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

Article abstract of DOI:10.1016/S0040-4039(02)01275-3

Olefination of α-silyl-, α-phosphoryl- and α-stannyl-stabilised phosphonate carbanions derived from cyclo-[L-AP4-D-Val] Li⁺4b-d^- allow a (Z)-selective access to the α,β-substituted vinylphosphonates 7A-E that have been transformed in

Full text of DOI:10.1016/S0040-4039(02)01275-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5909–5912
Diastereoselective synthesis of
4-alkylidene-2-amino-4-phosphonobutanoic acids
M. Carmen Ferna´ndez,† Mar´ıa Ruiz,* Vicente Ojea* and Jose´ M. Quintela
Departamento de Qu´ımica Fundamental, Universidade da Corun˜a, Campus da Zapateira s/n, 15071 A Corun˜a, Spain
Received 25 June 2002; revised 27 June 2002; accepted 28 June 2002
Abstract—Olefination of a-silyl-, a-phosphoryl- and a-stannyl-stabilised phosphonate carbanions derived from cyclo-[L-AP4-D-
Val] Li+4b–d− allow a (Z)-selective access to the a,b-substituted vinylphosphonates 7A–E that have been transformed into
enantiomerically pure 4-alkylidene AP4 derivatives 12A,B and 13A,C. According to semi-empirical (PM3) calculations, the
preference for like topologies in the intermediate adducts of the phosphonate addition step accounts for the highly (Z)-selective
course of the ‘tin-Peterson-like’ olefination. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
As part of an ongoing program aimed to the search of
agonists and antagonists for the group III of mGluRs,3
in this communication we wish to report the synthesis
of a series of (4Z)- and (4E)-alkylidene AP4 derivatives
1 in enantiomerically pure form (see Scheme 1). In this
area, we have recently found that electrophilic substitu-
As the major excitatory neurotransmitter in the central
nervous system, (S)-glutamic acid operates through
different classes and subtypes of ionotropic and
metabotropic glutamate receptors (iGluRs and
mGluRs, respectively) which constitute potential targets
for therapeutic intervention in a number of neurological
disorders.1 In particular, several phosphonic acid
isosters of glutamic acid, the 2-amino-4-phosphonobu-
tanoic acid (AP4) derivatives, have been found to have
potent and selective activity at group III of mGluRs
(mGluR4 and mGluR6-8).2 Therefore, there is consid-
erable interest in the development of practical and
versatile methodology for the preparation of AP4
derivatives, that may result in useful tools for charac-
terising the molecular pharmacology of the mGluRs.
tions on the bis-lactim ether derived from cyclo-[
-Val] 2a take place in a regioselective fashion, a to the
L-AP4-
D
phosphonate group, and allow a direct and stereoselec-
tive access to a variety of 4-substituted AP4 deriva-
tives.3a Based on these precedents we envisaged that
electrophilic substitutions on 2a with phosphonyl, silyl
or stannyl groups could be followed by Wadsworth–
Emmons or Peterson-like olefinations of carbonyl com-
pounds, giving rise to the vinylphosphonates 3,4 as
precursors of the targeted 4-alkylidene AP4 derivatives.
2. Results and discussion
O
EtO
EtO
X
H2N
CO2H
We first examined the olefination reactions of benzalde-
N
N
R
R
hyde, as model carbonyl compound, using the a-
N
N
OEt
OEt
trimethylsilyl-,
a-diethoxyphosphoryl-
and
R
PO3H2
a-triphenylstannyl-stabilised phosphonate carbanions
derived from bis-lactim ethers 2b–d. Towards this end,
the phosphonate carbanion Li+4b− was generated by
the addition of a-silylvinylphosphonate 65 to a solution
of lithium azaenolate 5, derived from (3R)-2,5-
diethoxy-3-isopropyl-3,6-dihydropyrazine,6 at −78°C in
THF, while Li+4c− and Li+4d− were prepared by adding
bis-lactim ethers 2c and 2d3a to solutions of LDA at
−78°C in THF (see Scheme 2).8 Benzaldehyde was
slowly added 15 min later, and the reaction mixtures
were gradually warmed to 0°C during 4 h. After
PO3Et2
1
PO3Et2
2a−d
3
Scheme 1. a, X=H; b, X=SiMe3; c, X=PO3Et2; d, X=
SnPh3.
