Diastereoselective synthesis of 4-substituted 2-amino-4-phosphonobutanoic acids

Article abstract of DOI:10.1016/S0957-4166(02)00082-4

Conjugate additions of the lithiated bis-lactim ether derived from cyclo-[Gly-D-Val] 1 to α-substituted vinylphosphonates 2 or electrophilic substitutions on the lithiated bis-lactim ether derived from cyclo-[L-AP4-D-Val] 5 allow direct and stereoselectiv

Full text of DOI:10.1016/S0957-4166(02)00082-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 233–237
Diastereoselective synthesis of 4-substituted
2-amino-4-phosphonobutanoic acids
M. Carmen Ferna´ndez,† Jose´ M. Quintela, Mar´ıa Ruiz* and Vicente Ojea*
Departamento de Qu´ımica Fundamental, Facultade de Ciencias, Universidade da Corun˜a, Campus da Zapateira, s/n, 15071
A Corun˜a, Spain
Received 29 January 2002; accepted 18 February 2002
Abstract—Conjugate additions of the lithiated bis-lactim ether derived from cyclo-[Gly-
D
-Val] 1 to a-substituted vinylphospho-
-AP4- -Val] 5 allow direct and
nates 2 or electrophilic substitutions on the lithiated bis-lactim ether derived from cyclo-[
L
D
stereoselective access to a series of 4-substituted AP4 derivatives 3 in enantiomerically pure form. © 2002 Elsevier Science Ltd.
All rights reserved.
The physical and structural similarity between the
phosphonic acid group and the biologically important
phosphate ester and carboxylic acid moieties gives 2-
amino-4-phosphonobutanoic acid (AP4) derivatives the
ability to act as substrate mimics and interfere with
significant enzymatic and receptor-mediated processes.
Thus, AP4 constitutes a glutamate analog where the
distal carboxylate group is replaced by a phosphonic
acid group. In this manner, several AP4 derivatives
have shown potent and selective agonistic character at
group III of the metabotropic glutamate receptors
(mGluRs), which play fundamental roles in the central
nervous system and are attractive targets for therapeu-
tic intervention in a number of neurological diseases.1,2
In addition, AP4 derivatives constitute non-hydrolyz-
able isosteres of O-phosphoserine and O-phospho-
threonine where the phosphoryl ester oxygen is
substituted by a methylene linkage. Such phosphonyl-
ated analogs have been incorporated into useful
peptides3 for the biochemical and immunochemical
investigation of the Ser/Thr protein kinases and phos-
phatases, which are recognized as key elements in the
regulation of cell function.4
bonyl compounds which were subsequently converted
to amino acids via Strecker reaction,5 or have been
reacted with halides,6a,b triflates3d,6c or carbonyl3b,d,e
functionalities located at the side chain of amino acid
derivatives. Alternative syntheses have relied on glycine
enolate equivalents for the alkylation,7 1,3-dipolar
cycloaddition8 and conjugate addition9 of suitable func-
tionalized phosphonates.
In this area, we have shown that conjugate additions of
lithiated bis-lactim ethers, derived from cyclo-[Gly-D-
Val] 1 (Scheme 1) and cyclo-[Ala-
D
-Val], to b-substi-
tuted vinylphosphonates enable
a stereocontrolled
access to enantiomerically pure 2-methyl and/or 3-sub-
stituted AP4 derivatives.9a–c Studying the reactivity of
the lithium azaenolate derived from cyclo-[Ala-D-Val],
OEt
Li
N
PO3Et2
conjugate
addition
N
R
OEt
1
2
4
HO2C
PO3H2
The extensive interest in AP4 derivatives has led to the
development of numerous syntheses, most of them
related to three major methodologies. Thus, phosphites
have been utilized for the conjugate addition to car-
NH2
R
OEt
2´
Y
PO3Et2
3
N
electrophilic
substitution
RX
N
4, Y = H
5, Y = Li
lithium
base
OEt
* Corresponding authors. Tel.: +34-981167000; fax: +34-981167065;
e-mail: ruizpr@udc.es; ojea@udc.es
† Present address: Ely Lilly, Alcobendas, Madrid.
