Organic catalysis of phospha-aldol condensation

Article abstract of DOI:10.1134/S1070363208110091

Phospha-aldol reaction of dialkylphosphites with carbonyl compounds is catalyzed by cinchonine alkaloids and thier modified derivatives to give optically active hydroxyphosphonates. The use of diastereomeric pairs of alkaloids allowed obtaining both optic

Full text of DOI:10.1134/S1070363208110091

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 11, pp. 2043–2051. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © A.O. Kolodyazhnaya, V.P. Kukhar, O.I. Kolodyazhnyi, 2008, published in Zhurnal Obshchei Khimii, 2008, Vol. 78, No. 11,
pp. 1808–1817.
Organic Catalysis of Phospha-Aldol Condensation
A. O. Kolodyazhnaya, V. P. Kukhar, and O. I. Kolodyazhnyi
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02094 Ukraine
e-mail:oikol123@rambler.ru
Received February 18, 2008
Abstract—Phospha-aldol reaction of dialkylphosphites with carbonyl compounds is catalyzed by cinchonine
alkaloids and thier modified derivatives to give optically active hydroxyphosphonates. The use of
diastereomeric pairs of alkaloids allowed obtaining both optical antipodes of hydroxyphosphonates. Cinchonine
alkaloids show the highest enantioselectivity as organic catalysts. It was found that ordinary crystallization of
some enantiomerically enriched hydroxyphosphonates leads to isolation of the enantiomerically pure
stereoisomers. Hydroxyphosphonic acids were obtained by hydrolysis of phosphonates. Fluoroalkylphos-
phonates were obtained by reaction with diethylaminotrifluorosulfurane (DAST).
DOI: 10.1134/S1070363208110091
In the recent years the asymmetric catalysis of
organic reactions with chiral natural compounds free
of metal atoms, known as organic catalysts, was
rapidly developing [1–3]. Organic catalysts like metal
complex catalysts are low molecular weight
compounds. At the same time they resemble enzymes
being substances modeling action of the latter.
Asymmetric organic catalysis offers doubtless advan-
tages over the metal complex catalysis since organic
catalysts are generally stable in the presence of the air
oxygen and moisture in contrast to metal complexes.
They are also cheaper and more available. Alkaloids
[3], amino acids [5], and other natural compounds [4–
10] are used as asymmetric organic catalysts. The most
effective organic catalysts were obtained on the base of
quinine [10] and L-proline derivatives [4, 8] that were
successfully used as catalysts of aldol reaction [6, 8],
Michael [7] and Henry [9] reactions, etc.
In this work we investigated catalytic action of
some cinchonine alkaloids and also already reported
by us [11] application of L-proline derivatives in the
phospha-aldol reaction (Abramov reaction).
H
H
H
H
OH
OH
HO
HO
N
N
N
N
O
O
N
N
N
N
QN
QND
CN
CND
Cinchonine alkaloids such as quinine (QN),
quinidine (QND), cinchonine (CN) and cinchonidine
(CND) catalyze addition reaction of dialkylphosphites
with aromatic aldehydes. This reaction was carried out
in toluene or in the absence of solvent, in the presence
of 20 mol% of alkaloid. The reaction progress was
monitored by TLC and 31Р NMR spectroscopy. The
ratio of diastereomers was determined using 31Р NMR
by measuring the integral intensity of the signals of
different diastereomers. Reaction proceeds slowly,
however with high yields of chiral hydroxyphos-
phonates, (S)- or (R)-(I). It is best to use the
2043

2044
KOLODYAZHNAYA et al.
concentrated (~30–50%) solutions of initial substances
in toluene since in the more dilute solutions reaction
proceeds very slowly or does not proceeds at all. From
1 to 3 days are needed for the reaction completing at 20°С.
OH
X
RO
P
H
H
RO
X
a
O
(S)-Ia_Id
O
(RO)2P(O)H +
OH
X
b
RO
RO
P
H
O
(R)-Ia_Id
R = (1R,2S,5R)-Mwnthyl-(1R,2S,5R)-Mnt; X = 2-NO2 (a); R = (1R,2S,5R)-Mnt; X = 2-MeO (b); R = Me, X = 2-MeO (c), R = Me,
X = 2-NO2 (d); a = QN, CN, b = QND, CND.
Asymmetric induction in the reaction of chiral
dimenthylphosphite with achiral aldehydes was much
higher at the catalysis with such chiral bases as
quinine, quinidine, cinchonine and cinchonidine, in
comparison with the reaction catalyzed by achiral
amines (triethylamine or DBU). Thus, the reaction of
dimenthylphosphite with 2-nitrobenzaldehyde in the
presence of cinchonidine gives rise to hydroxylphos-
phonate (R)-Ia with diastereomeric enrichment of
75%, whereas in the case of catalysis with DBU the
same hydroxyphosphonate was obtained only with
40% de. Unlike reaction catalyzed with quinine,
reaction of dimenthylphosphate with 2-nitrobenzal-
dehyde in the presence of DBU proceeded fast and
with self-heating, therefore the reaction mixture should
be cooled. Stereoselectivity of reaction catalyzed with
quinine and cinchonine was significantly higher than
in the case of reaction catalyzed with quinidine and
cinchonidine. This fact is due to the the effect of
double concerted versus non-concerted asymmetric
induction [12]. Stereochemical direction of reaction
changed depending on the nature and stereoselectivity
of the chiral catalyst. For example, according to the
NMR data reaction of dimenthylphosphite with 2-
nitrobenzaldehyde or 2-anisaldehyde in the presence of
quinine yielded predominantly (S)-hydroxyphos-
phonate, while in the presence of quinidine (R)-hyd-
roxyphosphonate formed. Analogously, reaction with
cinchonine produced (S)-hydroxyphosphonate, and
with cinchonidine, (R)-hydroxyphosphonate.
pure (S)- or (R)-hydroxyphosphonates with good
yields. Stereochemical purity of these compounds was
1
13
monitored by H and C NMR spectroscopy and also
by 31P NMR spectra in some chiral solvating media.
