Conjugate additions of 1-propenylphosphonates to metalated Schollkopf's bis-lactim ether: Stereocontrolled access to 2-amino-3-methyl-4- phosphonobutanoic acids

Article abstract of DOI:10.1021/jo991402w

Diastereoselectivity in the conjugate addition of metalated Schollkopf's bis-lactim ethers 5a-e to (E)- and (Z)-1-propenylphosphonates 4a,b was studied experimentally and theoretically and utilized to achieve a direct and stereocontrolled synthesis of all four diastereoisomers of 2-amino-3-methyl- 4-phosphonobutanoic acid, 6a,b and their enantiomers. The relative stereochemistry was assigned from an NMR study of cyclic derivatives 13a,b. According to semiempirical calculations, both in vacuo (PM3) or a dielectric continuum (PM3/COSMO), initial lithium-phosphoryl coordination, without an energy barrier, to form a solvated chelate complex is followed by the rate- determining reorganization to the 1,4-addition product through an eight- membered transition state. The translation of the Z,E geometry into a syn,anti configuration at the adducts originates from an orientational preference in the transition state for a compact disposition of the reaction partners.

Full text of DOI:10.1021/jo991402w

1984
J . Org. Chem. 2000, 65, 1984-1995
Con ju ga te Ad d ition s of 1-P r op en ylp h osp h on a tes to Meta la ted
Sch o1llk op f’s Bis-la ctim Eth er : Ster eocon tr olled Access to
2-Am in o-3-m eth yl-4-p h osp h on obu ta n oic Acid s
Vicente Ojea,*,† Mar´ıa Ruiz,† Gideon Shapiro, and Esteban Pombo-Villar*
Preclinical Research, Novartis Pharma Ltd., CH-4002 Basel, Switzerland
Received September 7, 1999
Diastereoselectivity in the conjugate addition of metalated Scho¨llkopf’s bis-lactim ethers 5a -e to
(E)- and (Z)-1-propenylphosphonates 4a ,b was studied experimentally and theoretically and utilized
to achieve a direct and stereocontrolled synthesis of all four diastereoisomers of 2-amino-3-methyl-
4-phosphonobutanoic acid, 6a ,b and their enantiomers. The relative stereochemistry was assigned
from an NMR study of cyclic derivatives 13a ,b. According to semiempirical calculations, both in
vacuo (PM3) or a dielectric continuum (PM3/COSMO), initial lithium-phosphoryl coordination,
without an energy barrier, to form a solvated chelate complex is followed by the rate-determining
reorganization to the 1,4-addition product through an eight-membered transition state. The
translation of the Z,E geometry into a syn,anti configuration at the adducts originates from an
orientational preference in the transition state for a compact disposition of the reaction partners.
Ch a r t 1. Agon ist a n d An ta gon ists of th e m Glu Rs
of Gr ou p III
In tr od u ction
L-Glutamic acid mediates fast excitatory transmission
at the majority of central nervous system synapses and
also participates in neuronal plasticity and neurotoxicity.1
Synaptically released glutamate exerts its effects via
activation of ligand-gated cation channels (the ionotropic
glutamate receptors) and metabotropic glutamate recep-
tors (mGluRs), which modulate intracellular second
messengers through G protein-coupled processes. Glutam-
ate receptors have attracted considerable attention be-
cause of their therapeutic potential for the treatment of
a range of chronic and acute CNS disorders with social
significance, such as stroke, epilepsy, and Alzheimer’s
disease.2 To date, mGluRs have been distinguished into
three groups, based on sequence homology, signal trans-
duction mechanisms, and agonist pharmacology. In par-
ticular, receptors of group III (subtypes mGluR4 and
mGluR6-8) are characterized by their selective response
to several phosphonic acid derivatives. Thus, they are
selectively activated by L-2-amino-4-phosphonobutanoic
acid (L-AP4, 1, see Chart 1) and competitively antago-
nized by the R-methylated derivatives of L-AP4 (MAP4,
2) and 4-phosphonophenylglycine (MPPG, 3).3 Biological
research on mGluRs function awaits the development of
more potent and selective agonist and antagonists, to
clearly define the potential of these receptors as drug
targets. As the molecular basis for the glutamate recog-
nition and binding at the mGluRs proteins has not been
elucidated yet, the development of high-affinity ligands
still relies on structural modification of established
structures and screening of new lead compounds. As part
of a project directed toward the design of new bioactive
phosphonates,4 we report now the diastereoselective
synthesis of all four diastereoisomers of 2-amino-3-
methyl-4-phosphonobutanoic acid, prepared in order to
study the stereochemical requirements for a potent
binding at group III of mGluRs.5
Although the additions of organometallic reagents to
electron-deficient alkenes constitute an important and
well-known method in asymmetric synthesis,6 and un-
saturated systems bearing phosphonate groups act as
acceptors with a variety of nucleophiles,7 few examples
can be found in the literature for stereoselective addi-
tions to alkenylphosphonates.8 For the synthesis of
nonproteinogenic amino acids, conjugate additions of
metalated Scho¨llkopf’s bis-lactim ethers to several un-
saturated systems have been shown as a valuable
protocol that enables reasonably high levels of stereo-
control at both R and â positions.9 These precedents
(4) Ojea, V.; Conde, S.; Ruiz, M.; Ferna´ndez, M. C.; Quintela, J . M.
Tetrahedron Lett. 1997, 38, 4311 and references therein.
(5) Part of this work was already presented as preliminary com-
munications: (a) Ojea, V.; Ruiz, M.; Vilar, J .; Quintela, J . M.
Tetrahedron: Asymmetry 1996, 7, 3335. (b) Ojea, V.; Ruiz, M.; Shapiro,
G.; Pombo-Villar, E. Tetrahedron Lett. 1994, 35, 3273.
(6) Perlmutter, P. In Conjugate Addition Reactions in Organic
Synthesis; Baldwin, J . E., Magnus, P. D., Eds.; Organic Chemistry
Series, Vol. 9; Pergamon: Oxford, 1992.
† Current address: Departamento de Qu´ımica Fundamental
e
Industrial, Facultade de Ciencias, Universidade da Corun˜a. Campus
A Zapateira s/n, 15071 A Corun˜a, Spain. E-mail: ojea@udc.es.
(1) CNS Neurotransmitters and Neuromodulators: Glutamate; Stone,
T. W., Ed.; CRC: Boca Raton, FL, 1995.
(2) (a) Kno¨pfel, T.; Gasparini, F. Drug Discovery Today 1996, 1, 103.
(b) Kno¨pfel, T.; Kuhn, R.; Allgeier, H. J . Med. Chem. 1995, 38, 1417.
(3) J ane, D. E.; Pittaway, K.; Sunter, D. C.; Thomas, N. K.; Watkins,
J . C. Neuropharmacology 1995, 34, 851. (b) J ane, D. E.; J ones, P. L.
St. J .; Pook, P. C.-K.; Tse, H.-W.; Watkins, J . C. Br. J . Pharmacol.
1994, 112, 809.
(7) (a) Afarinkia, K.; Binch, H. M.; Modi, C. Tetrahedron Lett. 1998,
39, 7419. (b) Baldwin, I. C.; Beckett, R. P.; Williams, J . M. J . Synthesis
1996, 34. (c) Zindel, J .; Meijere, A. Synthesis 1994, 190. (d) Minami,
T.; Motoyoshiya, J . Synthesis 1992, 333 and references therein. (e)
Darling, S. D.; Muralidharan, F. N.; Muralidharan, V. B. Tetrahedron
Lett. 1979, 30, 2757 and 2761. See also references cited in ref 5b.
10.1021/jo991402w CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/04/2000

