Diastereoselective synthesis of 2-amino-4-phosphonobutanoic acids by electrophilic substitution and tin-Peterson olefination of bis-lactim ethers derived from cyclo-[L-AP4-D-Val]

Article abstract of DOI:10.1021/jo061072x

Electrophilic substitutions on lithiated Schoellkopf's bis-lactim ethers derived from cyclo-[L-AP4-D-Val] take place regio- and stereoselectively at the α-position of the phosphonate ester. Subsequent olefination of α-silyl-, α-phosphoryl-, and α-stannyl-

Full text of DOI:10.1021/jo061072x

Diastereoselective Synthesis of 2-Amino-4-phosphonobutanoic Acids
by Electrophilic Substitution and Tin-Peterson Olefination of
Bis-lactim Ethers Derived from cyclo-[L-AP4-D-Val]
Mar´ıa C. Ferna´ndez,† Aniana D´ıaz, Juan J. Guill´ın, Olga Blanco, 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
ojea@udc.es; ruizpr@udc.es
ReceiVed May 25, 2006
Electrophilic substitutions on lithiated Scho¨llkopf’s bis-lactim ethers derived from cyclo-[L-AP4-D-Val]
take place regio- and stereoselectively at the R-position of the phosphonate ester. Subsequent olefination
of R-silyl-, R-phosphoryl-, and R-stannyl-stabilized phosphonate carbanions give rise exclusively to
vinylphosphonates. Both processes allow a direct and stereoselective access to a variety of 4-substituted
and 3,4-disubstituted 2-amino-4-phosphonobutanoic acids (AP4 derivatives) in enantiomerically pure form
that may be useful tools for characterizing the molecular pharmacology of metabotropic glutamate receptors
(mGluRs) of group III. The relative stereochemistry was assigned from X-ray diffraction analyses or
NMR studies of 1,2-oxaphosphorinane and other cyclic derivatives. In accordance to density functional
theory (DFT) calculations, the syn-selectivity in the electrophilic substitutions may originate from the
intervention of seven- and eight-membered chelate structures in which the bis-lactim ether moiety shields
one of the faces of the phosphonate carbanion. DFT calculations for the tin-Peterson olefination of
R-stannyl stabilized phosphonate carbanions indicate that rate and selectivity are determined in the initial
carbon-carbon bond formation step where the unlike transition structures leading to (Z)-vinylphosphonates
are favored both in the gas phase and in THF solution.
Introduction
such us brain ischemia, pain, psychiatric disorders, and neuro-
degenerative diseases. Thus, GluRs are valuable therapeutic
targets.2 GluRs are categorized into two main classes: ionotropic
glutamate receptors (iGluRs),3 which are ligand-gated ion
channels, and metabotropic glutamate receptors (mGluRs),
which are G-protein-coupled receptors involved in the regulation
of glutamate release and the modification of the postsynaptic
excitability to glutamate. There are currently eight known
subtypes of mGluRs, which can be classified into three
subgroups (groups I, II, and III) according to pharmacological
Glutamate is the most important excitatory neurotransmitter
in the central nervous system (CNS).1 After being released from
the presynaptic terminal, glutamate diffuses across the synaptic
cleft and binds to its receptors on the dendrites of the
postsynaptic neurons. Glutamate receptors (GluRs) are involved
in a variety of physiological functions, including neuronal
plasticity, long-term potentiation of synaptic activity, and
memory as well as in acute or chronic pathological processes
† Present address: Lilly S.A., Alcobendas, Madrid, Spain.
(1) (a) CNS Neurotransmitters and Neuromodulators: Glutamate; Stone,
T. W. Ed.; CRC: Boca Raton, Florida, 1995. (b) Parthasarathy, H. S., Ed.
Nature 1999, 399 (Suppl.), A1-A47. (c) Ozawa, S.; Kamiya, H.; Tsuzuki,
K. Prog. Neurobiol. 1998, 54, 581-618.
(2) Bra¨uner-Osborne, H.; Egebjerg, J.; Nielsen, E. O.; Madsen, U.;
Krogsgaard-Larsen, P. J. Med. Chem. 2000, 43, 2609-2645.
(3) The Ionotropic Glutamate Receptors; Monahan, D. T., Wenthold,
R. J., Eds.; Humana: Totowa, New Jersey, 1997.
10.1021/jo061072x CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/11/2006
6958
J. Org. Chem. 2006, 71, 6958-6974

Synthesis of 2-Amino-4-phosphonobutanoic Acids
CHART 1. Selective Ligands for the MGluRs of Group III
access to 3-substituted 2-amino-4-phosphonobutanoic acids 1
with 2,3-syn or 2,3-anti configurations (see Scheme 1).12
Nevertheless, the scope and the stereoselectivity of the corre-
sponding additions to R-substituted vinylphosphonates 8 were
found to be reduced, seriously compromising the utility of this
methodology for the synthesis of 4-substituted AP4 derivatives.
To develop an alternative approach to this class of com-
pounds, we decided to investigate the electrophilic substitution
processes on the bis-lactim ethers 2, derived from cyclo-[L-AP4-
D-Val]. On the basis of its potential role as first intermediates
resulting from the additions of 5 to vinylphosphonates 6,
phosphonate carbanions 3 should be accessible by treatment of
2 with an adequate base. Subsequent trapping of 3 with different
electrophilic reagents could give rise, selectively, to 2′-
substituted bis-lactim ether intermediates 4.13 We also envisaged
that the electrophilic substitutions on 3 with phosphoryl, silyl,
or stannyl groups could be followed by Wadsworth-Emmons
or Peterson-like olefinations of carbonyl compounds and could
give rise to vinylphosphonates 7 as precursors of 4-alkylidene
AP4 derivatives. Thus, in this paper we report in full detail the
application of such a methodology to the synthesis of a variety
of enantiomerically pure 4-substituted and 3,4-disubstituted AP4
derivatives 1,14 which may be useful for characterizing the
molecular pharmacology of the mGluRs of group III.
properties, signal transduction mechanisms, and sequence
similarity. Among the receptors of group III, mGluR4, mGluR7,
and mGluR8 are presynaptically localized and inhibit the release
of neurotransmitters, whereas mGluR6 receptors are exclusively
expressed by ON bipolar cells in the retina and play an important
role in the amplification of visual inputs. mGluRs of group III
are characterized by their response to several phosphonic amino
acid derivatives.4 They are selectively activated by L-2-amino-
4-phosphonobutanoic acid (L-AP4, see Chart 1) and competi-
tively antagonized by R-methylated derivatives of L-AP4
(MAP4) and 4-phosphonophenylglycine (MPPG).
Elucidation of the role that mGluRs play in the normal and
pathological functioning of the CNS still depends on the
development of more potent and subtype-selective pharmaco-
logical agents.Therefore, there is considerable interest in the
development of new synthetic methodologies for the preparation
of enantiomerically pure AP4 derivatives that may result in
useful tools for determining the requirements for receptor
binding and physiological responses at mGluRs of group III.
Three major strategies have been devised for the preparation
of AP4 derivatives. Phosphites have been reacted with func-
tionalized carbonyl compounds that were subsequently converted
to amino acids via Strecker reaction,5 or have been reacted with
halides,6 triflates,7 or carbonyl functionalities8 located at the side
chain of R-amino acid derivatives. Alternative synthesis have
relied on glycine enolate equivalents for the alkylation of,9 1,3-
dipolar cycloaddition to,10 or conjugate addition to11 suitable
functionalized phosphonates. In this area, we have shown that
conjugate additions of lithiated Scho¨llkopf’s bis-lactim ethers
5 to vinylphosphonates 6 with alkyl, aryl, or functionalized
substituents at the â-position allow a direct and stereocontrolled
Results and Discussion
Throughout this article, bis-lactim ethers, amino esters, amino
acids, and their derivatives will be referred to with numerals
followed by two letters, according to the central key depicted
in Chart 2. Numerals describe generic stereoisomers, and letters
are used to distinguish the identity of the substituents R3 and
R4 (or R5) at positions 3 and 4 (or 5) of the targeted AP4
derivatives.
Electrophilic Substitutions of Bis-lactim Ethers Derived
from cyclo-[L-AP4-D-Val]. We first studied the electrophilic
substitution processes on the bis-lactim ether 11aa, which was
derived from cyclo-[L-AP4-D-Val]. Preparation of this unsub-
stituted precursor was achieved by adaptation of the procedure
reported by Shapiro et al.11a for the synthesis of the O,O-diallyl
phosphonate derivative. Thus, addition of an equimolar solution
of bromoethylphosphonate 9 containing 5% of vinylphosphonate
10 to the lithium salt 5 in THF at -78 °C afforded bis-lactim
ether 11aa in 85% yield virtually free of the 2,5-cis diastere-
oisomer (see Scheme 2).15 The exceptionally high 2,5-trans
selectivity achieved in this “alkylation” can be understood
considering that the addition of the lithium salt 5 to vinylphos-
(4) (a) Filosa, R.; Marinozzi, M.; Constantino, G.; Brunsgaard Hermit,
M.; Thomsen, C.; Pellicciari, R. Bioorg. Med. Chem. 2006, 14, 3811-
3817. (b) Swanson, C. J.; Bures, M.; Johnson, M. P.; Linden, A.-M.; Monn,
J. A.; Schoepp, D. D. Nat. ReV. Drug DiscoVery 2005, 4, 131-144. (c)
Moldrich, R. X.; Chapman, A. G.; De Sarro, G.; Meldrum, B. S. Eur. J.
Pharmacol. 2003, 476, 3-16. (d) De Blasi, A.; Conn, P. J.; Pin, J.-P.;
Nicoletti, F. Trends Pharmacol. Sci. 2001, 22, 114-120. (e) Conn, P. J.;
Pin, J.-P. Annu. ReV. Pharmacol. Toxicol. 1997, 37, 205-237.
(5) (a) Crooks, S. L.; Robinson, M. B.; Koerner, J. F.; Johnson, R. L. J.
Med. Chem. 1986, 29, 1988-1995. (b) Johnson, R. L.; Rao, K. S. S. P.
Bioorg. Med. Chem. Lett. 2005, 15, 57-60. See also 4a and Massey, S.
M.; Monn, J. A.; Valli, M. J. U.S. Patent 5,958,960, 1999.
(10) (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.
(6) (a) Nair, S. A.; Lee, B.; Hangauer, D. G. Synthesis 1995, 810-814.
(b) Ma, D.; Ma, Z.; Jiang, J.; Yang, Z.; Zheng, C. Tetrahedron: Asymmetry
1997, 8, 889-893. (c) Bessieres, B.; Schoenfelder, A.; Verrat, C.; Mann,
A.; Ornstein, P.; Pedregal, C. Tetrahedron Lett. 2002, 43, 7659-7662. See
also: Hanrahan, J. R.; Taylor, P. C.; Errington, W. J. Chem. Soc., Perkin
Trans. 1 1997, 493-502.
