Preparation of the enantiomers of an N-methylpyrrole analogue of Troeger's base

Article abstract of DOI:10.1016/j.tetasy.2005.04.016

The enantiomers of bis(1-phenylethyl)-4,9-methano-1,6-dimethyl-4,5,9,10- tetrahydro-1H,6H-dipyrrolo-[3,2-b:3′,2′-f][1,5]diazocin-2, 7-dicarboxylate were obtained by crystallization-induced asymmetric transformation (CIAT). The CIAT was driven by the absol

Full text of DOI:10.1016/j.tetasy.2005.04.016

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1969–1974
Preparation of the enantiomers of an N-methylpyrrole
¨
analogue of TrogerÕs base
a
Martin Valık, Bohumil Dolensky´, Eberhardt Herdtweck and Vladimır Kral
a
b
a,
*
´
´
´
a
´
Institute of Chemical Technology Prague, Department of Analytical Chemistry, Technicka 5, Prague 6, 166 28, Czech Republic
bDepartment of Inorganic Chemistry, Technische, Universita¨t Mu¨nchen, Lichtenbergstraße, 4, D-85747 Garching, Germany
Received 7 March 2005; accepted 22 April 2005
Abstract—The enantiomers of bis(1-phenylethyl)-4,9-methano-1,6-dimethyl-4,5,9,10-tetrahydro-1H,6H-dipyrrolo-[3,2-b:30,20-f][1,5]-
diazocin-2,7-dicarboxylate were obtained by crystallization-induced asymmetric transformation (CIAT). The CIAT was driven
by the absolute configuration of the 1-phenylethyl groups present in their covalent structure. Thus, the first example of CIAT on
Tro¨gerÕs base derivatives in the absence of a resolving agent is reported.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
cyclophane in 28% yield by a predetermined ring closure
of chiral diamine via TB unit formation. This means
that only one enantiomer of the TB cyclophane is
formed. The formation of other stereoisomers would
give acyclic structures, which were not discussed. In
the second report, Maitra et al. used13,14 7-deoxycholic
acid as a particular chiral template for the formation
of TB derivatives. Unfortunately, the enantioselectivity
of the reactions varied from 0% to 70%.
The Tro¨gerÕs base1 (TB) derivatives (methano[1,5]-dia-
zocine derivatives) are compounds containing two nitro-
gens with fixed tetrahedron arrangement of their
moieties. This feature explains the unique V-shape
geometry (81–104ꢁ) and the inherent chirality of the
TB derivatives. These and other characteristics of TB
derivatives have attracted the attention of supramolecu-
lar chemists, and encouraged them to incorporate TB
units into skeletons of various receptors.2–4 The recep-
tors containing a TB unit have been found to be able
to recognize both achiral5,6 and chiral7–9 analytes, and
DNA.10–12 The chiral applications are especially promis-
ing. Unfortunately, the enantiomerically pure TB deriv-
atives with synthetically exploitable moieties suitable for
wider studies of chiral receptors based on the TB chiral-
ity are not commercially available. In fact, even their
enantioselective preparation on the laboratory scale
has not been satisfactorily solved yet. Thus, the question
of how to generate enantiomerically pure TB synthons
still remains. In general, the enantiomerically pure TB
derivatives can be obtained either by the enantioselective
formation or by resolution of racemic mixtures.
The resolution of racemic mixtures of TB derivatives has
been used more frequently. The first successful resolu-
tion of a TB derivative was described15 by Prelog and
Wieland in 1944. They reported a chromatographic sep-
aration of Tro¨gerÕs base 1 on a chiral stationary phase.
They also found that the standard procedure of resolu-
tion of racemic bases using a chiral acid as the resolving
agent was precluded by simultaneous racemization of 1.
