Diastereoselective synthesis of 2-amino-4-phosphonobutanoic acids by conjugate addition of lithiated schoellkopf's bislactim ethers to vinylphosphonates

Article abstract of DOI:10.1021/jo034707q

Conjugate additions of lithiated bislactim ethers derived from cyclo-[Gly-Val] and cyclo-[Ala-Val] to α, β, or α,β -substituted vinylphosphonates allow direct and stereoselective access to a variety of 3- or 4-monosubstituted and 2,3-, 2,4-, or 3,4-disubstituted 2-amino-4-phosphonobutanoic acids (AP4 derivatives) in enantiomerically pure form. The relative stereochemistry was assigned by X-ray diffraction analysis or NMR study of 1,2-oxaphosphorinane derivatives. Competitive eight-membered "compact" and "relaxed" transition-state structures are invoked to rationalize the stereochemical outcome of the conjugate additions.

Full text of DOI:10.1021/jo034707q

Dia ster eoselective Syn th esis of 2-Am in o-4-p h osp h on obu ta n oic
Acid s by Con ju ga te Ad d ition of Lith ia ted Sch o1llk op f’s Bisla ctim
Eth er s to Vin ylp h osp h on a tes
Mar´ıa Ruiz,* M. Carmen Ferna´ndez,† Aniana D´ıaz, J ose´ M. Quintela, 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
ruizpr@udc.es; ojea@udc.es
Received May 24, 2003
Conjugate additions of lithiated bislactim ethers derived from cyclo-[Gly-Val] and cyclo-[Ala-Val]
to R-, â-, or R,â-substituted vinylphosphonates allow direct and stereoselective access to a variety
of 3- or 4-monosubstituted and 2,3-, 2,4-, or 3,4-disubstituted 2-amino-4-phosphonobutanoic acids
(AP4 derivatives) in enantiomerically pure form. The relative stereochemistry was assigned by
X-ray diffraction analysis or NMR study of 1,2-oxaphosphorinane derivatives. Competitive eight-
membered “compact” and “relaxed” transition-state structures are invoked to rationalize the
stereochemical outcome of the conjugate additions.
In tr od u ction
particular, group III mGluRs are characterized by their
selective response to several phosphonic acid isosters of
glutamic acid. They are selectively activated by L-2-
amino-4-phosphonobutanoic acid (L-AP4, 1; see Chart 1)
and competitively antagonized by R-methylated deriva-
tives of L-AP4 (MAP4, 2) and 4-phosphonophenylglycine
(MPPG, 3). Therefore, there is considerable interest in
the development of practical and versatile asymmetric
methodologies for the preparation of AP4 derivatives that
may result in useful tools for delineating the require-
ments for receptor binding3e and physiological responses
at group III of the mGluRs.
As the principal excitatory neurotransmitter in the
mammalian central nervous system, (S)-glutamic acid
plays a pivotal role in the regulation and maintenance
of fast synaptic transmission and long-term potentiation/
depression. Besides its physiological functions, glutamic
acid is involved in a variety of neuropathologies including
epilepsy, stroke, nociception, cognitive disorders, and
Alzheimer’s disease.1 For many years, glutamate was
assumed to operate through specific ion-gated-channel
receptors, called ionotropic glutamate receptors.2 More
recently, the G-protein-coupled receptors for glutamate
(mGluRs) have been discovered and perceived as valuable
therapeutic targets.3 According to sequence similarity,
pharmacological profile, and effector system differences,
mGluRs have been classified into three groups. Among
the receptors of group III, mGluR4, mGluR7, and mGluR8
are presynaptically localized and inhibit the release of
glutamate and γ-aminobutyric acid, whereas mGluR6
receptors are exclusively expressed by ON bipolar cells
in the retina and play an important role in the amplifica-
tion of visual imputs. Due to the diversity of receptor
subtypes within this class and the paucity in the devel-
opment of tools for their study, the molecular pharmacol-
ogy of group III mGluRs is not yet well established. In
Three major strategies have been devised for the
preparation of AP4 derivatives. Phosphites have been
utilized for the conjugate addition to carbonyl compounds
which were subsequently converted to amino acids via
Strecker reaction,4 or have been reacted with halides,5
triflates,6 or carbonyl functionalities7 located at the side
chain of R-amino acid derivatives. Alternative syntheses
have relied on glycine enolate equivalents for the alky-
lation of,8 1,3-dipolar cycloaddition to,9 or conjugate
(4) Crooks, S. L.; Robinson, M. B.; Koerner, J . F.; J ohnson, R. L. J .
Med. Chem. 1986, 29, 1988-1995.
(5) (a) Nair, S. A.; Lee, B.; Hangauer, D. G. Synthesis 1995, 810-
814. (b) Ma, D.; Ma, Z.; J iang, J .; Yang, Z.; Zheng, C. Tetrahedron:
Asymmetry 1997, 8, 889-893.
† Present address: Lilly S.A., Alcobendas, Madrid, Spain.
(1) (a) CNS Neurotransmitters and Neuromodulators: Glutamate;
Stone, T. W., Ed.; CRC: Boca Raton, FL, 1995. (b) Parthasarathy, H.
S., Ed. Nature 1999, 399 (Suppl.), A1-A47.
(2) The Ionotropic Glutamate Receptors; Monahan, D. T., Wenthold,
R. J ., Eds.; Humana: Totowa, NJ , 1997.
(3) (a) De Blasi, A.; Conn, P. J .; Pin, J .-P.; Nicoletti, F. Trends
Pharmacol. Sci. 2001, 22, 114-120. (b) Bra¨uner-Osborne, H.; Egebjerg,
J .; Nielsen, E. O.; Madsen, U.; Krogsgaard-Larsen, P. J . Med. Chem.
2000, 43, 2609-2645. (c) Schoepp, D. D.; J ane, D. E.; Monn, J . A.
Neuropharmacology 1999, 38, 1431-1476. (d) Pellicciari, R.; Costan-
tino, G. Curr. Opin. Chem. Biol. 1999, 3, 433-440. (e) Bertrand, H.-
O.; Bessis, A.-S.; Pin, J .-P.; Acher, F. C. J . Med. Chem. 2002, 45, 3171-
3183.
(6) (a) Berkowitz, D. B.; Eggen, MJ .; Shen, Q.; Shoemaker, R. K. J .
Org. Chem. 1996, 61, 4666-4675. (b) Amori, L.; Costantino, G.;
Marinozzi, M.; Pellicciari, R.; Gasparini, F.; Flor, P. J .; Kuhn, R.;
Vranesic, I. Bioorg. Med. Chem. Lett. 2000, 10, 1447-1450.
(7) (a) Wiemann, A.; Frank, R.; Tegge, W. Tetrahedron 2000, 56,
1331-1337. (b) Perich, J . W. Int. J . Pept. Protein Res. 1994, 44, 288-
294.
(8) (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.
(9) (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.
10.1021/jo034707q CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/09/2003
7634
J . Org. Chem. 2003, 68, 7634-7645

