Chiral symmetric phosphoric acid esters as sources of optically active organophosphorus compounds

Article abstract of DOI:10.1016/S0957-4166(98)00166-9

Chiral symmetric di- and trialkylphosphites, derivatives of (-)-borneol, (-)-menthol and (-)-1,2:5,6-di-Oisopropylidene-α-D-glucofuranose, were studied as starting reagents for the preparation of chiral organophosphorus compounds. The reaction occurs by a

Full text of DOI:10.1016/S0957-4166(98)00166-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1645–1649
Chiral symmetric phosphoric acid esters as sources of optically
active organophosphorus compounds
Oleg I. Kolodiazhnyi,a,∗ Evgen V. Grishkun,a Serge Sheiko,a Oleg Demchuk,a
Holger Thoennessen,b Peter G. Jones b and Reinhard Schmutzler b,∗
aInstitute of Bioorganic Chemistry, National Academy of Sciences of Ukraine, Murmanskaya Street, 1, Kiev, 253094, Ukraine
bInstitut für Anorganische und Analytische Chemie der Technischen Universität, Postfach 3329, D-38023 Braunschweig,
Germany
Received 5 March 1998; accepted 24 April 1998
Abstract
Chiral symmetric di- and trialkylphosphites, derivatives of (−)-borneol, (−)-menthol and (−)-1,2:5,6-di-O-
isopropylidene-α-D-glucofuranose, were studied as starting reagents for the preparation of chiral organophos-
phorus compounds. The reaction occurs by asymmetric induction at the α-carbon atom of substituted α-
alkylphosphonates. The stereoselectivity of the reaction depends on the structure of the starting compounds and
the reaction conditions. The configuration of the alkylphosphonates was established by NMR spectroscopy, by
transformation into α-hydroxyalkylphosphonic acids and by X-ray crystal structure analysis. © 1998 Elsevier
Science Ltd. All rights reserved.
The past decade has witnessed high activity in the area of the asymmetric synthesis of organophos-
phorus compounds.1 As a result of the intensive studies, methods have been developed for the synthesis
of a variety of optically active organophosphorus compounds. Nevertheless, further investigations in this
area are desirable.
In this paper we propose chiral C2-symmetric dialkylphosphites (tricoordinated tautomeric form) and
C3-symmetric trialkylphosphites bearing chiral secondary alkoxy groups, as chiral non-racemic starting
compounds for the asymmetric synthesis of organophosphorus compounds. The symmetry reduces the
number of possible diastereomers, in particular the center of asymmetry on the phosphorus atom. We
studied the chiral symmetric phosphites under the conditions of the Kabachnik–Fields and the Pudovik
reactions, which provide optically active α-aminoalkylphosphonic and α-hydroxyalkylphosphonic acids,
possessing high biological activity.1–4 The absolute configuration at the α-position in α-substituted
phosphonic acids has been shown to be very important for biological activity,5 which makes the
asymmetric synthesis of these compounds both interesting and of practical significance.
∗
Corresponding authors. E-mail: oik@biophacs.kiev.ua
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00166-9

1646
O. I. Kolodiazhnyi et al. / Tetrahedron: Asymmetry 9 (1998) 1645–1649
The chiral phosphites 2a–c,3a,c have been synthesized by the reaction of optically active secondary
alcohols 1 [(1R,2S,5R)-(−)-menthol, [(1S)-endo]-(−)-borneol or (−)-1,2:5,6-di-O-isopropylidene-α-D-
glucofuranose] with phosphorus trichloride, in the presence of triethylamine as an acceptor of hydrogen
chloride, in very good yields (Scheme 1). The phosphites 2 and 3, obtained in a spectroscopically pure
state can be used for further reactions without special purification. Nevertheless we have additionally
purified the dibornylphosphite 2a by recrystallization from hexane, isolated the bis(glucofuranosyl)phos-
phite 2b by preparative column chromatography on silica gel, and purified the dimenthylphosphite
2c by vacuum distillation. The trivalent phosphorus compounds 3a and b were purified by column
chromatography under inert gas.5
Scheme 1.
The addition of aldehydes to dialkylphosphites 2 (the Pudovik reaction) proceeds only in the pres-
ence of strong bases, such as DBU. In the presence of weaker bases (triethylamine, DABCO) the
reaction does not proceed or is extremely slow. Studies of the reaction mixtures by 31P–{1H} NMR
showed high regioselectivity and good stereoselectivity of the reaction, resulting in the formation
of α-hydroxyphosphonates in high yields (Scheme 2). The stereoselectivity of the reaction depends
on the structures of the starting compounds and the reaction conditions. For instance, compound
4b was obtained in 78% diastereomeric purity (Fig. 1), whereas the diastereomeric excess in the
case of compound 4c was only 55% (Table 1). Crystallization from acetonitrile or hexane allows α-
hydroxyalkylphosphonates 4 to be obtained in ∼98–100% stereochemical purity.
Scheme 2.
This high level of asymmetric induction was also observed in the reaction of the C3-symmetric
triesters 3 (R*O=menthyl or 1,2:5,6-di-O-isopropylidene-α-D-glucofuranosyl) with aldehydes in the
presence of trimethylchlorosilane. The reaction proceded readily at room temperature without sol-
vent to give the silyl derivative ester 5, which was easily hydrolysed during isolation to yield α-
hydroxyalkylphosphonates (85–90%) as a mixture of diastereomers in the ratio of 12:1 (4a) and of 3:1

