An efficient synthesis of α- and β-aminophosphonic esters from α-amino acids

Article abstract of DOI:10.1016/S0040-4039(02)01035-3

Catalytic hydrogenation of N-Boc aziridine 2-phosphonates derived from 3-amino-2-hydroxyphosphonates affords N-Boc α-aminophosphonic esters in high enantiomerical purities. Alternatively, the α-hydroxy β-aminophosphonic esters can be reduced into β-aminop

Full text of DOI:10.1016/S0040-4039(02)01035-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5257–5260
An efficient synthesis of a- and b-aminophosphonic esters from
a-amino acids
Cyrille Pousset and Marc Larcheveˆque*
Laboratoire de Synthe`se Organique associe´ au CNRS, ENSCP, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Received 30 May 2002; accepted 31 May 2002
Abstract—Catalytic hydrogenation of N-Boc aziridine 2-phosphonates derived from 3-amino-2-hydroxyphosphonates affords
N-Boc a-aminophosphonic esters in high enantiomeric purities. Alternatively, the a-hydroxy b-aminophosphonic esters can be
reduced into b-aminophosphonic esters by radical deoxygenation. © 2002 Elsevier Science Ltd. All rights reserved.
Aminophosphonic acids are attractive substitutes for
aminocarboxylic acids in the design of enzyme
inhibitors. These phosphonic acids have found applica-
tions as potent active compounds with a large range of
biological activities: antibacterial agents,1 enzyme
inhibitors,2 haptens for catalytic antibodies,3 or anti
HIV agents.4 Presently, a number of methods are avail-
able for the synthesis of optically pure and enriched
a-aminophosphonic acids, via resolution, enzymatic
techniques, or asymmetric synthesis.5 An attractive
alternative route would be to control the reductive
opening of 2,3-aziridinophosphonates. Indeed, these
heterocycles may be prepared in an optically active
form by various methods such as Darzens-type conden-
sation of carbanions derived from chiral phospho-
namides,6 addition to chiral sulfinimides,7 cyclisation of
a-hydroxy b-aminophosphonates obtained by asymmet-
ric aminohydroxylation of unsaturated phosphonates8
or reduction of chiral 2H-azirinephosphonates.9 How-
ever, little is known concerning the regioselectivity of
the hydrogenolytic cleavage of these aziridines and
non-convergent results were reported for N-tosyl
aziridines.10
phonic acid derivatives. Applied to a-aminoaldehydes,
this reaction allows easy access to a-hydroxy b-
aminophosphonates. However, the diastereoselectivity
of this reaction is highly dependent on the nature of the
protecting group.11 We decided to study the N-Boc
derivatives because this protective group is one of the
most interesting in peptide synthesis. In a first experi-
ment, the aldehyde 1a derived from phenylalanine12 was
reacted at room temperature with trimethylsilylphos-
phite.13 After acid hydrolysis the corresponding phos-
phonates 2a and 3a were obtained in a 63:37 ratio
(Table 1, entry 1).14 In an effort to obtain better
diastereoselectivity, the same reaction was conducted at
low temperature in the presence of a Lewis acid. With
titanium tetrachloride, the reaction was slow enough
and the phosphonates were isolated in essentially the
same diastereomeric ratio (entry 2). The use of tin
tetrachloride allowed us to increase this ratio up to
80:20; however, we were unable to achieve total conver-
sion of the aldehyde. We then turned our attention
towards the activation of the nucleophile. Such an
activation by fluorides was previously reported15 and
using potassium fluoride in DMF at room temperature,
we obtained the phosphonates 2a and 3a in good yield
and satisfactory diastereomeric excess (entry 5). Similar
results were obtained with other aminoaldehydes.
We report here that the N-Boc-protected cis aziridines
derived from syn a-hydroxy b-aminophosphonates are
regioselectively hydrogenated to give optically enriched
a-aminophosphonates (Scheme 1).
