 15 prepared as above the ratio between the em- ether, a single diastereoisomer of 2 was obtained as a white crystal-
line solid (1.26 g, 62%). [α]D = +205.7 (c = 0.1, CHCl3), m.p. 104–
eriamine cation and the chloride anion is 1:1.5.
Finally we would like to point out that the (S)-enantio-
mer of phosphoemeriamine may be obtained in the same
way from adduct (+)-(RS,SC)-5.
1
105 °C. 31P NMR (CDCl3): δ = 20.8 ppm. H NMR (CDCl3): δ =
7.65–7.16 (m, 9 H, aromatic), 6.8 (dd, J = 15.8, J = 4.6 Hz, 1 H,
=CHPh), 6.25–6.30 (m, 1 H, CH=CHPh), 4.5 (t, J = 8.9 Hz, 1 H,
NHCH), 4.36 (dq, J = 4.3, J = 18.2 Hz, 1 H, CHNH), 4.20–4.00
(m, 4 H, CH2CH3), 2.42 (s, 3 H, CH3), 1.30 (t, J = 7.1 Hz, 6 H,
CH3CH2) ppm. 13C NMR (CDCl3): δ = 141.8, 141.3, 136.1, 135.9,
Conclusions
129.6, 128.6, 128.3, 126.8, 125.6, 121.9, 121.7, 63.3, 53.7 (d, JPC
=
156.2 Hz, PCH), 21.4, 16.4 ppm. MS (FAB): m/z = 408.3 [M + H].
C20H26NO4PS (407.46): calcd. C 58.99, H 6.38, P 7.62, N 3.44, S
7.86; found C 58.99, H 6.43, P 7.63, N 3.44, S 7.69.
In summary, we have demonstrated that chiral (S)-(p-tol-
ylsulfinyl)cinnamaldimine is a versatile reagent in the syn-
thesis of structurally diverse enantiopure APs. The easily
isolable diastereoisomerically pure α-amino and β-amino
adducts formed in a highly diastereoselective addition reac-
tion of PIII-nucleophiles and α-phosphonate carbanion to
this sulfinimine were converted into the corresponding
enantiopure unsaturated α-amino and β-aminophosphonic
acids. A new simple synthesis of enantiopure 2-amino-3-
phosphonopropanoic acid (9; phosphoaspartic acid) was
developed by using the β-amino adduct as a starting mate-
rial. However, based on the diastereoisomerically pure α-
amino adduct a stereoselective synthesis of the enantiopure
3-amino regioisomer of 9 has also been developed. The syn-
thetic utility of the β-amino adduct has been shown in the
first synthesis of (R)-phosphoemeriamine, which is an un-
known phosphonic analogue of emeriamine. The synthetic
approaches to known aminophosphonic acids compare
favourably in terms of the use of simple reagents and trans-
formations with the previously reported syntheses. Finally,
it should be pointed out that the diastereoisomerically pure
α-amino and β-amino adducts reported herein may be de-
veloped not only into chiral APs but also into diverse chiral
ligands containing, for example chiral phosphanes. Work in
this direction is in progress.
[(R)-1-Amino-3-phenylpropen-2-yl]phosphonic Acid (3): Aminophos-
phonate (+)-2 (0.27 g, 0.66 mmol) prepared as above was heated to
reflux with hydrochloric acid (36% aq. solution, 5 mL) for 5 h. Af-
ter cooling to room temperature the reaction mixture was extracted
with CHCl3 (3ϫ 5 mL). The aqueous layer was separated and the
solvents evaporated. The residue was dissolved in EtOH (5 mL)
and propylene oxide was added to pH ≈ 6. The precipitate was
filtered off, washed with EtOH and crystallized from H2O/EtOH
(1:1). The white crystals formed were washed with diethyl ether and
dried with P2O5 to give enantiomerically pure acid (+)-3 (0.1 g,
71%). [α]D = +5.6 (c = 1, 6 n HCl), m.p. 240–243 °C (decomp.).
1
31P NMR (D2O): δ = 12.98 ppm. H NMR (D2O): δ = 6.70–6.40
(m, 5 H, aromatic), 6.09 (dd, J = 15.95, J = 4.01 Hz, 1 H, =CHPh),
5.40 (dd, J = 15.95, J = 15.60, J = 8.90 Hz, 1 H, CH=CHPh), 3.45
(dd, J = 8.90, J = 16.30 Hz, 1 H, CHNH2) ppm. 13C NMR (D2O):
δ = 135.60, 133.09, 127.0, 126.9, 124.93, 115.4, 49.0 (d, JPC
=
149.5 Hz, PCH) ppm. C9H12NO3P (213.17): calcd. C 50.78, H 5.64,
N 6.57, P 14.54; found C 50.68, H 5.78, N 6.49, P 14.31.
(SSSC)-[3-Phenyl-1-(p-tolylsulfinylamino)propen-2-yl]-bis(diethyl-
amino)phosphane–Borane (4): Bis(diethylamino)chlorophosphane
(2.1 g, 10 mmol) in THF (10 mL) was cooled to 0 °C and borane–
methyl sulfide complex (5 mL) was added. The reaction mixture
was stirred at room temperature for 4 h and the solvent was re-
moved under vacuum affording bis(diethylamino)chlorophos-
phane–borane complex. It was dissolved in THF (10 mL) and
added slowly to lithium naphthalenide prepared from naphthalene
(2.56 g, 20 mmol) and cut lithium wire (0.14 g, 20 mmol) at –78 °C.