Access to 2-Amino-3-methyl-4-phosphonobutanoic Acids
J . Org. Chem., Vol. 65, No. 7, 2000 1985
Sch em e 1. Ster eocon tr olled Syn th esis of L-AP 4
Der iva tives
6 equiv of 1,2-dibromopropane for 14 h, phosphonate 8
was obtained (70% yield) together with O,O-diethyleth-
ylphosphonate as a side product (25%). Both compounds
and unreacted 1,2-dibromopropane could be easily sepa-
rated by distillation at reduced pressure. Dehydrobrom-
ination of 8 by treatment with DBU at 0 °C afforded the
desired (E)-1-propenylphosphonate 4a in good yield. (Z)-
1-Propenylphosphonate 4b was prepared directly and
stereospecifically by Pd(0)-catalyzed coupling of com-
mercial cis-1-bromo-1-propene (9) and diethyl phosphite,
as described in the literature.11 According to 31P NMR
analyses, propenylphosphonates 4a and 4b were obtained
with >98% (E)- and (Z)-configuration, respectively.
1-Propenylphosphonates 4a and 4b underwent a highly
stereoselective conjugate addition of lithiated Scho¨llkopf’s
bis-lactim ethers, in a fashion similar to that previously
reported for R,â-unsaturated carboxylic acid esters.9g
Slow addition of propenylphosphonates 4a or 4b to 1
equiv of 5a at -78 °C in THF, followed by immediate
acetic acid quenching and aqueous workup, gave mix-
tures of the desired adducts 10a and 10b in 33%
combined yield, along with 1:2 addition products 11 (see
Scheme 3). Integration of the 1H-decoupled 31P NMR
spectra of the crude reaction mixtures revealed a very
high asymmetric induction in the formation of both new
chiral centers, as well as complementary stereochemical
courses in the additions to both acceptors, only differing
in the geometry of the double bond. After the isolation
of the fractions containing the 1:1 addition products by
flash chromatography, integration of the pairs of doublets
corresponding to the isopropyl groups in the 1H NMR
spectra confirmed the formation of mixtures of adducts
10a /10b with 96:4 and 4:96 ratios in the cases a and b,
respectively. In this way, the diastereomeric excess of the
2,5-trans-2,1′-anti adduct 10a in the addition to the (E)-
1-propenylphosphonate 4a , and of the 2,5-trans-2,1′-syn
adduct 10b in the addition to (Z)-1-propenylphosphonate
4b, were both higher than 90%. Evidence supporting the
relative configuration on adducts was obtained by NMR
analyses. Thus, for 10b, the H-5 resonance appears at
Sch em e 2. P r ep a r a tion of
1-P r op en ylp h osp h on a tes 4a ,b
prompted us to explore the conjugate additions of meta-
lated bis-lactim ethers to alkenylphosphonates, as a new
approach to 2-amino-4-phosphonobutanoic acids. In this
paper, we wish to report our results on the face-selective
conjugate additions of metalated bis-lactim ethers 5a -e
to (E)- and (Z)-1-propenylphosphonates 4a ,b that allow
a direct and stereocontrolled access to optically pure AP4
analogues 6a ,b (see Scheme 1). To gain more insight into
the origin of the stereoselection in the addition process,
and assess its scope and limitations in asymmetric
synthesis, we have also carried out a theoretical analysis
of the possible reaction mechanisms. Thus, a semiem-
pirically optimized transition-state model that rational-
izes the stereochemical outcome of the addition process
is also put forward.
5
3.89 ppm, as a triplet with J H2H5 ) 3.5 Hz, typical for a
trans relation of substituents at the pyrazine ring.9e,f The
relative configurations at position 1′ were assigned on
the basis of the sets of NOEs observed for cyclic deriva-
tives of 10a ,b, as will be described below. Absolute
configurations follow from the use of bis-lactim ethers
derived from D-Val, as there is ample precedent.9
Exp er im en ta l Resu lts a n d Discu ssion
The preparation of the 1-propenylphosphonate esters
4a ,b was accomplished as depicted in Scheme 2. Al-
though Arbuzov reaction of triethyl phosphite with 1
equiv of 1,2-dibromopropane (7) was reported to be
completely unsuccessful,10 2-bromopropylphosphonate 8
could be obtained in good yield simply by using 7 in a
large excess. Thus, after refluxing triethyl phosphite and
Having shown the feasibility of synthesizing both anti
and syn adducts 10a ,b, the influence of additives and
reaction conditions on the yield and stereoselection of the
conjugate addition was examined, the most salient
results being summarized in Table 1. While addition of
12-crown-4 to the lithium azaenolate 5a prior to reaction
with acceptor 4a had no appreciable effect on the process,
in the presence of an excess of HMPA the same addition
proceeded with very low diastereoselectivity, giving rise
to a 2.1:1.0:0.9:0.5 mixture of all four possible stereoiso-
mers (see Table 1, entries 3 and 4). Thus, the disruptive
role of lithium solvation by HMPA highlights the impor-
tance of ordered lithium-chelated aggregates in the
stereochemical course of the addition process. Conversely,
the 12-crown-4 may simply replace solvent molecules in
its coordination to lithium, without modification of the
(8) (a) Enders, D.; Wahl, H.; Papadopoulos, K. Tetrahedron 1997,
53, 12961 and references therein. (b) Groth, U.; Richter, L.; Scho¨llkopf,
U. Tetrahedron 1992, 48, 117. (c) Bodalski, R.; Michalski, T.; Monk-
iewicz, J .; Pietrusiewicz, K. Addition of Lithium Dialkylcuprates to
R,â-Unsaturated Phosphoryl Compounds. In Phosphorus Chemistry;
Comstock, M. J ., Ed.; ACS Symposium Series 171; American Chemical
Society: Washington, DC, 1981; p 245.
(9) (a) Williams, R. M. Synthesis of Optically Active R-Amino Acids;
Baldwin, J . E., Magnus, P. D., Eds.; Organic Chemistry Series, Vol. 7;
Pergamon: Oxford, 1989. (b) Scho¨llkopf, U.; Pettig, D.; Schulze, E.;
Klinge, M.; Egert, E.; Benecke, B.; Noltemeyer, M. Angew. Chem., Int.
Ed. Engl. 1988, 27, 1194. (c) Pettig, D.; Scho¨llkopf, U. Synthesis 1988,
173. (d) Scho¨llkopf, U.; Schro¨der, J . Liebigs Ann. Chem. 1988, 87. (e)
Scho¨llkopf, U.; Ku¨hnle, W.; Egert, E.; Dyrbusch, M. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 480. (f) Hartwig, W.; Born, L. J . Org. Chem.
1987, 52, 4352. (g) Scho¨llkopf, U.; Pettig, D.; Busse, U.; Egert, E.;
Dyrbusch, M. Synthesis 1986, 737.
(10) Ford-Moore, A. H.; Howarth Williams, J . J . Chem. Soc. 1947,
1465.
(11) Hirao, T.; Masunaga, T.; Yamada, N.; Ohshiro, Y.; Agawa, T.
Bull. Chem. Soc. J pn. 1982, 55, 909.

1986 J . Org. Chem., Vol. 65, No. 7, 2000
Ojea et al.
Sch em e 3. Con ju ga te Ad d ition of 1-P r op en ylp h osp h on a tes 4a ,b to Meta la ted Bis-la ctim Eth er s 5a -e
Ta ble 1. Con ju ga te Ad d ition s of Meta la ted Bis-la ctim
formed adduct anion to the R,â-unsaturated acceptor.
Eth er s 5a -e to 1-P r op en ylp h osp h on a tes 4a ,b
Thus, to reduce the dimerization process, we carried out
yielda 10a :10b
the addition process using an excess of the azaenolate.
By using 2 equiv of the lithium azaenolate 5a , the yields
of the mixtures of 1:1 adducts resulting from the addition
to either 4a or 4b were increased to 62 or 66%, respec-
tively. In the presence of magnesium, the same conditions
led to 10a /10b with 27% yield (see Table 1, entries 9-11).
The mixtures of adducts 10a ,b could be isolated with
yields higher than 85% when 3 equiv of lithium azaeno-
late was used (see Table 1, entries 12 and 13). On the
basis of our previous studies on the conjugate addition
to vinylphosphonates,15 it was expected that the initial
anionic adduct would be effective in producing the
alkenylphosphonate 4a in situ, via dehydrohalogenation
of the 2-bromopropylphosphonate 8, thus suppressing
oligomerization. When mixtures of 4a /8 were added to
the lithium azaenolate, the anti adduct was obtained with
improved yields and with high diastereoselectivity (see
Table 1, entries 14-17). In this manner, using 1 equiv
of a mixture of 4a and 8 in a 1:2 ratio and 2 equiv of 5a ,
a mixture of 1:1 adducts containing 10a with 90%
diastereomeric excess could be isolated in 87% yield.
Apparently, the conjugate addition of lithium azaenolate
to the alkenylphosphonate 4a is faster than the elimina-
tion of 8, and the initially formed phosphonate carbanion
is more basic than the lithium azaenolate. In all cases,
the excess of Scho¨llkopf’s reagent could be recovered and
showed no racemization.16
The separation of 10a from 10b could be achieved by
medium-pressure liquid chromatography to provide prod-
ucts of high purity, with a diastereomeric excess higher
than 98%, on a multigram scale. Mild acid hydrolysis of
the bis-lactim ether provided the aminoesters 12a and
12b in excellent yield after removal of the valine ester
by chromatography (see Scheme 4). Vigorous acid hy-
drolysis of the amino esters allowed, after purification
by reversed-phase chromatography, the isolation of the
2-amino-3-methyl-4-phosphonobutanoic acids (6a and 6b)
in excellent yields. Starting from the Scho¨llkopf’s bis-
lactim ether derived from L-valine, the corresponding
enantiomers of 6a ,b were prepared in an analogous
fashion.
entry 5a
4a
4b
8
additive (equiv)
(%)
ratiob
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1
1
1
1
1
1
1
1
2
2
2
3
3
1
1
1
2
1
33
33
29
27
NR
NR
26
11
62
66
27
87
85
48
60
50
87
23:1
1:25
20:1
1:2.1
1
1
1
1
1
1
1
1
12-crown-4 (2)
HMPA (10)
SnCl2 (1)
CuBr2‚SMe2 (1)
TiCl(OiPr)3 (1)
MgBr2‚OEt2 (1)
13:1
40:1
21:1
1:22
40:1
23:1
1:24
18:1
19:1
19:1
19:1
1
1
1
1
MgBr2‚OEt2 (1)
0.10
0.33
0.50
0.33
0.90
0.66
0.50
0.66
a
Isolated yield of mixtures of adducts 10a /10b, after column
chromatography. Determined by integration of 31P NMR spectra.
b
NR ) no reaction was observed.
chelation control in the process. Several reports from
different groups have shown a strong increase in the
diastereoselectivity of aldol and conjugate additions of
metalated Scho¨llkopf’s bis-lactim ethers when the lithium
atom is exchanged by Sn(II),12 Cu(I),9d or Ti(IV).13 On the
basis of these precedents, azaenolate 5a was allowed to
react, in THF at low temperature, with stoichiometric
amounts of SnCl2, CuBr2‚SMe2, ClTi(OiPr)3, or MgBr2‚
OEt2, to produce the corresponding transmetalated aza-
enolates 5b-e,14 prior to the addition of the alkenylphos-
phonate 4a . No reaction was observed for the tin(II) and
copper(I) azaenolates (5b and 5c, respectively) under the
standard conditions (-78 °C, THF, 5 min) or with longer
reaction times and warming (up to 10 h and 0 °C, see
Table 1, entries 5 and 6). Reactions of 4a with the
titanium and magnesium azaenolates were complete at
low temperature in a few minutes but gave the mixtures
of adducts 10a /10b with lower yields. Switching the
metal to Ti or Mg did not change the stereochemical
course of the addition, but led to the anti adducts with a
slightly different selectivity. Thus, the anti/syn ratio
decreased to 13:1 by using the titanium azaenolate,
whereas a remarkable 40:1 ratio was observed in the
presence of magnesium (see Table 1, entries 7 and 8).
We reasoned that the chemical yield of 1:1 addition
products was lowered by further addition of the initially
Since none of the synthesized adducts, esters, or amino
acids provided crystals suitable for an X-ray crystal
structure determination, a cyclic derivative was sought
that could enable the assignment of the relative configu-
rations by 1H NMR spectroscopy. The six-membered
amino-oxaphosphorinane derivatives 13a ,b were attrac-
(12) (a) Ruiz, M.; Ojea, V.; Quintela, J . M. Synlett 1999, 204. (b)
Ruiz, M.; Ruanova, T. M.; Ojea, V.; Quintela, J . M. Tetrahedron Lett.
1999, 40, 2021. (c) Kobayashi, S.; Furuta, T.; Hayashi, T.; Nishijima,
M.; Hanada, K. J . Am. Chem. Soc. 1998, 120, 908.
(13) (a) Scho¨llkopf, U.; Bardenhagen, J . Liebigs Ann. Chem. 1987,
393. (b) Grauert, M.; Scho¨llkopf, U. Liebigs Ann. Chem. 1985, 1817.
(14) Hu¨nig, S.; Klaunzer, N.; Wenner, H. Chem. Ber. 1994, 127, 165.
(15) Shapiro, G.; Buechler, D.; Ojea, V.; Pombo-Villar, E.; Ruiz, M.;
Weber, H. P. Tetrahedron Lett. 1993, 34, 6255.
(16) Multigram quantities of Scho¨llkopf’s reagents were obtained
from Novartis kilo laboratory.

