Factors Influencing the Course of the Macrocyclization of α,ω-Diamines with Esters of α,ω-Dicarboxylic Acids

Article abstract of DOI:10.1002/hlca.200490004

The efficient synthesis of eight new macrocyclic amides (lactams) via reaction of diesters with diamines under normal dilution conditions is described. The role of intermolecular H-bond formation and steric hindrance is discussed based on ¹H- a

Full text of DOI:10.1002/hlca.200490004

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Factors Influencing the Course of the Macrocyclization of a,w-Diamines with
Esters of a,w-Dicarboxylic Acids
by Dorota Grykoa), Daniel T. Grykoa), Hanna Sierzputowska-Graczb), Piotr PiaÀtekc),
and Janusz Jurczak*a)c)
a) Institute of Organic Chemistry of the Polish Academy of Sciences, Kasprzaka 44/52, PL-01-224 Warsaw
(phone: ‡‡ 48226323221; fax: ‡‡ 48226326681; e-mail: jurczak@icho.edu.pl)
b) North Carolina State University, Raleigh, NC 27695-8204, USA
(phone: ‡‡ 1 (919) 5158907; fax: ‡‡ 1 (919) 5158908; e-mail: hanna gracz@ncsu.edu)
c) Warsaw University, Chemistry Department, Pasteura 1, PL-02-093 Warsaw
The efficient synthesis of eight new macrocyclic amides (lactams) via reaction of diesters with diamines
under normal dilution conditions is described. The role of intermolecular H-bond formation and steric
hindrance is discussed based on 1H- and 15N-NMR studies of appropriate model compounds. Principles for the
optimal choice of esters that can be efficiently transformed into diamides have been developed.
Introduction.
The architecture of naturally occurring macrocycles has long
provided the stimulus for the development of new methods for the synthesis of cyclic
polyaza and polyoxa compounds [1]. The synthesis of macrocycles possessing both N-
and O-atoms to produce receptors with distinct properties has been pursued by many
research groups due to the potential application of these compounds in medicine,
catalysis, and sensor technology, etc. Such macrocycles have been made by a variety of
methods, including high-dilution techniques [2] and routes based on template effects
[3]. The groups of Kimura [4] and Morphy [5] reported that, consistent with earlier
findings of Tabushi et al. [6], neither high-dilution nor templates are required for the
condensation of diesters with a,w-diamines to form macrocyclic diamides. Later, we
found that this reaction can even be carried out at room temperature [7] and that
various diesters, as long as they possess a heteroatom in a-position to the CˆO group,
are efficient substrates [8 11]. Structural elements such as OCH2CO2Me [8, 10a,b],
NCH2CO2Me [10c][11], or SCH2CO2Me [11], as well as derivatives of pyridine
[9][10d] and pyrazine [9], were successfully used, whereas esters of simple aliphatic
diacids (e.g., adipinate) were found to be unreactive unless high pressure was applied
[7b]. Recently, we have optimized the reaction conditions for macrocyclizations [11],
using MeONa as a catalyst, which speeds up the reaction, improves the yields, and
broadens the scope of the reaction by including less-reactive esters like dimethyl
phthalate. Our results showed that there is no template effect operating in these
reactions. Others have also made use of these (or similar) conditions for the synthesis of
a wide scope of macrocyclic amides [12][13].
Our interest in the reaction of diesters and diamines has been motivated not only by
its broad scope, but also by the amazing observation that standard dilution of reagents
is enough to obtain high yields of macrocyclization. For this reason and keeping with
our long-standing interest in diazacoronands, we undertook detailed studies to gain

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157
insight into the driving forces that govern such reactions. We chose 2,6-bis(carba-
moyl)pyridine or analogous model compounds in this study due to their function in
cation receptors [14], anion receptors [15], neutral-molecule receptors [16], knots [17],
dendrimers [18], and helical structures [19]. Additionally, dimethyl pyridine-2,6-
dicarboxylate (1) has already been used for the preparation of macrocyclic amides in
combination with a,w-diaminoalkanes [9b], a,w-diamino ethers [9a], and aliphatic
polyamines [12][20].