Noteworthy the extremely high optical rotation angles
of hydroxyphosphonate with ortho-nitrophenyl group
Ia ([α]D = 300–400 deg) not observed in any known
hydroxyphosphonate [13].
Achiral dimethylphosphite reacted with aromatic
aldehydes in the presence of chiral catalysts with low
stereoselectivity which did not exceed 30% ee. Reac-
tion in the presence of cinchonine or quinine gave
excess of (R)-hydroxyphosphonate as well as in case of
dimenthylphosphite, whereas reaction catalyzed with
cinchonidine or quinidine led to formation of a product
enriched by (S)-hydroxyphosphonate. It was estab-
lished that crystallization of the enantiomerically
enriched hydroxyphosphonates from appropriate sol-
vents resulted in their separation, allowing isolation of
enantiomerically pure compounds. For example, a
single crystallization of dimethylhydroxy-(2-nitro-
phenyl)methylphosphonate (ratio of enantiomers 6:4)
from diethyl ether gave optically pure product. We
also succeeded in purifying hydroxyphosphonate Ib by
the usual crystallization. Enantiomeric composition of
hydroxyphosphonates was determined by derivatiza-
tion with dimenthylchlorophosphite or using chiral
solvating reagents, in the presence of which signals
31
separation of various enantiomers occurred in the P
NMR spectra.
Crystallization of the mixture of dimenthylhyd-
roxyphosphonates diastereomers Ia, Ib gives optically
The crystallization of dimethylhydroxy-(2-nitro-
phenyl)methylphosphonate from two-phase solvent
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 11 2008

ORGANIC CATALYSIS OF PHOSPHA-ALDOL CONDENSATION
2045
system ethyl acetate–hexane led to formation of the
regularly shaped prismatic crystals. The two-phase
solvent system was prepared in such a manner that
phosphonate was dissolved in the bottom layer of ethyl
acetate and the top layer constited of pure hexane.
Crystallization of pure dimethyl (S)-hydroxy-(2-
nitrophenyl)methylphosphonate gave asymmetric left-
centered rhombic crystals under these conditions, and
crystallization of dimethyl (R)-hydroxy-(2-nitrophe-
nyl)methylphosphonate gave asymmetric right-centered
rhombic crystals.
The crystallization of enantiomerically enriched
phosphonate from the above solvent system gave both
left- and right-centered asymmetric rhombuses. In the
1H and 13C NMR spectra of some enantiomerically
enriched hydroxyphosphonates, specifically of
compound Ia, an interesting effect was revealed. In the
NMR spectra of these compounds signals of РСН–,
methoxy groups, and aromatic protons were doubled,
with integral intensity of these signals corresponding
to the ratio of enantiomers (Fig. 1).
6.4
(c)
3.80
(b)
(a)
6.4
6.3
6.2
3.9
3.8
3.7
3.6
Fig. 1. The 1Н NMR spectra of dimethylhydroxy-(2-nitrophenyl)methylphosphonate (Ia) at the different ratios of enantiomers R/S:
(a) ~ 0:100, (b) 1:3, and (c) 4:6.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 11 2008

2046
KOLODYAZHNAYA et al.
nate were found a sharply defined doublet of PCH-
proton and two doublets of diastereotropic signals of
CH3O-groups, which in the enantiomerically enriched
mixtures were doubled forming a double doublet
(РСН) and two double doublets (CH3O) respectively.
Similarly, signals of methoxy groups, the α-carbon
atom and carbon atoms of aromatic rings were split in
13
keeping with the ratio of enantiomers in the C NMR
spectra of the corresponding enantiomerically enriched
hydroxyphosphonates. The observed effect can be
explained by autosolvation and autoassociation of
chiral hydroxyphosphonate, therefore the latter acted
as a chiral solvating reagent causing resolution of
1
signals in the NMR spectra. Respectively, in both H
and 31P NMR spectra of racemic hydroxyphosphonates
resolution of enantiomeric signals occurred in the
presence of others chiral solvating reagents, for
example, quinine [14] (Fig. 2).
(c)
(b)
X-ray diffraction analysis showed clear alternation
of (S)- and (R)-stereoisomers in the crystal lattice of
racemic hydroxyphosphonate with ortho-nitrobenzene
rings located above the phosphorus atom. These rings
are capable of inducing strong deshielding effect, if, as
might be assumed, similar arrangement of molecules is
retained to some extent in solution (Fig. 3).
(a)
18
16
Fig. 2. The 31Р spectra of dimethylhydroxy-(2-nitrophenyl)-
methylphosphonate (Ia) in the presence of cinchonidine as
a chiral solvating reagent at different ratios of R/S-
enantiomers: (a) 4:6, (b) 9:1, and (c) ~100:0.
