were alkylated in the same way as above (2a and 3a).
Subsequent deprotection and the second alkylation followed to
afford cis- and trans-DO2A derivatives (2, 3) in 25–26% overall
yield based on starting cyclen. The reaction products were
purified by either recrystallization (2a, 2 and 3) or column
chromatography (alumina, ethyl acetate for 3a).
previously described method to give a mono-protected and tri-
alkylated cyclen compound (4a). Removal of the benzylox-
ycarbonyl protecting group by hydrogenation over Pd/C
afforded the tri-alkylated cyclen compound. The second
alkylation with tert-butyl bromoacetate, followed by deprotec-
tion of the tert-butyl group, led to theDO1A derivative (4). This
mono-protected cyclen also provides easy access to important
intermediates, DO3A–(OR)3 (R = tBu, Et, Bz) for the synthesis
of DOTA- and DO3A-based BFCs.14
In conclusion, all possible isomers with two different
pendents, DO1A, cis- and trans-DO2A and DO3A derivatives,
were synthesized by employing the same synthetic strategies. A
judicious choice of four different protecting groups was found
to be essential to the high-yield preparation of regioselective N-
alkylated cyclen compounds. All compounds are fully charac-
terized by 1H NMR, 13C NMR, and either elemental analysis or
high resolution mass spectroscopy. A mono-N-protected cyclen
compound, mono-N-Cbz-cyclen, was successfully prepared in
high yield without tedious chromatographic separation by one-
pot consecutive reactions of cyclen with chloral hydrate and
benzyl chloroformate and selective deprotection of the formyl
groups. All protection and deprotection steps are air-stable and
do not need harsh reaction conditions. Mono-N-Cbz-cyclen
could be used as a synthon in the preparation of a variety of
BFCs.
To prepare trialkylated cyclen derivatives, we needed to
devise an effective way to differentiate one of the nitrogen
atoms of cyclen. Although there are a few reports describing
mono-N protection, these methods use an excess of relatively
expensive cyclen, followed by laborious chromatographic
separation of mono-protected cyclen from di- and tri-protected
cyclen compound mixtures which have very similar Rf values,6
or protect three nitrogen atoms first using N,N-dimethylforma-
mide dimethyl acetal,13 Ts13 or Boc5 followed by conversion of
these intermediates to mono-protected cyclen compounds. In
these methods, the overall yield of mono-protection based on
cyclen is in the range of 25–50% owing to the low yield of the
protection step and the requisite chromatographic purification
of cyclen compounds. Our method utilizes a one-pot reaction by
first protecting three nitrogens with identical protecting groups
followed by protection of the fourth nitrogen. The three
identical protecting groups are subsequently removed to give
mono-protected cyclen with an easily removable benzyl
carbamate group (mono-N-Cbz-cyclen) (Scheme 2).
This work was supported by the United States Department of
Energy (DEFG02-087ER-60512).
Notes and references
‡ 1H NMR (CDCl3) d 3.02–3.65 (m, 16H), 5.07 (s, 2H), 7.27 (br s, 5H),
7.88–8.09 (m, 3H); 13C NMR (CDCl3) d 43.0, 43.7, 43.8, 44.1, 44.7, 45.0,
45.8, 46.7, 46.9, 47.6, 48.1, 48.8, 49.4, 49.8, 50.1, 50.4, 50.5, 50.8, 52.2,
53.5 (cyclen ring CH2), 67.5, 67.6 (CH2Ph), 127.9, 128.3, 128.6, 129.0 (Ph
ring CH), 135.8 (Ph ring C), 155.9, 156.8, 157.5 (CO2CH2Ph), 163.0, 163.4,
163.6, 163.8, 163.9, 164.3, 164.6, 165.1, 165.7, 165.9 (NCHO). Anal. Calcd
for C19H26N4O5·H2O: C, 55.87; H, 6.91; N, 13.72. Found: C, 55.31; H,
6.68; N, 13.04%. HRMS (ESI): m/z 413.1791 ([M + Na]+, C19H26N4O5Na,
calcd 413.1801).
Scheme 2 Reagents and conditions: i, chloral hydrate, EtOH, 60 °C; ii,
benzyl chloroformate, H2O; iii, 1 M HCl, 50 °C.
Three of the four nitrogen atoms of cyclen were protected by
formyl groups by reaction with four equivalents of chloral
hydrate in ethanol.9 We have found that four equivalents of
chloral hydrate relative to cyclen is enough to protect only three
nitrogen atoms of cyclen selectively but does not produce other
possible isomers such as mono-, di- and tetra-protected cyclen
compound. After evaporation of solvent to dryness, the product
was further reacted with an excess of benzyl chloroformate
without any purification. The pH of the aqueous mixture was
continuously maintained in the range of pH 4–9 for complete
reaction. The crude product was extracted with methylene
chloride and simply recrystallized from diethyl ether to give
pure 1,4,7-triformyl-10-(benzyloxycarbonyl)-1,4,7,10-tetraaza-
cyclododecane‡ (5) in quantitative yield. Due to the hindered
§ 1H NMR (D2O) d 3.19 (br s, 12H), 3.69 (br t, J = 5.1 Hz, 4H), 5.17 (s,
2H), 7.44 (br s, 5H); 13C NMR (D2O) d 45.8, 47.5, 48.2, 49.5, 71.6 (CH2Ph),
131.4, 131.8, 131.9, 138.7, 161.4 (CO2CH2). Anal. Calcd for
C
16H26N4O2·3HCl: C, 46.22; H, 7.03; N, 13.47; Cl, 25.58. Found: C, 45.67;
H, 7.42; N, 12.94; Cl, 25.34%. HRMS (FAB): m/z 307.2139 ([M + H]+,
16H27N4O2, calcd 307.2134).
C
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1
rotation of three formyl groups, the peaks in the H NMR
spectrum are broad, and more resonances than expected are
observed in the 13C NMR spectrum.9 The compound, 5, was
also ascertained by TLC [Rf
=
0.39 on alumina,
MeOH+CH2Cl2 (1+20)], elemental analysis and HR-MS. Mild
acidic treatment (1 M HCl, 50 °C) of 5 led to selective cleavage
of three formyl groups without attacking the Cbz group.
Elevated temperature and higher acidity could break the Cbz–N
bond to return to the starting cyclen itself. After complete
evaporation of the aqueous solution the crude product was
recrystallized from EtOH/Et2O to give the pure mono-protected
cyclen compound, 1-(benzyloxycarbonyl)-1,4,7,10-tetraazacy-
clododecane as the hydrochloride salt§ (6). The overall yield for
the two reactions based on cyclen is over 80%, which is much
higher than the previous mono-protection methods. The benzy-
loxycarbonyl group itself has advantages as a protecting group
for nitrogen atoms because it can be easily removed by catalytic
hydrogenation in addition to normal acidic hydrolysis.
13 D. D. Dischino, E. J. Delaney, J. E. Emswiler, G. T. Gaughan, J. S.
Prasad, S. K. Srivastava and M. F. Tweedle, Inorg. Chem., 1991, 30,
1265.
The mono-protected compound 1-(benzyloxycarbonyl)-
1,4,7,10-tetraazacyclododecane was then alkylated using the
14 J. Yoo, D. Reichert and M. J. Welch, unpublished results.
CHEM. COMMUN., 2003, 766–767
767