1-(a-Aminobenzyl)-2-naphthol: A new chiral auxiliary for the synthesis of enantiopure a-aminophosphonic acids

Article abstract of DOI:10.1002/chem.200802540

A new diastereoselective synthesis of a-aminophosphonates has been developed, based on the reaction, in the presence of trifluoroacetic acid, of trialkyl phosphites with chiral imines derived from (R)- or (S)-l-(ot- aminobenzyl)-2-naphthol. The reaction p

Full text of DOI:10.1002/chem.200802540

DOI: 10.1002/chem.200802540
1-(a-Aminobenzyl)-2-naphthol: A New Chiral Auxiliary for the Synthesis of
Enantiopure a-Aminophosphonic Acids
Kirill E. Metlushka,[a, b] Boris A. Kashemirov,[b] Viktor F. Zheltukhin,[a]
Dilyara N. Sadkova,[a] Bernd Bꢀchner,[c] Christian Hess,[c] Olga N. Kataeva,[a, c]
Charles E. McKenna,[b] and Vladimir A. Alfonsov*[a]
Abstract:
A
new diastereoselective
with high diastereoselectivity. The
major diastereomer can be separated
by crystallization from an appropriate
solvent. The relative configuration of
both chiral centers of the major diaste-
reomer was determined by single-crys-
tal X-ray structure analysis. The de-
sired a-aminophosphonic acids can be
obtained in enantiopure form by treat-
ment of the corresponding diastereo-
mers with HCl.
synthesis of a-aminophosphonates has
been developed, based on the reaction,
in the presence of trifluoroacetic acid,
of trialkyl phosphites with chiral imines
derived from (R)- or (S)-1-(a-amino-
benzyl)-2-naphthol. The reaction pro-
ceeds at room temperature in toluene
Keywords: aminophosphonic acids ·
asymmetric synthesis · Betti bases ·
chiral auxiliaries · imines
Introduction
drophosphoryl compounds,[5] and various types of asymmet-
ric catalysts[6] have been employed to induce chiral prefer-
ence; however, there is a continuing need to find new, acces-
sible, cheaper, and more efficient approaches to the stereo-
selective synthesis of a-aminophosphonic acids.
Recently, we reported a new synthesis and the enantiose-
paration of benzylidenes obtained from 1-(a-aminobenzyl)-
2-naphthols (Betti bases).[7] In the present work, we demon-
strate the potential of these readily available Betti adducts
as chiral inductors for the synthesis of enantiopure a-amino-
phosphonates.
a-Aminophosphonic acids are analogues of amino acids in
which the carboxylic acid group is replaced by a phosphonic
acid group. A number of a-aminophosphonic acids exhibit
biological activities, including inhibitory activity against bac-
teria and fungi.[1] As a result, the synthesis of racemic a-ami-
nophosphonates has been extensively investigated.[2] The
bioactivity of such compounds is usually found to depend on
their absolute configuration, so considerable attention is
now being focused on the preparation of enantiopure a-ami-
nophosphonates.[3] Stereoselective hydrophosphonylation of
imines (the Pudovik reaction) offers an attractive route to
the synthesis of such compounds. Chiral imines,[4] chiral hy-
Results and Discussion
It is well known that addition of trivalent phosphorus acid
derivatives to polar unsaturated compounds containing a
C=O group proceeds under mild conditions to form a-sub-
stituted alkyl phosphonates. For example, a-hydroxyphosph-
onates can be easily obtained from trialkyl phosphites and
aldehydes in the presence of chlorotrimethylsilane and min-
eral acids.[8] However, relatively few reactions of trialkyl
phosphites with compounds containing a C=N group have
been documented. The addition of triethylphosphite to
Schiff bases in phenol[9] was the first example described, and
trialkyl phosphites were subsequently shown to condense
with imino acids[10] and a,b-unsaturated aldimines in the
presence of formic acid.[11] It was established[11] that the acid
plays crucial roles by activating the imine and also by deal-
[a] K. E. Metlushka, Dr. V. F. Zheltukhin, D. N. Sadkova,
Dr. O. N. Kataeva, Prof. Dr. V. A. Alfonsov
Kazan Scientific Center of the Russian Academy of Sciences
A. E. Arbuzov Institute of Organic and Physical Chemistry
Arbuzov str. 8, Kazan 420088 (Russia)
Fax : (+7)8432-75-5322
E-mail: alfonsov@iopc.knc.ru
[b] K. E. Metlushka, Dr. B. A. Kashemirov, Prof. Dr. C. E. McKenna
Department of Chemistry, University of Southern California
Los Angeles, CA 90089-0744 (USA)
[c] Prof. Dr. B. Bꢀchner, Dr. C. Hess, Dr. O. N. Kataeva
IFW Dresden, Institute for Solid State Research
P.O. Box 270116, 01171 Dresden (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802540.