These 2-hydroxy 3-aminophosphonates were then con-
verted into N-Boc aziridines. In a first experiment 2d
was submitted after separation to a Mitsunobu reaction
Nucleophilic addition of phosphites to aldehydes con-
stitutes one of the simplest entries to a-hydroxyphos-
(triphenylphosphine–diisopropylazodicarboxylate
in
THF). However, a 2-t-butoxy-1,3-oxazoline resulting
from the intramolecular substitution of the activated
hydroxyl by the Boc carbonyl oxygen was isolated as
the main product. Mixtures of phosphonates 2 and 3
Keywords: aminophosphonic acid; aziridine; catalytic hydrogenation.
* Corresponding author. Fax: (33) 1 43 25 79 75; e-mail: larchm@
ext.jussieu.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01035-3

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C. Pousset, M. Larche6eˆque / Tetrahedron Letters 43 (2002) 5257–5260
Scheme 1.
Table 1. Stereoselective hydrophosphonylation of aldehydes 1
Entry
Aldehyde
Method
Temp. (time)
2:3
Yield (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1c
1d
1e
A
B
C
D
E
E
E
E
E
20°C (24 h)
−78°C (10 h)
−78°C (6 h)
0°C (20 h)
63:37
60:40
74:26
73:27
82:18
80:20
87:13
81:19
78:22
85
63
53
92
75
82
76
74
68
0°C (24 h)
20°C (24 h)
20°C (18 h)
20°C (15 h)
20°C (18 h)
A: (EtO)2P-OSiMe3, CH2Cl2; B: (EtO)2P-OSiMe3, TiCl4 (1.4 equiv.), CH2Cl2; C: (EtO)2P-OSiMe3, SnCl4 (1.4 equiv.), CH2Cl2; D: (EtO)2P(O)H,
CsF, neat; E: (EtO)2P(O)H, KF, DMF.
were then mesylated16 and, after separation of the
minor components, cyclised in the presence of potas-
sium carbonate in DMF to give pure cis aziridines
exclusively in excellent yields.17
Pd-on-carbon, the formation of compound 6 was
almost entirely suppressed. The (R) a-aminophospho-
nic esters 5 were then isolated in good yields and high
enantiomeric purities except for compound 4e which
showed a low reactivity (Table 2).18
These aziridines were then submitted to catalytic hydro-
genation. First, the reactions were carried out in etha-
nol in the presence of Pearlman catalyst. Phosphonates
resulting from a highly regiocontrolled b ring-opening
reaction were obtained in nearly quantitative yields.
However, unexpectedly, they were isolated as a 1:1
mixture of compounds 5 and 6, resulting from the
cleavage of the aziridine CꢀC bond. This result was
probably due to the presence of the Boc protecting
group which was not a powerful enough activating
group to transform the nitrogen atom into a good
leaving group.
However, in contrast with the Pearlman catalyst, the
use of Pd-on-carbon always led to the formation of a
small amount (1–3%) of the N-Boc-protected b-
aminophosphonic esters, a result which was established
Table 2. Hydrogenolysis of aziridines 4
Aziridine
5 (yield %)a
[h]2D0 (c, solvent)
Conf.
4a
4b
4c
ent-4d
4e
77
65
64
68
5
−14.1 (2.68, CHCl3)
−14.2 (3.45, CH2Cl2)
−27.0 (4.20, CHCl3)
+24.0 (3.45, CHCl3)
–
R
R
R
S
–
We then decided to modify the catalyst and were
pleased to observe that when the reaction was con-
ducted in the presence of a catalytic amount of 10%
a Isolated yield.

C. Pousset, M. Larche6eˆque / Tetrahedron Letters 43 (2002) 5257–5260
5259
Scheme 2. Reagents and conditions: (a) thiocarbonyldiimidazole (2 equiv.), (CH2Cl)2, 20°C, 20 h, 95%; (b) Et3SiH (10 equiv.),
(BzO)2 (2 equiv.), refluxing 1 h, 80–85%.
by comparing GLC and HPLC results of the crude
reaction mixture with authentic samples of racemic
b-aminophosphonic esters prepared by reductive ami-
nation of b-ketophosphonates.19 These compounds
resulting from the attack in the a-position of the phos-
phonate group were easily removed by flash
chromatography.