Access to 2-Amino-3-methyl-4-phosphonobutanoic Acids
J . Org. Chem., Vol. 65, No. 7, 2000 1987
Sch em e 4
F igu r e 1. PM3-optimized geometries for the cyclic derivatives
13a ,b, showing characteristic NOEs.
preferences of the substituents in a six-membered cyclic
transition state with a bipyramidal phosphorus atom may
account for this result, as was reported for the related
specific ring opening of cyclic phosphonates by alkox-
ides.18 The N-Boc and O-ethyl ester groups were cleaved
with trimethylsilyl bromide in THF at room temperature
to give 13a ,b as pure diastereoisomers.
Sch em e 5
A single chair conformation was observed for each
1
compound 13a ,b in the H NMR spectra (D2O, 400 MHz,
25 °C). For compound 13b, a doublet of triplets was
observed for H-5 at δ ) 3.24 with coupling constants of
9.1 and 3.1 Hz. The major coupling constant indicated a
diaxial relationship between H-5 and H-4, with a degen-
erate coupling of H-5 to H-6ax. Furthermore, the com-
1
plete set of NOE cross-peaks that were observed by H-
1H ROESY19 was consistent with this trans-stereochemical
assignment. The assignment of the cis configuration for
diastereoisomer 13a follows by elimination and is also
consistent with the NOEs observed for that compound.
The observed NOEs were supported by semiempirical
calculations: the refined geometries in the gas phase for
compounds 13a ,b were in agreement with the conforma-
tions in solution deduced from NMR spectroscopy, as
depicted in Figure 1. All these results allow us to assume
a 2,1′-anti configuration for adduct 10a and a 2,1′-syn
configuration for adduct 10b.
The stereoselectivity of the conjugate addition to pro-
penylphosphonates 4a and 4b is concordant with the
stereochemical course reported for the additions of lithi-
ated Scho¨llkopf’s bis-lactim ether to 2-alkenoates9e,f and
other (E)-alkenylphosphonates.20 The stereochemical out-
come of the process seems to be both reagent- and
substrate-controlled. While the influence of the chiral
glycine equivalent determines the absolute stereochem-
istry at the addition products, the relative configuration
of the new chiral centers exclusively depends on the
geometry of the propenylphosphonate. In this way, the
reaction results in an almost complete translation of the
Z or E geometry into a syn or anti configuration at the
1,4-addition products, as was previously observed with
other conjugate additions to stereodefined enolates.21
Com p u ta tion a l Resu lts: P M3 Tr a n sition Str u c-
tu r es a n d En er getics. On the basis of the experimental
data, Heathcock and Oare have proposed that low-
tive in this regard, because of the strong preference for
the chair conformation reported for similarly 4-methyl-
substituted systems (see Scheme 5).17 Conversion of
amino esters 12a ,b into such cyclic derivatives required
the selective reduction of the carboxylic ester in the
presence of the phosphonate group. Attempts to achieve
this reduction with lithium aluminum hydride in THF
resulted in complex mixtures of products, by simulta-
neous reduction of the phosphonic ester and epimeriza-
tion at the R-center. Sodium borohydride in refluxing
methanol caused transesterification of the carboxylic
ester and epimerization of the R-center, while with
calcium borohydride or DIBALH in THF there was no
reaction. Chemoselective reduction of the carboxylic ester
in the presence of the phosphonate was eventually
achieved on the N-Boc derivatives of amino esters 14a ,b,
employing lithium borohydride in anhydrous THF at
room temperature. Moreover, under these conditions,
cyclization of the reduction intermediates to afford the
N-Boc-amino-oxaphosphorinane derivatives 15a ,b was
observed. While 15a was obtained as one single dia-
stereoisomer, 15b was isolated as a mixture of epimers
at the phosphorus center in a 2.7:1 ratio, which could
not be separated by chromatography. The conformational
(18) (a) Thatcher, G. R. J .; Kluger, R. Adv. Phys. Org. Chem. 1989,
25, 99. (b) Hall, C. R.; Inch, T. D. Tetrahedron 1980, 36, 2059.
(19) Griesinger, C.; Ernst, R. R. J . Magn. Reson. 1987, 75, 261.
(20) Ojea, V.; Ferna´ndez, M. C.; Ruiz, M.; Quintela, J . M. Tetrahe-
dron Lett. 1996, 37, 5801.
(21) For a review of the stereochemistry of the Michael addition
reaction, see: (a) Leonard, J . Contemp. Org. Synth. 1994, 1, 387. (b)
Oare, D. A.; Heathcock, C. H. Top. Stereochem. 1989, 19, 227.
(17) (a) Berkowitz, D. B.; Eggen, M.-J .; Shen, Q.; Shoemaker, R. K.
J . Org. Chem. 1996, 61, 4666. (b) Bergesen, K.; Vikane, T. Acta Chem.
Scand. 1972, 26, 1794. For the conformational preferences of other
substituted 1,2-oxaphosphorinanes, see: Tasz, M. K.; Rodriguez, O.
P.; Cremer, S. E.; Hussain, M. S.; Mazhar-ul-Haque J . Chem. Soc.,
Perkin Trans. 2 1996, 2221, and references therein.

1988 J . Org. Chem., Vol. 65, No. 7, 2000
Ojea et al.
Sch em e 6. Rea ction P a th w a y P r op osed for th e
Ad d ition of Lith ia ted Sch o1llk op ’s Bis-la ctim Eth er
16 to 1-P r op en ylp h osp h on a tes 17a ,b
along with other minor isomers 20 with the 2,5-cis
configuration. According to such a model, the diastereo-
selective formation of trans adducts must originate from
a kinetic preference for the interaction through the Re
face of the azaenolate (trans to the isopropyl group), while
the syn/anti stereoselection relies on the energy difference
between the possible transition structures resulting from
the like or unlike approach of the azaenolate to the
prochiral faces of the Câ of the phosphonate.
We wished to employ a practical but reliable method
applicable to the present problem but also to other
molecular systems of future synthetic interest, consider-
ing larger alkenylphosphonates. Geometry optimization
of such systems using ab initio or density functional
theory methods may provide more accurate estimates,
but are more demanding of computing capabilities.
Hence, we have used semiempirical methods. Semi-
empirical calculations have progressed over the past few
years to a surprising level of accuracy and reliability and
nowadays are recognized as a rapid and useful tool in
the elucidation of the reaction mechanisms of large
molecular systems.26 For this study, we have used the
PM3 Hamiltonian,24 which is generally superior to MNDO
for the calculation of hypervalent molecules and appears
to be particularly suited for mechanistic studies on large
lithium amides and phosphonate carbanions.27 Although
the X-ray structure of a lithiated bis-lactim ether (derived
from cyclo-[Ala-Ala]) has been determined as a trisolvated
dimeric aggregate,28 freezing-point depression measure-
ments have shown an average degree of aggregation of
1.15 for the same compound at low-temperature diluted
ethereal solutions.29 Since lower reagent concentrations
and higher solvent concentrations will promote reaction
via the more highly solvated and less aggregated species,
the azaenolate 16 was considered in this analysis to react
as monomer, and complete dissociation of the possible
oligomeric clusters in strong donor solvent was assumed.
In this way, calculations in the gas phase have been
performed with discrete solvation of lithium as working
model. As water is an unrealistic ligand and is not
generally suitable because of its tendency to hydrogen
bond and dimethyl ether could originate crowded models
for highly solvated species, we chose ethylene oxide as
model for THF, which is conformationally more complex.
Computations were also performed within a dielectric
medium, mimicking the nonspecific solvation effect of
THF.
temperature enolate Michael additions to R,â-unsatu-
rated carbonyl compounds are kinetically controlled. By
analogy with the Zimmermann-Traxler model for aldol
additions, these authors suggested that the stereochem-
ical course of those processes can be rationalized by
assuming the participation of cyclic, rate-determining
transition structures.22 Bernardi et al. have studied this
hypothesis by ab initio methods and have verified that
eight-membered transition structures account for the
experimental results.23 On the basis of these precedents,
we have recently reported that competitive cyclic transi-
tion structures can be located on the MNDO and PM3
potential energy surfaces obtained for a minimal molec-
ular prototype of the bis-lactim/alkenylphosphonate sys-
tem. This competitive transition state model allowed a
qualitative rationalization of the observed stereoselec-
tivity trends for the conjugate addition.5a These results
prompted us to evaluate the efficiency of such transition
state model for the analysis of more realistic situations,
considering full substitution of the reaction partners and
also solvation effects. With this purpose we have carried
out a theoretical study of the addition of the lithiated bis-
lactim ether 16, derived from cyclo-[L-Val-Gly], to O,O-
dimethyl 1-propenylphosphonates 17a ,b (see Scheme 6),
both in vacuo (PM3 Hamiltonian)24 and within a dielec-
tric medium (using the COSMO solvation model).25
By analogy with previous theoretical studies,5a,23 the
reaction between the lithium azaenolate 16 and the
1-propenylphosphonates 17a ,b should involve an initial
phosphoryl-lithium coordination to form the stable
complexes 18a ,b. Subsequently, reorganization of these
intermediates through competing eight-membered tran-
sition structures would initially afford the addition
products as mixtures of the lithium phosphonate carban-
ions 2,5-trans-2,1′-anti-19a and 2,5-trans-2,1′-syn-19b,
We first examined the solvation equilibria for the
monomeric azaenolate 16 in the gas phase (see Scheme
7). To estimate the solvent effect on the stability of 16,
complete geometry optimizations for unsolvated, mono-
solvated, disolvated, and trisolvated structures were
carried out. In the unsolvated azaenolate u 16, the
lithium cation is stabilized by coordination with the
vicinal methoxy group. This interaction is maintained in
the mono and disolvated species m 16 and d 16, respec-
tively, but is lost in the trisolvated azaenolate t16. All
(22) Oare, D. A.; Henderson, M. A.; Sanner, M. A.; Heathkock, C.
H. J . Org. Chem. 1990, 55, 133 and references therein.
(23) (a) Bernardi, A. Gazz. Chim. Ital. 1995, 125, 539. (b) Bernardi,
A.; Capelli, A. M.; Cassinari, A.; Comotti, A.; Gennari, C.; Scolastico,
C. J . Org. Chem. 1992, 57, 7029.
(24) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209, and 221.
Lithium PM3 parameters: Anders, E.; Koch, R.; Freunscht, P. J .
Comput. Chem. 1993, 14, 1301.
(26) Stewart, J . J . P. Semiempirical Molecular Orbital Methods. In
Reviews in Computational Chemistry; Lipkowitz, K. B., Boyd, D. B.,
Eds.; VCH: New York 1990; Vol. 1, p 45.
(27) (a) Hilmersson, G.; Arvidsson, P. I.; Davidsson, O.; Hakansson,
M. J . Am. Chem. Soc. 1998, 120, 8143. (b) Koch, R.; Wiedel, B.; Anders,
E. J . Org. Chem. 1996, 61, 2523. (c) Koch, R.; Anders, E. J . Org. Chem.
1995, 60, 5861.
(28) Seebach, D.; Bauer, W.; Hansen, J .; Laube, T.; Schweizer, W.
B.; Dunitz, J . D. J . Chem. Soc., Chem. Commun. 1984, 853.
(29) Bauer, W.; Seebach, D. Helv. Chim. Acta 1984, 67, 1972.
(25) Klamt, A.; Schu¨u¨rmann, G. J . Chem. Soc., Perkin Trans. 2 1993,
799.