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Chem. Eur. J. 2009, 15, 6718 – 6722

FULL PAPER
kylating the phosphonium inter-
mediates formed en route to
the final products.
Our attempts to use formic
or acetic acids to promote the
reaction of trialkyl phosphites
with the Betti base imine 1a
(prepared from b-naphthol and
Scheme 2. Cyclic/acyclic tautomers of 1,3-diaryl-2,3-dihydro-1H-naphth
member from each pair of enantiomers B and C is shown.
ACHUTNGTRENNUG[1,2-e]ACHTUNTGREN[NUGN 1,3]oxazines. * Only one
hydrobenzamide[7a]
; Scheme 1)
We investigated the influence
of TFA on the tautomeric equi-
librium of 1,3-di(p-methoxy-
phenyl)-2,3-dihydro-1H-naphth-
A
E
with
1H NMR spectroscopy by using
an equimolar ratio of the start-
ing reagents in CDCl3. A com-
parison of the proton NMR
spectra obtained in the absence
or presence of TFA revealed
the following effects due to the
acid: 1) the proton signals at
carbon atoms C1 and C3 of tau-
tomers B and C are greatly di-
Scheme 1. Reaction of Betti base imines 1a–1c with trialkyl phosphites in the presence of trifluoroacetic acid
(TFA).
revealed reactions that proceeded very sluggishly, albeit
with moderate stereoselectivity (Table 1). Surprisingly, when
TFA or trichloroacetic acid was substituted for these stan-
minished, and the resonances shift to lower field; 2) the C1
proton resonance of tautomer A is shifted to the aromatic
3
region; and 3) the proton signal (doublet, JHH =9.5 Hz) of
the HC=N group of tautomer A is shifted downfield.
The ratio of the tautomers was 87.4 (A):12.6 (B+C). In
the absence of TFA, this ratio was only 57:43. These data
suggest that the added TFA protonates the imine nitrogen
atom in A (that is, it activates the C=N group for nucleo-
philic attack) and diminishes the formation of the oxazine
tautomers B and C. These data are in accordance with the
literature.[14]
Reactions of trimethyl- or triethylphosphite with imines
1a–1c (Scheme 1) were carried out in dry toluene with vigo-
rous stirring at room temperature for 1 h. The ratio of re-
agents was imine/TFA/trialkyl phosphite=1:1.1:3, and the
reactions were monitored by 31P NMR spectroscopy. Un-
reacted trialkyl phosphite, the TFA alkyl ester byproduct,
and other volatiles were removed in vacuo, and the products
were purified by column chromatography on silica gel. Total
yields and diastereomeric excesses (de) of the products are
given in Table 2. It is obvious from the results that trifluoro-
acetic acid affords a rapid and complete reaction to give the
desired products in good yields and with good stereoselec-
tivities.
Table 1. Influence of various acids on the rate and stereoselectivity of 2a
formation.
[12]
Acid
pKa
Reaction time
24 h
1 h
initial imine: 94%
acetic
4.76
no reaction
products: 6%
de=48%
initial imine: 91%
products: 9%
de=43%
formic
3.75
0.65
traces of products
trichloroacetic
trifluoroacetic
p-toluenesulfonic
reaction complete,
de=80%
reaction complete,
de=80%
reaction complete,
de=62%
reaction complete,
de=55%
–
0.23
–
–
–
ꢀ4.12
ꢀ8
4m HCl in
1,4-dioxane
dard acids, the desired aminophosphonate products were ob-
tained in much higher yield and with substantially better ste-
reoselectivity (Table 1; Scheme 1). Other strong acids (HCl,
p-toluenesulfonic acid) also accelerated the condensation
with 1a, but with somewhat decreased diastereoselectivity.