Synthesis of 2-Amino-4-phosphonobutanoic Acids
CHART 1. Selective Liga n d s for th e m Glu Rs of
Gr ou p III
SCHEME 2a
SCHEME 1
a
Legend: a , R3, R4 ) H; b, R3, R4 ) Me; c, R3 ) Bn; d , R3
)
CH2OBn; e, R3 ) CH2NHCbz; f, R3 ) i-Bu; g, R3 ) i-Pr; h , R3, R4
) Ph; i, R3 ) 3-C5H4N; j, R3 ) 2-C4H3S; k , R3 ) 2-C4H3O; l, R3
t-Bu; n , R4 ) PO3Et2; r , R4 ) NMe2; s, R4 ) OBn.
)
SCHEME 3a
addition to10 suitable functionalized phosphonates. In this
area, we have reported a direct approach to 2-amino-3-
methyl-4-phosphonobutanoic acids, in enantiomerically
pure form, by using a highly regio- and stereoselective
conjugate addition of metalated Scho¨llkopf’s bislactim
ethers to 1-propenylphosphonate esters.11 The high level
of π-facial discrimination found in these processes
prompted us to explore the scope and limitations of the
reactions between lithium azaenolates 5a and 5b, derived
from cyclo-[Gly-Val] and cyclo-[Ala-Val] (see Scheme 1)
and a series of vinylphosphonates 6 and 7, carrying
different functional groups at the R- and/or â-position.
Thus, in this paper we report in full detail the application
of such a methodology to the synthesis of a variety of
enantiomerically pure 3-, 4-, 2,3-, 2,4-, and 3,4-substi-
tuted AP4 derivatives 4, which may be useful for char-
acterizing the molecular pharmacology of the mGluRs of
group III.12
a
Legend: a , R3 ) H; d , R3 ) CH2OBn; f, R3 ) i-Bu; g, R3
)
i-Pr; h , R3 ) Ph; i, R3 ) 3-C5H4N; j, R3 ) 2-C4H3S; q, R3 ) SnPh3.
methyl phosphonate 8a with 2 equiv of LDA and diethyl
chlorophosphate (see Scheme 2).15 â-Substituted 1-vi-
nylphosphonates with (Z)-configuration, 7d a ,fa -ja , were
stereospecifically synthesized by either the acidic cleav-
age of (E)-R-triphenylstannylvinylphosphonates 7fq-
h q16 or the Pd(0)-catalyzed coupling of diethyl phosphite
and (Z)-1-bromo-1-alkenes17 13d ,i,j (see Scheme 3). The
required R-stannylvinylphosphonates were obtained by
condensation of isovaleraldehyde (10f), isobutyraldehyde
(10g), and benzaldehyde (10h ) with R-bis(triphenylstan-
Resu lts13
Syn th esis of Vin ylp h osp h on a tes. Representative
series of mono- and disubstituted vinylphosphonates were
prepared by known procedures, as depicted in Schemes
2-4. Monosubstituted vinylphosphonates 6ca -la , with
alkyl, aryl, or heteroaryl groups at the â-position and (E)-
configuration, were stereoselectively obtained by Wads-
worth-Emmons olefination of aldehydes 10c-l with the
lithium salt of tetraethyl methylenebisphosphonate,
Li+9a -,14 which was generated in situ by treatment of
(14) (a) Aboujaoude, E. E.; Lietje´, S.; Collignon, N.; Teulade, M. P.;
Savignac, P. Tetrahedron Lett. 1985, 26, 4435-4438. (b) Teulade, M.
P.; Savignac, P.; Aboujaoude, E. E.; Lie´tge, S.; Collignon, N. J .
Organomet. Chem. 1986, 304, 283-300. (c) Kiddle, J . J .; Babler, J . H.
J . Org. Chem. 1993, 58, 3572-3574.
(15) For previous syntheses of 2-(3-pyridyl)-, 2-(2-thiophenyl)-, 2-(2-
furyl)-, and 2-tert-butylvinylphosphonates 6ia , 6ja , 6k a , and 6la see,
respectively: (a) L’vova, S. D.; Kozlov, Yu. P.; Gunar, V. I. Zh. Obshch.
Khim. 1977, 47, 1251-1256. (b) Zyablikova, T. A.; Il’yasov, A. V.;
Mukhametzyanova, E. Kh.; Shermergorn, I. M. Zh. Obshch. Khim.
1982, 52, 287-291. (c) Andreae, S.; Seeboth, H. J . Prakt. Chem. 1979,
321, 353-360. (d) Palomo, C.; Aizpurua, J . M.; Garc´ıa, J . M.; Ganboa,
I.; Coss´ıo, F. P.; Lecea, B.; Lo´pez, C. J . Org. Chem. 1990, 55, 2498-
503.
(10) (a) Shapiro, G.; Buechler, D.; Ojea, V.; Pombo-Villar, E.; Ruiz,
M.; Weber, H.-P. Tetrahedron Lett. 1993, 34, 6255-6258. (b) Minowa,
N.; Hirayama, M.; Fukatsu, S. Tetrahedron Lett. 1984, 25, 1147-1150.
(11) Ojea, V.; Ruiz, M.; Shapiro, G.; Pombo-Villar, E. J . Org. Chem.
2000, 65, 1984-1995.
(12) Part of this work was already presented as preliminary com-
munications: (a) Ferna´ndez, M. C.; Quintela, J . M.; Ruiz, M.; Ojea, V.
Tetrahedron: Asymmetry 2002, 13, 233-237. (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.
(13) Throughout this paper, vinylphosphonates will be referred to
with numerals followed by two letters, to distinguish the identity of
their substituents R3 and R4, at the â- and R-positions, respectively,
while the addition products and their derivatives will be referred to
with numerals followed by three letters, to distinguish the identity of
the substituents at positions 2-4 of the targeted AP4 derivatives (R2,
R3, and R4, respectively).
(16) (a) Mimouni, N.; Al Badri, H.; About-J audet, E.; Collignon, N.
Synth. Commun. 1995, 25, 1921-1932. (b) Mimouni, N.; About-J audet,
E.; Collignon, N.; Savignac, P. Synth. Commun. 1991, 21, 2341-2348.
(17) Hirao, T.; Masunaga, T.; Yamada, N.; Ohshiro, Y.; Agawa, T.
Bull. Chem. Soc. J pn. 1982, 55, 909-913.
J . Org. Chem, Vol. 68, No. 20, 2003 7635