(7) (a) Berkowitz, D. B.; Eggen, M.-J.; 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.
(8) (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.
(9) (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.
(11) (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.
(12) (a) Ruiz, M.; Ferna´ndez, M. C.; D´ıaz, A.; Quintela, J. M.; Ojea, V.
J. Org. Chem. 2003, 68, 7634-7645. (b) Ojea, V.; Ruiz, M.; Shapiro, G.;
Pombo-Villar, E. J. Org. Chem. 2000, 65, 1984-1995.
(13) For previous asymmetric synthesis of phosphonic acids using
phosphoryl-stabilized carbanions, see: (a) Denmark, S. E.; Chen, Ch. T. J.
Am. Chem. Soc. 1995, 117, 11879-11897 and references therein. (b)
Hanessian, S.; Bennani, Y. L. Tetrahedron Lett. 1990, 31, 6465-6468.
(14) Part of this work already was presented as preliminary communica-
tions: (a) Ruiz, M.; Ojea, V.; Quintela, J. M.; Guill´ın, J. J. Chem. Commun.
2002, 1600-1601. (b) Ferna´ndez, M. C.; Quintela, J. M.; Ruiz, M.; Ojea,
V. Tetrahedron: Asymmetry 2002, 13, 233-237. (c) Ferna´ndez, M. C.;
Ruiz, M.; Ojea, V.; Quintela, J. M. Tetrahedron Lett. 2002, 43, 5909-
5912.
J. Org. Chem, Vol. 71, No. 18, 2006 6959

Ferna´ndez et al.
SCHEME 1
CHART 2
SCHEME 2
phonate 10 is much faster than the reaction with 9. The initially
formed phosphonate carbanion then is trapped by 9 in a
dehydrohalogenation reaction regenerating the acceptor 10.
Slow addition of the bis-lactim ether 11aa to a solution of
LDA in THF at -78 °C was followed 15 min later by the
dropwise addition of the electrophilic reagent. Reactions with
methyl iodide (MeI), trimethylsilyl chloride (TMSCl), N-
fluorobenzenesulfonimide (NFSi),16 Ph3SnCl, Et2CO3, Et2PO3-
Cl, triisopropylbenzenesulfonyl azide (trisyl-N3),17 DMF, or
(15) Addition of 9 to the lithium salt 5 under the described conditions9b
gave a mixture of 11aa and its 2,5-cis epimer in ca. 85:15 ratio. For previous
alkylations of lithiated bis-lactim ether with low diastereoselectivity, see:
(a) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M. J.
Org. Chem. 2001, 66, 4525-4542. (b) Adamczyk, M.; Akireddy, S. R.;
Reddy, R. E. Tetrahedron: Asymmetry 1999, 10, 3107-3110. (c) Bull, S.
D.; Chernega, A. N.; Davies, S. G.; Moss, W. O.; Parkin, R. M. Tetrahedron
1998, 54, 10379-10388.
HCO2Et took place rapidly at -78 °C. When necessary,
processes were quenched 5 min later by the addition of a proton
source. As the reaction with MoO5‚Py‚HMPA (MoOPH)18
(16) Differding, E.; Duthaler, R. O.; Krieger, A.; Ru¨egg, G. M.; Schmit,
C. Synlett 1991, 395-397.
(17) Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am.
Chem. Soc. 1990, 112, 4011-4030.
6960 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of 2-Amino-4-phosphonobutanoic Acids
SCHEME 3a
a Legend: b, R4 ) Me; c, R4 ) CHO; d, R4 ) CO2Et; e, R4 ) F; f, R4 ) OH; g, R4 ) PO3Et2; h, R4 ) SnPh3; i, R4 ) SiMe3; j, R4 ) N3.
TABLE 1. Electrophilic Substitutions on Li+11aa-
SCHEME 4
legend electrophile
H+ source
yield (%)a 12:13:14:15 ratiob
b
c
d
e
f
g
h
i
MeI
84
75
66
66
59
83
75
85
80
NR
NR
3:2:-:-
1:1:-:-
2:1:-:-
3:1:-:-
2:1:-:-
c
3:2:-:-
4:1:1:-
7:7:1:1
HCO2Et
Et2CO3
NFSi
MoOPH
Et2PO3Cl
Ph3SnCl
Me3SiCl
Trisyl-N3
BnBr
HOAc
HOAc
H2O
HOAc
j
k
l
HOAc/KOAc
DEAD
a Isolated yield of mixtures of adducts, after column chromatography.
b Determined by integration of the 31P NMR spectra of the crude mixtures.
c There is not anti/syn isomerism in this case. No reaction (NR) was observed
upon warming up to 0 °C.
material. Electrophilic fluorination with NFSi also afforded 2,5-
trans-2′,2′-difluorinated bis-lactim 16ae in 10% yield (see
Scheme 4). The use of 2 equiv of NFSi resulted in the complete
reaction of 11aa and a reduced ratio of mono- to difluorination
(4:3 instead of 11:1) with neither change in the combined yield
(72%) nor the level of 2,2′-syn stereoselectivity. When LDA
was added to the preformed equimolar mixture of 11aa and
NFSi, a 65% conversion to the monofluorinated products 12ae/
13ae was achieved. As the difluorination was completely
suppressed in this case, the yield of 12ae/13ae could be
increased to 78% by resubjecting the recovery material to these
fluorination conditions.
Having shown the feasibility of performing electrophilic
substitutions on lithiated bis-lactim ether 11aa, we explored the
extension of this reactivity to 1′-substituted bis-lactim ethers
derived from cyclo-[L-AP4-D-Val] using the methylation as the
model process. To determine the influence of the nature and
configuration of the substituent on the facial selectivity of the
methylation, bis-lactim ethers with phenyl- or isopropyl- groups
at the 1′-position and 2,1′-syn or 2,1′-anti configurations were
stereoselectively prepared. Following our recently reported
procedure,12a the conjugate additions of lithium salt 5 to
â-phenyl- and â-isopropyl-substituted vinylphosphonates of (Z)-
configuration afforded bis-lactim ethers 17ma and 17na with
2,5-trans-2,1′-syn configuration, while additions to the corre-
sponding (E)-vinylphosphonates gave rise to 2,5-trans-2,1′-anti
bis-lactims 18ma and 18na (see Scheme 5).
proceeded slowly at -78 °C, it was allowed to reach -10 °C
and was quenched with water after 4 h. Conversely, no reaction
was observed under these conditions or with longer reaction
times and warming (up to 10 h and 0 °C) with either benzyl
bromide or DEAD.
After workup, the 31P NMR analysis of the crude mixtures
revealed a highly regioselective course for the substitution
process, which led to the exclusive formation of mixtures of
2′-substituted bis-lactims 12-15ab-aj despite the literature9b,19
1
(see Scheme 3). Integration of the H decoupled 31P NMR
spectra also revealed moderate levels of asymmetric induction
at the substitution position, which depended on the nature of
the electrophilic reagent (see Table 1). In this way, methylation,
formylation, carboxylation, fluorination, hydroxylation, phos-
phorylation, and stannylation of 11aa took place with a complete
retention of the 2,5-trans configuration of the bis-lactim ether
and afforded mixtures of the 2,2′-anti and 2,2′-syn substituted
products 12ab-ah and 13ab-ah, respectively, with ratios
ranging from 1:1 to 3:1. In contrast, the silylation and the
azidation, which were regioselective 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 diastereoisomers.
Thus, the silylation led to a mixture of bis-lactims 12ai/13ai/
14ai in a 4:1:1 ratio, while the azides 12aj/13aj/14aj/15aj were
obtained in a 7:7:1:1 ratio.
Phosphonate carbanions Li+17ma-, Li+17na-, Li+18ma-,
and Li+18na- were generated by the addition of the corre-
sponding bis-lactim ethers to solutions of LDA at -78 °C in
THF. When methyl iodide was added to the phosphonate
carbanions as above, reactions also took place in a highly
regioselective fashion with complete retention of the configu-
ration at positions 2, 5, and 1′ and afforded mixtures of the
corresponding 2′-methylated bis-lactims in very good yields.
According to the 31P NMR analysis of the crude mixtures, the
methylation of 2,1′-syn phosphonate carbanions Li+17ma- and
After flash chromatography of the crude mixture, the fractions
containing the 2′-substituted bis-lactims were isolated in 59-
85% combined yield along with 5-15% of unreacted starting
(18) Vedejs, E.; Larsen, S. Org. Synth. 1986, 64, 127-137, and references
therein.
(19) Vassiliou, S.; Dimitropoulus, C.; Magriotis, P. A. Synlett 2003,
2398-2400.
J. Org. Chem, Vol. 71, No. 18, 2006 6961

Ferna´ndez et al.
SCHEME 5a
a Legend: m, R3 ) Ph; n, R3 ) i-Pr.
SCHEME 6a
a Legend: d, R4 ) CO2Et; g, R4 ) PO3Et2; h, R4 ) SnPh3; i, R4 ) SiMe3.
Li+17na- was found 1′,2′-anti stereoselective and furnished
mixtures of bis-lactims 19/20mb and 19/20nb with 1:3 and 1:6
ratios, respectively. Conversely, the reaction of the phosphonate
carbanions with 2,1′-anti configuration was not regular:
methylation of Li+18ma- also was found 1′,2′-anti stereo-
selective and gave a 3:1 mixture of bis-lactims 21mb and 22mb,
while the reaction of Li+18na- was 1′,2′-syn selective and
afforded 21nb and 22nb with 1:3 ratio. Upon crystallization
from hexanes, bis-lactim ether 21mb yielded crystals amenable
to X-ray structure determination, which allowed the confirmation
of its relative stereochemistry (see Supporting Information).
Olefination of Carbonyl Compounds with Bis-lactim
Ethers Derived from cyclo-[L-AP4-D-Val]. To explore further
the scope of these electrophilic substitutions, we examined the
olefination reactions of carbonyl compounds using the R-ethoxy-
carbonyl-, R-trimethylsilyl-, R-diethoxyphosphoryl-, and R-tri-
phenylstannyl-stabilized phosphonate carbanions derived from
bis-lactim ethers 12/13ad,ag-ai. Toward this end, Li+12ad-,
Li+12ag-, and Li+12ah- were prepared by adding 12ag or
mixtures of 12/13ad,ah to solutions of LDA at -78 °C in THF,
while phosphonate carbanion Li+12ai- was obtained free of its
2,5-cis diastereoisomer by adding R-trimethylsilylvinylphos-
phonate to a solution of lithium azaenolate 512a (see Scheme
6). Benzaldehyde, which was selected as a model carbonyl
compound, was slowly added 15 min later, and the reaction
mixtures were gradually warmed to 0 °C during 4 h. After the
reaction mixtures were subjected to quenching with acetic acid
and aqueous workup, the 2′-benzylidene substituted 2,5-trans
bis-lactims ethers 23am/24am and 25/26 were isolated in 56-
77% yield, along with 10-25% of unreacted starting materials.