Results and Discussion. There is a fundamental difference in the course of the
reaction of diacid dichlorides with diamines in toluene, CH2Cl2, or THF and that of
diesters with diamines in MeOH. What kind of forces lead to excellent yields of
macrocyclic products in the latter reaction? And why do acid chlorides at the same
concentration give rise to polycondensation products only? One has to note that diacid
dichlorides are usually far too reactive to give macrocyclic products under normal
conditions. Both reaction pathways involve the formation of the amide bond via the
reaction of the ester (or acid chloride) and the amino group to afford an intermediate
(referred to as −amino-amido-ester× and −amino-amido-acid chloride×, resp.) that can
cyclize to generate the respective diamide. Our initial notion was that MeOH
selectively mediates some form of preorganization of the −amino-amido-ester×
intermediate, which would increase the chance for ring closure vs. oligocondensation.
To verify our hypothesis, we designed a few experiments with selected diamines and
diesters to clarify some crucial issues. To check whether the presence of the amide H-
atom is crucial for effective macrocyclization, we carried out the reactions of 1 with two
secondary a,w-diamines of different lengths (Scheme 1). We expected that the
reactivity of the amines 2 and 3 [21] would be reduced by the N-Me groups as
Scheme 1

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Helvetica Chimica Acta Vol. 87 (2004)
compared to analogous primary diamines. In both cases, the yields of the macrocyclic
products 4 and 5 were significantly lower than the yields obtained with the
nonmethylated analogs (10 vs. 54% [15b], and 2.7 vs. 83% [9a], respectively). Even
in the presence of MeONa [11], the yield of 5 was still very low (4%), although the
conversion of 1 increased from 27 to 53%. These results may indicate that the low
yields of 4 and 5 result not only from effects of the N-methyl groups, but are also
attributable to the lack of some form of preorganization.
We already reported that dimethyl diesters lacking a heteroatom between the two
ester groups (like those originating from isophthalic acid and pyridine-3,5-dicarboxylic
acid) do not react with H2N[(CH2)2O]2(CH2)2NH2 in the absence of MeONa, whereas
very small amounts of di- and/or tetramides were formed in its presence [11]. Hence,
we came up with the hypothesis that the reactivity of the ester groups is at least as
crucial (or even more important than) the heteroatom between these groups. To verify
this hypothesis, we synthesized compounds 6 9 and tested their reactivities toward
diamines. The furane-2,5-dicarboxylate 6, which has an exceptionally high average
electron density and an O-atom between the ester groups, did not react with diamine
10, not even after 18 months (Scheme 2, Table 1). However, when MeONa was present,
diamide 11 could be obtained in 30% yield (Table 2). The results obtained for
isophthalates relative to 6 indicate that, when the reactivity of ester groups is increased
by addition of catalyst, the course of the reaction starts to depend on the presence (or
absence) of a heteroatom placed between the two ester groups.
Table 1. Degree of Conversion and Yields of Products in the Reactions of Diesters 1 and 6 9 with Diamine 10 (in
MeOH)
Ester
Reaction time
Conversion [%]
Dimerization
Product
Tetramerization
Yield [%]
Product
Yield [%]
1
6
7
8
9
7 d
365 d
7 d
7 d
7 d
97
0
99
100
100
12
11
13
15
20
83
0
83
2
14
6
0
0
6
32
16
21
4

Helvetica Chimica Acta Vol. 87 (2004)
159
Scheme 2
Table 2. Degree of Conversion and Yields of Products in the Reactions of Diesters 1 and 6 9 with Diamine 10 (in
MeOH containing 10 equiv. of NaOMe)
Ester
Reaction time
Conversion [%]
Dimerization
Product
Tetramerization
Yield [%]
Product
Yield [%]
1
6
7
8
9
12 h
7 d
100
100
12
11
84
36
14
4
0
12 h
12 h
100
100
15
20
2
67
16
21
6
26
Compound 7, an analog of 1 with an additional ester group in 4-position, could
theoretically undergo two different modes of macrocyclization (Scheme 2). However,
we found that 7 reacts with 10 exclusively in the 2- and 6-positions (Table 1). The yields

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Helvetica Chimica Acta Vol. 87 (2004)
of the diamides 12 and 13 were identical1), although in 7, the electron densities at all
ester groups is similar. These results further confirmed the role played by heteroatoms
in the macrocyclization process.
