Macrocyclic 14-membered ring diketal diamines: Synthesis, conformational analysis and 99mTc radiolabeling evaluation

Article abstract of DOI:10.1002/ejoc.200701151

Chiral and achiral macrocyclic diketal diamines, analogs of cyclams, were synthesized from the previously obtained corresponding diketal dilactams by reduction with lithium aluminum hydride in the presence of a trace amount of triethylamine. In the (15-30)×10^-3 M concentration range, the reaction led mainly to the expected doubly reduced compounds except in the trans-OMe substituted series (R = Ph, Me), in which it partially stopped at the single reduction stage. A conformational study conducted by liquid NMR spectroscopy and molecular mechanics calculations showed that the most stable conformations were either set in a rectangular [3434]-type structure for trans-OMe compounds 7b (R = Me) and 10b (R = H) or stabilized by two intramolecular NH...O hydrogen bonds for all the other macrocyclic diamines. Tc-99m radiolabeling with the nitrido-technetium core [TcN] ²⁺ gave ≈10-20% exchange yields. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701151

FULL PAPER
DOI: 10.1002/ejoc.200701151
Macrocyclic 14-Membered Ring Diketal Diamines: Synthesis, Conformational
Analysis and 99mTc Radiolabeling Evaluation
Radouane Affani,[a] Philippe Auzeloux,[b] Jean-Claude Madelmont,[b] and Denise Dugat*[a]
Keywords: Amines / Macrocycles / Reduction / Conformation analysis / Chelates / Technetium
Chiral and achiral macrocyclic diketal diamines, analogs of
cyclams, were synthesized from the previously obtained cor-
responding diketal dilactams by reduction with lithium alu-
minum hydride in the presence of a trace amount of triethyl-
and molecular mechanics calculations showed that the most
stable conformations were either set in a rectangular [3434]-
type structure for trans-OMe compounds 7b (R = Me) and
10b (R = H) or stabilized by two intramolecular NH···O hydro-
gen bonds for all the other macrocyclic diamines. Tc-99m ra-
diolabeling with the nitrido–technetium core [TcN]2+ gave
≈10–20% exchange yields.
amine. In the (15–30)ϫ10–3
M concentration range, the reac-
tion led mainly to the expected doubly reduced compounds
except in the trans-OMe substituted series (R = Ph, Me), in
which it partially stopped at the single reduction stage. A
conformational study conducted by liquid NMR spectroscopy
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
The design and synthesis of new macrocyclic ligands for
specific purposes is the subject of much ongoing work.
Among these compounds, 14-membered ring amines of the
cyclam type have been shown to complex a wide variety of
inorganic ions,[1,2] and more particularly technetium, with
which they form thermodynamically and kinetically stable
chelates.[3] These find important applications in diagnostic
nuclear medicine as receptor- or tumor-imaging agents,
often after coupling with peptides or antibodies.[4,5a] In re-
cent decades, the isotope 99mTc has become the most widely
used γ-emitter for radioscintigraphy owing to its physical
properties (t1/2 = 6 h, Eγ = 140 keV), availability from 99Mo,
and relatively low cost.[5]
Figure 1. General structure of cyclam, diketal dilactams and diketal
diamines.
Results and Discussion
Synthesis
We have focused on the synthesis,[6] conformation,[7] and
cationic recognition properties[8] of new diversely substi-
tuted 14-membered ring diketal dilactam macrocycles (Fig-
ure 1) for several years. Selective reduction of the lactam
link of these entities would yield diketal diamines, which
are analogs of cyclams. Here we report on the synthesis,
conformational analysis, and 99mTc labeling study of this
new class of compounds.
Chemistry
Macrocyclic diketal diamines were targeted by reduction
of the corresponding diketal dilactams, which were pre-
pared in two steps from β-amino alcohols (Scheme 1) and
obtained in two or three diastereoisomeric forms depending
on the achiral or chiral character of the starting compound,
as previously reported.[6]
Chiral series 1 and 2 provided three diastereoisomers
(Figure 2): an unsymmetrical isomer b, in which the two
OMe substituents are in a trans configuration and two iso-
mers a and c of C2 symmetry, in which the two OMe groups
are in a cis arrangement; a (minor isomer) and c (major
isomer) differ only by the trans or cis relationship of the
OMe and R groups. Achiral series 3 led to two isomers b
and c that both possessed some symmetry (center in b, C2
axis in c).[6a]
[a] Laboratoire SEESIB, UMR CNRS 6504, Université Blaise
Pascal de Clermont-Ferrand,
63177 Aubière, France
E-mail: denise.dugat@univ-bpclermont.fr
[b] Laboratoire de Chimie Physique et Minérale, UFR Pharmacie,
INSERM U484, Centre Jean Perrin, Université d’Auvergne,
63001 Clermont-Ferrand, France
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 2039–2048
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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R. Affani, P. Auzeloux, J.-C. Madelmont, D. Dugat
FULL PAPER
Table 1. Reduction of diketal dilactams 1b,c, 2b,c and 3b,c by
LAH[a] in THF.
Entry Substrate csubstrate NEt3
Time Conv.[b] Results[c]
[R]
[10–3 ] [equiv.] [h]
[%]
[%]
1
1c [Ph]
25
0.4
11
95
4c (30), 5c (8),
6 (8)
2[d]
3[d]
4
1b [Ph]
1b [Ph]
1b [Ph]
2b [Me]
25
40
14
12
0.1
0.1
0.1
0.1
10
10
10
18
88
83
85
93
4b (4), 5b (34)
4b (3), 5b (31)
4b (4), 5b (48)
7b (20), 8b (21),
9 (2)
5
6
7
8
9
2b [Me]
2b [Me]
2c [Me]
2c [Me]
3b [H]
25
30
25
30
15
30
0.2
0.2
0.1
0.1
0.2
0.2
18
20
18
20
8
94
93
88
94
79
93
7b (41), 8b (20)
7b (26), 8b (13)
7c (22)
7c (33)
10b (40)
10[d]
11
3c [H]
7
10c (40), 11c (3)
Scheme 1.
[a] Molar ratio of LAH/substrate = 10:1. [b] Conversion rate based
on the amount of recovered starting material. [c] Isolated yield by
column chromatography; at the end of the process, unidentified
polar compounds were invariably isolated in 13–22% yield, which
increased with the reaction time. [d] Inverse addition order of the
reactants imposed by the low solubility of the substrate in THF at
high concentration. In these cases, the hydride used as a commer-
cial THF solution was added to the substrate solution.
Figure 2. Structure and stereochemistry of diketal dilactams 1a,b,c,
2a,b,c and 3b,c.
The reduction study was conducted on the two major
isomers b and c of three series (1; 2: R2 = Me; 3: R = H).
A first investigation of the selective reduction of the amide
link of these compounds was made previously on macro-
cycle 1c with several reagents (BH3·Me2S, iBuAlH2, Red-
Al, LiAlH4).[9] The best results were obtained with lithium
aluminium hydride (LAH, 10 equiv.) in the presence of
small quantities of triethylamine, which reduced the effect
of a side elimination reaction attributable to the presence
of trace amounts of AlCl3 in the LAH.[9]
The same conditions were applied to the reduction of
dilactams 1b, 2b, 2c, 3b, and 3c, and in each case, the fol-
lowing were adjusted: (i) the concentration of the substrate, 6, 7b,c, 8b,c, 9, 10b,c and 11b,c.
Figure 3. Structure and stereochemistry of compounds 4b,c, 5b,c,
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Macrocyclic 14-Membered Ring Diketal Diamines
1
Table 2. Comparison of some H NMR spectroscopic data of aminolactams 5b, 8b and their dilactam precursors 1b, 2b, respectively.
Compd.
N4–H
δ [ppm]
N11–H
δ [ppm]
H7,H6A,H6B
pattern
∆ν6A,6B
[Hz]
H14,H13A,H13B
pattern[a]
∆ν13A,13B
[Hz]
1b
2b
5b
8b
7.62
7.04
7.62
7.03
6.77
6.00
1.30
1.98
3dd
3dd
3dd
3dd
120.3
108.0
88.0
ABX
ABX
1dd, 2dddd
1dd, 2dddd
3.7
11.6
112.0
76.0
68.0
[a] ABX system for ∆ν13A,13B Ͻ 5ϫJ13A,13B with J13A,13B = 13.4–14.2 Hz.
