Rational synthesis of all the four stereoisomers of 3-(trans-2- aminocyclopropyl)alanine

Article abstract of DOI:10.1070/MC2003v013n05ABEH001817

All the four stereoisomers of 3-(trans-2-aminocyclopropyl)alanine - a key constituent of the potential antitumor agent belactosin A -were prepared by simple catalytic hydrogenation of (2S,1′S,2′S)-, (2S,1′R,2′R)-, (2R,1′R,2′R)-, and (2R,1′S, 2′S)-3-(trans-2-nitro-cyclopropyl)alanines in 95, 93, 91 and 92% yields, respectively.

Full text of DOI:10.1070/MC2003v013n05ABEH001817

, 2003, 13(5), 199–200
Rational synthesis of all the four stereoisomers
of 3-(trans-2-aminocyclopropyl)alanine
Oleg V. Larionov, Sergei I. Kozhushkov, Melanie Brandl and Armin de Meijere*
Institut für Organische Chemie der Georg-August-Universität Göttingen, D-37077 Göttingen, Germany.
Fax: + 49 0 551 39 9475; e-mail: Armin.deMeijere@chemie.uni-goettingen.de
10.1070/MC2003v013n05ABEH001817
All the four stereoisomers of 3-(trans-2-aminocyclopropyl)alanine – a key constituent of the potential antitumor agent belactosin A –
were prepared by simple catalytic hydrogenation of (2S,1'S,2'S)-, (2S,1'R,2'R)-, (2R,1'R,2'R)-, and (2R,1'S,2'S)-3-(trans-2-nitro-
cyclopropyl)alanines in 95, 93, 91 and 92% yields, respectively.
Most of the over two dozen known naturally occurring amino
acids containing a cyclopropyl group, as well as most of the
NO2
cyclopropyl analogues of natural amino acids, are responsible
for interesting biological activities of compounds containing
them as constituents.1 Among such natural products, peptido-
O
lactone hormaomycin 1, which influences the secondary
H
O
metabolite production of certain bacteria,2 and recently isolated
belactosin A 2, which is interesting as a potential antitumor
agent and effects proteasome inhibition,3 are especially intriguing
as they contain previously unknown 3-(trans-2-nitrocyclo-
propyl)alanines [(NcP)ala] (2S,1'R,2'R)-3 and (2R,1'R,2'R)-3,
and 3-(trans-2-aminocyclopropyl)alanine [(AcP)ala] (2S,1'R,2'S)-4
as key constituents (Scheme 1).
NH HN
O
NH
N
HN
O
O
O
O
NO2
O
HN
Recently, Armstrong and Scutt4 reported an elegant multistep
synthesis of an epimer of naturally occurring (AcP)ala 4 starting
from commercially available, yet expensive, glycidol benzyl
ether with a key step like the one in our previously published
synthesis of 3,3-dideuterio-3-(trans-2-aminocyclopropyl)alanine
3,3-D2-rac-4.5 It is obvious that our recently developed asym-
metric synthesis of all the four diastereomers of (NcP)ala 3
(Scheme 1),6 which in terms of ease and productivity estab-
lished a big leap forward in comparison with the previously
reported multistep procedure,7 also offered itself as a rational
access to all the four stereoisomers of (AcP)ala 4 in multi-
gramme quantities simply by chemoselective reduction of the
nitro group in enantiomerically pure (NcP)ala 3.
HN
O
H
N
Cl
HO
1
O
H
N
H
N
O
H2N
CO2H
O
O
However, an attempted catalytic hydrogenation of the hydro-
chloride of racemic (NcP)ala rac-3·HCl in water, analogously
to the preparation of 2-(trans-2-aminocyclopropyl)glycine,7(b),(d)
furnished a non-separable mixture of starting rac-3·HCl, target
rac-4·HCl and the hydrochloride of racemic lysine rac-7·HCl
in different ratios (Scheme 2, Table 1). No improvement was
observed upon either varying the solvent, the catalyst or the
hydrogen pressure or by applying other reducing agents recom-
mended for the chemoselective reduction of aliphatic nitro into
amino derivatives,8 such as ammonium formate under palladium
catalysis or sodium borohydride under nickel catalysis (Table 1).
Most probably, protonation of the amino group on the three-
membered ring in the target molecule creates a kind of donor–
acceptor-substituted cyclopropane,9 which is particularly prone
to undergo ring opening under hydrogenation conditions.
However, catalytic hydrogenation of free rac-3 under neutral
2
H2N
NH2
H2N
NO2
CO2H
CO2H
4
3
O
O
H
H
N
H2N
NO2
Ni
CO2H
(2S,1'S,2'S)-3 (24%, ee 96%)
N
N
O
*
(S)-6 or (R)-6
H2N
NO2
i, NaH (1.2 equiv.)
DMF/MeCN
ii, 60% aq. AcOH
iii, 6 N aq. HCl, MeOH
reflux 7 min
CO2H
(2S,1'R,2'R)-3 (32%, ee 99%)
Table 1 Attempted chemoselective reduction of the nitro group in the
hydrochloride of racemic 2-(trans-2-nitrocyclopropyl)alanine (rac-3·HCl)
under various conditions at ambient temperature (see Scheme 2).
H2N
NO2
NO2
iv, DOWEX
I
Pressure
of H2/bar
(Reaction
time/h)
Yield (%)
Reducing
Entry agent
CO2H
(2R,1'R,2'R)-3 (22%, ee 96%)
H2N NO2
Solvent
rac-5
(catalyst)
rac-3·HCl rac-4·HCl rac-7·HCl
1
2
3
4
5
H2 (Pd/C)
H2 (Pd/C)
H2 (Pd/C)
H2 (PdCl2)
NaBH4
1 (24)
2 (60)
2 (20)
1 (96)
1 (20)
H2O
H2O
H2O
MeOH
MeOH
55
0
0
0
15
40
60
53
0
0
35
41
94
80
CO2H
3
(2R,1'S,2'S)- (18%, 99%)
ee
0
(NiCl2·6H2O)
HCO2NH4
(Pd/C)
Scheme 1
6
1 (20)
MeOH
10
0
83
– 199 –

