Synthesis of 2-amino-2-methyl-4-phosphonobutanoic acids by conjugate addition of lithiated bislactim ether derived from cyclo[Ala-D-Val] to vinylphosphonates

Article abstract of DOI:10.1055/s-1999-3176

Face-selective conjugate addition of lithiated Schollkopf's bislactim ether derived from cyclo[Ala-D-Val] 4 to prochiral vinylphosphonates 5a-c allows a direct and stereocontrolled access to optically pure MAP4 analogues, the 2-amino-2-methyl-4-phosphonob

Full text of DOI:10.1055/s-1999-3176

LETTER
1903
Synthesis of 2-Amino-2-methyl-4-phosphonobutanoic Acids by Conjugate
Addition of Lithiated Bislactim Ether Derived from Cyclo[Ala-D-Val] to
Vinylphosphonates
María Ruiz, Vicente Ojea*, M. Carmen Fernández, Susana Conde, Aniana Díaz, José M. Quintela*
Departamento de Química Fundamental e Industrial, Facultade de Ciencias, Universidade da Coruña. Campus A Zapateira s/n,
15071 A Coruña, Spain.
Fax 34-981-167065; E-mail: vocqfo@udc.es
Received 27 September 1999
Abstract: Face-selective conjugate addition of lithiated
Schˆllkopf’s bislactim ether derived from cyclo[Ala-D-Val] 4 to
prochiral vinylphosphonates 5a-c allows a direct and stereocon-
trolled access to optically pure MAP4 analogues, the 2-amino-2-
methyl-4-phosphonobutanoic acid derivatives 12-15. The relative
stereochemistry was assigned from NMR studies of the cyclic
derivatives 16 and 17. Eight-membered transition states are invoked
to rationalize the stereochemical outcome of the additions.
CO2H
H2N
CO2H
CO2H
H2N
H2N
PO3H2
PO3H2
PO3H2
MPPG (3)
L-AP4 (1)
MAP4 (2)
Key words: phosphonobutanoic acids, a-methyl a-amino acids,
conjugate addition, stereoselective synthesis, vinylphosphonates
Figure 1
In this area, we have recently developed a direct approach
to optically pure 2-amino-4-phosphonobutanoic acids, by
using a highly regio and stereoselective addition of the
lithium salt of bislactim ether derived from cyclo[L-Val-
Gly] to a variety of alkenylphosphonates.4b The high level
of p-facial selectivity found in these processes prompted
us to explore the scope of the reactions between the lithi-
um salt of bislactim ether 4, and prochiral vinylphospho-
nates 5a-c, that could result in a stereocontrolled access to
the desired 2-amino-2-methyl-4-phosphonobutanoic acid
derivatives 6 (see Scheme 1).
L-Glutamic acid mediates fast excitatory transmission at
the majority of central nervous system synapses, and also
participates in neuronal plasticity and neurotoxicity.1 Syn-
aptically released glutamate exerts its effects via activa-
tion of ligand-gated cation channels (ionotropic glutamate
receptors) and metabotropic glutamate receptors
(mGluRs), which modulate intracellular second messen-
gers through G protein-coupled processes. Glutamate
receptors have attracted considerable attention because
of their therapeutic potential for the treatment of a range
of chronic and acute central nervous system disorders
with social significance, such as stroke, epilepsy and
Alzheimer’s disease.2 To date, mGluRs have been distin-
guished into three groups, based on sequence homology,
signal transduction mechanisms and agonist pharmacol-
ogy. In particular, receptors of group III (mGluR4 and
mGluR6-8) are characterized by their selective response
to several phosphonic acid derivatives. Thus, they are se-
lectively activated by L-2-amino-4-phosphonobutanoic
acid (L-AP4, 1 in Figure 1) and competitively antagonized
by the a-methylated derivatives of L-AP4 (MAP4, 2) and
4-phosphonophenylglycine (MPPG, 3).3 Biological re-
search on mGluRs function eagerly demands the develop-
ment of more potent and selective agonist and antagonists.