(ii) the amount of NEt3, and (iii) the reaction time (Table 1, system characterizing H13A, H13B in 1b and 2b was changed
Figure 3). Entry 1 (Table 1) recalls the optimal formation into a multiplet. These observations indicate that the re-
conditions of phenyl diketal diamine 4c, which was invaria- duced carbonyl group was the 12-CO of chain 2 (Table 2).
bly accompanied by two other compounds: diketal amino-
lactam 5c and unsaturated ketal aminolactam 6.[9] These
correspond, respectively, to the singly reduced macrocycle
and to an elimination product, whose levels could be low-
ered either by using a higher substrate concentration for the
first one or by adding a small amount of NEt3 for the sec-
ond one,[9] as mentioned above. Reduction of phenyl diketal
dilactam 1b was then explored at three different concentra-
tions (Table 1, Entries 2–4). In all cases, the reaction seemed
to stop at the single reduction level to give rise almost exclu-
sively to diketal aminolactam 5b. In contrast, no trace of
unsaturated macrocycle 6 was detected in the present case,
as long as a certain amount of NEt3 (0.1 equiv.) was en-
gaged in the reaction. In the methyl series, the best forma-
tion conditions for diketal diamines 7b and 7c were found at
concentrations of 25ϫ10–3  and 30ϫ10–3 , respectively
(Table 1, Entries 6 and 9), and in the unsubstituted series at
15ϫ10–3  for 10b (Table 1, Entry 10) and 30ϫ10–3  for
10c (Table 1, Entry 11). In the last three cases, the reaction
led almost exclusively and directly to the expected doubly
reduced compounds.
Discussion
Comparison of the results obtained in the three series (R
= Ph, Me, H) shows that the reduction occurred more or
less easily depending on the nature of the substituent and
on the cis or trans stereochemistry of the OMe groups.
In the substituted series (R = Ph, Me), an identical ac-
cessibility of both carbonyl groups is observed on cis com-
pounds 1c and 2c, which offer a completely unhindered face
owing to the cis position of the four substituents. This led
(i) in the phenyl series, to the obtention of doubly reduced
compound 4c at high concentration (c = 25ϫ10–3 ),
whereas a lower concentration increased the amount of sin-
gly reduced compound 5c;[9] (ii) in the methyl series, to the
direct formation of macrocyclic diamine 7c, irrespective of
the concentration. Concerning trans-OMe derivatives 1b
and 2b, the 5-CO carbonyl group of chain 1 in which the
3-R and 7-OMe groups are in a trans location was more
difficult to reduce than the 12-CO group of chain 2 owing
to the hindrance of the two faces of the molecules at the
chain 1 level. This induced a degree of locking of the reac-
tion at the single reduction step, which led almost exclu-
sively to either aminolactam 5b in the phenyl series or a
mixture of diamine 7b and aminolactam 8b in the methyl
series.
In the unsubstituted series (R = H), the absence of sub-
stituents at C3 and C10 afforded the same accessibility to
both carbonyl groups of trans dilactam 3b and cis dilactam
3c and allowed the formation of diamines 10b and 10c in
similar yields.
In all series, the reduction occurred with moderate total
yields (33–61%), which were difficult to improve.[9] These
results may be explained by the presence of polar com-
pounds (Table 1) probably resulting from complexation be-
tween the generated diketal diamines and the Li+ cation,
which could therefore no longer catalyze the reaction,[10] as
previously reported for compound 4c.[9]
Characterization
The structure and stereochemistry of derivatives 4–11
were established from IR, MS, 1D NMR [1H,13C (J MOD)]
1
and 2D NMR [COSY H–1H, HSQC (heteronuclear single
quantum correlation), and sometimes HMBC (heteronuc-
lear multiple bond correlation)] spectroscopic data, which
allowed identification of all hydrogen and carbon atoms.
1
In the H and 13C NMR spectra, diamines 4c, 7c, and
10b,c, which all possess a symmetry element (C2 for 4c, 7c,
10c, center for 10b) showed only one signal for each pair of
identical groups of the macrocycle, whereas diamines 4b
and 7b exhibited double signals due to the asymmetry of
the two ring chains. Concerning trans-OMe aminolactams
5b and 8b, the reduced chain could be identified by com-
1
parison of their H NMR characteristics with those of di-
lactams 1b and 2b: (i) The amide NH chemical shifts: in
compounds 5b and 8b, the 4-NH doublet (δ =7.62 ppm) of
1b and 2b was still present, whereas the 11-NH signal was
shifted upfield. (ii) The signal form of protons H6A, H6B
Conformational Analysis
1H NMR Spectroscopic Data
The coupling constants of H7/H14 and H3/H10 with their
and H13A, H13B: in singly reduced compounds 5b and 8b, vicinal hydrogen atoms give information on their position
the 2dd of H6A, H6B were still present, whereas the ABX in the ring (Table 3).
Eur. J. Org. Chem. 2008, 2039–2048
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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R. Affani, P. Auzeloux, J.-C. Madelmont, D. Dugat
FULL PAPER
Table 3. Coupling constants (J, in Hz) of the H7, H14, H3, and H10 9–13 kJmol–1 of the global minimum (Supporting infor-
protons of the macrocyclic diketal diamines.
mation, Table S1) with energy differences ranging between
0.25 and 4.09 kJmol1 for the two first conformers. Hence,
conformers 2 will be taken into consideration exclusively
for compounds 4b, 4c, 10b, and 10c, which present a weak
∆Econf1 – conf2 Յ 2 kJmol–1 (4b: 1.24, 4c: 0.50, 10b: 1.03,
10c: 0.25 kJmol–1); this value is greater for 7b (4.09) and 7c
(3.67).
Compd.[a]
J7,6A J7,6B J14,13A J14,13B J3,2A J3,2B J10,9A J10,9B
4b
4c
7b
7.8
8.0
8.1
8.6
8.6
1.8
2.1
2.6
2.5
2.2
9.1
8.0
9.2
8.6
8.6
2.0
2.1
1.6
2.5
2.2
7.0
9.1
2.6
7.5
2.7
4.1
2.8
6.3
3.0
2.8
9.7
2.0
9.4
2.3
7.7
1.7
2.8
9.1
1.9
7.5
2.7
4.1
2.8
6.3
10.0
2.8
5.4
2.0
9.4
2.3
7.7
1.7
7c
10b[b]
10c[b]
7.2
2.7
7.2
2.7
The calculated H–H dihedral angles of all the diamines
point to (Table 4): (i) an axial position of the H7 and H14
protons (θH7,H6ax and θH14,H13ax = 174–178°) corresponding
to an energetically favorable equatorial location of the α
and β-OMe groups; (ii) identical axial positions of the H3
and H10 protons in cis-OMe chiral diamines 4c and 7c,
again corresponding to an energetically favorable equatorial
location of the 3,10-R substituents; (iii) different situations
of the two hydrogens in the trans-OMe compounds with
[a] For all compounds |J6A,6B| ≈ |J13A,13B| = 14.0–14.7 Hz and
|J2A,2B| ≈ |J9A,9B| = 9.5–10.2 Hz. [b] First line: H3A or H10A, second
line: H3B or H10B
.
Thus, in all three diamines 4, 7, and 10, the H7 and H14
protons, which exhibit large and small coupling constants
(J = 7.2–9.2 Hz and J = 1.6–2.7 Hz), very likely occupy an
axial position, which implies an equatorial situation of the
OMe groups. Also, in substituted amines 4 and 7, the H3
and H10 protons are characterized (i) in cis compounds 4c
and 7c, by a large and a small J value (J = 7.5–9.1 Hz and
J = 2.0–2.8 Hz), which are characteristic of axial hydrogen
atoms, and so of equatorial 3-R and 10-R substituents; (ii)
in trans derivatives 4b and 7b, by very different J values (J
= 9.7–10.0 Hz and J = 2.6–2.8 Hz) for protons H3 of 7b
and H10 of 4b, to which an axial location can be assigned,
and by two closer J values (J = 5.4–7.0 Hz and J = 1.9–
3.0 Hz) corresponding to an equatorial position for protons
H3 of 4b and H10 of 7b. These considerations allow the
identification of 3-Phax and 10-Pheq groups in 4b and 3-
Meeq and 10-Meax groups in 7b.
