Convenient and simplified approaches to w-monoprotected triaminopropane derivatives: Key intermediates for bifunctional chelating agent synthesis

Article abstract of DOI:10.1055/s-1998-2128

High yields of selectively Ar-protected-1,2,3-triaminopropanes (1,3 or 1,2 functionalized diamines) were obtained in 6 or 4 steps from diamino alcohols or aminodiols, respectively. These two multi-step procedures involve protection of the amino group, substitution of the hydroxy group by an azido group and selective reduction. The conditions for the first procedure allow the preparation of various Af2-monoprotected-l,2,3-triaminopropanes 6a, 6b, but the second one is more convenient for obtaining N¹-Boc-1,2,3-triaminopropane 6'. These two simplified procedures, which provide functionalized 1,2 or 1,3 diamines easily and with good overall yields, could be useful for the synthesis of : bifunctional chelating agents.

Full text of DOI:10.1055/s-1998-2128

PAPERS
1113
Convenient and Simplified Approaches to N-Monoprotected Triaminopropane
Derivatives: Key Intermediates for Bifunctional Chelating Agent Synthesis
Eric Benoist,* Anthony Loussouarn, Patricia Remaud, Jean-François Chatal, Jean-François Gestin
INSERM U463 (ex U211), Institut de biologie, Chimie des bioconjugués, 9 quai Moncousu, F-44093 Nantes cedex, France
Fax: +33(240)356697; E-mail: ebenoist@nantes.inserm.fr
Received 3 November 1997; revised 12 February 1998
Abstract: High yields of selectively N-protected-1,2,3-triamino-
mercially available compounds. This paper describes two
different approaches to the synthesizing of N1-monopro-
tected-1,2,3-triamine and N2-monoprotected-1,2,3-tri-
amine derivatives from diamino alcohols or aminodiols.
The products are easily attainable from inexpensive start-
ing materials, involve relatively few reaction steps, with
no fastidious purification at each step, and provide a good
overall yield.
propanes (1,3 or 1,2 functionalized diamines) were obtained in 6
or 4 steps from diamino alcohols or aminodiols, respectively.
These two multi-step procedures involve protection of the amino
group, substitution of the hydroxy group by an azido group and
selective reduction. The conditions for the first procedure allow
the preparation of various N2-monoprotected-1,2,3-triaminopro-
panes 6a, 6b, but the second one is more convenient for obtaining
N1-Boc-1,2,3-triaminopropane 6'. These two simplified proce-
dures, which provide functionalized 1,2 or 1,3 diamines easily and
with good overall yields, could be useful for the synthesis of
bifunctional chelating agents.
The first method used two diamino alcohols, 1,3-diamino-
propan-2-ol and 2,3-diaminopropan-1-ol, as starting ma-
terials. The former is commercially available, whereas the
latter can be synthesized in different ways.16 We used
Fritzberg’s method14 to prepare the latter compound from
Key words: diamino alcohols, aminodiols, functionalized
diamines, BCA intermediates
Vicinal and 1,3-diamino groups play an important role in 1,3-diaminopropan-2-ol, with an overall yield of 14%.
medicinal chemistry, particularly in metal chelation,1,2 However, Demirci recently developed a simple chiral
and can serve as intermediates in the synthesis of method using L-serine as starting material which gave a
polyamines,3 heteromacrocycles4 and bifunctional chelat- 33% yield.16b
ing agents (BCA).5–7 The latter compounds, which con-
The two diamino alcohols, N-protected by Boc or Z
tain a powerful metal chelating group and a second func-
(Schotten-Baumann reaction) derivatives, gave good
tional group that can serve as a reactive moiety to form
yields (Scheme 1). The hydroxy group of 1 and 1' was
covalent bonds with biological substances such as anti-
activated as its methanesulfonyl intermediate and con-
bodies, have been used for cancer diagnosis or therapy.8,9
verted into azides 3 and 3' by treatment with sodium azide
Synthesis of such compounds generally requires diamines
in dimethylformamide at 60–70˚C, giving an 85% yield.
bearing another reactive function for further bonding with
Selective reduction of the azido group with tin(II) chloride
biological substances. Although many approaches have
dihydrate in degassed methanol17 was rapid (~4 h), pro-
been developed for vicinal and 1,3-diamine synthesis, few
viding a high yield, whereas the N-protecting group re-
methods have concerned the preparation of intermediates
mained unaffected under the conditions employed. Vari-
allowing the inclusion of another functionalized group on
ous N-amino protecting groups such as Boc or Z can be
the molecule.
used in such mild conditions, but not in Nanjappan’s re-
Functionalized vicinal diamines are generally prepared duction conditions (H2 Pd/C, 3.5 atm).15
from amino acids which bear a reactive function (NH2,
After N-protection of the amino group of 4 and 4', we ob-
CO2H, etc.) on their lateral chain that can be used for fur-
tained stable N-triprotected triamines which could be
ther bonding with antibodies. The substitution of the ter-
stored for several months without degradation. Selective
minal acid function in the primary amine, either by reduc-
deprotection of two out of three amino groups gave
tion of an intermediate amide10 or nitrile11 or of the acid
N-monoprotected triamines 6 and 6' which could serve as
in alcohol followed by nucleophilic substitution,12,13 pro-
intermediates for BCA synthesis. This method provided for
duces the desired vicinal diamino group.