Keywords: tin-Peterson-like olefination; phosphono amino acid; PM3
semi-empirical calculations.
* Corresponding authors. Tel.: +34-981167000; fax: +34-981167065;
e-mail: ruizpr@udc.es; ojea@udc.es
† Present address: Lilly S.A., Alcobendas, Madrid. Spain.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01275-3

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M. C. Ferna´ndez et al. / Tetrahedron Letters 43 (2002) 5909–5912
place with an outstanding level of stereoselection giving
rise, exclusively, to the kinetically favoured (Z)-
vinylphosphonates.
The selective formation of (Z)-vinylphosphonate 7A in
the Wadsworth–Emmons olefination of benzaldehyde
with Li+4c− is remarkable, since the reactions of car-
bonyl compounds with lithioalkylidenebisphosphonates
have been reported to yield selectively b- and a,b-sub-
stituted vinylphosphonates with (E)-configuration.4g–l
Conversely, the stereochemical course of the ‘tin-Peter-
son-like’ olefinations with Li+4d− is similar to that
previously encountered in the preparation of other a,b-
substituted vinylphosphonates.4e The exclusive forma-
tion of the (Z)-vinylphosphonates 7A–D in the
reactions of the a-triphenylstannylphosphonate carban-
ion with aldehydes 9A–D can be understood as a
consequence of the preferential formation of the like
a-stannyl-b-alkoxyphosphonates which then irre-
versibly collapse to the (Z)-vinylphosphonates. Pre-
sumably, the higher stereoselectivity observed in the
present work may be accounted for the additional
coordination of the lithium cation with a nitrogen atom
of the bis-lactim ether moiety. In agreement with this
proposal, semi-empirical molecular orbital calculations
(PM3 Hamiltonian) for the addition process of Li+4d−
to benzaldehyde (9A) showed that the like transition
structure and the like intermediate adduct are preferred
to the unlike ones by 2.3 and 3.6 kcal/mol, respectively
(see Fig. 1).14–17
Scheme 2. Reagents and conditions: (i) THF, −78°C, 15 min;
(ii) LDA, THF, −78°C, 15 min; (iii) benzaldehyde, THF, −78
to 0°C, 4 h (70–85%). b, X=SiMe3; c, X=PO3Et2; d, X=
SnPh3.
quenching with acetic acid and aqueous work-up, the
2%-benzylidene substituted bis-lactim ethers 7A/8A were
isolated in 56–77% yield, along with 10–25% of unre-
acted starting materials.9,10 The analysis of the 31P
NMR spectra of the crude mixtures revealed different
levels of stereoselection in the formation of the new
double bond. Thus, olefinations with the a-trimethylsi-
lyl- and a-diethoxyphosphoryl-stabilised phosphonate
carbanions Li+4b− and Li+4c− led to mixtures of 2,5-
trans-2%Z and 2,5-trans-2%E bis-lactim ethers 7A/8A in
3:2 and 5:1 ratio, respectively. However, starting with
the 2%-triphenylstannyl substituted bis-lactim 2d, the
‘tin-Peterson-like’ olefination gave rise, exclusively, to
the (Z)-vinylphosphonate 7A. After chromatographic
separation of the 2%-benzylidenated bis-lactim ethers,
evidence supporting their relative configurations was
obtained from NMR analysis.11–13
Scheme 3. B, R1=(CH3)2CH, R2=H; C, R1=2-(C4H3S),
R2=H; D, R1=C6H5CHꢀCH, R2=H; E, R1+R2=-(CH2)5-.