H3eq and H10ax, i.e., 3-Phax and 10-Pheq in 4b, and H3ax
,
H10eq, i.e., 3-Meeq and 10-Meax in 7b. These results agree
with the above NMR spectroscopic data, but they underline
a difference between the conformations of the diamines and
dilactams: the invariable axial position of the 3,10-R sub-
stituents observed in dilactams 1b,c and 2b,c[7] is trans-
formed into a more favorable equatorial situation for both
R groups in cis diamines 4c and 7c and for one of them in
trans compounds 4b and 7b.
The torsion angles of the macrocyclic amines are given
in Table 5. All exhibit invariable transoid conformations
along the two bonds C14–O1–C2–C3, C7–O8–C9–C10
(Ϯ172–178°) and gauche conformations along the bonds
O1–C2–C3–N4, O8–C9–C10–N11 (Ϯ43–60°) and C5–C6–C7–
O8, C12–C13–C14–O1 (Ϯ59–67°). In contrast, the values of
the other angles correspond to trans (t) or gauche [g (posi-
tive value) or gЈ (negative value)] conformations depending
on the macrocycle stereochemistry and the nature of the
substituent.
Molecular Modeling
Monte-Carlo calculations indicate a high flexibility of
macrocyclic diamines 4b,c, 7b,c, and 10b,c, flexibility which
is slightly increased relative to that of the precursory dilac-
In trans-OMe compounds, a [3434] or gtggttgЈgЈtgЈgЈttg
tams through the loss of rigidity due to the two amide link conformation[7,11,12] corresponding to the ideal strain-free
reductions. Fifteen conformations are thus observed within “rectangular” diamond lattice structure of the 14-mem-
Table 4. Calculated H7–C7–C6–H6, H14–C14–C13–H13 and H3–C3–C2–H2, H10–C10–C9–H6 dihedral angles of the conformers (cf) of diketal
diamines 4b,c, 7b,c, and 10b,c.
Compd.
θ [°]
H7–C7–C6–H6ax H7–C7–C6–H6eq H14–C14–C13–H13ax H14–C14–C13–H13eq H3–C3–C2–H2ax H3–C3–C2–H2eq H10–C10–C9–H9ax H10–C10–C9–H9eq
4b cf 1
4b cf 2
4c cf 1
4c cf 2
7b cf 1
7c cf 1
10b cf 1[a]
–174
–175
+178
+179
+176
–177
+177
+67
+67
–65
–64
–66
+66
–64
+178
+178
+178
+179
–177
–177
–177
–63
–63
–65
–63
+65
+66
+65
+56
+54
–63
–64
–59
–61
+50
+57
+47
–73
–62
+58
–55
+64
–61
+57
+180
+179
–177
–172
–44
+176
–164
–45
–180
+61
–174
–55
–62
–62
–58
–54
+73
+57
–47
+73
+62
–58
–55
+64
+48
–72
–178
–180
+168
+176
+164
+45
+180
–61
–174
–55
10b cf 2[a]
10c cf 1[a]
10c cf 2[a]
+177
–175
+179
–64
+67
+61
–177
–175
+179
+64
+67
+60
–180
–61
+167
+48
[a] First line: H3ax and H10ax, second line: H3eq and H10eq
2042
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Eur. J. Org. Chem. 2008, 2039–2048

Macrocyclic 14-Membered Ring Diketal Diamines
Table 5. Torsional angles τ [°] for the conformers (cf) of macrocyclic diketal diamines 4b,c, 7b,c, and 10b,c (+40° Ͻ g Ͻ +85°, –40° Ͻ gЈ
Ͻ –85°, Ϯ156° Ͻ t Ͻ Ϯ180°).
Compd. Chain
τ [°]
Nomenclature
Structure
1
2
C14–O1–C2–C3 O1–C2–C3–N4
C2–C3–N4–C5
C3–N4–C5–C6
N4–C5–C6–C7
C5–C6–C7–O8
C6–C7–O8–C9
C7–O8–C9–C10 O8–C9–C10–N11 C9–C10–N11–C12 C10–N11–C12–C13 N11–C12–C13–C14 C12–C13–C14–O1 C13–C14–O1–C2
4b cf 1
4b cf 2
7b cf 1
10b cf 1
10b cf 2
4c cf 1
4c cf 2
7c cf 1
10c cf 1
10c cf 2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
–176
–174
–180
–177
–174
+172
–172
+173
+179
–179
–176
–176
–176
–78
+60
–57
+59
–58
+45
–44
+43
–43
–61
+61
–55
–54
–57
–49
+55
+55
–54
–54
–62
+46
+178
+162
–180
+165
+69
+177
+176
–179
+177
–179
–175
+176
–176
–178
+178
–174
–175
–174
–179
+170
+170
–84
–70
+72
–70
+66
–61
+66
–61
–64
+63
–63
+63
–63
+63
–64
–64
–64
–62
+65
+65
+67
+67
+60
+59
–177
–178
–178
–180
–78
tgttgЈgt-tgЈttggЈt
tgttgЈgt-tgЈttggЈt
En IIIb[a]
En IIIb[a]
+73
+171
–168
+168
–168
+73
–73
tggttgЈgЈ-tgЈgЈttggЈ IIb
–71
–77
+72
–77
tggttgЈgЈ-tgЈgЈttgg
tgЈttggЈt-tgttgЈgt
Ib [3434]
IIIb
–72
+77
–179
–179
–71
+169
–169
+158
+157
+156
+156
–156
–156
+173
+173
+173
–169
+64
+64
+65
+64
–65
tgЈttggЈgЈ-tgЈttggЈgЈ En IIc[a]
tgЈttggЈgЈ-tgЈttggЈgЈ En IIc[a]
–71
–70
–71
+175
+175
–178
–178
+178
+173
+72
+72
–172
–172
–176
–176
tgttgЈgg-tgttgЈgg
tgЈtgЈgЈgt-tgЈtgЈgЈgt Ic
tgЈtgЈgЈgt-tgttgЈgt IIIc
IIc
–65
–67
–84
–67
–83
–70
+166
–78
[a] En = Enantiomer of structure due to the (3R,10R,14S) configuration of phenyl macrocycles 4. To make comparison with the
(3S,10S,14R) methyl series and the (14R*) unsubstituted series we have to consider the (3S,10S,14R) enantiomer of 4b and 4c, the
designations of which would be tgЈttggЈttgttgЈgt and tgttgЈggtgttgЈgg, respectively.
bered ring compounds is observed for the symmetry center
For all these compounds, the average C–O, C–N, and C–
macrocycle 10b (conformer 1: structure Ib). Here, the trans- C bond lengths are 1.430, 1.471, and 1.535 Å, respectively
OMe groups are accommodated in the two opposite corners (Supporting Information, Table S3). In contrast, the hetero-
C7 and C14, defined by a gg or gЈgЈ sequence, whereas the atom distances are variable and depend on the structure.
C3 and C10 carbon atoms form the other two corners (Fig- Thus, the O1–O8, N4–N11, and O1(8)–N11(4) distances in-
ure 4). The oxygen O1 and O8 atoms are located on the crease in the order: cis-OMe compounds 4c, 7c, and 10c
“three-bond” sides and the nitrogen N4 and N11 atoms are (conf. 1, 2) (daverage: 3.549, 3.655, and 2.832 Å, respectively),
located on the “four bond” sides. The O1, N4 and O8, N11 trans-OMe compounds 4b (conf. 1, 2) and 10b (conf. 2) with
atoms are endo and point downwards and upwards, respec- hydrogen bonds (daverage: 3.969, 4.038, and 2.855 Å, respec-
tively; the N–H bonds form angles of ≈50° with the macro- tively), trans-OMe compounds 7b and 10b (conf. 1) without
cyclic plane. Methyl compound 7b presents a very close hydrogen bond (daverage: 5.035, 5.040, and 4.261 Å, respec-
conformation (structure IIb), which differs from Ib by the tively) (Table 6).
presence, at C14, of a “pseudocorner” characterized by a ggЈ
sequence that induces a slight distortion of the rectangular
shape. In compounds 4b (conformers 1 and 2) and 10b
(conformer 2), the macrocycles adopt an anangular confor-
mation (structure IIIb) derived from the above forms by
rotation of the NH bonds that are now directed inside the
cavity in a position parallel to the average cycle plane. This
arrangement allows the formation of two intramolecular
hydrogen bonds between the NH hydrogen atoms and the
endocyclic ketal oxygen atoms of the other chain (Figure 4;
Supporting Information, Table S2).