On the other hand, a couple of successful enantiosepara-
tions of TB derivatives using tartaric acid have been
reported.16–18 Talas et al. have realized that resolution
´
process can be disabled by the presence of water in the
resolving mixture.18 Wilen et al. have described19 a very
special case of resolving of TB enantiomers. They used
either (+)- or (ꢀ)-1,10-binaphthalene-2,20-diyl hydrogen-
phosphate as the resolving agent and observed, similarly
to Prelog, that the acidic resolving agent caused racemi-
zation of 1, however, this was the case only in the solu-
tion. In other words, while the ratio of the enantiomers
was nearly 1:1 in solution due to the racemization
process, the precipitated diastereomeric salt contained
To the best of our knowledge, only two examples of the
enantioselective preparation have been reported. In the
first, Webb et al. prepared8 enantiomerically pure TB
*
Corresponding author. E-mail: vladimir.kral@vscht.cz
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.04.016

´
M. Valık et al. / Tetrahedron: Asymmetry 16 (2005) 1969–1974
1970
the resolving agent and only one enantiomer. Such a
phenomenon is called crystallization-induced asymmet-
ric transformation (CIAT).
H N
HCl.
2
R
O
N
CH3
CH3
6a
O
Herein, we report the second example of CIAT on TB
derivatives. Moreover, in contrast to the described
example of CIAT on TB, we report the first example
of CIAT of TB derivative in the absence of a resolving
agent. Racemization is caused by hydrochloric acid
while CIAT is driven by enantiomerically pure (R)- or
(S)-1-phenylethyl groups present in the structure of the
TB derivatives.
aq. CH2O, aq.
r.t., 20
NOE
CH3
N
O
H3C
R N
O
R
R
O
R
N
N
CH3
CH3
2a
O
2. Results and discussion
NOE
+
NOE
The starting amines 6a and 6b were prepared by the
reactions shown in Scheme 1. 1-Methyl-4-nitro-2-tri-
chloroacetylpyrrole 3 was prepared as described else-
where.20 Subsequent alcoholysis20 of the trichloro-
acetyl group of 3 by (R)-1-phenylethanol 4a gave chiral
1-phenylethyl ester 5a. The following reduction was
achieved by nickel boride21 (Ni2B) to give amine 6a.
Note, that we did not observe the catalytic reduction
of 5a by NaBH4 in the presence of Ni2B as described22
for very similar structure (benzyl instead of 1-phenyl-
ethyl). In our case the amount of the formed amine 6a
was equal to the molar amount of applied Ni2B. The
same sequence of reactions was used for the preparation
of amine 6b starting from 3 and (S)-1-phenylethanol 4b.
CH3
N
O
H3C
S N
O
R
R
O
S
N
N
CH3
CH3
O
3a
NOE
Scheme 2. Prepared TB derivatives with selected observed NOE.
tried to convert 3a to 2a by diastereoisomerization, the
racemization of the TB unit only. We found that treat-
ment of 3a in methanol containing a catalytic amount
of aqueous HCl led to crystalline 2a in almost quantita-
tive yield (de ꢁ95%; de >99% after next crystallization
from methanol/dichloromethane). This process is
known as CIAT (vide supra).
Amine 6a [(R)-1-phenylethyl] was treated with an aque-
ous solution of formaldehyde to give the corresponding
TB derivative as a mixture of two diastereoisomers 2a
[(4R,9R) of TB unit] and 3a [(4S,9S) of TB unit] in a
1:1 ratio (Scheme 2). The absence of stereoselectivity is
not surprising because of the long distances between
the stereogenic centers (1-phenylethyls) from the reac-
tion centers (aminopyrrole groups). The crude product
was crystallized from diethyl ether to afford pure crys-
tals of 2a. Subsequent separation of the mother liquor
by column chromatography gave an additional portion
of pure 2a and impure 3a. We found that the purifica-
tion of 3a by either chromatographic techniques or crys-
tallization led to 3a (the best de being 90%). Thus, we
Amine 6b [(S)-1-phenylethyl] was used as the starting
compound for the preparation of compounds 2a and
3a (Scheme 3). The reaction of amine 6b with formalde-
hyde gave the corresponding TB derivative as a mixture
of two diastereoisomers 2b [(4R,9R) of TB unit] and 3b
[(4S,9S) of TB unit] in a 1:1 ratio, that is, with no stereo-
selectivity as expected. In this case we applied CIAT di-
rectly on the crude product and obtained pure 3b.