rapid synthesis of a large quantity of 1,2 and 1,3 diamines
Fritzberg developed another method for preparing differ- bearing another selectively protected amino group and gave
ent vicinal diamines functionalized by OH, CO2H, CN an excellent overall yield (44% for 1a, 42% for 1b and 58%
groups, which uses readily available and relatively inex- for 1').18 Moreover, purification was easy at each step. Al-
pensive 1,3-diaminopropan-2-ol as the starting material.14 though the synthesis of 6a and 6' required flash column
With the same starting compound, Nanjappan synthesized chromatography at the azide step, 6b was obtained with sat-
a 1,3-diamine functionalized by an NO2 group, which can isfactory purity without any chromatographic purification.
easily be reduced into an amino group.15
The alternative procedure for synthesizing N-monopro-
The need for a ready supply of functionalized diamines to tected triamine and particularly N1-monoprotected-1,2,3-
synthesize new and original BCAs led us to search for a triamine does not involve the intermediacy of synthesized
simple, convenient and general method for the preparation 2,3-diaminopropan-1-ol and uses inexpensive commer-
of 1,2 and 1,3 functionalized diamines starting from com- cially available aminodiols as starting materials.

SYNTHESIS
Papers
1114
Reagents and conditions: a) MsCl/Et3N, CH2Cl2, 0°C, 1 h; b) NaN3/DMF, 70°C, 15 h; c) SnCl2•2Η2O/MeOH, 4 h, r.t.; d) (Boc)2O/EtOH, 1 h,
r.t.; e) H2/Pd-C, 1 atm, overnight; f) ZCl/CH2Cl2, 1 h, r.t.; g) TFA, r.t., 30 min
Scheme 1
The initial procedure was the same as with the first meth- This procedure allowed N-monoprotected triamines to be
od. After protection of the amino group by (Boc)2O, treat- obtained at a good yield20 in only four steps without
ment of the two hydroxy groups of 7 and 7' with mesyl lengthy purifications, although reduction conditions limit-
(methanesulfonyl) chloride in the presence of triethyl- ed the choice of amino protecting groups to avoid the ef-
amine yielded the corresponding bismesylates 8 and 8', fects of catalytic hydrogenation.
which were converted into bisazides 9 and 9' (Scheme 2).
In summary, two simple approaches were developed to
The latter reaction was performed with sodium azide in
obtain 1,2 or 1,3 functionalized diamines. Reaction condi-
the presence of 15-crown-5 in dimethylformamide at
tions involving the use of various amino protecting groups
70˚C.19 The resulting diazides were purified by flash col-
allowed us to synthesize several N-monoprotected tri-
umn chromatography to provide pure 6a and 6' as oily
amines, and the use of aminodiols provided an alternative
products. Due to the presence of a secondary azido group,
means of synthesizing N1-monoprotected triamines with a
9' was prepared with a poorer yield than 9. Bisazide re-
high yield. These two methods could also be applied to
duction by tin chloride failed to produce a high yield of the
other diamino alcohols or aminodiols to obtain high yields
corresponding diamines, and purity was not satisfactory.
of new diamines bearing a protected amino group. We are
To avoid such problems, the bisazides were reduced using
currently exploring the synthesis of new N4-monoprotect-
catalytic hydrogenation (H2, 5% Pd/C under atmospheric
ed-1,2,4-triaminocyclohexane since such compounds
pressure for 9 and 3 atm for 9' overnight). Diamines 6a
with cyclohexanic semi-rigid structure21 could serve as in-
and 6' were obtained at a high yield. The infrared spec-
termediates for BCA synthesis.
trum showed no bands at 2200 cm–1, and a positive test
with fluorescamine for final 6a and 6' confirmed the pres-
ence of amino groups.
All chemicals were of the highest purity commercially available (Sig-
ma-Aldrich Co.). Solvents were purified by standard methods before
use and stored over 0.3 nm molecular sieves. Silica gel (230–
400 mesh, Carlo Erba) was purchased from Merck. TLC was per-
formed using precoated Kieselgel 60 plates F254 (TLC plates, Merck)
and was visualized by UV or iodine.
NMR spectra were recorded on a Bruker AC 250 apparatus
(62.896 MHz for 13C and 250.133 MHz for 1H). Chemical shifts are
indicated in δ values (ppm) downfield from internal TMS, and cou-
pling constants (J) are given in Hertz (Hz). Multiplicities were record-
ed as s (singlet), d (doublet), t (triplet) and m (multiplet). FAB+-mass
spectra were obtained on a Jeof SX 100 mass spectrometer using ni-
trobenzyl alcohol (NBA) as matrix. Infrared spectra were recorded on
KBr plates on an FTIR Mattson 1000. Melting points were deter-
mined on a 9200 electrothermal apparatus and are uncorrected. Mi-
croanalysis was performed by the Microanalytical Department of the
CNRS (Vernaison Center).
Reagents and conditions: a) (Boc)2O/EtOH, 1 h, r.t.; b) MsCl/Et3N/
CH2Cl2, 0°C, 1 h; c) NaN3/15-crown-5/DMF, 70 °C, 15 h; d) H2/Pd-
C/MeOH, 1 or 3 atm, overnight
CAUTION: Because of their potentially explosive character, all re-
actions involving azido or bis(azido) compounds were carried out
with the appropriate protection under a well ventilated hood.