Access to 2-Amino-3-methyl-4-phosphonobutanoic Acids
J . Org. Chem., Vol. 65, No. 7, 2000 1989
Sch em e 7. Solva tion Equ ilibr ia for Aza en ola te
16a
this coordination proceeds by replacement of a solvent
molecule from the solvated azaenolate. The unsolvated
(u 18a ,b) and monosolvated (m 18a ,b) complexes main-
tain the coordination between the lithium and vicinal
methoxy groups, already shown by the parent azaeno-
lates m 16 and d 16. This interaction is not present in the
disolvated complexes d 18a ,b. Lithium coordination re-
quirements in the intermediate complexes are satisfied
with only two solvent molecules, and the interaction with
the vicinal methoxy group is no longer necessary. In this
manner, the addition of the first solvent molecule is
clearly exothermic, while the introduction of the second
ligand reduces the enthalpy of the systems by less than
1 kcal/mol. Most stable conformations found for the
complexes show the lithium atom above the plane of the
pyrazine ring, providing a synclinal disposition between
the lithium-coordinated phosphonate and the isopropyl
group (trans coordination). Disolvated complexes also
differ from the unsolvated and monosolvated ones by the
geometry of the complexation. While disolvated struc-
tures show a positive NLiOP dihedral angle, approaching
the propenyl moiety to one methoxy group (syn coordina-
tion), unsolvated and monosolvated complexes present
a negative NLiOP dihedral angle, enabling an interaction
between the propenyl and isopropyl groups (anti coordi-
nation).
a
Enthalpies in kcal/mol (gas-phase values in parentheses;
condensed-phase values in brackets).
Sch em e 8. Selected Solva tion Equ ilibr ia for
Coor d in a tion Com p lexes 18a ,ba
Because of the reduced freedom of motion, each solva-
tion process should also be unfavorable entropically. In
this way, saturation of the lithium center on azaenolate-
propenylphosphonate complexes by coordination to sol-
vent is not necessarily a thermodynamically favored
process. Thus, in addition to the disolvated complexes,
with the lowest heats of formation, monosolvated species
may also be important intermediates in the reaction
pathway. In this way, we decided to analyze all possible
rearrangements, considering both the mono- and the
disolvated lithium-coordinated complexes. The reorgani-
zation of the intermediate complexes must enable the
formation of a single bond connecting two chiral centers.
Such rearrangements can proceed with four different
configurations in the transition state. Thus, four different
pathways, consequence of the interaction of both prochiral
faces of the enolate and both prochiral faces of the
acceptor, were initially considered for the rearrangement
of mono- and disolvated complexes. As low energy
conformations with either s-cis or s-trans configuration
on the propenylphosphonate moiety were accessible for
the all the lithium-coordinated complexes (m 18a , m 18b,
d 18a , and d 18b), to compute all competitive transition
structures eight different starting geometries were in fact
studied for each complex. To define the potential energy
profile for these rearrangements, the distance between
the R-carbon of the enolate (C2) and the â-carbon of the
propenylphosphonate (C1′) was used as the reaction
coordinate. The reaction paths were calculated by sys-
tematically reducing the forming single bond length from
3.8 to 1.8 Å, while all the remaining geometrical param-
eters were optimized.
a
Enthalpies in kcal/mol (gas-phase values are in parentheses;
condensed-phase values are in brackets). Numbers for series a are
on the left side, while numbers in italics are for series b).
the solvation enthalpies are negative. The first solvent
molecule is the most effective: the heat of solvation is
13.49 kcal/mol, while the second and the third solvent
molecules reduce the energy of the systems by only 9.81
and 1.31 kcal/mol, respectively. Higher solvated forms
of the azaenolate were not examined, because of the small
stabilization afforded by addition of the last solvent
molecule.
In the gas phase, addition of azaenolate to propenyl-
phosphonates 17a ,b proceeds first by the exothermic
formation of the lithium-coordinated complexes 18a ,b
shown in Scheme 8. These complexes are formed with
no apparent reaction barriers. It is likely that in solution
Full optimization of the geometries corresponding to
the maximum potential energy along the selected paths
in the rearrangement of m 18a , the monosolvated complex
derived from the (E)-1-propenylphosphonate, enabled the
location of only four transition structures (m 21-24a , see
Figure 2), each one of them giving rise to a different
stereoisomer of the addition product. These geometries,
which maintain the coordination between lithium and

1990 J . Org. Chem., Vol. 65, No. 7, 2000
Ojea et al.
F igu r e 3. PM3-optimized geometries for the transition states
located in the rearrangement of d 18a . Distances in Å (gas-
phase values are in parentheses and condensed-phase values
are in brackets). Hydrogen atoms are omitted, except for the
new stereocenters.
F igu r e 2. PM3-optimized geometries for the transition states
located in the rearrangement of m 18a . Distances in Å (gas-
phase values are in parentheses and condensed-phase values
are in brackets). Hydrogen atoms are omitted, except for the
new stereocenters.
in Figure 3), while the optimization of the unlike ones
yielded geometries with a relaxed propenyl/pyrazine
interaction (models m 23a and m 24a in Figure 2, and
d 23a and d 24a in Figure 3). As for the (E)-propenyl-
derived transition states, the compact approaches result
in anti configuration (while the relaxed ones afford the
syn relationship), the orientation of the propenyl group
with respect to the azaenolate moiety is the responsible
for the energetic differentiation of the prosyn/ proanti
diastereomeric transition structures. In addition, in both
the mono- and disolvated series, the two protrans transi-
tion states were determined to be lower in energy than
the corresponding procis, conveniently correlating the
high face-selectivity showed by lithiated bis-lactim ethers
in Michael additions (see Table 2). Thus, PM3 calcula-
tions determine the compact pro(trans,anti) geometries
m 21a and d 21a as the most favored, in accordance with
the experimental trend. Moreover, the differences of
activation enthalpies between the compact pro(trans,anti)
geometries and any of the most favored procis or prosyn
transition structures are in agreement with the observed
diastereomeric ratios.
Following the same strategy for the analysis of the
rearrangement of the (Z)-propenyl derived intermediate
complexes m 18b and d 18b, similar results were ob-
tained. Full optimization of the selected starting geom-
etries also led to the location of four diastereomeric
transition structures in each of the solvation series:
m 21-24b and d 21-24b (only the disolvated geometries
are shown in Figure 4). All transition structures are
characterized by a similar length in the forming single
CC bond (2.07-2.14 Å) and an antiperiplanar, syn-
vicinal methoxy group, show almost the same C(2)C(1′)
bond distance (between 2.09 and 2.12 Å), an anticlinal
C(2)C(3)NLi angle (ca. 137°), and a synperiplanar LiOPC
angle (lower than 5°). A synclinal conformation at the
CCPO moiety is also found in all the transition struc-
tures, suggesting that the addition actually takes place
by azaenolate attack on the acceptor moiety with an s-cis
oriented phosphoryl group.
Similar study of the rearrangement of d 18a , the
disolvated complex derived from the (E)-1-propenylphos-
phonate, also led to the location of four diastereomeric
transition structures d 21-24a (see Figure 3). The di-
solvated transition states showed almost the same values
for the forming CC bond length and the CCNLi, LiOPC,
and CCPO dihedral angles as the monosolvated ones. The
procis disolvated transition structures, d 22a and d 24a ,
presented a weak interaction between the lithium cation
and the vicinal methoxy group (binding distances longer
than 2.38 Å), while the protrans ones, d 21a and d 23a ,
are characterized by the absence of such coordination.
Both in the mono- and disolvated series, the geometries
resulting from the like and unlike approaches of the
azaenolate moiety to the Câ of the propenyl group clearly
differ in sense of the synclinal arrangement around the
forming CC bond. The like approximations resulted in
compact dispositions30 of the donor/acceptor moieties
(models m 21a and m 22a in Figure 2 and d 21a and d 22a
(30) A compact approach was also proposed in other conjugate
additions: (a) Cave´, C.; Desmae¨le, D.; d’Angelo, J .; Riche, C.; Chiaroni,
A. J . Org. Chem. 1996, 61, 4361. (b) Sevin, A.; Tortajada, J .; Pfau, M.
J . Org. Chem. 1986, 51, 2671.