Having shown the feasibility of performing the olefina-
tion process on the bis-lactim ethers derived from
cyclo-[
L
-AP4-
D
-Val]
without
compromising
the
integrity of its chiral centers, a series of vinylphospho-
nates 7B–E was prepared in moderate yield, by applica-
tion of the ‘tin-Peterson-like’ reaction to various
structurally diverse carbonyl compounds (see Scheme
3). Thus, solutions of isobutyraldehyde (9B), 2-thienyl-
carboxaldehyde (9C), cinnamaldehyde (9D) or ciclohex-
anone (9E) in THF were added dropwise to solutions of
Li+4d− in THF at −78°C, and the reaction mixtures
were gradually warmed to 0°C during 4 h. After
quenching with acetic acid and aqueous work-up,
vinylphosphonates 7B–E were isolated in 50–61% yield,
along with 10–32% of unreacted starting materials.9–11
As was previously encountered in the reaction of Li+4d−
with benzaldehyde, after inspection of the 31P NMR
spectra of the crude mixtures obtained in the reactions
with the aldehydes 9B, 9C, and 9D, we could not detect
any absorption corresponding to the minor (E)-iso-
mers. Thus, the ‘tin-Peterson-like’ olefinations of either
a-branched, a,b-unsaturated, aromatic or heteroaro-
matic aldehydes using the a-triphenylstannylphospho-
Figure 1. Competitive like and unlike intermediate adducts
located at the PM3 level for the reaction of Li+4d− with 9A in
the presence of one THF molecule. Hydrogen atoms are
omitted, except for the chiral centers. Relative energies to the
monosolvated coordination complex Li+4d−·9A are in kcal/
mol.
nate lithium salt derived from cyclo-[L-AP4-D-Val] take

M. C. Ferna´ndez et al. / Tetrahedron Letters 43 (2002) 5909–5912
5911
Mild acid hydrolysis of the pyrazine moiety of the
References
vinylphosphonates 7A–C and 8A (0.25N HCl, THF, rt,
1–5 h) provided the corresponding amino esters 10A–C
and 11A in good yields (75–90%) after the removal of
the valine ester by chromatography (see Fig. 2).
Hydrolysis of amino esters 10A,B and 11A to the
corresponding amino acids 12A,B and 13A was accom-
plished by heating in concentrated hydrochloric acid
(12N HCl, reflux, 3 h). Hydrolysis of the thienyl substi-
tuted amino ester 10C required a sequential treatment
with trimethylsilyl bromide (CH2Cl2, rt, 40 h) and
lithium hydroxide (H2O, rt, 2 h). Under these condi-
tions, complete isomerisation of the double bond to
afford the corresponding (E)-vinylphosphonic acid 13C
was observed. After purification by reversed phase
chromatography, the 4-alkylidene AP4 derivatives
12A,B and 13A,C were isolated in good yields (68–
89%).18
1. Bra¨uner-Osborne, H.; Egebjerg, J.; Nielsen, E. O.; Mad-
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2609–2645.
2. Schoepp, D. D.; Jane, D. E.; Monn, J. A. Neuropharma-
cology 1999, 38, 1431–1476.
3. (a) Ferna´ndez, M. C.; Quintela, J. M.; Ruiz, M.; Ojea, V.
Tetrahedron: Asymmetry 2002, 13, 233–237; (b) Ojea, V.;
Ruiz, M.; Shapiro, G.; Pombo-Villar, E. J. Org. Chem.
2000, 65, 1984–1995; (c) Ruiz, M.; Ojea, V.; Ferna´ndez,
M. C.; Conde, S.; D´ıaz, A.; Quintela, J. M. Synlett 1999,
1903–1906.
4. For previous synthesis of vinylphosphonates mediated by
Peterson-like or Wadsworth–Emmons olefinations of car-
bonyl compounds, see: (a) Minami, T.; Motoyoshiya, J.