The TB unit formation can take place at a- or b-position
of N-methylpyrrole ring of the amine 6. Thus, three pos-
sible regioisomers can be formed as a mixture of one
asymmetric (ab) and two symmetric (aa and bb) ones.
The connectivity structures of all the prepared TB deriv-
atives 2a,b, 3a, and 3b were identical and were estab-
lished by detailed analyses of 1H, 13C, 1D NOESY,
gHSQC, gHMBC, and gCOSY NMR experiments.
For example, the NOE between N-methyl protons and
both CH2 protons (Scheme 2) and correlation between
pyrrole proton and carbonyl carbon in gHMBC
(Scheme 3) gave clear evidence that the cyclization (TB
derivative formation) took place selectively at a-position
of the pyrrole ring. We have no indication of the forma-
tion of other TB derivatives. This means that the pyr-
role ring is attacked at the a-position exclusively (and
not at the less reactive b-position). These findings are
in accordance with previously observed total regioselec-
tivity for the benzyl ester of the corresponding TB
derivatives.23
O2N
O2N
CCl3
O
*
i)
H
N
CH3
N
CH3
O
CH3
3
O
5a, 5b
OH
H3C
ii)
*
H
H N
HCl.
2
4a, 4b
O
*
H
N
CH3
CH3
O
(R)- for series a
(S)- for series b
6a, 6b
Scheme 1. Reagents and conditions: (i) NaH, THF, 4a gave 88% 5a,
and 4b gave 82% 5b; (ii) Ni2B, aqueous concd HCl, methanol, 99% 6a,
97% 6b.

´
M. Valık et al. / Tetrahedron: Asymmetry 16 (2005) 1969–1974
1971
2a with 3a. Compounds 2a and 3a have similar but not
identical 1H and 13C NMR spectra. Compounds 2b and
3a have identical NMR spectra (2b is enantiomer of 3a)
and diastereoisomerization of 2b led to the formation of
the mixture of 3b and 2b (1:1). Thus, the absolute con-
figuration of the TB unit of 2b is (4R,9R). Compound
HCl.
H2N
S
O
N
CH3
CH3
6b
O
aq. CH2O, aq. HCl
r.t., 20 h
3b had an identical NMR spectra as 2a with a specific
20
D
rotation ½aꢂ ¼ þ192. This proves that 3b is enantiomer
gHMBC
of 2a. Thus, the absolute configuration of the TB unit of
3b is (4S,9S).
CH3
N
O
O
H3C
H
N
R
S
S
O
R
N
H
N
CH3
O
3. Conclusion
CH3
gHMBC
2b
+
In summary, our results exemplify how the usually
undesirable facile racemization of the TB unit can be
exploited in the preparation of enantiomerically pure
TB derivatives. We have shown that chiral resolving
agent is unnecessary while the Ôsource of chiralityÕ is
present in structure of TB derivative. Moreover, our
synthetic approach allows the preparation of any of
the enantiomers 2a and 3b on a large scale with an over-
all yield >40%. Utilization of 2a and 3b as building
blocks for the synthesis of compounds containing the
enantiomerically pure TB unit with the goal to prepare
chiral selective receptors is in progress.
gHMBC
CH3
N
O
O
H3C
H
S N
S
S
O
O
S
N
H
N
CH3
3b
CH3
gHMBC
Scheme 3. Prepared TB derivatives with selected observed correlation
in gHMBC.
The absolute configurations of the derivatives 2 and 3
were confirmed by a combination of many experimental
results and analyses. The configuration of 2a was deter-
mined by single crystal X-ray structural analysis (Fig. 1).
The absolute configurations of 1-phenylethyl groups of
2a were known to be (R) as are in the starting alcohol.