Scheme 2

SYNTHESIS
August 1998
1115
Synthesis from Diamino Alcohols:
N,N'-Bis(benzyloxycarbonyl)-1-methanesulfonyl-2,3-diaminopro-
pane (2'):
N,N'-Bis(benzyloxycarbonyl)-1,3-diaminopropan-2-ol (1a):
This compound was prepared according to the literature14 and puri-
fied by crystallization from EtOAc/hexane; white needles; yield:
70%; mp 122°C.
White powder; yield: 90%; mp 82–83°C.
MS (FAB+): m/z = 437 (M+H)+.
1H NMR (CDCl3): δ = 2.95 (3 H, s, CH3), 3.38 (2 H, m, CH2N), 4.00
(1 H, m, CH), 4.25 (2 H, m, CH2OSO2), 5.08 (4 H, m, CH2O), 5.44 (1
H, m, NH), 5.76 (1 H, d, NH, 3J1H = 7.3 Hz), 7.33 (10 H, s, Harom).
13C NMR (CDCl3): δ = 37.2 (CH3), 41.3 (CH2N), 50.9 (CHN), 67.2
(CH2O), 68.2 (CH2OSO2), 128.0–128.6 (CHarom), 136.1 (Carom),
156.2 (CO), 157.4 (CO). IR (KBr): ν = 3348, 3032, 2943, 2895, 1700,
1533, 1458, 1354, 1250, 1173, 1066 cm–1.
MS (FAB+): m/z = 359 (M+H)+.
1H NMR (CDCl3): δ = 3.26 (4 H, m, CH2N), 3.75 (1 H, qt, CH, 3J4H
= 5.2 Hz), 5.09 (4 H, s, CH2O), 5.49 (2 H, t, NH, 3J2H = 5.7 Hz), 7.33
(10 H, s, Harom).
13C NMR (CDCl3): δ = 44.5 (CH2N), 67.7 (CH2O), 71.1 (CHO),
128.7–129.2 (CHarom), 136.7 (Carom), 158.2 (CO). IR (KBr): ν = 3494,
3328, 3062, 2935, 2880, 1685, 1558, 1294, 1158, 1002 cm–1.
Azides 3a, 3b, 3'; General Procedure:
N,N'-Bis(di-tert-butoxycarbonyl)-1,3-diaminopropan-2-ol (1b):
This compound was prepared according to the literature15b and puri-
fied by recrystallization from Et2O/hexane (15:85; v/v); white pow-
der; yield: 93%; mp 101°C.
NaN3 (2.60 g, 40 mmol) was added to a stirred solution of the appro-
priate N-protected mesylates 2a, 2b, 2' (10 mmol) in anhyd DMF
(30 mL). The mixture was heated at 60–70°C for 12 h. After cooling,
the solution was poured into H2O and extracted with EtOAc (5 × 50
mL). Organic phases were collected, dried (Na2SO4), filtered and
evaporated. Pure products were obtained after crystallization from
hexane (N-Boc compound, 2b) or flash chromatography (N-Z com-
pound, 2a and 2') using CH2Cl2/EtOAc (90:10; v/v) as eluent.
MS (FAB+): m/z = 291 (M+H)+.
1H NMR (CDCl3): δ = 1.43 (18 H, s, CH3), 3.20 (4 H, m, CH2N), 3.70
(1 H, qt, CH, 3J4H = 5.5 Hz), 3.95 (1 H, m, OH), 5.30 (2 H, m, NH).
13C NMR (CDCl3): δ = 28.4 (CH3), 43.5 (CH2N), 70.8 (CHO), 79.7
[C(CH3)3]) 157.2 (CO).
IR (KBr): ν = 3300, 2980, 2931, 1675, 1533, 1270, 1170, 1005 cm–1.
N,N'-Bis(benzyloxycarbonyl)-2-azido-1,3-diaminopropane (3a):
White crystals; yield: 88%; mp 91°C.
N,N'-Bis(benzyloxycarbonyl)-2,3-diaminopropan-1-ol (1'):
This compound was prepared according to Fritzberg’s method,14 us-
ing a 5-step synthesis to obtain an overall yield of 14%. Demirci has
recently developed an asymmetrical synthesis16b to obtain each iso-
mer of the 2,3-diaminopropan-1-ol (overall yield: 33%) which was 1'
precursor; white crystals; mp 104°C.
MS (FAB+): m/z = 384 (M+H)+.
1H NMR (CDCl3): δ = 3.16–3.47 (4 H, m, CH2N), 3.66 (1 H, m, CH),
5.11 (4 H, s, CH2O), 5.46 (2 H, m, NH), 7.38 (10 H, s, Harom).
13C NMR (CDCl3): δ = 41.6 (CH2N), 61.1 (CHN3), 67.5 (CH2O),
128.5–129.0 (CHarom), 136.6 (Carom), 157.2 (CO). IR (KBr): ν = 3340,
3028, 2898, 2118, 1714, 1589, 1504, 1309, 1242, 1144, 1000 cm–1.
Anal. C19H21N5O4 (383.4): Calcd C, 59.52; H, 5.52; N, 18.27; found:
C, 59.25; H, 5.53; N, 17.88.
MS (FAB+): m/z = 359 (M+H)+.
1H NMR (CDCl3): δ = 3.10–3.96 (6 H, m, CH + CH2 + OH), 5.10 (4
H, s, CH2O), 5.47 (2 H, m, NH), 7.33 (10 H, s, Harom).