Access to 2-Amino-3-methyl-4-phosphonobutanoic Acids
J . Org. Chem., Vol. 65, No. 7, 2000 1991
Ta ble 2. Hea ts of F or m a tion , En er gy Ba r r ier s (k ca l/m ol), a n d Im a gin a r y F r equ en cies (cm -1) for th e Tr a n sition
Str u ctu r es Loca ted in th e Ad d ition of 16 to (E)-P r op en ylp h osp h on a te 17a , in Va cu o (E ) 1, P M3), or a P ola r iza ble
Dielectr ic Con tin u u m (E ) 12.13, P M3/COSMO)
ꢀ ) 1
ni(vi)
ꢀ ) 12.13
ni(vi)
compd
confign
∆H°
∆qH°
∆∆qH°
∆H°
∆qH°
∆∆qH°
m 21a
m 22a
m 23a
m 24a
d 21a
d 22a
d 23a
d 24a
trans,anti
cis,anti
trans,syn
cis,syn
trans,anti
cis,anti
trans,syn
cis,syn
-240.46
-237.12
-239.07
-238.44
-252.16
-247.73
-250.30
-247.88
1 (-405.1)
1 (-394.6)
1 (-395.1)
1 (-238.4)
1 (-403.6)
1 (-386.6)
1 (-397.4)
1 (-382.9)
22.21
0.00
3.34
1.39
2.02
0.00
4.42
1.85
4.28
-250.17
-247.66
-248.48
-248.36
-263.13
-259.47
-260.50
-260.01
1 (-466.2)
1 (-477.3)
1 (-459.9)
1 (-483.1)
1 (-462.1)
1 (-481.2)
1 (-459.2)
1 (-470.3)
28.31
0.00
2.51
1.69
1.81
0.00
3.66
2.63
3.12
18.68
25.44
Although some uncertainty remains resulting from the
PM3 tendency to overestimate the stability of the initially
formed complexes,31 the activation barriers to the re-
arrangement in both (E)- and (Z)-series appear to de-
crease under the influence of solvent molecules. Thus,
in the gas phase, the reaction paths involving disolvated
intermediate complexes and disolvated transition struc-
tures seems to be favored over those with participation
of monosolvated species (∆∆qH(mono-di) ) 3.53 and 1.08
kcal/mol in the (E)- and (Z)-propenyl series, respectively).
To further study the influence of the solvent in the
reaction path, the geometries of all intermediates and
transition states as calculated in vacuo were reoptimized
in a dielectric medium simulating THF using the COS-
MO technique.25 The effect of the dielectric medium on
the structures of azaenolates, chelate complexes, and
transition structures was rather small, with solvent-
induced bond length changes up to 0.03 Å. Nevertheless,
the solvation equilibria and the energetic profile for the
rearrangement in the dielectric medium clearly differ
from those encountered in the gas phase. Nonspecific
solvation has a significant stabilizing effect on the
energies of all the structures. In addition, enthalpies of
solvation were calculated lower in the dielectric con-
tinuum than in the gas phase. Thus, in THF, the
solvation equilibria for the azaenolates and coordination
complexes seem to be dominated by the disolvated and
monosolvated species, d 16 and m 18a ,b, respectively (see
Schemes 7 and 8). Nonspecific solvation of the transition
states (with less charge-localized geometries) was to be
less exothermic than that for the coordination complexes,
thus increasing the enthalpies of activation for the
rearrangement by ca. 6 kcal/mol (see Tables 2 and 3).
Differential nonspecific solvation effects on the competi-
tive transition states are also rather small, and thus the
differences in energy between the reoptimized transition
structures also correlates with the experimental stereo-
selection in the conjugate addition to either (Z)- and (E)-
1-propenylphosphonates.
F igu r e 4. PM3-optimized geometries for the transition states
located in the rearrangement of d 18b. Distances in Å (gas-
phase values are in parentheses and condensed-phase values
are in brackets). Hydrogen atoms are omitted, except for the
new stereocenters.
periplanar, and synclinal conformation for the CCNLi,
LiOPC, and CCPO moieties, respectively. The protrans
disolvated transition structures of this series also showed
no coordination between the lithium cation and the
vicinal methoxy group. As previously calculated for the
rearrangement of the complexes derived from (E)-1-
propenylphosphonates, the protrans transition states
were determined to be more stable than their procis
counterparts, and the like and unlike approximations
were also optimized to energetically differentiated com-
pact and relaxed geometries. Again, PM3 calculations
showed a kinetic preference for a compact disposition of
the reaction couple in the transition structures. Never-
theless, in this case, the compact geometries presented
an ul topicity, enabling the reversal of the π-face selectiv-
ity of the rearrangement. Thus, the energy gap between
the pro(trans,syn) and the competing diastereomeric
transition states conveniently reproduces the sense and
degree of the stereoselection in the additions to (Z)-
propenylphosphonates (see Table 3).
Con clu sion
In conclusion, the conjugate additions of metalated
Scho¨llkopf’s bis-lactim ethers to 1-propenylphosphonates
take place regio- and stereoselectively. The reaction
results in an almost complete translation of the Z/E
geometry into a syn/anti configuration at the 1,4-addition
products. In this way, the stereochemical outcome of the
conjugate addition is shown to be both reagent- and
substrate-controlled. While the influence of the chiral
(31) Opitz, A.; Koch, R.; Katritzky, A. R.; Fan, W.-Q.; Anders, E. J .
Org. Chem. 1995, 60, 3743.

1992 J . Org. Chem., Vol. 65, No. 7, 2000
Ojea et al.
Ta ble 3. Hea ts of F or m a tion , En er gy Ba r r ier s (k ca l/m ol), a n d Im a gin a r y F r equ en cies (cm -1) for th e Tr a n sition
Str u ctu r es Loca ted in th e Ad d ition of 16 to (Z)-P r op en ylp h osp h on a te 17b, in Va cu o (E ) 1, P M3), or a P ola r iza ble
Dielectr ic Con tin u u m (E ) 12.13, P M3/COSMO)
ꢀ ) 1
ni(vi)
ꢀ ) 12.13
ni(vi)
compd
confign
∆H°
∆qH°
∆∆qH°
∆H°
∆qH°
∆∆qH°
m 21b
m 22b
m 23b
m 24b
d 21b
d 22b
d 23b
d 24b
trans,syn
cis,syn
trans,anti
cis,anti
trans,syn
cis,syn
trans,anti
cis,anti
-236.32
-234.31
-232.73
-232.36
-246.09
-244.30
-244.75
-240.01
1 (-409.5)
1 (-403.5)
1 (-402.2)
1 (-401.6)
1 (-413.9)
1 (-396.9)
1 (-406.1)
1 (-408.2)
21.07
0.00
2.01
3.59
3.96
0.00
1.78
1.34
5.97
-247.80
-245.53
-242.73
-243.88
-256.66
-255.98
-255.38
-251.80
1 (-476.6)
1 (-481.3)
1 (-477.4)
1 (-489.2)
1 (-484.5)
1 (-465.7)
1 (-457.4)
1 (-472.6)
27.87
0.00
2.26
5.07
3.92
0.00
0.68
1.28
4.76
19.99
33.13
and s-cis or s-trans configuration at the CCPO moiety. Only
for the most important conformers located in this search the
isopropyl and COPOC rotamers were also studied.
glycine equivalent determines the absolute stereochem-
istry, the relative configuration at the addition products
exclusively depends on the geometry of the acceptor. In
addition, a semiempirically optimized model that ration-
alizes the stereochemical course of the conjugate addition
has been devised. Both PM3 and PM3/COSMO calcula-
tions support the rate-determining reorganization of
intermediate chelate complexes through competitive
eight-membered transition states. According to this
model, the stereochemical response of the conjugate
addition to the acceptor geometry originates from an
orientational preference in the cyclic transition states for
a compact disposition of the reaction partners. The level
of π-facial discrimination delivered by the metalated
azaenolate/1-propenylphosphonate couple enables a ste-
reocontrolled access to 2-amino-3-methyl-4-phosphono-
butanoic acids, which may result in useful tools for
determining the requirements for receptor binding and
physiological responses at mGluRs of group III.
Gen er a l Meth od s. All moisture-sensitive reactions were
performed under an argon atmosphere using oven-dried
glassware. Reagents and solvents were purchased and used
without further purification unless otherwise stated. HMPA
was dried over 4 Å molecular sieves, THF was distilled from
sodium/benzophenone, and CH2Cl2 was distilled from calcium
hydride. Reactions were monitored by thin-layer chromatog-
raphy carried out on 0.25 mm E. Merck silica gel plates (60F-
254) using iodine or ninhydrin as developing agents. E. Merck
silica gel 60 and RP-18 (both 230-400 mesh) were used for
liquid chromatography separations. Melting points are uncor-
rected. IR spectra were obtained as liquid film or as KBr
pellets. Unless otherwise indicated, 1H NMR spectra were
recorded at 360 MHz. 13C NMR and 31P NMR spectra were
recorded at 90.6 and 145.8 MHz, respectively, with broad-band
1H decoupling. Recognition of methyl, methylene, methine, and
quaternary carbon nuclei in 13C spectra rests on the J -
1
modulated spin-echo sequence. H and 13C assignments were
confirmed with the aid of 13C,1H 2D-correlation experiments,
as previously described.35 In the carbon spectra, all peaks for
which a coupling constant is reported are doublets due to
phosphorus coupling. Mass spectra (EI) were obtained with
an ionization voltage of 70 eV, and FABMS spectra were
recorded using thioglycerol as a matrix. Elemental analyses
were performed at Servicios Xerais de Apoio a´ Investigacio´n
of Universidade da Corun˜a.
Exp er im en ta l Section
Com p u ta tion a l Meth od s. All calculations have been
performed using the MOPAC 9732 module of Chem3D Pro
program.33 All structures were fully optimized at the restricted
Hartree-Fock level of theory with the PM3 method,24 using
the eigenvector following routine (TS keyword for transition-
state refinement) under the more rigorous criteria of the
keyword PRECISE (gradient norm < 0.03). Solvent dielectric
effects of THF were simulated with the COSMO technique,25
using a relative permittivity of 12.13 for THF at -78 °C34
(keyword EPS ) 12.13, with RSOLV ) 2 to account for the
larger size of THF with respect to water), and using 60 surface
segments per atom to construct a solvent-accessible surface
area based on van der Waals radii (keyword NSPA ) 60).
Maxima were characterized as first-order transition structures
by normal-mode analyses, yielding a single imaginary fre-
quency, and their nature was verified by internal reaction
coordinate calculations to reactants and products. Conforma-
tional space accessible for each of the reported transition
structures was studied in the following way: two different
rotamers for the isopropyl group (those with the tertiary
carbon pointing to the lithium atom, or pointing to the imidate
moiety), three rotamers for each solvent molecule (located by
performing grid (3 × 3) calculations on disolvated species), and
all the gauche-gauche conformations for the COPOC moiety
were analyzed. In the study of the conformational space
accessible to the coordination complexes, a systematic search
on CCNLi, CNLiO, and NLiOP dihedral angles with a step
size of 120° was performed first, starting from geometries with
syn or anti coordination (with respect to the isopropyl group)
Multigram quantities of both enantiomers of 2,5-diethoxy-
3-isopropyl-3,6-dihydropyrazine were obtained from Novartis
kilo laboratory. Diethyl (Z)-1-propenylphosphonate (4b) was
11
prepared as reported.
Dieth yl 2-Br om op r op ylp h osp h on a te (8). A mixture of
triethyl phosphite (15 g, 90 mmol) and 1,2-dibromopropane
(57 mL, 547 mmol) was heated to reflux for 14 h under an
argon atmosphere. After removal of the excess of dibromopro-
pane in vacuo, Kugelrohr distillation of the residue gave 16.3
g (70%) of bromophosphonate 8 as a colorless oil: bp 90 °C
(0.13 mbar); Rf 0.52 (silica gel, AcOEt/hexane 2:1); IR (film) ν
1250 (PdO), 1055, 1027, 963 (POC), 509 (CBr) cm-1; 1H NMR
(CDCl3) δ 1.34 (t, J ) 7.1 Hz, 6H), 1.85 (d, J ) 6.6 Hz, 3H),
2.38 (ddd, J ) 17.8, 15.3, 9.3 Hz, 1H), 2.56 (ddd, J ) 19.7,
15.3, 5.0 Hz, 1H), 4.07-4.17 (m, 4H), 4.35-4.47 (m, 1H); 13C
NMR (CDCl3) δ 16.4 (J ) 6.2 Hz, CH3), 27.4 (J ) 5.1 Hz, CH3),
38.2 (J ) 134.7 Hz, CH2), 41.7 (CH), 61.8 (J ) 6.5 Hz, CH2),
62.0 (J ) 6.5 Hz, CH2); 31P NMR (CDCl3) δ 25.55; EIMS m/z
261/259 (M+, 100/100), 179 (M+ - Br, 98), (M+ - C4H9Br, 95).
Dieth yl (E)-1-P r op en ylp h osp h on a te (4a ). DBU (12.9
mL, 86.2 mmol) was added dropwise over a cooled (0 °C)
solution of bromophosphonate 8 (15 g, 57.7 mmol) in CH2Cl2
(180 mL). The mixture was stirred for 1 h, the solvent was
evaporated, and the crude product was purified by flash
chromatography (silica gel, AcOEt/hexane 2:1-3:1) to give 4a
(8.7 g, 85%) as a colorless oil: Rf 0.33 (silica gel, AcOEt/hexane
1
2:1); H NMR (200 MHz, CDCl3) δ 1.27 (t, J ) 7.2 Hz, 6H),
(32) Revised version of MOPAC93, Fujitsu Ltd, Tokyo, J apan 1993.
(33) CS Chem3D Pro, version 4.0; Molecular Modeling and Analysis
Program; CambridgeSoft Corporation: Cambridge, MA 02139, 1997.
(34) Carvajal, C.; To¨lle, K. J .; Smid, J .; Szwarc, M. J . Am. Chem.
Soc. 1965, 87, 5548.
(35) Pombo-Villar, E.; Boelsterli, J .; Cid, M. M.; France, J .; Fuchs,
B.; Walkinshaw, M.; Weber, H.-P. Helv. Chim. Acta 1993, 76, 1203
and pertinent references therein.

