A new approach to the synthesis of selectively protected (2S)-1,2,4-triaminobutane derivatives

Article abstract of DOI:10.1055/s-2005-869989

An efficient synthesis of selectively protected (2S)-1,2,4-triaminobutane from L-glutamic acid via (2S)-N⁴-benzyloxycarbonyl-2,4- diaminobutanamid is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869989

SHORT PAPER
2281
A New Approach to the Synthesis of Selectively Protected (2S)-1,2,4-
Triaminobutane Derivatives
S
electively Protect
d
ed
(
2
S
)-1,2,4
a
-Triaminob
m
utane Derivatives P. Treder,*a Aleksandra Walkowiak,a Włodzimierz Zgoda,b Ryszard Andruszkiewicza
a
Department of Pharmaceutical Technology and Biochemistry, Gdaꢀsk University of Technology, G. Narutowicza St 11/12,
80-952 Gdaꢀsk, Poland
Fax +48(58)3471144; E-mail: ryszarda@chem.pg.gda.pl
b
Department of Medicinal Chemistry, Medical University of Gdaꢀsk, Dꢁbinki St 1, 80-952 Gdaꢀsk, Poland
Received 24 January 2005; revised 29 March 2005
acid derivatives (Scheme 1). These compounds may be di-
rectly used for the preparation of heterocyclic compounds.
Abstract: An efficient synthesis of selectively protected (2S)-
1,2,4-triaminobutane from L-glutamic acid via (2S)-N4-benzyloxy-
carbonyl-2,4-diaminobutanamid is described.
(2S)-N4-benzyloxycarbonyl-2,4-diaminobutanoic acid (2)
was obtained directly from L-Glu (1) by a modification of
the reported procedures applying Schmidt rearrangement
conditions14,15 and copper complexes method.15–18 In the
second step of the reaction, there was no need to use the
pure (2S)-2,4-diaminobutanoic acid. In order to avoid the
laborious isolation of (2S)-2,4-diaminobutanoic acid, a
crude mixture of (2S)-2,4-diaminobutanoic acid and L-
Glu was converted into copper complexes and reacted
with benzyl chloroformate. Pure 2 was precipitated from
the reaction mixture after decomposition of the copper
complexes with EDTA in 1 M HCl18 when pH was adjust-
ed to 4–5. (2S)-N4-Benzyloxycarbonyl-2,4-diaminobu-
tanoic acid methyl ester16 was prepared under standard
reaction conditions and converted into (2S)-N4-benzyl-
oxycarbonyl-2,4-diaminobutanamide (3), applying the re-
ported amino acids amides preparation method.7,8 Then,
(2S)-N4-benzyloxycarbonyl-2,4-diaminobutanamide (3)
was reduced with diborane in THF (diborane selectively
reduces amides2,7,8,19–25 in the presence of alkoxycarbonyl
groups22–25) yielding the selectively N4-protected (2S)-
1,2,4-triaminobutane derivative 4. The diborane reduction
of 3, however under reported amino acids reductions con-
ditions,7,8 gave a complex mixture of various reaction
products. In fact, the amide was reduced but also a signif-
icant loss of the benzyloxycarbonyl protecting group was
Key words: amides, amines, amino acids, protecting groups, re-
ductions
Vicinal diamines are important ligands for metal
complexes1–5 and useful substrates for heterocyclic com-
pound synthesis.5–8 1,2,4-Triaminobutane derivatives
were previously applied for preparation of dicarboxylic
acids bis(1,2,4-triaminebutane-N4)amides with two vici-
nal diamines. These compounds were used for synthesis
of bis[platinum(II)] complexes capable of interstrand-
DNA binding.9–12 It is known, however, that only one
method for chiral and selectively protected 1,2,4-triami-
nobutane has been reported.9–11 The final products were
obtained as a result of multi-step synthesis from L- or D-
pyroglutamic acid methyl ester via L- or D-(5-hydroxy-
methyl)-2-pyrrolidone and L- or D-4,5-diaminopentanoic
acid derivatives.
Natural a-amino acids with one functional group in the
side chain may be regarded as a useful source for the syn-
thesis of 1,2-diamines bearing a third functional
group.5,6,13 We have developed a novel method for the
preparation of selectively protected (2S)-1,2,4-triamino-
butane starting from L-glutamic acid as a source of chiral-
ity via (2S)-N4-benzyloxycarbonyl-2,4-diaminobutanoic
Scheme 1
SYNTHESIS 2005, No. 14, pp 2281–2283
x
x.
x
x
.