13C NMR (CDCl3): δ = 41.3 (CH2N), 53.2 (CHN), 61.9 (CH2OH),
67.3 (CH2O), 67.6 (CH2O), 128.4–129.0 (CHarom), 136.5, 136.6
(Carom), 156.8 (CO), 158.4 (CO). IR (KBr): ν = 3404, 3300, 3064,
2950, 2880, 1691, 1552, 1261, 1012 cm–1.
N,N'-Bis(di-tert-butoxycarbonyl)-2-azido-1,3-diaminopropane (3b):
White powder; yield: 84%; mp 89–90°C.
MS (FAB+): m/z = 316 (M+H)+.
1H NMR (CDCl3): δ = 1.44 (18 H, s, CH3), 3.15–3.40 (4 H, m,
3
CH2N), 3.65 (1 H, qt, CH, J4H = 5.5 Hz), 5.11 (2 H, m, NH).13C
Mesylates 2a, 2b, 2'; General Procedure:
NMR (CDCl3): δ = 28.3 (CH3), 40.8 (CH2N), 60.9 (CH), 79.9
[C(CH3)3], 156.2 (CO).
MeSO2Cl (1.9 ml, 24 mmol) was gently added to a stirred suspension
of the N-protected alcohols 1a, 1b, 1' (20 mmol) and Et3N (3.04 g,
30 mmol) in CH2Cl2 (100 mL) at 0°C. Once the addition was complete,
the mixture became a clear solution which was stirred for 1 h at 0°C and
30 min at r.t. The solution was successively washed with 1 N HCl
(100 mL), H2O (100 mL), 10% aq Na2CO3 solution (100 mL) and brine
(100 mL). The organic phase was dried (Na2SO4), filtered and concen-
trated under vacuum to give a clear yellow solid which, when heated in
hexane, afforded a white powder after cooling and filtration.
IR (KBr): ν = 3340, 2980, 2937, 2120, 1687, 1523, 1282, 1111 cm–1.
N,N'-Bis(benzyloxycarbonyl)-1-azido-2,3-diaminopropane (3'):
White powder; yield: 86%; mp: 90–92°C.
MS (FAB+): m/z = 384 (M+H)+.
1H NMR (CDCl3): δ = 3.37 (2 H, m, CH2N), 3.45 (2 H, m, CH2N3),
3.90 (1 H, m, CH), 5.03 (4 H, s, CH2O), 5.26 (1 H, m, NH), 5.50 (1
H, d, NH, 3J1H = 7.9 Hz), 7.33 (10 H, s, Harom).
13C NMR (CDCl3): δ = 42.5 (CH2N), 51.3 (CHN), 52.1 (CH2N3), 67.1
(CH2O), 128.1–128.6 (CHarom), 136.2 (Carom), 156.2 (CO), 158.0
(CO). IR (KBr): ν = 3321, 3065, 2945, 2891, 2102, 1692, 1541, 1452,
1322, 1265, 1153, 1058 cm–1.
N,N'-Bis(benzyloxycarbonyl)-2-methanesulfonyl-1,3-diaminopro-
pane (2a): White powder; yield: 92%; mp 93–94°C.
MS (FAB+): m/z = 437 (M+H)+.
1H NMR (CDCl3): δ = 2.83 (3 H, s, CH3), 3.40 (4 H, m, CH2N), 4.70
(1 H, qt, CH, 3J4H = 5.7 Hz), 5.11 (4 H, s, CH2O), 5.51 (2 H, t, NH,
3J2H = 6.0 Hz), 7.31 (10 H, s, Harom).
Anal. C19H21N5O4 (383.4): Calcd C, 59.52; H, 5.52; N, 18.27; found:
C, 59.40; H, 5.48; N, 17.91.
13C NMR (CDCl3): δ = 38.8 (CH3), 42.0 (CH2N), 67.8 (CH2O), 79.2
(CH), 128.8–129.2 (CHarom), 136.8 (Carom), 157.6 (CO). IR (KBr): ν
= 3272, 3077, 2962, 1687, 1550, 1454, 1342, 1287, 1173, 921 cm–1.
Amines 4a, 4b, 4'; General Procedure:
SnCl2•2 Η2O (1.24 g, 5.5 mmol) was added to a degassed solution of
azides 3a, 3b, 3' (5 mmol) in MeOH (40 mL) at r.t. The same quantity
of tin(II) was added after 1 h, and 0.4 equiv (0.29 g, 1.3 mmol) after
30 min. The solution was stirred again for 1 h, and the reaction was
then stopped by adding satd Na2CO3 solution. After filtration of the
precipitate, the filtrate was evaporated. The residue was extracted
with CH2Cl2 (100 mL). The organic phase was washed with brine (2
× 50 mL), dried (Na2SO4) and concentrated to dryness to afford a
yellow oily product which solidified slowly. The resulting solid,
when heated in a mixture of hexane/CH2Cl2 (95/5; v,v) gave the cor-
responding amine as a white powder after filtration.
N,N'-Bis(di-tert-butoxycarbonyl)-2-methanesulfonyl-1,3-diamino-
propane (2b) White powder; yield: 93%; mp 135–136°C.
MS (FAB+): m/z = 384 (M+H)+.
1H NMR (CDCl3): δ = 1.44 (18 H, s, CH3), 3.10 (3 H, m, CH3SO2),
3.30–3.40 (4 H, m, CH2N), 4.66 (1 H, qt, CH, 3J4H = 4.9 Hz), 5.20 (2
H, m, NH).
13C NMR (CDCl3): δ = 28.3 (CH3), 38.2 (CH3SO2), 40.8 (CH2N),
79.1 (CHO), 80.0 [C(CH3)3], 156.3 (CO).