, 2003, 13(5), 199–200
These achievements, which constitute an overall six-step
enantioselective synthesis of (AcP)ala 4 from inexpensive
achiral and racemic starting materials, not only facilitate the
forthcoming total synthesis of belactosin A 2 but also approach
to synthetic analogues of naturally occurring small peptides to
modify their biological activity. For example, the (2S,1'S,2'R)-
3-(trans-2-aminocyclopropyl)alanine [(2S,1'S,2'R)-4] has re-
cently been incorporated instead of the corresponding (NcP)ala
[(2S,1'R,2'R)-3] in the side chain of hormaomycin 1 in order
to be able to test the potential biological activity of modified
peptidolactones of the hormaomycin type.
rac-3·HCl
H2N
NH3Cl
NH3Cl
ClH3N
NO2
[H]
CO2H
Conditions
CO2H
rac-4·HCl
rac-3·HCl
H2N
CO2H
rac-7·HCl
This work was supported by Deutsche Forschungsgemein-
schaft (SFB 416, Project A3) and Bayer AG (Leverkusen). We
are indebted to BASF AG, Bayer AG, Chemetall GmbH, and
Degussa AG for generous gifts of chemicals. We are grateful
to Professor Yu. N. Belokon, A. N. Nesmeyanov Institute of
Organoelement Compounds (Moscow), for fruitful discussions,
and to Dr. B. Knieriem for his careful reading of the final
manuscript.
Scheme 2
conditions in anhydrous methanol afforded the desired cyclo-
propyl-containing rac-4 as the sole product.
Under these conditions, (2S,1'R,2'S)-, (2S,1'S,2'R)-,
(2R,1'S,2'R)-, and (2R,1'R,2'S)-3-(2-aminocyclopropyl)alanines
4 were obtained from corresponding (2S,1'S,2'S)-, (2S,1'R,2'R)-,
(2R,1'R,2'R)-, and (2R,1'S,2'S)-3-(2-nitrocyclopropyl)alanines 3
in 95, 93, 91 and 92% yields, respectively (Scheme 3).†
References
1 (a) J. Salaün and M. S. Baird, Curr. Med. Chem., 1995, 2, 511; (b)
J. Salaün, Top. Curr. Chem., 2000, 207, 1; (c) J. Pietruszka, Chem. Rev.,
2003, 103, 1051; (d) F. Gnad and O. Reiser, Chem. Rev., 2003, 103, 1603;
(d) L. A. Wessjohann, W. Brandt and T. Thiemann, Chem. Rev., 2003,
103, 1625.
H2N
NO2
H2N
NH2
CO2H
(2S,1'R,2'S)-4 (95%, ee 96%)
CO2H
(2S,1'S,2'S)-3
2 (a) N. Andres, H. Wolf, H. Zähner, E. Rössner, A. Zeeck, W. A. König
and V. Sinnwell, Helv. Chim. Acta, 1989, 72, 426; (b) E. Rössner,
A. Zeeck and W. A. König, Angew. Chem., 1990, 102, 84 (Angew. Chem.,
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3 (a) A. Asai, A. Hasegawa, K. Ochiai, Y. Yamashita and T. Mizukami, J.
Antibiotics, 2000, 53, 81; (b) A. Asai, T. Mizukami, Y. Yamashita,
S. Akinaga, S. Ikeda and Y. Kanda, Eur. Patent, 1166781, 2002 (Chem.
Abstr., 2002, 133, 120677h).
H2N
NO2
H2N
NH2
CO2H
CO2H
(2S,1'S,2'R)-4 (93%, ee 99%)
(2S,1'R,2'R)-3
H2N
H2, Pd/C (10 mol%)
NO2
NO2
H2N
NH2
MeOH, 20 °C,
4 A. Armstrong and J. N. Scutt, Org. Lett., 2003, 5, 2331.
5 M. Brandl, S. I. Kozhushkov, K. Loscha, O. V. Kokoreva, D. S. Yufit,
J. A. K. Howard and A. de Meijere, Synlett, 2000, 1741.
24 h
CO2H
CO2H
(2R,1'S,2'R)-4 (91%, ee 96%)
(2R,1'R,2'R)-3
6 O. V. Larionov, T. F. Savel’eva, K. A. Kochetkov, N. S. Ikonnikov,