The condensation products of 1-(a-aminobenzyl)-2-naph-
thol with benzaldehydes are systems of equilibrating tauto-
mers comprising acyclic imine structures with corresponding
naphthoxazines (Scheme 2).[13]
We studied the influence of different solvents on the ste-
reoselectivity of the reaction of imine 1a, TFA, and triethyl-
phosphite (molar ratio of 1a:TFA:triethylphosphite acid=
1:1.1:3) at room temperature (Table 3). The data show that
the diastereoselectivity is significantly decreased (from 80 to
33%) if the solvent is changed from toluene to acetonitrile.
A possible explanation for this result is participation of the
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V. A. Alfonsov et al.
Table 2. Diastereoselectivity of hydrophosphonylation of compounds 1a–
1c
with trimethylphosphite in the presence of TFA (Scheme 3).
As predicted, the stereoselectivity was significantly lower
(de=32%), which confirms that the OH group of the naph-
thol moiety plays a key role in the stereocontrol of the reac-
tion of 1a with trialkyl phosphites in the presence of TFA.
When (R)-(ꢀ)-1a was used, enantiopure (>98%) (R,R)-
(ꢀ)-2d was obtained after recrystallization of the diastereo-
merically enriched 2d product from toluene. A single crystal
derived from this preparation was studied by X-ray diffrac-
tion, which established the absolute configuration and re-
vealed four independent molecules in the asymmetric unit,
all of which have different ethoxy-group conformations (see
Figure 1 in the Supporting Information). This conformation-
al flexibility allows close packing in the crystal. (S,S)-(+)-
2d, (S,S)-(+)-6a, and (S,S)-(+)-6b were obtained similarly
from imine enantiomers (S)-(+)-1a, (S)-(+)-5a and (S)-
(+)-5b, respectively (Scheme 4).
dp [ppm]
Product
X
Yield[%]
de value[b] [%]
[a]
[a]
D1
D2
R=CH3
2a
2b
2c
H
OCH3
Br
74.5
76.7
81.7
24.55
25.79
23.74
25.88
27.09
24.98
83
81
79
R=C2H5
2d
2e
2 f
H
OCH3
Br
76.0[c]
86.2
90.3
22.19[d]
22.51
21.19
23.71[d]
24.03
22.56
80[d]
66
84
[a] D1: major diastereomer; D2: minor diastereomer. [b] Values of diaste-
reomeric excesses were measured before and after purification by
column chromatography. [c] Yield of isolated pure diastereomer D1 (see
the Experimental Section). [d] Chemical shifts and diastereomeric excess-
es were measured in the reaction mixture (see the Experimental Sec-
tion).
For comparison, (ꢁ)-2d obtained from racemic 1d was
recrystallized from both toluene and benzene. X-ray diffrac-
tion analysis of resultant single crystals showed isostructural
solvates in the unit cell, with a 2:1 solute/solvent ratio (see
Figure 2 in the Supporting Information).
Table 3. Influence of different solvents on reaction stereoselectivity.
Solvent
de[%]
toluene
benzene
carbon tetrachloride
chloroform
dichloromethane
1,4-dioxane
nitrobenzene
tetrahydrofuran
acetonitrile
80
79
77
77
56
44
41
35
33
To complete the new synthetic route, there remained the
task of converting the chiral phosphonate esters into the cor-
responding a-aminophosphonic acids with preservation of
the stereochemistry at the a-carbon atom. (R)-(+)-7a, (S)-
(ꢀ)-7a, (S)-(ꢀ)-7b, and (S)-(ꢀ)-7c were obtained from
(R,R)-(ꢀ)-2d, (S,S)-(+)-2d, (S,S)-(+)-6a, and (S,S)-(+)-6b
in 76–88% yield by treatment at 808C with concentrated
HCl in 1,4-dioxane (Scheme 4). The specific optical rota-
tions of the acid products were identical to the literature
values, and the enantiopurity was confirmed by NMR spec-
troscopy by using a-cyclodextrin as a chiral shift reagent.[16]
It should be noted that the configurations in the final prod-
ucts (R or S) are the same as
naphthol hydroxy group in a polar bond to the solvent,
which would disfavor intramolecular stabilization of one dia-
stereomer relative to the other. To test this surmise, the
OMe derivative of 1a was prepared[15] and allowed to react
those of the chiral inductors
used to produce them.
