Investigation of diketopiperazines containing a guanidino-functionalized sidechain as potential catalysts of enantioselective strecker reactions

Article abstract of DOI:10.1002/ejoc.200500044

Diketopiperazine 1 consisting of L-(γ-guanidino-α-amino) butyric acid and L-phenylalanine was synthesized as the hydroacetate and as the hydronitrate. Its structure was confirmed by X-ray analysis. In contrast to reports in the litera ture (Lipton et al.)

Full text of DOI:10.1002/ejoc.200500044

SHORT COMMUNICATION
Investigation of Diketopiperazines Containing a Guanidino-Functionalized
Sidechain as Potential Catalysts of Enantioselective Strecker Reactions
[a]
[a]
[a]
[b]
Christian Becker, Christine Hoben, Dieter Schollmeyer, Günther Scherr, and
Horst Kunz*[
a]
Keywords: Enantioselective catalysis / Strecker reaction / α-amino acid derivatives / Diketopiperazines
Diketopiperazine 1 consisting of
L
-(γ-guanidino-α-amino)bu-
ture (Lipton et al.), compound 1 does not induce enantiose-
levtive catalysis of Strecker reactions.
tyric acid and -phenylalanine was synthesized as the hy-
L
droacetate and as the hydronitrate. Its structure was con-
firmed by X-ray analysis. In contrast to reports in the litera-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Enantiomerically pure amino acids are of much interest
as building blocks for biologically active compounds, addi-
tives for animal feed or as starting materials for syntheses
of chiral molecules. The Strecker reaction[ still plays an
important role in the synthesis of amino acids. Most indus-
trial syntheses of amino acids include enzymatic resolutions
of racemic mixtures,[ although efficient stereoselective
1]
2]
[3]
Strecker reactions based on chiral auxiliaries or enanti-
[
4]
oselective catalysts, have been developed during the past
years.
For certain application we had been interested in a metal
salt-free preparation of amino acids. The asymmetric
Scheme 1. a) CF
3
COOH/CH
2
Cl
2
2 3
(2:15); b) THF/H O/NEt
Strecker reaction catalyzed by cyclic dipeptide 1 formed (50:50:1) 83%; c) H /Pd-C (10%), THF/MeOH (3:1), 0.2% AcOH,
2
Ͼ98%. Boc: tert-butyloxycarbonyl; Z: benzyloxycarbonyl.
from l-(γ-guanidino-α-amino)butyric acid and l-phenylala-
nine according to Lipton et al.[ seemed a particularly
5]
promising procedure. This catalyst was synthesized as de-
presence of 0.2% acetic acid afforded the catalyst 1 as the
hydroacetate in analytically pure form. Compound 1 was
[
5]
4
scribed via diketopiperazine 2 obtained from l-(N -tert-
butyloxycarbonyl)-2,4-diaminobutyric acid and l-phenylal-
anine (Scheme 1).
hardly soluble in water, optical rotation had therefore to be
2
0
measured in dimethylformamide [([α] = –41.1 (c = 1,
D
However, the physical properties of compound 2 we iso-
[
5]
25
DMF); ref. ([α] = –43.3 (c = 3.1, H O)].
[6]
D
2
lated differed dramatically in optical rotation and solubil-
ity from those reported in the literature.[ Compound 2 was
soluble in methanol only after the addition of dichloro-
All efforts to use diketopiperazine 1 as a catalyst in the
enantioselective Strecker synthesis turned out quite disap-
5]
pointing. Exposure of N-benzhydrylbenzaldimine
5
[
5]
methane. In contrast to the data given in the literature,
the reaction of N-deprotected 2 with 3,5-dimethylpyrazol-
-carboxamidinium nitrate gave the desired 4-guanidino
(1 mmol) to HCN (2 mmol) in 3.6 mL of methanol at
–
25 °C in the presence of diketopiperazine 1 afforded
1
[8]
racemic aminonitrile 6 in moderate yield (Scheme 2).
compound as a mixture with impurities, which could not
be separated by HPLC. Therefore, after removal of the Boc
group from 2 the guanidino group was introduced by the
reaction with N,NЈ-dibenzyloxycarbonyl-(S)-methyl-isothi-
[
7]
ourea 3 to furnish the double Z-protected diketopiperaz-
ine 4. Hydrogenolyses of the Z-protecting groups in the
[
[
a] Institut für Organische Chemie der Universität Mainz,
Duesbergweg 10–14, 55128 Mainz, Germany
Scheme 2.
b] Global Polymer Research – Functional Intermediate Polymers
Polyurethanes, BASF Aktiengesellschaft, GKF/C-B1,
Without addition of 1 the reaction proceeded slightly
faster. Also changing solvents, origin of HCN or N-substi-
6
7056 Ludwigshafen, Germany
Eur. J. Org. Chem. 2005, 1497–1499
DOI: 10.1002/ejoc.200500044
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1497