The configuration of the TB unit in 2a was then estab-
4. Experimental
1H, 13C, 1D NOESY, gHSQC, gHMBC, and gCOSY
NMR spectra were obtained with Varian Gemini 300
1
HC (300.1 MHz for H NMR and 75.5 MHz for 13C
NMR spectra) at 23 ꢁC in CDCl3 or (CD3)2SO. The cor-
relation NMR techniques were applied for the assign-
ment of chemical shifts to atoms of the molecules. The
chemical shifts are given in ppm relative to (CH3)4Si.
Mass spectra were recorded with a VG Analytical
ZAB-EQ spectrometer. Thin-layer chromatography
was performed on Merck Silica gel 60 F254 TLC plates.
For column chromatography, neutral silica gel SiliTech
lished as (4R,9R). In addition, the negative specific rota-
20
D
tion of 2a ½aꢂ ¼ ꢀ193 is consistent with the known19
specific rotation of (5R,11R)-isomer of the Tro¨gerÕs
base. The fact that compound 3a is formed from 6a
together with 2a (Scheme 2) and the reaction does not
affect the configuration of 1-phenylethyl groups leads to
the conclusion that the configuration of 3a differs from
the one of 2a only by the configuration of the TB unit.
Thus, the configuration of the TB unit of 3a is (4S,9S).
The diastereomorphism of 2a and 3a was additionally
confirmed by acid catalyzed diastereoisomerization,
wherein the exclusive racemization of the TB unit takes
place, and both 2a and 3a give identical 1:1 mixtures of
˚
32–63, 60 A (ICN Biomedicals) was used. The enantio-
meric as well as diastereomeric purity of 2a and 3b
was determined by HPLC with b-cyclodextrin stationary
phase; column ChiraDex (Merck) 250 · 4 mm, 5 lm;
mobile phase methanol–water (75:25).
4.1. Preparation of (R)-1-phenylethyl 1-methyl-4-nitro-
pyrrole-2-carboxylate 5a
To a stirred solution of (R)-1-phenylethanol (6.00 g,
49.2 mmol) in THF (80 mL) at 0 ꢁC ca. 50 mg
(2.1 mmol) of NaH was added. Then a solution of
1-methyl-4-nitro-2-trichloroacetylpyrrole
3
(13.5 g,
49.7 mmol) in THF (40 mL) was added in 10 min. The
reaction mixture was allowed to warm up to room tem-
perature under stirring. After 20 h the mixture was con-
centrated to 40 mL in vacuo. The residue was diluted
with dichloromethane and washed with aqueous p-tolu-
enesulfonic acid. The organic layer was dried over so-
dium sulfate and evaporated to dryness. The obtained
solid was crystallized from MeOH to give 5a (10.45 g,
Figure 1. ORTEP plot of the solid-state structure of the compound 2a.
Thermal ellipsoids are drawn at the 50% probability level. Majority of
˚
hydrogen atoms are omitted for clarity. Selected bond lengths [A]: O2–
˚
C9 1.211(2), O4–C23 1.208(2); selected distances [A]: N2–N3 2.47,
C13–C19 3.20, N1–N4 5.54, C9–C23 9.00; the angle between pyrrole
rings is about 110ꢁ.

´
M. Valık et al. / Tetrahedron: Asymmetry 16 (2005) 1969–1974
1972
78%) as white needles. The mother liquor from crystal-
lization was evaporated and the residue separated by
column chromatography (silica, petroleum ether–dichlo-
romethane from 4:6 to 0:1) to give additional portion of
5a (1.36 g, 10%).
17.3 mmol) by Ni2B (8.00 g) gave 4.72 g (97%) of 6b.
Compound 6b has identical NMR spectra with 6a.