At this point, we decided to test a compound possessing the two CO2Me groups in
a-position to N-atoms, but lacking a heteroatom between the ester groups, compound 8
being such a representative. Here, the ester groups were very reactive, and 8 was
completely consumed in the reaction with 10 within 12 h in the absence of catalyst.
Nevertheless, only very small amounts of diamide 15 (2%) and tetramide 16 (6%) were
formed in this reaction (Scheme 2, Tables 1 and 2), along with a number of very polar
compounds. Neither prolongation of the reaction nor addition of MeONa changed the
results.
Another important issue was the effect of substrate conformation (rigidity) on the
yield of macrocyclic products. As reported [7][9], the rigidity of an ester might
influence the yields of diamides, depending on the length of the a,w-diamine used, but
no such studies have been made with rigid diamines. Therefore, we designed the
optically active diamine 17 [8] as a rigid analog of 1,4-diaminobutane, restricted by a
dioxolane ring. Consequently, in the reaction with 1, the intermediate 18 was sterically
hindered, preventing ring closure. Indeed, this reaction led to the formation of the
open-chain compounds 18 (54%) and 19 (4%) instead of the corresponding cyclic
tetramide formed with butane-1,4-diamine [9b] (Scheme 3). Also, under high-pressure
conditions, which increase the rate of the reaction [7b][22], no cyclic products were
isolated.
Scheme 3
1
)
Small amounts of tetramer (14) were found only in the reaction with 1, but not with 7.

Helvetica Chimica Acta Vol. 87 (2004)
161
To investigate solvent effects, we studied the product distribution of the model
reaction between 1 and 10 in various solvents Table 3.
Table 3. Solvent Effects in the Cyclization of Diester 1 with Diamine 10. Conditions: 7 d, r.t.
Solvent
Conversion of 1 [%]
Yield of 12 [%]
Yield of 14 [%]
Toluene
THF
CHCl3
MeCN
MeNO2
DMF
0.1
0.3
8
70
49
8
27
57
83
2
5
5
6
58
EtOH
MeOH
H2O
64
97
100
100
neat
21
traces
The model reaction, when performed in nonpolar solvents such as toluene, THF, or
CHCl3, resulted in almost quantitative recovery of the ester 1. This means that the
reactivity of the ester group towards amino groups in nonpolar solvents is very low.
More-polar solvents like MeCN and MeNO2 gave rise to totally different results. While
the conversion of the ester was very high in MeCN, no cyclic products were obtained.
Under similar conditions, the conversion was ca. 50% in MeNO2, and diamide 12 was
obtained in 8% yield. The conversion was also ca. 50% in DMF, but the yield of 12
increased to 27%. In EtOH, the conversion of 1 was 64%, and the yield of 12 was 57%,
i.e., the ratio conversion yield was roughly the same as for MeOH (Table 3).
Apparently, the reaction in EtOH is slower than in MeOH, but the ring closure seems
to be similar mechanistically. The reaction in H2O led to total ester hydrolysis, but,
surprisingly, the reaction of a neat mixture of 1 and 10 led to as much as 21% of the
diamide. Hence, even in such a −concentrated solution×, the reaction still leads to
macrocyclic products.
