Self-reproduction of chirality on α-aminophosphonates: Asymmetric synthesis of α-alkylated diethyl pyrrolidin-2-yl-phosphonate

Article abstract of DOI:10.1016/j.tetlet.2004.04.009

A simple method for the asymmetric synthesis of α-substituted diethyl pyrrolidin-2-yl-phosphonate is described. The chiral oxazolopyrrolidine phosphonate was alkylated diastereospecifically with an alkyl halide. The key intermediate is an α-phosphonate-stabilized carbanion that can be alkylated without loss of optical activity and a single enantiomer of product was formed exclusively in 10-80% yield. The configurational assignment of the products relied on ¹H-¹H NOESY analysis of the alkylated oxazolopyrrolidine phosphonates. This represents an unprecedented case of self-regeneration of stereocenters (SRS) of cyclic aminophosphonates. The enantiomerically pure α-aminophosphonate diethyl-(2S)-(2-methylpyrrolidin- 2-yl)-phosphonate, a surrogate of 2-methyl proline, was obtained upon hydrogenolysis of the chiral auxiliary in 83% yield.

Full text of DOI:10.1016/j.tetlet.2004.04.009

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5175–5177
Self-reproduction of chirality on a-aminophosphonates: asymmetric
synthesis of a-alkylated diethyl pyrrolidin-2-yl-phosphonate
Mohamed Amedjkouh* and Kristina Westerlund
Organic Chemistry, Department of Chemistry, G€oteborg University, SE-412 96 G€oteborg, Sweden
Received 20 January 2004; revised 24 March 2004; accepted 2 April 2004
Abstract—A simple method for the asymmetric synthesis of a-substituted diethyl pyrrolidin-2-yl-phosphonate is described. The
chiral oxazolopyrrolidine phosphonate was alkylated diastereospecifically with an alkyl halide. The key intermediate is an a-
phosphonate-stabilized carbanion that can be alkylated without loss of optical activity and a single enantiomer of product was
formed exclusively in 10–80% yield. The configurational assignment of the products relied on 1H–1H NOESY analysis of the
alkylated oxazolopyrrolidine phosphonates. This represents an unprecedented case of self-regeneration of stereocenters (SRS) of
cyclic aminophosphonates. The enantiomerically pure a-aminophosphonate diethyl-(2S)-(2-methylpyrrolidin-2-yl)-phosphonate, a
surrogate of 2-methyl proline, was obtained upon hydrogenolysis of the chiral auxiliary in 83% yield.
Ó 2004 Elsevier Ltd. All rights reserved.
a-Aminophosphonates and their derivatives are impor-
tant compounds possessing diverse and useful biological
activities.1 Owing to their analogy to amino acids, they
have found applications ranging from medicine to
agriculture, for example, as antibiotics,2 enzyme inhibi-
tors,3 anti-cancer agents,4 and herbicides.5 These bio-
logical properties are mostly associated with the
tetrahedral structure of the phosphonyl group acting as
a ‘transition-state analogue’.6
We also demonstrate that chiral cyclic a-amin-
ophosphonates with a phosphonate carbanion func-
tionality can be alkylated at the a-position to
phosphorus and nitrogen by applying the Self-Regen-
eration of Stereocenters (SRS) principle.8 To our
knowledge little attention has been paid to such com-
pounds, although in previous work, the asymmetric
preparation of 1,2-diaminoalkane-2-phosphonic acid
derivatives was reported, however, the authors started
from a mixture of diastereoisomers of 1 to obtain
compounds 2 (Scheme 1).9
Recently, cyclic a-aminophosphonates have found
promising applications as surrogates of proline,
increasing the need for their syntheses in enantiomeri-
cally pure form.7
We considered that oxazolopyrrolidine phosphonate 4
would be an interesting candidate-substrate to prepare
cyclic aminophosphonates alkylated at the a-position.
The deprotonation would involve formation of a reso-
nance stabilized phosphonate carbanion and subsequent
In the present paper, we report a general method for the
preparation of cyclic a-branched aminophosphonates.