Ruiz et al.
nyl)methylphosphonate carbanion Li+11q -, while the
(Z)-1-bromo-1-alkenes 13d ,i,j were generated in situ by
the Pd(0)-catalyzed hydrogenolysis18 of 3-benzyloxy-
methyl, 3-(3-pyridyl)- and 3-(2-thiophenyl)-substituted
1,1-dibromopropenes 12d ,i,j with tributyltin hydride.
Vinylphosphonates with methyl, phenyl, trimethylsilyl,
triphenylstannyl, or benzyloxy groups at the R-position
(6a b, 6a h , 6a p , 6a q, and 6a s, respectively) were syn-
thesized by an extension of the procedures described
above for the â-substituted series (see Scheme 2). Thus,
treatment of ethyl-, benzyl-, and benzyloxymethylphos-
phonates 8b, 8h , and 8s, respectively, with 2 equiv of
LDA and diethyl chlorophosphate led to the correspond-
ing substituted methylenebisphosphonate lithium salts
Li+9b-, Li+9h -, and Li+9s-, which reacted with formal-
dehyde (10a ) to afford the R-methyl-,19a R-phenyl-,19b and
R-benzyloxyvinylphosphonates 6a b, 6a h , and 6a s in good
yields. Sequential treatment of methyl phosphonate 8a
with 3 equiv of LDA, diethyl chlorophosphate, trimeth-
ylsilyl chloride, and formaldehyde led to the R-trimethyl-
silylvinylphosphonate19c,d 6ap (not shown in the schemes).
Reaction of R-bis(triphenylstannyl)methylphosphonate
carbanion Li+11q - with formaldehyde gave the R-tri-
phenylstannylvinylphosphonate 6a q (see Scheme 3).
R,â-Disubstituted vinylphosphonates were also pre-
pared by Wadsworth-Emmons or Peterson olefinations.
Thus, addition of 10g to the phosphonate carbanion
Li+9b-, generated in situ from ethylphosphonate 8b,
LDA, and diethyl chlorophosphate, led to a mixture of
the (E)- and (Z)-vinylphosphonates 6gb and 7gb in a 5:1
ratio (see Scheme 2). Olefination of 10h in the same
conditions was completely stereoselective, and afforded
(E)-vinylphosphonate 6h b in 77% yield. Conversely,
sequential treatment of ethylphosphonate 8b with LDA
and triphenylstannyl chloride, followed by the addition
of 10g or 10h , led to the corresponding â-substituted
R-methylvinylphosphonates as mixtures of (E)-isomers
(6gb or 6h b) and (Z)-isomers (7gb or 7h b) in a 1:5 ratio
(see Scheme 4). Starting with the R,R-bis(trimethylsilyl)-
methylphosphonate 14, reaction with LDA and 10h
afforded a 1:4.4 mixture of the (E)- and (Z)-R-trimethyl-
silylvinylphosphonates19d 6h p and 7h p .
SCHEME 4a
a
Legend: g, R3 ) i-Pr; h , R3 ) Ph.
3
6ca -la , with (E)-configuration, J H-P (cis) values range
3
from 21.6 to 22.9 and J C-P (trans) values range from 19.6
to 25.0.20
Ad d ition s to th e â-Su bstitu ted Vin ylp h osp h o-
n a tes. We first examined the additions of Scho¨llkopf’s
bislactims derived from cyclo-[L-Val-Gly] and cyclo-[D-Val-
d,l-Ala] ((S)-15a and (R)-15b, respectively) to the â-sub-
stituted acceptors. Vinylphosphonates 6ca -k a and
7d a ,fa -ja underwent a stereoselective conjugate addi-
tion of lithium azaenolates 5a ,b, in a fashion similar to
that previously reported for 1-propenylphosphonates,11
acrylate and cinnamate esters,21 nitroolefines,22 and vinyl
sulfones.23 In this manner, slow addition of n-BuLi to a
solution of bislactim ether (S)-15a in THF at -78 °C was
followed 15 min later by the dropwise addition of the
acceptors 6ca -k a or 7d a ,fa -ja . Reactions took place
rapidly, and after quenching with acetic acid and aqueous
workup, 1H-decoupled 31P NMR analyses of the crude
mixtures revealed the formation of mixtures of 1:1 and
1:2 addition products 16-18a ca -a k a and 20a ca -a k a ,
respectively (see Scheme 5). In an analogous fashion, slow
addition of â-phenylvinylphosphonate 6h a or 7h a over
a solution of 1.2 equiv of the lithium azaenolate (R)-5b
at low temperature led, after quenching and aqueous
workup, to mixtures of 1:1 adducts 16bh a and 17bh a ,
According to 31P NMR analyses, all the â-substituted
vinylphosphonates were obtained after chromatography
with diastereomeric excesses higher than 98%. The
configurations of the new â-substituted vinylphospho-
nates 6d a , 6ea , 7d a , and 7ja were assigned on the basis
virtually free of 1:2 addition byproducts (according to 31
P
NMR analysis). Conversely, no reaction was observed
under these conditions or with longer reaction times and
warming (up to 10 h and 0 °C) when â-tert-butylvi-
nylphosphonate 6la was used as the acceptor partner.
The ratio between 1:1 and 1:2 adducts was found to
be dependent on the nature of the â-substituent of the
acceptor. Thus, â-alkylvinylphosphonates 6ca -ga and
3
3
of the J H-P and the J C-P observed in the 1H and 13C
3
NMR spectra. Thus, for 7d a ,fa -ja , J H-P (trans) values
range from 49.3 to 53.2 Hz and J C-P (cis) values range
3
from 7.8 to 10.6 Hz, which are characteristic for the
vinylphosphonates with (Z)-configuration. Conversely, for
(18) Uenishi, J .; Kawahama, R.; Yonemitsu, O. J . Org. Chem. 1998,
63, 8965-8975 and references therein.
(20) (a) Gorenstein, D. G. Prog. Nucl. Magn. Reson. Spectrosc. 1983,
16, 1-98. (b) Phosphorus-31 NMR Spectral Properties in Compound
Characterization and Structural Analysis; Quin, L. D., Verkade, J . G.,
Eds.; Wiley: New York, 1994.
(19) For previous syntheses of 6a b, 6a h , 6a p , 22, and 23 see: (a)
Skowronska, A.; Dybowski, P. Heteroat. Chem. 1991, 2, 55-61. (b) Han,
L.-B.; Tanaka, M. J . Am. Chem. Soc. 1996, 118, 1571-1572. (c) Kouno,
R.; Okauchi, T.; Nakamura, M.; Ichikawa, J .; Minami, T. J . Org. Chem.
1998, 63, 6239-6246. (d) Chang, K.; Ku, B.; Oh, D. Y. Bull. Korean
Chem. Soc. 1989, 10, 320-321. (e) Gerber, J . P.; Modro, T. A.; Wagener,
C. C. P.; Zwierzak. Heteroat. Chem. 1991, 2, 643-649. (f) Yamashita,
M.; Morizane, T.; Fujita, K.; Nakatani, K.; Inokawa, S. Bull. Chem.
Soc. J pn. 1987, 60, 812-814. (g) 23 was prepared by bromination of
2-hydroxycyclopentylphosphonic acid diethyl ester, which was obtained
from 2-diethoxyphosphorylcyclopentanone. See: Koo, L.; Wiemer, D.
F. J . Org. Chem. 1991, 56, 5556-5560.
(21) (a) J ane, D. E.; Chalmers, D. J .; Howard, J . A. K.; Kilpatrick,
I. C.; Sunter, D. C.; Thompson, G. A.; Udvarhelyi, P. M.; Wilson, C.;
Watkins, J . C. J . Med. Chem. 1996, 39, 4738-4743. (b) Hartwig, W.;
Born, L. J . Org. Chem. 1987, 52, 4352-4358. (c) Scho¨llkopf, U.; Pettig,
D.; Busse, U.; Egert, E.; Dyrbusch, M. Synthesis 1986, 737-740.
(22) Scho¨llkopf, U.; Ku¨hnle, W.; Egert, E.; Dyrbusch, M. Angew.
Chem., Int. Ed. Engl. 1987, 26, 480-482.
(23) Shapiro, G.; Buechler, D.; Marzi, M.; Schmidt, K.; Gomez-Lor,
B. J . Org. Chem. 1995, 60, 4978-4979.
7636 J . Org. Chem., Vol. 68, No. 20, 2003

Synthesis of 2-Amino-4-phosphonobutanoic Acids
SCHEME 5a
a
Legend: c, R3 ) Bn; d , R3 ) CH2OBn; e, R3 ) CH2NCbz; f, R3 ) i-Bu; g, R3 ) i-Pr; h , R3 ) Ph; i, R3 ) 3-C5H4N; j, R3 ) 2-C4H3S; k ,
R3 ) 2-C4H3O.
TABLE 1. Ad d ition of Lith iu m Aza en ola tes 5a ,b to â-Su bstitu ted Vin ylp h osp h on a tes 6a a -la a n d 7d a ,fa -ja
1:1 adducts
azaenolate
(equiv)
acceptor
(confign)
yielda
(%)
16:17:18
yielda of
20 (%)
entry
R3
ratiob
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
5a (1.1)
5a (1.1)
5a (1.1)
5a (1.1)
5a (1.1)
5a (1.1)
5a (1.1)
5a (1.1)
5a (1.1)
5a (1.1)
5a (1.1)
5a (1.1)
5a (1.1)
5a (1.1)
5a (1.1)
5a (2.2)
5a (2.2)
5a (2.2)
5a (2.2)
5a (2.2)
5a (2.2)
5a (2.2)
5a (2.2)
5b (1.2)
5b (1.2)
5b (1.2)
6ca (E)
6d a (E)
7d a (Z)
6ea (E)
6ga (E)
6h a (E)
6h a (E)
7h a (Z)
6ia (E)
7ia (Z)
6ja (E)
6ja (E)
7ja (Z)
6k a (E)
6la (E)
6ca (E)
6d a (E)
7d a (Z)
6ea (E)
6fa (E)
7fa (Z)
6ga (E)
7ga (Z)
6h a (E)
6h a (E)
7h a (Z)
Bn
39
65
50
63
43
88
88
87
81
84
92
92
84
85
NR
55
82
89
77
89
85
61
80
75
75
83
97:2.5:0.5
99:0.5:0.5
8.0:92:0.0
94:5.2:0.8
95:3.5:1.5
98:0.7:1.3
72:19:9.0c
5.0:93:2.0
97:1.0:2.0
3.5:96:0.5
97:2.0:1.0
63:20:17c
2.5:97:0.5
97:1.0:2.0
26
17
15
21
41
5
5
5
5
5
CH2OBn
CH2OBn
CH2NHCbz
i-Pr
Ph
Ph
Ph
3-C5H4N
3-C5H4N
2-C4H3S
2-C4H3S
2-C4H3S
2-C4H3O
t-Bu
4
4
4
4
Bn
97:2.5:0.5
99:0.5:0.5
8.0:92:0.0
94:5.2:0.8
97:3.0:0.0
13:86:1.0
95:3.5:1.5
18:81:1.0
97:3.0:0.0
50:50:0.0c
4.0:96:0.0
16
13
5
9
3
4
23
5
d
d
CH2OBn
CH2OBn
CH2NHCbz
i-Bu
i-Bu
i-Pr
i-Pr
Ph
Ph
Ph
d
a
b
Isolated yield of mixtures of adducts, after column chromatography. NR ) no reaction was observed. Determined by integration of
the 31P NMR spectra of the crude mixtures. c Reaction performed at 0 °C instead of -78 °C. No 1:2 addition products were observed in
d
the 31P NMR spectra of the crude mixtures.
7d a ,ga ,h a (with benzyl, benzyloxymethyl, benzyloxycar-
bonylaminomethyl, isobutyl, or isopropyl groups) gave
rise to mixtures of 1:1 adducts in 39-63% yield, while
â-arylvinylphosphonates 6h a -k a and 7h a -k a (with
phenyl, 3-pyridyl, 2-furyl, or 2-thiophenyl groups) gave
the corresponding 1:1 addition products with 80-92%
yield (compare entries 1-5 and 6-14 in Table 1). We
reasoned that conversion to 1:1 adducts was lowered by
further addition of the initially formed adduct anion to
the â-alkyl-substituted vinylphosphonates. To reduce the
dimerization of these acceptors, we carried out the
addition process using an excess of azaenolate. By using
2 equiv of the lithium azaenolate (S)-5a , the yields of the
mixtures of 1:1 adducts resulting from the addition to
vinylphosphonates 6ca -ga or 7d a ,ga ,h a were increased
to 61-89%, without modification of the stereoselectivity
of the process (see entries 16-23 of Table 1). The excess
of Scho¨llkopf’s reagent could be almost completely recov-
ered and showed no racemization.
After isolation of the fractions containing the 1:1
1
adducts by flash chromatography, integration of the H-
decoupled 31P NMR spectra (or the pairs of doublets
corresponding to the isopropyl groups in the 1H NMR
spectra) revealed a high level of asymmetric induction
in the formation of the new chiral centers, as well as
complementary stereochemical outcomes in the additions
J . Org. Chem, Vol. 68, No. 20, 2003 7637