Conclusions
We have demonstrated
a
simple, inexpensive, and effi-
cient approach to enantiopure
Scheme 3. Reaction of the methylated derivative of 1,3-diphenyl-2,3-dihydro-1H-naphthACHTUNTRGENNUG[1,2-e]ACHTUNGTREN[NGUN 1,3]oxazine (3)
with trimethylphosphite and TFA.
a-aminophosphonic
acids,
based on the reaction of chiral
benzylidenes derived from 1-(a-
aminobenzyl)-2-naphthol (Betti
bases) with trialkyl phosphites
in the presence of TFA, isola-
tion of the major diastereo-
meric products by crystalliza-
tion from an appropriate sol-
vent, and hydrolysis with hydro-
chloric acid.
Scheme 4. a-Aminobenzylphosphonic acid synthesis.
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Chem. Eur. J. 2009, 15, 6718 – 6722

Stereoselective Synthesis of a-Aminophosphonates
FULL PAPER
de>98%; m.p. 125–1268C; ½aꢂ2D0 =+205 (c=1.0 in CHCl3); 1H NMR
Experimental Section
(400 MHz, CDCl3): d=1.03, 1.44 (2t, 3J
ACTHNUGTRNEUNG(H,H)=7 Hz, 6H; CH3CH2OP),
3.59–3.69 (m, 1H; CH3CH2OP), 3.84–3.94 (m, 1H; CH3CH2OP), 4.10 (d,
1
General: H NMR spectra were recorded on an AVANCE-400 spectrom-
2J
ACHTNUTRGNE(NUG P,H)=22.4 Hz, 1H; H C P), 4.19–4.29 (m, 2H; CH3CH2OP), 5.55 (s,
ꢀ ꢀ
eter with CDCl3 as the solvent and tetramethylsilane as the external ref-
erence. 31P NMR spectra were recorded on a CXP-100 spectrometer with
CDCl3 as the solvent and 85% H3PO4 as the external reference. The fol-
lowing abbreviations are used to indicate multiplicities: s: singlet; d: dou-
blet; t: triplet; m: multiplet. IR spectra were recorded on a Vector 22
spectrometer (from KBr pellets). Column chromatography was per-
formed on silica gel (silica gel L 100/400). EI mass spectra were obtained
by using a TRACE MS “Finnigan MAT” instrument operating at 70 eV
with an ion-source temperature of 2008C. Data processing was carried
out by using the “Xcalibur” program. Optical rotations were measured
on a Perkin–Elmer 341 polarimeter.
1H; Cnaphth C H), 7.18–7.77 ppm (m, 16H; Harom); 31P NMR (100 MHz,
ꢀ ꢀ
ꢀ
ꢀ
CDCl3): dP =22.2 ppm; IR: n˜ =1022, 1049 (C O P), 1241 (P=O),
3227 cmꢀ1 (NH); EIMS (70 eV): m/z (%): 475.2 (36) [M+], 338.2 (100)
[M+ {P(O)
(OEt)2}], 231.1 (100) [M+ {P(O)
N
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
elemental analysis: calcd (%) for C28H30NO4P: C 70.72, H 6.36, N 2.95, P
6.51; found: C 70.55, H 6.24, N 2.89, P 6.47.