Boc
Boc
Boc
N
N
N
1) Base/THF/-75 °C
+
R
R
2) RX
N
N
N
PO(OMe)
PO(OMe)
PO(OMe)
2
2
2
cis/trans mixture
1
2a
2b
Scheme 1.
* Corresponding author. Tel.: +46-31-772-2895; fax: +46-31-772-3840; e-mail: mamou@chem.gu.se
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.009

5176
M. Amedjkouh, K. Westerlund / Tetrahedron Letters 45 (2004) 5175–5177
Ph
i
ii
OMe
MeO
O
(EtO) OP
N
O
O
Bt
N
2
BtH
+
OH
NH
2
Ph
4 (3R,5S,7aS)
Ph
5 (3R,5S,7aS)
Bt = benzotriazol-1-yl
Scheme 2. Reagents and conditions: i, (a) 0.1 M HCl, 50 °C, 1 h (b) CH2Cl2, rt, 20 h; ii, P(OEt)3 (2 equiv), ZnCl2 (0.3 equiv), CH2Cl2, 0 °C, overnight.
Table 1
reaction with an electrophile would be expected to
proceed diastereoselectively under the directing effect of
the remaining stereogenic center in the bicyclic system
(Scheme 2).
R
1) Base
(EtO)2OP
(EtO)2OP
N
O
N
O
2) Electrophile
Ph
4 (3R,5S,7aS)
Ph
Oxazolopyrrolidine 5 was obtained according to the
method described by Katritzky et al.10 Thus, benzo-
triazole, (R)-phenylglycinol, and 2,5-dimethoxy-
tetrahydrofuran (as an equivalent of succinaldehyde)
reacted at room temperature via a double Robinson–
Schopf condensation to yield compound 5 as a single
diastereoisomer as shown by NMR analysis and con-
firmed by comparison with literature data.10 Subsequent
Arbuzov reaction in the presence of the mild Lewis acid
ZnCl2 (30 mol %), converted 5 into the desired oxazol-
opyrrolidine phosphonate 4 as the only diasteroisomer.
Attempts to obtain 4 directly by replacing benzotriazole
with triethyl phosphite in the initial reaction mixture
resulted in a mixture of two diastereoisomers.
6a (3R,5S,7aS): R = Me
6b (3R,5S,7aS): R = Et
6c (3R,5S,7aS): R = n-Pr
6d (3R,5S,7aS): R = Bn
Entry
Base
Product Time
Conversion
(%)a;b
1
2
3
4
5
6
7
8
LDA/BuLi (1:1)
LDA/BuLi (2:1)
LDA/BuLi (2:2)
BuLi (1 equiv)
BuLi (2 equiv)
BuLi (2 equiv)
BuLi (2 equiv)
BuLi (2 equiv)
6a
6a
6a
6a
6a
6b
6c
6d
Overnight
90 min
90
60
Overnight
Overnight
90 min
95
86
95 (80)
52 (35)
62 (41)
10
Overnight
90 min
60 min
a Determined by GC/MS analysis.
We first investigated the methylation of the oxazolo-
pyrrolidine phosphonate 4 using LDA and LHMDS.
However, with 1 equiv of such a base, we observed no
product formation. When deprotonation of 4 was car-
ried out with LDA/BuLi the desired product 6a was
obtained with 90% conversion. This trend in reactivity
has been observed previously with such substrates. The
use of an equivalent of BuLi, in excess, was explained by
the necessity to break the hydrogen bond between the
amine and the Li-nucleophile.11 However better results
in the alkylation reaction were obtained when using
BuLi as base, and 95% conversion into 6a was observed
(entry 5, Table 1).12
b Isolated yields after column chromatography separation in paren-
theses.
H7a
(EtO)2 OP
Me
N
O
H2
H3
Ph
H2'
6a (3R,5S,7aS)
Figure 1.
Following this method, we next evaluated various other
electrophiles for alkylation of 4 as shown in Table 1.
While iodomethane and higher iodoalkanes were
employed successfully in the alkylation reaction to
provide 6a–d in yields ranging from 10% to 80%, the
very reactive allyl bromide did not give rise to the
desired product. It is not yet clear whether BuLi in
excess reacts with allyl bromide.