Absolute configuration of compounds was con-
firmed using the classical approach developed by
1
31
In the case of the enantiomerically pure compounds
and racemates (ratio of enantiomers 50:50) this effect
was not observed and also signals were not separated.
This effect also was not observed and signals were not
separated when the excess of one of enantiomers was
Mosher and based on the analysis of H and P NMR
spectra of diastereomeric derivatives obtained by
derivatization of phosphonates at OH group with (S)-
methylamygdalic acid chloride [15, 16]. The various
orientation of the mandelates phenyl ring leads to
selective shielding or deshielding of P(O)(OR)2-
groups, as a result of which in the O-acylated
1
less than 10%. Thus, in H NMR spectrum of the
enantiomerically pure dimethylhydroxyarylphospho-
O3
С6
С9
С5
С4
0
c
а
O6
P1
С7
С1
С3
O5
С2
O1
O4
b
N1
O2
С8
Fig. 3. X-ray diffraction analysis of dimethylhydroxy-(2-nitrophenyl)methylphosphonate (Ia).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 11 2008

ORGANIC CATALYSIS OF PHOSPHA-ALDOL CONDENSATION
2047
compounds the signals of (S)-diastereomers appear
downfield from the signals of (R)-diastereomers.
Hillman reaction [20, 21]. We obtained a new
representative of oxazatwistanes III.
Modification of quinine with benzylation at the
hydroxy group by known method [17–19] gave a more
effective organic catalyst II providing the higher
reaction stereoselectivity.
Reaction
of
dimethylphosphite
with
2-
nitrobenzaldehyde in the presence of oxazatwistane III
afforded the enantiomerically enriched hydroxy-
phosphonate with higher content of (S)-enantiomer
(>50% ee), which was isolated in pure form after
recrystallization from ether.
H
HO
N
N
O
H
OH
O
H3PO4
KBr
N
N
H
N
N
BnO
N
III
BnBr
O
Esters of substituted hydroxybenzylphosphonic
acids were hydrolyzed with hydrochloric acid in water-
dioxane solution to form the corresponding hydroxy-
phosphonic acids IV. Note a very high value of optical
rotation angle of 2-nitrophenyl(hydroxy)methylphos-
phonic acid ([α]D20 = 500 deg).
N
II
Oxazatwistane III was found to be the most
effective organic catalyst as compared with parent
cinchonidine. It was obtained by the intramolecular
cyclization of cinchonidine in the presence of phos-
phoric acid and potassium bromide. Some
representatives of oxazatwistanes were described
earlier and used as organic catalysts of the Baylis–
Hydroxyphosphonates readily reacted with diethyl-
aminotrifluorosulfurane (DAST) at room temperature
affording fluorophosphonates V with high yields and
stereospecificity. Fluorophosphonates were purified by
crystallization from hexane.
OH
X
OH
F
X
X
RO
RO
RO
Et2NSF3
H2O
H2O3P
P
P
H
H
H
RO
HCl
O
O
(S)-IVa, IVb
(S)-Ia, Ib
(R)-Va, Vb
OH
OH
X
X
RO
H2O
HCl
P
H2O3P
H
H
RO
O
(R)-Ia, Ib
(R)-IVa, IVb
R = Mnt, X = OMe (а); R = Mnt, X = H (b).
Addition of glyceraldehyde acetonide to dimethyl-
and dimenthylphosphite in the presence of cinchonine
alkaloids proceeded slowly, apparently because of
poor basicity of alkaloids. As a result glyceraldehyde
had an opportunity to polymerize substantially with
formation of the difficultly separated mixture of
compounds containing a product of addition with low
yield. Therefore the more basic L-prolinole was used
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 11 2008

2048
KOLODYAZHNAYA et al.
as catalyst, in the presence of which reaction
proceeded rapidly and stereoselectively giving the
addition product with good yield.
EXPERIMENTAL
The 31Р and Н NMR spectra were recorded on a
Varian VXR-300 spectrometer (126.16 and 300 МHz
respectively). Chemical shifts are given against
external reference 85% Н3РО4 (31Р) and internal
reference ТМS (1Н). The optical rotation angles were
measured on a Polax-2L polarimeter (Japan). The
melting points are not corrected. Silica gel Merck 60
was used for column chromatography. Reactions were
carried out in inert atmosphere (Ar). Reagents (Merck,
Fluka) were used without special purification. Solvents
were distilled over Na (THF, in the presence of
benzophenone) and Р4О10 (CH2Cl2).
1
O
O
HO
O
Cat
(RO)2P(O)H +
O
O
P
O
OR
OR
(S,R)-VI
R = (1R,2S,5R)Menthyl, Cat = L-prolynole.
Di[(1S,2R,5R)-menthyl)]
(S)-hydroxy(2-nitro-
phenyl)methylphosphonate (S)-Ia. To a mixture of
0.01 mol of dimenthylphosphite and 0.01 mol of 2-
nitrobenzaldehyde in 5 ml of THF was added 0.002 mol
of quinine or cinchonine as a catalyst. The mixture was
kept for 48 h. In the NMR spectrum of the reaction
mixture we observed signals of two diastereomers at δP
20.3 and 19.9 ppm in the ratio as above mentioned.
The optically pure (S)-diastereomer was isolated by
crystallization from acetonitrile. The other diastereo-
mer was isolated by crystallization from hexane. Yield
35%, mp 150–159°C (MeCN), [α]D20 396 (0.6, CHCl3).