Ruiz et al.
SCHEME 6a
to vinylphosphonates with (E)- and (Z)-configuration.
Additions of azaenolate (S)-5a to vinylphosphonates
6ca -k a and 7d a ,fa -ja led to mixtures of isomers 16/
17/18a ca -a k a with ratios ranging from 99:0.5:0.5 to 2.5:
97:0.5, while additions of (R)-5b to 6h a and 7h a resulted
in mixtures of adducts 16bh a and 17bh a with 97:3 and
4:96 ratios, respectively. Thus, azaenolates (S)-5a and
(R)-5b underwent highly 2,5-trans-selective conjugate
additions to the â-substituted vinylphosphonates, in
which the (E)- or (Z)-configuration of the acceptor was
predominantly translated into adducts with 2,1′-anti or
2,1′-syn configuration. In this manner, the observed
diastereomeric ratios of the major adducts, the 2,5-trans-
2,1′-anti isomers 16a ca -a k a ,bh a in the additions to
6ca -k a and the 2,5-trans-2,1′-syn isomers 17a d a ,a fa -
a h a ,bh a in the additions to 7d a ,fa -h a , ranged from 93%
to 99% and from 81% to 97%, respectively. The correla-
tion between azaenolate and acceptor geometries was
found to be weaker with the (Z) acceptors, particularly
with the â-alkyl-substituted ones (compare entries 17 and
18, 20 and 21, and 22 and 23 of Table 1). Product
distribution of the conjugate addition was found to be
markedly dependent on the reaction temperature. When
the addition of azaenolate (S)-5a to vinylphosphonate
6h a or 6ja was performed at 0 °C, the mixtures of 1:1
adducts were obtained in similar yields but containing
the isomers 16/17/18a h a ,a ja in 72:19:9.0 and 63:20:17
ratios, respectively (see entries 7 and 12). Also, addition
of azaenolate (R)-5b to vinylphosphonate 6h a at 0 °C
gave a mixture of adducts 16/17bh a with a 1:1 ratio in
75% yield (see entry 25).
Ad d ition s to th e r-Su bstitu ted Vin ylp h osp h o-
n a tes. Having shown the feasibility of performing ste-
reoselective additions of lithiated bislactims to â-substi-
tuted vinylphosphonates, we explored the extension of
this reactivity to a series of R-substituted vinylphospho-
nates. Upon addition of vinylphosphonates 6a b,a h ,a m -
a q to 1 equiv of azaenolate (R)-5a at -78 °C in THF,
reactions took place within 5 min. Conversely, no reaction
was observed after 10 h and warming to 0 °C in the case
of the vinylphosphonates 6a r and 6a s, with R-dimethyl-
amino and R-benzyloxy substituents, respectively. After
quenching with acetic acid and workup, 31P NMR analy-
sis of the crude mixtures revealed the formation of
mixtures of 1:1 and 1:2 adducts in the reactions of
6a h ,a m -a q, and of 1:2 adducts along with oligomeriza-
tion products in the reaction of 6a b (see Scheme 6).
Both the ratio between 1:1 and 1:2 adducts and the
stereoselectivity of the addition were found markedly
dependent on the nature of the R-substituent of the
acceptor (see Table 2). Vinylphosphonates 6a m and
6a n with an electron-withdrawing substituent, as the
ethoxycarbonyl or the diethoxyphosphoryl group, gave
rise to the 1:1 adducts in lower proportion than vi-
nylphosphonates 6a h ,a o-a q (with phenyl, phosphory-
loxy, silyl, or stannyl groups) probably due to the
increased electron deficiency and higher acceptor char-
acter of the former acceptors. Conversion of the vi-
nylphosphonates 6a m and 6a q to the desired 1:1 adducts
could be increased as above for the â-series, simply by
using an excess of the lithium azaenolate. Thus, after
chromatographic separation the fractions containing the
1:1 adducts 16-19a a h ,a a m -a a q were isolated in mod-
erate to good yields.
a
Legend: a , R2, R4 ) H; b, R2, R4 ) Me; h , R4 ) Ph; m , R4
)
)
CO2Et; n , R4 ) PO3Et2; o, R4 ) OPO3Et2; p , R4 ) SiMe3; q, R4
SnPh3; r , R4 ) NMe2; s, R4 ) OBn.
TABLE 2. Ad d ition s of Lith iu m Aza en ola tes 5a ,b to
r-Su bstitu ted Vin ylp h osp h on a tes 6a b,a h ,a m -a s
1:1 adducts
azaenolate yielda 16:17:18:19 yielda of yielda of
acceptor
R4
(equiv)
(%)
ratiob
20 (%) 21 (%)a
6a b
6a h
6a h
6a h
Me
Ph
Ph
Ph
5a (1.1)
5a (1.1)
5a (1.1)
5a (1.1)
5a (1.2)
5a (2.2)
5a (1.2)
42
5
5
27
85
74
89
25
56
35
83
72
62
42
78
NR
NR
86
86
86
1:1:-:-
1:1:-:-c
3:2:-:-d
4:4:3:3
3
6a m CO2Et
6a m CO2Et
65
42
25
8
11
4
4:4:3:3
6a n
6a o
6a p
6a p
6a q
6a q
6a r
6a s
6a h
6a h
6a h
PO3Et2
OPO3Et2 5a (1.2)
3:2e
1:1:-:-
1:1:-:-
3:2:-:-c
1:1:-:-
1:1:-:-
TMS
TMS
SnPh3
SnPh3
NMe2
OBn
Ph
5a (1.2)
5a (1.2)
5a (1.1)
5a (2.2)
5a (1.2)
5a (1.2)
5b (1.2)
5b (1.2)
5b (1.2)
42
15
3:1:-:-
6:1:-:-c
10:7:-:-g
f
f
f
Ph
Ph
a
Isolated yield of mixtures of adducts, after column chroma-
tography. NR ) no reaction was observed upon warming to 0 °C.
b
Determined by integration of the 31P NMR spectra of the crude
mixtures. c 2,4,6-Tri-tert-butylphenol as proton source. Cinchone
d
or cinchonidine as proton source. e There is no anti/syn isomerism
in this case. f No 1:2 addition products were observed in the 31P
g
NMR spectra of the crude mixtures. Quenching with acetic acid
at rt.
The addition to vinylphosphonates 6a h ,a o-a q took
place in
a
highly diastereoselective fashion and
led, exclusively, to the formation of 2,5-trans adducts
16a a h ,a a o-a a q and 17a a h ,a a o-a a q (see Figure 1),
while acceptors 6a m and 6a n gave rise to mixtures of
all the possible 2,5-trans and 2,5-cis adducts 16-
19a a m ,a a p . The poor trans selectivity observed in the
conjugate additions to 6a m and 6a n may derive from the
higher reactivity of vinylphosphonates 6a m and 6a n .24
We reasoned that the formation of 1:1 mixtures of
adducts 16/17a a h ,a a o-a a q should take place with
quenching by a nonselective protonation of the phospho-
nate carbanions arising from the 2,5-trans-selective
addition to vinylphosphonates 6a h ,a o-a q. Such phos-
(24) Low diastereoselectivities have been reported in certain alky-
lations of Sho¨llkopf’s bislactim ethers. See: (a) Ma, C.; Liu, X.; Li, X.;
Flippen-Anderson, J .; Yu, S.; Cook, J . M. J . Org. Chem. 2001, 66, 4525-
4542. (b) Shinohara, H.; Fukuda, T.; Iwao, M. Tetrahedron 1999, 55,
10989-11000. (c) Adamczyk, M.; Akireddy, S. R.; Reddy, R. E.
Tetrahedron: Asymmetry 1999, 10, 3107-3110.
7638 J . Org. Chem., Vol. 68, No. 20, 2003