Access to 2-Amino-3-methyl-4-phosphonobutanoic Acids
J . Org. Chem., Vol. 65, No. 7, 2000 1993
1.87 (ddd, J ) 6.8, 2.3 Hz, 3H), 4.02-4.17 (m-dq, 4H), 5.62
(ddq, J ) 21.0, 16.6, 2.3 Hz, 1H), 6.74 (ddq, J ) 21.5, 16.6, 6.8
Hz, 1H).
H-5), 4.04 (t, J ) 3.5 Hz, 1H, H-2), 4.08-4.20 (m, 8H, OCH2);
13C NMR (CDCl3) δ 14.3 (OCH2CH3), 14.4 (OCH2CH3), 15.3 (J
) 9.7 Hz, CHCH3), 16.4 (J ) 6.2 Hz, POCH2CH3), 16.7
(CH(CH3)2), 19.0 (CH(CH3)2), 29.2 (J ) 139.3 Hz, C-2′), 31.1
(J ) 2.5 Hz, C-1′), 32.1 (CH(CH3)2), 59.0 (J ) 11.3 Hz, C-2),
60.4 (OCH2CH3), 60.5 (OCH2CH3), 60.8 (C-5), 61.4 (J ) 6.4
Hz, POCH2CH3), 162.1 (CN), 163.4 (CN); 31P NMR (CDCl3) δ
33.00; FABMS m/z 391 (MH+, 100). Anal. Calcd for
Gen er a l P r oced u r e for Mich a el Ad d ition s of Meta -
la ted Sch o1llk op ’s Bis-la ctim Eth er s to 1-P r op en ylp h os-
p h on a tes. Meth od A. A solution of n-BuLi (1.0-3.0 equiv,
2.5 M in hexane) was added to a stirred solution of the bis-
lactim ether in THF (1.0-3.0 equiv, 10 mL/mmol) at -78 °C,
and the mixture was stirred for 1 h. Then, a solution of the
propenyl phosphonate 4a ,b or a mixture of bromophosphonate
8 and propenylphosphonate 4a (1.0 equiv, see Table 1, entries
1, 2, 9, 10, and 12-17) in THF (2 mL/mmol) was added
dropwise. After being stirred at -78 °C for 5 min, the reaction
was quenched with AcOH. 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 AcOEt. The combined organic layers were dried
(Na2SO4) and evaporated, and the residue was purified by
gradient flash chromatography (silica gel, AcOEt/hexane 2:1-
4:1) to yield pure adducts as colorless oils. Meth od B. A
solution of n-BuLi (1.0 or 2.0 equiv, 2.5 M in hexane) was
added to a stirred solution of the bis-lactim ether (1.0 or 2.0
equiv) in THF (10 mL/mmol) at -78 °C, and the mixture was
stirred for 1 h. Then, a solution of the additive (12-crown-4,
HMPA, SnCl2, CuBr2‚SMe2, TiCl(OiPr)3 or MgBr2‚OEt2, see
Table 1, entries 3-8 and 11) in THF was added. The mixture
was stirred for 1 h, and a solution of propenylphosphonate 4a
(1.0 equiv) in THF (2 mL/mmol) was added dropwise. After
being stirred at -78 °C for 5 min (or warming up to 0 °C for
10 h, see Table 1, entries 5 and 6) the reaction was quenched
with AcOH and worked up as described in method A.
(2S,5R,1′R)-3,6-Dieth oxy-2-[2-(d ieth oxyp h osp h or yl)-1-
(m eth yl)eth yl]-2,5-dih ydr o-5-isopr opylpyr azin e ((+)-10a).
Propenylphosphonate 4a (10.35 g, 58.1 mmol) and (3R)-2,5-
diethoxy-3-isopropyl-3,6-dihydropyrazine (22.4 g, 105.5 mmol)
were allowed to react according to the general procedure
(method A), yielding after column chromatography 13.4 g of
(+)-10a (59%) as a colorless oil: Rf 0.46 (silica gel, AcOEt);
C
18H35N2O5P: C, 55.37; H, 9.04; N. 7.17. Found: C, 55.59; H,
9.23; N, 6.99.
(2R,5S,1′R)-3,6-Dieth oxy-2-[2-(d ieth oxyp h osp h or yl)-1-
(m eth yl)eth yl]-2,5-d ih yd r o-5-isop r op ylp yr a zin e ((+)-10b)
was prepared following the same procedure, from 4b (3.0 g,
16.8 mmol) and (3S)-2,5-diethoxy-3-isopropyl-3,6-dihydro-
pyrazine (10.7 g, 50.4 mmol), to yield 5.37 g (82%) of a colorless
oil: [R]20 ) +14.5 (c 1.0, CH2Cl2).
D
Eth yl (2S,3R)-2-Am in o-4-d ieth oxyp h osp h or yl-3-m eth -
ylbu ta n oa te ((+)-12a ). A solution of adduct (+)-10a (9.37 g,
24.0 mmol) in 200 mL of THF and 240 mL of 0.25 N HCl was
stirred at room temperature for 24 h. Then, the solvent was
evaporated to half its initial volume (below 40 °C), and the
aqueous solution was made basic (pH ∼10) by the addition of
NaHCO3 followed by concentrated ammonia. The aqueous
layer was extracted with CH2Cl2, and the combined organic
layers were dried (Na2SO4) and evaporated. The crude mixture
of methyl valinate and amino ester (+)-12a was purified by
flash chromatography (silica gel, AcOEt to AcOEt/MeOH 8:1)
to yield 6.4 g (95%) of (+)-12a as a colorless oil: Rf 0.36 (silica
gel, AcOEt/MeOH 10:1); [R]20D ) +10.6 (c 1.0, CH2Cl2); IR (film)
ν 3375, 3280 (NH2), 1732 (CdO), 1243 (CO, PdO), 1057, 1028
(POC) cm-1; 1H NMR (CDCl3) δ 1.11 (d, J ) 6.8 Hz, 3H), 1.26
(t, J ) 7.1 Hz, 3H), 1.30 (t, J ) 7.1 Hz, 6H), 1.58 (brs, 2H),
1.61 (ddd, J ) 17.9, 15.3, 10.1 Hz, 1H), 2.01 (ddd, J ) 18.5,
15.3, 3.2 Hz, 1H), 2.16-2.32 (m, 1H), 3.32 (dd, J ) 5.2, 1.0
Hz, 1H), 4.04-4.10 (m, 4H), 4.17 (dq, J ) 7.1, 1.7 Hz, 2H); 13
C
NMR (CDCl3) δ 14.3 (CH3), 16.4 (J ) 6.1 Hz, CH3), 17.4 (J )
3.3 Hz, CH3), 28.1 (J ) 141.0 Hz, CH2), 32.9 (J ) 3.0 Hz, CH),
59.6 (J ) 16.1 Hz, CH), 60.9 (CH2), 61.4 (J ) 6.4 Hz, CH2),
61.5 (J ) 6.4 Hz, CH2), 174.7 (CO); 31P NMR (CDCl3) δ 31.96;
FABMS m/z 282 (MH+, 100).
[R]20 ) +24.3 (c 1.0, CH2Cl2); IR (film) ν 1690 (CdN), 1237
D
(PdO), 1059, 1030 (POC) cm-1; H NMR (CDCl3) δ 0.69 (d, J
1
) 6.8 Hz, 3H, CH(CH3)2), 1.02 (d, J ) 6.8 Hz, 3H, CH(CH3)2),
1.21 (d, J ) 6.8 Hz, 3H, CHCH3), 1.25-1.36 (m, 12H,
OCH2CH3), 1.45-1.52 (m, 2H, H-2′), 2.25 (dsp, J ) 6.8, 3.0
Hz, 1H, CH(CH3)2), 2.51-2.65 (m, 1H, CH(CH3)), 3.86-3.91
(m, 2H, H-2, H-5), 4.00-4.22 (m, 8H, OCH2); 13C NMR (CDCl3)
δ 14.3 (OCH2CH3), 16.4 (J ) 6.2 Hz, POCH2CH3), 16.6
(CH(CH3)2), 17.1 (CHCH3), 19.0 (CH(CH3)2), 27.8 (J ) 141.0
Hz, C-2′), 32.0 (CH(CH3)2, C-1′), 60.6 (J ) 11.9 Hz, C-2), 60.6
(OCH2CH3), 60.7 (C-5), 60.9 (OCH2CH3), 61.2 (J ) 6.4 Hz,
POCH2CH3), 61.4 (J ) 6.4 Hz, POCH2CH3), 161.9 (CN), 163.5
(CN); 31P NMR (CDCl3) δ 32.91; FABMS m/z 391 (MH+, 100).
Anal. Calcd for C18H35N2O5P: C, 55.37; H, 9.04; N. 7.17.
Found: C, 55.65; H, 8.89; N, 7.41.
Eth yl (2R,3S)-2-a m in o-4-d ieth oxyp h osp h or yl-3-m eth -
ylbu ta n oa te ((-)-12a ) was prepared following the same
procedure, starting from 5.5 g of adduct (-)-10a to yield 3.56
g (90%) of a colorless oil: [R]20 ) -10.7 (c 1.0, CH2Cl2). Anal.
D
Calcd for C11H24NO5P: C, 46.97; H, 8.60; N. 4.98. Found: C,
46.69; H, 8.45; N, 5.08.
Eth yl (2S,3S)-2-Am in o-4-d ieth oxyp h osp h or yl-3-m eth -
ylbu ta n oa te ((+)-12b). Amino ester (+)-12b was prepared
as described above for the 2,3-anti isomers, starting from 2.6
g of adduct (-)-10b to yield 1.74 g (93%) of a colorless oil: Rf
0.38 (silica gel, AcOEt/MeOH 10:1); [R]20 ) +20.5 (c 1.0,
D
CH2Cl2); IR (film) ν 3375, 3280 (NH2), 1733 (CdO), 1240 (CO,
PdO), 1056, 1028 (POC) cm-1; 1H NMR (CDCl3) δ 0.94 (dd, J
) 6.9, 1.0 Hz, 3H), 1.27 (t, J ) 7.1 Hz, 3H), 1.34 (t, J ) 7.1
Hz, 3H), 1.35 (t, J ) 7.1 Hz, 3H), 1.55 (brs, 2H), 1.70 (ddd, J
) 22.5, 15.4, 7.1 Hz, 1H), 2.02 (ddd, J ) 22.3, 15.4, 6.9 Hz,
1H), 2.39-2.53 (m, 1H), 3.64 (d, J ) 3.5 Hz, 1H), 4.03-4.15
(m, 4H), 4.18 (dq, J ) 7.1, 2.7 Hz, 2H); 13C NMR (CDCl3) δ
14.2 (CH3), 15.3 (J ) 11.1 Hz, CH3), 16.4 (J ) 6.1 Hz, CH3),
29.6 (J ) 139.8 Hz, CH2), 31.7 (CH), 57.7 (J ) 10.4 Hz, CH),
60.9 (CH2), 61.4 (J ) 6.4 Hz, CH2), 174.9 (CO); 31P NMR
(CDCl3) δ 31.44; FABMS (thioglycerol) m/z 282 (MH+, 100).
Anal. Calcd for C11H24NO5P: C, 46.97; H, 8.60; N. 4.98.
Found: C, 47.17; H, 8.88; N, 5.12.
(2R,5S,1′S)-3,6-Dieth oxy-2-[2-(d ieth oxyp h osp h or yl)-1-
(m eth yl)eth yl]-2,5-d ih yd r o-5-isop r op ylp yr a zin e ((-)-10a )
was prepared following the same procedure, from 4a (7.1 g,
40.0 mmol) and (3S)-2,5-diethoxy-3-isopropyl-3,6-dihydro-
pyrazine (25.5 g, 120.1 mmol), to yield 12.8 g (82%) of a
colorless oil: [R]20 ) -24.3 (c 1.0, CH2Cl2).
D
(2S,5R,1′S)-3,6-Dieth oxy-2-[2-(d ieth oxyp h osp h or yl)-1-
(m eth yl)eth yl]-2,5-dih ydr o-5-isopr opylpyr azin e ((-)-10b).
Propenylphosphonate 4b (2.4 g, 13.47 mmol) and (3R)-2,5-
diethoxy-3-isopropyl-3,6-dihydropyrazine (8.58 g, 40.41 mmol)
were allowed to react according to the general procedure
(method A), yielding after column chromatography 4.34 g of
(-)-10b (83%) as a colorless oil: Rf 0.46 (silica gel, AcOEt);
Eth yl (2R,3R)-2-a m in o-4-d ieth oxyp h osp h or yl-3-m eth -
ylbu ta n oa te ((-)-12b) was prepared following the same
procedure, starting from 3.7 g of adduct (+)-10b to yield 2.45
[R]20 ) -14.6 (c 1.1, CH2Cl2); IR (film) ν 1692 (CdN), 1236
D
(PdO), 1058, 1033 (POC) cm-1; H NMR (CDCl3) δ 0.70 (d, J
g (92%) of a colorless oil: [R]20 ) -20.4 (c 1.0, CH2Cl2).
1
D
) 6.8 Hz, 3H, CH(CH3)2), 0.77 (d, J ) 6.8 Hz, 3H, CHCH3),
1.02 (d, J ) 6.8 Hz, 3H, CH(CH3)2), 1.26 (t, J ) 7.1 Hz, 3H,
OCH2CH3), 1.27 (t, J ) 7.1 Hz, 3H, OCH2CH3), 1.32 (t, J )
7.1 Hz, 3H, OCH2CH3), 1.33 (t, J ) 7.1 Hz, 3H, OCH2CH3),
1.80 (ddd, J ) 17.8, 15.5, 7.6 Hz, 1H, H-2′), 2.16 (ddd, J )
18.2, 15.5, 6.2 Hz, 1H, H-2′), 2.24 (dsp, J ) 6.8, 3.5 Hz, 1H,
CH(CH3)2), 2.63-2.71 (m, 1H, H-1′), 3.89 (t, J ) 3.5 Hz, 1H,
(2S,3R)-2-Am in o-3-m eth yl-4-p h osp h on obu ta n oic Acid
((+)-6a ). A solution of amino ester (+)-12a (360 mg, 1.28
mmol) was heated to reflux for 5 h in 7 mL of HCl 12 N. The
solvent was evaporated under reduced pressure, and the amino
acid hydrochloride was dried in vacuo overnight (10-3 mbar,
50 °C). The residue was dissolved in 4 mL of absolute EtOH,
and propylene oxide (4 mL) was added dropwise. The white