After stirring for 30 min, a solution of (+)-(S)-sulfinimine 1
(0.6187 g, 2.3 mmol) in THF (5 mL) was added dropwise and the
reaction mixture was stirred for 4 h at –78 °C. Then, after warming
the reaction mixture to room temperature and quenching with an
aqueous solution of NH4Cl, the organic layer was separated. The
aqueous phase was extracted with ethyl ether and the combined
organic layers were dried with MgSO4 and the solvents evaporated.
The crude product was purified by flash chromatography (silica gel,
CH2Cl2/MeOH, 4:0.1) to afford borane complex (+)-4 as a white
solid (0.76 g, 72%). [α]D = +67.7 (c = 1.22, CHCl3), m.p. 130–
132 °C. 31P NMR (CDCl3): δ = 90.74 (m) ppm. 1H NMR (CDCl3):
δ = 7.60–6.95 (m, 10 H, =CHPh, aromatic), 5.85–5.75 (m, 1 H,
Experimental Section
General: Thin layer chromatography (TLC) was conducted on Sil-
ica Gel 60 F254 TLC purchased from Merck. Column chromatog-
raphy was performed with Merck Silica Gel (70–230 mesh). NMR
spectroscopic data were recorded at 20 °C with a Bruker AV 200
1
and Bruker AV III 500 instruments: H data at 200 MHz, 31P data
at 81 MHz and 13C data at 125 MHz. Mass spectra including
HRMS were measured with a Finnigan MAT 95 spectrometer by
using the FAB technique. Optical rotation measurements were car-
ried out with a Perkin–Elmer MC 241 photopolarimeter at room
temperature (20–22 °C).
(SS,RC)-Diethyl [3-Phenyl-1-(p-tolylsulfinylamino)propen-2-yl]phos-
phonate (2): Diethyl phosphite (1.053 g, 7.6 mmol) in THF (10 mL) CH=CHPh), 4.90–4.70 (m, 2 H, CHNH), 3.40–3.10 (m, 4 H,
was cooled under nitrogen to –78 °C and lithium bis(trimethylsilyl)- CH2CH3), 3.10–2.84 (m, 4 H, CH2CH3), 2.02 (s, 3 H, CH3), 1.16
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O21589
/KAP1
Date: 04-03-13 11:16:22
Pages: 11
P. Ły z wa, J. Błaszczyk, L. Sieron´, M. Mikołajczyk
˙
FULL PAPER
(t, J = 7.0 Hz, 3 H, CH3CH2), 0.92 (t, J = 7.0 Hz, 3 H,
(RS,SC)-Diethyl [4-Phenyl-2-(p-tolylsulfinylamino)buten-3-yl]phos-
phonate (5): According to the procedure described above from di-
ethyl methanephosphonate (3.31 g, 21.8 mmol) dissolved in THF
(15 mL) and (–)-(R)-sulfinimine 1 (5.86 g, 21.8 mmol) in THF
(30 mL), title phosphonate (+)-5 was obtained (7.42 g, 81%). [α]D
= + 73.2 (c 1.27, CHCl3). C21H28NO4PS (421.49): calcd. C 59.84,
H 6.69, P 7.35, N 3.32, S 7.60; found C 59.79, H 6.38, P 7.89, N
3.45, S 7.36.
CH3CH2) ppm. 13C NMR (CDCl3): δ = 141.61, 140.51, 133.0,
132.8, 129.1, 128.2, 127.3, 126.2, 126.0, 125.7, 46.1 (d, JPC
65.13 Hz, PCH), 40.3, 20.9, 14.1, 13.5 ppm. HRMS: calcd. for
C24H40N3PSOB [M H] 460.4431; found 460.2727.
=
+
C24H39BN3OPS (459.44): calcd. C 62.74, H 8.55, N 9.15, S 6.98, P
6.74; found C 62.80, H 8.30, N 9.08, S 6.88, P 6.78.
[(S)-1-Amino-3-phenylpropen-2-yl]phosphonic Acid (3): Borane com-
plex (+)-4 (0.76 g, 1.65 mmol) was heated to reflux with hydrochlo-
ric acid (36%, 5 mL) for 5 h. Acid (–)-3 formed was isolated from
the reaction mixture according to the procedure described for the
(+)-(R)-enantiomer of acid 3 as white crystals (0.35 g, 75%). [α]D
= –5.6 (c = 1.18, 6N HCl), m.p. 240–243 °C. 31P NMR (D2O): δ =
12.94 ppm. C9H12NO3P (213.17): calcd. C 50.78, H 5.64, N 6.57,
P 14.54; found C 50.43, H 5.61, N 6.55, P 14.26.
[(S)-2-Amino-4-phenylbuten-3-yl]phosphonic Acid (6): Acid hydroly-
sis of phosphonate (+)-5 (0.45 g, 1.07 mmol) under elaborated stan-
dard conditions (36% aq. HCl, reflux, 5 h) afforded acid (–)-6 as
white crystals (0.158 g, 65%). [α]D = – 4.5 (c 0.98, 6N HCl), m.p.
218–228 °C. 31P NMR (D2O): δ = 17.98 ppm. HRMS: calcd. for
C10H15NPO3 [M + H] 228.0788; found 228.0789. C10H14NO3P
(227.20): calcd. C 52.90, H 6.21, N 6.17, P 13.57; found C 52.64,
H 6.28, N 6.19, P 13.49.
