Productive asymmetric synthesis of all four diastereomers of 3-(trans-2-nitrocyclopropyl)alanine from glycine with (S)- or (R)-2-[(N-benzylprolyl)amino]benzophenone as a reusable chiral auxiliary

Article abstract of DOI:10.1002/ejoc.200390131

All four diastereomers of 3-(trans-2-nitrocyclopropyl)alanine (3) were prepared by asymmetrically induced α-C alkylation of the glycine moiety in the [(S)- or (R)-Schiff base] Ni^II complex 7, employing racemic trans-1-(iodomethyl)-2-nitrocyclopropane (8) as the alkylating agent. A notable difference in solubility between the two diastereomeric products 9a/9b [when (S)-7 was used as starting material] or 9d/9e [when (R)-7 was employed] allowed for their separation from the same reaction mixture. All the diastereomers of 3-(trans-2-nitrocyclopropyl)alanine (3) were produced upon brief exposure of the alkylation products 9 to dilute hydrochloric acid, with subsequent purification by ion-exchange chromatography and crystallization. The absolute configurations of the nickel complexes 9a-e were estabhshed by X-ray crystallographic analyses. In addition, the X-ray crystal structure of (2S, 1′S,2′R)-3 was determined to confirm the convergence of the configurations of the parent nickel complexes 9 with those of the amino acids 3 derived from them. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390131

FULL PAPER
Productive Asymmetric Synthesis of All Four Diastereomers of
3-(trans-2-Nitrocyclopropyl)alanine from Glycine with (S)- or
(R)-2-[(N-Benzylprolyl)amino]benzophenone as a Reusable Chiral Auxiliary[‡]
Oleg V. Larionov,[a] Tatyana F. Savel’eva,[b] Konstantin A. Kochetkov,[b]
Nikolai S. Ikonnokov,[b] Sergei I. Kozhushkov,[a] Dmitrii S. Yufit,[c] Judith A. K. Howard,[c]
Viktor N. Khrustalev,[b] Yuri N. Belokon,*[b] and Armin de Meijere*[a]
Dedicated to Professor Irina Beletskaya on the occasion of her 70th birthday
Keywords: Amino acids / Asymmetric synthesis / Chiral auxiliaries / Nickel / Nitrocyclopropylalanine
All four diastereomers of 3-(trans-2-nitrocyclopropyl)alanine
(3) were prepared by asymmetrically induced α-C alkylation
sure of the alkylation products 9 to dilute hydrochloric acid,
with subsequent purification by ion-exchange chromato-
of the glycine moiety in the [(S)- or (R)-Schiff base]NiII com- graphy and crystallization. The absolute configurations of the
plex 7, employing racemic trans-1-(iodomethyl)-2-nitrocyclo- nickel complexes 9a−e were established by X-ray crystallo-
propane (8) as the alkylating agent. A notable difference in
solubility between the two diastereomeric products 9a/9b
[when (S)-7 was used as starting material] or 9d/9e [when
(R)-7 was employed] allowed for their separation from the
same reaction mixture. All the diastereomers of 3-(trans-2-
nitrocyclopropyl)alanine (3) were produced upon brief expo-
graphic analyses. In addition, the X-ray crystal structure of
(2S,1ЈS,2ЈR)-3 was determined to confirm the convergence of
the configurations of the parent nickel complexes 9 with
those of the amino acids 3 derived from them.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
of certain bacteria,[2] and the recently isolated belactosin A
(2), which exhibits an antitumor activity,[3] are especially
intriguing, as they contain the previously unknown 3-
(trans-2-nitrocyclopropyl)alanine [(NcP)Ala, 3] and 3-
(trans-2-aminocyclopropyl)alanine [4, (AcP)Ala] as key
constituents.
Feeding experiments with deuterium-labelled (NcP)Ala
(3) as well as (AcP)Ala (4) have disclosed that the appropri-
ate strain of Streptomyces griseoflavus incorporates the
(2S,1ЈS,2ЈR) and (2R,1ЈS,2ЈR) diastereomers of 3-(trans-2-
nitrocyclopropyl)alanine (3), but not 4 in hormaomycin.[4]
Nature makes use of cyclopropyl groups even in amino
acids, and most of the over two dozens of known naturally
occurring amino acids containing a cyclopropyl group as
well as most of the cyclopropyl analogues of natural amino
acids, are responsible for the observed biological activities
of compounds containing them as constituents.[1] Among
such natural products, the peptidolactone hormaomycin
(1), which influences the secondary metabolite production
[‡]
Cyclopropyl Building Blocks for Organic Synthesis, 87. Part 86:
A. de Meijere, I. D. Kuchuk, V. V. Sokolov, T. Labahn, K.
Rauch, M. Es-Sayed, T. Krämer, Eur. J. Org. Chem., in press. Furthermore, it has recently been established that
Part 85: M. Knoke, A. de Meijere, Synlett, submitted.
(2S,1ЈS,2ЈR)-3 acquires the exocyclic position in 1, while
[a]
[b]
[c]
Institut für Organische Chemie der Georg-August-Universität
(2R,1ЈS,2ЈR)-3 is incorporated in the hexapeptolide ring
constituent of the pentapeptidic ring.[5] On the other hand,
the 3-(trans-2-aminocyclopropyl)alanine (4) moiety in be-
lactosin A (2) possesses the (2S,1ЈR,2ЈS) configuration.[3]
Hence, there is an apparent need for a convergent and pro-
ductive access to at least three diastereomers of the amino
acid 3, from which 4 can be prepared,[6] in enantiomerically
pure form.
Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
Fax: (internat.) ϩ 49-551/399475
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
A. N. Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences,
Vavilova Str. 28, 119991 Moscow, Russia
Fax: (internat.) ϩ 7-095/1355085
E-mail: yubel@ineos.ac.ru
Department of Chemistry, University of Durham,
South Rd., Durham DH1 3LE, UK
Eur. J. Org. Chem. 2003, 869Ϫ877  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0305Ϫ0869 $ 20.00ϩ.50/0
869

Y. N. Belokon, A. de Meijere et al.
FULL PAPER
Both natural amino acids 3 and 4 can be prepared from
the same precursor, (trans-2-nitrocyclopropyl)methanol (5),
which was used in the previously reported syntheses of
(2RS,1ЈR,2ЈS)- and (2S,1ЈRS,2ЈRS)-3.[6]
The C-alkylation of (S)-7 with (1S,2S)-8 occurred fast
and quantitatively in a dimethylformamide/acetonitrile (1:2)
mixture, using NaH as a base (Scheme 1). As monitored by
TLC, almost all (S)-7 was consumed within 30 min to give
the alkylation product 9a in 84% yield after acidic workup
and crystallization from a dimethylformamide/acetonitrile
(1:2) mixture. As evidenced by an X-ray crystal structure
analysis (Figure 1, A), the α-C atom bearing the trans-(2-
nitrocyclopropyl)methylene moiety in 9a, had an (S) config-
uration. Thus, the absolute configuration of the two chiral
centers in the trans-2-nitrocyclopropyl group of 9a is
(1ЈR,2ЈS), which is the same as that of the initial iodide
(1S,2S)-8 (the perceived change of the configuration at C-1
of the cyclopropane ring in 9a is only a change in the CIP
nomenclature order of the substituents according to the se-
quence rules).