Table 6. Interatomic distances [Å] of the O–O, N–N, and O–N
bonds for the conformers (cf) of diketal diamines 4b,c, 7b,c, and
10b,c.
Com-
d [Å]
pound
O1–O8 N4–N11 O1–N11 O8–N4 O1–N4 O8–N11
4b cf 1
4b cf 2
4c cf 1
4c cf 2
7b cf 1
7c cf 1
10b cf 1
10b cf 2
10c cf 1
10c cf 2
3.957
3.967
3.602
3.635
5.032
3.517
5.038
3.984
3.403
3.589
4.018
4.024
3.404
3.379
5.060
3.468
5.021
4.072
3.830
4.196
2.846
2.866
2.822
2.809
4.251
2.828
4.255
2.863
2.841
2.899
2.843
2.848
2.824
2.836
4.283
2.828
4.255
2.863
2.841
2.795
2.801
2.791
2.744
2.767
2.704
2.750
2.681
2.833
2.768
2.871
2.790
2.798
2.735
2.689
2.685
2.750
2.682
2.833
2.768
2.667
In cis-OMe compounds, identical N4–H···O8 and N11–
H···O1 hydrogen bonds, which is consistent with C2 sym-
metry, are observed for all the studied conformers that are
generally characterized by the presence of two corners
either in C5, C12 [10c (conf. 1): structure Ic] or in C7, C14
[4c (conf. 1 and 2), 7c: structure IIc]. An anomaly occurs
Finally, we note that the centrosymmetric, endodentate,
for 10c (conf. 2), in which the absence of a corner in C12 anangular structure IIIb of 10b (conformer 2), corresponds
induces a loss of symmetry, which is no longer in agreement to the most stable conformation of cyclam,[13] whereas the
with the NMR spectroscopic data.
structure Ib of 10b (conformer 1) is close to the [3434]-B
Eur. J. Org. Chem. 2008, 2039–2048
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2043

R. Affani, P. Auzeloux, J.-C. Madelmont, D. Dugat
FULL PAPER
was thus performed in two steps by a published procedure:
(i) the intermediate nitrido–technetium [TcϵN]intV was pre-
pared by acid reduction of a [99mTc]-pertechnetate(VII)
solution by using triphenylphosphane as a reducing agent
and N-methyl-S-methyldithiocarbazate (MDTCZ) as a ni-
trogen (N3–) donor, (ii) the ligand exchange reaction was
then carried out under basic conditions (pH 9.4)
(Scheme 2).[15,16]
Scheme 2.
The radiolabeling yields were measured by autoradiogra-
phy of the spots obtained after thin-layer chromatography.
No exchange was observed with diketal aminolactams 5, 8,
and 11. In contrast, for most of the diketal diamines except
phenyl derivative 4c, the yields ranged from 11 to 18% (4c:
0%, 7b: 11%, 7c: 17%, 10b: 18%, 10c: 14%); the best re-
sults were obtained with cis-OMe methyl compound 7c and
trans-OMe unsubstituted macrocycle 10b. The exchange
values do not seem sensitive to the dimensional variations
of the macrocyclic cage of the studied chelates (Table 6), as
cis and trans diamines gave nearly identical results.
Though low, these values are encouraging. They should
be appreciably increased by introduction of C- or N-pivot
pendant arms with electron-donor atoms liable to partici-
pate in the complex formation, as previously observed with
differently C-substituted cyclams [substituent: 4-(amino-
methyl)benzyl, labeling yield: 13%; substituent: 2-hydroxy-
5-(aminomethyl)phenyl, labeling yield: 72%].[4b]
Figure 4. Top view representations of some diketal diamine macro-
cycles (conformer 1) by molecular modeling: (a) 10b: structure Ib,
(b) 10c: structure Ic, (c) 7b: structure IIb, (d) 7c: structure IIc, (e)
4b: enantiomer of structure IIIb, (f) 4c: enantiomer of structure IIc.
Intramolecular hydrogen bonds are indicated by green dashed lines
with the corresponding interatomic distances.
Conclusions
Six macrocyclic diketal diamines were prepared by re-
duction of the corresponding diketal dilactams previously
synthesized in two steps from chiral and achiral β-amino
alcohols.[6] The reaction was performed with lithium alu-
minium hydride in the presence of a trace amount of trieth-
ylamine, which prevented a side elimination reaction. In a
15–30ϫ10–3  concentration range, it led mainly to the
conformation[13b,14] of 4H-cyclam4+ with, however, a differ-
ence in the position of the heteroatoms: endo in 10b and
exo in 4H-cyclam4+ [14b]
.
Tc-99m Radiolabeling
The study was performed on diketal amines 4c, 7b,c, and doubly reduced compounds in the unsubstituted series (R
10b,c, and on the corresponding singly reduced compounds: = H) and in the cis-OMe substituted series (R = Ph, Me).
amino lactams 5b,c, 8b, and 11c. Of the two cores, [TcN]2+ In contrast, in the trans-OMe substituted series, the 5-CO
and [TcO2]+, generally used for 99mTc cyclam labeling,[3,4] carbonyl group of chain 1 was reduced with difficulty owing
the first one was selected for the present study because its to the hindrance of the two macrocycle faces.
incorporation conditions in the ligands are compatible with
A conformational study of the obtained macrocyclic di-
the presence of ketal functionalities known to be sensitive amines was conducted by liquid NMR spectroscopy and
to any acidic medium. Labeling of the diketal macrocycles molecular mechanics calculations. Both techniques showed
2044
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2039–2048

Macrocyclic 14-Membered Ring Diketal Diamines
(0.01–0.02 equiv./LAH). The reaction mixture was heated at reflux
for 8–10 h. The excess amount of hydride was destroyed by the
addition of H2O (10 equiv./LAH). The precipitates were filtered
and washed with THF and CH2Cl2. The organic layer was dried
with MgSO4 and evaporated in vacuo. Purification by flash
chromatography (silica gel, AcOEt/MeOH or Et2O/MeOH) led to
diketal diamines and diketal aminolactams.
that the conformations depended closely on: (i) the nature
of the 3,10-R substituents and (ii) the stereochemistry of
the ketal OMe groups, which invariably occupied an ener-
getically favorable equatorial position in all compounds.
Thus, in trans-OMe macrocycles 10b (R = H) and 7b (R =
Me), the most stable conformation corresponded exactly or
closely to the rectangular [3434] structure, with the NH
bonds directed away from each side of the ring. In contrast,
(3R,7S,10R,14S)-Diphenyl Diketal Diamine 4c, (3R,7S,10R,14S)-
in trans-OMe macrocycle 4b (R = Ph) and in all cis-OMe Diphenyl Diketal Aminolactam 5c, and (3R,7S,10R,14S)-Diphenyl
Unsaturated Ketal Aminolactam 6: The preparation of these com-
derivatives 4c, 7c, and 10c, the conformations were set by
the presence of two NH···O intramolecular hydrogen bonds
that imposed to the N–H bond a position parallel to the
cyclic plane.
Tc-99m radiolabeling by using the nitrido–technetium
core [TcN]2+ gave approximately 10–20% exchange yields,
which can probably be increased by introducing substitu-
ents with electron-donor atoms.
pounds was described previously.[9]
(3R,7R,10R,14S)-Diphenyl
Diketal
Diamine
4b
and
(3R,7R,10R,14S)-Diphenyl Diketal Aminolactam 5b: These com-
pounds were prepared from diketal dilactam 1b (66.4 mg,
0.15 mmol), LiAlH4 (57 mg, 1.5 mmol, 10 equiv.), NEt3 (1  solu-
tion in THF, 15 µL, 15 µmol, 0.01 equiv./LAH), and THF
(10.7 mL, csubstrate = 14ϫ10–3 ) according to method A (reaction
time 10 h). The excess amount of hydride was destroyed by the
addition of H2O (270 µL, 15 mmol). Chromatography (AcOEt/
MeOH, gradient 100:0–90:10) afforded diketal diamine 4b (2.1 mg,
5.1 µmol, 4%) and diketal aminolactam 5b (26 mg, 61 µmol, 48%)
with 85% conversion rate. Data for 4b: Rf = 0.20 (AcOEt/MeOH,
Experimental Section
General Remarks: Solvents were dried as follows: tetrahydrofuran
(THF) was distilled from benzophenone ketyl, CH2Cl2 was re-
fluxed and distilled from CaH2, CH3OH was distilled from magne-
sium. The organic layers were dried with Mg2SO4. Thin-layer
chromatography (TLC) analysis was performed on aluminium
plates precoated with silica gel (Merck 60 F254). Visualization was
accomplished by UV light or developed by spraying with a ceric
sulfate and ammonium molybdate acid solution. Flash chromatog-
raphy was carried out with silica gel (Merck 0.040–0.063 mm). Op-
tical rotations were measured at the sodium D line (589 nm) by
using a 1-dm quartz cell with a JASCO DIP-370 apparatus. IR
spectra were recorded with a Perkin–Elmer 881 spectrophotometer.