(SS,RC)-Diethyl [4-Phenyl-2-(p-tolylsulfinylamino)buten-3-yl]phos-
phonate (5): Diethyl methanephosphonate (2.43 g, 16 mmol) in
THF (10 mL) was cooled under nitrogen to –78 °C and LiHMDS
(16 mmol) in THF (10 mL) was added. The reaction mixture was
stirred for 1 h at this temperature. Then, a solution of (+)-(S)-sulf-
inimine 1 (4.3 g, 16 mmol) in THF (25 mL) was added dropwise
and the reaction mixture was stirred at –78 °C for 5 h. After this
time, the reaction was quenched with an aqueous solution of
NH4Cl (10 mL) and extracted with CH2Cl2 (3ϫ 10 mL). The or-
ganic layer was dried with MgSO4 and the solvents evaporated.
The crude product consisted of two diastereoisomers in a 9:1 ratio
[31P NMR assay, δP = 28.3 (major), δP = 27.5 ppm (minor)] and
was purified by flash chromatography (silica gel, CH2Cl2/MeOH,
20:1) and crystallized from ethyl ether affording a single dia-
stereoisomer of (–)-5 as white crystals (4.37g, 65%). [α]D = –72.9
(c = 0.93, CHCl3), m.p. 75–76 °C. 31P N: δ = MR (CDCl3); δ =
(SS,RC)-Diethyl [3-Hydroxy-2-(p-tolylsulfinylamino)propane]phos-
phonate (7): Methanol (25 mL) was cooled to –78 °C and a steam
of ozone was bubbled through until the blue colour of unreacted
ozone was noticeable. Then, a solution of aminophosphonate (–)-
5 (1.34 g, 3.18 mmol) in dry CH2Cl2 (10 mL) was added dropwise
(the reaction mixture remains blue) and stirring was continued for
15 min before dry oxygen was bubbled through the reaction mix-
ture to remove an excess of ozone. Then, NaBH4 (1.2 g, 31.6 mmol)
was added at –78 °C and the reaction mixture was stirred for 3 h
at this temperature and then for 2 h at room temperature. After
extraction with CHCl3 (3ϫ 15 mL), the organic layer was dried
with MgSO4 and the solvents evaporated. Column chromatography
(silica gel, CH2Cl2/MeOH, 20:1) and crystallization from diethyl
ether gave desired product (+)-7 as a white solid (0.89 g, 80%).
[α]D = +105.2 (c = 1.48, CHCl3), m.p. 85–87 °C. 31P NMR
28.3 ppm. 1H NMR (CDCl3): δ = 7.65–7.16 (m, 9 H, aromatic), (CDCl3): δ = 28.6 ppm. 1H NMR (CDCl3): δ = 7.60–7.20 (AB syst.,
6.4 (d, J = 15.8 Hz, 1 H, =CHPh), 6.10 (dd, J = 15.8, J = 6.5 Hz,
1 H, CH=CHPh), 5.6 (d, J = 6.9 Hz, 1 H, NHCH), 4.3 (dq, J =
4 H, aromatic), 4.95 (d, J = 9.25 Hz, 1 H, NHCH), 4.15 (q, J =
7.0 Hz, 2 H, CH2CH3), 4.05 (q, J = 7.0 Hz, 2 H, CH2CH3), 3.94–
6, J = 24 Hz, 1 H, CHNH), 4.1 (q, J = 7.3 Hz, 2 H, CH2CH3), 4.0 3.52 (m, 3 H, CHNH, CH2O), 2.37 (s, 3 H, CH3), 2.23 (dd, J =
(q, J = 7.3 Hz, 2 H, CH2CH3), 2.31 (s, 3 H, CH3), 2.44–2.13 (m, 2 6.20, J = 12.28 Hz, 2 H, CH2P), 1.33 (t, J = 7.0 Hz, 3 H, CH3CH2),
H, CH2P), 1.32 (t, J = 7 Hz, 3 H, CH3CH2), 1.22 (t, J = 7 Hz, 3 1.29 (t, J = 7.0 Hz, 3 H, CH3CH2) ppm. 13C NMR (CDCl2): δ =
H, CH3CH2) ppm. 13C NMR (CDCl3): δ = 141.1, 136.3, 130.9, 141.2, 129.35, 125.8, 65.4, 61.7, 53.0, 29.5 (d, JPC = 139.0 Hz,
129.6, 128.4, 127.6, 126.4, 126.0, 124.4, 61.8, 48.8, 33.3 (d, JPC
=
PCH2), 21.1, 16.4 ppm. MS (FAB): m/z = 350 [M + H].
137.7 Hz, PCH2), 21.2, 16.4 ppm. HRMS: calcd. for C21H29O4PSN C14H24NO5PS (349.38): calcd. C 48.13, H 6.92, N 4.03, S 9.18, P
[M + H] 422.1554; found 422.1555. C21H28NO4PS (421.49): calcd.
C 59.84, H 6.69, P 7.35, N 3.32, S 7.60; found C 59.79, H 6.53, P
7.66, N 3.14, S 8.34.
8.87; found C 48.11, H 6.98, N 4.00, S 9.18, P 9.10.