IR (KBr): ν = 3380, 2975, 2933, 1705, 1521, 1340, 1178, 918 cm–1.

SYNTHESIS
Papers
1116
N1,N3-Bis(benzyloxycarbonyl)-1,2,3-triaminopropane (4a):
White powder; yield: 90%; mp 92–93°C.
N-Z Protection of 4b:
Benzyl chloroformate (2.05 g, 12 mmol) was added slowly to a stirred
solution of amine 4b (2.89 g, 10 mmol) in CH2Cl2 (30 mL). After 1 h at
r.t., the solvent was removed under reduced pressure. The residue was
extracted with EtOAc (2 × 30 mL), and the organic phase was dried
(Na2SO4), filtered and evaporated. The residue was heated in a hexane/
CH2Cl2 mixture (95:5; v/v), cooled and filtered to afford a white powder.
MS (FAB+): m/z = 358 (M+H)+.
1H NMR (CDCl3): δ = 1.28 (2 H, m, NH2), 2.96–3.26 (5 H, m, CH2N
+ CH), 5.10 (4 H, s, CH2O), 5.46 (2 H, m, NH), 7.35 (10 H, s, Harom).
13C NMR (CDCl3): δ = 44.2 (CH2N), 51.1 (CH), 66.8 (CH2O), 128.1–
128.5 (CHarom), 136.4 (Carom), 157.2 (CO).
IR (KBr): ν = 3423, 3029, 2898, 1712, 1506, 1454, 1242, 1140, 1000
N1,N3-Bis(di-tert-butoxycarbonyl)-N2-(benzyloxycarbonyl)-1,2,3-tri-
aminopropane (5b): White powder; yield: 65%; mp 142–143°C.
MS (FAB+): m/z = 424 (M+H)+.
cm–1.
N1,N3-Bis(di-tert-butoxycarbonyl)-1,2,3-triaminopropane (4b):
White powder; yield: 90%; mp 90°C.
1H NMR (CDCl3): δ = 1.43 (18 H, s, CH3), 3.15–3.28 (4 H, m, CH2N),
3.62 (1 H, m, CH), 5.08 (2 H, s, CH2O), 5.33 (2 H, m, NH), 5.89 (1 H, m,
NH), 7.31 (5 H, s, Harom).13C NMR (CDCl3): δ = 28.3 (CH3), 41.1
(CH2N), 53.2 (CH), 66.7 (CH2O), 79.8 (CIV-O), 128.0–128.5 (CHarom),
136.4 (Carom), 156.5 (CO), 157.1 (CO).
MS (FAB+): m/z = 290 (M+H)+.
1H NMR (CDCl3): δ = 1.41 (20 H, s, CH3 + NH2), 2.88 (1 H, m, CH),
3.07 (4 H, m, CH2N), 5.29 (2 H, m, NH).
13C NMR (CDCl3): δ = 28.4 (CH3), 43.9 (CH), 51.3 (CH2N), 79.3
[C(CH3)3], 156.6 (CO).
IR (KBr): ν = 3358, 3037, 2981, 2937, 1686, 1533, 1452, 1286, 1245,
1174, 1061 cm–1.
IR (KBr): ν = 3400–3280, 2977, 2921, 1710, 1589, 1502, 1282, 1147,
Anal. C21H33N3O6 (423.5): C, 59.56; H, 7.85; N, 9.92; found C,
59.51; H, 7.97; N, 9.96.
1010 cm–1.
N2,N3-Bis(benzyloxycarbonyl)-1,2,3-triaminopropane (4'):
White powder; yield: 89%; mp 88°C.
N-Deprotection of 5a and 5'; General Procedure:
A stirred solution of 5a or 5' (3 mmol) and 5% Pd/C (0.3 equiv; w/w)
in MeOH (30 ml) was kept under H2 at 1 bar pressure overnight. The
catalyst was filtered and the filtrate concentrated to dryness to afford
an oily product usable for BCA synthesis without any further purifi-
cation.
MS (FAB+): m/z = 358 (M+H)+.
1H NMR (CDCl3): δ = 1.64 (2 H, m, NH2), 2.76–3.65 (5 H, m, CH2N
+ CH), 5.07 (4 H, s, CH2O), 5.43 (1 H, m, NH), 5.52 (1 H, m, NH),
7.31 (10 H, s, Harom).
13C NMR (CDCl3): δ = 41.1 (CH2N), 41.9 (CH2N), 52.4 (CH), 66.8
(CH2O), 66.9 (CH2O), 128.0–128.5 (CHarom), 136.5 (Carom), 156.5
(CO), 157.0 (CO).
N2-(Di-tert-butoxycarbonyl)-1,2,3-triaminopropane (6a): Oil; yield:
90%.
MS (FAB+): m/z = 190 (M+H)+.
IR (KBr): ν = 3373, 3025, 2957, 2848, 1700, 1526, 1450, 1227, 1140,
1040 cm–1.
1H NMR (MeOD): δ = 1.45 (9 H, s, CH3), 2.57 (2 H, dd, CH2N, 3J1H
3
3
3
= 7.3, J1H = 13.2 Hz), 2.77 (2 H, dd, CH2N, J1H = 5.3, J1H
=
13.2 Hz), 3.84 (1 H, m, CH). 13C NMR (CDCl3): δ = 29.1 (CH3), 44.6
(CH2N), 56.9 (CH), 80.5 [C(CH3)3], 158.0 (CO).