1Н NMR spectrum, CDCl3, δ, ppm: 0.61 d (3 Н, СН3,
JНН 6.9 Hz), 0.066 d (3Н, СН3, JНН 6.9 Hz), 0.71 d
(3Н, СН3, JНН 6.9 Hz), 0.83 d (3Н, СН3,JНН 6.9 Hz),
0.86 d (3Н, СН3, JНH 6.9 Hz), 0.87 d (3Н, СН3, JНН
6.9 Hz), 1.00–1.6 m (14H, СН3 and CH), 1.90 m [1Н,
CH(CH3)2], 2.15 m [1Н, CH(CH3)2], 4.2 m (2H,
OCH), 6.1 d (1Н, СНP, JНН 16.5 Hz), 4.2 s (1Н, ОН),
7.4 m (1Н, ArH), 7.6 m (1Н, ArH), 7.9 m (2Н, ArH).
31Р NMR spectrum, CDCl3, δP, ppm: 19.4. Found, %:
N 2.75; Р 6.38. C27 H44 NO6P. Calculated, %: N 2.75;
Р 6.08.
The synthesized hydroxyphosphonate VI was hyd-
rolyzed to form 1,2,3-trihydroxyphosphonate VIIa.
Then hydroxyphosphonate VI was transformed into
fluorophosphonate VIII, which in turn was converted
into 1-fluoro-2,3-dihydroxypropylphosphonate IX
after removal of acetonide. Reaction of hydroxyl-
phosphonate VI with DAST readily proceeded at room
temperature to give fluorophosphonate VIIIa in high
yield. Fluorophosphonate VIIIa was purified by
crystallization from hexane or by flash-chromatography.
OH
OH
O
O
HO
O
OH
F
OH
F
O
P(OR)2
P(OR)2
O
P(OR)2
(R,R)-IXa
(R,R)-VIIIa
(S,R)-VIIa, VIIb
R = Mnt (a), Н (b).
Absolute configuration of hydroxyphosphonate
(S,R) VI we determined earlier by X-ray diffraction
analysis [22]. Removal of acetonide protection in
compound VI does not involve the asymmetric centers,
therefore absolute configuration of compounds VIIa,
VIIb should be the same (S,R). As known from
published data [13, 23], replacing hydroxy group with
the fluorine atom at the tetrahedral carbon atom occurs
with inversion of configuration. Hence absolute
configuration of compounds VIII, IX should be (R,R).
Di(1S,2R,5R-menthyl) (R)-hydroxy(2-nitrophe-
nyl)methylphosphonate (R)-Ia was obtained analo-
gously using quinidine as a catalyst. [α]D20 +300° (c 0.6,
1
CHCl3). Н NMR spectrum, CDCl3, δ, ppm: 0.61 d
(3Н, СН3, JНН 6.9 Hz), 0.066 d (3Н, СН3, JНН 6.9 Hz),
0.71 d (3Н, СН3, JНН 6.9 Hz), 0.83 d (3Н, СН3, JНН
6.9 Hz), 0.86 d (3Н, СН3, JНH 6.9), 0.87 d (3Н, СН3,
JНН 6.9 Hz), 1.00–1.6 m (14H, СН3 and CH), 1.90 m
[1Н, CH(CH3)2], 2.15 m [1Н, CH(CH3)2], 4.2 m (2H,
OCH), 6.1 d (1Н, СНP, JНН 16.5 Hz), 4.2 s (1Н, ОН),
7.4 m (1Н, ArH), 7.6 m (1Н, ArH), 7.9 m (2Н, ArH).
31Р NMR spectrum, CDCl3, δP, ppm: 21.37. Found, %:
N 2.75; Р 6.38. C27 H44 NO6P. Calculated, %: N 2.75;
Р 6.08.
1,2,3-Trihydroxypropylphosphonic acid and 2,3-
dihydroxy-1-fluoropropylphosphonic acid are interest-
ing synthetic blocks for obtaining of C–P analogs of
glycerylphosphates [24].
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ORGANIC CATALYSIS OF PHOSPHA-ALDOL CONDENSATION
2049
cinchonidine as a catalyst. The optically pure (R)-
diastereomer was isolated by crystallization from
diethyl ether with the yield of 20%. Crystallization from
chloroform–hexane mixture gives a racemic product.
Yield 60%, mp 109–110°С (ether), [α]D20 +498 (c 1,
MeOH) [10]. 1Н NMR spectrum, CDCl3, δ, ppm: 3.7 d
(OCH3, J 10.5 Hz), 3.74 d (OCH3, J 10.5 Hz), 5.64 s
(OH), 6.28 d (PCH, JHP 14.4), 7.99 t (J 7.5); 7.67 t, (J
7.5); 7.44 t (J 7.5, H–Ar). 13С NMR spectrum, CDCl3,
δС, ppm: 147.85 d {[C6(Ar), J 7 Hz}, 133.35 d (J 3 Hz),
132.95, 129.25 d (J 5 Hz), 126.8 d {J 3Hz, [C2(Ar)–C5
Di[(1R,2S,5R)-(–)-menthyl] (S)-hydroxy-(2-metoxy-
phenyl)methylphosphonate (S)-Ib was obtained
analogously to compound Ia. Yield 74%, mp 116–
1
117°C, [α]D20 –75.2 (c 0.66, CHCl3). Н NMR spec-
trum, C6D6, δ, ppm: 0.60 d (3Н, СН3, JНН 6.9 Hz),
0.52 d (3Н, СН3, JНН 6.9 Hz), 0.73 d (3Н, СН3, JНН
6.9 Hz), 0.79 m (6Н, 2СН3), 0.84 d (3Н, СН3, JНН
6.9 Hz), 0.92–1.54 m (14H, СН2 and CH), 2.14 m
[1Н, CH(CH3)2], 2.40 m [1Н, CH(CH3)2], 3.59 (3Н,
ОСН3), 4.17 m (1Н, ОСН), 4.03 m (1Н, ОСН), 4.54 s
(1Н, ОН), 5.24 d (1Н, СНР, JНН 13.2 Hz), 6.59 d
(1Н, ArH, JНН 8.1 Hz), 6.80 t (1Н, ArH, JНН 7.9 Hz),
7.04 t (1Н, ArH, JНН 7.9 Hz), 7.60 d (1Н, ArH, JНН
7.5 Hz). 31Р NMR spectrum, CDCl3, δP, ppm: 20.98
[25].