Mass spectra were performed with either a HP 5989B (CI), a micro
Q-TOF Waters (ESI), or a ZabSpec TOF Micromass (ESI) appara-
97:3, 2 elutions). [α]2D5 = –52.0. (c = 0.14, CHCl ). IR (CHCl ): ν
˜
3
3
= 3430 and 3360 (NH) cm–1. 1H NMR and COSY 1H–1H
(400 MHz, CDCl3): δ = 1.67 (dddd, 2J = 16.0 Hz, 3J = 6.1, 1.8,
1.5 Hz, 1 H, 6-HB), 1.71 (dddd, 2J = 14.7 Hz, J = 6.2, 2.0, 1.5 Hz,
3
1 H, 13-HB), 2.01 (m, 2 H, 6-HA, 13-HA), 2.27 (br. s, 2 H, 2 NH),
2.53 (ddd, J = 10.6 Hz, J = 10.2, 1.0 Hz, 1 H, 12-HB), 2.64 (m,
2
3
2 H, 5-HB, 12-HA), 2.72 (ddd, J = 12.3 Hz, J = 6.8, 2.7 Hz, 1 H,
5-HA), 3.14 (s, 3 H, OCH3), 3.29 (s, 3 H, OCH3), 3.42 (dd, 2J =
9.6 Hz, 3J = 10.0 Hz, 1 H, 9-HB), 3.62 (dd, 2J = 9.7 Hz, 3J = 3.0 Hz,
2
3
1 H, 2-HB), 3.78 (dd, 2J = 9.7 Hz, J = 7.0 Hz, 1 H, 2-HA), 3.86
3
(dd, 2J = 9.6 Hz, 3J = 2.8 Hz, 1 H, 9-HA), 3.95 (dd, 3J = 10.0,
3
2.8 Hz, 1 H, 10-H), 4.02 (dd, J = 7.0, 3.0 Hz, 1 H, 3-H), 4.56 (dd,
3J = 7.8, 1.8 Hz, 1 H, 7-H), 4.68 (dd, 3J = 9.1, 2.0 Hz, 1 H, 14-H),
7.25–7.42 (m, 10 H, 10 Ar-H) ppm. 13C NMR and HSQC
(100 MHz, CDCl3): δ = 31.7 (C-6), 31.9 (C-13), 42.7 (C-5), 44.1
(C-12), 50.7 (OCH3), 52.5 (OCH3), 61.5 (C-3), 63.6 (C-10), 66.6
(C-2), 73.4 (C-9), 104.6 (C-14), 105.2 (C-7), 127.2–128.7 (10 Ar-
CH), 140.4 (2 Ar-C) ppm. MS (CI): m/z (%) = 415 (93) [M + H]+,
1
1
tus. 1D (1H and 13C-J MOD) and 2D (COSY H–1H, HSQC H–
13C) NMR spectra were recorded with a Bruker Avance 400 spec-
trometer (1H: 400 MHz; 13C: 100 MHz), and 2D HMBC 1H–13C
were recorded with an Avance 500 apparatus long dist 7.7 Hz (1H:
500 MHz; 13C: 125 MHz). The solvent (CDCl3) was taken as an
internal reference (δ = 7.27 ppm for 1H and 77.1 ppm for 13C
NMR). Protons and carbon atoms were assigned according to the
numbering indicated in Figure 3. Splitting patterns are designated
as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.
383 (100) [M
+ H –
CH3OH]+. HRMS (ESI): calcd. for
C24H35N2O4 [M + H]+ 415.2597; found 415.2584. Data for 5b: Rf
= 0.40 (AcOEt/MeOH, 97:3, 2 elutions). [α]2D5 = –46.9 (c = 0.51,
CHCl ). IR (CHCl ): ν = 3420 (NH), 1682 (CO) cm–1. H NMR
1
˜
3
3
1
and COSY H–1H (400 MHz, CDCl3): δ = 1.30 (br. s, NH amine),
Synthesis of Macrocyclic Diketal Dilactams 1b,c, 2b,c, and 3b,c: The
2
3
1.68 (dddd, J = 14.2 Hz, J = 6.0, 1.8, 0.4 Hz, 1 H, 13-HB), 1.96
(dddd, 2J = 14.2 Hz, 3J = 10.4, 9.4, 2.2 Hz, 1 H, 13-HA), 2.53 (ddd,
2J = 11.1 Hz, 3J = 10.4, 0.4 Hz, 1 H, 12-HB), 2.63 (dd, 2J = 15.8 Hz,
preparation of these compounds was previously described.[6]
General Procedure for the Reduction of Diketal Dilactams
3J = 1.6 Hz, 1 H, 6-HB), 2.65 (ddd, J = 11.1 Hz, J = 6.0, 2.2 Hz,
2
3
Method A: To a suspension of LiAlH4 (10 equiv.) in dry THF
(0.5 mL for 1 mol of LAH) was added NEt3 (0.01–0.04 equiv./
LAH) and dropwise a solution of diketal dilactam (1 equiv.) in dry
THF (csubstrate = 14–30ϫ10–3 ). The reaction mixture was heated
at reflux whilst stirring for 7–20 h. The excess amount of hydride
was destroyed by the addition of H2O (10 equiv./LAH). The pre-
cipitates were filtered and washed with THF and CH2Cl2. The or-
ganic layer was dried with MgSO4 and evaporated in vacuo. Purifi-
cation by flash chromatography (silica gel, Et2O/MeOH) led to di-
ketal diamines and diketal aminolactams.
1 H, 12-HA), 2.85 (dd, 2J = 15.8 Hz, J = 8.1 Hz, 1 H, 6-HA), 2.95
3
2
3
(s, 3 H, OCH3), 3.35 (s, 3 H, OCH3), 3.51 (dd, J = 9.6 Hz, J =
10.1 Hz, 1 H, 9-HB), 3.75 (dd, 2J = 9.7 Hz, 3J = 3.0 Hz, 1 H, 2-
HB), 3.89 (dd, 2J = 9.6 Hz, J = 2.6 Hz, 1 H, 9-HA), 3.96 (dd, J =
3
3
2
3
10.1, 2.6 Hz, 1 H, 10-H), 4.05 (dd, J = 9.7 Hz, J = 3.2 Hz, 1 H,
2-HA), 4.66 (dd, J = 9.4, 1.8 Hz, 1 H, 14-H), 4.80 (dd, J = 8.1,
1.6 Hz, 1 H, 7-H), 5.24 (ddd, 3J = 7.4, 3.2, 3.0 Hz, 1 H, 3-H), 7.25–
7.42 (m, 10 H, 10 Ar-H), 7.62 (d, 3J = 7.4 Hz, 1 H, NH amide)
ppm. 13C NMR and HSQC (100 MHz, CDCl3): δ = 31.6 (C-13),
41.0 (C-6), 44.4 (C-12), 50.3 (OCH3), 52.7 (C-3), 53.4 (OCH3), 63.5
(C-10), 68.8 (C-2), 73.3 (C-9), 101.0 (C-7), 104.4 (C-14), 126.8–
128.6 (10 Ar-CH), 139.9 (Ar-C), 140.0 (Ar-C), 168.2 (CO) ppm.