In an effort to elucidate the biosynthetic pathway leading
to 1, we have recently prepared a deuterium-labelled speci-
men of racemic 3[4a,4c] and 4.[4c,7] A procedure for the pre-
paration of the enantiomerically enriched precursors
(1R,2R)-5 and (1S,2S)-5 (ee 92%) had also been de-
veloped.[7] Since the naturally occurring amino acids 3 and
4 have not yet been synthesized in stereoisomerically pure
form, we are prompted to report our results on the syn-
thesis of all four diastereomers of 3. With these in hand,
the amino acid (2S,1ЈR,2ЈS)-4 also becomes readily access-
ible by reduction of the nitro group.[6d]
Among different synthetic approaches to enantiomer-
ically pure α-amino acids,[8] the asymmetrically induced C-
alkylation has shown its outstanding utility over the past
decade, due to the simplicity of the experimental procedures
and their general applicability.[9] 2-[(N-Benzylprolyl)amino]-
benzophenone (BPB, 6) has proved to be an efficient chiral
auxiliary for the synthesis of more than 100 enantiomer-
ically pure proteinogenic and non-proteinogenic α-amino
acids.[10] The synthetic protocols make use of the NiII com-
plexes of the Schiff bases derived from (S)- or (R)-6 and
simple amino acids (glycine or alanine). The amino acid
moiety becomes a sufficiently strong CϪH acid to undergo
a set of electrophilic reactions in the presence of ordinary
bases like NaH, NaOH, KOH, or K2CO3. This approach
has also been successfully used by other research groups.[11]
Trace amounts of other diastereomers of 9 were observed
1
in the thin layer chromatogram (TLC) and H NMR spec-
Results and Discussion
The initial aim was to develop an efficient procedure for
the alkylation of the chiral nickel complex (S)-7 {[(S)-BPB/
Gly]NiII} with enantiomerically enriched (ee ϭ 92%) trans-
1-(iodomethyl)-2-nitrocyclopropane (1S,2S)-8, which was
derived from the corresponding alcohol (1S,2S)-5 by treat-
ment with iodine, triphenylphosphane and imidazole.[7]
Scheme 1. Alkylation of the nickel complex (S)-7 with (1S,2S)-8;
structure 10 is derived from the X-ray crystallographic structure of
9c (Figure 1, C)
870
Eur. J. Org. Chem. 2003, 869Ϫ877

Synthesis of All Four Diastereomers of 3-(trans-2-Nitrocyclopropyl)alanine
FULL PAPER
Scheme 2. Preparation of the iodide rac-8 from the dibromoester 11
panecarboxylate (12)[6c,6d] was significantly improved.
(Scheme 2). The addition of the dibromo ester 11 to a mix-
ture of nitromethane and potassium carbonate in DMSO
increased the yield of 12 from 31 to 59%. Reduction of the
ester 12 with lithium aluminum hydride (inverse addition of
its solution in diethyl ether) afforded the racemic alcohol 5
in 98% yield. It is noteworthy, that the yield of the reduction
product 5 drops drastically to a meager 25%, if the ester 12
is added to a solution of lithium aluminum hydride (the
usual mode of addition). The alcohol 5 was converted into
the iodide 8 in 93% yield by treatment with iodine, imida-
Figure 1. Molecular structures of the nickel complexes 9a [A, (S)
configuration in the proline and (2S,1ЈR,2ЈS) in the (NcP)Ala moi-
ety], 9b [B, (S) configuration in the proline and (2S,1ЈS,2ЈR) in
the (NcP)Ala moiety], 9c [C, (S) configuration in the proline and
(2R,1ЈS,2ЈR) in the (NcP)Ala moiety], and (2S,1ЈS,2ЈR)-3-(trans-2-
nitrocyclopropyl)alanine (3·0.5H2O, D) in the crystal (displacement
ellipsoids are shown at the 50% probability level)[15]
trum of the reaction mixture. These could have arisen from zole and triphenylphosphane.[13]
incomplete (ee ϭ 92%) enantiomeric enrichment of the em-
The racemic iodide 8 was employed in the alkylation of
ployed (1S,2S)-8 and also from the competing electrophilic (S)-7 (Scheme 3). After complete consumption (indicated
attack at the hindered re side of the anionic intermediate by TLC) of (S)-7 (ca. 40 min), the excess base was quenched
10 (Scheme 1).
with 60% aqueous acetic acid. This led to the formation of
Although this procedure proved to be successful, it has a precipitate that was composed of 9a and 9b in a ratio of
the severe disadvantage of employing two chiral auxiliaries 85:15 and weighed 44% of the total theoretically obtainable
[i.e. a chiral oxazolidinone derivative[12] for the synthesis of mixture of diastereomeric products. On the other hand, a
(1S,2S)-5,[7] and the nickel complex (S)-7 for the alkylation mixture of the same 9a and 9b but in a ratio of 25:75 was
step] en route to the amino acid 3 with three stereogenic secured from the liquid phase after an aqueous workup and
centers, and the synthetic sequence for the enantiomerically column chromatography. This fraction accounted for 41%
enriched alcohol 5 comprises several tedious and low- of the expected alkylation product. Thus, the combined
yielding steps. A better alternative appeared to be the al- yield of 9a and 9b was 85%, both readily available in dia-
kylation of (S)-7 with the racemic iodide 8 and subsequent stereomerically enriched forms. The diastereomeric ratios of
separation of the diastereomeric products.
9a and 9b varied to the extent of 2Ϫ4% for the obtained
The racemic iodide 8 was prepared in three simple steps, fractions, depending upon run and scale, with the average
starting from tert-butyl 2,3-dibromopropionate (11). First, values of 85:15 and 25:75 (9a/9b) for the precipitate and the
the known synthesis of tert-butyl trans-2-nitrocyclopro- liquid phase fractions, respectively.
Scheme 3. Diastereomeric distribution of products after the alkylation of (S)-7 with racemic iodide 8
Eur. J. Org. Chem. 2003, 869Ϫ877
871

Y. N. Belokon, A. de Meijere et al.
FULL PAPER
Recrystallization of the fraction enriched in 9a from di- only in 30% yield. Interestingly, a minute amount (2Ϫ3%)
methylformamide/acetonitrile afforded 9a with diastereo-
meric excesses varying between 95 and 98%. All physical
data of this product are identical to those of 9a obtained
by alkylation of (S)-7 with (1S,2S)-8. An X-ray crystal
structural analysis was, however, performed to confirm
the expected (2S,1ЈR,2ЈS) configuration of the (NcP)Ala
moiety (Figure 1, A).