(Ar)]}, 124.7 d {J J 161 Hz, P–
3 Hz, [C1(Ar)]}, 65.88 d (
C), 54.9 d (J 7 Hz, CH3aO), 54.05 d ( J 7 Hz, CH3bO).
31Р NMR spectrum, CDCl3, δP, ppm: 23.0. Found, %:
Р 11.93. C9H12NO6P. Calculated, %: P 11.86.
Di[(1R,2S,5R)-(–)-menthyl]-(R)-hydroxy-(2-me-
thoxyphenyl)methylphosphonate (R)-Ib was ob-
tained analogously to compound (R)-Ia and purified by
crystallization from hexane or acetonotrile. Yield 50%,
mp 138°С, [α]D20 –56.4° (c 1, toluene). 1Н NMR
spectrum, C6D6, δ, ppm: 0.7–1.0 m (CH3), 1.1–1.23 m
(CH2+CH), 3.4 s (OH), 3.55 s (OCH3), 4.0 d. t (OCH,
JHH 2.3 Hz, JHH 4.1 Hz), 5.17 d (CHP, JHP 11 Hz), 6.6–
6.8 m (C6H4), 7.0–7.2 m (C6H4). 31Р NMR spectrum,
CDCl3, δP, ppm: 21.49 [25].
3-Ethyl-5-qunolin-4-yl-4-oxa-1-azatricyclo[4.4.0.03,8]-
decane (III). To 10 ml of phosphoric acid was added
1 g of cinchonidine and 3.5 g of potassium bromide.
The mixture was heated at 100°С for 48 h. Then it was
cooled and washed with aqueous alkali till pH 7. To
the mixture of aqueous ammonia was added to pH 8.
The product was extracted with chloroform. The
solvent was removed under a vacuum, and the residue
was purified by column chromatography on silica gel
(Rf 0.54, Silufol, MeOH:CHCl3 1:3). Color-less crystal
product. Yield 50%, mp 250–255°С. 1Н NMR
spectrum, CDCl3, δ, ppm: 1.02 t (J 7.5 Hz, 3H), 1.24
d. d (J 13.6 Hz, 1H), 1.40–1.8 m (4H), 2.21–2.19 m
(1H), 2.7 d (J 15 Hz, 1H), 2.9–3.3 m (1H), 3.0 d. d (J
9.0 Hz, 4 Hz, 1H), 3.4 d (J 4.0 Hz, 1H), 3.6 d (J 13.8 Hz,
1H), 6,05 s (1H), 7.5 t (J 7.5 Hz, 1H), 7.73 t (J 4 Hz,
1H), 7.75 d (J 4.5 Hz, 1H), 7.97 d (J 8.5 Hz, 1 H), 8.1
d (J 8.5 Hz, 1 H), 7.99 br.s (1H), 8.6 d (J 4.0 Hz, 1H).
Found, %: C 77.54; H 7.51; N 9.50. C19H22N2O.
Calculated, %: C 77.52; H 7.53; N 9.52.
Dimethyl (S)-hydroxy-(2-nitrophenyl)methylphos-
phonate (S)-Id. To a cooled to 0°С mixture of 1.1 g of
(0.01 mol) of dimethylphosphite and 1.5 g (0.01 mol)
of 2-nitrobenzaldehyde in 2 ml of toluene was added
0.002 mol of cinchonine. The mixture was kept for 48 h.
Then solvent was removed. In the 31Р NMR spectrum
of the reaction mixture signals of two diastereomers at
δP 23.0 and 23.09 were recorded in the presence of
cinchonidine as the chiral solvating reagent. The
optically pure (S)-diastereomer was isolated by
crystallization from diethyl ether. Yield 25%.
Crystallization from chloroform–hexane mixture gives
a racemic product. Yield 60%, mp 109–110°С (ether),
(S)-[Hydroxy(2-nitrophenyl)methyl]phosphonic
acid (S)-IV. A solution of 1 g of hydroxymethyl-
phosphonate II in 50 ml of dioxane was placed into a
flask, and 25 ml of 6 N hydrochloric acid was added.