The presence of a strong intramolecular H-bond in the solid-state structure of both
macrocyclic and nonmacrocyclic pyridine-2,6-dicarboxamides is well-known [9][23]. In
light of the above results, it would, nevertheless, be unreasonable to propose that an
intramolecular H-bond is responsible for the preorganization of the −amino-amido-
ester×. Such a bond would be much stronger in CDCl3 or toluene than in MeOH, which
is a strong competitor, but MeOH is a solvent in which macrocylization is most
effective. However, intermolecular H-bonds between MeOH molecules and the
intermediary −amino-amido-ester× might be responsible for the observed high yields of
the macrocyclization. Such a H-bond array would, undoubtedly, also comprise the
heteroatom placed between the two ester groups. Yet, there might be an alternative
explanation for some of the above results, namely that the H-atom placed between the
CO2Me groups of 7 and 8 might pose a steric hindrance for the amide H-atom, which
would prevent the remaining free amine arm from turning towards the second ester
group. To distinguish steric from H-bond effects, we synthesized ester 9, which
possesses an N-oxide moiety. Clearly, an O-atom causes much more significant steric
hindrance than a H-atom, but may still form a H-bond with an amide NH or other
groups. The reaction of ester 9 with amine 10 was carried out under standard conditions,

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and also in the presence of MeONa (Tables 1 and 2). Under uncatalyzed conditions, the
yield of diamide 20 was only 4%, and that of tetramide 21 was 32% (Table 1). In
contrast, in the presence of MeONa, the yield of 19 increased to 67%, while that of 21
remained essentially the same (Table 2). These results strongly suggest that steric
hindrance can significantly change the mode of complexes of macrocyclization, without
necessarily hampering the success of the reaction.
With all of these results in hand, we conducted comparative NMR studies in MeOH
and two solvents that hamper macrocyclization (CDCl3 and CD3CN). Ester 1, the
macrocyclic diamide 12, and N2,N6-dimethylpyridine-2,6-dicarboxamide (22) were
chosen as model compounds. We recorded 1H-, and 13C-, and 15N-NMR spectra.
Recently, 15N-NMR spectroscopy has been successfully used to determine the
coordination mode of macrocylic amides [14d]. Given that N-atoms indeed participate
in H-bond interactions, 15N-NMR spectra could provide excellent insight into these
processes. Our assumption was that there was a strong intramolecular H-bond in 12, at
least in nonpolar solvents. If so, the chemical shifts of NPy (pyridyl N-atom) and NHCO
should be susceptible to changes in the strength of intramolecular H-bonds. As
expected, there was an upfield shift of ca. 8 ppm for NPy of 1 vs. 12 in CD3OD (Table 4).
However, NPy of 22 showed the same chemical shift as in 12, which suggests that there is
a H-bond in both cases (no differentiation). The same conclusion can be draw for the
chemical shifts of the amide NH groups: basically, there is no difference for 22 in all
three solvents. These results, unfortunately, do not confirm the role of a putative
intramolecular H-bond in the reaction. Also, the comparisons of the chemical shifts of
NH for 12 and 22 are not conclusive. The observation that only in MeOH there is no
difference between the NH resonances of 12 and 22, however, may be important.
Analyses of COSY and other correlation spectra did not reveal any differences.
1
Table 4. 15N- and H-NMR Chemical Shifts of N-Atoms and Amide NH Groups of Compounds 1, 12, and 22
Solvent
Atom(s)
15N-NMR
Atom(s)
1H-NMR
12
1
12
22
22
CD3OD
CDCl3
NHCO
NPy
NHCO
NPy
NHCO
NPy
161.3
236.3
160.7
235.7
160.4
235.7
159.2
237.2
158.0
235.4
158.4
236.2
NHCO
NHCO
NHCO
8.95
8.95
244.4
246.3
246.5
8.1
8.75
8.66
CD3CN
8.34
Conclusions.
The reactions of diesters with diamines depend on both the
structures of both substrates and the type of solvent used. Our detailed study has led to

Helvetica Chimica Acta Vol. 87 (2004)
163
the following conclusions. 1) There is a need to strictly distinguish the reactivity of the
ester groups [11] from the molecule×s ability to efficiently organize an intermolecular
H-bond array between the intermediary −amino-amido-ester× and MeOH molecules.