N-Boc Protection of 4a and 4'; General Procedure:
Di-tert-butyl dicarbonate (2.5 mL, 12 mmol) was added slowly to a
stirred solution of amine 4a or 4' (10 mmol) in EtOH (30 ml). After
1 h at r.t., the solvent was removed under reduced pressure. The resi-
due was extracted with EtOAc (2 × 25 mL), and the organic phase
was dried (Na2SO4), filtered and evaporated. The residue was heated
in a hexane/CH2Cl2 mixture (95:5; v/v), cooled and filtered to give a
white powder.
IR (KBr): ν = 3430, 2979, 2912, 1708, 1589, 1502, 1315, 1242, 1166,
1004 cm–1. Anal. C8H19N3O2 (189.3): Calcd C, 59.77; H, 10.12; N,
22.20; found C, 59.51; H, 9.97; N, 21.96.
N1-(Di-tert-butoxycarbonyl)-1,2,3-triaminopropane (6'): Oil; yield:
90%.
MS (FAB+): m/z = 190 (M+H)+.
1H NMR (CDCl3): δ = 1.41 (9 H, s, CH3), 1.66 (4 H, s, NH2), 2.49–
2.57 (1 H, m), 2.75–2.81 (2 H, m), 2.95–3.06 (1 H, m), 3.11–3.41 (1
H, m), 5.20 (1 H, s, NH).
N1,N3-Bis(benzyloxycarbonyl)-N2-(di-tert-butoxycarbonyl)-1,2,3-tri-
aminopropane (5a): White powder; yield: 95%; mp 128–129°C.
MS (FAB+): m/z = 458 (M+H)+.
13C NMR (CDCl3): δ = 28.4 (CH3), 44.7 (CH2N), 45.9 (CH2N), 53.3
(CH), 79.3 [C(CH3)3]), 156.4 (CO).
1H NMR (CDCl3): δ = 1.43 (9 H, s, CH3), 3.27 (4 H, m, CH2N), 3.61
(1 H, m, CH), 5.10 (4 H, s, CH2O), 5.33 (1 H, m, NH), 5.54 (2 H, m,
NH), 7.35 (10 H, s, Harom). 13C NMR (CDCl3): δ = 28.4 (CH3), 41.6
(CH2N), 58.0 (CH), 67.0 (CH2O), 79.7 [C(CH3)3], 128.1–128.5
(CHarom), 136.3 (Carom), 156.0 (CO), 157.5 (CO).
IR (KBr): ν = 3358, 2980, 2920, 1691, 1531, 1363, 1282, 1173 cm–1.
Anal. C8H19N3O2 (189.3): Calcd C, 50.77; H, 10.12; N, 22.20; found
C, 50.91; H, 10.21; N, 22.02.
IR (KBr): ν = 3430, 3014, 2900, 1712, 1586, 1502, 1313, 1242, 1145,
N-Deprotection of 5b;
1001 cm–1.
Bis(trifluoroacetic acid)-N2-(benzyloxycarbonyl)-1,2,3-triaminopro-
pane Salt (6b):
Anal. C24H31N3O6 (457.5):C, 63.01; H, 6.83; N, 9.18; found: C,
62.84; H, 6.85; N, 9.10.
Trifluoroacetic acid (2.3 mL, 30 mmol) was added to a solution of 5b
(1.269 g, 3 mmol) in CH2Cl2 (3 mL). The mixture was stirred at 0°C
for 30 min, and the solution was then concentrated to dryness to af-
ford a white solid usable for BCA synthesis without any further puri-
fication; white powder; yield: 99%; mp 175–177°C.
N2,N3-Bis(benzyloxycarbonyl)-N1-(di-tert-butoxycarbonyl)-1,2,3-tri-
aminopropane (5'): White powder; yield: 93%; mp 79–80°C.
MS (FAB+): m/z = 458 (M+H)+.
1H NMR (MeOD): δ = 3.00–3.09 (2 H, dd, CH2, 3J1H = 10.1, 2J1H
=
1H NMR (CDCl3): δ = 1.45 (9 H, s, CH3), 3.20–3.95 (5 H, m, CH2 +
CH), 5.22 (5 H, m, CH2O + NH), 5.80 (2 H, m, NH), 7.37 (10 H, s,
Harom). 13C NMR (CDCl3): δ = 28.3 (CH3), 40.5 (CH2), 41.5 (CH2),
53.1 (CH), 66.8 (CH2O), 67.0 (CH2O), 79.9 [C(CH3)3], 128.0–128.5
(CHarom), 136.3 (Carom), 156.3 (CO), 157.3 (CO), 157.7 (CO).
IR (KBr): ν = 3340, 3034, 2976, 2945, 2824, 1699, 1524, 1454, 1250,
1165, 1067 cm–1.
13.2 Hz), 3.17–3.24 (2 H, dd, CH2, 3J1H = 4.0, 2J1H = 13.2 Hz), 4.08–
4.22 (1 H, CH), 5.13 (2 H, CH2O), 7.28–7.43 (5 H, m, Harom).
13C NMR (MeOD): δ = 42.3 (CH2N), 49.7 (CH), 68.6 (CH2O), 120.5
(CF3, JCF = 293 Hz), 129.5, 129.8 (CHarom), 138.0 (Carom), 158.9
(CO), 163.5 (CO, JCCF = 35 Hz).
IR (KBr): ν = 3300–2820, 1684, 1624, 1552, 1464, 1429, 1269, 1197,
1134, 1034 cm–1.