(R)-3-(Diethoxyphosphoryl)-2-(p-tolylsulfonylamino)propanoic Acid
(8): To a solution of (+)-7 (0.467 g, 1.33 mmol) in a mixture of
CCl4 and MeCN (1:1, 8 mL) was added water (8 mL), RuCl3 (3 mg)
and NaIO4 (2.29 g, 10.7 mmol). The heterogeneous mixture was
stirred for 4 h at room temperature. After this time, water (20 mL)
and CHCl3 (20 mL) were added. The organic layer was separated
and water layer extracted with CHCl3 (3ϫ 5 mL). The combined
organic fraction was dried with MgSO4 and the solvents evapo-
rated. The residue was washed with petroleum ether (3ϫ 5 mL) to
[(R)-2-Amino-4-phenylbuten-3-yl]phosphonic Acid (6): Phosphonate
(–)-5 (0.2 g, 0.47 mmol) was heated to reflux with hydrochloric acid
(36% aq., 5 mL) for 5 h. The reaction mixture was cooled to room
temperature and extracted with CHCl3 (3ϫ 5 mL). The aqueous
layer was separated and the solvents evaporated. The residue was
dissolved in EtOH (5 mL) and propylene oxide added to pH ≈ 6.
The precipitate was filtered off, washed with EtOH and crystallized
from H2O/EtOH (1:1). The white crystals formed were washed with give pure product (+)-8 as white crystals (0.405 g, 80%). [α]D
=
diethyl ether and dried with P2O5 to give pure acid (+)-6 as white
crystals (0.068 g, 63%). [α]D = +4.5 (c = 1, 6N HCl), m.p. 218–
+64.2 (c = 0.43, CHCl3), m.p. 125–126 °C. 31P NMR(CDCl3): δ =
1
26.7 ppm. H NMR (CDCl3): δ = 7.59–7.29 (AB, 4 H, aromatic),
228 °C (decomp.). 31P NMR (D2O): δ = 17.98 ppm. 1H NMR 5.93 (d, J = 5.9 Hz, 1 H, NHCH), 4.15 (q, J = 7.0 Hz, 2 H,
(D2O): δ = 7.26–6.11 (m, 5 H, aromatic), 6.58 (d, J = 15.89 Hz, 1
H, =CHPh), 5.99 (dd, J = 15.89, J = 8.6 Hz, 1 H, CH=CHPh),
CH2CH3), 4.05 (q, J = 7.0 Hz, 2 H, CH2CH3), 4.00–3.9 (m, 1 H,
CHNH), 2.50 (dd, J = 17.9, J = 5.4 Hz, 2 H, CH2P), 2.41 (s, 3 H,
4.20–3.95 (m, 1 H, CHNH2), 2.08 (dd, J = 19.05, J = 7.12 Hz, 2 CH3), 1.34 (t, J = 7.0 Hz, 3 H, CH3CH2), 1.30 (t, J = 7.0 Hz, 3 H,
H, CH2P) ppm. 13C NMR (D2O): δ = 135.8, 135.0, 128.79, 127.0, CH3CH2) ppm. 13C NMR (CDCl3): δ = 170.6 (C=O), 143.8, 135.9,
126.8, 123.0, 65.8, 49.7, 30.6 (d, JPC = 136.7 Hz, PCH2) ppm.
HRMS: calcd. for C10H15NPO3 [M + H] 228.0786; found 228.0789.
C10H14NO3P (227.20): calcd. C 52.90, H 6.21, N 6.17, P 13.57;
found C 52.64, H 6.24, N 6.08, P 14.35.
129.7, 127.3, 62.8, 50.9, 29.5 (d, JPC = 139.0 Hz, PCH2), 21.0,
16.2 ppm. HRMS: calcd. for C14H23NPSO7 [M + H] 380.0942;
found 380.0933. C14H21NO7PS (378.36): calcd. C 44.33, H 5.85, N
3.69, P 8.20, S 8.45; found C 44.33, H 5.94, N 3.75, P 8.35, S 8.55.
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21589
/KAP1
Date: 04-03-13 11:16:22
Pages: 11
Asymmetric Synthesis of Diverse Aminophosphonic Acids
(R)-2-Amino-3-phosphonopropanoic Acid (9): The acid (+)-8 (0.5 g, evaporated and the crude product was purified by column
1.32 mmol) prepared as above and phenol (0.37 g, 3.98 mmol) were
heated to reflux with hydrobromic acid (40%, 20 mL) for 14 h. Af-
ter cooling to room temperature, water (30 mL) was added and
reaction solution extracted with CHCl3 (15 mL). The aqueous layer
was separated and the solvents evaporated. The residue was dis-
solved in EtOH (10 mL) and propylene oxide was added to pH ≈ 6.