The complex 9a with de ϭ 95% was decomposed by treat-
ment with 6  hydrochloric acid (Scheme 4) to give the
crude amino acid (2S,1ЈR,2ЈS)-3, NiCl2, and the insoluble
hydrochloride of (S)-6. The latter was recovered by filtra-
tion to the extent of 90Ϫ95%, and after brief drying in va-
cuo was reused for the preparation of (S)-7.[14] The crude
amino acid (2S,1ЈR,2ЈS)-3 was purified by eluting the re-
sulting filtrate through a pad of DOWEX resin in Hϩ form
with 5Ϫ7% aqueous ammonia. A single crystallization from
aqueous ethanol afforded the product (2S,1ЈR,2ЈS)-3
([α]2D0 ϭ ϩ72.7, c ϭ 0.3 in H2O) with de ϭ 99% (chiral
HPLC) and in 67% yield from 9a.
of
the
diastereomer
9c
{[(S)-BPB/(2R,1ЈS,2ЈR)-
(NcP)Ala]NiII} (Figure 1, C) was collected from a sample
of 9b with a spatula, due to a tremendous difference in crys-
tal sizes of the two diastereomers. Therefore, this 75:25 mix-
ture of 9b and 9a was decomposed without further purifica-
tion with 6  hydrochloric acid (Scheme 4) and the crude
amino acid, after ion-exchange purification using DOWEX
Monosphere 650C resin, was twice recrystallized from
aqueous ethanol to give (2S,1ЈS,2ЈR)-3 ([α]2D0 ϭ Ϫ55.6, c ϭ
0.32 in water) with diastereomeric and enantiomeric purity
Ͼ 96% (chiral HPLC) and in 55% yield.
Similarly, (R)-7 underwent smooth alkylation with rac-8,
to give, after quenching with 60% aqueous acetic acid, 42%
of a mixture of 9d and 9e (ca. 86:14 ratio) as a precipitate,
while the workup of the reaction liquor afforded 40% of
this diastereomeric mixture but in ca. 27:73 ratio
(Scheme 5). The absolute configurations of the (NcP)Ala
moiety in 9d and 9e were determined to be (2R,1ЈS,2ЈR)
and (2R,1ЈR,2ЈS), respectively, by X-ray structural analyses
(mirror images of 9a and 9b, Figure 1, A, B). Samples of 9d
and 9e with diastereomeric purities Ͼ 95% were obtained
as was described above for 9a and 9b.
(2R,1ЈS,2ЈR)-3 and (2R,1ЈR,2ЈS)-3 with de in the range
of 95Ϫ99% were prepared from 9d (de, 94Ϫ96%) and a 9d/
9e mixture (25:75), according to the same procedures as was
outlined for (2S,1ЈR,2ЈS)-3 and (2S,1ЈS,2ЈR)-3 (Scheme 4).
The molecular geometries of the nickel complexes de-
rived from the chiral auxiliary 6 have been studied intens-
ively along with the development of this method for the
synthesis of enantiomerically pure α-amino acids.[10,11] It
was shown,[16] that the conformationally most labile parts
of the molecule are the benzyl group and the five-membered
ring of the proline moiety, while the coordination around
the nickel atom is more constant. In all four cases of the
diastereomers 9abde the slightly distorted square coordina-
tion of Ni atoms remains virtually identical (Figure 2, A)
and only the conformations of the side chains differ slightly.
In all these molecules the phenyl rings of the benzyl groups
adopt a syn orientation with respect to the Ni atom and are
almost parallel to the coordination plane of the metal atom
with the shortest intramolecular contacts between the ipso-
C atom of the benzyl group and the Ni atom in the range
Scheme 4. Isolation of (NcP)Ala (3) from the corresponding nickel
complexes 9
The fraction enriched in 9b (75:25) (Scheme 3), proved to
be hardly separable by column chromatography. However,
diastereomerically pure 9b was obtained by slow crystalliza-
tion of this 75:25 mixture of 9b and 9a from MeOH, albeit
˚
of 2.91Ϫ3.10 A. However, in the case of the molecule 9c
Scheme 5. Diastereomeric distribution of products after the alkylation of (R)-7 with racemic iodide 8
872
Eur. J. Org. Chem. 2003, 869Ϫ877

Synthesis of All Four Diastereomers of 3-(trans-2-Nitrocyclopropyl)alanine
FULL PAPER
Experimental Section
General Remarks: H and 13C NMR spectra were recorded at 250,
300, 600 (1H), and 62.9, 75.5 [13C, additional DEPT (Distortionless
Enhancement by Polarization Transfer)] MHz on Bruker AM 250,
AMX 300, and Inova 600 instruments in CDCl3 solutions unless
otherwise specified, δ in ppm, J in Hz. IR: Bruker IFS 66 (FT-IR)
spectrometer, measured as KBr pellets or oils between KBr plates.
MS (EI): Finnigan MAT 95 spectrometer. X-ray crystal structure
analysis of 9aϪe and 3: the X-ray single crystal data were collected
at 120(1) K with a Bruker CCD SMART 1 K (3, 9b, c, and e) and
SMART 6000 (9a and d) diffractometers, equipped with Oxford
Cryostream cooling devices, using graphite-monochromated Mo-
Kα radiation. Crystallographic details and parameters of the data
collection and refinement are given in Table 1. The structure solu-
tions and refinements on F2 were performed with the Bruker
SHELXTL program suite. The hydrogen atoms in structures 3, 9a,
and 9c were located in difference Fourier syntheses and refined
isotropically. The hydrogen atoms in the structures 9b, 9d, and 9e
were placed in calculated positions and refined in ‘‘riding mode’’
with a 1.2-fold isotropic displacement parameter of the correspond-
ing C atom. Disordered parts of molecules 9c and 9e were refined
with fixed site occupation factors of 0.5. CCDC-194678
[(2S,1ЈR,2ЈS)-3ϫ0.5H2O], -194679 (9a), -194680 (9b), -194681
(9c), -194682 (9d), and -194683 (9e) contain the supplementary
crystallographic data for this paper.[15] Optical rotations:
PerkinϪElmer 241 digital polarimeter, 1-dm cell. Diastereomeric
purities of the nickel complexes 9 were determined by integration
of the corresponding peaks in 1H NMR spectra. Diastereomeric
and enantiomeric purities of the amino acids 3 were determined by
HPLC on a chiral column [Crownpak CR (ϩ) or (Ϫ), eluent 2%
aq. HClO4 (5 mL HClO4/1 L water) ϩ 2% MeOH; UV detection
at 210 nm]. M.p.: Büchi 540 capillary melting point apparatus, un-
corrected values. TLC: MachereyϪNagel precoated sheets,
0.25 mm Sil G/UV254. Column chromatography: Merck silica gel,
grade 60, 230Ϫ240 mesh. Starting materials: Diethyl ether and
THF were distilled from sodium benzophenone ketyl, CH2Cl2 and
1
Figure 2. Graphical superposition of molecular structures of the
Ni complexes 9abde (A), 9ac (B) and crystal packing of the amino
acid (2S,1ЈS,2ЈR)-3 (C) in the crystal
˚
DMF from molecular sieves 4 A, acetonitrile from P4O10. Com-
(Figure 1, C), in which the benzyl and the (2-nitrocyclopro-
pyl)methylene groups are on the same side of the Ni atom,
the conformation of the molecule is very different (Figure 2,
B). The coordination polyhedron of the Ni atom is inverted
in order to avoid close steric contacts between bulky side
groups and there is no longer close contact between the
benzyl group and the metal atom. The disordering of the
proline ring in 9c confirms the conformational flexibility of
this part of the molecule.