1994 J . Org. Chem., Vol. 65, No. 7, 2000
Ojea et al.
precipitate immediately formed was filtered, dried, and puri-
fied by reversed-phase flash chromatography, eluting with
water to give (+)-6a (236 mg, 94%) as a colorless solid: mp
155.7 (CO), 171.3 (CO); 31P NMR (CDCl3) δ 31.17; FABMS m/z
382 (MH+, 17), 326 ([M - C4H8]H+, 10), 282 ([M - C5H9O2]-
H+, 100).
(EtOH) > 80 °C (dec); Rf 1.0 (RP-18, H2O); [R]20 ) +33.8 (c
D
(4S,5R)-5-[N-(ter t-Bu toxyca r bon yl)a m in o]-2-eth oxy-4-
m eth yl-2-oxo-1,2-oxa p h osp h or in a n e (15a ). Over a cooled
suspension (0 °C) of LiBH4 (214 mg, 9.83 mmol) in 70 mL of
dry THF was added dropwise a solution of 14a (2.5 g, 6.56
mmoL) in 20 mL of THF, and the resulting mixture was stirred
for 16 h at room temperature. Then, the reaction mixture was
cooled to 0 °C, and HCl 2 N was added to reach pH ) 7. THF
was evaporated and the aqueous phase extracted with AcOEt,
dried (Na2SO4), and evaporated. The crude material was
purified by flash chromatography (silica gel, AcOEt/hexane 3:1
to AcOEt) to give 1.41 g (73%) of 15a as a colorless solid: mp
(AcOEt) 121-124 °C; Rf 0.34 (silica gel, AcOEt/hexane 3:1);
1.0, H2O); IR (KBr) ν 3430 (OH), 2976 (NH2), 1727 (CdO), 1257
(CO), 1122 (PdO), 1040, 931 (POH) cm-1 1H NMR (D2O) δ
;
1.16 (d, J ) 6.8 Hz, 3H, CH3), 1.77 (ddd, J ) 18.1, 15.3, 9.1
Hz, 1H, H-4), 1.82 (ddd, J ) 19.2, 15.3, 6.1 Hz, 1H, H-4), 2.45-
2.58 (m, 1H, H-3), 4.08 (d, 3.6 Hz, 1H, H-2); 13C NMR (D2O) δ
18.7 (J ) 6.4 Hz, CH3), 33.1 (C-3), 33.8 (J ) 128.8 Hz, C-4),
61.0 (J ) 12.8 Hz, C-2), 174.3 (CO); 31P NMR (D2O) δ 23.80;
FABMS m/z 198 (MH+, 100), 152 ([M - CO2]H+, 18).
(2R,3S)-2-Am in o-3-m eth yl-4-p h osp h on obu ta n oic a cid
((-)-6a ) was prepared following the same procedure, starting
from 620 mg of amino ester (-)-12a to yield 378 mg (89%) of
a colorless solid: [R]22 ) -34.2 (c 1.0, H2O).
[R]20 ) +74.8 (c 1.0, CH2Cl2); IR (KBr) ν 3285 (NH), 1701
D
D
(CdO), 1279 (PdO) cm-1 1H NMR (CDCl3) δ 1.05 (dd, J )
;
(2S,3S)-2-Am in o-3-m eth yl-4-p h osp h on obu ta n oic Acid
((+)-6b). Amino acid (+)-6b was prepared following the same
procedure as described above for the 2,3-anti-amino acids 6a ,
starting from 500 mg of amino ester (+)-12b to yield 321 mg
(91%) of a colorless solid: mp (EtOH) > 80 °C (dec); Rf 1.0
6.7, 3.4 Hz, 3H, CHCH3), 1.36 (t, J ) 7.1 Hz, 3H, OCH2CH3),
1.44 (s, 9H, C(CH3)3), 1.65 (ddd, J ) 15.4, 13.1 Hz, 1H, H-3),
1.85 (ddd, J ) 19.1, 15.4, 4.1 Hz, 1H, H-3), 2.22-2.37 (m, 1H,
H-4), 3.80 (brd, J ) 9.4 Hz, 1H, H-5), 4.08-4.23 (m, 4H, OCH2),
5.20 (brd, J ) 9.4 Hz, 1H, NH); 13C NMR (CDCl3) δ 16.4 (J )
5.8 Hz, OCH2CH3), 19.7 (J ) 18.8 Hz, CHCH3), 26.4 (J ) 125.9
Hz, C-3), 28.3 (C(CH3)3), 33.4 (J ) 6.5 Hz, C-4), 49.5 (J ) 4.1
Hz, C-5), 61.1 (J ) 6.5 Hz, POCH2), 72.7 (J ) 6.8 Hz, C-6),
77.0 (C(CH3)3) 155.3 (CO); 31P NMR (CDCl3) δ 23.35; FABMS
m/z 294 (MH+, 15), 238 ([M - C4H8]H+, 60), 194 ([M - C5H9O2]-
H+, 100).
(RP-18, H2O); [R]20 ) +14.2 (c 1.0, H2O); IR (KBr) ν 3441
D
(OH), 3275 (NH2), 1733 (CdO), 1257 (C-O), 1030, 920 (POH)
cm-1 1H NMR (D2O) δ 1.15 (d, J ) 7.1 Hz, 3H, CH3), 1.74
;
(ddd, J ) 18.5, 15.3, 7.8 Hz, 1H, H-4), 1.87 (ddd, J ) 18.7,
15.3, 6.1 Hz, 1H, H-4), 2.55-2.70 (m, 1H, H-3), 4.08 (d, J )
3.4 Hz, 1H, H-2); 13C NMR (D2O) δ 18.6 (J ) 6.4 Hz, CH3),
32.9 (C-3), 33.7 (J ) 132.5 Hz, C-4), 61.2 (J ) 6.0 Hz, C-2),
174.7 (CO); 31P NMR (D2O) δ 23.80; FABMS m/z 198 (MH+,
100), 152 ([M - CO2]H+, 25).
(4R,5R)-5-[N-(ter t-Bu toxyca r bon yl)a m in o]-2-eth oxy-4-
m eth yl-2-oxo-1,2-oxa p h osp h or in a n e (15b) was prepared
following the same procedure as described above for 15a ,
starting from 1.1 g of N-Boc-amino ester 14b, to yield 621 mg
(73%) of a colorless oil (2 diastereoisomers, 2.7:1): Rf 0.35
(silica gel, AcOEt/hexane 3:1); IR (film) ν 3260 (NH), 1713
(CdO), 1271 (PdO) cm-1; 1H NMR (CDCl3) δ (signals for major
diastereoisomer): 1.12 (dd, J ) 6.5, 3.5 Hz, 3H), 1.35 (t, 7.1
Hz, 3H), 1.44 (s, 9H), 1.56-1.69 (m, 1H), 1.98-2.08 (m, 2H),
3.45-3.59 (m, 1H), 3.76 (dt, J ) 10.7, 3.8 Hz, 1H), 4.10-4.31
(m, 3H), 4.40 (brd, 1H); 31P NMR (CDCl3) δ 23.95 (major), 25.78
(minor); FABMS m/z 294 (MH+, 14), 238 ([M - C4H8]H+, 60),
194 ([M - C5H9O2]H+, 100).
(2R,3R)-2-Am in o-3-m eth yl-4-p h osp h on obu ta n oic a cid
((-)-6b) was prepared following the same procedure, starting
from 600 mg of amino ester (-)-12b to yield 389 mg (92%) of
a colorless solid: [R]20 ) -13.9 (c 1.0, H2O).
D
Eth yl (2R,3S)-2-[N-(ter t-Bu toxyca r bon yl)a m in o]-4-d i-
eth oxyp h osp h or yl-3-m eth ylbu ta n oa te (14a ). A solution of
the amino ester (-)-12a (2.0 g, 7.1 mmol), Na2CO3 (566 mg,