4.5. Preparation of bis(1-phenylethyl)-4,9-methano-1,6-
dimethyl-4,5,9,10-tetrahydro-1H,6H-dipyrrolo-[3,2-b:30,
20-f][1,5]diazocin-2,7-dicarboxylate 2a/3a
Compound 5a: Mp 80–82 ꢁC. 1H NMR (CDCl3): d 1.65
(3H, d, J = 6.6 Hz, CHCH3), 3.95 (3H, s, NCH3), 6.03
(1H, q, J = 6.6 Hz, CHCH3), 7.28–7.43 (5H, m, CH–
Ph), 7.49 (1H, d, J = 2.2 Hz, CHCCO), 7.58 (1H, d,
J = 2.2 Hz, CHNCH3). 13C NMR (CDCl3): d 22.36
(CH3CH), 37.91 (NCH3), 73.12 (CH3CH), 112.72
(CHCCO), 123.11 (CCO), 125.91 (o-CH of Ph), 127.57
(CHNCH3), 128.10 (p-CH of Ph), 128.62 (m-CH of
Ph), 135.20 (CNO2), 141.18 (ipso-C of Ph), 159.36
(CO). EA for C14H14N2O4: calcd C, 61.31; H, 5.14; N,
Hydrochloride amine 6a (9.50 g, 33.8 mmol) was dis-
solved in methanol (140 mL), and 36% aqueous formal-
dehyde (18 mL) at which point concd HCl (18 mL) was
added. The reaction mixture was stirred for 20 h at
room temperature, then concentrated in vacuo to one
half of the original volume (mainly to remove MeOH),
diluted with water and alkalized with aqueous ammonia
to pH 14 and extracted with dichloromethane. The com-
bined organic layers were washed with brine, dried over
Na2SO4, and evaporated to dryness. The crude product
was diluted with minimum amount (ca. 50 mL) of
diethyl ether, which caused 2a precipitation as light
brown crystals (2.21 g, de ꢁ95%, 25% yield). The
mother liquor from crystallization was evaporated and
the residue separated by column chromatography (silica,
dichloromethane–ethyl acetate 7:3) to give 2a (0.30 g,
de >95%; 3% yield) and 3a (4.75 g) contaminated by
2a and side products (purity about 50%). Crude 3a from
chromatography was subjected to crystallization-
induced asymmetric transformation by treatment with
methanol (50 mL) and concd aqueous HCl (two drops).
Pure 2a was obtained as white crystals (2.72 g). All por-
tions of 2a were combined and crystallized from dichlo-
romethane/methanol to give colorless crystals of 2a
(4.91 g, de >99%, 55% yield). The part with pure 2a
(370 mg) was dissolved in methanol (15 mL) and concd
aqueous HCl (0.6 mL). The solution containing 2a and
3a in the ratio 1:1 (HPLC) was neutralized by aqueous
ammonia (0.8 mL). This caused precipitation of 2a
(167 mg, de 90%, 45% yield). Diastereoisomer 3a
(184 mg, de 70%, 50% yield) was obtained by diluting
the mother liquor with water followed by extraction into
dichloromethane, drying over Na2SO4, and evaporation
to dryness. Subsequent chromatographic separation of
3a partially improved purity of 3a (de 90%).
10.21. Found C, 60.89; H, 5.17; N, 10.22. MS (FAB)
20
m/z: 275 (M+H)+. ½aꢂ ¼ ꢀ117 (c 0.226, CHCl3).
D
4.2. Preparation of (S)-1-phenylethyl 1-methyl-4-nitro-
pyrrole-2-carboxylate 5b
The (S)-enantiomer 5b was prepared by the same syn-
thetic procedure as for 5a. Reaction of 3 (6.40 g,
23.6 mmol) with (S)-1-phenylethanol (2.83 g, 23.2
mmol) gave 5.22 g (82%) of 5b. Compound 5b has iden-
tical melting point and NMR spectra as 5a.