Molecules of (2S,1ЈS,2ЈR)-3 in the crystal are associated
in sheets, parallel to the x0y plane, by an extensive network
of NϪH···O and O(water)ϪH···O hydrogen bonds (Fig-
ure 2, C). There are a number of relatively close CϪH···O
pounds (R)- and (S)-6,[14] (R)- and (S)-7,[14] and 11,[6c,6d] were pre-
pared as described elsewhere. DOWEX Monosphere 650C ion-ex-
change resin was purchased from Fluka. All other chemicals were
used as commercially available (Merck, Acro˜s, BASF, Bayer,
Hoechst, Degussa AG). All reactions were conducted under nitro-
gen. Organic extracts were dried with MgSO4.
tert-Butyl trans-2-Nitrocyclopropanecarboxylate[6c,6d] (12): A 4-L
three-necked flask, equipped with a mechanical stirrer and a 500-
mL dropping funnel, was charged with anhydrous K2CO3 (856 g,
6.2 mol), DMSO (2 L), and nitromethane (141.3 g, 125.3 mL,
2.31 mol). The mixture was stirred at ambient temperature for
20 min. The dropping funnel was filled with the dibromo ester 11
(617 g, 2.14 mol), which was then added dropwise within 15 h,
contacts between adjacent sheets. The directions of these maintaining the temperature of the contents at 30Ϫ35 °C. After
˚
the addition of 11 had been completed, the reaction mixture was
vigorously stirred for 30 h. It was then poured into a 6-L separating
funnel with ice-cold water (1.5 L), and the suspension was extracted
with diethyl ether (5 ϫ 500 mL). The combined organic layers were
washed with water (3 ϫ 500 mL), dried, concentrated under re-
duced pressure, and the residue was distilled bulb-to-bulb at
100Ϫ120 °C under reduced pressure (0.05 Torr). The distillate was
fractionated at 0.5 Torr to give the ester 12 (236 g, 59%), as a waxy
contacts as well as the H···O distances (2.5Ϫ2.7 A) corre-
spond to the weak attractive CϪH···O interactions of CH
groups of cyclopropane rings.[17]
The diastereomeric amino acids 3 tend to form stable
crystalline semihydrates, as was shown by the elemental
analyses
of
(2S,1ЈR,2ЈS)-3,
(2R,1ЈS,2ЈR)-3,
and
(2R,1ЈR,2ЈS)-3. This was also confirmed by an X-ray crystal
structure elucidation of (2S,1ЈS,2ЈR)-3 (Figure 1, D). The
water can be removed, however, on drying in vacuo at 70
°C over a period of 3Ϫ4 d.
1
solid; b.p. 72Ϫ75 °C (0.5 Torr), m.p. 34 °C. H NMR (250 MHz):
δ ϭ 1.46 (s, 9 H), 1.67 (ddd, J ϭ 6.0, 7.5, 7.5 Hz, 1 H), 2.00 (ddd,
J ϭ 6.0, 10.5, 4.5 Hz, 1 H), 2.64 (ddd, J ϭ 3.0, 7.5, 10.5 Hz, 1 H),
Eur. J. Org. Chem. 2003, 869Ϫ877
873

Y. N. Belokon, A. de Meijere et al.
FULL PAPER
Table 1. Crystal and data collection parameters for compounds (2S,1ЈS,2ЈR)-3 and 9a؊e
9a
9b
9c
9d
9e
(2S,1ЈS,2ЈR)-3
Empirical formula
Formula mass
Crystal size [mm]
Crystals
C31H30N4NiO5
597.30
C6H10N2O4ϫ0.5H2O
183.17
0.18 ϫ 0.16 ϫ 0.04 0.46 ϫ 0.20 ϫ 0.06 0.37 ϫ 0.20 ϫ 0.14 0.20 ϫ 0.12 ϫ 0.12 0.18 ϫ 0.08 ϫ 0.07 0.26 ϫ 0.18 ϫ 0.03
tetragonal
P41212
9.9924(3)
9.9924(3)
55.176(2)
90
90
90
5509.2(3)
8
1.440
monoclinic
P21
10.4310(4)
8.8255(3)
14.9390(6)
90
92.04(2)
90
1374.39(9)
2
orthorhombic
P212121
9.7686(4)
14.8822(6)
18.3546(8)
90
90
90
2668.4(2)
4
1.487
tetragonal
P43212
9.9946(1)
9.9946(1)
55.195(1)
90
90
90
5513.5(1)
8
1.439
monoclinic
P21
10.4309(4)
8.8239(3)
14.9327(5)
90
91.98(2)
90
1373.60(8)
2
monoclinic
C2
9.8099(6)
6.3597(4)
13.6047(8)
90
96.05(3)
90
844.04(9)
4
Space group
˚
a [A]
˚
b [A]
˚
c [A]
α [°]
β [°]
γ [°]
3
˚
V [A ]
Z
D [calculated, g·cmϪ3
]
1.443
0.755
624
1.444
0.755
624
1.441
0.124
388
µ [mmϪ1
F(000)
]
0.753
2496
0.777
1248
0.752
2496
θ range [°]
2.07Ϫ29.00
60595
7343
1.95Ϫ28.00
12337
6476
2.22Ϫ30.31
23087
7229
2.07Ϫ27.50
29979
6306
1.95Ϫ29.00
15515
7016
3.01Ϫ26.00
3100
1550
Refl. collected
Refl. independent
Rint
0.0818
0.0318
0.0234
0.0370
0.0442
0.0404
Absorption correction numerical
semi-empirical from equivalents
Parameters refined
GOOF
490
0.935
376
1.056
466
1.090
490
1.145
376
1.020
158
1.091
R1 [I Ͼ 2σ(I)]
wR2
R1(F)
wR2(F2)
Absolute structure
parameter
0.0369
0.0731
0.0684
0.0819
Ϫ0.04(1)
0.0553
0.1372
0.0629
0.1426
Ϫ0.01(1)
0.0295
0.0722
0.0326
0.0735
0.011(8)
0.0291
0.0709
0.0345
0.0733
Ϫ0.02(1)
0.0443
0.0866
0.0612
0.0930
0.01(1)
0.0512
0.1213
0.0605
0.1262
could not be
determined
0.246, Ϫ0.258
Largest diff. peak,
0.395, Ϫ0.293
0.452, Ϫ0.322
0.499, Ϫ0.307
0.268, Ϫ0.216
0.405, Ϫ0.313
Ϫ3
˚
hole [e·A
]
4.53 (ddd, J ϭ 3.0, 4.5, 7.5 Hz, 1 H) ppm. 13C NMR: (62.9 MHz):
δ ϭ 17.06 (CH3), 26.07 (CH2), 27.9 (CH2), 59.1 (CH2), 82.64 (C),
mixture was stirred at ambient temperature for 3 h. It was then
poured into a 4-L separating funnel containing diethyl ether (1 L).
The resulting suspension was washed with 20% aq. Na2S2O3
(3 ϫ 0.8 L) and water (0.5 L). The organic fraction was dried with
MgSO4 and concentrated under reduced pressure. The residue was
covered with a hexane/diethyl ether (1:1) mixture (1.5 L) and stirred
at ambient temperature for 1 h. The precipitate was filtered off and
discarded. The filtrate was concentrated under reduced pressure.
The crude product was purified by column chromatography (silica
gel; hexane/diethyl ether, 12:1; Rf ϭ 0.11) to give 42.3 g (93%) of
167.9 (C) ppm. IR: ν˜ ϭ 3115, 2908, 1776, 1558, 1361, 1000 cmϪ1
.