2
0
0
5
Advanced online publication: 13.07.2005
DOI: 10.1055/s-2005-869989; Art ID: T01005SS
© Georg Thieme Verlag Stuttgart · New York

2282
A. P. Treder et al.
SHORT PAPER
1H NMR (500 MHz, DMSO-d6–TFA): d = 1.82–2.00 (m, 2 H,
CHCH2), 3.15 (ddd, J1 = 7.4 Hz, J2 = 13.7 Hz, J3 = 8.3 Hz, 2 H,
CH2CH2), 3.92 (dd, J1 = 5.3 Hz, J2 = 10.9 Hz, 1 H, CH2CH), 5.05
(s, 2 H, CH2Ph), 7.28–7.33 (m, 6 H, C6H5, NH), 8.08–8.17 (br s, 3
unavoidable. Ultimately, it was found that reaction time (5
h) and slightly lowered temperature (55 °C) were suffi-
cient for completion of this reaction. Due to a good solu-
bility of the free diamine in the aqueous phase, (2S)-N4-
benzyloxycarbonyl-1,2,4-triaminobutane (4) was extract-
ed with Et2O from saturated NaCl solution. The free ami-
no groups in 4 were protected with tert-butoxycarbonyl
groups using di-tert-butoxycarbonyldicarbonate (Boc2O)
yielding (2S)-N4-benzyloxycarbonyl-N1,N2-di-tert-but-
oxycarbonyl-1,2,4-triaminobutane (5). The product was
finally purified by column chromatography. The benzyl-
oxycarbonyl group was removed by hydrogenolysis (5%
Pd/C) to afford (2S)-N1,N2-di-tert-butoxycarbonyl-1,2,4-
triaminobutane (6).
+
H, NH3 ).
13C NMR (200 MHz, D2O–TFA): d = 32.7, 39.1, 53.2, 70.0, 130.6,
131.2, 131.6, 139.1, 161.4, 174.4.
Anal. Calcd for C12H16N2O4: C, 57.13; H, 6.39; N, 11.10. Found: C,
57.04; H, 6.43; N, 10.97.
(2S)-N4-Benzyloxycarbonyl-2,4-diaminobutanamide (3)
(2S)-N4-Benzyloxycarbonyl-2,4-diaminobutanoic acid (2, 5.13 g,
20 mmol) was dissolved in 5.7 M absolute MeOH–HCl (27 mL) and
absolute MeOH (15 mL). The reaction mixture was kept for 48 h at
r.t. The volatiles were evaporated under reduced pressure. The res-
idue was dissolved in CHCl3 (200 mL) and washed with sat.
Na2CO3 solution to adjust pH of the water to about 9. The organic
phase was separated, dried (MgSO4) and evaporated yielding an
oily ester (4.07 g, 75%). The oil was dissolved in 24% MeOH–NH3
(40 mL) and kept for 72 h at r.t. under TLC control. The volatiles
were evaporated under reduced pressure yielding a white precipitate
of the amide. It was crystallized from MeOH–Et2O–hexane. Yield:
3.84 g (94%); mp 112–114 °C; [a]D24 +4.3 (c = 2, EtOH).
In conclusion, we have developed a five-step method for
the preparation of selectively protected (2S)-1,2,4-triami-
nobutane derivatives from L-glutamic acid which is short-
er than the reported method starting from L-pyroglutamic
acid methyl ester.9–11 The total yield of the selectively pro-
tected triamine synthesis was 13% in comparison to the
reported 27%. The yield was mainly limited by the first
reaction (Schmidt rearrangement) but commercially
available selectively protected (2S)-2,4-diaminobutanoic
acid derivatives could be used as well. Moreover, the re-
action conditions can be easily adapted to the preparation
of (2S)-1,2,4-triaminobutane derivatives as well as their
(R)-isomer in large quantities.
1H NMR (500 MHz, DMSO-d6–TFA): d = 1.80–1.92 (m, 2 H,
CHCH2), 3.03–3.17 (m, 2 H, CH2CH2), 3.72 (dd, J1 = 5.8 Hz, J2 =
11.8 Hz, 1 H, CH2CH), 5.03 (s, 2 H, CH2Ph), 6.95 (s, 1 H, NH),
7.28–7.39 (m, 5 H, C6H5), 7.61 (s, 1 H, NH), 7.87 (br s, 1 H, NH),
+
8.11 (s, 3 H, NH3 ).
13C NMR (200 MHz, DMSO-d6): d = 35.5, 38.0, 52.9, 65.5, 128.0,
128.6, 137.5, 156.4, 177.6.
Anal. Calcd for C12H17N3O3: C, 57.36; H, 6.82; N, 16.72. Found: C,
57.23; H, 6.70; N, 16.65.