The precipitate was filtered off, washed with EtOH (5 mL) and
crystallized from H2O/EtOH (1:1). The white crystals formed were
washed with hexane and dried with P2O5 to give pure acid (+)-9
(0.14 g, 63%). [α]D = +8.1 (c = 0.93, H2O); ref.[17b] αD: +8.0 (c 0.5
chromatography (silica gel, CH2Cl2/MeOH, 20:1) giving corre-
sponding mesylate (+)-12 as a colourless oil (0.55 g, 90%). [α]D
=
+75.4 (c = 1.83, CHCl3). 31P NMR (CDCl3): δ = 26.7 ppm. 1H
NMR (CDCl3): δ = 7.62–7.28 (AB, 4 H, aromatic), 5.25 (d, J =
4.92 Hz, 1 H, NHCH), 4.19–4.07 (m, 6 H, CH2OMs, CH2CH3),
3.90–3.75 (m, 1 H, CHNH), 2.97 [s, 6 H, (CH3)2N] 2.40 (s, 3 H,
CH3), 2.30 (dd, J = 6.0, J = 12 Hz, 2 H, CH2P), 1.33 (t, J = 7.0 Hz,
3 H, CH3CH2), 1.30 (t, J = 7.0 Hz, 3 H, CH3CH2) ppm. 13C NMR
(CDCl3): δ = 141.6, 140.5, 129.5, 125.8, 71.6, 62.6, 47.9, 37.2, 29.3
(d, JPC = 137.8 Hz, PCH2), 21.2, 16.2 ppm. HRMS: calcd. for
, H2O), m.p. 225–226 °C; ref.[17f] 224–226 °C. 31P NMR (D2O): δ = C15H27NPS2O2 [M + H] 428.0962; found 428.0966. C15H26NO7PS2
18.1 ppm. 1H NMR (D2O): δ = 3.90–4.20 (m, 1 H, CHNH2), 2.00– (427.47): calcd. C 42.15, H 6.08, N 3.28, S 15.01, P 7.25; found C
2.40 (m, 2 H, CH2P) ppm.
42.13, H 6.11, N 3.12, S 14.44, P 6.61.
(SS,RC)-Diethyl [2-Hydroxy-1-(p-tolylsulfinylamino)propane]phos-
phonate (10): According to the procedure described for the synthe-
sis of (+)-7, phosphonate (+)-2 (0.24 g, 0.59 mmol) was subjected
to ozonolysis and then reduction with NaBH4 (0.217 g, 5.9 mmol).
The crude product was purified by column chromatography
(CH2Cl2/MeOH, 20:1) and crystallized from diethyl ether affording
diastereoisomerically pure hydroxyphosphonate (+)-10 as a white
(SS,RC)-Diethyl 3-Dimethylamino-2-[(p-tolylsulfinylamino)propane]-
phosphonate (13): To a solution of mesylate (+)-12 (1.49 g,
0.35 mmol) in THF (5 mL), Me2NH (2 m solution in THF, 9 mL)
was added and the reaction mixture was stirred overnight at 40 °C.
The solvent was evaporated and CH2Cl2 (10 mL) was added. After
washing with water (2ϫ 5 mL) the organic layer was separated.
The water fraction was extracted with CH2Cl2 (2ϫ 5 mL). The
combined organic layers were dried with MgSO4. After removal of
solid (0.195 g, 99%). [α]D = +3.2 (c = 0.1, CHCl3), m.p. 103–
1
107 °C. 31P NMR (CDCl3): δ = 21.5 ppm. H NMR (CDCl3): δ = the solvent and purification by column chromatography pure prod-
7.39–7.59 (AB, 4 H, aromatic), 5.2 (dd, J = 8.3, J = 10.3 Hz, 1 H,
OH), 4.75 (d, J = 8.2 Hz, 1 H, NHCH), 4.2–3.8 (m, 5 H, CHP,
CH2CH3), 3.6–3.2 (m, 2 H, CH2O), 2.34 (s, 3 H, CH3), 1.25–1.16
uct (+)-13 was obtained as a pale yellow oil (0.85 g, 65%). [α]D =
+122.0 (c = 2.15, CHCl3). 31P NMR (CDCl3): δ = 28.6 ppm. 1H
NMR (CDCl3): δ = 7.62–7.25 (AB, 4 H, aromatic), 5.25 (d, J =
(m, 6 H, CH3CH2) ppm. 13C NMR (CDCl3): δ = 141.6, 137.4, 5.9 Hz, 1 H, NHCH), 4.08 (q, J = 7.0 Hz, 2 H, CH2CH3), 4.06 (q,
129.4, 126.5, 62.5, 61.5, 53.2 (d, JPC = 150.3 Hz, PCH), 21.1, J = 7.0 Hz, 2 H, CH2CH3), 3.78–3.60 (m, 1 H, CHNH), 2.58–2.39
16.1 ppm. MS (FAB): m/z = 336.1 [M + H]. C13H22NO5PS
(335.35): calcd. C 46.56, H 6.61, P 9.24, N 4.1, S 9.56; found C
46.83, H 6.65, P 9.56, N 4.23, S 9.34.
(m, 2 H, CH2P), 2.37 (s, 3 H, CH3), 2.34–2.15 (m, 2 H, CH2P),
2.09 [s, 6 H, (CH3)2N], 1.32 (t, J = 7.0 Hz, 3 H, CH3CH2), 1.3 (t,
J = 7.0 Hz, 3 H, CH3CH2) ppm. 13C NMR (CDCl3): δ = 141.8,
141.15, 129.4, 125.75, 63.3, 61.7, 45.4, 45.1, 30.1 (d, JPC
=
(R)-3-Amino-3-phosphonopropanoic Acid (11): Triphenylphosphane
(0.2 g, 1.49 mmol) and isopropyl diazocarboxylate (0.3 mL,
1.49 mmol) in CH2Cl2 (5 mL) were stirred under nitrogen at 0 °C
for 30 min. Then, phosphonate (+)-10 (0.2 g, 0.597 mmol) was
added dropwise and stirring was continued for 30 min. After that,
KCN (0.2 g, 2.98 mmol) was added and the reaction mixture was
stirred under nitrogen at room temperature for 24 h. Addition of
water (10 mL) resulted in two layers that were separated. The aque-
ous layer was extracted with CHCl3 (3ϫ 5 mL) and the combined
organic layers were dried with MgSO4 and the solvents evaporated.