MS (EI): m/z ϭ 187 (1) [Mϩ], 114 (100), 100 (23), 71 (7), 67 (36),
55 (8), 41 (4).
rac-(trans-2-Nitrocyclopropyl)methanol[6c,6d] (rac-5) from the Ester
12: A 1  solution of LiAlH4 in diethyl ether (110 mmol, 110 mL)
was added dropwise at Ϫ10 °C over 3 h to a stirred solution of the
ester 12 (37.44 g, 0.20 mol) in anhydrous diethyl ether (350 mL).
The reaction mixture was stirred at ambient temperature for 1 h,
whereafter a saturated aqueous solution of Na2SO4 (84 mL) was
added dropwise at Ϫ5 °C. The resulting slurry was stirred at ambi-
ent temperature for 1.5 h. The liquid organic layer was separated,
and the solids were suspended in water (200 mL), and extracted
with diethyl ether (5 ϫ 100 mL). The organic phases were com-
bined with the reaction liquid layer, dried, and concentrated at re-
duced pressure. The residue was purified by column chromato-
graphy (silica gel; hexane/diethyl ether, 1:1; Rf ϭ 0.17) to give
22.97 g (98%) of the alcohol rac-5 as a colorless oil. 1H NMR
(250 MHz): δ ϭ 1.21 (ddd, J ϭ 5.9, 6.9, 8.1 Hz, 1 H), 2.02Ϫ2.09
(m, 1 H), 2.12 (br. s), 2.39Ϫ2.45 (m, 1 H), 3.15 (dd, J ϭ 4.2, 4.9 Hz,
2 H), 4.17 (ddd, J ϭ 4.2, 4.2, 6.9 Hz, 1 H) ppm. 13C NMR
(62.9 MHz): δ ϭ 3.6 (CH2), 22.0 (CH2), 26.1 (CH), 62.9 (CH) ppm.
MS (DCI): m/z ϭ 135 (100) [M ϩ NH4ϩ].
1
rac-8 as a colorless oil. H NMR (250 MHz): δ ϭ 1.21 (ddd, J ϭ
5.9, 6.9, 8.1 Hz, 1 H), 2.02Ϫ2.09 (m, 1 H), 2.39Ϫ2.45 (m, 1 H), 3.15
(dd, J ϭ 4.2, 4.9 Hz, 2 H), 4.17 (ddd, J ϭ 4.2, 4.2, 6.9 Hz, 1 H)
ppm. 13C NMR (62.9 MHz): δ ϭ 3.6 (CH2), 22.0 (CH2), 26.1 (CH),
62.9 (CH) ppm. IR: ν˜ ϭ 3098, 2961, 2897, 1547, 1435, 1369, 571
cmϪ1. MS (EI): m/z ϭ 227 (8) [Mϩ], 181 (18), 100 (22), 86 (27),
54 (91).
Alkylation of (S)-7 with (1S,2S)-8. Preparation of 9a: A suspension
of (S)-7 (3.45 g, 6.92 mmol) in a mixture of DMF (3.4 mL) and
MeCN (6.9 mL) was degassed with two freeze-pump-thaw cycles at
Ϫ50 °C. NaH (0.33 g, 60% in oil, 8.30 mmol) and (1S,2S)-8 (1.65 g,
7.27 mmol) were then added. The cooling bath was removed, and
the reaction mixture was vigorously stirred for 40Ϫ50 min. When
the temperature rose to 0 °C, the reaction flask was immersed into
an ice/water bath to maintain the low temperature. Upon consump-
tion of all (S)-7 (TLC monitoring; CHCl3/acetone, 7:1; Rf ϭ 0.12),
60% aqueous AcOH (3.40 mL) was added slowly to avoid much
foaming. After an additional 5 min of stirring, the reaction mixture
rac-trans-1-(Iodomethyl)-2-nitrocyclopropane (rac-8): Solid iodine
(96.14 g, 0.378 mol) was added in small portions at Ϫ5 °C over a
period of 40 min to a solution of the alcohol 5 (22.9 g, 0.196 mol),
PPh3 (89.53 g, 0.34 mol), and imidazole (24.1 g, 0.357 mol) in a
mixture of Et2O (580 mL) and MeCN (390 mL), and the reaction was poured into a 100-mL separating funnel, containing water
874 Eur. J. Org. Chem. 2003, 869Ϫ877

Synthesis of All Four Diastereomers of 3-(trans-2-Nitrocyclopropyl)alanine
(40 mL). The resulting slurry was extracted with CHCl3 (m, 2 H), 7.45Ϫ7.51 (m, 3 H), 7.58Ϫ7.62 (m, 1 H), 7.63Ϫ7.68 (m,
FULL PAPER
(3 ϫ 25 mL). The combined organic fractions were dried and con-
centrated under reduced pressure. The crude product was dissolved
in hot DMF (27 mL) and precipitated with MeCN (47.5 mL). The
mother liquor was concentrated under reduced pressure and the
residue was triturated with a mixture of DMF (1.8 mL) and MeCN
2 H), 8.02Ϫ8.12 (m, 3 H) ppm. 13C NMR: δ ϭ 17.9 (CH2), 21.6
(CH), 23.9 (CH2), 30.6 (CH2), 36.3 (CH2), 57.2 (CH2), 59.4 (CH),
63.2 (CH2), 68.6 (CH), 70.0 (CH2), 120.8 (CH), 123.7 (CH), 126.0
(C), 127.3 (CH), 127.4 (CH), 128.8 (CH) 129.0 (CH), 129.1 (CH),
129.5 (CH), 130.2 (CH), 131.5 (CH), 132.5 (CH), 133.3 (CH), 133.4
(2.1 mL) over a period of 1 h. The precipitate of 9a (de ϭ 95Ϫ98%) (C), 133.6 (C), 142.5 (C), 171.1 (C), 178.5 (C), 180.6 (C) ppm. IR:
was filtered off, combined with the first crop and dried in vacuo at
ν˜ ϭ 3097, 3069, 2969, 2928, 2876, 1668, 1655, 1583, 1539, 1436,
50 °C to give 3.47 g (84%) of 9a (de ϭ 96%). A second crystalliza-
1362, 1339, 1256, 1165, 1079, 1059, 1028, 970, 895, 755, 702, 668,
tion afforded 9a with de Ͼ 98% as a light red solid, m.p. 270 °C 570, 480 cmϪ1. MS (EI): m/z ϭ 596.2 (31) [Mϩ], 552.2 (35), 537.6
(decomp.), [α]2D0 ϭ ϩ2401 (c ϭ 0.1, MeOH). 1H NMR (250 MHz):
(2), 497.2 (3), 453.2 (7), 439.2 (12), 347.1 (7), 320.1 (1), 217.1 (17),
δ ϭ 0.49Ϫ0.58 (m, 1 H), 1.05Ϫ1.20 (m, 1 H), 1.7Ϫ1.84 (m, 1 H), 161.1 (14), 160.1 (100), 91.1 (21), 44 (5).