Synthesis of 2-Amino-4-phosphonobutanoic Acids
SCHEME 7a
a
Reagents and conditions: (a) (i) 6,7h b,h m ,h p ,h q, THF, -78
°C, 5 min; (ii) HOAc; (b) (i) BuLi, THF, -78 °C, 30 min; (ii) HOAc;
(c) Bu4NF, THF, rt, 10 min. Legend: m , R4 ) CO2Et; p , R4
SiMe3; q, R4 ) SnPh3.
)
F IGURE 1. Adducts obtained from R-substituted vinylphos-
phonates. Legend: h , R4 ) Ph; m , R4 ) CO2Et; n , R4 ) PO3-
Et2; o, R4 ) OPO3Et2; p , R4 ) SiMe3; q, R4 ) SnPh3.
phosphonate carbanions, originating as intermediates in
the conjugate additions of azaenolates 5a ,b to R-substi-
tuted vinylphosphonates, might react with electrophilic
reagents with synthetically useful levels of stereoselec-
tion.25
phonate carbanions should be sufficiently stabilized,
probably by chelation of the lithium with the phosphoryl
oxygen and a nitrogen atom of the bislactim ring (as
depicted in Scheme 13), thus suppressing transmetala-
tion processes that could compromise the integrity of the
newly formed chiral center at position 2. With these ideas
in mind and pursuing a more stereoselective synthesis
of the 4-substituted AP4 derivatives, we decided to study
the effect of different proton sources in the additions to
R-substituted vinylphosphonates. We examined first the
addition of azaenolate (R)-5a to the R-phenylvinylphos-
phonate 6a h using a bulky proton source. When the
intermediate adduct anion was allowed to react with
2,4,6-tri-tert-butylphenol in THF at -78 °C for 1 h prior
to the addition of HOAc, no asymmetric induction oc-
curred in the protonation. Nevertheless, when the same
treatment was performed with the intermediate anion
generated in the addition of (R)-5a to the R-trimethylsi-
lylvinylphosphonate 6a p , the 2,5-trans adducts 16a a p
and 17a a p were obtained in 62% yield with a 3:2 ratio.
Attempting to increase the diastereoselectivity, chiral
proton sources were examined next. When cinchonine or
cinchonidine was used as the proton source as above, the
addition of azaenolate (R)-5a to vinylphosphonate 6a h
furnished a mixture of the 2,5-trans-2,2′-anti and 2,5-
trans-2,2′-syn products 16a a h and 17a a h in a 3:2 ratio
and 89% combined yield.
Addition of azaenolate (R)-5b to R-phenylvinylphos-
phonate 6a h also took place regio- and stereoselectively,
to afford a mixture of 2,5-trans adducts 16ba h /17ba h
in a 3:1 ratio and 86% yield. When the intermediate
adduct was allowed to react with 2,4,6-tri-tert-butylphe-
nol in THF at -78 °C for 1 h prior to the addition of
HOAc, a 16ba h /17ba h mixture was obtained in a 6:1
ratio. Thus, the 2,2′-anti stereoselectivity was remarkable
in these cases, and could not be completely suppressed
by increasing the temperature of the quenching. When
the addition of acetic acid was carried out at rt, the
mixture 16ba h /17ba h was obtained in similar yield, and
16ba h was formed with a diastereomeric excess of 17%
over its epimer 17ba h .
Ad d ition s to th e r,â-Disu bstitu ted Vin ylp h osp h o-
n a tes. To explore further the scope of the conjugate
additions of lithiated bislactim ethers to vinylphospho-
nates, we examined the additions to a series of R,â-
disubstituted vinylphosphonates with either (E)- or (Z)-
configuration. Reaction of lithium azaenolate (R)-5a and
the â-phenylvinylphosphonates 6h m ,h p ,h q and 7h p ,h q,
with ethoxycarbonyl, trimethylsilyl, or triphenylstannyl
groups at the R-position, took place rapidly in THF at
-78 °C. Conversely, no reaction was observed in the same
conditions for the vinylphosphonates 6h b and 7h b, with
a methyl group at the R-position, nor in the case of a â,â-
dimethyl-substituted vinylphosphonate.
According to the 31P NMR spectra of the crude mix-
tures, additions to the R-substituted â-phenylvinylphos-
phonates were highly stereoselective, and led to the
exclusive formation of the 2,5-trans adducts, as pairs of
epimers at the 2′-position with either 2,1′-anti or 2,1′-
syn configuration (16 and 17, respectively, in Scheme 7).
Demetalation of the 2′-trimethylsilyl-substituted adducts
with tetrabutylammonium fluoride at rt, and of the 2′-
triphenylstannyl-substituted adducts by treatment with
n-BuLi at -78 °C followed by quenching with HOAc, gave
mixtures of the 2,5-trans-2,1′-anti and 2,5-trans-2,1′-syn
adducts 16a h a and 17a h a , respectively. In this manner,
additions to 6h p and 6h q were found 2,1′-anti-selective
(as was previously observed for other vinylphosphonates
with a trans relationship between the phosphorus and
the â-substituent) and furnished mixtures of the adducts
16/17a h p and 16/17a h q with 8:1 and 3:1 ratios, respec-
tively, in excellent yields. Thus, increasing the bulk of
the R-substituent R4 from trimethylsilyl (in 6a h p ) to
triphenylstannyl (in 6a h q) resulted in lower anti selec-
tivity in the conjugate addition (see Table 3). Conversely,
(25) Prompted by these results, we have studied the electrophilic
substitutions and the olefination processes of lithiated bislactim ethers
derived from cyclo-[L-AP4-D-Val]; see: (a) Ferna´ndez, M. C.; Quintela,
J . M.; Ruiz, M.; Ojea, V. Tetrahedron: Asymmetry 2002, 13, 233-237.
(b) Ruiz, M.; Ojea, V.; Quintela, J . M.; Guill´ın, J . J . Chem. Commun.
2002, 1600-1601. (c) Ferna´ndez, M. C.; Ruiz, M.; Ojea, V.; Quintela,
J . M. Tetrahedron Lett. 2002, 43, 5909-5912.
Although low diastereoselectivities were achieved at
this stage, the protonation experiments revealed that the
J . Org. Chem, Vol. 68, No. 20, 2003 7639