3. Hirschmann, R.; Smith, A. B., III; Taylor, C. M.;
Benkovic, P. A.; Taylor, S. D.; Yager, K. M.; Sprengler,
P. A.; Benkovic, S. J. Science 1994, 265, 234.
4. (a) Powers, J. C.; Boduszek, B.; Oleksyszyn, J. PCT Int.
Appl. WO 9,529,691, 1995; (b) Alonso, E.; Alonso, E.;
Solis, A.; del Pozo, C. Synlett 2000, 698–700.
5. For reviews, see: (a) Kukhar, V. P.; Soloshonok, V. A.;
Solodenko, V. A. Phosphorus Sulfur Silicon Relat. Elem.
1994, 92, 239; (b) Kolodiazhnyi, O. I. Tetrahedron: Asym-
metry 1998, 9, 1279–1332. See also: (c) Burk, M. J.;
Stammers, T. A.; Straub, J. A. Org. Lett. 1998, 1, 387–
390; (d) Hammerschmidt, F.; Wuggenig, F. Tetrahedron:
Asymmetry 1999, 10, 1709–1721; (e) Davis, F. A.; Lee, S.;
Yan, H.; Titus, D. D. Org. Lett. 2001, 3, 1757–1760.
6. Hanessian, S.; Bennani, Y. L.; Herve´, Y. Synlett 1993,
35–36.
7. (a) Davis, F. A.; McCoul, W. Tetrahedron Lett. 1999, 40,
249–252; (b) Davis, F. A.; McCoul, W.; Titus, D. D. Org.
Lett. 1999, 1, 1053–1055.
8. (a) Cravotto, G.; Giovenzana, G. B.; Pagliarin, R.;
Palmisano, G.; Sisti, M. Tetrahedron: Asymmetry 1998, 9,
745–748; (b) Thomas, A. A.; Sharpless, K. B. J. Org.
Chem. 1999, 64, 8379–8385.
Hydrogenolysis of the trans aziridine obtained by cycli-
sation of the mesylate derived from the anti phospho-
nate 3a was also regioselective and, as expected, gave
the (S) a-aminophosphonic ester ent-5a of opposite
configuration. However, probably due to steric hin-
drance and to a more difficult approach of the trans
aziridine moiety near the catalyst surface, hydrogenoly-
sis was more difficult to achieve and only resulted in
63% yield.
The easy access to 3-amino-2-hydroxyphosphonates
allowed us to elaborate a simple method for synthesis-
ing optically active b-aminophosphonic esters, the
preparation of which are rare enough.20 Our approach
was based on the reductive deoxygenation of the
hydroxyphosphonates 2 and 3. In a first approach, the
mesylates derived from these phosphonates were
reacted with lithium triethylborohydride, a reagent
known to easily cleave the CꢀO bond of sulfonates.21
However, due to its basic properties, this reducing
agent afforded the aziridines 4 only. We turned then
our attention towards the radical cleavage of imida-
zolylthiocarbonates.22 These compounds were prepared
in nearly quantitative yields by reaction of aminohy-
droxyphosphonates with thiocarbonyldiimidazole. Fur-
ther reduction of these intermediates with triethylsilane
in the presence of benzoylperoxide afforded N-Boc-pro-
tected b-aminophosphonic esters 7 in good yields and
high optical purities (Scheme 2).23
9. Palacios, F.; Ochoa de Renata, A. M.; Gil, J. I. Tetra-
hedron Lett. 2000, 41, 5363–5366.
10. For b-opening, see: Zygmunt, J. Tetrahedron 1985, 41,
4979–4982. See also Refs. 6 and 7. For a-opening, see:
Ref. 9.
11. (a) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E. Tetra-
hedron Lett. 1990, 31, 5587–5590; (b) Stowasser, B.; Budt,
K. H.; Jian-Qi, L.; Peyman, A.; Ruppert, D. Tetrahedron
Lett. 1992, 33, 6625–6628; (c) Yokomatsu, T.; Yamagishi,
T.; Shibuya, S. Tetrahedron: Asymmetry 1993, 4, 1401–
1404; (d) Wroblewski, A. E.; Piotrowska, D. G. Tetra-
hedron 1998, 54, 8123–8132.