Scheme 1. Approaches to 4-substituted AP4 derivatives.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00082-4

234
M. C. Ferna´ndez et al. / Tetrahedron: Asymmetry 13 (2002) 233–237
we also observed remarkable stereoselection in the 1,4-
addition when O,O-diethyl 1-phenylethenylphospho-
nate was used as the acceptor.9b These precedents
prompted us to explore the scope and limitations of the
additions of lithiated bislactim 1 to a series of a-substi-
tuted vinylphosphonates 2, which could result in a
direct route to enantiomerically pure 4-substituted AP4
derivatives 3, useful for delineating the requirements for
receptor binding and physiological responses at group
III of the mGluRs.
quenching with acetic acid and work-up, 31P NMR
analysis of the crude mixtures revealed the formation of
mixtures of 1:1 and 1:2 addition products (6–9b–g and
10a–g, respectively) along with oligomerization prod-
ucts in the reaction of 2a (see Scheme 2).
Both the ratio between 1:1 and 1:2 adducts and the
stereoselectivity of the addition were found to be
markedly dependent on the nature of the a-substituent
of the acceptor (see Table 1). Thus, vinylphosphonates
2f and 2g with an electron-withdrawing substituent as
the methoxycarbonyl or the diethoxyphosphoryl group,
gave rise to the 1:1 adducts in lower proportion than
vinylphosphonates 2b–e (with phenyl, silyl, stannyl or
phosphoryloxy groups) probably due to the increased
electron deficiency and higher acceptor character of the
former acceptors. Moreover, the addition to vinylphos-
phonates 2b–e took place in a highly diastereoselective
fashion and led to the exclusive formation of 2,5-trans
adducts 6b–e and 7b–e (see Fig. 1), while acceptors 2f
and 2g gave rise to mixtures of all of the possible
2,5-trans and 2,5-cis adducts.14,15 In cases d and f,
conversion to the desired 1:1 adducts could be
increased simply by using an excess of the lithium
azaenolate.16 After chromatographic separation, the
fractions containing the adducts 6–9b–g were isolated in
moderate to good yields. Evidence supporting their
relative configuration was obtained by NMR analy-
sis.17,18 The assignment of absolute configurations fol-
low from the use of bis-lactim ethers derived from
Aimed toward the development of an alternative
approach to the AP4 derivatives 3, we decided to
investigate the electrophilic substitution processes on
the bis-lactim ether 4,7b derived from cyclo-[
L-AP4-D-
Val]. Based on its potential role as first intermediate
resulting from the addition of 1 to the unsubstituted
vinylphosphonate,9d the phosphonate carbanion
5
should be accessible by treatment of 4 with an adequate
base. Subsequent trapping of 5 with different elec-
trophilic reagents (RX) could give rise to 2%-substituted
bis-lactim ethers as precursors of the targeted 4-substi-
tuted AP4 derivatives.10
To this end, (3R)-2,5-diethoxy-3-isopropyl-3,6-dihydro-
pyrazine was prepared from glycine and
D
-valine11 and
was transformed into (2S,5R)-3,6-diethoxy-2-[2-(di-
ethoxyphosphoryl)ethyl]-2,5-dihydro-5-isopropylpyra-
zine 4,13 while a-substituted vinylphosphonates were
obtained according to the literature. Upon addition of
vinylphosphonates 2a–g to one equivalent of 1 at
−78°C in THF, reactions took place rapidly. After
D
-Val, as there is ample precedent.14
OEt
OEt
PO3Et2
PO3Et2
OEt
N
N
PO3Et2
N
R
N
R
a,b
(60-98%)
N
1 + 2a-g
N
R
OEt
OEt
6
7
(2,5-trans-2,2´-anti)
(2,5-trans-2,2´-syn)
6-9b-g
OEt
OEt
OEt
OEt
PO3Et2
PO3Et2
PO3Et2
R
PO3Et2
R
N
N
N
oligomers (11a)
N
R
R
N
N
10a-g
OEt
OEt
OEt
9
8
(2,5-cis-2,2´-syn)
(2,5-cis-2,2´-anti)
Scheme 2. Conjugate additions of 1 to vinylphosphonates
2a–g. (a) THF, −78°C, 5 min. (b) AcOH, −78°C to rt.