As the molecular basis for the glutamate recognition and
binding at the mGluRs proteins has not been elucidated
yet, the development of high affinity ligands still relies on
structural modification of established structures and
screening of new lead compounds. As part of a project di-
H2N
1R
CO2H
R2
R2
EtO
N
R1
R3
R3
N
OEt
Et2O3P
H2O3P
a R1=R3=H, R2=Ph
b R1=R2=H, R3=Ph
c R2=R3=H, R1=Ph
6
5a-c
4
Scheme 1
To this end, (3R,6S,R)-2,5-diethoxy-3-isopropyl-6-meth-
yl-3,6-dihydropyrazine (4) was prepared from alanine and
D-valine,5 while vinylphosphonates 5a6 and 5b7 were pre-
pared as described in the literature. 1-Phenylethenylphos-
phonate 5c8 was obtained by condensation of
formaldehyde and the sodium salt of tetraethyl phenyl-
methylenebisphosphonate, which was in turn generated
from diethyl benzylphosphonate.6
4
rected to the design of new bioactive phosphonates we
report now the diastereoselective synthesis of several
MAP4 derivatives, prepared in order to study the stereo-
chemical requirements for a potent binding at group III of
mGluRs.
Synlett 1999, No. 12, 1903–1906 ISSN 0936-5214 © Thieme Stuttgart · New York

1904
M. Ruiz et al.
LETTER
Thus, slow addition of 2-phenylethenylphosphonates 5a,b The separation of the diastereomeric mixtures could be
over a solution of 1.2 equivalents of the lithium salt 7 at achieved by medium pressure liquid chromatography
low temperature led (after quenching with acetic acid, (mixtures AcOEt-hexane, SiO2 230-400 mesh) to provide
aqueous workup and removal side products by flash chro- products of high purity (diastereomeric excesses higher
matography) to mixtures of adducts 8+9 in good yields than 98%) on a multigram scale.10 Vigorous acid hydroly-
(see Scheme 2). Integration of the 1H-decoupled 31P NMR sis of the adducts 8-11 (12 M hydrochloric acid, reflux,
spectra of the crude reaction mixtures revealed opposite 30-40 h) allowed, after removal of the auxiliary D-valine
stereochemical courses in the additions to acceptors with by reverse phase chromatography (H2O, RP-18 230-400
E- and Z-geometry (5a and 5b, respectively), as well as a mesh), the isolation of the amino acids 12, 13, 14 and 15
very high asymmetric induction in the formation of new as their hydrochloride salts in good yields (78-95%, see
chiral centers in both cases. In this way, the observed di- Figure 2).12
astereomeric excesses of the major adducts, the 2,5-trans-
2,1’-anti isomer 8 in case a and the 2,5-trans-2,1’-syn iso-
mer 9 in case b, were greater than 90%.
H2N
Ph
H2N
CO2H
CO2H
H2O3P
H2O3P
Ph
13
12
EtO
N
EtO
N
H2N
Ph
H2N
i 5a or 5b
ii AcOH
Ph
EtO
Li
N
N
N
OEt
OEt
CO2H
H2O3P
CO2H
H2O3P
N
THF, -78 °C
(75 or 83%)
OEt
Ph
Ph
15
14
PO3Et2
PO3Et2
7
Figure 2
8
9
Scheme 2
Since none of compounds 8-15 provided crystals suitable
for X-ray diffraction analysis, we decided to transform
amino acids 13 and 15 to the corresponding oxaphospho-
rinane derivatives 16 and 17. The strong preference for
Addition to 1-phenylethenylphosphonate 5c also took
place regio and stereoselectively, to afford a mixture of
adducts 10+11 in a combined yield of 86%. As creation of
stereocenter at C2’ takes place during the quenching of
the reaction, by protonation of the initially formed anionic
intermediate, diastereoselective formation of the 2,5-
trans-2,2’-anti isomer 10 (with a diastereomeric excess of
50% over the 2,5-trans-2,2’-syn isomer 11) is remarkable.
The asymmetric induction at C2’ could not be completely
suppressed by increasing the temperature of the quench-
ing. When the addition of acetic acid was carried out at
room temperature, the mixture 10+11 was obtained in
similar yield, and 10 was formed with a diastereomeric
excess of 17% over its epimer 11. Evidence supporting the
assignment of the relative configurations was obtained by
NMR analyses of cyclic derivatives, as depicted in Figure
3. Absolute configurations follow from the use of 4, de-
rived from D-valine, as there is ample precedent.9
chair conformation in solution reported for substituted
4b,13
1,2-oxaphosphorinanes
would make such six-mem-
bered cyclic compounds amenable to the assignment of
their relative configuration on the basis of NMR studies.
Thus, after temporary protection of the acidic functional-
ities at amino acids 13 and 15 (hexamethyldisilazane, re-
flux, 12 h), chemoselective reduction of the carboxylic
ester in the presence of the phosphonate group (lithium
borohydride in tetrahydrofuran at room temperature) gave
rise to amino alcohols 18 and 19, in good yields (73 and
78%, respectively). Cyclization to the corresponding
amino-oxaphosphorinanes took place by heating of the
amino alcohols in thionyl chloride (see Scheme 4).