The reaction mixture was allowed to stand for 3 days
at 80°C. The hydrolysis progress was followed by 31Р
NMR spectroscopy. After the reaction completion the
solvent was removed. Yield 85%, [α]D20 –490 (c 1,
1
[α]2D0 –495 (c 1, MeOH) [10]. Н NMR spectrum,
CDCl3, δ, ppm: 3.7 d (OCH3, JHH 10.5 Hz), 3.74
(OCH3, JHH 10.5 Hz), 5.64 s (OH), 6.28 d (PCH, JHP
14.4 Hz), 7.99 t (H–Ar, J 7.5 Hz). 13С NMR spectrum,
CDCl3, δС, ppm: 147.85 d J 7 [C6(Ar)], 133.35 d J 3,
132.95, 129.25 d, J 5, 126.8 d, J 3 [C2(Ar)–C5(Ar)],
124.7 d, J 3 [C1(Ar)], 65.88 d J 161 (P–C), 54.9 d J 7
1
MeOH) [10]. Н NMR spectrum, CD3OD, δ, ppm: 5 d
(PCH), 7.5–8.0 m (C6H4). 31Р NMR spectrum, CН3ОН,
δP, ppm: 15. Found, %: N 6.21; P 13.17. C7H8NO6P.
Calculated, %: N 6.01; P 13.29.
a
b
(CH3 O), 54.05 d J 7 (CH3 O). 31Р NMR spectrum,
CDCl3, δP, ppm: 23.0. Found, %: С 41.45; Н 4.71.
C9H12NO6P. Calculated, %: C 41.39; H 4.63.
(R)-[Hydroxy(2-nitrophenyl)methyl]phosphonic
acid (R)-IV. Yellowish oil. Yield 85%, [α]D20 +490 (c 1,
Dimethyl (R)-hydroxy(2-nitrophenyl)methylphos-
phonate (R)-Id was obtained analogously using
1
MeOH). Н NMR spectrum, CD3OD, δ, ppm: 5 d
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 11 2008

2050
KOLODYAZHNAYA et al.
(PCH), 7.5–8.0 m (C6H4). 31Р NMR spectrum, CН3ОН,
δP, ppm: 17. Found, %: N 6.21; P 13.17. C7H8NO6P.
Calculated, %: N 6.01; P 13.29.
CDCl3, δ, ppm: 0.76 d (J 7.0 Hz, 6H, CH3-Mnt), 0.87 d
(J 6.6 Hz, 12H, (CH3)2CH-Mnt), 1.1–2.2 m (CH2 +
CH-Mnt), 1.33 s, 1.40 s (6H, (CH3)2C), 1.62 d (J 11.1
Hz, CH-Mnt, 2H), 2.1-2.27 m (CH-Mnt, 2H), 2.65 s (J
12 Hz, 1H,OH), 4.05 d. t (J 6.6 Hz, J 10.5 Hz,
OCHCH2+PCH), 4.23 d.t, J 7 Hz (J ABX-system, JAB
6 Hz, CH2), 4.39 m 2H, CH2). 31Р NMR spectrum,
CDCl3, δP, ppm: 20.9.
Di-(1R,2S,5R)-menthyl (S)-[flouro(2-anisyl)methyl]-
phosphonate (S)-Va. To a solution of 0.01 mol of di-
(1R,2S,5R)-menthyl[hydroxy(2-anisyl)methyl]phos-
phonate in chloroform was added 0.015 mol of DAST,
and the mixture was kept for 2 h at room temperature.
Then the solvent was distilled off. The residue was
recrystallyzed from hexane. Yield 60% after crystal-
lization, mp 90–93°C, [α]D20 –70 (c 1, CHCl3). 1Н NMR
spectrum, CDCl3, δ, ppm: 0.71 d (3 Н, СН3, JНН 6.9 Hz),
0.72 d (3Н, СН3, JНН 6.9 Hz), 0.74 d (3Н, СН3, JНН
6.9 Hz), 0.80 d (3Н, СН3, JНН 6.9 Hz), 0.81 d (3Н,
СН3, JНН 6.9 Hz), 0.83 d (3Н, СН3, JНН 6.9 Hz), 1.40–
2.6 m (14H, СН3 and CH), 2.00 m [1Н, CH(CH3)2],
2.4 m [1Н, CH(CH3)2], 3.75 s (OCH3), 4.1 m (2H,
CHO), 5.35 d. d (1Н, СНP, JНP 8.5 Hz, JНF 45 Hz), 6.9
m, 7.4 m (5Н, ArH). 31Р NMR spectrum, CDCl3, δP,
ppm: 15,5 d. d (JPF 130 Hz, JHP 8.5 Hz). 19F NMR
(R,R)-Diastereomer containing small impurity of
(S,R)-diastereomer was isolated by column chromato-
graphy (hexane–ethyl acetate 4:1). Yield 5–15%
1
(depending on a catalyst nature). Н NMR spectrum,
CDCl3, δP, ppm: 20.0 in agreement with that of VI we
had reported ealier [22].
Di[(1R,2S,5R)-menthyl] (S,R)-1,2,3-trihydroxy-
propylphosphonate (VIIa). To a solution of 0.005 mol
of compound I in 5 ml of dioxane was added 2–3 ml of
concentrated hydrochloric acid. The mixture was kept
for a night. The solution was evaporated under a
vacuum and the residue was recrystallized from
hexane. Yield 90%, mp 108–109°С (needles), [α]D20 –60
2
spectrum, δF, ppm: 198.7 d.d (2JPF 89, JHP 45 Hz).
Found, %: C 67.72; H 9.34. C28H46FO4P. Calculated,
%; C 67.72; H 9.34.