Figure 1. Diastereomeric 2%-substituted bis-lactim ethers 6–9.
Table 1. Selectivity and yields in the conjugate addition of 1 to vinylphosphonates 2a–g
Case
R
1 (equiv.)
1:1 adducts
10 (%)
11 (%)
(%)
6/7/8/9
2a
2b
2c
2d
2d
2e
2f
Me
Ph
TMS
SnPh3
SnPh3
OPO3Et2
CO2Et
CO2Et
PO3Et2
1.1
1.1
1.2
1.1
2.2
1.2
1.2
2.2
1.2
–
–
42
5
11
42
15
8
65
42
25
27
–
–
–
–
–
–
–
–
85
72
42
78
83
25
56
35
1:1:–:–
1:1:–:–
1:1:–:–
1:1:–:–
1:1:–:–
4:4:3:3
4:4:3:3
3:2a
2f
2g
a Refers to the 6g/8g ratio (there is no anti/syn isomerism in case g).

M. C. Ferna´ndez et al. / Tetrahedron: Asymmetry 13 (2002) 233–237
235
We reasoned that the formation of 1:1 mixtures of
adducts 6b–e/7b–e should take place with quenching by
a non-selective protonation of the 2,5-trans-phospho-
nate carbanions arising from the stereoselective addi-
tion to vinylphosphonates 2b–e. Such phosphonate
carbanions should be sufficiently stabilized,19 thus sup-
pressing transmetallation processes that could compro-
mise the integrity of the newly formed stereogenic
center at position 2. With these ideas in mind and
pursuing a more general and stereoselective route to
4-substituted AP4 derivatives, we decided to explore the
scope and limitations of the electrophilic substitution
process, ‘via enolate’, on the bis-lactim ether 4.
Mild acid hydrolysis of the 2%-substituted bis-lactims
6a–c,e,g and 7a–c,e,g provided the corresponding 2,4-
anti or 2,4-syn amino esters 12 or 13 (see Scheme 4) in
high yields after removal of the valine ester by chro-
matography. Hydrolysis of these amino esters was
accomplished by either heating in concentrated hydro-
chloric acid (in cases a, b, and g) or sequential treat-
ment with lithium hydroxide and trimethylsilyl bromide
(in cases c and e). After purification by reversed phase
chromatography, the 4-substituted AP4 derivatives 3a–
c,e,g, either in the 2,4-anti or in the 2,4-syn series, were
isolated in high yields.
Slow addition of bis-lactim ether 4 to a solution of
LDA in THF at −78°C was followed, after 15 min at
the same temperature, by the dropwise addition of the
electrophilic reagent. The reactions were quenched 5
min later by adding a proton source. After the work-
up, the 31P NMR analysis of the crude mixtures
revealed a highly regioselective course for the substitu-
tion process, which, in spite of the literature,20 led to
the exclusive formation of 2%-substituted bis-lactims 6–
8a,c–g (see Scheme 3).
Since none of compounds 3, 6–9, 12 or 13 provided
crystals suitable for X-ray diffraction analysis, we
decided to derivatize the amino esters to the corre-
sponding 1,2-oxaphosphorinanes. The strong prefer-
ence for chair conformations in solution reported for
related oxaphosphorinanes3d,9a–c,21 would make such
derivatives amenable for the assignment of their relative
configuration on the basis of NMR studies. Thus, after
protection of the amino group as a tert-butylcarba-
mate, chemoselective reduction of the carboxylic ester
took place with partial cyclization to N-Boc-amino-
oxaphosphorinanes. Finally, cleavage of the N-Boc and
O-ethyl ester groups by treatment with trimethylsilyl
bromide yielded 14a–c and 15a–c (see Scheme 5).