O
H2N
Ph
P
OH
i,ii
iii
H2O3P
NH2
13
15
O
(83%)
(73%)
OH
Ph
18
16
EtO
Ph
EtO
Ph
N
N
Ph
i 5c
ii AcOH
H2N
Ph
O
N
N
iii
OEt
OEt
i,ii
7
P
OH
H2O3P
THF, -78 °C
NH2
O
(62%)
(78%)
OH
(86%)
19
PO3Et2
10
PO3Et2
17
i. HMDS, H2SO4, ∆, 12h. ii. LiBH4 2M in THF, r.t., 24 h. iii. SOCl2, ∆, 14h.
11
Scheme 3
Scheme 4
Synlett 1999, No. 12, 1903–1906 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Amino-2-methyl-4-phosphonobutanoic Acids
1905
1
Both compounds 16 and 17 showed in their H NMR
spectra (200 MHz, D2O, r.t.) a pattern of signals suitable
for the study of their conformation and relative stereo-
chemistry by NOE difference spectroscopy.14 The analy-
ses of the sets of observed NOEs confirmed the presence
of chair conformations in solution, and allowed to con-
clude a trans disposition of the amino and phenyl groups
for amino-oxaphosphorinane 16, while a cis configuration
was assigned for 17. This results were supported by force
field and semiempirical calculations (see Figure 3).15
OEt
OEt
R1
N
H
N
R3
H
THF
THF
N
O
THF
N
R2
EtO
Li
R2
Li
OEt
P
P
THF
OEt
O
R3
EtO
relaxed TS
1R
OEt
OEt
compact TS
Figure 4
H
OEt
N
H
THF
THF
N
EtO
H
Li
OEt
O
P
Ph
OEt
H+ approach
20
Figure 3
Figure 5
Translation of Z- or E-geometry of the acceptor into a syn-
or anti-configuration at the 1,4-addition products was pre-
viously encountered in other conjugate additions of lithi-
ated bislactim ethers (derived from cyclo[Val-Gly]) to
In conclusion, the conjugate addition of lithiated bislactim
ethers derived from cyclo[Ala-Val] to prochiral vi-
nylphosphonates takes place regio and stereoselectively.
For b-substituted vinylphosphonates, the reaction results
in an almost complete translation of the E (or Z) geometry
into a 2,1’-anti- (or 2,1’-syn) configuration at the adducts.
Thus, the level of p-facial discrimination delivered by this
reagent/substrate couple enables a stereoregulated access
to a variety of optically pure 2-amino-2-methyl-4-
phosphonobutanoic acid derivatives, potential antagonists
at mGluRs of type III.
a,b-unsaturated
systems
(2-alkenoates17
and
alkenylphosphonates4b). Thus, the stereochemical course
of the additions of lithium salt of 4 to acceptors 5a,b can
be rationalized by extending the transition state model
proposed for the 1,4-additions of lithiated bislactim ethers
derived from cyclo[Val-Gly] to alkenylphosphonates.18 In
this way, an initial lithium-phosphoryl coordination to
form a chelate complex, followed by a rate-determining
reorganization through competitive eight-membered cy-
clic transition structures, can also account for the stereo-
chemical features of these conjugate additions. According
to such a model, the 2,1’-anti/syn stereoselection relies on
the energy difference between the TSs resulting from the
like or unlike approach of the Si face of the enolate (trans
to the isopropyl group) to the prochiral faces of the Cb at
the alkenyl moiety. As previously found for other conju-
gate additions of lithiated bislactim ethers to alkenyl and
1,3-butadienylphosphonates, the stereochemical response
of the reaction to the acceptor geometry can be rational-
ized by invoking a strong kinetic preference for the com-
pact transition states over the relaxed counterparts (see
figure 4).
Acknowledgement
Financial support from Xunta de Galicia (XUGA 10306A98) and
CICYT (SAF970184) is gratefully acknowledged. M. C. F., S. C.
and A. D. thank Universidade da Coruña for the grants awarded.
References and Notes
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Fernández, M. C.; Ruiz, M.; Quintela, J. M. Tetrahedron Lett.
1996, 37, 5801.
The stereoselective protonation of the phosphonate car-
banion resulting from the addition to 5c suggests the in-
volvement of a cyclic chelate complex like 20 (see Figure
5). Axial protonation (under stereoelectronic control) or
the approach of the electrophile to the less hindered face
of the cyclic phosphonate carbanion, may account for the
2,2’-anti stereoselection in this case.