ACHUTNGRENUN(G S,S)-O,O-Diethyl[1-{(2’-hydroxynaphth-1’-yl)}HCATUNGTREN(NGUN phenyl)methylamino]-1-
(4-tolyl)methylphosphonate ((S,S)-(+)-6a): This compound was obtained
by using the same procedure as that for 2d, from (S)-(+)-5a. Crystalliza-
tion method: the solvent was evaporated, the oily residue taken up in tol-
uene and cyclohexane (1:1; 1 mL), and the mixture was left to stand in
the cold for 1 week. The crystalline product was filtered off, washed with
a small amount of diethyl ether, and dried to give aminophosphonate
General synthesis of a-aminophosphonate dialkyl esters: Trimethyl- or
triethylphosphite (2.7 mmol) in absolute toluene (3 mL) was added to a
rapidly stirred suspension of compounds 1a–1c and 3 (0.9 mmol) in abso-
lute toluene (3 mL). Excess phosphite is required due to a minor side re-
action that forms the dialkyl ester. TFA (0.113 g, 0.99 mmol) in absolute
toluene (3 mL) was added dropwise to the resulting suspension over 2–
3 min to form a homogeneous solution. After the mixture had been
stirred at room temperature for 1 h, the solvent, TFA ester, and excess
trialkyl phosphite were removed in vacuo at or below 508C. The viscous
residue was analyzed by 31P NMR spectroscopy to determine the de
value and was then purified on silica gel with elution with benzene and
ethyl acetate (1:1 for 2b, 2:1 for 2a, 3:1 for 2c and 4, 4:1 for 2e, and 6:1
for 2 f).
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
7 Hz, 6H; CH3CH2OP), 2.44 (s, 3H; CH3), 3.59–3.69 (m, 1H;
CH3CH2OP), 3.85–3.95 (m, 1H; CH3CH2OP), 4.05 (d, 2J
ACHTNUTRGNE(NUG P,H)=22.2 Hz,
ꢀ ꢀ
ꢀ ꢀ
1H, H C P), 4.18–4.27 (m, 2H; CH3CH2OP), 5.56 (s, 1H; Cnaphth C H),
7.18–7.77 ppm (m, 15H,
H
arom); 31P NMR (100 MHz, CDCl3): dP =
ꢀ1
ꢀ
ꢀ
21.8 ppm; IR: n˜ =1021, 1051 (C O P), 1246 (P=O), 3233 cm (NH);
EIMS (70 eV): m/z (%): 489.2 (2) [M+], 352.3 (10) [M+ꢀ{P(O)
ACHTUNGTRENNUNG(OEt)2}],
231.2 (52) [M+ꢀ{P(O)
(OEt)2}ꢀ{p-CH3 C6H4 CH2 NH2}]; elemental
ꢀ ꢀ ꢀ
G
analysis: calcd (%) for C29H32NO4P: C 71.15, H 6.59, N 2.86, P 6.33;
found: C 71.11, H 6.44, N 2.84, P 6.32.
O,O-Diethyl-[1-{(2’-hydroxynaphth-1’-yl)}ACTHNUTRGNEU(GN phenyl)methylamino]-1-(phe-
ACHUTNGRENUN(G S,S)-O,O-Diethyl[1-{(2’-hydroxynaphth-1’-yl)}HCATUNGTREN(NGUN phenyl)methylamino]-1-
nyl)methylphosphonate (2d): Triethylphosphite (4.482 g, 27 mmol) in ab-
solute toluene (9 mL) was added to a vigorously stirred suspension of 1a
(3.033 g, 9 mmol) in absolute toluene (15 mL). Within 3 min, TFA
(1.129 g, 9.9 mmol) in absolute toluene (9 mL) was added dropwise to
produce a homogeneous solution, which was stirred at room temperature
for 1 h. After partial evaporation to a volume of 10 mL, the mixture was
kept cold for 1 week. The resulting crystals were filtered off, washed with
a small amount of diethyl ether, and dried in vacuo to give aminophosph-
(4-bromophenyl)methylphosphonate ((S,S)-(+)-6b): This compound was
obtained by using the same procedure as that for 2d, from (S)-(+)-5b.