2.04Ϫ2.31 (m, 2 H), 2.42Ϫ2.58 (m, 2 H), 2.59Ϫ2.79 (m, 2 H),
Alkylation of (R)-7 with rac-8. Preparation of 9d and 9e: The reac-
3.46Ϫ3.60 (m, 3 H), 3.57 (d, J ϭ 12.5 Hz, 1 H), 3.90Ϫ3.99 (m,
2 H), 4.42 (d, J ϭ 12.7 Hz, 1 H), 6.60Ϫ6.67 (m, 2 H), 6.88Ϫ6.92
(m, 1 H), 7.10Ϫ7.21 (m, 2 H), 7.25Ϫ7.41 (m, 3 H), 7.42Ϫ7.61 (m,
3 H), 8.05Ϫ8.16 (m, 3 H) ppm. 13C NMR: δ ϭ 18.5 (CH2), 21.9
(CH), 24.0 (CH2), 30.8 (CH2), 36.8 (CH2), 57.4 (CH2), 58.7 (CH),
63.4 (CH), 68.9 (CH), 70.2 (CH2), 120.8 (CH), 123.7 (CH), 126.0
(C), 127.3 (CH), 127.4 (CH), 128.8 (CH), 128.9 (CH), 129.0 (CH),
129.5 (CH), 130.2 (CH), 131.5 (CH), 132.5 (CH), 133.3 (CH), 133.4
(C), 133.6 (C), 142.5 (C), 171.1 (C), 178.5 (C), 180.6 (C) ppm. IR:
ν˜ ϭ 3072, 3028, 2968, 2877, 1666, 1625, 1589, 1537, 1437, 1368,
1341, 1257, 1165, 1080, 1060, 1016, 965, 897, 756, 702, 682, 570,
486 cmϪ1. MS (EI): m/z ϭ 596.2 (28) [Mϩ], 552.2 (32), 497.2 (3),
453.2 (6), 439.2 (12), 347.1 (7), 217.1 (17), 161.1 (14), 160.1 (100),
91.1 (21), 44 (5). C31H30N4NiO5 (597.3): calcd. C 62.34, H 5.06, N
9.38; found C 62.26, H 5.29, N 9.25.
tion was carried out with (R)-7 (5.80 g, 11.64 mmol), NaH (0.558 g,
60% in mineral oil, 13.97 mmol), and rac-8 (2.77 g, 12.22 mmol) in
a mixture of DMF (5.8 mL) and MeCN (11.6 mL) as described
above for the alkylation with (1S,2S)-8. When all (R)-7 had been
consumed (TLC monitoring; CHCl3/acetone, 7:1; Rf ϭ 0.12), 60%
aqueous AcOH (1.3 mL) was added slowly. After an additional
5 min of stirring, the reaction mixture was filtered through a G4
fritted glass filter. The solid fraction (2.96 g, dr ഠ 86:14) was dis-
solved in hot DMF (36 mL) and precipitated with MeCN (42 mL)
to give 2.23 g of 9d (de ϭ 97%). The mother liquor was concen-
trated under reduced pressure, and the residue was triturated with
a mixture of DMF (2.3 mL) and MeCN (2.8 mL) over a period of
1 h. The precipitate of 9d (de ϭ 94Ϫ96%) was filtered off, combined
with the first crop, and dried in vacuo at 50 °C to give 2.40 g of 9d
(de ϭ 94%) [35% based on (R)-7]. The filtrate obtained after the
trituration was combined with the liquid phase of the reaction mix-
Alkylation of the Nickel Complex (S)-7 with rac-trans-1-(Iodo-
methyl)-2-nitrocyclopropane (8). Preparation of 9a and 9b: The reac- ture, and poured into a 250-mL separating funnel, containing water
tion was carried out with (S)-7 (32.85 g, 65.94 mmol), NaH (3.16 g,
60% in mineral oil, 79.1 mmol), and rac-8 (15.71 g, 69.23 mmol) in
(60 mL). The resulting slurry was extracted with CHCl3
(3 ϫ 50 mL). The combined organic fractions were dried with
a mixture of DMF (32 mL) and MeCN (65 mL) as described above MgSO4 and concentrated under reduced pressure. The residue was
for the alkylation with (1S,2S)-8. Upon consumption of all (S)-7 purified by column chromatography (silica gel; CHCl3/acetone, 7:1;
(TLC monitoring; CHCl3/acetone, 7:1; Rf ϭ 0.12), 60% aqueous Rf ϭ 0.25) to give 2.77 g (40%) of a mixture of 9e and 9d in a ca.
AcOH (7 mL) was added slowly to avoid foaming. After an addi-
tional 5 min of stirring, the reaction mixture was filtered through
a G4 fritted glass filter. The solid fraction (17.33 g, 44%, dr ϭ
85:15) was dissolved in hot DMF (205 mL) and precipitated with
77:23 ratio. This was used for the preparation of (2R,1ЈR,2ЈS)-3
without further diastereomeric enrichment. A sample of the al-
kylation product 9e (0.12 g) with de Ͼ 98% was obtained as de-
scribed for 9b. 9d: Light red solid, m.p. 270 °C (decomp.), [α]2D0
ϭ
MeCN (236 mL) to give 10.16 g of 9a (de ϭ 95Ϫ98%). The mother Ϫ2406 (c ϭ 0.1, MeOH). 1H NMR (250 MHz): δ ϭ 0.49Ϫ0.57 (m,
liquor was concentrated under reduced pressure, and the residue 1 H), 1.05Ϫ1.20 (m, 1 H), 1.71Ϫ1.84 (m, 1 H), 2.04Ϫ2.33 (m, 2 H),
(7.02 g) was triturated with a mixture of DMF (13 mL) and MeCN 2.42Ϫ2.58 (m, 2 H), 2.59Ϫ2.79 (m, 2 H), 3.46Ϫ3.60 (m, 3 H), 3.57
(15.8 mL) over a period of 1 h. The precipitate of 9a (3.85 g, de ϭ
94Ϫ96%) was filtered off, combined with the first crop and dried
in vacuo at 50 °C to give 14.01 g of 9a (de ϭ 95Ϫ97%) (36% based
on 7). The filtrate obtained after the trituration, was combined with
the liquid phase of the reaction mixture, and poured into a 1-L
(d, J ϭ 12.5 Hz, 1 H), 3.91Ϫ3.99 (m, 2 H), 4.42 (d, J ϭ 12.7 Hz,
1 H), 6.60Ϫ6.67 (m, 2 H), 6.88Ϫ6.92 (m, 1 H), 7.10Ϫ7.21 (m, 2 H),
7.24Ϫ7.40 (m, 3 H), 7.42Ϫ7.61 (m, 3 H), 8.02Ϫ8.15 (m, 3 H) ppm.