Anal. C24H31N3O6 (457.5): Calcd C, 63.01; H, 6.83; N, 9.18; found
C: 63.19, H: 6.86, N: 8.99.
Anal. C15H21F6N3O6 (453.4): C, 39.10; H, 4.13; found C, 38.88; H, 4.18.

SYNTHESIS
August 1998
1117
Synthesis from Aminodiols
N2-(Di-tert-butoxycarbonyl)-1,3-diazidopropane (9): Oil; yield:
81%.
Protection of Aminodiols; General Procedure:
MS (FAB+): m/z = 242 (M+H)+.
Di-tert-butyl dicarbonate (2.5 mL, 12 mmol) was gently added
to a stirred solution of serinol (2-aminopropane-1,3-diol) or 3-ami-
nopropane-1,2-diol (10 mmol) in EtOH (30 mL). After 1 h at r.t., the
solvent was removed under reduced pressure. The residue was ex-
tracted with EtOAc (2 × 25 mL), and the organic phase was dried
(Na2SO4), filtered and evaporated. The residue was heated in hexane,
cooled and filtered to afford white needles.
1H NMR (CDCl3): δ = 1.46 (9 H, s, CH3), 3.38–3.46 (2 H, dd, CH2N,
3J1H = 6.0, 2J1H = 12.3 Hz), 3.50–3.57 (2 H, dd, CH2N, 3J1H = 5.0, 2J1H
= 12.3 Hz), 3.88 (1 H, m, CH), 4.80 (1 H, d, NH, 3J1H = 7.8 Hz). 13
C
NMR (CDCl3): δ = 28.4 (CH3), 49.3 (CH), 51.7 (CH2N3), 80.3
[C(CH3)3], 154.9 (CO).
IR (KBr): ν = 3225, 2972, 2906, 2102, 1714, 1500, 1306, 1165,
1001 cm–1.
Anal. C8H15N7O2 (241.3): Calcd C, 39.83; H, 6.27; N, 40.64; found
C, 40.03; H, 6.25; N, 40.32.
N2-(Di-tert-butoxycarbonyl)propane-1,3-diol (7): Oil; yield: 94%;
mp 87–88°C.
MS (FAB+): m/z = 192 (M+H)+.
N3-(Di-tert-butoxycarbonyl)-1,2-diazidopropane (9'): Oil; yield:
69%.
1H NMR (CDCl3): δ = 1.43 (9 H, s, CH3), 3.70–4.18 (7 H, m, CH,
CH2, OH), 5.48 (1 H, m, NH).
MS (FAB+): m/z = 242 (M+H)+.
13C NMR (CDCl3): δ = 28.4 (CH3), 53.2 (CHN), 62.3 (CH2O), 79.9
[C(CH3)3]), 156.5 (CO).
1H NMR (CDCl3): δ = 1.44 (9 H, s, CH3), 3.10–3.20 (1 H, m, HCHN),
3
2
3.28–3.37 (2 H, dd, HCHN + HCHN3, J1H = 7.0, J1H = 12.9 Hz),
3.43–3.50 (1 H, dd, HCHN3, 3J1H = 4.1, 2J1H = 12.9 Hz), 3.73 (1 H,
m, CH), 4.92 (1 H, m, NH). 13C NMR (CDCl3): δ = 28.7 (CH3), 42.5
(CH2N), 53.0 (CH2N3), 61.7 (CHN3), 80.5 [C(CH3)3], 156.2 (CO).
IR (KBr): ν = 3365, 2979, 2106, 1695, 1512, 1274, 1168, 965 cm–1.
Anal. C8H15N7O2 (241.3): Calcd C, 39.83; H, 6.27; N, 40.64; found
C, 39.97; H, 6.21; N, 40.86.
IR (KBr): ν = 3323, 2995, 2887, 1686, 1536, 1427, 1367, 1249, 1172,
1040 cm–1.
N1-(Di-tert-butoxycarbonyl)propane-1,2-diol (7'): Oil; yield: 87%;
mp 85°C.
MS (FAB+): m/z = 192 (M+H)+.
1H NMR (CDCl3): δ = 1.44 (9 H, s, CH3), 3.23–3.73 (7 H, m, CH,
CH2, OH), 5.16 (1 H, m, NH).
13C NMR (CDCl3): δ = 28.5 (CH3), 40.7 (CH2N), 62.9 (CH2O), 65.1
(CHO), 80.2 [C(CH3)3], 157.0 (CO).
Reduction of Diazides 9 and 9b; General Procedure:
A stirred solution of 9 or 9' (3 mmol) and 5% Pd/C (0.5 equiv, w/w)
in MeOH (30 mL) was kept under H2 at 1 bar pressure for 9 and 3 bar
for 9' overnight. The catalyst was filtered and the filtrate concentrated
to dryness to afford an oily product usable in subsequent steps without
further purification.
IR (KBr): ν = 3360, 2980, 2840, 1689, 1523, 1427, 1370, 1260,
1140 cm–1.
Mesylates 8, 8'; General Procedure:
Mesylates 8 and 8' were synthesized according to the general proce-
dure described for the preparation of mesylates 2, but using 2.4 equiv
of methanesulfonyl and 3.0 equiv of Et3N (instead of 1.2 and
1.5 equiv). After treatment, the residue, heated in hexane/CH2Cl2 (95/
5; v/v), afforded a white solid after cooling and filtration.