MS (CI): m/z (%) = 429 (100) [M + H]+, 397 (36) [M + H –
3
3
Method B: To a solution of diketal dilactam (1 equiv.) in dry THF
(csubstrate = 15–40ϫ10–3 ), was added, dropwise whilst stirring, a
solution of LiAlH4 (1  solution in THF, 10 equiv.) and NEt3
Eur. J. Org. Chem. 2008, 2039–2048
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2045

R. Affani, P. Auzeloux, J.-C. Madelmont, D. Dugat
FULL PAPER
CH3OH]+, 192 (16), 121 (15), 105 (54). HRMS (ESI): calcd. for MeOH, gradient: 100:0–0:100) afforded diketal diamine 7b
C24H33N2O5 [M + H]+ 429.2390; found 429.2391.
(10.8 mg, 37.2 µmol, 20%), diketal aminolactam 8b (11.9 mg,
39.1 µmol, 21%), and unsaturated ketal aminolactam 9 (1.0 mg,
3.7 µmol, 2%) with 93% conversion rate. Data for 9: Rf = 0.60
(3S,7S,10S,14R)-Dimethyl Diketal Diamine
7b
and
(3S,7S,10S,14R)-Dimethyl Diketal Aminolactam 8b: These com-
pounds were prepared from diketal dilactam 2b (63.7 mg,
0.20 mmol), LiAlH4 (76 mg, 2.0 mmol, 10 equiv.), NEt3 (1  solu-
tion in THF, 40 µL, 40 µmol, 0.02 equiv./LAH), and THF (8.0 mL,
csubstrate = 25ϫ10–3 ) according to method A (reaction time 18 h).
The excess amount of hydride was destroyed by the addition of
H2O (360 µL, 20 mmol). Chromatography (Et2O/MeOH, gradient
100:0–0:100) afforded diketal diamine 7b (22.4 mg, 77.1 µmol,
41%) and diketal aminolactam 8b (11.4 mg, 37.6 µmol, 20%) with
94% conversion rate. Data for 7b: Rf = 0.20 (MeOH, 3 elutions).
(MeOH, 3 elutions). IR (CHCl ): ν = 3426 (NH), 1662 (CO), 1604
˜
3
(C=C) cm–1. H NMR and COSY H–1H (400 MHz, CDCl3): δ =
1
1
3
3
1.04 (d, J = 6.4 Hz, 3 H, Me-10), 1.29 (d, J = 6.9 Hz, 3 H, Me-
3), 1.78 (br. s, 1 H, NH amine), 1.90 (dddd, J = 14.6 Hz, 3J = 6.5,
2
1.8, 1.0 Hz, 1 H, 13-HB), 2.06 (dddd, J = 14.6 Hz, J = 10.5, 9.5,
2
3
1.5 Hz, 1 H, 13-HA), 2.51 (ddd, J = 10.6 Hz, J = 10.5, 1.0 Hz, 1
2
3
H, 12-HB), 2.97 (m, 2 H, 12-HA, 10-H), 3.30 (s, 3 H, OCH3), 3.51
(dd, J = 9.2 Hz, J = 2.8 Hz, 1 H, 2-HB), 3.77 (dd, J = 9.2 Hz,
2
3
2
3J = 1.6 Hz, 1 H, 2-HA), 3.90 (ABX system, part AB, 2J = 10.0 Hz,
3J = 13.0, 1.0 Hz, ∆ν = 6.2 Hz, 2 H, 9-HA, 9-HB), 4.29 (dqdd, J
3
[α]2D5 = +21.23 (c = 0.68, CHCl ). IR (CHCl ): ν = 3337 (NH) cm–1.
˜
3
3
3
= 7.0, 6.9, 2.8, 1.6 Hz, 1 H, 3-H), 4.57 (dd, J = 9.5, 1.8 Hz, 1 H,
14-H), 4.96 (d, J = 6.9 Hz, 1 H, 6-H), 6.45 (d, J = 6.9 Hz, 1 H,
1H NMR and COSY H–1H (400 MHz, CDCl3): δ = 1.00 (d, J =
1
3
3
3
6.4 Hz, 3 H, Me-10), 1.11 (d, 3J = 6.6 Hz, 3 H, Me-3), 1.82 (dddd,
3
7-H), 7.48 (d, J = 7.0 Hz, 1 H, NH lactam) ppm. MS (ESI): m/z
2J = 14.0 Hz, J = 4.8, 1.6, 1.5 Hz, 1 H, 13-HB), 1.83 (dddd, J =
3
2
(%) = 295 (100) [M + Na]+, 273 (24) [M + H]+, 241 (44) [M + H –
CH3OH]+. HRMS (ESI): calcd. for C13H25N2O4 [M + H]+
273.1814; found 273.1829.
14.6 Hz, 3J = 6.0, 3.1, 2.6 Hz, 1 H, 6-HB), 1.94 (dddd, 2J = 14.6 Hz,
3J = 8.1, 7.3, 2.6 Hz, 1 H, 6-HA), 2.05 (dddd, J = 14.0 Hz, J =
10.8, 9.2, 2.4 Hz, 1 H, 13-HA), 2.30 (br. s, 2 H, 2 NH), 2.55 (ddd,
2J = 12.0 Hz, 3J = 10.8, 1.5 Hz, 1 H, 12-HB), 2.68 (ddd, 2J =
2
3
(3S,7R,10S,14R)-Dimethyl Diketal Diamine 7c: This compound
11.0 Hz, 3J = 7.3, 3.1 Hz, 1 H, 5-HB), 2.88 (m, 4 H, 3-H, 5-HA, 10- was prepared from diketal dilactam 2c (63.7 mg, 0.20 mmol), Li-
H, 12-HA), 3.14 (dd, J = 9.5 Hz, J = 9.7 Hz, 1 H, 2-HB), 3.28 (s,
AlH4 (76 mg, 2.0 mmol, 10 equiv.), NEt3 (1  solution in THF,
2
3
2
3 H, OCH3), 3.33 (s, 3 H, OCH3), 3.54 (ABX system, part AB, J 20 µL, 20 µmol, 0.01 equiv./LAH), and THF (6.7 mL, csubstrate
=
= 9.7 Hz, 3J = 5.4, 1.9 Hz, ∆ν = 6.9 Hz, 2 H, 9-HA, 9-HB), 3.77
(dd, 2J = 9.5 Hz, 3J = 2.6 Hz, 1 H, 2-HA), 4.56 (dd, 3J = 8.1, 2.6 Hz,
30ϫ10–3 ) according to method A (reaction time 20 h). The ex-
cess amount of hydride was destroyed by the addition of H2O
(360 µL, 20 mmol). Chromatography (Et2O/MeOH, gradient
100:0–0:100) afforded diketal diamine 7c (18.0 mg, 62 µmol, 33%)
3
1 H, 7-H), 4.61 (dd, J = 9.2, 1.6 Hz, 1 H, 14-H) ppm. 13C NMR
and HSQC (100 MHz, CDCl3): δ = 16.1 (H3C-10), 17.1 (H3C-3),
32.2 (C-13), 32.3 (C-6), 42.2 (C-5), 43.5 (C-12), 50.6 (OCH3), 52.1
(C-10), 52.6 (OCH3), 52.9 (C-3), 69.2 (C-9), 72.8 (C-2), 104.1 (C-
14), 104.3 (C-7) ppm. MS (ESI): m/z (%) = 313 (31) [M + Na]+,
291 (100) [M + H]+, 259 (18) [M + H – CH3OH]+. HRMS (ESI):
calcd. for C14H31N2O4 [M + H]+ 291.2284; found 291.2296. Data
for 8b: Rf = 0.40 (MeOH, 3 elutions). [α]2D5 = +8.89 (c = 0.74,
with 94% conversion rate. Rf = 0.30 (MeOH, 3 elutions). [α]2D5
=
+53.4 (c = 0.97, CHCl ). IR (CHCl ): ν = 3332 (NH amine) cm–1.