1
Integration of the H decoupled 31P NMR spectra also
revealed moderate levels of asymmetric induction at the
substitution position, depending upon the nature of the
electrophilic reagent (see Table 2). In this way, for the
cases a,d–g, the substitution processes took place with a
complete retention of the 2,5-trans configuration,
affording mixtures of the 2,2%-anti and 2,2%-syn products
6/7 in 1:2 or 2:3 ratios. In contrast, the silylation of 5,
though regio- and stereoselective at the 2%-position,
took place with a significant degree of racemization at
position 2, and led to mixtures of the 2,5-cis and
2,5-trans products 6c/7c/8c in a 1:4:1 ratio.
The analysis of the sets of observed NOEs confirmed a
cis configuration for all the oxaphosphorinanes 14a–c,
while a trans relationship was assigned to the oxaphos-
phorinanes 15a–c. These results allow us to assume a
2,2%-syn configuration for the major substitution prod-
ucts. The syn selectivity in the substitution process can
EtO2C
(72-92%)
PO3Et2
HO2C
PO3H2
a
b or c
6
(63-95%)
NH2
R
NH2 R´
2,4-anti-3a-c,e,g
12a-c,e,g
EtO2C
PO3Et2
HO2C
PO3H2
b or c
a
7
(75-90%)
(85-90%)
NH2
R
NH2 R´
2,4-syn-3a-c,e,e´
13a-c,e,e´
Scheme 4. Hydrolysis of 2%-substituted bis-lactim ethers 6 and
7. (a) 0.25N HCl, THF, rt, 1–15 h. (b) 12N HCl, reflux, 6 h.
(c) i: LiOH, H2O, rt, 1 h. ii: TMSBr, CH2Cl2, rt, 48 h. iii:
MeOH. Legend: a, R=R%=Me; b, R=R%=Ph; c, R=R%=
TMS; e, R=OPO3Et2, R%=OPO3H2; e%, R=R%=OH; g, R=
PO3Et2, R%=PO3H2.
Scheme 3. Electrophilic substitutions on bis-lactim ether 4.
(a) LDA, THF, −78°C, 15 min. (b) RX, THF, −78°C, 5 min.
(c) AcOH or H2O, −78°C to rt.
Table 2. Selectivity and yields in the electrophilic substitu-
tions on 5
O
P
O
P
HO
O
HO
O
R
R
H+ source
(%) 6/7/8
a,b,c
a,b,c
Case
R
Electrophile
12a-c
13a-c
(26-65%)
(23-60%)
14a-c
15a-c
a
c
d
e%
f
Me
MeI
–
–
–
84
85
75
59
66
83
2:3:–
1:4:1
2:3:–
1:2:–
2:3:–
1:–a
NH2
NH2
TMS
SnPh3
OH
CO2Et
PO3Et2
TMSCl
SnPh3Cl
MoOPH
CO3Et2
Et2PO3Cl
Scheme 5. Transformation of amino esters 12,13a–c into their
oxaphosphorinane derivatives 14,15a–c. (a) (Boc)2O, diox-
ane:H2O, rt, 2–7 h. (b) i: LiBH4, THF, 0°C, 15 h–4 d. ii: H2O.
(c) i: TMSBr, CH2Cl2, rt, 15 h. ii: MeOH. Legend: a, R=Me;
b, R=Ph; c, R=TMS.
H2O
AcOH
AcOH
g
a Refers to the 6g/8g ratio (there is not anti/syn isomerism in case g).

236
M. C. Ferna´ndez et al. / Tetrahedron: Asymmetry 13 (2002) 233–237
be rationalized considering the involvement of a cyclic
phosphonate carbanion such as 5 with preferential
approach of the electrophile with an axial trajectory to
its less hindered face (see Scheme 3).
parini, F.; Flor, P. J.; Kuhn, R.; Vranesic, I. Bioorg. Med.
Chem. Lett. 2000, 10, 1447–1450.
7. (a) Soloshonok, V. A.; Belokon, Y. N.; Kuzmina, N. A.;
Maleev, V. I.; Svistunova, N. Y.; Solodenko, V. A.;
Kukhar, V. P. J. Chem. Soc., Perkin Trans. 1 1992,
1525–1529; (b) Scho¨llkopf, U.; Busse, U.; Lonsky, R.;
Hinrichs, R. Liebigs Ann. Chem. 1986, 2150–2163.