O. I. Kolodiazhnyi et al. / Tetrahedron: Asymmetry 9 (1998) 1645–1649
1647
Fig. 1. 31P NMR spectrum of 4b
Table 1
Addition of symmetric phosphites 2 and 3 to aldehydes and aldimines
(4d). The α-hydroxyphosphonate 4d was obtained in ∼100% stereoisomeric purity as white crystals after
one recrystallization of the diastereomeric mixture from hexane.
The diesters 4a and 4b are cleanly hydrolysed with aqueous HCl in dioxane to give the (R)-α-
hydroxybenzylphosphonic acid 6, the configuration of which has been described.6a,b The structure
1
of compounds 4 was confirmed by mass spectroscopy and H, 13C and 31P NMR spectroscopy; the
diastereoisomeric excesses were determined by HPLC and 31P–{1H} NMR spectra.7,8
Good stereoselectivity was also observed in the reaction of phosphites 1–3 with aldehydes and
amines (the Kabachnik–Fields reaction; Scheme 3). The reaction proceeds at room temperature or upon
heating (∼60–80°C) to give α-aminophosphonic acid diesters in high yield and good stereoselectivity:
de=50 (7a), 33 (7b) and 90% (7c). Crystallization of α-aminophosphonates from hexane furnishes the
stereochemically pure species 7. The hydrolysis of 7a,b with 2 N HCl in aqueous dioxane yields the
(R)-α-aminobenzylphosphonic acid 8, whose absolute configuration has been described.4b
The absolute (R)-configuration of (−)-dibornyl α-(N-benzyl)aminophosphonate 7a was confirmed by
X-ray crystal analysis (Fig. 2).7
In conclusion, we have shown that the readily and cheaply available phosphites (R*O)2PHO and
(R*O)3P are efficient starting compounds for the asymmetric synthesis of organophosphorus compounds,
including the preparation of enantiomerically pure α-hydroxy- and α-aminoalkylphosphonous acid
derivatives on a multigram scale. Detailed studies of this reaction and other reactions of chiral symmetric
phosphites are currently underway and will be reported in due course.

1648
O. I. Kolodiazhnyi et al. / Tetrahedron: Asymmetry 9 (1998) 1645–1649
Scheme 3.
Fig. 2. The molecular structure of 7a
Acknowledgements
O. I. Kolodiazhnyi acknowledges Deutsche Forschungsgemeinschaft for financial support. We are
grateful to BASF AG, BAYER AG and HOECHST AG for the generous gifts of chemicals used in
this research.
References
1. Kolodiazhnyi O. I. Tetrahedron: Asymmetry 1998, 9, 1279.
2. Valentine Jr. D. Asymmetric Synthesis; Morrison J. D., Scott J. W., Ed.; Academic Press: Orlando, San Diego, New York,
1984, Vol. 4, pp. 267–312.
3. (a) Tasz M. K., Gamliel A., Rodriguez O. P., Lane T. M., Cremer S. E., Bennett D. W. J. Org. Chem. 1995, 60, 6281. (b)
Blazis V. J., Koeller K. J., Spilling C. D. Tetrahedron: Asymmetry 1994, 5, 499. (c) Rath P., Spilling C. D. Tetrahedron
Lett. 1994, 35, 227. (d) Sum V., Kee T. P. J. Chem. Soc., Perkin Trans. 1 1993, 1778. (e) Sum V., Kee T. P. J. Chem. Soc.,
Perkin Trans. 1 1993, 2701. (f) Warren S., Wyatt P. Tetrahedron: Asymmetry 1996, 7, 989.
4. (a) Patel D. V., Rielly-Gauvin D. E. Tetrahedron Lett. 1990, 31, 5587. (b) Denmark S. E., Chatani N., Pansare S. V.,
Tetrahedron 1992, 48, 2191. (c) Sikorski J. A., Miller M. J., Braccolino D. S., Cleary D. G., Corey S. D., Font J. L., Gruis
K. J., Han C. Y., Lin K. C., Pansegrau P. D., Ream J. E., Schnur D., Shah A., Walker M. C. Phosphorus, Sulfur and Silicon
1993, 76, 115. (d) Stowasser B., Budt K.-H., Jian-Qi L., Peyman A., Ruppert D. Tetrahedron Lett. 1992, 33, 6625.

O. I. Kolodiazhnyi et al. / Tetrahedron: Asymmetry 9 (1998) 1645–1649
1649
5. (a) Hammerschmidt F., Völlenkle H. Liebigs Ann. Chem. 1989, 577. (b) Yokomatsu T., Shibuia S. Tetrahedron: Asymmetry
1992, 3, 377. (c) Maier L. Phosphorus, Sulfur and Silicon 1993, 76, 119. (d) Kameani T., Kigasawa K., Hiragi M.
Heterocycles 1981, 16, 1205.
6. Blazis V. J., Koeller K. J., Spilling C. D. J. Org. Chem. 1995, 60, 931.
7. (a) Data for 2a: yield 85%; purified by column chromatography (silica gel 60, hexane:ethyl acetate, 1:1); Rf 0.38; 31P NMR
(δ, ppm, CDCl3): 8.34, d, J 725 Hz; MS m/z 567 (M+); [α]D −13.5 (c 0.02, toluene). Data for 2b: yield 75%; 31P NMR
(δ, ppm, CDCl3): 7.6 (dt, 1JHP 689 Hz, 3JHP 81 Hz); [α]D −24.5 (c 0.15, ethyl acetate). The preparations of compounds
2–7 will be described in detail: Kolodiazhnyi O. I., Grishkun E. V., Sheiko S., Demchuk O., Thoennessen H., Jones P.,
Schmutzler R. Russ. Chem. Bull., in press.
8. The NMR spectra were recorded on a Varian VXR-300MHz spectrometer. HPLC analyses were performed on a
Milichrom-1A (Russia) Silasorb DEA column. Commercially available chiral alcohols (1R,2S,5R)-(−)-menthol, [(1S)-
endo]-(−)-borneol and (−)-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose of 98% enantiomeric purity were used in this
work.