Synthesis 1992, 333–349 and references cited therein; (b)
Carey, F. A.; Court, A. S. J. Org. Chem. 1972, 37,
939–943; (c) Aboujaoude, E. E.; Lietje´, S.; Collignon, N.;
Teulade, M. P.; Savignac, P. Synthesis 1986, 934–937; (d)
Binder, J.; Zbiral, E. Tetrahedron Lett. 1986, 27, 5829–
5832; (e) Mimouni, N.; About-Jaudet, E.; Collignon, N.;
Savignac, P. Synth. Commun. 1991, 21, 2341–2348; (f)
Mimouni, N.; Al-Badri, H.; About-Jaudet, E.; Collignon,
N. Synth. Commun. 1995, 25, 1921–1932; (g) Gupta, A.;
Sacks, K.; Khan, S.; Tropp, B. E.; Engel, R. Synth.
Commun. 1980, 10, 299–304; (h) Aboujaoude, E. E.;
Lietje´, S.; Collignon, N.; Teulade, M. P.; Savignac, P.
Tetrahedron Lett. 1985, 26, 4435–4438; (i) Teulade, M. P.;
Savignac, P.; Aboujaoude, E. E.; Lie´tge, S.; Collignon, N.
J. Organomet. Chem. 1986, 304, 283–300; (j) Kiddle, J. J.;
Babler, J. H. J. Org. Chem. 1993, 58, 3572–3574; (k)
Perlikowska, W.; Mphahlele, M. J.; Modro, T. A. J.
Chem. Soc., Perkin Trans. 2 1997, 967–970; (l) Iorga, B.;
Eymery, F.; Savignac, P. Tetrahedron Lett. 1998, 39,
4477–4480; (m) Chang, K.; Ku, B.; Oh, D. Y. Synth.
Commun. 1989, 19, 1891–1898.
3. Conclusion
In conclusion, reactions of benzaldehyde with a-silyl-,
a-phosphoryl- and a-stannyl-stabilised phosphonate
carbanions derived from cyclo-[L-AP4-D-Val] take
place without compromising the chiral integrity of the
bis-lactim ether, giving rise to vinylphosphonates with
different level of (Z)-stereoselection. The ‘tin-Peterson-
like’ olefination of structurally diverse carbonyl com-
pounds using the lithiated a-triphenylstannylphos-
phonate were found completely (Z)-stereoselective, and
allowed a direct access to a series of 4-alkylidene AP4
derivatives in enantiomerically pure form, that may
result in useful tools for the study of group III of
mGluRs. Work is now underway to explore the (Z)-
selective Wadworth–Emmons olefinations with Li+4c−
and to extend these methodologies to the synthesis of
4-alkylidene derivatives of glutamate.
5. a-Trimethylsilylvinylphosphonate 6 was prepared by the
Wadsworth–Emmons olefination of formaldehyde with
the lithium salt derived from O,O-diethyl trimethylsilyl-
methylenebisphosphonate, which was, in turn, generated
in situ by treatment of the lithium salt of O,O-diethyl
methylphosphonate with diethylchlorophosphate and
trimethylsilyl chloride. See Ref. 4h.
Acknowledgements
Financial
support
from
Xunta
de
Galicia
6. Cyclo-[Gly-D-Val] was obtained as described by Rose et
(PDGIT00PXI10305PR) and the Ministerio de Ciencia
y Tecnolog´ıa (BQU2000-0236) is gratefully acknowl-
edged. The authors are indebted to Centro de Super-
computacio´n of Galicia for providing with the
computer facilities.
al. Treatment of this compound with triethyloxonium
tetrafluoroborate allowed the preparation of (3R)-2,5-
diethoxy-3-isopropyl-3,6-dihydropyrazine. 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-dimethoxy-3-isopropyl-3,6-dihydropyrazine
can be synthesised7 or purchased from E. Merk.
7. Bull, S. D.; Davies, S. G.; Moss, W. O. Tetrahedron:
Asymmetry 1998, 9, 321–327.
8. For investigations on the structure, the reactivity and the
stereoselectivity of phosphorus(V)-stabilised carbanions,
see: Denmark, S. E.; Chen, C.-T. J. Am. Chem. Soc.