12. The N-Boc aminoaldehydes were prepared by diisobutyl-
aluminium hydride reduction of the corresponding esters.
See: (a) Ito, A.; Takahashi, R.; Baba, Y. Chem. Pharm.
Bull. 1975, 23, 3081–3087; (b) Rich, D. H.; Sun, E. T.;
Boparai, A. S. J. Org. Chem. 1978, 43, 3624–3626.
13. Evans, D. A.; Hurst, K. M.; Takacs, J. M. J. Am. Chem.
Soc. 1978, 100, 3467–3477.
Thus, by using the stereoselective condensation of a-
aminoaldehydes with diethylphosphonates, we suc-
ceeded to synthesise a- or b-aminophosphonates at will
in high enantiomeric purities.
14. 31P NMR was found to be the most convenient method
for determining the diastereomeric ratio of phosphonates
2 and 3. In all cases, the syn isomer appears downfield
compared to the anti isomer11 (2a: 24.11 ppm, 3a: 23.68
ppm in CDCl3).
15. Texier-Boullet, F.; Foucaud, A. Synthesis 1982, 165–167.
16. It is noteworthy that the mesylates were considerably
more crystalline and easier to purify by flash chromato-
graphy than the starting hydroxyphosphonates.
17. The cyclisations were conducted by heating the mesylates
derived from 2 at 80°C in pure DMF for 4 hours: yields:
References
1. Allen, J. G.; Arthenton, F. R.; Hall, M. J.; Hassall, C.
H.; Holmes, S. W.; Lambert, R. W.; Nisbet, L. J.;
Ringrose, P. S. Nature 1978, 272, 56–58.
2. (a) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood,
J. M. J. Med. Chem 1989, 32, 1652–1661; (b) Smith, W.
W.; Bartlett, P. A. J. Am. Chem. Soc. 1998, 120, 4622–
4628 and references cited therein.

5260
C. Pousset, M. Larche6eˆque / Tetrahedron Letters 43 (2002) 5257–5260
4a: 82%; 4b: 92%; 4c: 83%; 4d: 77%; 4e: 79%. The
20. (a) Sauveur, F.; Collignon, N.; Guy, A.; Savignac, P.
Phosphorus Sulfur 1983, 14, 341; (b) Mikolajczyk, M.;
Lyzwa, P.; Drabiwicz, J.; Wieczorek, M. W.; Blaszczyk,
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21. Holder, R. W.; Matturo, M. G. J. Org. Chem. 1977, 42,
2166–2168.
stereochemical assignment of the aziridines was based on
the large ring proton coupling constants observed for the
cis isomers (3JHH: 6–7 Hz for the cis isomers and 2–3 Hz
for the trans isomers); cf. Refs. 8 and 9.
18. The enantiomeric purities were measured by chiral GLC
(25 m Chirasil -Val from Chrompack) for 5a (92%), 5c
22. Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. Tetra-
hedron Lett. 1991, 32, 7187–7190.
D
(92%) and 5d (94%). In order to confirm the R absolute
configuration, the phosphonate 5c was deprotected with
trifluoroacetic acid and the optical rotation of the result-
ing free aminophosphonate {[h]2D0=−13 (c 1.9, CHCl3)}
compared with those of the literature: [h]2D0=−11 (c 1.9,
CHCl3), 82% e.e. See: Gajda, T. Tetrahedron: Asymmetry
1994, 5, 1965–1972.
23. The reaction was conducted on the mixture of 2 and 3:
Total yields from 2+3: (S)-7a (76%): [h]2D0=−8 (c 1.40,
CH2Cl2); (S)-7b (70%): [h]2D0=−7 (c 1.0, CH2Cl2); (S)-7e
(74%): [h]2D0=−9 (c 2.05, CH2Cl2). Optical purities were
measured by HPLC (Chiracel-OD from Daicel; hexane:2-
propanol 9:1) for 7a (e.e.: 98%) and 7b (e.e.: 98%) or by
GLC (50 m XE60-S-Valine-S-a-PEA from Chrompack)
for 7e (e.e.: 95%).
19. Varlet, J. M.; Collignon, N.; Savignac, P. Tetrahedron
1981, 21, 3713–3721.