The high diastereoselectivity and the retention of con-
figuration observed in the alkylation reaction may be
associated with the carbanion structure itself.
Solution state studies have shown that P(V) phospho-
nate-stabilized carbanions have a tendency for coordi-
nation of the metal center via the oxygen atom.13 With
closely related complexes such as Liþ6a there is no
coordination to the carbanion itself. It was found that the
carbanion was stabilized in either rotational conforma-
tion, that is parallel or perpendicular, with a low barrier
to rotation about the P–C bond. It is reasonable to sug-
gest that Liþ6a exists in a conformation where the
carbanion lone pair will lie in parallel to the acceptor
orbital rà P@O (hyperconjugation), with the additional
coordination of the nitrogen donor group to lithium.
Thus, the introduction of the alkyl group occurs with
retention of configuration. It is also likely that the reac-
tion is a kinetically controlled endo alkylation (Fig. 2).14
Interestingly, only one diastereoisomer was formed with
all alkylating reagents, with the newly introduced alkyl
1
group on the endo-face. This was proved by H and 31P
NMR analysis and by gas chromatography. In the case
1
of 6a, the H NMR spectrum had well resolved signals
at room temperature and its stereochemical assignment
1
was based on careful H–1H NOESY analysis. It was
found that a NOE existed between the protons of the
methyl in the a-position and H3 and H2 but not with H7a
(Fig. 1).

M. Amedjkouh, K. Westerlund / Tetrahedron Letters 45 (2004) 5175–5177
5177
6. Jacobsen, E. N.; Bartlett, P. A. J. Am. Chem. Soc. 1981,
103, 654–657.
C lone pair
σ*(P=O)
7. Boduszek, B.; Oleksyszyn, J.; Kam, C.-M.; Selzler, J.;
Smith, R. E.; Powers, J. C. J. Med. Chem. 1994, 37, 3969–
3976.
8. Seebach, D.; Sting, A.; Hoffman, M. Angew. Chem., Int.
Ed. 1996, 35, 2708–2748.
OEt
OEt
O
Ph
P
N
O
Li
9. Studer, A.; Seebach, D. Heterocycles 1995, 40, 357–378.
10. Katritzky, A. R.; Cui, X. L.; Yang, B.; Steel, P. J. J. Org.
Chem. 1999, 64, 1979–1985.
Li+6a
Figure 2.
11. Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624–
1654.
12. Diethyl
(3R,5S,7aS)-5-methyl-3-phenylhexahydropyr-
rolo[2,1-b]-[1,3]oxazol-5-yl-phosphonate 6a. At )78 °C,
n-BuLi (1.8 mmol, 2.26 M) was added to a solution of 4
(250 mg, 0.8 mmol) and the reaction mixture was allowed
to warm to room temperature. MeI (186 lL, 3.0 mmol)
was added and the resulting mixture was stirred at room
temperature for 90 min. The reaction was quenched by
addition of saturated aqueous NH4Cl solution. The
aqueous layer was extracted with Et2O. The combined
organic layer was washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The product
was purified by column chromatography using hexane/
EtOAc (2/1) as eluent system giving 6a (218 mg, 80%) as a
R
1. Pd(OH) /C, H ,
HCl-MeOH
2
2
Me
(EtO) OP
N
O
2
(EtO) OP
2
N
2. NaOH
H
Ph
6a (3R,5S,7aS)
7a (2S)
Scheme 3.
The chiral auxiliary in phosphonate 6a was readily re-
moved by hydrogenolysis with Pd(OH)2/C in HCl/
MeOH. Purification by flash chromatography eluting
with CH2Cl2/MeOH (98/2) afforded diethyl (2S)-(2-
methylpyrrolidin-2-yl)phosphonate 7a in 83% yield as a
yellow oil.15 a-Aminophosphonate (2S)-7a could be a
valuable precursor of a chiral version of the nitrone spin
trap (5S)-5-(diethoxyphosphoryl)-5-methyl-1-pyrroline
N-oxide (DEPMPO).16 This study is currently underway
in our group (Scheme 3).
yellow oil.