1995, 117, 11879–11897 and references cited therein.
9. The starting material could almost be completely recov-
ered, and showed no racemisation. Thus, the yield of the
olefination could be increased to 70–85% by resubjecting
recovered starting material to the same reaction
conditions.
R
Et2O3P
R
Ph
R
10A−C
11A
NH2
NH2
NH2
NH2
CO2Et
Et2O3P
H2O3P
CO2Et
12A,B
13A,C
H2O3P
CO2Et
CO2H
Figure 2. A, R=C6H5; B, R=(CH3)2CH; C, R=2-(C4H3S).

5912
M. C. Ferna´ndez et al. / Tetrahedron Letters 43 (2002) 5909–5912
10. All new compounds gave satisfactory microanalysis, IR,
MS and NMR data.
Fock level of theory with the PM3 method,17 using the
eigenvector following routine (TS keyword for transition
state refinement) under the more rigorous criteria of the
keyword PRECISE (gradient norm <0.01). The reported
intermediate adducts were verified as minima by the
absence of negative eigenvalues in the vibrational fre-
quency analysis. For each located transition structure
only one imaginary frequency was found in the diago-
nalised Hessian matrix, and their nature verified by inter-
nal reaction coordinate calculations to the chelate
complexes and intermediate adducts. Conformational
space accessible for each reported structure was studied
considering two different rotamers for the isopropyl (with
the tertiary carbon pointing to the nitrogen or to the
imidate group) and the methoxy groups (pointing to the
nitrogen atom or to the substituents of the bis-lactim
ether), three rotamers for the THF molecule and gg, ga,
ag and aa conformations for the COPOC moiety. Ethyl
groups were replaced by methyl groups to remove addi-
tional degrees of conformational freedom in the models.
16. MOPAC93, Fujitsu Ltd, Tokyo, Japan, 1993.
11. For either 7B–E or 8A H-5 resonance appears between
3.86 and 3.98 ppm, as a triplet with 5JH2H5 close 3.5 Hz,
typical for a trans relation of substituents at the pyrazine
ring.12 The configurations of the vinylphosphonate moi-
3
3
ety were assigned on the basis of the JHP and the JCP
observed in the 1H and 13C NMR spectra, due to the
coupling of H-3% and C-4% with the phosphorous atom at
the b position. Thus, for 7A–D, 3JH3%–P (trans) values
3
range from 44.4–49.3 Hz and JC4%–P (cis) values range
from 7.8–12.1 Hz, which are characteristic for the
vinylphosphonates with a (Z)-configuration. Conversely,
3
for 8A, with a (E)-configuration, JH3%–P (cis)=24.9 Hz
3
and JC4%–P (trans)=23.1 Hz.
12. Busch, K.; Groth, U. M.; Ku¨hnle, W.; Scho¨llkopf, U.
Tetrahedron 1992, 48, 5607–5618.
13. Selected data for compound 7A: 1H NMR (200 MHz,
CDCl3) l 0.72 (d, J=6.8 Hz, 3H (CH3
J=6.8 Hz, 3H (CH3)CH), 1.08 (t, J=7.0 Hz, 3H,
OCH2CH3), 1.09 (t, J=7.0 Hz, 3H, OCH2CH3), 1.25 (t,
J=7.0 Hz, 3H, OCH2CH3), 1.29 (t, J=7.0 Hz, 3H,
OCH2CH3), 2.28 (dsp, J=6.8, 3.4 Hz, 1H (CH3)CH),
6 )CH), 1.07 (d,
6
6
6
17. (a) Stewart, J. J. P. J. Comp. Chem. 1989, 10, 209–220
and 221–264; (b) For lithium PM3 parameters, see:
Anders, E.; Koch, R.; Freunscht, P. J. Comp. Chem.
1993, 14, 1301–1312.