Crystallization method: the solvent was evaporated, the residue was dis-
solved in benzene and cyclohexane (1:1; 1 mL), and the mixture was left
to stand in the cold for 1 week. The resulting crystals were filtered off,
washed with a small amount of diethyl ether, and dried to give amino-
phosphonate (S,S)-(+)-6b (0.95 g, 57%); de>98%; m.p. 162–1638C;
½aꢂ2D0 =+142 (c=1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.07,
1
onate 2d (3.25 g, 76%); de>98%; m.p. 140–1428C; H NMR (400 MHz,
1.44 (2t, 3J
ACTHNUGTRNE(NUG H,H)=7 Hz, 6H; CH3CH2OP), 3.67–3.77 (m, 1H;
CDCl3): d=1.03, 1.46 (2t, 3J
ACHTNUTRGNE(UNG H,H)=6.9 Hz, 6H; CH3CH2OP), 3.59–3.69
CH3CH2OP), 3.89–3.98 (m, 1H; CH3CH2OP), 4.07 (d, 2J
ACHTNUTRGNE(NUG P,H)=22.4 Hz,
(m, 1H; CH3CH2OP), 3.85–3.95 (m, 1H; CH3CH2OP), 4.12 (d, 2J
ACTHNUTRGNE(NUG P,H)=
ꢀ ꢀ
ꢀ ꢀ
1H; H C P), 4.20–4.28 (m, 2H; CH3CH2OP), 5.51 (s, 1H; Cnaphth C H),
ꢀ ꢀ
22.6 Hz, 1H; H C P), 4.20–4.32 (m, 2H; CH3CH2OP), 5.56 (s, 1H;
arom); 31P NMR (100 MHz, CDCl3): dP =
Cnaphth C H), 7.21–7.78 ppm (m, 16H;
H
arom); 31P NMR (100 MHz,
7.22–7.78 ppm (m, 15H;
H
ꢀ ꢀ
ꢀ1
ꢀ
ꢀ
21.37 ppm; IR: n˜ =1023, 1058 (C O P), 1229 (P=O), 3224 cm (NH);
ꢀ
ꢀ
CDCl3): dP =22.25 ppm; IR: n˜ =1019, 1047 (C O P), 1237 (P=O),
EIMS (70 eV): m/z (%): 554.2 (8) [M+], 417.2 (20) [M+ꢀ{P(O)
ACHTUNGTRENNUNG(OEt)2}],
3226 cmꢀ1 (NH); EIMS (70 eV): m/z (%): 475.2 (100) [M+], 338.2 (100)
231.2 (100) [M+ꢀ{P(O)
(OEt)2}ꢀ{p-Br C6H4 CH2 NH2}]; elemental
ꢀ ꢀ ꢀ
G
[M+ꢀ{P(O)
(OEt)2}], 231.1 (100) [M+ꢀ{P(O)
(OEt)2}ꢀ{Ph CH2 NH2}];
ꢀ ꢀ
U
analysis: calcd (%) for C28H29BrNO4P: C 60.66, H 5.27, Br 14.41, N 2.53,
P 5.59; found: C 60.54, H 5.34, Br 14.30, N 2.48, P 5.52.
elemental analysis: calcd (%) for C28H30NO4P: C 70.72, H 6.36, N 2.95, P
6.51; found: C 70.94, H 6.27, N 2.89, P 6.37.