˜
3
3
1
3
1H NMR and COSY H–1H (400 MHz, CDCl3): δ = 1.06 (d, J =
6.6 Hz, 6 H, 2 Me), 1.87 (dddd, 2J = 14.4 Hz, 3J = 7.4, 2.5, 1.2 Hz,
2 H, 6-HB, 13-HB), 2.00 (dddd, J = 14.4 Hz, J = 9.7, 8.6, 2.2 Hz,
2
3
3
2 H, 6-HA, 13-HA), 2.58 (ddd, 2J = 11.1 Hz, J = 9.7, 1.2 Hz, 2 H,
CHCl ). IR (CHCl ): ν = 3407 and 3340 (NH), 1660 (CO) cm–1. 5-HB, 12-HB), 2.75 (br. s, 2 H, 2 NH), 2.86 (m, 4 H, 3-H, 10-H, 5-
˜
3
3
1H NMR and COSY H–1H (400 MHz, CDCl3): δ = 1.04 (d, J = HA, 12-HA), 3.30 (s, 6 H, 2 OCH3), 3.53 (ABX system, part AB,
1
3
3
3
6.4 Hz, 3 H, Me-10), 1.25 (d, J = 6.7 Hz, 3 H, Me-3), 1.87 (ddt,
2J = 10.2 Hz, J = 7.5, 2.0 Hz, ∆ν = 25.3 Hz, 4 H, 2-HA, 2-HB, 9-
2J = 14.2 Hz, J = 6.4, 1.5 Hz, 1 H, 13-HB), 1.98 (br. s, 1 H, NH
HA, 9-HB), 4.62 (dd, J = 8.6, 2.5 Hz, 2 H, 7-H, 14-H) ppm. 13C
3
3
2
3
amine), 2.06 (dddd, J = 14.2 Hz, J = 10.5, 9.3, 2.0 Hz, 1 H, 13-
NMR and HSQC (100 MHz, CDCl3): δ = 16.7 (H3C-3, H3C-10),
31.8 (C-6, C-13), 43.0 (C-5, C-12), 51.5 (2 OCH3), 52.5 (C-3, C-
10), 69.4 (C-2, C-9), 103.8 (C-7, C-14) ppm. MS (ESI): m/z (%) =
HA), 2.55 (dd, 2J = 15.8 Hz, J = 1.5 Hz, 1 H, 6-HB), 2.59 (ddd, 2J
3
= 12.6 Hz, J = 10.5, 1.5 Hz, 1 H, 12-HB), 2.72 (dd, J = 15.8 Hz,
3
2
3J = 8.2 Hz, 1 H, 6-HA), 2.93 (dqd, J = 9.3, 6.4, 2.0 Hz, 1 H, 10- 313 (81) [M + Na]+, 291 (100) [M + H]+, 259 (22) [M + H –
3
H), 2.94 (ddd, 2J = 12.6 Hz, 3J = 6.4, 2.0 Hz, 1 H, 12-HA), 3.23
(dd, 2J = 9.7 Hz, 3J = 9.3 Hz, 1 H, 9-HB), 3.30 (s, 3 H, OCH3),
3.35 (s, 3 H, OCH3), 3.45 (dd, 2J = 9.6 Hz, 3J = 2.2 Hz, 1 H, 2-
CH3OH]+. HRMS (ESI): calcd. for C14H31N2O4 [M + H]+
291.2284; found 291.2295.
(7S*,14R*)-Diketal Diamine 10b: This compound was prepared
from diketal dilactam 3b (58.0 mg, 0.20 mmol), LiAlH4 (1  THF
solution, 2 mL, 2.0 mmol, 10 equiv.), NEt3 (1  solution in THF,
HB), 3.72 (dd, 2J = 9.6 Hz, J = 2.1 Hz, 1 H, 2-HA), 3.78 (dd, 2J =
3
9.7 Hz, 3J = 2.0 Hz, 1 H, 9-HA), 4.21 (dqdd, 3J = 7.5, 6.7, 2.2,
2.1 Hz, 1 H, 3-H), 4.60 (dd, 3J = 9.3, 1.5 Hz, 1 H, 14-H), 4.69 (dd,
40 µL, 40 µmol, 0.02 equiv./LAH), and THF (11.3 mL, csubstrate
=
3J = 8.2, 1.5 Hz, 1 H, 7-H), 7.03 (d, J = 7.5 Hz, 1 H, NH lactam)
3
15ϫ10–3 ) according to method B (reaction time 8 h). The excess
amount of hydride was destroyed by the addition of H2O (360 µL,
20 mmol). Chromatography (Et2O/MeOH, gradient 100:0–0:100)
afforded diketal diamine 10b (16.6 mg, 63.2 µmol, 40%) with 79%
conversion rate. Rf = 0.30 (MeOH/NH4OH, 99.5:0.5, 2 elutions).
ppm. 13C NMR and HSQC (100 MHz, CDCl3): δ = 16.1 (H3C-
10), 17.7 (H3C-3), 31.9 (C-13), 40.8 (C-6), 43.8 (C-12), 44.9 (C-3),
50.9 (OCH3), 53.1 (C-10), 53.2 (OCH3), 69.6 (C-2), 71.5 (C-9),
100.7 (C-7), 104.4 (C-14), 168.1 (CO) ppm. MS (ESI): m/z (%) =
305 (100) [M + H]+, 273 (42) [M + H – CH3OH]+, 247 (11), 215 (7).
HRMS (ESI): calcd. for C14H29N2O5 [M + H]+ 305.2076; found
305.2063.
IR (CHCl ): ν = 3300 (NH) cm–1. 1H NMR and COSY 1H–1H
˜
3
2
(400 MHz, CDCl3): δ = 1.27 (br. s, 2 H, 2 NH), 1.87 (dddd, J =
14.5 Hz, 3J = 7.0, 2.2, 2.0 Hz, 2 H, 6-HB, 13-HB), 2.02 (dddd, J =
2
3
2
(3S,10S,14R)-Dimethyl Unsaturated Ketal Aminolactam 9: This
compound was obtained from diketal dilactam 2b (63.7 mg,
0.20 mmol), LiAlH4 (76 mg, 2.0 mmol, 10 equiv.), NEt3 (1  solu-
tion in THF, 20 µL, 20 µmol, 0.01 equiv./LAH), and THF
(16.5 mL, csubstrate = 12ϫ10–3 ) according to method A (reaction
time 18 h). The excess amount of hydride was destroyed by the
addition of H2O (360 µL, 20 mmol). Chromatography (Et2O/
14.5 Hz, J = 9.9, 8.6, 2.5 Hz, 2 H, 6-HA, 13-HA), 2.70 (ddd, J =
11.9 Hz, 3J = 9.9, 2.0 Hz, 2 H, 5-HB, 12-HB), 2.77 (ddd, 2J =
12.3 Hz, 3J = 4.1, 2.3 Hz, 2 H, 3-HB, 10-HB), 2.87 (ddd, 2J =
12.3 Hz, 3J = 9.4, 2.7 Hz, 2 H, 3-HA, 10-HA), 2.88 (ddd, 2J =
12.0 Hz, 3J = 7.1, 2.5 Hz, 2 H, 5-HA, 12-HA), 3.32 (s, 6 H, 2
OCH3), 3.54 (ddd, 2J = 10.0 Hz, 3J = 9.4, 2.3 Hz, 2 H, 2-HB, 9-
HB), 3.90 (ddd, J = 10.0 Hz, J = 4.1, 2.7 Hz, 2 H, 2-HA, 9-HA),
2
3
2046
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2039–2048

Macrocyclic 14-Membered Ring Diketal Diamines
4.60 (dd, 3J = 8.6, 2.2 Hz, 2 H, 7-H, 14-H) ppm. 13C NMR and
HSQC (100 MHz, CDCl3): δ = 32.0 (C-6, C-13), 46.0 (C-5, C-12),
49.5 (C-3, C-10), 51.9 (2 OCH3), 66.0 (C-2, C-9), 104.5 (C-7, C-14)
ppm. MS (ESI): m/z (%) = 263 (100) [M + H]+, 231 (37) [M + H –
CH3OH]+. HRMS (ESI): calcd. for C12H27N2O4 [M + H]+
263.1971; found 263.1973.
Tc-99m Radiolabeling
General: [99mTc] Sodium pertechnetate was purchased from Centre
Jean Perrin (Clermont-Ferrand). All solvents were degassed under
an atmosphere of argon before used. TLC radioactive spots were
scanned and recorded by using an AMBIS 101 detector equipped
with a computer-controlled multiwire proportional counter.