Because the unreacted bis-lactim ethers 12/13ad,ag,ah could
almost completely be recovered and showed no racemization,
the yield of these olefinations could be increased to 70-85%
by resubjecting the recovered material to the same reaction
conditions.
Analysis of the 1H and 31P NMR spectra of the crude mixtures
revealed different stereochemical courses and selectivities in
the Wadsworth-Emmons olefinations. Thus, R-ethoxycarbonyl-
stabilized phosphonate carbanion Li+12ad- led to a 1:6 mixture
of cinnamates 25 and 26 with 2,5-trans-(2′Z) and 2,5-trans-(2′E)
configurations, respectively,20 while olefination with the R-di-
ethoxyphosphoryl-substituted phosphonate carbanion Li+12ag-
took place with (Z)-stereoselection and afforded vinylphospho-
nates 23am and 24am in a 5:1 ratio. This result is remarkable,
because lithioalkylidenebisphosphonates have been reported to
selectively produce â- and R,â-substituted vinylphosphonates
with (E)-configuration in their reactions with carbonyl com-
pounds.21 Peterson olefinations of phosphonate carbanions
Li+12ah- and Li+12ai- showed markedly different levels of
(Z)-stereoselection. In this way, the R-trimethylsilyl-stabilized
phosphonate carbanion led to vinylphosphonates 23am and
24am in a 3:2 ratio. When starting with the R-triphenylstannyl
substituted bis-lactims 12/13ah, the olefination gave rise
exclusively to the (Z)-vinylphosphonate 23am. The stereochem-
(20) Stereochemical assignments for the cinnamate derivatives 25 and
26 were consistent with the sets of observed NOEs (see Scheme 6).
(21) (a) Gupta, A.; Sacks, K.; Khan, S.; Tropp, B. E.; Engel, R. Synth.
Commun. 1980, 10, 299-304. (b) Aboujaoude, E. E.; Lietje´, S.; Collignon,
N.; Teulade, M. P.; Savignac, P. Tetrahedron Lett. 1985, 26, 4435-4438.
(c) Teulade, M. P.; Savignac, P.; Aboujaoude, E. E.; Lie´tge, S.; Collignon,
N. J. Organomet. Chem. 1986, 304, 283-300. (d) Kiddle, J. J.; Babler, J.
H. J. Org. Chem. 1993, 58, 3572-3574. (e) Perlikowska, W.; Mphahlele,
M. J.; Modro, T. A. J. Chem. Soc., Perkin Trans. 2 1997, 967-970. (f)
Iorga, B.; Eymery, F.; Savignac, P. Tetrahedron Lett. 1998, 39, 4477-
4480. (g) Chang, K.; Ku, B.; Oh, D. Y. Synth. Commun. 1989, 19, 1891-
1898.
6962 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of 2-Amino-4-phosphonobutanoic Acids
SCHEME 7a
a Legend: m, R5 ) Ph; n, R5 ) i-Pr; o, R5 ) 2-C4H3S; p, R5 ) CHCHPh.
SCHEME 8
ical course of the tin-Peterson olefination with Li+12ah- is
similar to that previously encountered in the preparation of other
R,â-substituted vinylphosphonates.22
Prompted by the excellent stereoselectivity achieved in the
benzylidenation of the R-triphenylstannyl-stabilized phosphonate
carbanion Li+12ah-, we prepared a series of vinylphosphonates
23am-aq in moderate yield by application of these tin-
Peterson reactions to various structurally diverse carbonyl
compounds (see Scheme 7). Thus, solutions of isobutyraldehyde,
2-thienylcarboxaldehyde, cinnamaldehyde, or cyclohexanone in
THF were added dropwise to solutions of Li+12ah- in THF at
-78 °C, and the reaction mixtures were gradually warmed to 0
°C during 4 h. After the reaction mixtures were subjected to
quenching with acetic acid and aqueous workup, vinylphos-
phonates 23an-aq were isolated in 50-61% yield along with
10-32% of unreacted starting materials. After inspection of the
31P NMR spectra of the crude mixtures, we could not detect
any absorption corresponding to the minor (E)-isomers, as was
previously encountered in the reaction of Li+12ah- with
benzaldehyde. Thus, the tin-Peterson olefinations of either
R-branched, R,â-unsaturated, aromatic, or heteroaromatic al-
dehydes using the R-triphenylstannylphosphonate lithium salt
derived from cyclo-[L-AP4-D-Val] took place with an outstand-
ing level of stereoselection giving rise exclusively to the
kinetically favored (Z)-vinylphosphonates.
to the phosphonate carbanion Li+11aa- and of its possible
reaction pathways with two model electrophiles: methyl iodide
and trimethylsilyl chloride. Because low reagent concentration
will promote the reaction via the more highly solvated and less
aggregated species,24 complete dissociation of the possible
oligomeric clusters was assumed by considering discrete sol-
vation of the lithium with two THF molecules.25 The geometry
optimizations were performed using a B3LYP density functional
theory (DFT) procedure26 with the cc-pVDZ basis set27 and a
small-core relativistic pseudopotential (PP) for I.28 Single point
energy calculations of the bulk solvent effect also were
performed in THF (ꢀ ) 7.52) using Tomasi’s PCM method29
at the B3LYP/cc-pVTZ-PP level27 (see Computational Methods
in Supporting Information).
Conformer search for the seven- and the eight-membered
chelate complexes of disolvated Li+11aa- gave four different
families of structures. These sets were characterized by either
a “compact” or an “extended” disposition of the phosphonate
and bis-lactim ether moieties due to synclinal or anticlinal
N(1)C(2)C(1′)C(2′) dihedrals, respectively. Most stable members
of each family display a nearly planar sp2 carbanionic carbon
Finally, catalytic hydrogenation of the vinylphosphonates
23am or 24am afforded a 1:2 mixture of 2,2′-syn and 2,2′-anti
2′-benzylated bis-lactim ethers, 12ak and 13ak, respectively,
which could not be prepared by treatment of Li+11aa- with
benzyl bromide.
Computational Studies. Stereochemical Model for the
Electrophilic Substitution on Bis-lactim Ethers Derived from
cyclo-[L-AP4-D-Val]. The origin of π-facial stereoselectivity of
enolates and related carbanions remains a controversial area of
investigation.23 A combination of torsional strain, stereoelec-
tronic effects, steric factors, and chelation may be operative in
defining the stereochemical outcome for the electrophilic
substitutions on lithium phosphonate carbanion Li+11aa-. In
this manner, the observed 2,2′-syn selectivity can be rationalized
by considering the involvement of seven- or eight-membered
intermediate chelate complexes such as i7 or i8, which should
react with the electrophile by its less hindered face (See Scheme
8).
(24) Abbotto, A.; Streitwieser, A.; Schleyer, P. v. R. J. Am. Chem. Soc.
1997, 119, 11255-11268. (b) Abbotto, A.; Leung, S. S.-W.; Streitwieser,
A. J. Am. Chem. Soc. 1998, 120, 10807-10813.
(25) The microsolvation approach has been successfully used for the
theoretical study of numerous other solvated lithium compounds, see:
Mogali, S.; Daville, K.; Pratt, L. M. J. Org. Chem. 2001, 66, 2368-2373
and references therein.
(26) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Lee,
C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785-789.
(27) (a) Davidson, E. R. Chem. Phys. Lett. 1996, 260, 514-518. (b)
Woon, D. E.; Dunning, T. H., Jr. J. Chem. Phys. 1993, 98, 1358-1371. (c)
Dunning, T. H., Jr. J. Chem. Phys. 1989, 90, 1007-1023.
(28) Peterson, K. A.; Figgen, D.; Goll, E.; Stoll, H.; Dolg, M. J. Chem.
Phys. 2003, 119, 11113-11123.
(29) (a) Cossi, M.; Scalmani, G.; Rega, N.; Barone, V. J. Chem. Phys.
2002, 117, 43-54. (b) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106,
5151-5158.
To gain more insight into the stereocontrol elements deter-
mining the selectivity of these substitutions, we have performed
a computational study of the conformational space accessible
(22) Mimouni, N.; About-Jaudet, E.; Collignon, N.; Savignac, P. Synth.
Commun. 1991, 21, 2341-2348.
(23) (a) Soteras, I.; Lozano, O.; Go´mez-Esque´, A.; Escolano, C.; Orozco,
M.; Amat, M.; Bosch, J.; Luque, F. J. J. Am. Chem. Soc. 2006, 128, 6581-
6588. (b) Ando, K. J. Am. Chem. Soc. 2005, 127, 3964-3972. (c) Ikuta,
Y.; Tomoda, S. Org. Lett. 2004, 6, 189-192. (d) Ando, A.; Green, N. S.;
Li, Y.; Houk, K. N. J. Am. Chem. Soc. 1999, 121, 5334-5335.
J. Org. Chem, Vol. 71, No. 18, 2006 6963

Ferna´ndez et al.
SCHEME 9
electrophiles on the four different chelate complexes were
analyzed next. The approach of methyl iodide to the Re-face of
the carbanionic carbon at the chelate intermediates led to the
location of four 2,2′-syn transition structures that were desig-
nated as c7s, e7s, c8s, and e8s, respectively. The corresponding
methylations through the Si-faces of the chelate complexes gave
rise to four transition structures in the 2,2′-anti reaction pathway
that were designated as c7a, e7a, c8a, and e8a. In an analogous
fashion, eight different transition structures (from c7s to e8a)
were located for the reaction of the intermediate chelate
complexes with trimethylsilyl chloride.
In the gas phase, the most favorable transition structure for
the methylation was e7s, which was derived from the extended
seven-membered chelate complex e7 (see Figure 1). This syn
transition structure was favored 1.9 kcal/mol over the corre-
sponding most favorable anti transition structure e8a, which also
showed an extended conformation derived from the eight-
membered intermediate e8 (see Table 3). The syn transition
structure e7s showed a staggered arrangement of all the vicinal
bonds at the carbanionic carbon undergoing the hybridization
change and no visible steric interactions, while the anti transition
structure e8a occurred with a rather eclipsed arrangement
(C(2)C(1′)C(2′)CH3 dihedral angle is 26°) and exhibited a
repulsive interaction between a hydrogen of the incoming
electrophile and one nitrogen of the bis-lactim ring. The distance
between these two atoms was 2.40 Å, which was shorter than
the sum of their van der Waals radii (2.75 Å).