1
(c 2, CHCl3). Н NMR spectrum, CDCl3, δ, ppm:
0.782 d, (J 6.9 Hz, 3H, (CH3)2C), 0.778 d (J 6.6 Hz,
3H, (CH3)2C), 0.887 d (J 6.0 Hz, 6H, CH3-Mnt), 0.895
d (J 6.6 Hz, 6H, CH3-Mnt), 1.0–1.5 m (CH2 + CH-
Mnt), 1.626 m (2H, H-Mnt), 1.662 m (2H, H-Mnt),
2.131 (2H, H-Mnt), 2.234 m (2H,H-Mnt), 2.74 s (3H,
OH), 3.831 m (ЗH, POCH, 2H), 3.899 m (PCH, 1H),
4.234 m (2Н, CH2). 31P NMR spectrum, CDCl3, δ,
ppm: 22.51 [22,26].
Di[(1R,2S,5R)-menthyl] fluoro(phenyl)methyl-
phosphonate (S)-Va was obtained similarly and
purified column chromatography. Yield 80%. 1Н NMR
spectrum, CDCl3, δ, ppm: 0.54 d (3 Н, СН3, JНН 6.9 Hz),
0.57 d (3Н, СН3, JНН 6.9 Hz), 0.7 d (3Н, СН3, JНН 6.9
Hz), 0.73 d (3Н, СН3, JНН 6.9 Hz), 0.83 d (3Н, СН3,
JНН 6.9 Hz), 0.85 d (3Н, СН3, JНН 6.9 Hz), 1.40–2.6 m
(14H, СН3 and CH), 2.00 m [1Н, CH(CH3)2], 2.4 m
[1Н, CH(CH3)2], 4.16 m (2H, OCH), 5.4 d.d (1Н, J
7.5 Hz, J 45.6 Hz), 7.1–7.4 m (5Н, ArH). 31Р NMR
spectrum, CDCl3, δP, ppm: 14,5 d. d (JPF 87 Hz, JHP
8.5 Hz). 19F NMR spectrum, δF, ppm: 198.7 d.d (2JPF
(S,R)-1,2,3-Trihydroxypropylphosphonic
acid
(VIIb). 0.005 mol of VI was dissolved in 40% hydro-
chloric acid in dioxane and was kept at 80°С for 48 h.
Then the solution was evaporated under a vacuum. The
residue was dissolved in 4 ml of alcohol and 0.01 mol
of cyclohexylamine was added. Cyclohexylammo-
nium salt was filtered off.
2
86 Hz, JHP 45 Hz). Found, %: F 4.17; P 6.69.
C27H44FO3P. Calculated, %: F 4.07; P 6.64.
Di[(1R,2S,5R)-menthyl] (S,R)-2,3-О-isopropyl-
idene-1,2,3-trihydroxypropylphosphonate (VI). To
a mixture of 0.01 mol of dimenthylphosphite and
0.012 mol of glyceraldehyde acetonide in 5 ml of THF
cooled to 0°С was added 0.0005 mol of catalyst. In the
NMR spectrum of the reaction mixture we observed
signals of two diastereomers at δP 20.9 and 19.98 ppm
in the ratio as above mentioned. Solvents were distilled
off, the residue was purified by column chromato-
graphy and crystallized. The optically pure (S,R)-
diastereomer was isolated by two successive crystal-
lizations from acetonitrile. Yield 50%, mp 90°C
Yield 65%, mp >200oC (decomp.). 1Н NMR
spectrum, CD3OD + CDCl3, δ, ppm: 0.9–1.2 m (2H,
CH2), 1.6 m (4H, CH2), 1.75 m (4H, CH2), 2.7 m (2H,
CH2), 3.1 s (4H, OH), 3.4–3.6 m (2H, NH + CH). 31Р
NMR spectrum, CD3OD, δP, ppm: 18.1. Found, %: P
11.03. C9H22NO6P. Calculated, %: P 11.42.
Di[(1R,2S,5R)-menthyl] (S,R)-[(2,2-dimethyl-1,3-
dioxolan-4-yl)-fluoromethylphosphonate (VIIIa) was
obtained analogously to compound (S)-Va. Product
was purified by column chromatography. Yield 60%.
1Н NMR spectrum, CDCl3, δ, ppm: 0.78 d (3Н, СН3,
JНН 6.9 Hz), 0.80 d (3Н, СН3, JНН 6.9 Hz), 0.96 d
1
(prisms), [α]D20 –65 (c 2, CHCl3). Н NMR spectrum,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 11 2008

ORGANIC CATALYSIS OF PHOSPHA-ALDOL CONDENSATION
2051
8. List, B., Lerner, R.A., and Barbas, C.F., J. Am. Chem.
Soc., 2000, vol. 122, no. 10, p. 2395.
9. Bernardi, L., Fini, F., Herrera, R.P., Ricci, A., and
Sgarzani, V., Tetrahedron, 2006, vol. 62, no. 2, p. 375.
10. Smaardijk, Ab.A., Noorda, S., van Bolhuis, F., and
Wynberg, H., Tetrahedron Lett., 1985, vol. 26, no. 4,
p. 493.