While the reactivity allows for significant conversion of an ester, the heteroatom placed
between CO2Me groups leads to higher yields of macrocyclic diamides. 2) Esters that
are both reactive and possess a suitably placed heteroatom (e.g., esters of aliphatic acids
bearing OCH2CO2Me [8][10a,b], NCH2CO2Me [10c][11], or SCH2CO2Me [11]
moieties, as well as esters of pyridine-2,6-dicarboxylic and analogous acids) are perfect
substrates that give macrocyclic diamides in at least 40% yield. 3) Esters that are not
reactive (e.g., esters of simple aliphatic diacids [7b], except for oxalates [24] and
malonates [6a][13b], as well as esters possessing OCH2CH2CO2Me [11], furan, pyrrole,
an tiophene derivatives, etc., can be forced to react with diamines in the presence of
basic catalyst (or under high-pressure) to give macrocylic products in moderate to good
yields. 4) Potentially reactive diesters with an unsuitably placed hetaroatom (e.g., 8 or
tartrates) do not afford macrocyclic products in acceptable yields, not even in the
presence of a basic catalyst. 5) All primary a,w-diamines are good substrates for the
macrocyclization reaction, except for sterically congested ones. Reactions with
secondary a,w-diamines lead to only traces of macrocyclic diamides. 6) MeOH is the
best solvent for this kind of macrocyclization reaction. The reactivity of 1 in all
nonpolar solvents is very low and increases gradually as the polarity of the solvent
increases (Table 3). These observations clarify to some extent the phenomenon of
efficient macrocylization and should help to direct the wise choice of the optimal
substrates and conditions for this type of reaction.
Experimental Part
General. Column chromatography (CC) was carried out on silica gel (Kieselgel 60, 200 400 mesh).
Compounds 3 [21] and 17 [8], as well as diesters 1 [12], 6 [25], 8 [26], and 9 [27], were prepared according to
literature procedures. All other diamines were distilled prior to use. Melting points (m.p.) were measured on a
Kˆfler type hot-stage apparatus (Boetius), uncorrected. 1H- and 13C-NMR Spectra were recorded on Varian
Gemini (200 and 50 MHz, resp.) and/or Bruker AM-500 (500 and 125 MHz, resp.) spectrometers, in CDCl3 or
CD3OD; chemical shifts d in ppm relative to SiMe4 (ˆ0.00 ppm), coupling constants J in Hz. High-resolution
mass spectrometry (HR-MS): AMD-604 Intectra instrument, in the electron-impact (EI), liquid secondary-ion
(LSI), or electrospray-ionization (ESI) mode.
Pulsed-Field NMR Experiments. All experiments were performed on a Bruker AVANCE-500 Spectrometer
at 500 MHz, equipped with an Oxford narrow-bore magnet, an SGI INDY host workstation, and XWINMR
software (Vers. 2.5). The instrument was equipped with three frequency channels with a wave-form memory
and an amplitude-shaping unit, a three-channel gradient control unit (GRASP III), a variable-temperature, a
precooling, and a temperature-stabilization unit. For all measurements, a 1 H/BB (109Ag-31P) triple-axis gradient
probe (ID500-5EB; Nalorac Gryogenic Corp), with 5 mm i.d. was used. The NMR probe was tuned to the 13
(125.75 MHz) or the 15N frequency (50.67 MHz). All spectra were acquired at a temp. of 298 K, with SiMe4 as
C
1
1
an internal standard. A combination of 2D homonuclear H- and heteronuclear H-, 15N-, and 13C-correlated
experiments were applied to study the structures of the compounds under investigation. The standard
instrumental parameters for acquisition of the gradient 2D COSY, 2D HMQC, and 2D HMBC were applied.
Data were processed with the Bruker software XWINMR 2.5 using standard-processing parameters.
Trimethyl Pyridine-2,4,6-tricarboxylate (7). The synthesis was performed based on the procedure of H¸nig
and Wehner [28] for a similar compound. 2,4,6-Trimethylpyridine (5.26 g, 43 mmol) was dissolved in conc.