Ruiz et al.
TABLE 3. Ad d ition s of Lith iu m Aza en ola te (R)-5a to
r,â-Disu bstitu ted Vin ylp h osp h on a tes 6,7h b,h m ,h p ,h q
TABLE 4. Ad d ition of Lith ia ted Bis-la ctim Eth er (R)-5a
to Cyclop en ten ylp h osp h on a te
azaenolate acceptor
(equiv)
(confign) R3
yielda 16:17
16
17
acceptor
24
25
R4
(%) ratiob,c ratiob,d ratiob,d
azaenolate
(equiv)
equiv equiv yielda
A:B:C:D:E
yielda
(%)
5a (1.1) 6h b (E) Ph Me
5a (1.1) 7h b (Z) Ph Me
NR
NR
of 22
of 23
(%)
isomeric ratiob
5a (2.0)
5a (2.0)
5a (2.0)
5a (2.0)
5a (1.0)
5a (1.0)
5a (1.0)
5a (1.0)
5a (2.0)
5a (2.0)
5a (2.0)
5a (2.0)
1.00
1.00
1.00
1.00
0.50
0.33
0.50
0.33
0.50
0.33
0.20
0.10
50
50
50
50
35
27
35
27
59
75
56
10
34:-:7:32:27c
48:2:1:17:33d
47:5:7:12:29e
51:7:6:10:26f
20
20
20
20
15
2
15
2
12
8
5a (1.1) 6h m (E) Ph CO2Et 87
5a (1.1) 6h p (E) Ph SiMe3 90
5a (1.1) 7h p (Z) Ph SiMe3 80
5a (1.1) 6h q (Z) Ph SnPh3 93
5a (1.1) 7h q (E) Ph SnPh3 87
1:3
8:1
3:4
3:1
15:1
1:1
4:1
8:1
4:1
4:1
2:3
1:1
2:1
2:1
1:1
0.50
0.66
0.50
0.66
0.50
0.66
0.80
0.80
a
Isolated yield of mixtures of adducts, after column chroma-
tography. NR ) no reaction was observed upon warming to 0 °C.
b
Determined by integration of the 31P NMR spectra of the crude
58:11:6:12:13
64:11:5:10:10
64:12:4:10:10
77:9:-:14:-
mixtures. c 2,1′-anti:2,1′-syn ratio. Epimeric ratio at position 2′.
d
4
a
Isolated yield of mixtures of adducts, after column chroma-
SCHEME 8
b
tography. Determined by integration of the absorptions with δ
32.57, 34.00, 36.03, 36.20, and 36.34 ppm in the 31P NMR spectra
of the crude mixtures. c HOAc as proton source. 2,4,6-Tri-tert-
d
butylphenol as proton source. e Cinchone as proton source. f Cin-
chonidine as proton source.
the conjugate addition to vinylphosphonates,10a,11 it was
expected that the initial anionic adduct would be effective
in producing cyclopentenylphosphonate 22 in situ, via
dehydrohalogenation of the 2-bromocyclopentylphospho-
nate 23,19g thus suppressing dimerization. When mix-
tures of 22/23 were added to the lithium azaenolate (R)-
5a , the 1:1 adducts 24 were obtained with improved
yields and higher diastereoselectivities. In this manner,
using a mixture of 22 and 23 in a 1:2 ratio and 2 equiv
of (R)-5a , the fraction of 1:1 adducts was isolated in 75%
yield, containing a mixture of 24A/24B/24C/24D/24E in
a 64:11:5:10:10 ratio. Apparently, the initially formed
cyclopentylphosphonate carbanion is more basic and less
nucleophilic than the lithium azaenolate.
Tr a n sfor m a tion of th e Ad d ition P r od u cts in to
Mon o- a n d Disu bstitu ted AP 4 Der iva tives. After
separation of the mixtures of addition products by flash
chromatography, all the 1′-substituted adducts, the ad-
ducts with phenyl, trimethylsilyl, or triphenylstannyl
groups at position 2′, and four of the five cyclopentylated
adducts could be isolated with diastereomeric excesses
higher than 98%. Conversion of the addition products into
the desired 2-amino-4-phosphonobutanoic acid deriva-
tives was straightforward. Mild acid hydrolysis of the
1′-substituted bislactims 16a ca -a k a and 17a d a ,a fa -
a ja provided the corresponding 2,3-anti or 2,3-syn amino
esters 26a ca -a k a and 29a d a ,a fa -a ja in high yields
after removal of the valine ester by chromatography
(see Scheme 9). Subjecting the 2′-substituted bislactims
16a a h ,a a o,a a p and 17a a h ,a a o,a a p to the same reaction
conditions furnished the 2,4-anti or 2,4-syn amino esters
26a a h ,a a n -a a p and 29a a h ,a a n -a a p . Hydrolysis of the
amino esters was accomplished by either heating in
concentrated hydrochloric acid (in the cases of a ca -a ja ,
and a a h ) or sequential treatment with lithium hydroxide
and trimethylsilyl bromide (in the cases of a d a , a a o, and
a a p , with benzyloxymethyl, diethoxyphosphoryloxy, or
trimethylsilyl groups). After purification by reversed-
phase chromatography, the monosubstituted AP4 deriva-
tives in the 2,3-anti, 2,4-anti, 2,3-syn, and 2,4-syn series
(27a ca ,a fa -a ja , 27a a h ,a a o,a a p , 30a d a ,a fa -a ja , and
30a a h ,a a o,a a p ) were isolated in high yields. Upon
additions to 7h p and 7h q, with a cis relationship between
the phosphonate group and the â-phenyl group, were
nonregular and produced mixtures of adducts 16/17a h p
and 16/17a h q with 3:4 and 15:1 ratios, respectively. On
the basis of the stereochemical course described above
for the additions to 6a p and 6a h , a 2,2′-anti stereose-
lectivity can also be assumed for the protonation of the
intermediate R-trimethylsilyl- and R-triphenylstannyl-
stabilized phosphonate carbanions arising from the ad-
ditions to 6h p ,h q and 7h p ,h q. Addition to the R-(di-
ethoxyphosphoryl)-substituted cinnamate ester 6h m ,
with a cis relationship between the phenyl and carboxy-
late groups, resulted in a 1:3 mixture of the corresponding
2,1′-anti and 2,1′-syn adducts. This moderate syn selec-
tivity is in accordance with previous results reported for
the additions of Scho¨llkopf’s bislactims to other R,â-
unsaturated carboxylates of (Z)-configuration.21
Addition of 2 equiv of lithium azaenolate (R)-5a to
cyclopentenylphosphonate 2219e,f at -78 °C in THF
required 1 h to be complete. After quenching with acetic
acid, aqueous workup, and removal of the excess of
Scho¨llkopf’s reagent by chromatography, mixtures of the
corresponding 1:1 adducts 24A-E and 1:2 adducts 25
were obtained in 50% and 20% yields, respectively (see
Scheme 8). According to the 31P NMR spectra of the crude
reactions, the mixtures of 1:1 adducts contained five
different isomers. Using acetic acid, cinchonine, cinchoni-
dine, or 2,4,6-tri-tert-butylphenol as the proton source in
the additions to 22, the ratios of the isomers 24A/24B/
24C/24D/24E were 34:-:7:32:27, 48:2:1:17:33, 47:5:7:12:
29, and 51:7:6:10:26, respectively (see Table 4). Conver-
sion to the desired 1:1 adducts could not be significantly
increased by using higher excesses of Scho¨llkopf’s re-
agent. Nevertheless, on the basis of previous studies on
7640 J . Org. Chem., Vol. 68, No. 20, 2003

Synthesis of 2-Amino-4-phosphonobutanoic Acids
SCHEME 9a
F IGURE 2. Disubstituted AP4 analogues.
F IGURE 3. Aryl-inside or folded conformation of bislactim
ethers.
ure 2) were isolated as their hydrochloride salts in 78-
95% yield. Heating of amino ester 31 in 12 N HCl for 5
h afforded the corresponding amino acid 32 (Figure 2)
in 82% yield.
a
Reagents and conditions: (a) 0.25 N HCl, THF, rt, 8-15 h
Det er m in a t ion of t h e R ela t ive Con figu r a t ion s.
Evidence supporting the relative configurations of the
addition products was obtained by NMR analyses. For
compounds 16 and 17 in the cases of a ca -a k a , a a h ,
a a p -a a o, and for three of the cyclopentylated adducts
24, the H5 resonance appears between 3.25 and 4.25
(72-93%); (b) 12 N HCl, reflux, 6 h (85-98%); (c) KOH, H2O, rt,
1 h (88%); (d) (i) 25 M NH4OH, reflux, 48 h; (ii) Dowex-H+, 1%
NH4OH (94%); (e) (i) LiOH, H2O, rt, 1 h; (ii) (TMS)Br, CH2Cl2, rt,
48 h; (iii) MeOH (63-95%). Legend: c, R3 ) Bn; d , R3 ) CH2OBn,
X ) O, Y ) K; e, R3 ) CH2NHCbz, X ) NH, Y ) H; f, R3 ) i-Bu;
g, R3 ) i-Pr; h , R3, R4 ) Ph; i, R3 ) 3-C5H4N; j, R3 ) 2-C4H3S; k ,
R3 ) 2-C4H3O; o, R4 ) OPO3Et2, R4* ) OPO3H2; p , R4 ) SiMe3.
5
ppm, as a triplet with J H2-H5 close to 3.5 Hz, which is
general for the trans relationship of substituents at the
pyrazine ring. Conversely, the NMR spectra of adducts
18a ca -a k a and one of the cyclopentylated isomers show
the absorption corresponding to H5 at similar δ, as a
crystallization from water, amino acid 27a fa yielded
crystals amenable to X-ray structure determination,
allowing the confirmation of its 2,3-anti stereochemistry
(see the Supporting Information). Hydrolysis of amino
ester 26a d a in hydrochloric acid took place with simul-
taneous cyclization to lactone 28a d a , while amino ester
26a ea afforded in the same conditions a 2:1 mixture of
the corresponding amino acid 27a ea and lactam 28a ea .
By heating this mixture in boiling NH4OH, the amino
acid:lactam ratio decreased to 1:7. Amino acid 27a d a was
obtained as its potassium salt by basic hydrolysis of the
lactone 28a d a .
Mild acid hydrolysis (0.25 N HCl, THF, rt) of the
1′,2′-disubstituted bislactim ether 24A, obtained as the
major isomer in the addition of 5a to 22 + 23, provided
the corresponding amino ester 31 (Figure 2) in 83% yield
after chromatography. On the other hand, hydrolysis
of the 2,1′- and 2,2′-disubstituted bislactims required
some experimentation: treatment of 16b h a ,b a h and
17bh a ,ba h with 0.25 N HCl in THF, 3 equiv of p-
toluenesulfonic acid in EtOH/H2O (7:3), or an excess of
TFA in THF/H2O (1:2), at rt for 3 days, only gave
mixtures of the intermediate dipeptides. Hydrolysis was
eventually accomplished by heating of the 2-methylated
bislactims in 12 N HCl for 30-40 h. Thus, after separa-
tion of the auxiliary D-valine by reversed-phase chroma-
tography, amino acids 27ba h ,bh a and 30ba h ,bh a (Fig-
5
doublet of doublets with a J H2-H5 close to 6.5 Hz, which
is typical of a cis relationship at the bislactim ring.26 Also
1
characteristic of the H NMR spectra of 2,5-cis adducts
18a h a -a k a , with an aromatic substituent at position 1′,
is the unusually low-frequency chemical shifts observed
for the protons of one of the methyl groups of the
isopropyl substituent, which appear between -0.19 and
0.31 ppm at 20 °C in CDCl3. This shielding (∆δ between
-0.30 and -0.80 with respect to the same absorptions
in 2,5-trans adducts 16,17a h a -a k a ) may be caused by
the preference for an “aryl-inside” or “folded” conforma-
tion in solution (see Figure 3),27 in which the protons of
one of the methyl groups lie within the region of the
aromatic ring current of the substituent at position 1′.
The relative configurations at position 1′ were assigned
on the basis of the sets of NOEs observed for cyclic
(26) See, for instance: Busch, K.; Groth, U. M.; Ku¨hnle, W.;
Scho¨llkopf, U. Tetrahedron 1992, 48, 5607-5618.
(27) Aryl-inside or folded conformations have been determined in
the solid state (according to X-ray analysis) for bislactim ethers with
trans configuration (see ref 22) and also for cis-diketopiperazines28 in
solution.
(28) Apperley, D.; North, M.; Stokoe, R. B Tetrahedron: Asymmetry
1995, 6, 1869-1872 and references therein.
J . Org. Chem, Vol. 68, No. 20, 2003 7641