C. Becker, C. Hoben, D. Schollmeyer, G. Scherr, H. Kunz
SHORT COMMUNICATION
Figure 1. X-ray structure analysis of hydronitrate of 1.
4
136; e) U. D. Wermuth, I. D. Jenkins, R. C. Bott, K. A. Briel,
tution pattern (p-MeO-C H -CH -, allyl) of the substrate
6
4
2
G. Smith, Austr. J. Chem. 2004, 57, 461.
did not provide any enantioselectivity in those reactions.
Performing the reaction at higher temperature (22 °C) or
application of the N-allylimine improved only the yield of
racemic product up to Ͼ80%. These aberrations of chemi-
cal and mentioned physical properties of compound 1 syn-
thesized by us at first raised the suspicion of an epimeriz-
ation during the cyclization step which forms the diketopip-
[
4] a) M. Takamura, Y. Hamashima, H. Usuda, M. Kanai, M.
Shibasaki, Angew. Chem. 2000, 112, 1716; Angew. Chem. Int.
Ed. 2000, 39, 1650; b) H. Ishitani, S. Komiyama, S. Kobayashi,
Angew. Chem. 1998, 110, 3369; Angew. Chem. Int. Ed. 1998,
3
1
7, 3186; c) M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc.
998, 120, 5315; d) J. R. Porter, K. W. Kuntz, M. L. Snapper,
A. H. Hoveyda, J. Am. Chem. Soc. 2000, 122, 2657–2658; e)
E. J. Corey, M. J. Gronan, Org. Lett. 1999, 1, 157; f) theoretical
considerations: J. Li, W.-Y. Jiang, K.-L. Han, G.-Z. He, C. Li,
J. Org. Chem. 2003, 68, 87896; g) Review: L. Yet, Angew. Chem.
Int. Ed. 2001, 40, 875; Angew. Chem. 2001, 113, 900.
5] M. S. Iyer, K. M. Gigstad, N. D. Namedev, M. Lipton, J. Am.
Chem. Soc. 1996, 118, 4910–4911.
[
8]
erazine ring 2.
Only an X-ray structure analysis could clarify the stereo-
chemistry of diketopiperazine 1. After numerous unsuccess-
ful efforts the hydronitrate of 1 finally crystallized. It was
[
obtained from the hydroacetate by treatment with nitric [6] 2: [α] 2D 0 = –23.1 (c = 0.5, MeOH/CH Cl , 1:1); ref.[5] {[α]25
2
2
D
=
acid and evaporation to dryness.[ This X-ray analysis (Fig-
ure 1) shows that the nitrate anions net the diketopiperazine
molecules in two almost orthogonal plains through hydro-
gen bonding to the guanidinium and cycloamide groups.
The X-ray analysis in particular gives evidence, that the di-
ketopiperazine we had synthesized in fact is structure 1.
However, this compound 1 definitely is not an enantiose-
lective catalyst of the Strecker reaction at 0 °C, –25 °C or
9]
–3.1 (c = 9.0, MeOH)}.
[
[
7] B. Lal, A. K. Gangopadhyay, Tetrahedron Lett. 1996, 37, 2483.
8] Experimental procedure: A solution of imine 5 (1 mmol) and
catalyst 1 (20 μmol) in 3 mL of dry methanol under argon was
cooled to –25 °C. A 3 m solution of HCN either generated from
H SO and KCN or in situ from TMSCN was added by sy-
2
4
ringe. The solution was stirred at –25 °C for 12 h and then
warmed to room temperature. Methanol and excess HCN were
removed by evaporation and the crude aminonitrile was puri-