Synlett 1999, No. 12, 1903–1906 ISSN 0936-5214 © Thieme Stuttgart · New York

1906
M. Ruiz et al.
LETTER
(5) Schöllkopf, U.; Groth, U.; Westphalen, K.-O.; Deng. C.
Synthesis 1981, 969. Alternatively, (3R,6S,R)- and (3S,6S,R)-
3-isopropyl-2,5-dimethoxy-6-methyl-3,6-dihydropyrazine
can be purchased from Merck-Schuchardt.
(6) Teulade, M. P.; Savignac, P.; Aboujaoude, E. E.; Liétge, S.;
Collignon, N. J. Organomet. Chem. 1986, 304, 283.
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(10) All new compounds have been isolated in a pure analytical
form after chromatography (on SiO2 or RP-18), and their
spectral data (EIMS or FABMS, NMR and IR) were
consistent with the proposed structure. Spectral data obtained
for compounds 5a-c are in full agreement with those
previously reported in refs. 6, 11 and 8, respectively.
(11) Cristau, H.-J.; Yangkou Mbianda, X.; Beziat, Y.; Gasc, M.-B.
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135.1 (d, J = 8.3 Hz) (Ph), 173.2 (C-1); [a]D23 = +20.6
(c = 0.8, H2O).
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NOE experiments were recorded in a BRUKER AC200
spectrometer, using the NOEMULT.AU software for
ASPECT3000 computers.
(15) Minimum energy conformations for compound 16 and 17
were located using MMX force field as implemented in
PCModel v5 and GMMX v1.6 programs.16a The geometries of
the most important conformers were fully optimised by
semiempirical molecular orbital calculations, using the PM3
Hamiltonians included the MOPAC97 16b module of CS
Chem3D Pro.16c The refined geometry in the gas phase was in
agreement with the conformation in solution deduced from 1H
NOE spectroscopy, as depicted in Fig.3.
(12) Selected data for amino acids:12.HCl:13C NMR (50 MHz,
D2O) d:21.7 (CH3), 29.7 (d, J = 134.6 Hz, C-4), 48.3 (d,
J = 2.0 Hz, C-3), 65.1 (d, J = 17.3 Hz, C-2), 129.5, 130.0,
130.2, 137.0 (d, J = 2.0 Hz) (Ph), 174.7 (C-1); [a]D20 = -23.7
(c = 0.5, H2O). 13.HCl:13C NMR (50 MHz, D2O) d:21.0
(CH3), 29.8 (d, J = 136.4 Hz, C-4), 48.8 (d, J = 2.2 Hz, C-3),
66.5 (d, J = 17.2 Hz, C-2), 130.9, 131.3, 132.0, 138.5 (Ph),
176.2 (C-1); [a]D20 = -3.4 (c = 0.7, H2O). 14.HCl:13C NMR
(50 MHz, D2O) d:21.7 (CH3), 37.4 (C-3), 41.9 (d, J = 133.0
Hz, C-4), 60.9 (d, J = 17.6 Hz, C-2), 129.0 (d, J = 3.3 Hz),
130.0 (d, J = 3.0 Hz), 130.2 (d, J = 6.3 Hz), 135.9 (d, J = 8.3
Hz) (Ph), 173.6 (C-1); [a]D27 = +8.1 (c = 0.4, H2O).
(16) a) PCModel version 5 (Molecular Modelling Software) and
GMMX version 1.6. (Global Conformational Search
Program), from Serena Software, Bloomington, IN 47402,
USA. b) Revised version of MOPAC93, Fujitsu Ltd, Tokyo,
Japan 1993. c) CS Chem3D Pro, version 4.0. Molecular
Modeling and Analysis Program from CambridgeSoft
Corporation, Cambridge, MA 02139, USA.
(17) Schöllkopf, U.; Pettig, D.; Busse, U.; Egert, E.; Dyrbusch, M.
Synthesis 1986, 737.
(18) Ojea, V.; Ruiz, M.; Vilar, J.; Quintela, J. M. Tetrahedron:
Asymmetry 1996, 7, 3335.
15.HCl:13C NMR (50 MHz, D2O) d:23.4 (CH3), 37.4 (C-3),
41.0 (d, J = 134.7 Hz, C-4), 60.9 (d, J = 16.6 Hz, C-2), 128.8
(d, J = 3.6 Hz), 129.5 (d, J = 2.7 Hz), 130.2 (d, J = 6.6 Hz),
Article Identifier:
1437-2096,E;1999,0,12,1903,1906,ftx,en;L14399ST.pdf
Synlett 1999, No. 12, 1903–1906 ISSN 0936-5214 © Thieme Stuttgart · New York