The crude cyanide formed (δp = 20.2 ppm) was used for the next
reaction step [heating to reflux with hydrochloric acid (36%,
10 mL) for 5 h]. After cooling to room temperature, the reaction
solution was extracted with CHCl3 (3ϫ 5 mL). The aqueous layer
was separated and the solvents evaporated. The residue formed was
dissolved in EtOH (10 mL) and propylene oxide was added to pH
≈ 6. The precipitate was filtered off, washed with EtOH, and crys-
tallized from H2O/EtOH (1:1). The crystals formed were washed
with diethyl ether and dried with P2O5 affording product (–)-11
(0.053 g, 53%). [α]D = –35.2 (c = 0.54, H2O); ref.[18a] [α]D = –32.6
138.1 Hz, PCH2 ), 21.25, 16.3 ppm. HRMS: calcd. for
C16H30N2PSO4 [M + H] 377.1667; found 377.1664. C16H29N2O4PS
(376.45): calcd. C 51.56, H 7.71, N 7.44, S 8.51, P 8.24; found C
50.82, H 7.76, N 7.28, S 8.77, P 8.32.
(SS,RC)-[3-(Dimethoxyphosphoryl)-2-(p-tolylsulfinylamino)propyl]-
trimethylammonium Iodide (14): To a solution of (+)-13 (0.297 g,
0.792 mmol) prepared as above in acetone (10 mL), methyl iodide
(0.12 g, 0.95 mmol) was added dropwise under nitrogen. The reac-
tion mixture was stirred at room temperature for 4 h. The acetone
was evaporated, water (10 mL) was added and extracted with
CH2Cl2 (3ϫ 2 mL). The aqueous extract was evaporated and the
oily residue was dissolved in CH2Cl2 (5 mL). The organic solution
was dried with MgSO4 and evaporated to afford the crude product
(light brown solid) that after column chromatography (CH2Cl2/
MeOH, 20:1) gave the desired iodide as a yellowish solid (0.22 g,
1
73%), m.p. 55–60 °C. 31P NMR (CDCl3): δ = 26.1 ppm. H NMR
(CDCl3): δ = 7.76–7.31 (AB, 4 H, aromatic), 4.48–4.36 (m, 1 H,
NHCH), 4.25–4.00 (m, 4 H, CH2CH3), 3.94–3.75 (m, 2 H, CH2),
3.08 [s, 9 H, (CH3)3N], 3.10–2.80 (m, 1 H, CHNH), 2.50–2.32 (m,
2 H, CH2P), 2.43 (s, 3 H, CH3), 1.37 (t, J = 7.0 Hz, 3 H, CH3CH2),
1.32 (t, J = 7.0 Hz, 3 H, CH3CH2) ppm. 13C NMR (CDCl3):δ =
142.6, 140.1, 130.1, 125.5, 67.9, 62.4, 54.8, 43.4 (d, JPC = 118.7 Hz,
PCH2), 21.3, 16.3 ppm. HRMS: calcd. for C17H32PSNO4 [M+]
391.1823; found 391.1820.
1
(c = 1.0, H2O). 31P NMR (D2O): δ = 8.4 ppm. H NMR (D2O): δ
= 4.1–3.90 (m, 1 H, CHP), 3.80–3.60 (m, 1 H, CH2COOH), 3.60–
3.40 (m, 1 H, CH2COOH) ppm.
(SS,RC)-Diethyl [3-Mesyloxy-2-(p-tolylsulfinylamino)propane]phos-
phonate (12): To a solution of phosphonate (+)-7 (0.5 g, 1.43 mmol)
and Et3N (0.288 g, 2.86 mmol) in THF (5 mL) cooled to 0 °C was
added dropwise mesyl chloride (0.245 g, 2.15 mmol) and the reac-
tion mixture was stirred at this temperature for 1 h. The reaction
progress was monitored by TLC (CH2Cl2/MeOH, 20:1). Then,
water (10 mL) was added and the mixture was extracted with
(R)-[2-Amino-3-(trimethylammonio)propane]phosphonic Acid Hy-
drochloride (15): Ammonium salt 14 (0.187 g, 0.48 mmol) was
heated to reflux with concd. hydrochloric acid (9 mL) and acetic
acid (3 mL) for 5 h. Then, water (10 mL) was added and extracted
with CH2Cl2 (4ϫ 10 mL). The aqueous layer was evaporated to
CH2Cl2 (3 ϫ 5 mL). The organic layer was dried with MgSO4, give the light yellow oil. It was dissolved in EtOH (5 mL) and neu-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O21589
/KAP1
Date: 04-03-13 11:16:22
Pages: 11
P. Ły z wa, J. Błaszczyk, L. Sieron´, M. Mikołajczyk
˙
FULL PAPER
[11]
For asymmetric synthesis of unsaturated aminophosphonates,
see: a) T. Akiyama, H. Morita, J. Itoh, K. Fuchibe, Org. Lett.