TABLE 2. Relative Energies, Dipole Moments, and Populations
Calculated for Models of Disolvated Li+11aa-
gas phase
THF
rel Ea
rel Ed
model (kcal/mol) population (%)b µc (D) (kcal/mol) population (%)b
c7
e7
c8
e8
2.0
0.2
2.9
0.0
0.35
37.96
0.04
8.4
5.0
7.7
6.0
0.0
4.3
3.3
4.0
100
0
0
Methylation through e7s and e8a, which are the major
transition structures in the gas phase, almost vanished in THF
solution. Instead, two transition structures (c7s and c8a) that
do not proceed in the gas phase and are characterized by
compact conformations of higher dipole moment became the
most important structures in solution. Both transition structures
showed an almost perfect staggered arrangement of all the
vicinal bonds at the carbanionic carbon (C(2)C(1′)C(2′)CH3
dihedral angle higher than 176°) and no visible steric interactions
with the incoming electrophile. In THF solution, the syn
transition structure c7s was calculated to be 1.4 kcal/mol more
favorable than the anti transition structure c8a. Other competitive
transition structures showed repulsive interactions with the
electrophile (c7a and c8s), torsional strain (all four), or loss of
hyperconjugative stabilization (c7a and e8s) due to nearly
eclipsed arrangements at the carbanionic carbon, and these
transition structures were found to be higher in energy (see
Supporting Information, Figure S3).
61.65
0
a Calculated at B3LYP/cc-pVTZ-PP//B3LYP/cc-pVDZ-PP level. b Rela-
tive abundance calculated at 195.15 K (-78 °C). c Calculated dipole moment
in debyes. d Calculated at B3LYP/cc-pVTZ-PP//B3LYP/cc-pVDZ-PP level
using the PCM method.
(sum of the angles at the carbons ) 358-360°) and a
synperiplanar C(1′)C(2′)P(OLi) dihedral, which allows an
effective hyperconjugative stabilization by carbanionic lone-
pair overlap with an appropriate σ*(P-O) orbital. In the gas
phase, the two most stable extended intermediates (e7 and e8,
see Scheme 9) were calculated to be more than 1.8 kcal/mol
lower in energy than the most stable compact ones (c7 and c8).
Because of their higher dipole moments, the compact chelate
complexes were more susceptible to the electrostatic field of
the solvent and were found to be more stable than the extended
conformers in the polarizable continuum. In particular in THF
solution, the most stable compact seven-membered chelate
complex c7 was calculated to be more than 3.3 kcal/mol lower
in energy than the rest of the intermediates (see Table 2 and
Supporting Information, Figure S2).
While the extended chelate complexes e7 and e8 have both
faces of the carbanionic carbon accessible to the electrophile,
the Si-face of c7 and the Re-face of c8 appear effectively
shielded by the bis-lactim ether. Thus, a combination of steric
factors, chelation, and solvent effects may determine the
stereoselectivity of the electrophilic substitution. In solution,
the major syn product may be derived from the most stable
seven-membered chelate intermediate (c7) by reaction through
its less hindered face, while the formation of the secondary anti
product could require the approach of the electrophile to the
more crowded face of c7, or the intervention of a less-stabilized
eight-membered chelate complex like c8. To test this hypothesis,
the reaction pathways for both 2,2′-anti and 2,2′-syn attack of
For the silylation process, the transition structures e8s and
e7a were calculated as the most stable in the gas phase (see
Table 3). As previously found for the methylation process, the
extended transition structures vanished in THF, and the compact
transition structures c7s and c8a, which have higher dipole
moments, became the most favorable syn and anti transition
structures, respectively. These transition structures lay in
different positions along the reaction coordinate, with C-Si
bond lengths of 2.5 and 2.9 Å for c7s and c8a, respectively
(see Figure 2). In addition, the syn transition structure c7s
showed a nearly staggered arrangement at the carbanionic carbon
(C(2)C(1′)C(2′)Si dihedral angle of 155°), while the anti
transition structure c8a occurred with an eclipsed arrangement.
In agreement with the experimental trend, the syn transition
structure c7s was found to be 4.9 kcal/mol lower in energy than
the anti transition structure c8a in the THF solution (see Table
3).
6964 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of 2-Amino-4-phosphonobutanoic Acids
FIGURE 1. Chem3D representations for the most favored transition structures located (at B3LYP/cc-pVDZ-PP level) for the anti and syn attacks
of MeI on Li+11aa-. Relative energies in the gas phase (at B3LYP/cc-pVTZ-PP+ZPVEC level) and in THF (at B3LYP/cc-pVTZ-PP (PCM) level)
are shown in parentheses and brackets, respectively (kcal/mol). Newman projections are views along C(2′)C(1′) bonds. The hydrogen atoms are
omitted for clarity except at chiral and reaction centers.
TABLE 3. Relative Energies and Dipole Moments Calculated for
Transition Structures
erentially adopted compact conformations (with higher dipole
moments) in which the bis-lactim ether moiety effectively
shielded one of the faces of the carbanionic carbon and furnished
facial bias in the electrophilic substitution process. The higher
syn selectivity observed in the silylation process can be
understood as a consequence of an increased torsional strain in
the anti transition structures because of the higher steric
requirements of the trimethylsilyl group.
Stereochemical Model for the Olefination of Bis-lactim
Ethers Derived from cyclo-[L-AP4-D-Val]. We have shown
that tin-Peterson olefinations of aldehydes 27m-p using the
R-triphenylstannyl-stabilized phosphonate carbanion Li+12ah-
take place with complete (Z)-selectivity and give rise to
vinylphosphonates 23am-ap (See Scheme 7). To identify the
selectivity-determining step and localize the factors that influ-
ence the stereochemical outcome of the process, we have studied
the tin-Peterson benzylidenation of Li+12ah- by using com-
putational methods.
Although Peterson olefinations with stabilized anions afford
stereoselectivities comparable to those obtained with Wittig-
type reactions, experimental and theoretical efforts devoted to
elucidate its mechanistic details have been scattered.30 It is
generally accepted that Peterson olefination involves formation
and cleavage of a four-membered intermediate. When carban-
ions are stabilized by functional groups capable of chelation
control, stepwise mechanisms seem to be favored over the
concerted ones in both the formation and the cleavage steps.
By analogy with previous theoretical studies on the closely
methylation
THF
silylation
THF
vacuo
E rela
vacuo
model
rel Ea,b
µc
rel Ed,b
µc
rel Ed
c7s
e7s
c8s
e8s
c7a
e7a
c8a
e8a
0.0
1.8
5.3
4.3
7.1
3.6
1.4
6.4
15.9
14.3
14.4
19.7
16.9
14.3
14.5
13.1
2.3
0.0
4.9
2.9
6.4
2.1
3.1
1.9
0.0
6.3
15.1
6.8
10.9
7.8
4.9
19.4
15.6
15.3
17.2
17.0
16.4
17.0
15.5
3.0
2.4
12.4
0.0
9.4
1.3
1.4
6.4
7.5
a Calculated at B3LYP/cc-pVTZ-PP//B3LYP/cc-pVDZ-PP level, in kcal/
mol. b Calculated using the PCM method in kcal/mol. c Dipole moment in
debyes. d Calculated at B3LYP/cc-pVTZ//B3LYP/cc-pVDZ level in kcal/
mol.
In summary, the computational models reproduced the sense
and degree of stereoselection in the reactions of phosphonate
carbanion Li+11aa- with methyl iodide and trimethylsilyl
chloride: syn transition structures are favored over the anti
counterparts in both processes, and the energy difference
between the competitive transition structures was greater for
the silylation than for the methylation. Nevertheless, the
calculated syn/anti ratios (assuming a Boltzmann distribution
of the transition structures at -78 °C) were considerably higher
than the experimental values. The modeling studies provided
some valuable insight to rationalize the stereochemical results
of the substitutions. Calculations suggested that the syn selectiv-
ity in the electrophilic substitutions of Li+11aa- may have
originated from the intervention of seven- and eight-membered
chelate structures. In THF solution, these intermediates pref-
(30) (a) van Staden, L. F.; Gravestock, D.; Ager, D. J. Chem. Soc. ReV.
2002, 31, 195-200. (b) Kano, N.; Kawashima, T. The Peterson and related
reactions. In Modern Carbonyl Olefination; Takeda, T., Ed; Wiley-VCH:
Weinheim, Germany, 2004; pp 18-103.
J. Org. Chem, Vol. 71, No. 18, 2006 6965

Ferna´ndez et al.
FIGURE 2. Chem3D representations for the most favored transition structures located (at B3LYP/cc-pVDZ level) for the anti and syn attacks of
TMSCl on Li+11aa-. Relative energies in the gas phase (at B3LYP/cc-pVTZ+ZPEC level) and in THF (at B3LYP/cc-pVTZ (PCM) level) are
shown in parentheses and brackets, respectively (kcal/mol). Newman projections are views along C(2′)C(1′) bonds. The hydrogen atoms are omitted
for clarity except at chiral and reaction centers.
SCHEME 10
related Peterson olefinations with the R-silyl ester enolates,31
the stepwise pathway for the reaction between the R-stannyl-
stabilized phosphonate carbanion (SP, see Scheme 10) and
benzaldehyde should involve an initial phosphonate carbanion
addition to the carbonyl group (C-C bond formation) to form
a lithium-coordinated oxyanion intermediate (I1) and be fol-
lowed by an O-Sn bond formation to afford a 1,2-oxastannet-
anide intermediate (I2). Subsequently, cleavage of the C-Sn
bond to give a new phosphonate-stabilized carbanion (I3) would
be followed by lithium stannoxide elimination (C-O bond
cleavage) to yield the vinylphosphonates (VP). If the elimination
step is fast and phosphonate carbanions I3 are not long-lived
enough for C-C bond rotation, crossover between the diaster-
eomeric pathways should not take place. According to this
hypothesis, the selective formation of (Z)-vinylphosphonate,
(Z)-VP, must originate from a kinetic preference for the unlike
intermediates or transition structures (ul-I1-4 and ul-TS1-3,
respectively).
Because intermediates I1-3 depicted in Scheme 10 contain
additional stereocenters on the bis-lactim moiety (R group), two
different topologies can be present in either the like or unlike
reaction channels. Thus, four diastereomeric pathways are
possible depending on the face selectivity of both phosphonate
carbanion SP and aldehyde. The initial transition structures were
designated by a code of two letters in which the first label
corresponds to the configuration of the former carbonyl carbon
and the second is the configuration of the carbanion at the
R-position. By extension, the like reaction channels giving rise
to (E)-vinylphosphonate through (Re,Re) and (Si,Si) interactions
were designated as RR and SS pathways, respectively, while
the unlike channels giving rise to (Z)-vinylphosphonate through
(Re,Si) and (Si,Re) interactions were designated as RS and SR
pathways, respectively. For this study, we also have considered
discrete solvation of the lithium with one or two THF molecules.