20
D
6a ½aŠ )50.66 (c 2.60, EtOH); 1H NMR (400 MHz,
CDCl3) d 1.11 (t, J ¼ 7:2 Hz, 3H), 1.15 (t, J ¼ 6:9 Hz, 3H),
1.42 (d, JH–P ¼ 16 Hz, 3H), 1.87–2.04 (m, 2H), 2.26–2.32
(m, 1H), 2.38–2.46 (m, 1H), 3.63 (t, J ¼ 8:4 Hz, 1H), 3.92–
4.01 (m, 4H), 4.26 (m, 1H), 4.60 (m, 1H), 5.03 (m, 1H),
7.20–7.22 (m, 1H), 7.26–7.31 (m, 2H), 7.40–7.42 (m, 2H);
13C NMR d 16.6, 16.7, 18.9, 28.9, 34.9, 61.8, 62.6, 62.7,
64.3, 74.5, 99.6, 126.9, 128.4, 130.3, 143.6; MS (EI): m=z
339, 202, 138.
13. Izod, K. Coord. Chem. Rev. 2002, 227, 153–173.
14. (a) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake, J.
F. J. Am. Chem. Soc. 1997, 119, 4565–4566; (b) Ando, K.;
Green, N. S.; Li, Y.; Houk, K. N. J. Am. Chem. Soc. 1999,
121, 5334–5335.
15. Diethyl (2S)-(2-methylpyrrolidin-2-yl)phosphonate 7a.
Compound 6a (0.76 g, 2.24 mmol) was dissolved in meth-
anolic HCl (30 mL). Palladium hydroxide on carbon (20%
by weight, 120 mg) was added and the mixture was
hydrogenated at a pressure of 4 atm at room temperature
for 24 h. The catalyst was removed by filtration and the
solvent was removed under vacuum. The residue was
dissolved in CH2Cl2 and washed with aqueous 1 M NaOH.
The organic layer was dried over Na2SO4 and concen-
trated. The product was purified by column chromato-
In summary, a-alkylated pyrrolidine phosphonate pre-
cursors have been prepared. To this the end Self
Regeneration of Stereocenter strategy was successfully
applied to phosphonate stabilized carbanions. Further
studies are in progress in our group on the scope of this
methodology.
References and notes
1. (a) Kukhar, V. P.; Hudson, H. R. Aminophosphonic and
Aminophosphinic Acids; John Wiley: Chichester, 2000; (b)
Kafarski, P.; Lejczak, B. Phosphorus Sulfur Silicon 1991,
63, 193–215.
2. Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med.
Chem. 1986, 29, 29–40, and references cited therein.
3. De Lombaert, S.; Blanchard, L.; Tan, T.; Sakane, Y.;
Berry, C.; Ghai, R. D. Bioorg. Med. Chem. Lett. 1995, 5,
145–150.
4. Kafarski, P.; Lejczak, B. Current Med. Chem.: Anti-
Cancer Agents 2001, 1, 301–312.
5. Emsley, J.; Hall, D. The Chemistry of Phosphorus; Harper
and Row: London, 1976.
graphy using CH2Cl2/methanol (98/2) as eluent giving 7a
20
D
(0.42 g, 83%) as a yellow oil: ½aŠ +1.52 (c 2.60, EtOH); 1H
NMR (400 MHz, CDCl3) d 1.32 (t, J ¼ 6:9 Hz, 6H), 1.36
(d, JH–P ¼ 15:2 Hz, 3H), 1.60–1.90 (m, 3H), 2.16–2.25 (m,
1H), 2.96–3.07 (m, 2H), 4.26 (q, J ¼ 6:9 Hz, 4H); 13C NMR
16.8, 24.3, 25.9, 34.8, 47.3, 58.9, 60.5, 62.4, 62.7; MS (EI):
m=z 221, 205, 162, 138, 111, 83.
16. Frejaville, C.; Karoui, H.; Tuccio, B.; Le Moigne, F.;
Culcasi, M.; Pietri, S.; Lauricella, R.; Tordo, P. J. Med.
Chem. 1995, 38, 258–265.