(3Н, СН3, JНН 6.9 Hz), 0.88 d (3Н, СН3, JНН 6.9 Hz),
0.90 d (3Н, СН3, JНН 6.9 Hz), 1.40–2.6 m (14H, СН3
and CH), 2.00 m [1Н, CH(CH3)2], 2.4 m [1Н, CH
(CH3)2], 2.98, 3.08 (CH3), 4.16 m (2H, OCH), 3.85 d.
d (1Н, J 13.2 Hz, J 78 Hz, PCH), 3.44 m (CH2O), 4.24
m (2H, CHO). 19F NMR spectrum, δ, ppm: 196.2 d
(2JPF 50). Found, %: F 3.78; P 6.39. C26H48FO5.
Calculated, %: F 3.87; P 6.31.
11. Kolodiazhnaya, A.O., Kukhar, V.P., and Kolodiazh-
nyi, O.I., Abstract of Papers, XVII Intern. Conf. on
Phosph. Chem. (ICPC-17), Xiamen, 2007, p. 110.
Di[(1R,2S,5R)-menthyl] (R,R)-1-fluoro-2,3-dihyd-
rooxypropylphosphonate (IXa) was obtained
analogously to compound (S)-VIIa. The product was
12. Kolodiazhnyi, O.I., Tetrahedron, 2003, vol. 59, no. 32,
p. 5923.
1
purified by column chromatography. Yield 65%. Н
13. Kolodiazhnyi, O.I., Tetrahedron: Asymmetry, 2005,
vol. 16, no. 20, p. 3295.
14. Kolodiazhnaya, A.O., Kukhar, V.P., and Kolodiazh-
nyi, O.I., Zh. Obshch. Khim., 2006, vol. 74, no. 8, p. 1398.
NMR spectrum, CDCl3, δ, ppm: 0.77 d (J 6.9 Hz, 3H,
(CH3)2C), 0.78 d [J 6.6 Hz, 3H, (CH3)2C], 0.89 d (J
6.6 Hz, 6H, CH3-Mnt), 0.89 d (J 6.6 Hz, 6H, CH3-
Mnt), 1.0–1.5 m (CH2 + CH-Mnt), 1.67 m (2H, H-
Mnt), 1.66 m (2H, H-Mnt), 2.13 m (2H, H-Mnt), 2.23
m (2H,H-Mnt), 2.9 s (3H, OH), 3.8 m (2H, POCH),
3.9–4 m (PCH + OCH, 2H), 4.23 m (2Н, CH2). 31P
NMR spectrum, CDCl3, δ, ppm: 17.8. Found, %: P
6.89. C22H44FO5P. Calculated, %: P 6.87.
15. Dale, J.A. and Mosher, H.S., J. Am. Chem. Soc., 1973,
vol. 95, no. 2, p. 512.
16. Kozlowski, J.K., Rath, N.P., and Spilling, C.D.,
Tetrahedron, 1995, vol. 51, no. 23, p. 6385.
17. Li, H., Wang, Y., Tang, L., and Deng, L., J. Am. Chem.
Soc., 2004, vol. 126, no. 32, p. 9906.
18. Liu, X., Li, H., and Deng, L., Org. Lett., 2005, vol. 7,
ACKNOWLEDGMENTS
no. 1, p. 167.
19. Marcelli, T., van der Haas, R.N.S., van Maarseveen, J.H.,
This research was carried out at a financial support
of the National Academy of Sciences of Ukraine.
and Hiemstra, H., Synlett, 2005, no. 18, p. 2817.
20. Braje, W., Frackenpohl, J., Langer P., and Hoff-
mann, H.M.R., Tetrahedron, 1998, vol. 54, no. 14, p. 3495.
REFERENCES
21. Iwabuchi, Y., Nakatani, M., Yokoyama, N., and
Hatakeyama, S., J. Am. Chem. Soc., 1999, vol. 121,
no. 43, p. 10219.
1. France, S., Guerin, D. J., Miller, S. J., and Lectka, Th.,
Chem. Rev., 2003, vol. 103, no. 8, p. 2985.
22. Kolodiazhnaya, A.O., Kukhar, V.P., Chernega, A.N.,
and Kolodiazhnyi, O.I., Tetrahedron Asymmetry, 2004,
vol. 15, no. 13, p. 1961.
2. Hoffmann, H.M.R. and Frackenpohl, J., Eur. J. Org.
Chem., 2004, p. 4293.
3. Horikawa, M., Busch-Petersen, J., and Corey, E.J.,
23. Smyth, M.S., Ford, Jr.H., and Burke, Jr.T.R.,
Tetrahedron Lett., 1999, vol. 40, no. 20, p. 3843.
Tetrahedron Lett., 1992, vol. 33, no. 29, p. 4137.
4. List, B., Tetrahedron, 2002, vol. 58, no. 28, p. 5573.
24. Nieschalk, J., Batsanov, A., Hagan, D., and Ho-
5. Jarvo, E.R and Miller, S.J., Tetrahedron, 2002, vol. 58,
ward, J. A.K., Tetrahedron, 1996, vol. 32, no. 1, p. 165.
no. 13, p. 2481.
25. Nesterov, V. and Kolodyazhnyi, O.I., Zh. Obshch.
Khim., 2006, vol. 76, no. 7, p. 1068.
6. List, B., Synlett, 2001, no. 11, p. 1675.
26. Kolodiazhnaya, A.O., Kukhar, V.P., and Kolodiazh-
nyi, O.I., Zh. Obshch. Khim., 2004, vol. 74, no. 6, p. 965.
7. Dalko, P.I. and Moisan, L., Angew. Chem., Int. Ed.,
2004, vol. 43, no. 39, p. 5138.
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