2005, 7, 2583–2585; b) K. C. Kumaraswamy, S. Kumaraswamy,
K. S. Kumar, C. Muthiah, Tetrahedron Lett. 2005, 46, 3347–
3351; c) S. Nakamura, H. Nakashima, A. Yamamura, N. Shib-
ata, T. Toru, Adv. Synth. Catal. 2008, 350, 1209–1212; d) T.
Akiyama, H. Morita, P. Bachu, K. Mori, M. Yamanaka, T.
Hirata, Tetrahedron 2009, 65, 4950–4956; e) P. S. Bhadury, Y.
Zhang, S. Zhang, B. Song, S. Yang, D. Hu, Z. Chen, W. Xue,
L. Jin, Chirality 2009, 21, 547–557; f) W. Xu, S. Zhang, S.
Yang, L.-H. Jin, P. S. Bhadury, D.-Y. Hu, Y. Zhang, Molecules
2010, 15, 5782–5796.
A. Armstrong, N. Deacon, C. Donald, Synlett 2011, 16, 2347–
2350.
J. L. Garcia Ruano, E. Torrente, I. Alonso, M. Rodriguez,
A. M. Martin-Castro, A. DeglЈInnocenti, L. Frateschi, A. Cap-
perucci, J. Org. Chem. 2012, 77, 1974–1982.
tralized with propylene oxide. The white solid formed was filtered
off, washed with EtOH (2ϫ 1 mL) and Et2O (3 mL) and dried with
P2O5 affording product (–)-15 as white crystals (0.07 g, 75%). [α]D
= –9.2 (c = 1.1, H2O), m.p. 237–239 °C. 31P NMR (D2O): δ =
16.24 ppm. 1H NMR (D2O): δ = 4.14–4.00 (m, 1 H, CHNH2),
3.90–3.66 (m, 2 H, CH2), 3.18 [s, 9 H, (CH3)3N], 2.11–1.97 (m, 2
H, CH2P) ppm. 13C NMR (D2O): δ = 66.4, 52.3, 41.9, 29.9 (d,
JPC = 129.8 Hz, PCH2) ppm. HRMS: calcd. for C6H18N2PO2 [M+]
197.1051; found 197.1055. C6H18Cl15N2O3P (250.37): calcd. C
28.81, H 7.26, N 11.21; found C 29.32, H 7.75, N 10.75.
Supporting Information (see footnote on the first page of this arti-
cle): All 31P, 1H and 13C NMR spectroscopic data, and MS or
HRMS data of synthesized compounds. X-ray crystal structure for
compound (–)-15.
[12]
[13]
[14]
[15]
See also: F. A. Davis, S. Lee, H. Yan, D. D. Titus, Org. Lett.
2001, 3, 1757–1760.
G. Barozzino Consiglio, P. Queval, A. Harrison-Marchand, A.
Mordini, J.-F. Lohier, O. Delacroix, A.-C. Gaumont, M. Ge-
rard, J. Maddaluno, H. Oulyadi, J. Am. Chem. Soc. 2011, 133,
6472–6480.
Acknowledgments
We gratefully acknowledge financial support form the Ministry of
Science and Higher Education of Poland (in part within the frame
of grant number PBZ-KBN-126/T09/2004).
[16]
D. D. Schoepp, B. G. Johnson, Neurochem. 1989, 53, 273–278.
[1] A. Mucha, P. Kafarski, Ł. Berlicki, J. Med. Chem. 2011, 54,
5955–5980.
[17] For previous syntheses of 3, see: a) J. M. Villanueva, N. Collig-
non, A. Guy, P. Savignac, Tetrahedron 1983, 39, 1299–1305; b)
E. C. R. Smith, L. A. McQuaid, J. W. Paschal, J. DeHoniesto,
J. Org. Chem. 1990, 55, 4472–4474; c) V. A. Soloshonok, Yu. N.
Belokon, N. A. Kuzmina, V. I. Maleev, N. Yu. Svistunova,
V. A. Solodenko, V. P. Kukhar, J. Chem. Soc. Perkin Trans. 1
1992, 1525–1529; d) S. B. Kim, J. S. Han, Y. J. Kim, S.-I. Hong,
J. Korean Chem. Soc. 1994, 38, 516–520; e) T. Yokomatsu, M.
Sato, S. Shibuya, Tetrahedron: Asymmetry 1996, 7, 2743–2754;
f) G. Reyes-Rangel, V. Maranon, C. G. Avila-Ortiz, C.
Anaya de Parrodi, L. Quintero, E. Juaristi, Tetrahedron 2006,
62, 8404–8409; g) O. I. Kolodyazhnyi, O. O. Kolodyazhnaya,
Russ. J. Gen. Chem. 2010, 80, 2519–2520.
[2] For an excellent monograph, see: Aminophosphonic and Amino-
phosphinic Acids: Chemistry and Biological Activity (Eds.: V. P.
Kukhar, H. R. Hudson), John Wiley & Sons, New York, 2000.
[3] For recent reviews, see: a) P. Kafarski, B. Lejczak, Curr. Med.
Chem.: Anticancer Agents 2001, 1, 301–312; b) F. Palacios, C.