Ruiz et al.
SCHEME 10a
SCHEME 11a
a
Reagents and conditions: (a) (Boc)2O, NaHCO3, Na2CO3,
dioxane/H2O (1:1), rt, 3 h (89-98%); (b) (i) 1.5 M LiBH4, THF, rt,
3 h; (ii) MeOH (87% or 98%) (c) (i) 1.5 M LiBH4, THF, rt, 16 or 48
h; (ii) MeOH (78%); (d) TFA/H2O (1:1), rt, 5 h (92%); (e) (i) (TMS)Br,
CH2Cl2, rt, 13-23 h; (ii) MeOH (70-77%).
a
Reagents and conditions: (a) (Boc)2O, NaHCO3, Na2CO3,
dioxane/H2O (1:1), rt, 2-7 h (89-96%); (b) (i) 1.5 M LiBH4, THF,
rt, 1-4 d; (ii) MeOH (58-96%); (c) (i) (TMS)Br, CH2Cl2, rt, 13-23
h; (ii) MeOH (75-83%); (d) n-BuLi, THF, rt, 24 h (45%); (e)
BnOCOCl, NaHCO3, Na2CO3, dioxane/H2O (1:1), rt, 24 h (63%);
(f) H2, Pd/C, MeOH/H2O (2:1), rt, 5 h (92%). Legend: h , R4 ) Ph;
p , R4 ) SiMe3.
derivatives, as will be described below. Absolute configu-
rations follow from the use of bislactim ethers derived
from L- and D-Val, as there is ample precedent.22
corresponding N-Boc-aminooxaphosphorinane as a 3:1
mixture of epimers at the phosphorus center. In the same
conditions, reduction and cyclization of the N-Boc-amino
ester 39 was complete in 3 h, and furnished the corre-
sponding bicyclic derivative (2:1 mixture of epimers at
the phosphorus) in excellent yield. Carbamate 35a h a was
selectively cleaved by treatment with TFA in water (1:1
mixture) at rt for 5 h, to furnish 36a h a in 92% yield.
The N-Boc and O-ethyl ester groups were cleaved with
trimethylsilyl bromide in CH2Cl2 at rt to give 38a h a and
40 as pure diastereoisomers.
Reduction of the 4-phenyl- and 4-trimethylsilyl-sub-
stituted carbamates 33a a h ,a a p and 37a a h ,a a p with
lithium borohydride in THF at rt took place within hours,
but cyclization of the intermediates was unsatisfactory
or did not occur at all after 4 days (see Scheme 11). Thus,
carbamates 33a a h ,a a p , with anti configuration, gave
mixtures of the alcohols 34a a h ,a a p and oxaphosphori-
nanes 35a a h ,a a p (as 4:1 mixtures of epimers at the
phosphorus center) in 66-67% and 26-27% yields,
respectively. Treatment of 35a a h with trimethylsilyl
bromide in CH2Cl2 at rt gave 36a a h as one diastereo-
isomer. On the other hand, reduction of carbamates
37a a h ,a a p , with syn configuration, afforded exclusively
the alcohols 41a a h ,a a p in 58-98% yield. Cyclization of
the syn-alcohol 41a a h could be partially achieved in the
conditions of Berkowitz29b (n-Buli, THF, rt, 24 h, 45%
yield), but unfortunately, it was accompanied with 28%
racemization R to the phosphorus atom. Cyclization of
the trimethylsilyl-substituted alcohol to the oxaphospho-
rinane 38a a p was eventually achieved after cleavage of
the protecting groups, by treatment of the δ-hydroxy-
phosphonic acid 42a a p with benzyl chloroformate in
basic media followed by the catalytic hydrogenolysis of
the benzyl carbamate.
Since none of the synthesized adducts, esters, or amino
acids (other than 27a fa ) provided crystals suitable for
X-ray crystal structure determination, cyclic deriva-
tives were sought that could enable the assignment of
the relative configurations by NOESY. Six-membered
aminooxaphosphorinane derivatives were attractive
in this regard, because of the strong preference for the
chair conformation reported for several substituted sys-
tems.29 Conversion of amino esters 26a a h ,a a p ,a h a and
29a a h ,a a p ,a h a and amino acids 30ba h ,bh a into such
cyclic derivatives was achieved according to Schemes 10-
12, by extending the applicability of previously developed
methodology.11,25
Chemoselective reduction of the carboxylic ester in
the presence of the phosphonate was accomplished on
the N-Boc derivatives of amino esters 33a a h ,a a p ,a h a ,
37a a h ,a a p ,a h a , and 39, employing lithium borohydride
in THF at rt (see Scheme 10). Reduction of 33a h a under
these conditions was complete in 3 h, and after quenching
with methanol, workup, and chromatography, alcohol
34a h a could be isolated in 87% yield. Moreover, when
the reduction mixture was stirred for 13 h further at rt,
cyclization of the intermediates was observed, to afford
the N-Boc-aminooxaphosphorinane 35a h a as a single
diastereoisomer of (R)-configuration at the phosphorus
center. Cyclization of the intermediates in the reduction
of N-Boc-amino ester 37a h a required 48 h, and gave the
(29) (a) Harvey, T. C.; Simiand, C.; Weiler, L.; Withers, S. G. J . Org.
Chem. 1997, 62, 6722-6725. (b) Berkowitz, D. B.; Eggen, M.-J .; Shen,
Q.; Shoemaker, R. K. J . Org. Chem. 1996, 61, 4666-4675. (c) Tasz, M.
K.; Rodriguez, O. P.; Cremer, S. E.; Hussain, M. S.; Mazhar-ul-Haque
J . Chem. Soc., Perkin Trans. 2 1996, 2221-2226. (d) Lane, T. M.;
Rodriguez, O. P.; Cremer, S. E.; Bennett, D. W. Phosphorus, Sulfur
Silicon Relat. Elem. 1995, 103, 63-75. (e) Bergesen, K.; Vikane, T.
Acta Chem. Scand. 1972, 26, 1794-1798. See also refs 11 and 25.
7642 J . Org. Chem., Vol. 68, No. 20, 2003