H2SO4 (150 ml). After cooling to 08, CrO3 (39 g, 0.39 mol) was added in small portions over 3 h. The mixture
was heated to 758 for 24 h, poured into a mixture of ice/H2O (0.5 l), and kept at 48. After 3 d, pyridine-2,4,6-
tricarboxylic acid precipitated (7.0 g, 33mmol; 76.3%) as light violet crystals, which were suspended in MeOH

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Helvetica Chimica Acta Vol. 87 (2004)
(40 ml) containing conc. H2SO4 (0.7 ml). The mixture was refluxed overnight. After cooling in a refrigerator,
crystals separated and were collected to afford 7 (4.5 g, 41% over two steps). M.p. 149 1518 (lit. 154.58 [29]). IR
1
(KBr): 3080, 1747, 1442, 1365, 1280, 1242, 1163, 999, 757, 719, 690. H-NMR (250 MHz, CDCl3): 8.81 (s, 2 H);
4.07 (s, 6 H); 4.05 (s, 3 H). 13C-NMR (50 MHz, CDCl3): 164.2; 163.7; 149.2; 140.1; 126.3; 53.2; 53.1. Anal. calc.
for C11H11NO6 (253.21): C 52.18, H 4.38, N 5.33; found: C 51.94, H 4.38, N 5.09.
General Procedures for the Synthesis of Macrocyclic Amides. Method A: An equimolar 0.1m soln. of a,w-
diamine and dimethyl dicarboxylate in anh. MeOH was left at ambient temp. over a period of at least 7 d. The
solvent was evaporated, and the residue was purified by CC (SiO2; CH2Cl2 with 0.5 10% MeOH).
Method B: Na Metal (2.30 g, 100 mmol) was added to anh. MeOH (100 ml). Then, the mixture was cooled
to 58, and the a,w-diamine (10 mmol) and dimethyl dicarboxylate (10 mmol) were added. This mixture was left
at ambient temp. over a period of at least 12 h. The solvent was evaporated, and the residue was purified by CC
(SiO2; CH2Cl2 with 0.5 10% MeOH).
3,12-Dimethyl-6,9-dioxa-3,12,18-triazabicyclo[12.3.1]octadeca-1(17),14(18),15-triene-2,13-dione (4). Meth-
od A: 2.7%. Method B: 4.0%. M.p. 186 1898. 1H-NMR (200 MHz, CDCl3): 8.18 (d, J ˆ 7.3, 2 H); 8.09 7.87
(m, 1 H); 3.90 3.38 (m, 12 H); 3.19 (s, 6 H). 13C-NMR (50 MHz, CDCl3): 162.3; 148.0; 139.4; 124.0; 70.6;
‡
‡
69.10; 47.2; 38.8. HR-MS: 307.1528 (M , C15H2N3O4 ; calc.: 307.1532).
3,6,14,17-Tetramethyl-3,6,14,17,23,24-hexaazatricyclo[17.3.1.18,12]tetracosa-1(23),8,10,12(24),19,21-hexaene-
2,7,13,18-tetraone (5). Method A: 10.1%. Colorless crystals. M.p. 245 2498. IR (KBr): 3436, 3010, 2924, 1636,
1501, 1418, 1353, 1315, 1076, 840, 759, 645. 1H-NMR (200 MHz, CDCl3): 7.9 8.1 (m, 2 H); 7.8 7.9 (m, 4 H);
4.2 4.4 (m, 4 H); 3.6 3.8 (m, 4 H); 3.22 (s, 12 H). 13C-NMR (50 MHz, CDCl3): 168.2; 152.4; 138.5; 125.4; 47.7;
‡
41.7. EI-MS: 438 (50.5, M ), 410 (20.3), 367 (23.0), 354 (44.8), 190 (22.5), 176 (20.0), 163 (32.6), 162 (38.9), 161
(65.7), 149 (45.4), 148 (100), 106 (30.5), 105 (31.4), 78 (30.9), 77 (33.8). Anal. calc. for C22H26N6O4 (438.48):
C 60.26, H 5.98, N 19.17; found: C 59.98, H 6.10, N 18.97.
15,16-Dimethoxy-6,9,17-trioxa-3,12-diazabicyclo[12.2.1]heptadeca-1(16),14-diene-2,13-dione (11). Meth-
od B: 36%. Colorless crystals. M.p. 182 1838. IR (KBr): 3436, 2905, 1667, 1570, 1525, 1341, 1206, 1101, 841,
609, 565. 1H-NMR (500 MHz, CDCl3): 7.23 (br. s, 2 H); 4.19 (s, 6 H); 3.71 (s, 2 H); 3.6 3.7 (m, 2 H); 3.56
(q, J ˆ 5.0, 2 H). 13C-NMR (125 MHz, CDCl3): 157.2; 144.3; 128.9; 70.8; 68.6; 62.4; 38.4; 29.7. EI-MS: 328 (100,
‡
‡
‡
M ), 196 (38), 182 (32), 168 (40), 154 (34), 83 (29.0). HR-LSI-MS: 328.1293 (M , C14H20N2O7 ; calc.:
328.1271). Anal. calc. for C14H20N2O7 (328.32): C 51.22, H 6.14, N 8.53; found: C 51.31, H 6.38, N 8.70.