The geometry optimizations were performed using a B3LYP
DFT procedure with three different layers of basis set: 6-31G-
(d)32 for the critical parts of the reacting systems, 3-21G*33 at
the substituents to model steric effects, and the cc-pVDZ basis
(31) Gillies, M. B.; Tonder, J. E.; Tanner, D.; Norrby, P.-O. J. Org. Chem.
2002, 67, 7378-7388.
6966 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of 2-Amino-4-phosphonobutanoic Acids
FIGURE 3. Synclinal (sc), anticlinal (ac), antiperiplanar (ap), and synperiplanar (sp) starting geometries for transition structure location in the RR
diastereomeric pathway.
set27 and a small-core relativistic pseudopotential (PP) for Sn34
(see Computational Details in Supporting Information). Single
point energy calculations also were performed at the B3LYP/
cc-pVTZ-PP level both in the gas phase and of the bulk solvent
effect in THF (ꢀ ) 7.52) using Tomasi’s PCM method.29
In the gas phase, addition of the phosphonate carbanion SP
to benzaldehyde proceeds first by the exothermic formation of
a disolvated lithium-coordinated complex dC (see Figure S4 of
Supporting Information). Reorganization of this complex to the
four possible 1,2-oxastannetanides RR-I2, RS-I2, SR-I2, and SS-
I2 was studied next. Five different families of starting geom-
etries, which were characterized by a synperiplanar, synclinal,
anticlinal, or antiperiplanar disposition of the carbonyl and
triphenylstannyl moieties, were analyzed in each of the diaster-
eomeric pathways (see Figure 3).
In the nucleophilic addition of the phosphonate carbanion to
the carbonyl group, all the monosolvated transition structures
were found to be higher in energy than the disolvated ones. In
addition, most favorable transition structures arising from the
synperiplanar geometries also were found to be higher in energy
than those located by optimization of the antiperiplanar,
anticlinal, and synclinal ones (see Table S4 of Supporting
Information). The antiperiplanar transition structures (TS1-ap,
see Figure S5 of Supporting Information) were calculated as
the most stable ones and showed an energy gap of 2.0 kcal/
mol between the like and the unlike reaction channels, which
corresponded very well to experimental (Z)-preference. Nev-
ertheless, these transition structures were expected to be
nonproductive, as they led to antiperiplanar oxyanion intermedi-
ates (I1-ap) that had to surpass energy barriers of 11.6-22.7
kcal/mol for rotation around the new C-C bond to the synclinal
geometries required for 1,2-oxastannetanide formation (see
Figures S6 and S7 and additional discussion about torsional
transition structures in Supporting Information). Conversely, the
anticlinal and synclinal transition structures (TS1-sc and TS1-
ac, see Figure 4) led to synclinal oxyanion intermediates (I1-
sc, see Figure S8 of Supporting Information) which underwent
direct cyclization to the corresponding 1,2-oxastannetanides
without energy barriers for rotation around the P-C bond. Any
attempts to localize transition structures for O-Sn bond
formation (TS2) were unsuccessful in all the diastereomeric
pathways.
energy barriers of 7.7, 8.1, 9.9, and 10.3 kcal/mol in the SR,
RS, RR, and SS pathways, respectively. In this manner, the
initial C-C bond formation step favored unlike transition
structures over the like counterparts. The most stable unlike
transition structure, SR-TS1-sc, was 2.2 kcal/mol lower in energy
than the most favorable transition structure in the like reaction
channel, RR-TS1-sc. In SR-TS1-sc, the distance between the
anionic oxygen and one of the triphenylstannyl hydrogens was
2.37 Å, which indicated a hydrogen bond interaction. This
interaction was not possible for the like transition structures
(RR-TS1-sc and SS-TS1-sc) and therefore could contribute to
the energy difference between like and unlike reaction channels
as previously reported in theoretical studies of the Horner-
Wadsworth-Emmons olefinations.35 This energy difference also
could be derived from the steric repulsion in the like transition
structures (see Figure 4). Thus, in RR-TS1-sc the distance
between a hydrogen at the triphenylstannyl group and a carbon
at the phenyl substituent of the aldehyde was 2.57 Å, which
was less than the sum of their van der Waals radii (2.90 Å).
Transition structures SR-TS1-sc and RR-TS1-sc lay in almost
the same position along the reaction coordinate with a C-C
bond forming distance of 2.30 Å and are characterized by
synclinal N(1)C(2)C(1′)C(2′) angles and antiperiplanar C(2)C-
(1′)C(2′)C(3′) angles.
Most stable 1,2-oxastannetanide intermediates showed a
puckered ring where the tin atom is located over the plane of
the three equatorial ligands,36 while the lithium cation main-
tained a tetrahedral environment because of coordination to the
oxygen atoms of the 1,2-oxastannetanide moiety, the phosphoryl
group, and two THF molecules (see Figure S9 of Supporting
Information). In the gas phase, the like 1,2-oxastannetanide
intermediates SS-I2 and RR-I2 were calculated slightly lower
in energy than the unlike isomers. The 1,2-oxastannetanide
intermediates I2 underwent cleavage of the C-Sn bond quite
easily, with activation energies between 1.8 and 5.4 kcal/mol,
to yield the phosphonate-stabilized carbanions I3. Transition
structures TS3 are relatively late with the C-Sn bond being
weak at 3.00-3.20 Å (see Figure 5 and Figure S10 of
Supporting Information). The most stable transition structure
for C-Sn bond cleavage was located in the SR pathway, as
was previously found for the 1,2-oxastannetanide formation.
Thus, SR-TS3 is calculated to be 2.1 kcal/mol lower in energy
According to the calculations, the synclinal and anticlinal
transition structures (TS1-sc and TS1-ac) offered the lowest
energy pathways for the 1,2-oxastannetanide formation with
(35) (a) Brandt, P.; Norrby, P.-O.; Martin, I.; Rein, T. J. Org. Chem.
1998, 63, 1280-1289. (b) For a recent theoretical evaluation of the binding
energies of anions to simple arenes, see: Bryantsev, V. S.; Hay, B. P. J.
Am. Chem. Soc. 2005, 127, 8282-8283.
(36) The X-ray crystallographic analysis of a pentacoordinated 1,2-
oxastannnetanide has revealed a structure close to a square pyramid rather
than a trigonal bipyramid. See: Kawashima, T.; Iwama, N.; Okazaki, R. J.
Am. Chem. Soc. 1993, 115, 2507-2508.
(32) Francl, M. M.; Pietro, W. J.; Hehre, W. J.; Binkley, J. S.; Gordon,
M. S.; DeFrees, D. J.; Pople, J. A. J. Chem. Phys. 1982, 77, 3654-3665.
(33) Binkley, J. S.; Pople, J. A.; Hehre, W. J. J. Am. Chem. Soc. 1980,
102, 939-947.
(34) Peterson, K. A. J. Chem. Phys. 2003, 119, 11099-11112.
J. Org. Chem, Vol. 71, No. 18, 2006 6967

Ferna´ndez et al.
FIGURE 4. Chem3D representations for the most favored anticlinal or synclinal transition structures located (at B3LYP/6-31|3-21G(d)|PP level)
for C-C bond formation in the tin-Peterson olefination. Relative energies in the gas phase (at B3LYP/cc-pVTZ-PP+ZPEC level) and in THF (at
B3LYP/cc-pVTZ-PP (PCM) level) are shown in parentheses and brackets, respectively (kcal/mol). The hydrogen atoms are omitted for clarity
except at chiral and prochiral centers.
FIGURE 5. Chem3D representations for the most favored transition structures located (at B3LYP/6-31|3-21G(d)|PP level) for C-Sn bond cleavage
of 1,2-oxastannetanide intermediates in the like and unlike reaction channels. Relative energies in the gas phase (at B3LYP/cc-pVTZ-PP+ZPEC
level) and in THF (at B3LYP/cc-pVTZ-PP (PCM) level) are shown in parentheses and brackets, respectively (kcal/mol). The hydrogen atoms are
omitted for clarity except at chiral centers.
than SS-TS3, which is the most stable transition structure in
the like reaction channel.
monosolvated series determined bridged structures for I3m and
TS4m and seven- or eight-membered chelate structures for VPm
(see Figures 6, 7, and S13 of Supporting Information).
Different from previous stationary points in the reaction
profile, phosphonate-stabilized carbanion intermediates, transi-
tion structures for lithium stannoxide elimination, and final
Z-vinylphosphonates were found to be lower in energy in the
monosolvated series (I3m, TS4m, and VPm, respectively) than
in the disolvated ones (I3d, TS4d, and VPd) (see Figures S11,
S12, and S13 and Table S4 of Supporting Information). All the
monosolvated geometries showed a four-coordinated cation
because of the interaction of the lithium with a nitrogen (or
oxygen) of the bis-lactim moiety and with the oxygen atoms of
the phosphoryl group, the stannyloxy moiety, and one THF
molecule. Thus, lithium coordination requirements in the
Formation of the phosphonate-stabilized intermediates I3m
was calculated to be more exothermic than the preceding steps
along the reaction path, and subsequent barriers to transition
structures TS4m were relatively low (between 0.1 and 3.6 kcal/
mol). The O-C bond to the triphenylstannyl group was weak
at more than 1.5 Å in all the diastereomeric structures I3m (see
Figure 6), as previously seen in related Peterson olefinations.31
The lifetime of the intermediates I3m was likely to be short,
therefore making the likehood of isomerization and potential
loss of steric control because of C-C rotation fairly low. The
monosolvated transition structure of lowest energy for the C-O
6968 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of 2-Amino-4-phosphonobutanoic Acids
FIGURE 6. Chem3D representations for the most stable monosolvated phosphonate carbanion intermediates I3m located at B3LYP/6-31|3-21G-
(d)|PP level. Relative energies in the gas phase (at B3LYP/cc-pVTZ-PP+ZPEC level) and in THF (at B3LYP/cc-pVTZ-PP (PCM) level) are shown
in parentheses and brackets, respectively (kcal/mol). The hydrogen atoms are omitted for clarity except at chiral centers.
FIGURE 7. Chem3D representations for the most stable monosolvated transition structures TS4m located at B3LYP/6-31|3-21G(d)|PP level for
the O-C bond cleavage. Relative energies in the gas phase (at B3LYP/cc-pVTZ-PP+ZPEC level) and in THF (at B3LYP/cc-pVTZ-PP (PCM)
level) are shown in parentheses and brackets, respectively (kcal/mol). The hydrogen atoms are omitted for clarity, except at chiral centers.
bond cleavage was located again in the SR pathway, which was
favored over the RR counterpart by 0.6 kcal/mol (see SR-TS4m
and RR-TS4m in Figure 7). Finally, formation of vinylphos-
phonates VPm was computed to be highly exothermic. The main
energetic features calculated in the gas phase for the four
diastereomeric pathways are shown in the Figure 8.
the initial carbon-carbon bond formation step in which the
synclinal transition structures leading to (Z)-vinylphosphonates
were favored by more than 1.4 kcal/mol, in accordance with
experiment.