Macrocycle Labeling: Four solutions were successively introduced
in a reaction vial placed under an argon atmosphere: (1) a solution
of N-methyl-S-methyldithiocarbazate (MDTCZ, 1 mg, 7.4 µmol) in
ethanol (0.4 mL, c = 18.4ϫ10–3 ), (2) a solution of PPh3 (1 mg,
3.8 µmol) in ethanol (0.2 mL, c = 19.0ϫ10–3 ), (3) a solution of
HCl in water (0.1 mL, 1 ), and (4) a solution of 99mTcO4Na (28.8
MBq, 0.78 mCi, total technetium: 1.0 ng, 5.4 pmol) in normal sa-
line (2.7 mL). The mixture was heated to 70 °C for 30 min and then
cooled to room temperature. The pH was adjusted by adding
NaOH (0.1 mL, 1 ) and a buffer solution of NaHCO3/Na2CO3
(9:1, pH 9.4). A part (0.7 mL) of this mixture was introduced, un-
der an atmosphere of argon, in a second reaction vial containing a
solution of the ligand (2.4–4.2 µmol) in ethanol (0.7 mL). The re-
sulting mixture was heated to 70 °C for another 30 min. A thin-
layer chromatography (aluminium oxide, CH2Cl2/MeOH, 94:6)
gave radioactive spots corresponding to the following radiochemi-
cal yields: 4c-TcN (0%), 7b-TcN (11%), 7c-TcN (17%), 10b-TcN:
(18%), and 10c-TcN (14%).
(7R*,14R*)-Diketal Diamine 10c and (7R*,14R*)-Diketal Amino-
lactam 11c: These compounds were prepared from diketal dilactam
3c (58 mg, 0.20 mmol), LiAlH4 (76 mg, 2.0 mmol, 10 equiv.), NEt3
(1  solution in THF, 20 µL, 20 µmol, 0.01 equiv./LAH), and THF
(6.7 mL, csubstrate = 14ϫ10–3 ) according to method A (reaction
time 7 h). The excess amount of hydride was destroyed by the ad-
dition of H2O (360 µL, 20 mmol). Chromatography (Et2O/MeOH,
gradient 100:0–0:100) afforded diketal diamine 10c (19.5 mg,
74.4 µmol, 40%) and diketal aminolactam 11c (1.5 mg, 5.6 µmol,
3%) with 93% conversion rate. Data for 10c: Rf = 0.25 (MeOH/
NH OH, 99.5:0.5, 2 elutions). IR (CHCl ): ν = 3350 (NH) cm–1.
˜
4
3
1H NMR and COSY H–1H (400 MHz, CDCl3): δ = 1.89 (dddd,
1
2J = 14.7 Hz, J = 7.9, 2.7, 2.5 Hz, 2 H, 6-HB, 13-HB), 1.98 (dddd,
3
2J = 14.7 Hz, J = 7.8, 7.2, 2.2 Hz, 2 H, 6-HA, 13-HA), 2.72 (br. s,
3
2 H, 2 NH), 2.77 (m, 4 H, 3-HB, 10-HB, 5-HB, 12-HB), 2.89 (m, 4
H, 3-HA, 10-HA, 5-HA, 12-HA), 3.35 (s, 6 H, 2 OCH3), 3.61 (ddd,
2J = 9.8 Hz, 3J = 7.7, 1.7 Hz, 2 H, 2-HB, 9-HB), 3.89 (ddd, 2J =
9.8 Hz, 3J = 6.3, 2.8 Hz, 2 H, 2-HA, 9-HA), 4.62 (dd, 3J = 7.2,
2.7 Hz, 2 H, 7-H, 14-H) ppm. 13C NMR and HSQC (100 MHz,
CDCl3), HMBC (125 MHz, CDCl3): δ = 31.1 (C-6, C-13), 44.9 (C-
5, C-12), 48.9 (C-3, C-10), 53.4 (2 OCH3), 65.7 (C-2, C-9), 104.5
(C-7, C-14) ppm. MS (ESI): m/z (%) = 275 (31) [M + Na]+, 263
(100) [M + H]+, 231 (14) [M + H – CH3OH]+. HRMS (ESI): calcd.
for C12H27N2O4 [M + H]+ 263.1971; found 263.1982. Data for 11c:
Supporting Information (see footnote on the first page of this arti-
cle): Molecular modeling data for all calculated diketal diamine
structures; relative energy of the 15 first conformers of compounds
4, 7, and 10; interatomic distances between the NH hydrogen atoms
and the endocyclic acetalic oxygen atoms of diketal diamines 4, 7,
and 10; bond lengths C–O, C–N, and C–C of diketal diamines 4,
7, and 10.
R = 0.45 (MeOH/NH OH, 99.5:0.5, 2 elutions). IR (CHCl ): ν =
˜
f
4
3
3400, 3360, 3280 (NH), 1655 (CO) cm–1. 1H NMR and COSY 1H–
1H (400 MHz, CDCl3): δ = 1.83 (dddd, 2J = 14.4 Hz, 3J = 7.2, 2.5,
2.2 Hz, 1 H, 13-HB), 1.95 (dddd, 2J = 14.4 Hz, 3J = 8.7, 7.9, 2.5 Hz, Acknowledgments
2
1 H, 13-HA), 2.20 (br. s, 1 H, NH amine), 2.52 (dd, J = 14.8 Hz,
2
3
3J = 2.0 Hz, 1 H, 6-HB), 2.67 (ddd, J = 11.4 Hz, J = 8.7, 2.5 Hz,
The authors wish to thank F. Pelissier for technical assistance, B.
Légeret for mass spectrometry, J. Guyot for molecular modeling,
(ddd, 2J = 12.7 Hz, 3J = 6.8, 2.6 Hz, 1 H, 10-HB), 2.82 (m, 2 H, and the PAC (Plan Auvergne Cancer) for financial support.
10-HA, 12-HA), 3.18 (ddd, 2J = 14.0 Hz, 3J = 9.0, 4.0, 2.5 Hz, 1 H,
1 H, 12-HB), 2.69 (dd, J = 14.8 Hz, J = 7.7 Hz, 1 H, 6-HA), 2.77
2
3
2
3-HB), 3.32 (s, 3 H, OCH3), 3.35 (s, 3 H, OCH3), 3.55 (ddd, J =
[1] a) E. Kimura, Tetrahedron 1992, 48, 6175–6217 and references
3
2
3
9.5 Hz, J = 9.0, 1.5 Hz, 1 H, 2-HB), 3.58 (ddd, J = 9.7 Hz, J =
cited therein; b) F. Bellouard, F. Chuburu, J. J. Yaouanc, H.
Handel, Y. Le Mest, Eur. J. Org. Chem. 1999, 3257–3261; c) G.
Dubois, C. Reyé, R. J. P. Corriu, S. Brandès, F. Denat, R. Guil-
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F. Rascalou, H. Chollet, J. L. Babouhot, F. Denat, R. Guilard,
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6.8, 2.6 Hz, 1 H, 9-HB), 3.76 (dddd, 2J = 14.0 Hz, 3J = 7.0, 5.8,
1.5 Hz, 1 H, 3-HA), 3.80 (ddd, J = 9.5 Hz, J = 5.8, 2.5 Hz, 1 H,
2
3
2-HA), 3.85 (ddd, J = 9.7 Hz, J = 6.8, 2.6 Hz, 1 H, 9-HA), 4.56
2
3
3
3
(dd, J = 7.9, 2.2 Hz, 1 H, 14-H), 4.75 (dd, J = 7.7, 2.0 Hz, 1 H,
7-H), 6.95 (br. s, 1 H, NH lactam) ppm. 13C NMR and HSQC
(400 MHz, CDCl3): δ = 31.6 (C-13), 39.3 (C-3), 40.8 (C-6), 45.3
(C-12), 48.8 (C-10), 53.0 (OCH3), 53.8 (OCH3), 64.4 (C-9), 65.8
(C-2), 100.6 (C-7), 104.2 (C-14), 169.2 (CO) ppm. MS (ESI): m/z
(%) = 315 (53) [M + K]+, 299 (80) [M + Na]+, 277 (100) [M +
H]+, 263 (11), 245 (14) [M + H – CH3OH]+, 219 (12). HRMS (ESI):
calcd. for C12H25N2O5 [M + H]+ 277.1763; found 277.1776.
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Eur. J. Org. Chem. 2008, 2039–2048
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2047

R. Affani, P. Auzeloux, J.-C. Madelmont, D. Dugat
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Received: December 5, 2007
Published Online: February 20, 2008
2048
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2039–2048