S. I. Kozhushkov, D. S. Yufit, J. A. K. Howard, V. N. Khrustalev, Y. N.
Belokon and A. de Meijere, Eur. J. Org. Chem., 2003, 869. In this paper,
the configurations of the four diastereomers of 3-(trans-2-nitrocyclo-
propyl)alanines 3 were drawn correctly, but the R,S-nomenclature was
applied wrongly.
7 (a) J. Zindel, A. Zeeck, W. A. König and A. de Meijere, Tetrahedron
Lett., 1993, 34, 1917; (b) J. Zindel and A. de Meijere, Synthesis, 1994,
190; (c) J. Zindel and A. de Meijere, J. Org. Chem., 1995, 60, 2968; (d)
J. Zindel, Dissertation, Universität Göttingen, 1993.
8 (a) D. Lucet, L. Toupet, T. L. Gall and C. Mioskowski, J. Org. Chem.,
1997, 62, 2682; (b) S. Ram and R. E. Ehrenkaufer, Tetrahedron Lett.,
1984, 25, 3415; (c) A. R. Khomutov, J. J. Vepsaelaeinen, J. Jouko, A. S.
Shetsov, T. Hyvoenen and T. A. Keinaenen, Tetrahedron, 1996, 52, 13751.
9 For the most recent review see: H.-U. Reissig and R. Zimmer, Chem.
Rev., 2003, 103, 1151, and references 4–6 cited therein.
H2N
H2N
NH2
CO2H
CO2H
(2R,1'R,2'S)-4 (92%, ee 99%)
(2R,1'S,2'S)-3
Scheme 3
†
General procedure for hydrogenative transformation of the [(NcP)ala]
diastereomers into the corresponding (aminocyclopropyl)alanines
[(AcP)ala]. To a solution of enantiomerically pure amino acid 3
(348 mg, 2.0 mmol) in anhydrous MeOH (160 ml) was added Pd/C
(Merck, 10% Pd, 0.2 mmol, 0.21 g). The mixture was vigorously stirred
under H2 (1 bar) at 20 °C for 24 h. The catalyst was filtered off, the
filtrate was concentrated under reduced pressure to give desired
(2S,1'R,2'S)-, (2S,1'S,2'R)-, (2R,1'S,2'R)-, and (2R,1'R,2'S)-3-(trans-2-
aminocyclopropyl)alanines 4 in 95, 93, 91 and 92% yields, respectively,
after recrystallization from PriOH–H2O.
(2S,1'R,2'S)-4: colourless solid, mp 148 °C (decomp.), [a]D20 +29.3°
(c 0.6, H2O). H NMR (250 MHz, D2O) d: 0.60 (ddd, 1H J 5.9, 6.3,
1
7.2 Hz), 0.77 (m, 1H), 0.97 (m, 1H), 1.68 (m, 1H), 1.81 (m, 1H), 2.28
(m, 1H), 3.66 (t, 1H, J 6.2, 6.2 Hz). 13C NMR (62.9 MHz, D2O) d: 13.97
(CH2), 17.07 (CH), 31.67 (CH), 36.51 (CH2), 57.24 (CH), 179.66 (C).
IR (n/cm–1): 3629, 3056, 2953, 1733, 1630, 1587.
(2S,1'S,2'R)-4: colourless solid, mp 150 °C, [a]D20 –37.8° (c 0.4, H2O).
1H NMR (250 MHz, D2O) d: 0.60 (ddd, 1H, J 5.8, 6.5, 7.3 Hz), 0.76 (m,
1H), 0.92 (m, 1H), 1.71 (m, 1H), 1.80 (m, 1H), 2.23 (m, 1H), 3.63 (ddd,
1H, J 5.7, 5.7, 5.8 Hz). 13C NMR (62.9 MHz, D2O) d: 14.19 (CH2),
17.33 (CH), 31.88 (CH), 36.70 (CH2), 57.82 (CH), 179.69 (C). IR
(n/cm–1): 3359, 3072, 2927, 1617, 1406, 1322.
(2R,1'S,2'R)-4: colourless solid, mp 153 °C (decomp.), [a]D20 –29.1°
(c 0.4, H2O). 1H, 13C NMR and IR spectra are virtually identical to those
of (2S,1'R,2'S)-4.
(2R,1'R,2'S)-4: colourless solid, mp 148 °C (decomp.), [a]D20 +37.7°
(c 0.6, H2O). 1H, 13C NMR and IR spectra are virtually identical to those
of (2S,1'S,2'R)-4.
Received: 30th June 2003; Com. 03/2143
– 200 –