Methyl 2,13-Dioxo-6,9-dioxa-3,12,18-triazabicyclo[12.3.1]octadeca-1(18),14,16-triene-16-carboxylate (13).
Method A: 83%. Colorless crystals. M.p. 241 2438. IR (KBr): 3401, 3386, 2909, 2882, 1735, 1691, 1530, 1451,
1264, 1241, 1117, 1097, 653. 1H-NMR (200 MHz, CDCl3): 8.8 8.9 (m, 4 H); 4.02 (s, 3 H); 3.6 3.8 (m, 12 H).
13C-NMR (50 MHz, CDCl3): 164.4; 161.8; 149.4; 141.3; 123.3; 70.6; 68.4; 53.0; 38.9. HR-MS: 337.1264 (M ,
C15H19N3O6 ; calc.: 337.1274). Anal. calc. for C15H19N3O6 (337.33): C 53.41, H 5.68, N 12.46; found: C 53.51,
‡
‡
H 5.58, N 12.50.
6,9-Dioxa-3,12,15,17-tetraazabicyclo[12.3.1]octadeca-1(18),14,16-triene-2,13-dione (15). Method A: 2%.
Method B: 2%. Colorless crystals. M.p. 183 1848. 1H-NMR (500 MHz, CDCl3): 9.22 (d, J ˆ 1.3, 1 H); 8.68
(d, J ˆ 1.3, 1 H); 8.30 (br. t, J ˆ 5.5, 2 H); 3.6 3.8 (m, 12 H). 13C-NMR (125 MHz, CDCl3): 162.0; 156.9; 115.7;
‡
‡
70.3; 69.4; 39.5. HR-LSI-MS: 281.1243 ([M ‡ H] , C12H17N4O4 ; calc.: 281.1250).
6,9-Dioxa-3,12,18-triazabicyclo[12.3.1]octadeca-1(18),14,16-triene-2,13-dione 18-Oxide (20). Method A:
4%. Method B: 67%. Colorless crystals. M.p. 241 2438. IR (KBr): 3173, 2913, 2879, 1696, 1683, 1560, 1386,
1097. 1H-NMR (400 MHz, CDCl3): 11.60 (br. s, 2 H); 8.32 (d, J ˆ 7.9, 2 H); 7.57 (t, J ˆ 7.9, 1 H); 3.5 3.7
(m, 12 H). 13C-NMR (100 MHz, CDCl3): 158.7; 143.2; 128.7; 127.5; 71.1; 68.6; 39.4. HR-ESI-MS: 318.1076
‡
‡
([M ‡ Na] , C13H17N3O5Na ; calc.: 318.1060). Anal. calc. for C13H17N3O5 (295.29): C 52.88, H 5.80, N 14.23;
found: C 52.64, H 5.79, N 14.12.
6,9,23,26-Tetraoxa-3,12,15,17,20,29,32,34-octaazatricyclo[29.3.1.114,18]hexatriaconta-
1(35),14,16,18(36),31,33-hexaene-2,13,19,30-tetraone (16). Method A: 6%. Method B: 6%. Colorless crystals.
M.p. 216 2188. IR (KBr): 3333, 2939, 1694, 1518, 1423, 1269, 1141, 1102, 1077, 665. 1H-NMR (200 MHz,
CF3COOD): 9.30 (s, 2 H); 8.93 (s, 2 H); 3.6 4.2 (m, 24 H). 13C-NMR (50 MHz, CF3COOD): 160.5; 158.7;
‡
‡
119.0; 98.1; 72.1; 71.4; 42.1. HR-LSI-MS: 561.2417 ([M ‡ H] , C24H33O8N8 ; calc.: 561.2421). Anal. calc. for
C24H32N8O8 ¥ 2 H2O (596.59): C 48.32, H 6.08, N 18.78; found: C 48.00, H 6.25, N 18.87.