fied by flash chromatography (SiO
2
, cyclohexane/ethyl acetate,
–70 °C, neither as the hydroacetate nor as the hydronitrate.
1
0:1) to afford aminonitrile 6 as a colourless solid, 93.2 mg
1
Since the reaction proceeds in a clear solution under the
(34%), m. p. 101 °C. H NMR (CDCl
3
, 200 MHz, ppm): δ =
3
[
5,8]
7.67–7.24 (m, 15 H, Ar), 5.32 (s, 1 H, CHAr ), 4.65 (d, J =
conditions applied,
polymorphism of the solid diketo-
2
3
13
[
5]
11.2 Hz, 1 H, ϪCH–CN), 2.21 (d, J = 11.2 Hz, 1 H, NH).
NMR (CDCl , 50 MHz, ppm): δ = 142.9, 141.3, 135.1 (Cipso),
29.1, 128.9, 128.1, 127.4, 127.3 (Ar), 118.9 (CN), 65.7, 52.5
(CAr /C–CN). C H N : calcd. C 84.52, H 6.08, N 9.39;
C
piperazine does not play any role in the process.
It should be mentioned, that the corresponding arginine-
derived diketopiperazine c-[Arg-Phe][10] also does not cata-
lyze the Strecker reaction of aldimines.
3
1
2
21 18
2
found C 84.32, H 6.18, N 9.39.
Comparison of NMR-data of herein synthesized compound 1
with those described in ref.[ gives no information, particularly
for there is no signal assignment given in the supporting infor-
mation pages of ref.[ Spectra measured in DMSO show sig-
nificant differences, however, it is not obvious which salt of 1
5]
5]
[
[
1] A. Strecker, Ann. Chem. Pharm. 1850, 75, 27.
2] a) H. Gröger, K. Drauz, in Asymmetric Catalysis on Industrial
Scale: Challenges, Approches and Solutions (Eds.: H. U. Blaser,
E. Schmidt) Wiley-VCH, Weinheim 2004, p. 131; b) O. May, S.
Verseck, A. S. Bommarius, K. Drauz, Org. Proc. Res. Dev.
is described in ref.[ The HR-MS data given in ref. do not
5]
[5]
match the formula given.
Crystal structure for 1·HNO
352.36 g•mol , size of crystal 0.128× 0.128× 0.256 mm ,
triclin, P1, a = 9.242(3) Å, b = 9.502(4) Å, c = 11.449(4) Å, α
= 112.66(2)°, β = 104.91(3)°, γ = 98.91(3)°, V = 859.4(6) Å , z
= 2, dcalcd. = 1.362 g•cm , μ (Cu-K
372, T = –130 °C; R = 0.0857, wR
+
×NO –
3
: [C14
H
20
N
5
O
2
3
], M
r
=
–
1
3
2
002, 6, 452.
[
3] a) R. M. Williams, Synthesis of Optically Active α-Amino Acids,
Pergamon, Oxford, 1989; b) R. M. Williams, J. A. Hendrix,
Chem. Rev. 1992, 92, 889; c) R. O. Duthaler, Tetrahedron 1994,
3
–
3
–1
α
) = 0.89 mm , F(000) =
2
= 0.2220 for 5530 reflec-
5
0, 1539; d) G. Zech, H. Kunz, Chemistry Eur. J. 2004, 10,
1498
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 1497–1499

Diketopiperazines as Potential Catalysts of Enantioselective Strecker Reactions
SHORT COMMUNICATION
[9] Hydronitrate of 1: m.p. 235 °C (dec.). [α]2
2
= –27.3 (c = 1,
tions. CCDC-250616 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
D
DMSO).
2
0
[10] c-[L-Arg-l-Phe]: [α]
D
3
= 11.3 (c = 1, CF COOH).
Received: January 18, 2005
Eur. J. Org. Chem. 2005, 1497–1499
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1499