5.34 mmol), and NaHCO3 (532 mg, 6.34 mmol) in 50 mL of
dioxane and 50 mL of H2O at 0 °C was treated with Boc2O
(1.8 g, 8.31 mmol). The mixture was stirred at room temper-
ature for 1 h, after which time it was concentrated to half its
initial volume and extracted with CH2Cl2. The combined
organic layers were dried (Na2SO4) and concentrated in vacuo.
The crude material was purified by flash chromatography
(silica gel, AcOEt/hexane 3:1 to AcOEt) to give 2.57 g (95%) of
14a as a colorless oil: Rf 0.38 (silica gel, AcOEt/hexane 3:1);
(4S,5R)-5-Am in o-2-h ydr oxy-4-m eth yl-2-oxo-1,2-oxaph os-
p h or in a n e (13a ). BrTMS (0.32 mL, 2.45 mmol) was added
dropwise over a cooled (0 °C) solution of 15a (300 mg, 1.02
mmol) in 6 mL of dry CH2Cl2, and the mixture was stirred for
12 h. The reaction was quenched with MeOH, and the solvent
was removed in vacuo. The crude material was purified by
reversed-phase flash chromatography eluting with water to
give 204 mg (82%) of HBr.13a as a colorless solid: Rf 0.90 (RP-
[R]20 ) -12.9 (c 1.0, CH2Cl2); IR (film) ν 3276 (NH), 2981,
D
2935 (CH), 1745, 1714 (CdO), 1250 (CO), 1167 (PdO) cm-1
;
1H NMR (CDCl3) δ 1.13 (d, J ) 6.9 Hz, 3H), 1.23-1.35 (m,
9H), 1.44 (s, 9H), 1.61 (ddd, J ) 18.2, 15.3, 10.1 Hz, 1H), 1.86
(ddd, J ) 20.6, 15.3, 2.9 Hz, 1H), 2.32-2.46 (m, 1H), 4.06-
4.24 (m, 7H), 5.40 (brd, J ) 8.0 Hz, 1H); 13C NMR (CDCl3) δ
14.2 (CH3), 16.4 (J ) 5.9 Hz, CH3), 17.4 (CH3), 28.3 (CH3), 28.6
(J ) 141.4 Hz, CH2), 31.9 (CH), 58.6 (J ) 16.0 Hz, CH), 61.4
(CH2), 61.5 (J ) 6.4 Hz, POCH2), 61.7 (J ) 6.4 Hz, POCH2),
79.9 (C), 155.3 (CO), 171.0 (CO); 31P NMR (CDCl3) δ 30.92;
FABMS m/z 382 (MH+, 36), 326 ([M - C4H8]H+, 29), 282 ([M
- C5H9O2]H+, 100).
18, H2O); [R]20 ) +35.6 (c 1.2, H2O); IR (film) ν 2906 (NH3+),
D
1262 (PdO), 969 (POH) cm-1; 1H NMR (400 MHz, D2O) δ 1.16
(dd, J ) 7.4, 2.9 Hz, 3H, CH3), 1.61 (dt, J ) 15.3, 13.6 Hz, 1H,
H-3), 1.87 (ddd, J ) 18.0, 15.3, 4.4 Hz, 1H, H-3), 2.48-2.60
(m, 1H, H-4), 3.48-3.52 (m, 1H, H-5), 4.25 (ddd, J ) 20.6, 13.6,
2.2 Hz, 1H, H-6), 4.23 (ddd, J ) 13.6, 5.1, 2.2 Hz, 1H, H-6);
13C NMR (DMSO-d6) δ 18.9 (J ) 16.0 Hz, CH3), 26.7 (J ) 123.0
Hz, C-3), 30.7 (J ) 6.1 Hz, C-4), 50.1 (J ) 4.3 Hz, C-5), 67.9 (J
) 5.8 Hz, C-6); 31P NMR (CDCl3) δ 20.73; FABMS m/z 166
(MH+, 100).
Eth yl (2R,3R)-2-[N-(ter t-Bu toxyca r bon yl)a m in o]-4-d i-
eth oxyp h osp h or yl-3-m eth ylbu ta n oa te (14b). Prepared fol-
lowing the same procedure as described above for 14a , starting
from 1.0 g of amino ester (-)-12b. Purification by flash
chromatography (silica gel, AcOEt/hexane 3:1 to AcOEt)
afforded 1.29 g (96%) of 14b as a colorless oil: Rf 0.38 (silica
gel, AcOEt/hexane 3:1); [R]20D ) -20.2 (c 0.9, CH2Cl2); IR (film)
ν 3265 (NH), 2980, 2935 (CH), 1745, 1714 (CdO), 1250 (CdO),
1164 (PdO) cm-1; 1H NMR (CDCl3) δ 1.02 (d, J ) 6.9 Hz, 3H),
1.27-1.35 (m, 9H), 1.44 (s, 9H), 1.58 (ddd, J ) 17.3, 15.5, 9.6
Hz, 1H), 2.00 (ddd, J ) 19.5, 15.5, 3.8 Hz, 1H), 2.50-2.60 (m,
1H), 4.05-4.24 (m, 6H), 4.37 (brd, 1H), 5.20 (brd, J ) 8.1 Hz,
1H); 13C NMR (CDCl3) δ 14.2 (CH3), 15.8 (J ) 4.8 Hz, CH3),
16.4 (J ) 6.0 Hz, CH3), 28.3 (CH3), 29.3 (J ) 141.0 Hz, CH2),
31.4 (J ) 2.3 Hz, CH), 58.2 (J ) 15.9 Hz, CH), 61.4 (OCH2),
61.5 (J ) 6.8 Hz, POCH2), 61.6 (J ) 6.8 Hz, POCH2), 79.9 (C),
(4R,5R)-5-Am in o-2-h ydr oxy-4-m eth yl-2-oxo-1,2-oxaph os-
p h or in a n e (13b). Prepared following the same procedure as
described above for 13a , starting from 300 mg of N-Boc-amino
ester 15b to yield 211 mg (84%) of a colorless solid: mp > 200
°C (dec); Rf 0.90 (RP-18, H2O); [R]20 ) +7.6 (c 0.95, H2O); IR
D
(KBr) ν 3035 (NH3+), 1256, 1236 (PdO), 991 (POH) cm-1; H
1
NMR (400 MHz, D2O) δ 1.20 (dd, J ) 7.4, 2.2 Hz, 3H, CH3),
1.61 (dt, J ) 10.8, 15.1 Hz, 1H, H-3ax), 1.97 (ddd, J ) 17.0,
15.1, 4.0 Hz, 1H, H-3ec), 2.22-2.38 (m, 1H, H-4), 3.24 (dt, J )
3.2, 9.1 Hz, 1H, H-5), 4.10 (dt, J ) 15.4, 9.1 Hz, 1H, H-6ax),
4.35 (ddd, J ) 15.4, 11.8, 3.2 Hz, 1H, H-6ec); 13C NMR (DMSO-
d6) δ 19.1 (J ) 14.2 Hz, CH3), 28.2 (J ) 124.9 Hz, C-3), 31.7 (J
) 6.2 Hz, C-4), 51.3 (J ) 4.8 Hz, C-5), 65.7 (J ) 5.6 Hz, C-6);
31P NMR (CDCl3) δ 21.44; FABMS m/z 166 (MH+, 100).

Access to 2-Amino-3-methyl-4-phosphonobutanoic Acids
J . Org. Chem., Vol. 65, No. 7, 2000 1995
Z-matrixes and heat of formation of the PM3-optimized
structures. This material is available free of charge via the
Internet at http://pubs.acs.org.
Ack n ow led gm en t. M.R. and V.O. thank the Euro-
pean Union (COMMET program) and Xunta de Galicia
(XUGA 10306A98) for the grants awarded.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra for
compounds 10a ,b, 12a ,b, 6a ,b, 14b, 15a , and 13b, as well as
J O991402W