Synthesis of 2-Amino-4-phosphonobutanoic Acids
SCHEME 12a
a
Reagents and conditions: (a) (i) HMDS, H2SO4, reflux, 12 h;
(ii) 1.5 M LiBH4, 2 M in THF, rt, 24 h; (ii) MeOH (73% or 78%);
(b) SOCl2, reflux, 14 h (62% or 83%).
After temporary protection of the acidic functionalities
at amino acids 30ba h and 30bh a (hexamethyldisilazane,
reflux, 12 h), reduction with lithium borohydride gave
rise to amino alcohols 42ba h and 42bh a in good yields
(see Scheme 12). Cyclization to the corresponding oxa-
phosphorinanes 38ba h and 38bh a took place by heating
the amino alcohols in thionyl chloride.
A single chair conformation was observed for each
compound 35a h a , 36a a h , 38a a h , 38a a p , 38a h a , 38ba h ,
1
38bh a , and 40 in the H NMR spectra (D2O, 500 or 200
MHz, 25 °C). The lactone 28a d a , the lactam 28a ea , and
all the oxaphosphorinanes, with the exception of 36a a h ,
showed patterns of signals suitable for the study of their
1
relative stereochemistry by NOESY. After the H NMR
assignments were corroborated by COSY experiments,
the analysis of the sets of observed NOEs allowed the
assignment of the relative configuration of the stereo-
genic centers formed in the conjugate addition. The
observed NOEs were supported by PM3/COSMO semi-
empirical calculations:30 the refined geometries for the
cyclic derivatives in a polarizable dielectric continuum
(simulating water) were in agreement with the confor-
mations in aqueous solution deduced from NMR spec-
troscopy, as depicted in Figure 4. Thus the stereochem-
istry of lactone 28a d a and lactam 28a ea was determined
as 3,4-trans, while oxaphosphorinanes 35a h a and 40
showed a 4,5-cis configuration. These results and the
X-ray crystal structure analysis for 27a fa allow us to
assume a 2,1′-anti configuration for the major isomers
16a ca -a k a ,bh a resulting from the additions of lithium
azaenolates to the â-substituted vinylphosphonates with
(E)-configuration. The assignment of 2,1′-syn configura-
tion for the major isomers 17a d a ,a fa -a h a ,bh a in the
additions to the â-substituted acceptors with (Z)-config-
uration follows by elimination and is also consistent with
the NOEs observed for the oxaphosphorinanes 38a h a
and 38bh a , which showed a 4,5-trans configuration. The
3,5-cis configuration determined for the oxaphosphori-
nanes 38a a h , 38a a p , 38ba h , and 40 enables the assign-
ment of a 2,2′-syn configuration for the minor isomers
17a a h ,a a p ,ba h , obtained from the additions to R-sub-
stituted acceptors, and a 1′,2′-cis configuration for the
major adduct 24A, arising from the addition to cyclopen-
tenylphosphonate.
F IGURE 4. PM3/COSMO-optimized geometries for the cyclic
derivatives, showing characteristic NOEs.
of the acceptor into syn or anti configuration at the 1,4-
addition products was previously encountered in other
conjugate additions of lithiated bislactim ethers (derived
from cyclo-[Val-Gly]) to 1-propenylphosphonates,10b,11
acrylate and cinnamate esters,21 nitroolefines,22 and vinyl
sulfones.23,31 The stereochemical course of the additions
of lithium azaenolates 5a ,b to R-substituted, â-substi-
tuted, or R,â-disubstituted vinylphosphonates can be
rationalized by extending the transition-state model that
was semiempirically optimized for the additions of 5a to
1-propenylphosphonates.11 In this way, an initial lithium-
phosphoryl coordination to form a chelate complex, 43,
followed by a rate-determining reorganization through
competitive eight-membered transition-state structures
Discu ssion of Ster eoch em ica l Mod els for th e
Con ju ga te Ad d ition . Translation of (Z)- or (E)-geometry
(31) For reviews of the stereochemistry of the Michael addition
reaction, see: (a) Leonard, J . Contemp. Org. Synth. 1994, 1, 387-415.
(b) Oare, D. A.; Heathcock, C. H. Top. Stereochem. 1989, 19, 227-
406.
(30) (a) PM3: Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209-
220, 221-264. (b) COSMO: Klamt, A.; Schu¨u¨rmann, G. J . Chem. Soc.,
Perkin Trans. 2 1993, 799-805.
J . Org. Chem, Vol. 68, No. 20, 2003 7643

Ruiz et al.
SCHEME 13. P r op osed Tr a n sition -Sta te Str u ctu r es a n d In ter m ed ia te P h osp h on a te Ca r ba n ion s
(TSs), can account for the stereochemical features of the
present conjugate additions (see Scheme 13). According
to such a model, 2,1′-anti/syn stereoselection relies on the
energy difference between the “compact” (chair-like) and
“relaxed” (boat-like) TSs resulting from the approach of
the reactive face of the azaenolate (trans to the isopropyl
group) to the prochiral faces of the â-carbon atom of the
acceptor. Thus, the preferential translation of the (Z)- or
(E)-geometry of the â-substituted vinylphosphonate into
a 2,1′-syn or 2,1′-anti configuration at the 1,4-addition
products must originate from a clear kinetic preference
for the compact TSs over the relaxed counterparts. We
speculate that secondary order hyperconjugative interac-
tions between the π systems of the acceptor and donor
partners in the compact TSs may contribute to this
preference. Conversely, nonbonding interactions between
the ethoxy groups of the bislactim ring and bulky R3c
substituents can reduce the energy gap between the
competitive TSs, thus accounting for the lower 2,1′-syn
selectivity in the additions to the â-alkyl vinylphospho-
nates with (Z)-configuration.
The stereochemical outcome observed in the addition
to the R,â-substituted acceptors can be understood in
similar terms. Nonbonding interactions between the
bislactim and the R-substituent of the acceptor (R4) raise
the energy of the compact TSs, and the relaxed TSs also
become important in these cases. Thus, for the acceptors
with a trans relationship between the phosphorus atom
and the â-substituent (R3t), increasing the bulk of the
R-substituent (from H to SiMe3 and to SnPh3) results in
a closer energy for the competing TSs and a reduced anti
selectivity (the anti/syn dr being diminished from >18:1
to 8:1 and 3:1). Moreover, the preference for the compact
TSs is not maintained in the additions to the R,â-
substituted acceptors with a cis relationship between the
phosphorus atom and the â-substituent, probably due to
simultaneous interactions between both R4 and R3c
substituents and the bislactim moiety in such TSs. Thus,
translation of the (E)-geometry of the R-triphenylstannyl-
substituted vinylphosphonate 7h q into a 2,1′-anti con-
figuration of the major addition products 17a h q can be
rationalized by invoking the preference for the relaxed
TS.
R-substituted acceptors can be rationalized by considering
the involvement of cyclic chelate complexes such as
Li+44-. Thus, approach of the proton with an axial
trajectory to the less hindered face of the cyclic phospho-
nate carbanion may account for the 2,2′-anti stereose-
lection observed in the additions.
Con clu sion s
In summary, the scope and limitations of the conjugate
additions of Scho¨llkopf’s reagents to substituted vi-
nylphosphonates have been studied. It has been shown
that the reactions of lithiated bislactim ethers derived
from cyclo-[Gly-Val] and cyclo-[Ala-Val] with R-, â-, or
R,â-substituted vinylphosphonates take place regio- and
stereoselectively at low temperature. For the vinylphos-
phonates with alkyl, aryl, or functionalized substituents
at the â-position, the conjugate addition results in a
preferential translation of the (E)- or (Z)-geometry into
2,1′-anti or 2,1′-syn configuration at the addition prod-
ucts. The level of stereoselection attained in the additions
to R-substituted and R,â-disubstituted vinylphosphonates
was found markedly dependent on the nature of the
R-substituent of the acceptor, but these reactions allowed
the preparation of enantiomerically pure compounds with
phenyl, silyl, stannyl, or phosphoryloxy groups R to the
phosphorus atom. Although low diastereoselectivities
were achieved at this stage, protonation experiments
revealed that the intermediate phosphonate carbanions
might react with electrophilic reagents with synthetically
useful levels of stereoselection. The stereochemical out-
comes of the conjugate additions have been rationalized
by invoking competitive eight-membered TSs. According
to this model, the stereochemical response of the addition
to the acceptor geometry originates from an orientational
preference in the TSs for a compact (chair-like) disposi-
tion of the reaction partners, which may reduce non-
bonding interactions and increase secondary order hy-
perconjugative interactions between the π systems of the
acceptor and donor moieties. Finally, the addition prod-
ucts have been efficiently transformed into a variety of
3- or 4-monosubstituted and 2,3-, 2,4-, or 3,4-disubsti-
tuted AP4 derivatives in enantiomerically pure form,
which may result in useful tools for the study of group
III of mGluRs.
The stereoselective protonation of the intermediate
phosphonate carbanions arising from the additions to the
7644 J . Org. Chem., Vol. 68, No. 20, 2003

Synthesis of 2-Amino-4-phosphonobutanoic Acids
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for all new compounds and crystal-
lographic data for 27a fa . This material is available free of
charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We gratefully acknowledge the
Ministerio de Ciencia y Tecnolog´ıa (Grant BQU2000-
0236) for financial support, and Novartis Pharma for
the generous gift of bislactim ethers derived from cyclo-
[Val-Gly]. We also thank Dr. Miguel A. Maestro for
resolving the X-ray structure.
J O034707Q
J . Org. Chem, Vol. 68, No. 20, 2003 7645