6,9,23,26-Tetraoxa-3,12,20,29,35,36-hexaazatricyclo[29.3.1.114,18]hexatriaconta-1(35),14,16,18(36),31,33-
hexaene-2,13,19,30-tetraone 35,36-Dioxide (21). Method A: 32%. Method B: 26%. Colorless crystals. M.p. 234
2448. IR (KBr): 3436, 3221, 2925, 2875, 1681, 1535, 1518, 1390, 1116. H-NMR (400 MHz, CDCl3): 10.88 (br. s,
2 H); 8.53 (d, J ˆ 8.0, 2 H); 7.58 (t, J ˆ 8.0, 1 H); 3.6 3.8 (m, 12 H). 13C-NMR (100 MHz, CDCl3): 159.4; 141.4;
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‡
‡
130.9; 127.5; 69.9; 69.2; 39.7. HR-ESI-MS: 613.2212 ([M ‡ Na] , C26H34N6O10Na ; 613.2229). Anal. calc. for
C26H34N6O10 (590.58): C 52.88, H 5.80, N 14.23; found: C 52.63, H 5.94, N 14.02.
Methyl 6-({[(4R,5R)-5-(aminoethyl)-2-phenyl-1,3-dioxolan-4-yl]methylamino}carbonyl)pyridine-2-car-
1
boxylate (18; diastereoisomer mixture). Method A: 54%. [a]2D3 ˆ À9.8 (c ˆ 1.0, DMSO). H-NMR (500 MHz,
CDCl3): 8.90 (br. t, 1 H); 8.4 8.3 (m, 1 H); 8.20 (m, 1 H); 8.00 (m, 1 H); 7.6 7.2 (m, 5 H); 6.00 (s, 0.5 H); 5.93
(s, 0.5 H); 4.3 3.5 (m, 4 H); 3.99 (s, 1.5 H); 3.98 (s, 1.5 H); 3.2 2.9 (m, 2 H); 2.28 (br. s, 2 H). 13C-NMR
(125 MHz, CDCl3): 164.8; 164.1; 163.9; 149.9; 149.8; 146.6; 146.5; 138.5; 138.5; 137.2; 137.2; 129.5; 129.4; 128.4;
128.3; 127.3; 127.3; 126.7; 126.6; 126.6; 126.4; 125.4; 125.4; 125.0; 103.5; 103.4; 81.7; 80.4; 79.3; 78.2; 52.8; 43.5;
‡
‡
43.4; 41.1; 41.0. HR-LSI-MS: 372.1558 ([M ‡ H] , C19H22N3O5 ; calc.: 372.1559).
Methyl 6-({[(4R,5R)-5-({[6-(Methoxycarbonyl)pyridin-2-yl]carbonylamino}methyl)-2-phenyl-1,3-dioxo-
lan-4-yl]methylamino}carbonyl)pyridine-2-carboxylate (19). Method A: 4%. [a]2D3 ˆ À24.8 (c ˆ 1.0, CHCl3).
1H-NMR (200 MHz, CDCl3): 8.62 (t, J ˆ 5.4, 2 H); 8.42 8.34 (m, 2 H); 8.22 (m, 2 H); 8.00 (m, J ˆ 7.8, 2 H);
7.6 7.3 ( m, 5 H); 6.03 (s, 1 H); 4.4 4.2 (m, 2 H); 4.00 (s, 3 H); 3.98 (s, 3 H); 4.0 3.8 (m, 4 H). 13C-NMR
(50 MHz, CDCl3): 164.9; 164.0; 149.8; 149.8; 146.6; 146.6; 138.5; 129.6; 128.4; 127.3; 126.8; 125.5; 103.8; 78.9;
‡
‡
52.9; 40.8; 40.7. HR-MS: 534.1746 (M , C27H26N4O8 ; calc.: 534.1751).
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Received July 9, 2003