1H NMR spectra were recorded on Varian Unity Plus 500 MHz
spectrometer. 13C NMR spectra were recorded on a Varian Gemini
200 MHz spectrometer. The optical rotations were measured on a
POLAMAT A Carl Zeiss Jena Polarimeter. Microanalyses were
performed on a Carlo Erba CHNS-O-EA1180 instrument for C, H,
N. Melting points are uncorrected.
(2S)-N4-Benzyloxycarbonyl-1,2,4-triaminobutane (4)
(2S)-N4-Benzyloxycarbonyl-2,4-diaminobutanamide (3, 2.09 g,
8.33 mmol) was added to anhyd THF (48 mL). The reaction flask
was flushed with Ar and cooled in an ice bath. Next 2.8 M THF–
BH3 (15 mL, 42 mmol) was slowly added. The reaction mixture was
warmed in 55 °C for 5 h. The solution was cooled in an ice bath and
absolute MeOH (15 mL) was added. The mixture was kept at r.t.
overnight. Next 5.7 M absolute MeOH–HCl (3.7 mL) was added
and the volatiles were evaporated under reduced pressure. The oily
residue was dissolved in absolute MeOH (15 mL) and evaporated.
The last action was repeated three times to remove the volatile bo-
ron compounds. The residue was dissolved in H2O (10 mL), acidi-
fied to pH = 2 with concd HCl and washed with Et2O (3 × 5 mL).
Next the water phase was saturated with NaCl, alkalized with 10 M
NaOH and extracted with Et2O (8 × 15 mL). The ethereal phase was
dried with Na2CO3 and evaporated under reduced pressure yielding
an oil of crude (2S)-N4-benzyloxycarbonyl-1,2,4-triaminobutane
(1.32 g, 67%). The product was pure enough for further step of the
synthesis. It was stored as dichloride salt. Small samples of the
product (tens to hundreds mg) were purified by ion exchange chro-
matography (Amberlit IRC 50/NH4+ in a gradient of Et3N (0.005–
0.4 M). The product was also separated by column chromatography
(Sephadex LH-20, MeOH); [a]D24 –3.4 (c = 2, EtOH).
(2S)-N4-Benzyloxycarbonyl-2,4-diaminobutanoic Acid (2)
L-Glu (1, 12.5g, 85 mmol) was dissolved in concd H2SO4 (43 mL)
and CHCl3 (26 mL) was added. To the stirred solution of amino acid
NaN3 (6.8 g, 105 mmol) was added in small portions over 3 h. The
obtained solution was warmed for 5–6 h at 50–60 °C. After cooling
the reaction mixture was poured on ice and the organic phase was
removed. The water phase was neutralized with hot saturated solu-
tion of Ba(OH)2. The precipitate of BaSO4 was filtered, washed
with water and the filtrate was concentrated to ca. 50 mL. Cop-
per(II) acetate (10 g, 50 mmol) was added and the solution was re-
fluxed for 1 h and then cooled to r.t. The deep blue solution was
neutralized to pH = 7.4 and filtered. The filtrate was mixed with di-
oxane (50 mL) and benzyl chloroformate (6.3 mL, 44 mmol) was
added followed by solid NaOH (to adjust the pH to 9). The mixture
was stirred for 24 h at r.t. The blue precipitate of amino acids copper
complexes was filtered and washed with water, EtOH and Et2O. The
blue solid was dissolved in a solution of EDTA (6.32 g, 17 mmol)
in 1 M HCl (100 mL). The insoluble residue was removed by filtra-
tion. The pH of the filtrate was adjusted to 5–6 with 10 M NaOH
and the solution was kept in a refrigerator overnight. The slightly
blue precipitate was filtered and the operation of copper complexes
decomposition with EDTA (1.5 g, 4 mmol) in 1 M HCl (70 mL) was
repeated. The white solid product was precipitated when pH of the
solution was again adjusted to 4–5. Yield: 5.65 g (26.4%); mp 225–
227 °C (Lit.16 mp 223 °C).
1H NMR (500 MHz, DMSO-d6–TFA): d = 1.68–1.82 (m, 2 H,
CHCH2), 3.02–3.07 (m, 2 H, CH2CH), 3.12–3.17 (m, 2 H,
CH2CH2), 3.34–3.43 (m, 1 H, CH2CH), 5.05 (s, 2 H, CH2Ph), 7.25–
+
7.40 (m, 6 H, C6H5, NH), 7.83–8.25 (br s, 6 H, 2 × NH3 ).
13C NMR (200 MHz, DMSO-d6): d = 30.7, 36.5, 41.1, 47.3, 65.7,
128.0, 128.7, 137.3, 156.4.
Anal. Calcd for C12H21Cl2N3O2: C, 46.46; H, 6.82; N, 13.55. Found:
C, 46.50; H, 6.74; N, 13.67.