13C NMR: δ ϭ 18.5 (CH2), 21.9 (CH), 24.0 (CH2), 30.8 (CH2),
36.8 (CH2), 57.4 (CH2), 58.7 (CH), 63.4 (CH2), 68.9 (CH), 70.2
separating funnel with water (350 mL). The resulting slurry was (CH2), 120.8 (CH), 123.7 (CH), 126.0 (C), 127.3 (CH), 127.4 (CH),
extracted with CHCl3 (3 ϫ 300 mL). The combined organic frac-
tions were dried with MgSO4 and concentrated under reduced pres-
sure. The residue was purified by column chromatography (silica
gel; CHCl3/acetone, 7:1; Rf ϭ 0.25) to give 16.15 g (41%) of a mix-
128.8 (CH) 128.9 (CH), 129.0 (CH), 129.5 (CH), 130.2 (CH), 131.5
(CH), 132.5 (CH), 133.3 (CH), 133.4 (C), 133.6 (C), 142.5 (C),
171.1 (C), 178.5 (C), 180.6 (C) ppm. IR: ν˜ ϭ 3072, 3028, 2968,
2878, 1666, 1625, 1589, 1537, 1437, 1368, 1341, 1257, 1165, 1080,
ture of 9b and 9a in a 75:25 ratio. This was used for the preparation 1060, 1015, 965, 897, 756, 702, 682, 570, 486 cmϪ1. MS (EI):
of (2S,1ЈS,2ЈR)-3 without further diastereomeric enrichment. A
m/z ϭ 596.2 (28) [Mϩ], 552.2 (32), 497.2 (3), 453.2 (6), 439.2 (12),
sample of the alkylation product 9b (0.392 g) with de Ͼ 98% was 347.1 (7), 217.1 (17), 161.1 (14), 160.1 (100), 91.1 (21), 44 (5). 9e:
isolated after slow concentration of the saturated solution of the
Dark red solid, m.p. 260 °C (decomp.), [α]2D0 ϭ Ϫ2329 (c ϭ 0.1,
9b/9a mixture (dr ϭ 75:25, 1.12 g) in MeOH (ca. 4 mL). 9b: Dark MeOH). 1H NMR: δ ϭ 0.92 (ddd, J ϭ 6.7, 6.7, 7.4 Hz, 1 H),
red solid, m.p. 263 °C (decomp.), [α]2D0 ϭ ϩ2340 (c ϭ 0.1, MeOH).
1.41Ϫ1.49 (m, 1 H), 1.86Ϫ1.94 (m, 1 H), 2.08Ϫ2.24 (m, 3 H),
2.39Ϫ2.57 (m, 2 H), 2.58Ϫ2.71 (m, 1 H), 3.32Ϫ3.37 (m, 1 H)
1H NMR: δ ϭ 0.92 (ddd, J ϭ 6.7, 6.7, 7.4 Hz, 1 H), 1.41Ϫ1.49 (m,
1 H), 1.86Ϫ1.94 (m, 1 H), 2.08Ϫ2.24 (m, 3 H), 2.39Ϫ2.57 (m, 2 H), 3.44Ϫ3.58 (m, 3 H), 3.53 (d, J ϭ 12.7 Hz, 1 H), 3.99 (dd, J ϭ 3.5,
2.58Ϫ2.71 (m, 1 H), 3.32Ϫ3.37 (m, 1 H) 3.44Ϫ3.58 (m, 3 H), 3.53 8.6 Hz, 1 H), 4.41 (d, J ϭ 12.5 Hz, 1 H), 6.85 (d, J ϭ 7.5 Hz, 2 H),
(d, J ϭ 12.7 Hz, 1 H), 3.99 (dd, J ϭ 3.5, 8.6 Hz, 1 H), 4.41 (d, J ϭ 7.10Ϫ7.20 (m, 1 H), 7.25Ϫ7.37 (m, 2 H), 7.45Ϫ7.51 (m, 3 H),
12.5 Hz, 1 H), 6.85 (d, 7.5 Hz, 2 H), 7.10Ϫ7.20 (m, 1 H), 7.25Ϫ7.37 7.58Ϫ7.62 (m, 1 H), 7.63Ϫ7.68 (m, 2 H), 8.02Ϫ8.12 (m, 3 H) ppm.
Eur. J. Org. Chem. 2003, 869Ϫ877
875

Y. N. Belokon, A. de Meijere et al.
FULL PAPER
13C NMR: δ ϭ 17.9 (CH2), 21.6 (CH), 23.9 (CH2), 30.6 (CH2),
(ddd, J ϭ 6.8, 6.8, 7.4 Hz, 1 H), 1.81Ϫ1.99 (m, 3 H), 2.01Ϫ2.18
36.3 (CH2), 57.2 (CH2), 59.4 (CH), 63.2 (CH2), 68.6 (CH), 70.0 (m, 1 H), 3.84 (dd, J ϭ 6.0, 6.0 Hz, 1 H), 4.38 (ddd, J ϭ 3.0, 3.9,
(CH2), 120.8 (CH), 123.7 (CH), 126.0 (CH2), 127.3 (CH), 127.4
6.9 Hz, 1 H) ppm. 13C NMR: δ ϭ 20.5 (CH2), 24.4 (CH), 33.8
(CH), 128.8 (CH) 129.0 (CH), 129.1 (CH2), 129.5 (CH), 130.2 (CH2), 56.3 (CH), 61.7 (CH), 174.1 (C) ppm. IR: ν˜ ϭ 3345, 3103,
(CH), 131.5 (CH), 132.5 (CH), 133.3 (CH), 133.4 (C), 133.6 (C), 2923, 1542, 1443, 1368, 1301, 1252, 882, 671, 567, 505 cmϪ1. MS
142.5 (C), 171.1 (C), 178.5 (C), 180.6 (C) ppm. IR: ν˜ ϭ 3097, 3067,
(DCI): m/z ϭ 366.1 (11) [2 M ϩ NH4ϩ], 349.1 (2) [2 M ϩ Hϩ],
2969, 2927, 2876, 1668, 1654, 1583, 1539, 1436, 1362, 1339, 1256, 319.1 (3), 209.0 (24) [M ϩ NH3 ϩ NH4ϩ], 192.0 (100) [M ϩ
1165, 1078, 1059, 1028, 970, 895, 755, 702, 668, 570, 480 cmϪ1. MS NH4ϩ], 175.0 (5) [M ϩ Hϩ], 145.0 (20), 128.0 (3).
(EI): m/z ϭ 596.2 (31) [Mϩ], 552.2 (35), 537.6 (2), 497.2 (3), 453.2
(2R,1ЈS,2ЈR)-2-Amino-3-(2-nitrocyclopropyl)propionic
Acid
(7), 439.2 (12), 347.1 (7), 320.1 (1), 217.1 (17), 161.1 (14), 160.1
(100), 91.1 (21), 44 (5).
[(2R,1ЈS,2ЈR)-3-(2-Nitrocyclopropyl)alanine, 3] from 9d: The amino
acid (2R,1ЈS,2ЈR)-3 (0.28 g, 61%) was prepared from 9d (1.6 g,
2.68 mmol) according to GP1. A single crystallization of the crude
amino acid, isolated after elution from the DOWEX ion-exchange
column, afforded (2R,1ЈS,2ЈR)-3 with de ϭ 96% as a colorless solid,
m.p. 198Ϫ200 °C (decomp.), [α]2D0 ϭ Ϫ72.2 (c ϭ 0.32, H2O). 1H
NMR (300 MHz, D2O): δ ϭ 1.37 (ddd, J ϭ 6.8, 6.8, 7.4 Hz, 1 H),
1.84Ϫ1.99 (m, 2 H), 2.08Ϫ2.20 (m, 2 H), 3.84 (dd, J ϭ 6.5, 6.5 Hz,
1 H), 4.38 (ddd, J ϭ 3.0, 3.9, 6.9 Hz, 1 H) ppm. 13C NMR
(62.9 MHz): δ ϭ 21.3 (CH2), 25.2 (CH), 34.4 (CH2), 56.8 (CH),
62.1 (CH), 173.9 (C) ppm. IR: ν˜ ϭ 3335, 3093, 2595, 1589, 1536,
1441, 1398, 1371, 1309, 878, 683, 539, 503 cmϪ1. MS (DCI): m/z ϭ
366.1 (11) [2 M ϩ NH4ϩ], 349.1 (2) [2 M ϩ Hϩ], 319.1 (3), 209.0
(23) [M ϩ NH3 ϩ NH4ϩ], 192.0 (100) [M ϩ NH4ϩ], 175.0 (5) [M
ϩ Hϩ], 145.0 (19), 128.0 (3). C6H10N2O4·0.5H2O (183.2) calcd. C
39.34, H 6.04, N 15.29; found C 39.14, H 5.84, N 15.12.