6
6
6
2.48 (ddd, J=20.5, 14.5, 8.8 Hz, 1H, H-1%), 3.17 (ddd,
J=14.3, 12.7, 4.4 Hz, 1H, H-1%), 3.80–4.23 (m, 9H, H-5,
1
18. Selected data for amino acid 12A: H NMR (200 MHz,
OCH6 2CH3), 4.25–4.34 (m, 1H, H-2), 7.27–7.51 (m, 5H,
Ph), 7.20 (d, J=44.4 Hz, 1H, H-3%); [h]2D0=−24 (CH2Cl2,
D2O) l 2.64 (ddd, J=17.1, 14.9, 8.6 Hz, 1H, H-3), 2.98
(dt, J=15.0, 4.7 Hz, 1H, H-3), 4.01 (dd, J=8.5, 4.5 Hz,
1H, H-2), 6.97 (d, J=41.5 Hz, 1H, H-5), 7.15–7.32 (m,
5H, Ph); [h]2D8=−14 (H2O, c=1.1). Selected data for
1
c=1.1). Selected data for compound 8A: H NMR (200
MHz, CDCl3) l 0.75 (d, J=6.8 Hz, 3H (CH3
(d, J=6.8 Hz, 3H (CH3)CH), 1.17–1.38 (m, 12 H,
OCH2CH3), 2.21 (dsp, J=6.8, 3.9 Hz, 1H (CH3)CH),
2.67–3.08 (m, 2H, H-1%), 3.91 (t, J=3.4 Hz, 1H, H-5),
3.93–4.27 (m, 8H, OCH2CH3), 4.41–4.50 (m, 1H, H-2),
6 )CH), 1.02
6
1
amino acid 13A: H NMR (200 MHz, D2O) l 2.75 (ddd,
6
6
J=15.9, 9.2 Hz, 1H, H-3), 3.03 (dt, J=15.9, 4.9 Hz, 1H,
H-3), 3.97 (dd, J=9.2, 4.9 Hz, 1H, H-2), 7.14–7.32 (m,
6H, H-5, Ph); [h]2D8=−49 (H2O, c=1.1). Selected data for
amino acid 12B: 1H NMR (200 MHz, D2O) l 0.76 (d,
6
7.24–7.49 (m, 5H, Ph), 7.66 (d, J=24.9 Hz, 1H, H-3%);
[h]2D2=+142 (CH2Cl2, c=0.4).
J=6.1 Hz, 6H (CH6 3)CH), 2.37–2.70 (m, 2H, H-3), 2.70–
14. For previous theoretical studies of olefinations with phos-
phoryl-stabilised carbanions, see: (a) Motoyoshiya, J.;
Kusaura, T.; Kokin, K.; Yokoya, S.-i.; Takaguchi, Y.;
Narita, S.; Aoyama, H. Tetrahedron 2001, 57, 1715–1721;
(b) Ando, K. J. Org. Chem. 1998, 63, 8411–8416; (c)
Brandt, P.; Norrby, P.-O.; Martin, I.; Rein, T. J. Org.
Chem. 1998, 63, 1280–1289.
2.91 (m, 1H, H-6), 3.97 (t, J=6.7 Hz, 1H, H-2), 5.84 (dd,
J=44.1, 11.0 Hz, 1H, H-5); [h]2D8=+8 (H2O, c=0.7).
1
Selected data for amino acid 13C: H NMR (200 MHz,
D2O) l 2.67 (td, J=15.5, 11.6 Hz, 1H, H-3), 3.23 (ddd,
J=18.3, 15.4, 3.3 Hz, 1H, H-3), 3.76 (dd, J=11.6, 3.5
Hz, 1H, H-2), 6.98 (dd, J=4.9, 3.7 Hz, 1H, Ar), 7.22 (d,
J=3.7 Hz, 1H, Ar), 7.31 (d, J=22.0 Hz, 1H, H-5), 7.41
(d, J=5.5 Hz, 1H, Ar); [h]2D3=−62 (H2O, c=0.2).
15. Calculations have been performed with MOPAC93.16
Structures were fully optimised at the restricted Hartree–