Synthesis 2005, No. 14, 2281–2283 © Thieme Stuttgart · New York

SHORT PAPER
Selectively Protected (2S)-1,2,4-Triaminobutane Derivatives
2283
(2S)-N4-Benzyloxycarbonyl-N1,N2-di-tert-butoxycarbonyl-
1,2,4-triaminobutane (5)
Acknowledgment
(2S)-N4-Benzyloxycarbonyl-1,2,4-triaminobutane (4, 1.55 g, 6.5
mmol) was dissolved in MeOH (30 mL) and di-tert-butyldicarbon-
ate (2.85 g, 13.1 mmol) was added, followed by Et3N (1.8 mL, 13.1
mmol). The reaction mixture was stirred for 24 h at r.t. The volatiles
were evaporated under reduced pressure and the residue was dis-
solved in EtOAc (100 mL) and washed with 1 M KHSO4 (3 × 30
mL). The organic phase was dried (MgSO4) and evaporated under
reduced pressure yielding a white precipitate. The product was pu-
rified by column chromatography (silica gel, EtOAc–petroleum
ether, 1:1,5) and crystallized from EtOAc–hexane. Yield: 1.99 g
(70%); mp 118–120 °C (Lit.10 mp 122–123 °C); [a]D24 –23.9 (c = 2,
EtOH) {Lit.10 [a]D23 –23.8, (c = 2, EtOH)}.
The authors are indebted to Dr Zgoda Chemical Research Consul-
ting & Production and the Faculty of Chemistry, Gdaꢀsk University
of Technology for financial support.
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H, (CH3)3C] 1.65–1.74 (m, 2 H, CHCH2), 2.95–3.04 (m, 1 H,
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4.96–5.03 (br s, 1 H, NH), 5.1 (AB system, J1 = 12.2 Hz, J2 = 23.4
Hz, 2 H, CH2Ph), 5.63–6.71 (br s, 1 H, NH), 7.28–7.38 (m, 5 H,
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80.4, 129.1, 129.2, 129.7, 138.7, 158.7, 158.9, 159.0.
Anal. Calcd for C22H35N3O6: C, 60.39; H, 8.06; N, 9.60. Found: C,
60.24; H, 8.00; N, 9.71.
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(2S)-N1,N2-Di-tert-butoxycarbonyl-1,2,4-triaminobutane (6)
(2S)-N4-Benzyloxycarbonyl-N1,N2-di-tert-butoxycarbonyl-1,2,4-
triaminobutane (5, 1.70 g, 3.89 mmol) was dissolved in MeOH (40
mL) and AcOH (0.8 mL) was added. The solution was hydrogenat-
ed for 5 h (5% Pd/C). When the reaction was finished, the catalyst
was filtered and the volatiles were evaporated under reduced pres-
sure. The residue was dissolved in 1 M KHSO4 (40 mL) and washed
with Et2O (20 mL). The water phase was saturated with NaCl, alka-
lized with 1 M NaOH and extracted with Et2O (4 × 40 mL). The
ethereal phase was dried (MgSO4) and evaporated under reduced
pressure yielding a white solid product (1.12 g, 95%); mp 75–77 °C
(Lit.10 mp 78–80 °C). The product was also turned into acetate by
dissolving in Et2O and adding appropriate equivalent of AcOH. The
(2S)-N1,N2-di-tert-butoxycarbonyl-1,2,4-triaminobutane
acetate
was precipitated as a white solid; mp 130–131 °C; [a]D24 –7.2 (c =
2, EtOH).
1H NMR (500 MHz, CDCl3): d = 1.40 [s, 9 H, (CH3)3C], 1.43 [s, 9
H, (CH3)3C], 1.52–1.58 (m, 1 H, CHCH2), 1.81–1.90 (m, 1 H,
CHCH2), 2.00 (s, 3 H, CH3COO–), 2.82–2.88 (m, 1 H, CH2CH2),
2.95–3.05 (m, 1 H, CH2CH2), 3.15–3.30 (m, 2 H, CH2CH), 3.65–
3.78 (m, 1 H, CH2CH), 4.95–5.20 (br s, 4 H, NH), 5.43–5.48 (br s,
1 H, NH).
13C NMR (200 MHz, MeOD): d = 24.4, 29.0, 32.3, 38.3, 45.3, 49.3,
80.6, 80.8, 159.0, 180.4.
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Tetrahedron 1998, 54, 10671.
Anal. Calcd for C16H33N3O6: C, 52.87; H, 9.15; N, 11.56. Found: C,
52.90; H, 9.05; N, 11.48.
Synthesis 2005, No. 14, 2281–2283 © Thieme Stuttgart · New York