Transformation of the Substituted Bis-lactim Ethers into
AP4 Derivatives. After separation of the mixtures of substitution
or olefination products by chromatography, the 2′-substituted
bis-lactim ethers 12ae-ak, 13ae,af,ah-ak, 14ai, 23am-aq,
24am, 25, and 26, the 1′,2′-disubstituted bis-lactim ethers 19mb,
20mb,nb, 21mb,nb, and 22mb,nb, and the 2′,2′-difluorinated
bis-lactim ether 16ae could be isolated with diastereomeric
excesses (de) higher than 98%. Conversion of the substituted
bis-lactim ethers into the desired 2-amino-4-phosphonobutanoic
acid derivatives was straightforward. Mild acid hydrolysis of
2′-substituted bis-lactim ethers 12ab/13ab, 12ae-ag,ai-ak, and
13ae,ai-ak provided the corresponding 2,4-syn or 2,4-anti
amino esters 27ab,ae-ag,ai-ak and 31ab,ae,af,ai-ak in high
yields after the removal of the valine ester by chromatography
(see Scheme 11). Subjecting the vinylphosphonates 23am-ap
and 24am to the same reaction conditions furnished the (4Z)-
or (4E)-amino esters 27am-ap and 31am (Scheme 12). In an
analogous manner, hydrolysis of the 2′,2′-difluorinated bis-
lactim ether 16ae and the 1′,2′-disubstituted bis-lactims ethers
19mb, 20mb,nb, 21mb,nb, and 22mb,nb afforded the 4,4-
difluorinated amino ester 33ae and the 3,4-disubstituted amino
esters 35mb, 37mb,nb, 39mb,nb, and 41mb,nb (Scheme 13).
Hydrolysis of the amino esters 27ab,ae,ag,ak,am,an, 31ab,-
ae,ak,am, 33ae, 35mb, 37mb,nb, 39mb,nb, and 41mb,nb to
the corresponding amino acids 28ab,ae,ag*,ak,am,an, 32ab,-
The energetic profile for the tin-Peterson olefination in a
dielectric medium simulating THF is shown in Figure 9. In
solution, the activation energy for the initial C-C bond
formation was reduced by more than 1.5 kcal/mol in the most
favored like and unlike pathways. Thus, nonspecific solvation
effects facilitated the rate-determining step but maintained the
(Z)-selective course of the olefination. Nonspecific solvation
of the transition structures TS3 (with less charge-localized
geometries) were less exothermic than for the 1,2-oxastannet-
anide intermediate I2, thus increasing the activation energies
for the C-Sn bond cleavage by more than 2.0 kcal/mol.
Differential nonspecific solvation effects on the competitive
transition structures for C-Sn and C-O bond cleavage were
markedly different. (Z)-Selectivity for the C-Sn bond cleavage
in solution was increased by more than 1.2 kcal/mol, while the
energy gap between the like and unlike pathways for C-O bond
cleavage almost vanished in THF solution.
In summary, in accordance to DFT calculations, the tin-
Peterson olefination of R-stannyl-stabilized phosphonate car-
banions proceeded through an initial addition to the carbonyl
group, followed by 1,2-oxastannnetanide formation, carbon-
tin bond cleavage, and then carbon-oxygen cleavage. Com-
putations indicated that rate and selectivity were determined in
J. Org. Chem, Vol. 71, No. 18, 2006 6969

Ferna´ndez et al.
SCHEME 11a
a Reagents and conditions: (a) 0.25 N HCl, THF, rt, 0.5-15 h (72-
94%); (b) 12 N HCl, reflux, 2.5-8 h (83-100%); (c) (i) (TMS)Br, CH2Cl2,
rt, 38 h; (ii) MeOH (67-100%); (d) (i) LiOH, H2O, rt, 1 h; (ii) Dowex-H+,
H2O (76-100%) Legend: b, R4 ) Me; e, R4 ) F; f, R4 ) OH; g, R4 )
PO3Et2; g*, R4 ) PO3H2; i, R4 ) SiMe3; j, R4 ) N3; k, R4 ) Bn.
FIGURE 8. Energy profile for the tin-Peterson olefination in the gas
phase. B3LYP/cc-pVTZ-PP+ZPEC energies relative to the disolvated
complex dC are in kcal/mol. Color code for the diastereomeric
pathways: SR-blue; RS-turquoise; RR-red; SS-orange.
SCHEME 12a
a Reagents and conditions: (a) 0.25 N HCl, THF, rt, 1-5 h (75-90%);
(b) 12 N HCl, reflux, 3 h (63-83%); (c) (i) (TMS)Br, CH2Cl2, rt, 38 h; (ii)
MeOH; (d) (i) LiOH, H2O, rt, 1 h; (ii) Dowex-H+, H2O (94%). Legend:
m, R5 ) Ph; n, R5 ) i-Pr; o, R5 ) 2-C4H3S; p, R5 ) CHCHPh.
water, amino acid 32ak yielded crystals amenable to X-ray
structure determination, which allowed the confirmation of its
2,4-anti stereochemistry (see Supplementary Information). Hy-
drolysis of trimethylsilyl and azido substituted amino esters
27ai,aj and 31ai,aj required a treatment with trimethylsilyl
bromide to yield the phosphonic acid intermediates 29ai,aj and
33ai,aj, which were subsequently hydrolyzed to the correspond-
ing amino acids 28ai,aj and 32ai,aj with lithium hydroxide.
Under these conditions, the thienyl-substituted amino ester 27ao
underwent complete isomerization of the olefinic double bond
to afford the (4E)-vinylphosphonic acid 32ao. After purification
by reversed phase chromatography, mono- and disubstituted
AP4 derivatives in the 2,4-anti, 2,4-syn, (4Z)-, and (4E)-series
were isolated in high yields.
FIGURE 9. Energy profile for the tin-Peterson olefination in THF.
B3LYP/cc-pVTZ-PP (PCM) free energies relative to the disolvated
complex dC are in kcal/mol. Color code for the diastereomeric
pathways: SR-blue; RS-turquoise; RR-red; SS-orange.
ae,ak,am, 34ae, 36mb, 38mb,nb, 40mb,nb, and 42mb,nb was
accomplished by heating in concentrated hydrochloric acid. In
the same conditions, amino ester 27af afforded a 3:1 mixture
of amino acid 28af and lactone 30af. Upon crystallization from
The formylated bis-lactim ethers 12ac and 13ac were stirred
in 0.25 M hydrochloric acid under a hydrogen atmosphere and
a palladium catalyst that enabled an intramolecular reductive
6970 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of 2-Amino-4-phosphonobutanoic Acids
SCHEME 13a
SCHEME 14a
a Reagents and conditions: (a) 0.1 N HCl, H2 (1 atm), Pd/C, rt, 3 h
(69%); (b) 12 N HCl, reflux, 6 h (83%); (c) H2 (1 atm), PtO2, H2O, rt, 16
h (90%); (d) NH4OH, reflux, 24 h (94%).
Because none of the bis-lactim ethers, esters, or amino acids
(other than 21mb and 32ak) provided crystals suitable for X-ray
crystal structure determination, cyclic derivatives were sought
that could enable the assignment of the relative configurations
by NOESY. Six-membered amino-oxaphosphorinane derivatives
were attractive because of the strong preference for the chair
conformation reported for several substituted systems.40 Conver-
sion of amino esters 27ab,ae, 31ab,ae, 37mb,nb, and 41nb into
such cyclic derivatives was achieved according to Scheme 15,
by extending the applicability of previously developed meth-
odology.12 Chemoselective reduction of the carboxylic ester in
the presence of the phosphonate was accomplished on the N-Boc
derivatives of amino esters 43ab,ae, 47ab,ae, 51mb,nb, and
54nb by employing lithium borohydride in THF at room
temperature. Reduction of 4-methyl-N-Boc-aminoesters 43ab
and 47ab under these conditions were complete in 4 h and, after
the mixtures of reduction were subjected to quench with
methanol, workup, and chromatography, alcohols 44ab and
48ab could be isolated in high yields. Moreover, when the
mixtures of reduction were stirred 68 h further at room
temperature, cyclization of the intermediates were observed to
afford the N-Boc-amino-oxaphosphorinanes 45ab and 49ab as
single diastereoisomers at the phosphorus center. Cyclization
of the intermediates in the reduction of 4-fluoro-N-Boc-amino
esters 43ae and 47ae required only 8 h and gave the corre-
sponding N-Boc-amino-oxaphosphorinanes 45ae and 49ae as
1:1 and 3:1 mixtures of epimers, respectively. In the same
conditions, reduction and cyclization of the 3,4-disubstituted-
N-Boc amino esters 51mb,nb and 54nb were complete in 20 h
and furnished the corresponding N-Boc-amino-oxaphosphori-
a Reagents and conditions: (a) 0.25 N HCl, THF, rt, 1-40 h (78-90%);
(b) 12 N HCl, reflux, 2.5-10 h (80-96%). Legend: m, R3 ) Ph; n, R3 )
i-Pr.
amination after the hydrolysis of the pyrazine ring which led
to a 8:1 mixture of the proline esters 27ac and 31ac (Scheme
14). Hydrolysis of 27ac and 31ac was accomplished by heating
in 12 N HCl for 6 h, which gave a 8:1 mixture of 2,4-cis and
2,4-trans phosphonoprolines 28ac and 32ac. Catalytic hydro-
genation of R-azidophosphonic acid37 28aj gave the correspond-
ing R-aminophosphonic acid 28ar, which led to lactam 30ar
in excellent yield by heating in aqueous ammonia.
Determination of the Relative Configurations. Evidence
supporting the relative configurations of the substitution and
olefination products was obtained by NMR analyses. For
compounds 12ab,ae,ag,ai,aj, 13ab,ae,af,ah-aj, 16ae, 19mb,
20mb,nb, 21mb, 22mb, 23an-aq, and 24am, H-5 resonance
5
appeared between 2.94 and 3.98 ppm as a triplet with JH2H5
close to 3.5 Hz, which is general of the trans relationship of
substituents at the pyrazine ring. The configurations of the
vinylphosphonate moiety in the bis-lactim ethers were assigned
on the basis of the 3JHP and the 3JCP observed in the 1H and 13
C
(38) (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.