General Procedure (GP1) for the Decomposition of the Nickel Com-
plexes 9 and Isolation of the Amino Acids 3: 6  aq. HCl (175 mL)
was added to a vigorously stirred suspension of 9 (21.0 g,
35.16 mmol) in refluxing methanol (90 mL). The mixture was
gently heated under reflux for 7Ϫ10 min. The resulting green syrup
was concentrated under reduced pressure at 40 °C. The solid res-
idue was taken up with hot water (260 mL). The precipitate was
filtered off, washed with water (70 mL), and dried to give 6·HCl
(13.32 g, 90% recovery) as a colorless solid. The filtrate was com-
bined with the washings, neutralized to pH ϭ 6.0 with 25% aque-
ous ammonia (ca. 6 mL), and extracted with CHCl3 (3 ϫ 300 mL).
The combined organic layers were dried and concentrated under
reduced pressure to give another portion of 6 (0.54 g, overall 94%
recovery). The aqueous fraction was concentrated to ca. 60 mL and
neutralized with 25% ammonia to pH ϭ 6.5. The amino acid 3
was separated from the nickel salts by elution of the neutralized
concentrate through an Hϩ-form DOWEX ion-exchange resin
(type as above) column (ca. 150 g of resin) with 5Ϫ7% aqueous
ammonia. The fraction of the eluate that showed red pigmentation
on developing with ninhydrin, was collected. This was concentrated
under reduced pressure at 40Ϫ45 °C. The crude amino acid 3 was
dissolved in hot water (17 mL). The hot turbid solution was filtered
and diluted with ethanol (28 mL). The precipitate, formed after
storing at 0 °C for 1 h, was filtered off, washed with cold ethanol
(10 mL), and dried in vacuo at 40 °C to give 3.9Ϫ4.0 g (64Ϫ65%)
of the amino acid 3.
(2R,1ЈR,2ЈS)-2-Amino-3-(2-nitrocyclopropyl)propionic
Acid
[(2R,1ЈR,2ЈS)-3-(2-Nitrocyclopropyl)alanine, 3] from a 9e/9d (77:23)
Mixture: The amino acid (2R,1ЈR,2ЈS)-3 (0.32 g, 42%) was pre-
pared from a 9e/9d (75:25) mixture (2.60 g, 4.35 mmol) according
to GP1. Twofold crystallization of the crude amino acid, isolated
after elution from the DOWEX ion-exchange column, gave
(2R,1ЈR,2ЈS)-3 with de ϭ 96% as a colorless solid, m.p. 199Ϫ202
°C (decomp.), [α]2D0 ϭ ϩ56.3 (c ϭ 0.3, H2O). H NMR (300 MHz,
1
D2O): δ ϭ 1.37 (ddd, J ϭ 6.8, 6.8, 7.4 Hz, 1 H), 1.80Ϫ1.99 (m,
3 H), 2.01Ϫ2.18 (m, 1 H), 3.84 (dd, J ϭ 6.0, 6.0 Hz, 1 H), 4.38
(ddd, J ϭ 3.0, 3.9, 6.9 Hz, 1 H) ppm. 13C NMR: δ ϭ 20.5 (CH2),
24.4 (CH), 33.8 (CH2), 56.3 (CH), 61.7 (CH), 174.1 (C) ppm. IR:
ν˜ ϭ 3345, 3103, 2923, 1541, 1443, 1368, 1301, 1252, 882, 671, 567,
505 cmϪ1. MS (DCI): m/z ϭ 366.1 (11) [2 M ϩ NH4ϩ], 349.1 (2)
[2 M ϩ Hϩ], 319.1 (3), 209.0 (24) [M ϩ NH3 ϩ NH4ϩ], 192.0
(100) [M ϩ NH4ϩ], 175.0 (5) [M ϩ Hϩ], 145.0 (20), 128.0 (3).
C6H10N2O4·0.25H2O (178.7) calcd. C 40.34, H 5.92, N 15.68;
found C 40.29, H 5.90, N 15.38.
(2S,1ЈR,2ЈS)-2-Amino-3-(2-nitrocyclopropyl)propionic
Acid
[(2S,1ЈR,2ЈS)-3-(2-Nitrocyclopropyl)alanine, 3] from 9a: The amino
acid (2S,1ЈR,2ЈS)-3 (5.5 g, 67%) was prepared from 9a (28.5 g,
47.18 mmol) according to GP1. A single crystallization of the crude
amino acid, obtained after elution from the DOWEX ion-exchange
column, afforded (2S,1ЈR,2ЈS)-3 with de ϭ 99% as a colorless solid,
m.p. 200Ϫ202 °C (decomp.), [α]2D0 ϭ ϩ72.7 (c ϭ 0.3, H2O). 1H
NMR (300 MHz, D2O): δ ϭ 1.31 (ddd, J ϭ 6.4, 6.4, 7.3 Hz, 1 H),
1.84Ϫ1.99 (m, 2 H), 2.08Ϫ2.20 (m, 2 H), 3.84 (dd, J ϭ 6.5, 6.5 Hz,
1 H), 4.38 (ddd, J ϭ 3.0, 3.9, 6.9 Hz, 1 H) ppm. 13C NMR
(62.9 MHz): δ ϭ 21.3 (CH2), 25.2 (CH), 34.4 (CH2), 56.8 (CH),
62.1 (CH2), 173.9 (C) ppm. IR: ν˜ ϭ 3335, 3095, 2604, 1589, 1536,
1441, 1398, 1371, 1309, 878, 683, 540, 503 cmϪ1. MS (DCI): m/z ϭ
366.1 (11) [2 M ϩ NH4ϩ], 349.1 (2) [2 M ϩ Hϩ], 319.1 (3), 209.0
(23) [M ϩ NH3 ϩ NH4ϩ], 192.0 (100) [M ϩ NH4ϩ], 175.0 (5) [M
ϩ Hϩ], 145.0 (19), 128.0 (3). C6H10N2O4 (174.1) calcd. C 41.38, H
5.79, N 16.09; found C 41.17, H 5.67, N 16.04.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB, 416, Project A3), the Fonds der Chemischen Industrie, and
the EPSRC (UK). O. V. L. is indebted to the Degussa-Hermann-
Schlosser-Stiftung for a graduate fellowship. D. S. Y. thanks the
EPSRC (UK) for financial support. The authors are grateful to the
companies BASF AG, Bayer AG, Chemetall GmbH, and Degussa
AG for generous gifts of chemicals, to Dr. B. Knieriem, Göttingen,
for his careful proofreading of the final manuscript.
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