This procedure gave corresponding diamines 6a and 6' in excellent
yields (99%).
We are grateful to J. Lebreton (UMR CNRS 6513, Nantes, France)
for helpful discussions. This work was supported by a grant from the
“Comité Départemental de la Ligue Nationale Contre le Cancer,
Département des Deux-Sèvres”.
N2-(Di-tert-butoxycarbonyl)-1,3-dimethanesulfonylpropane (8):
white powder; yield: 82%; mp 86–87°C.
MS (FAB+): m/z = 348 (M+H)+.
1H NMR (CDCl3): δ = 1.44 (9 H, s, CH3), 3.07 (6 H, s, CH3SO2),
4.25–4.37 (5 H, m, CH2N + CH), 5.09 (1 H, d, NH, 3J1H = 7.6 Hz).
13C NMR (CDCl3): δ = 28.2 (CH3), 37.5 (CH3SO2), 48.5 (CH), 66.9
(CH2O), 80.8 [C(CH3)3], 154.9 (CO).
(1) Kasina, S.; Fritzberg, A.R.; Johnson, D.L.; Eshima, D. J. Med.
Chem. 1986, 29, 1933.
(2) (a) Gutsche, C.D.; Mei, G.C. J. Am. Chem. Soc. 1985, 107,
7964.
(b) De Riemer, L.H.; Meares, C.F.; Goodwin, D.A.; Diamanti,
C.I. J. Lab. Comp. Radiopharm. 1981, 18, 1517.
(3) (a) Bergeron, R. J.; Feng, Y.; Weimar, W. R.; McManis, J. S.;
Dimova, H.; Porter, C.; Raisler, B.; Phantiel, O. J. Med. Chem.
1997, 40, 1475.
IR (KBr): ν = 3255, 2983, 2843, 1702, 1510, 1358, 1169, 1000 cm–1.
Anal. C10H21NO8S2 (347.4): Calcd C, 34.57; H, 6.09; O, 36.84; found
C, 34.47; H, 5.96; O, 36.46.
N1-(Di-tert-butoxycarbonyl)-1,2-dimethanesulfonylpropane (8'):
White powder; yield: 69%; mp 82–84°C.
(b) Araujo, S. M. P. J.; Ragnarsson, M.; Amaral Trigo, J. S. A.;
Almeida, L. S. J. Chem. Research 1996, 366.
MS (FAB+): m/z = 348 (M+H)+.
1H NMR (CDCl3): δ = 1.42 (9 H, s, CH3), 3.07 (3 H, s, CH3SO2), 3.10
(3 H, s, CH3SO2), 3.45 (2 H, m, CH2N), 4.20–4.37 (1 H, dd, HCH,
3J1H = 2.8, 2J1H = 11.8 Hz), 4.42–4.47 (1 H, dd, HCH, 3J1H = 5.5, 2J1H
= 11.8 Hz), 4.92 (1 H, m, CH), 5.14 (1 H, m, NH). 13C NMR (CDCl3):
δ = 28.3 (CH3), 37.7 (CH3SO2), 38.4 (CH3SO2), 41.0 (CH2N), 66.1
(CH2O), 68.0 (CHO), 80.3 [C(CH3)3], 156.0 (CO).
(c) Bradshaw, J. S.; Krakowiak, K. E.; Izatt, R. M. Tetrahedron
1992, 48, 4475.
(4) Cox, J.P.L.; Craig, A.S.; Helps, I.M.; Jankowski, K.J.; Parker,
D.; Eaton, M.A.W.; Millickan, A.T.; Millar, K.; Beeley,
N.R.A.; Boyce, B.A.; J. Chem. Soc., Perkin Trans. 1 1990,
2567.
(5) Sundberg, M.W.; Meares, C.F.; Goodwin, D.A.; Diamanti, C.I.
J. Med. Chem. 1974, 17, 1304.
(6) (a) Kung, H.F.; Guo, Y.Z.; Yu, C.C.; Billigs, J.; Subramanyam,
W.; Calabrese, J.C. J. Med. Chem. 1989, 32, 433.
(b) Gustavson, L.M.: Rao, T.N.; Jones, D.S.; Fritzberg, A.R. Te-
trahedron Lett. 1991, 32, 5485.
IR (KBr): ν = 3400, 2979, 2857, 1710, 1523, 1355, 1176, 925 cm–1.
Anal. C10H21NO8S2 (347.4): Calcd C, 34.57; H, 6.09; O, 36.84; found
C, 34.76; H, 6.01; O 36.48.
Azides 9, 9'; General Procedure:
Azides 9 and 9' were synthesized according to the general procedure
described for the azides 3, but using 6.0 equiv of NaN3 (instead of
4.0 equiv) and 15-crown-5 (0.1 equiv). Pure oily products were ob-
tained after flash chromatography using CH2Cl2 as eluent for 9 and
CHCl3 and then CH2Cl2 as eluent for 9'.
(7) (a) Mishra, A.K.; Gestin, J-F.; Benoist, E.; Faivre-Chauvet, A.;
Chatal, J-F. New J. Chem. 1996, 20, 585.
(b) Gestin, J-F.; Benoist, E.; Loussouarn, A.; Mishra, A.K.;
Faivre-Chauvet, A.; Chatal, J-F. New J. Chem. 1997, 21, 1021.

SYNTHESIS
Papers
1118
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aminopropan-1-ol.
(13) Kokotos, G.; Markidis, T.; Constantinou-Kokotou, V. Synthesis
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