(39) Scho¨llkopf, U.; Ku¨hnle, W.; Egert, E.; Dyrbusch, M. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 480-482.
(40) (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 references 11.
NMR spectra because of the coupling of H-3′ and C-4′ with
the phosphorus atom at â-position. Thus, for 23am-ap (see
3
Scheme 7), JH3′-P (trans) values ranged from 44.4 to 49.3 Hz
and 3JC4′-P (cis) values ranged from 7.8 to 12.1 Hz, which are
characteristic for the vinylphosphonates with a (Z)-configuration.
3
Conversely, for 24am with an (E)-configuration, JH3′-P (cis)
) 24.9 Hz and 3JC4′-P (trans) ) 23.1 Hz.38 Absolute configura-
tions followed from the use of bis-lactim ethers derived from
L- and D-Val as there is ample precedent.39
(37) Hanessian, S.; Bennani, Y. L. Synthesis 1994, 1272-1274.
J. Org. Chem, Vol. 71, No. 18, 2006 6971

Ferna´ndez et al.
SCHEME 15a
FIGURE 10. PM3/COSMO-optimized geometries for cyclic deriva-
tives, showing characteristic NOEs.
semiempirical calculations.41 The refined geometries for the
cyclic derivatives in a polarizable dielectric continuum (simulat-
ing water or chloroform) were in agreement with the conforma-
tions in solution deduced from NMR spectroscopy, as depicted
in Figure 10.
Conclusion
The electrophilic substitutions of lithiated bis-lactim ethers
derived from cyclo-[L-AP4-D-Val] took place regioselectively
R to the phosphonate group with a variable level of stereose-
lection depending on the nature of the electrophilic reagent and
the pattern of substitution at the â-position. DFT calculations
suggested that the stereoselectivity in these substitutions may
have originated from the intervention of seven- and eight-
membered lithium chelate structures. In THF solution, these
intermediates preferentially adopt compact conformations (with
higher dipole moments) in which the bis-lactim ether moiety
effectively shields one of the faces of the carbanionic carbon
and furnishes facial bias in the substitution. The olefination of
benzaldehyde with R-silyl-, R-phosphoryl- and R-stannyl-
stabilized phosphonate carbanions derived from cyclo-[L-AP4-
D-Val] took place without compromising the chiral integrity of
the bis-lactim ether, giving rise to vinylphosphonates with a
different level of (Z)-stereoselection. In addition, the tin-
Peterson reactions of the R-triphenylstannylphosphonate car-
banion with structurally diverse carbonyl compounds were found
completely (Z)-stereoselective. According to DFT calculations,
this olefination proceeded with a stepwise mechanism through
an initial nucleophilic addition of the phosphonate carbanion
to the carbonyl group, followed by 1,2-oxastannnetanide forma-
tion, carbon-tin bond cleavage, and then carbon-oxygen
cleavage. Computations indicated that rate and selectivity were
determined in the initial carbon-carbon bond formation step
in which the transition structures leading to (Z)-vinylphospho-
nates were favored by more than 1.4 kcal/mol. Finally, both
the electrophilic substitutions and the tin-Peterson olefinations
of lithiated bis-lactim ethers derived from cyclo-[L-AP4-D-Val]
have been shown as a convenient approach to a variety of
4-substituted and 3,4-disubstituted 2-amino-4-phosphonobu-
a (a) (Boc)2O, NaHCO3, Na2CO3, dioxane/H2O 1:1, rt, 2-7 h (83-96%);
(b) (i) 1.5 LiBH4, THF, rt, 4 h; (ii) MeOH (90 or 93%); (c) (i) 1.5 LiBH4,
THF, rt, 8-72 h; (ii) MeOH (63-99%); (d) (i) TMSBr, CH2Cl2, rt, 15-27
h; (ii) MeOH (82-92%). Legend: b, R4 ) Me; e, R4 ) F; m, R3 ) Ph; n,
R3 ) i-Pr.
nanes 52mb,nb and 55nb as single diastereoisomers at the
phosphorus center. The N-Boc and O-ethyl ester groups of
intermediates 45ab,ae, 49ab,ae, and 52nb were cleaved with
trimethylsilyl bromide in CH2Cl2 at room temperature to give
the aminooxaphosphorinanes 46ab,ae, 50ab,ae, and 53nb as
pure diastereoisomers. Crystallization of 46ae and 52mb (from
water) and 55nb (from hexanes) yielded crystals amenable to
X-ray structure determination, which allowed the confirmation
of their relative configurations (see Supporting Information).
A single chair conformation was observed for oxaphospho-
rinanes 46ab and 53nb in the 1H NMR spectra. These
compounds, pyrrolidine 28ac, and lactam 30ar showed patterns
of signals suitable for the study of their relative stereochemistry
1
by NOESY. After we corroborated the H NMR assignments
by COSY experiments, the analysis of the sets of observed
NOEs allowed the assignment of the relative configuration of
the stereogenic centers formed in the electrophilic substitution.
Thus, stereochemistry of pyrrolidine 28ac was determined as
2,4-cis, while lactam 30ar and oxaphosphorinane 46ab showed
3,5-trans and 3,5-cis configuration, respectively. A 3,4-cis-4,5-
trans configuration also was concluded for oxaphosphorinane
53nb. The observed NOEs were supported by PM3/COSMO
(41) (a) PM3: Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209-220,
and 221-264. (b) COSMO: Klamt, A.; Schu¨u¨rmann, G. J. Chem. Soc.,
Perkin Trans. 2 1993, 799-805.
6972 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of 2-Amino-4-phosphonobutanoic Acids
26
[R]D -7.4 (c 2.4, CH2Cl2); IR (film) ν 1685 (CdN), 1225 (Pd
tanoic acids in enantiomerically pure form that may be useful
tools for the study of group III of mGluRs.
O), 1015 (POC) cm-1; H NMR (CDCl3) δ 0.67 (d, J ) 6.8 Hz,
1
3H), 0.99 (d, J ) 6.9 Hz, 3H), 1.18-1.37 (m, 12H), 2.12-2.47
(m, 2 H), 2.70 (dtt, J ) 27.3, 14.7, 3.5 Hz, 1H), 3.87 (t, J ) 3.5
Hz, 1H), 4.00-4.38 (m, 9H); 13C NMR (CDCl3) δ 14.2 (CH3),
16.3 (d, J ) 5.6 Hz, CH3), 16.7 (CH3), 19.0 (CH3), 31.7 (CH),
37.7 (dt, J ) 19.2, 14.9 Hz, CH2), 50.4 (t, J ) 3.9 Hz, CH), 60.6
(CH), 60.7 (CH2), 60.8 (CH2), 64.4 (d, J ) 6.4 Hz, CH2), 121.0
(dt, J ) 270.0, 216.0 Hz, C), 161.5 (C), 163.1 (C); 31P NMR
(CDCl3) δ 7.4 (t, J ) 107.0 Hz); 19F NMR (CDCl3) δ -110.6 (dd,
J ) 298.5, 107.0 Hz), -112.6 (dd, J ) 298.5, 107.0 Hz); FABMS
(thioglycerol) m/z 414 ((M + 2)+, 20), 413 (MH+, 100). Anal. Calcd
for C17H31F2N2O5P: C, 49.51; H, 7.58; N, 6.79. Found: C, 49.35;
H, 7.41; N, 6.94.
Olefination of Bis-lactim Ethers Derived from cyclo-[L-AP4-
D-Val]. General Procedure. A solution of 12/13ad,ah or 12ag
(0.94 mmol) in THF (8 mL) was added dropwise to a stirred
solution of LDA (1.22 mmol) in THF (30 mL) at -78 °C, and the
mixture was stirred for 15 min. Then a solution of the carbonyl
compound (1.12 mmol) in THF (2 mL) was added dropwise, and
the reaction was slowly warmed to reach 0 °C after ca. 4 h. The
reaction was quenched with AcOH (1.5 mmol, 10% in THF), the
crude reaction mixture was warmed to room temperature, and the
solvent was removed in vacuo. The resulting material was diluted
with water and was extracted with EtOAc. The combined organic
layers were dried (Na2SO4) and evaporated, and the residue was
purified by gradient flash chromatography to yield olefination
products as colorless oils.
Wadsworth-Horner-Emmons Benzylidenation. In accor-
dance to the general procedure, the reaction of 12ag (0.48 g) with
benzaldehyde (0.11 mL) gave 0.34 g (77%) of a mixture of
vinylphosphonates 23am/24am in a 5:1 ratio and 48 mg (10%) of
the starting compound after chromatography (silica gel, EtOAc/
hexanes 1:2).
Tin-Peterson Benzylidenation. In accordance to the general
procedure, the reaction of 12/13ah (0.68 g) with benzaldehyde (0.11
mL) gave 0.24 g (56%) of bis-lactim 23am and 0.17 g (25%) of
the starting compound after chromatography (silica gel, EtOAc/
hexanes 1:2).
Peterson Benzylidenation. A solution of n-BuLi (0.37 mL, 2.5
M in hexane, 1 equiv) was added to a stirred solution of (3R)-2,5-
diethoxy-3-isopropyl-3,6-dihydropyrazine (0.20 g, 0.94 mmol) in
THF (10 mL) at -78 °C, and the mixture was stirred for 30 min.
Then, a solution of R-trimethylsilylvinylphosphonic acid diethyl
ester (0.26 g, 1.15 equiv) in THF (5 mL) was added dropwise, and
the mixture was stirred for 15 min. Then a solution of benzaldehyde
(0.11 mL) in THF (2 mL) was added dropwise, and the reaction
was slowly warmed to reach 0 °C after ca. 4 h. The reaction was
quenched with AcOH (1.5 mmol, 10% in THF), the crude reaction
mixture was warmed to room temperature, and the solvent was
removed in vacuo. The resulting material was diluted with water
and extracted with EtOAc. The combined organic layers were dried
(Na2SO4) and evaporated, and the residue was purified by gradient
flash chromatography to yield 0.31 g (70%) of a mixture of
vinylphosphonates 23am/24am in a 3:2 ratio and 46 mg (11%) of
a mixture of 12/13ai.
Experimental Section
General Procedure for the Electrophilic Substitution on
Li+11aa-. A solution of 11aa (0.72 g, 1.92 mmol) in THF (8 mL)
was added dropwise to a stirred solution of LDA (2.4 mmol) in
THF (20 mL) at -78 °C, and the mixture was stirred for 15 min.
Then a solution of the electrophilic reagent (2.3 mmol) in THF (2
mL) was added dropwise, the mixture was stirred for 5 min, and
the reaction was quenched with AcOH or H2O (10% in THF). The
crude reaction mixture was warmed to room temperature, and the
solvent was removed in vacuo. The resulting material was diluted
with water and extracted with EtOAc. The combined organic layers
were dried (Na2SO4) and evaporated, and the residue was purified
by gradient flash chromatography to yield substitution products as
colorless oils.