General procedure for the synthesis of a-aminophosphonic acids: 12n
HCl (1.2 g) was added to a solution of phosphonate ester ((R,R)-(ꢀ)-2d,
(S,S)-(+)-2d, (S,S)-(+)-6a, or (S,S)-(+)-6b; 0.63 mmol) in 1,4-dioxane
(3 mL). The reaction mixture was kept at 808C for 7 h, then 12n HCl
(1.2 g) was again added and the reaction mixture was maintained at 808C
for 7 h. After evaporation of the volatile compounds, the solid residue
was washed with ethyl acetate heated to reflux (2ꢂ5 mL) to leave a
brownish solid, which was filtered off. The ethyl acetate layer was ex-
tracted with distilled water (3ꢂ5 mL). The solid was dissolved in the
combined aqueous phases, and the resulting mixture was heated to reflux
with charcoal to give a colorless solution, which, after evaporation of the
solvent, gave the a-aminophosphonic acid product as a crystalline solid
(dried in vacuo). The optical purity of the enantiomeric products was es-
tablished through comparison of the experimental specific optical rota-
tions with those reported in the literature (see the Supporting Informa-
tion) and also by 31P NMR spectroscopy with a-cyclodextrin as a chiral
discriminating agent, according to the procedure of Kafarski and co-
workers.[16]
ACHTUNGTRENNUNG(R,R)-O,O-Diethyl[1-{(2’-hydroxynaphth-1’-yl)}HCATUNGTREN(NGUN phenyl)methylamino]-1-
(phenyl)methylphosphonate ((R,R)-(ꢀ)-2d): This compound was ob-
tained by using the same procedure as that for 2d, from (R)-(ꢀ)-1a. The
scale was decreased 3 times, and the reaction mixture was partially
evaporated to 1.5 mL before crystallization. The resulting crystals were
filtered off, washed with a small amount of diethyl ether, and dried in
vacuo to give aminophosphonate (R,R)-(ꢀ)-2d (0.74 g, 52%); de>98%;
m.p. 125–1268C; ½aꢂ2D0 =ꢀ208 (c=1.0 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=1.03, 1.44 (2t, 3J
ACHTNUGTRENUNG(H,H)=7 Hz, 6H; CH3CH2OP), 3.59–3.68
(m, 1H; CH3CH2OP), 3.85–3.94 (m, 1H; CH3CH2OP), 4.10 (d, 2J
ACTHNUTRGNE(NUG P,H)=
ꢀ ꢀ
22.4 Hz, 1H; H C P), 4.20–4.29 (m, 2H; CH3CH2OP), 5.55 (s, 1H;
H
arom); 31P NMR (100 MHz,
ꢀ ꢀ
Cnaphth C H), 7.21–7.77 ppm (m, 16H;
ꢀ
ꢀ
CDCl3): dP =22.2 ppm; IR: n˜ =1021, 1049 (C O P), 1241 (P=O),
3226 cmꢀ1 (NH); EIMS (70 eV): m/z (%): 475.2 (38) [M+], 338.2 (100)
[M+ꢀ{P(O)
(OEt)2}], 231.1 (100) [M+ꢀ{P(O)
(OEt)2}ꢀ{Ph CH2 NH2}];
ꢀ ꢀ
U
elemental analysis: calcd (%) for C28H30NO4P: C 70.72, H 6.36, N 2.95, P
6.51; found: C 70.59, H 6.34, N 2.94, P 6.52.
ACHTUNGTRENNUNG(S,S)-O,O-Diethyl[1-{(2’-hydroxynaphth-1’-yl)}HCATUNGTREN(NGUN phenyl)methylamino]-1-
Complete experimental procedures for the preparation of enantiopure
(R)-(ꢀ)-1a, (S)-(+)-1a, (S)-(+)-5a, and (S)-(+)-5b, synthetic methods
and physical data for compounds 2a, 2b, 2c, 2e, 2 f, 4, (R)-(+)-7a, (S)-
(ꢀ)-7a, (S)-(ꢀ)-7b, and (S)-(ꢀ)-7c, 1H NMR spectra for (R,R)-(ꢀ)-2d,
(phenyl)methylphosphonate ((S,S)-(+)-2d): This compound was obtained
by using the same procedure as that for 2d, from (S)-(+)-1a. The crystal-
line product was filtered off, washed with a small amount of diethyl
ether, and dried to give aminophosphonate (S,S)-(+)-2d (0.68 g, 48%);
Chem. Eur. J. 2009, 15, 6718 – 6722
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www.chemeurj.org
6721

V. A. Alfonsov et al.
(S,S)-(+)-2d, (S,S)-(+)-6a, and (S,S)-(+)-6b, 31P NMR spectra from the
experiments with a-cyclodextrin, specific optical rotation analysis data,
and crystallographic data for single crystals of 2d are presented in the
Supporting Information.
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Acknowledgements
This work was supported by the Civilian Research and Development
Foundation (grant no. RUC2-2638-KA-05) and the Russian Foundation
for Basic Research (grant no. 07-03-00617). The authors are grateful to
Dr. R. Z. Musin for mass spectrometry measurements and to Dr. S. K.
Latypov and S. V. Ktomas for carrying out the NMR experiments.
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Received: December 4, 2008
Published online: May 28, 2009
6722
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Chem. Eur. J. 2009, 15, 6718 – 6722