8. (a) Casas, J.; Grigg, R.; Na´jera, C.; Sansano, J. M. Eur.
J. Org. Chem. 2001, 1971–1982; (b) Matoba, K.;
Yonemoto, H.; Fukui, M.; Yamazaki, T. Chem. Pharm.
Bull. 1984, 32, 3918–3925.
9. (a) Ojea, V.; Ruiz, M.; Shapiro, G.; Pombo-Villar, E. J.
Org. Chem. 2000, 65, 1984–1995; (b) Ruiz, M.; Ojea, V.;
Ferna´ndez, M. C.; Conde, S.; D´ıaz, A.; Quintela, J. M.
Synlett 1999, 1903–1906; (c) Ojea, V.; Ferna´ndez, M. C.;
Ruiz, M.; Quintela, J. M. Tetrahedron Lett. 1996, 37,
5801–5804; (d) Shapiro, G.; Buechler, D.; Ojea, V.;
Pombo-Villar, E.; Ruiz, M.; Weber, H.-P. Tetrahedron
Lett. 1993, 34, 6255–6258; (e) Minowa, N.; Hirayama,
M.; Fukatsu, S. Tetrahedron Lett. 1984, 25, 1147–1150.
10. For previous asymmetric syntheses of phosphonic acids
using phosphoryl-stabilized carbanions, see: (a) Den-
mark, S. E.; Chen, Ch. T. J. Am. Chem. Soc. 1995, 117,
11879–11897 and references cited therein; (b) Hanessian,
S.; Bennani, Y. L. Tetrahedron Lett. 1990, 31, 6465–6468.
In conclusion, either the conjugate additions of lithiated
bis-lactim ether derived from cyclo-[Gly- -Val] to a-
D
substituted vinylphosphonates or the electrophilic sub-
stitutions on the bis-lactim ether derived from
cyclo-[L-AP4-D-Val] take place regio- and stereoselec-
tively. Although the level of stereoselection attained in
these processes depends on the nature of the a-sub-
stituent or the electrophilic reagent, they allow a direct
access to a variety of 4-substituted AP4 derivatives in
enantiomerically pure form. Work is now underway to
extend these methodologies to the synthesis of 4-alkyli-
dene derivatives of glutamate and AP4. Evaluation of
the biological activity of these amino acids is currently
in progress.
Acknowledgements
We gratefully acknowledge the Ministerio de Ciencia y
Tecnolog´ıa (BQU2000-0236) and the Xunta de Galicia
(PGIDT00PXI10305PR) for financial support.
11. cyclo-[Gly-D-Val] was obtained as described by Rose et
al. Treatment of this compound with triethyloxonium
tetrafluoroborate allowed the preparation of the 2,5-
diethoxy pyrazine derivative. See Rose, J. E.; Leeson, P.
D.; Gani, D. J. Chem. Soc., Perkin Trans. 1 1995, 157–
165. Alternatively, both enantiomers of the related 2,5-
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1
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from an increased reactivity of acceptors 2f and 2g, as
was suggested by the Editor.
16. The excess of the Scho¨llkopf reagent could be almost
completely recovered and showed no racemization.
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between 3.67 and 3.91 ppm, as a triplet with 5JH2H5
close to 3.5 Hz, typical for a trans relation of substituents
at the pyrazine ring (see Ref. 17). The relative configura-
tions at position 2% were assigned on the basis of the sets
of NOEs observed for the 1,2-oxaphosphorinane deriva-
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19. Probably by chelation of the lithium with the phosphoryl
oxygen and a nitrogen atom of the bis-lactim ring, as
depicted in Scheme 3.

M. C. Ferna´ndez et al. / Tetrahedron: Asymmetry 13 (2002) 233–237
237
20. The lithium salt of the bis-lactim ether derived from
cyclo-[ -AP4- -Val] was reported to react with alkyl
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D
L
bromides to yield, exclusively, 2-alkylated bis-lactims. See
Ref. 7b.