Fluoration of 11aa. Method A. General procedure was followed
using 2 equiv of LDA (4.8 mmol) and N-fluorobenzenesulfonimide
(NFSi) as the electrophilic reagent. The crude material was purified
by flash chromatography (silica gel, EtOAc/hexanes 1:1 ratio) to
give 0.55 g (ca. 72%) of a mixture of bis-lactims 12ae/13ae/16ae
in an 8.2:2.7:1.0 ratio. Method B. General procedure was followed
using 2 equiv of NFSi (1.32 g, 4.00 mmol) as an electrophilic
reagent. The crude material was worked up as described in method
A to give 0.55 g (72%) of a mixture of bis-lactims 12ae/13ae/16a
in a 3:1:3 ratio. Method C. A solution of LDA (4.8 mmol) in THF
(20 mL) was added dropwise to a solution of 11aa (1.92 mmol)
and NFSi (0.63 g, 1.92 mmol) in THF (15 mL) at -78 °C. After
being stirred at -78 °C for 5 min, the reaction was quenched with
AcOH (10% in THF) and worked up as described in method A to
give 0.14 g of 11aa (20%) along with 0.49 g (65%) of a mixture
of bis-lactims 12ae/13ae in a 3:1 ratio. Separation of the components
of this mixture was accomplished by flash chromatography (silica
gel, EtOAc/hexanes, from 1:4 to 2:1 ratio).
Data for (2S,5R,2′S)-3,6-diethoxy-2-[2-(diethoxyphosphoryl)-2-
fluoroethyl]-2,5-dihydro-5-isopropylpyrazine (12ae): colorless oil;
[R]D26 -21.6 (c 2.9, CH2Cl2); IR (film) ν 1685 (CdN), 1235 (Pd
1
O), 1025 (POC) cm-1; H NMR (CDCl3) δ 0.72 (d, J ) 6.9 Hz,
3H), 1.02 (d, J ) 6.9 Hz, 3H), 1.22-1.39 (m, 12H), 1.72 (m, 1H),
2.22 (dsp, J ) 6.9, 3.4 Hz, 1H), 2.65 (m, 1H), 3.92 (t, J ) 3.4 Hz,
1H), 4.00-4.30 (m, 9H), 5.34 (ddt, J ) 47.0, 12.0, 1.5 Hz, 1H);
13C NMR (CDCl3) δ 14.1 (CH3), 16.3 (d, J ) 4.5 Hz, CH3), 16.9
(CH3), 18.9 (CH3), 32.0 (CH), 35.1 (dd, J ) 20.0, 2.7 Hz, CH2),
50.4 (dd, J ) 14.0, 2.7 Hz, CH), 60.5 (CH2), 60.6 (CH2), 60.7
(CH), 62.9 (d, J ) 6.5 Hz, CH2), 63.2 (d, J ) 6.5 Hz, CH2), 85.3
(dd, J ) 179.0, 172.0 Hz, CH), 162.5 (C), 163.3 (C); 31P NMR
(CDCl3) δ 19.6 (d, J ) 74.3 Hz); 19F NMR (CDCl3) δ -213.7 (d,
J ) 74.3 Hz); FABMS (thioglycerol) m/z 396 ((M + 2)+, 23), 395
(MH+, 100). Anal. Calcd for C17H32FN2O5P: C, 51.77; H, 8.18;
N, 7.10. Found: C, 51.85; H, 8.01; N, 7.38.
Data for (2S,5R,2′R)-3,6-diethoxy-2-[2-(diethoxyphosphoryl)-2-
fluoroethyl]-2,5-dihydro-5-isopropylpyrazine (13ae): colorless oil;
22
[R]D +6.7 (c 0.8, CH2Cl2); IR (film) ν 1685 (CdN), 1235 (Pd
1
O), 1025 (POC) cm-1; H NMR (CDCl3) δ 0.72 (d, J ) 6.8 Hz,
3H), 1.02 (d, J ) 6.9 Hz, 3H), 1.24-1.39 (m, 12H), 2.13-2.64
(m, 3H), 3.95 (t, J ) 3.4 Hz, 1H), 4.00-4.30 (m, 9H), 5.03 (ddt,
J ) 47.0, 10.0, 3.4 Hz, 1H); 13C NMR (CDCl3) δ 14.1 (CH3), 14.3
(CH3), 16.3 (d, J ) 6.0 Hz, CH3), 16.6 (CH3), 18.9 (CH3), 32.0
(CH), 34.4 (dd, J ) 19.4, 2.7 Hz, CH2), 55.5 (dd, J ) 13.0, 3.0
Hz, CH), 60.6 (CH2), 62.8 (d, J ) 6.5 Hz, CH2), 63.1 (d, J ) 6.5
Hz, CH2), 86.0 (dd, J ) 179.4, 172.5 Hz, CH), 162.4 (C), 164.3
(C); 31P NMR (CDCl3) δ 19.0 (d, J ) 74.7 Hz); 19F NMR (CDCl3)
δ -212.2 (d, J ) 74.8 Hz); FABMS (thioglycerol) m/z 396 ((M +
2)+, 23), 395 (MH+, 100). Anal. Calcd for C17H32FN2O5P: C, 51.77;
H, 8.18; N, 7.10. Found: C, 51.96; H, 8.31; N, 7.07.
Data for (2S,5R,2′Z)-3,6-diethoxy-2-[2-(diethoxyphosphoryl)-3-
20
phenylprop-2-enyl]-2,5-dihydro-5-isopropylpyrazine (23am): [R]D
-24.4 (c 1.1, CH2Cl2); IR (film) ν 1690 (CdN), 1235 (PdO), 1028
(POC) cm-1; H NMR (CDCl3) δ 0.72 (d, J ) 6.8 Hz, 3H), 1.07
1
(d, J ) 6.8 Hz, 3H), 1.08 (t, J ) 7.0 Hz, 3H), 1.09 (t, J ) 7.0 Hz,
3H), 1.25 (t, J ) 7.0 Hz, 3H), 1.29 (t, J ) 7.0 Hz, 3H), 2.28 (dsp,
J ) 6.8, 3.4 Hz, 1H), 2.48 (ddd, J ) 20.5, 14.6, 8.8 Hz, 1H), 3.17
(ddd, J ) 14.2, 12.7, 4.4 Hz, 1H), 3.80-4.23 (m, 8H), 4.25-4.34
(m, 1H), 7.20 (d, J ) 44.4 Hz, 1H), 7.27-7.51 (m, 5H); 13C NMR
(CDCl3) δ 14.3 (CH3), 15.9 (d, J ) 7.1 Hz, CH3), 16.7 (CH3),
19.0 (CH3), 31.6 (CH), 41.0 (d, J ) 2.1 Hz, CH2), 55.1 (d, J ) 2.5
Hz, CH), 60.6 (CH), 60.6 (CH2), 61.4 (d, J ) 6.0 Hz, CH2), 126.7
(d, J ) 174.6 Hz, C), 127.6 (CH), 127.9 (CH), 128.9 (CH), 136.6
Data for (2S,5R)-3,6-diethoxy-2-[2-(diethoxyphosphoryl)-2,2-
difluoroethyl]-2,5-dihydro-5-isopropylpyrazine (16ae): colorless oil;
J. Org. Chem, Vol. 71, No. 18, 2006 6973

Ferna´ndez et al.
(d, J ) 7.8 Hz, C), 147.0 (d, J ) 7.9 Hz, CH), 162.8 (C), 162.9
(C); 31P NMR (CDCl3) δ 18.4; FABMS (thioglycerol) m/z 465
(MH+, 100). Anal. Calcd for C24H37N2O5P: C, 62.05; H, 8.03; N,
6.03. Found: C, 61.74; H, 8.29; N, 6.16.
Acknowledgment. We gratefully acknowledge Ministerio
de Ciencia y Tecnolog´ıa (Spain) and the European Regional
Development Fund (Projects BQU200-0236 and BQU2003-
00692) and Xunta de Galicia (PGIDIT05BTF10301PR) for
financial support, and Novartis Pharma for the generous gift of
bis-lactim ethers derived from cyclo-[Val-Gly]. We also thank
Dr. Miguel A. Maestro, Dr. Alberto Ferna´ndez, and Dr. Ana I.
Balana for resolving the X-ray structures. The authors are
indebted to Centro de Supercomputacio´n de Galicia for provid-
ing the computer facilities. O.B. thanks Xunta de Galicia for
an “Isidro Parga Pondal” position at Universidade da Corun˜a.
Data for (2S,5R,2′E)-3,6-diethoxy-2-[2-(diethoxyphosphoryl)-3-
20
phenylprop-2-enyl]-2,5-dihydro-5-isopropylpyrazine (24am): [R]D
+141.9 (c 0.4, CH2Cl2); IR (film) ν 1690 (CdN), 1240 (PdO),
1035 (POC) cm-1; H NMR (CDCl3) δ 0.75 (d, J ) 6.8 Hz, 3H),
1
1.02 (d, J ) 6.8 Hz, 3H), 1.17-1.38 (m, 12H), 2.21 (dsp, J ) 6.8,
3.9 Hz, 1H), 2.48-3.08 (m, 2H), 3.91 (t, J ) 3.4 Hz, 1H), 3.93-
4.27 (m, 8H), 4.41-4.50 (m, 1H), 7.24-7.49 (m, 5H), 7.66 (d, J
) 24.9 Hz, 1H); 13C NMR (CDCl3) δ 14.3 (CH3), 16.3 (d, J ) 5.3
Hz, CH3), 17.0 (CH3), 19.0 (CH3), 32.1 (CH), 32.9 (d, J ) 9.3 Hz,
CH2), 53.9 (CH), 60.5 (CH), 60.9 (CH2), 61.7 (d, J ) 7.0 Hz, CH2),
61.9 (d, J ) 7.0 Hz, CH2), 127.3 (d, J ) 174.2 Hz, C), 128.2 (CH),
129.2 (CH), 135.5 (J ) 23.1 Hz, C), 145.5 (J ) 11.7 Hz, CH),
163.1 (C), 163.5 (C); 31P NMR (CDCl3) δ 22.6; FABMS (thioglyc-
erol) m/z 465 (MH+, 100). Anal. Calcd for C24H37N2O5P: C, 62.05;
H, 8.03; N, 6.03. Found: C, 62.39; H, 8.10; N, 6.31.
Supporting Information Available: Experimental procedures
and full characterization of new compounds. Crystallographic data
for compounds 21mb, 32ak, 46ae, 52mb, and 55nb. Computational
methods, Cartesian coordinates, and absolute energies for all the
models reported. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO061072X
6974 J. Org. Chem., Vol. 71, No. 18, 2006