Alonso, J. M. de los Santos, Curr. Org. Chem. 2004, 8, 1481–
1494; c) Ł. Berlicki, P. Kafarski, Curr. Org. Chem. 2005, 9,
1829–1850; d) F. Palacios, C. Alonso, J. M. de los Santos,
Chem. Rev. 2005, 105, 899–931; e) M. Mikołajczyk, J. Drabow-
icz, P. Łyzwa, in: Enantioselective Synthesis of β-Amino Acids
˙
(Eds.: E. Juaristi, V. A. Soloshonok), J. Wiley, London, 2005,
p. 261–276; f) V. D. Romanenko, V. P. Kukhar, Chem. Rev.
2006, 106, 3868–3935; g) J. A. Ma, Chem. Soc. Rev. 2006, 35,
630–636; h) I. P. Beletskaya, M. M. Kabachnik, Mendeleev
Commun. 2008, 18, 113–120; i) M. Ordonez, H. Rojas-Cabrera,
C. Cativiela, Tetrahedron 2009, 65, 17–49; j) F. Orsini, G. Sello,
M. Sisti, Curr. Med. Chem. 2010, 17, 264–289; k) Z. H. Kudzin,
M. H. Kudzin, J. Drabowicz, C. V. Stevens, Curr. Org. Chem.
2011, 15, 2015–2071; l) V. D. Romanenko, M. V. Shevchuk,
V. P. Kukhar, Curr. Org. Chem. 2011, 15, 2774–2801.
[18] a) A. Vasella, R. Voeffray, Helv. Chim. Acta 1982, 65, 1953–
1964; b) J. Kowalik, J. Zygmunt, P. Mastalerz, Phosphorus Sul-
fur Relat. Elem. 1983, 18, 393–396.
[19] a) S. Shinagawa, T. Kanamaru, S. Horada, M. Asai, H. Oka-
zaki, J. Med. Chem. 1987, 30, 1458–1463; b) R. Castagnani, F.
De Angelis, E. De Fusco, F. Giannessi, D. Misiti, D. Meloni,
M. O. Tinti, J. Org. Chem. 1995, 60, 8318–8319; c) R. C. An-
derson, M. Balestra, P. A. Bell, R. O. Deems, W. S. Fillers, J. E.
Foley, J. D. Fraser, W. R. Mann, M. Rudin, E. B. Villhauer, J.
Med. Chem. 1995, 38, 3448–3450; d) F. Giannessi, P. Chiodi,
M. Marzi, P. Minetti, P. Pessotto, F. De Angelis, E. Tassoni, R.
Conti, F. Giorgi, M. Mabilia, N. Dell’llomo, S. Muck, M. O.
Tinti, P. Carminati, A. Arduini, J. Med. Chem. 2001, 44, 2383–
2386; e) G. Calvisi, N. DellЈllomo, F. De Angelis, R. Dejas, F.
Giannessi, M. O. Tinti, Eur. J. Org. Chem. 2003, 4501–4506.
[20] For synthesis of the phosphocarnitine enantiomers, see: M. Mi-
kołajczyk, J. Łuczak, P. Kiełbasin´ski, J. Org. Chem. 2002, 67,
7872–7875.
[4] M. Mikołajczyk, P. Łyzwa, J. Drabowicz, M. W. Wieczorek, J.
˙
Błaszczyk, Chem. Commun. 1996, 1503–1504.
[5] M. Mikołajczyk, P. Łyzwa, J. Drabowicz, Tetrahedron: Asym-
˙
metry 1997, 8, 3991–3994.
[6] M. Mikołajczyk, P. Łyzwa, J. Drabowicz, Tetrahedron: Asym-
˙
metry 2002, 13, 2571–2576.
[7] M. Mikołajczyk, J. Organomet. Chem. 2005, 690, 2488–2496.
[8] P. Łyzwa, M. Mikołajczyk, Heteroat. Chem. 2011, 22, 594–598.
˙
[9] F. A. Davis, R. E. Reddy, J. M. Szewczyk, G. V. Reddy, P. S.
Portonovo, H. Zang, D. Fanelli, R. T. Reddy, R. Zhou, P. J.
Caroll, J. Org. Chem. 1997, 62, 2555–2563.
[21] CCDC-867834 contains the supplementary crystallographic
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.
[10] For reviews on asymmetric hydrophosphonylation, see: a) Ł.
Albrecht, A. Albrecht, H. Krawczyk, K. A. Jørgensen, Chem.
Eur. J. 2010, 16, 28–48; b) P. S. Bhadury, H. Li, Synlett 2012,
23, 1108–1131.
Received: November 26, 2012
Published Online: ᭿
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21589
/KAP1
Date: 04-03-13 11:16:22
Pages: 11
Asymmetric Synthesis of Diverse Aminophosphonic Acids
Asymmetric Synthesis
Starting from sulfinimine (+)-(S)-1, as a
single reagent, the synthesis of diverse
enantiopure aminophosphonic acids was
accomplished. In addition to the synthesis
of unsaturated α- and β-aminophosphonic
acids, the first synthesis of (–)-(R)-phos-
phoemeriamine and new approaches to
(+)-(R)-2-amino-3-phosphonopropanoic
acid (8) and its 3-amino regioisomer 11 are
reported.
P. Ł y z˙wa,* J. Błaszczyk, L. Sieron´,
M. Mikołajczyk* ............................ 1–11
Asymmetric Synthesis of Structurally Di-
verse Aminophosphonic Acids by Using
Enantiopure N-(p-Tolylsulfinyl)cinnamald-
imines as Reagents
Keywords: Synthetic methods / Asymmetric
synthesis / Diastereoselectivity / Amino-
phosphonic acids
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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11