The design and synthesis of a novel organophosphorus compound containing the structure of both β-amino acid and β-aminophosphonate

Article abstract of DOI:10.1016/j.cclet.2010.03.035

A novel organophosphorus compound containing the structure of both b-amino acid and b-aminophosphonate is designed and synthesized. Arbuzov reaction with P(OEt)₃, the N-Boc protected iodide 3 cannot provide the desired product but 2-oxazolidinone 4 because of the neighboring-group participation of the Boc moiety. To avoid the intramolecular participation of the carbamates, the Ts protecting group is employed and the Ts-protected iodide 5 affords the target product successfully.

Full text of DOI:10.1016/j.cclet.2010.03.035

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Chinese Chemical Letters 21 (2010) 810–812
www.elsevier.com/locate/cclet
The design and synthesis of a novel organophosphorus
compound containing the structure of both
b-amino acid and b-aminophosphonate
Han Bing Teng
College of Chemical Engineering, Wuhan University of Technology, Wuhan 430070, China
Received 24 November 2009
Abstract
A novel organophosphorus compound containing the structure of both b-amino acid and b-aminophosphonate is designed and
synthesized. Arbuzov reaction with P(OEt)3, the N-Boc protected iodide 3 cannot provide the desired product but 2-oxazolidinone 4
because of the neighboring-group participation of the Boc moiety. To avoid the intramolecular participation of the carbamates, the
Ts protecting group is employed and the Ts-protected iodide 5 affords the target product successfully.
# 2010 Han Bing Teng. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: b-Amino acid; b-Aminophosphonate; Neighboring-group participation; Arbuzov reaction; Amino-protecting group
b-Amino acids (b-AAs) play a significant role in medicinal chemistry. They are the structural units of b-peptides,
compounds with better pharmacological profiles than natural peptides and natural products containing b-amino acid
units exhibit antibiotic, antifungal, cytotoxic, and other pharmacological properties [1,2]. On the other hand, b-
aminophosphonates have received considerable attention as a result of their increasing applications in enzyme
inhibitors, agrochemicals or pharmaceuticals [3,4]. In our previous work [5], we have synthesized L-
phosphinothricin which is organophosphorus compound containing the structure of a-amino acid and exhibits
strong herbicidal activity. The search for the preparation of organophosphorus compounds 1 is of particular interest
because of its special structure of both b-amino acid and b-aminophosphonate. This compound can be synthesized
from commercially available aspartic acid which has the moiety of b-amino acid. Retrosynthetic analysis is depicted
in Scheme 1.
Unfortunately, when protecting group (PG) was t-butoxycarbonyl (Boc), the Arbuzov reaction of P(OEt)3 with
iodide 3 [6] did not give 1, the desired target, but plenty of a new compound without the moiety of diethyl phosphonate.
1HNMR, 13CNMR and MS indicated the product was 2-oxazolidinone 4 [7]. A further experiment by only refluxing
iodide 3 in a little toluene for 8 h was performed to investigate that if iodide 3 could react by itself without P(OEt)3.
The result showed that no 2-oxazolidinone 4 formed by TLC and the iodide 3 did not disappear either. All of these
indicated that P(OEt)3 should catalyze the reaction, namely the iodide 3 underwent an intramolecular reaction in the
catalysis of P(OEt)3 (Scheme 2).
E-mail address: wdthb@163.com.
1001-8417/$ – see front matter # 2010 Han Bing Teng. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.03.035

H.B. Teng / Chinese Chemical Letters 21 (2010) 810–812
811
Scheme 1.
Scheme 2.
The reaction was hypothesized to be a result of intramolecular attack of the carbonyl oxygen of the Boc protecting
group on the alkyl iodide to form the intermediate shown in Scheme 3 [8]. Attack of P(OEt)3 on the t-butyl position of
the intermediate afforded the unexpected product 4.
Base on this hypothesis, when the target compound 1 expected to be obtained according to the above route, the
carbamates should be unsuitable to use as amino-protecting groups in iodide 2, because these protecting groups could
all perform an intramolecular reaction via neighboring-group participation. Replaced iodine group with bromine
group could be an alternative strategy, but it would not avoid the intramolecular reaction essentially despite bromide
had a lower reactivity [9].
So p-toluenesulfonyl (Ts), a non-carbamate amino-protecting group, was employed and the Ts-protected iodide 5
was designed. This compound was difficult to be synthesized from L-aspartic acid by a modification of the procedure
of Ref. [6], but it can be obtained directly according to another literature procedure [10]. The following Arbuzov
reaction of P(OEt)3 with iodide 5 carried out very smoothly and it provided the target compound 6 [11] with 70% yield
(Scheme 4).
In conclusion, the synthesis of the novel organophosphorus compound containing the structure of both b-amino
acid and b-aminophosphonate has been described. It involves the Arbuzov reaction of N-Boc protected iodide 3 with
P(OEt)3 affords the unexpected 2-oxazolidinone 4 and a hypothesis of neighboring-group participation of the
Scheme 3.
Scheme 4.

812
H.B. Teng / Chinese Chemical Letters 21 (2010) 810–812
carbamates has been invoked to explain the result. Moreover, when Ts, a non-carbamate amino-protecting group, is
employed, the target compound has been obtained successfully.
References
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[2] A. Jose, R.R. Paul, R. Mohan, et al. Synthesis 11 (2009) 1829.
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20
[7] Date of compound 4: yield, 64%; m.p. 77–78 8C; ½aꢀD ꢁ 66:1 (c 1, CH2Cl2); 1H NMR (300 MHz, CDCl3): d 2.62 (dd, 1H, J = 6.0 and 17.1 Hz),
2.71 (dd, 1H, J = 8.0 and 16.8 Hz), 3.73 (s, 3H), 4.07 (dd, 1H, J = 6.0 and 8.7 Hz), 4.20-4.29 (m, 1H), 4.57 (t, 1H, J = 8.7 Hz), 6.29 (br, 1H). 13
C
NMR (150 MHz, CDCl3): d 39.55, 49.09, 52.38, 69.72, 159.53, 171.08. MS: m/z 182 [M+Na]+. Anal. Calcd. for C6H9NO4: C, 45.28; H, 5.70;
N, 8.80. Found: C, 45.05; H, 5.82; N, 9.08.
[8] W.P. Malachowski, J.K. Coward, J. Org. Chem. 59 (1994) 7625.
[9] J.K. Coward, R. Lok, J. Org. Chem. 38 (1973) 2546.
[10] C. Ensch, M. Hesse, Helv. Chim. Acta 85 (2002) 1659.
[11] Date of compound 6: 1H NMR (300 MHz, CDCl3): d 1.20–1.31 (m, 9H), 2.04 (dd, 2H, J = 18.1 and 4.5 Hz), 2.58–2.85 (m, 2H), 3.87–4.07 (m,
7H), 5.98 (d, 1H, J = 8.1 Hz), 7.30 (d, 2H, J = 7.2 Hz), 7.76 (d, 2H, J = 7.5 Hz). MS: m/z 422[M+H]+.