4.3. Preparation of hydrochloride of (R)-1-phenylethyl 1-
methyl-4-aminopyrrole-2-carboxylate 6a
Freshly prepared nickel boride Ni2B (16.00 g) and 5a
(10.36 g, 37.8 mmol) were added to MeOH (260 mL)
and 1 M hydrochloric acid (90 mL). The resulting sus-
pension was stirred at 70 ꢁC until starting 5a was present
in the reaction mixture (followed by TLC). After each
hour, 2 mL of concd hydrochloric acid was slowly added
to the reaction mixture. The reaction mixture was
filtrated, and the filter cake washed with MeOH
(3 · 30 mL). All liquid portions were combined and
concentrated in vacuo to 100 mL (mainly to remove
MeOH), diluted with water, and extracted by dichloro-
methane. The organic layer was washed with brine and
concentrated to give crude 6a (10.49 g, 99%), which
was used for the preparation of 2a/3a without further
purification.
1
Compound 2a: Mp 210–214 ꢁC. H NMR (CDCl3): d
1.59 (6H, d, J = 6.6 Hz, CHCH3), 3.64 (6H, s, NCH3),
3.95 (2H, d, J = 16.2 Hz, endo CHHN), 4.08 (2H, s,
NCH2N), 4.36 (2H, d, J = 16.2 Hz, exo CHHN), 6.00
(2H, q, J = 6.6 Hz, CHCH3), 6.81 (2H, s, CHCN),
7.23–7.41 (10H, m, CH–Ph). 13C NMR (CDCl3): d
22.61 (CHCH3), 32.58 (NCH3), 52.24 (CCH2N), 68.95
(NCH2N), 71.47 (CHCH3), 110.14 (CHCN), 120.13
(CCO), 125.75 (o-CH of Ph), 127.04 (CCH2N), 127.62
(p-CH of Ph), 128.45 (m-CH of Ph), 131.19 (CNCH2),
142.25 (ipso-C of Ph), 160.39 (CO). EA for
C31H32N4O4: calcd C, 70.97; H, 6.15; N, 10.68. Found
1
Compound 6a: H NMR (DMSO-d6): d 1.53 (3H, d,
J = 6.6 Hz, CHCH3), 3.82 (3H, s, NCH3), 5.93 (1H, q,
J = 6.4 Hz, CHCH3), 6.85 (1H, dd, J = 2.3 and 1.1 Hz,
CHCCO), 7.24 (1H, d, J = 1.5 Hz, CHNCH3), 7.25–
7.42 (5H, m, CH–Ph), 10.00–10.20 (3H, br s, +NH3).
13C NMR (DMSO-d6): d 22.26 (CH3), 36.56 (CH3),
71.65 (CH), 111.58 (CH), 113.86 (C), 120.94 (C),
123.89 (CH), 125.71 (2 · CH), 127.71 (CH). 128.43
(2 · CH), 141.75 (C), 158.93 (C).
C, 70.51; H, 6.20; N, 10.71. MS (FAB) m/z: 525
20
D
(M+H)+. ½aꢂ ¼ ꢀ193 (c 0.649 g/100 mL CH2Cl2).
Single crystal X-ray structure determination of compound
2a: C31H32N4O4, Mr = 524.61, colorless fragment
(0.25 · 0.38 · 0.76 mm3), monoclinic, P21 (No. 4), a =
4.4. Preparation of hydrochloride of (S)-1-phenylethyl 1-
methyl-4-aminopyrrole-2-carboxylate 6b
˚
˚
˚
c = 15.3275(2) A,
14.8985(2) A,
b = 6.2410(1) A,
3
˚
The (S)-enantiomer 6b was prepared by the same syn-
thetic procedure as 6a. Reduction of 5b (4.75 g,
b = 109.2101(5)ꢁ, V = 1345.82(3) A , Z = 2, dcalcd
=
1.295 g cmꢀ3, F000 = 556, l = 0.087 mmꢀ1. Preliminary

´
M. Valık et al. / Tetrahedron: Asymmetry 16 (2005) 1969–1974
1973
examination and data collection were carried out on a j-
CCD device (NONIUS MACH3) with an Oxford Cryo-
systems cooling system at the window of a rotating an-
ode (NONIUS FR591) with graphite-monochromated
Compound 3b: Mp 208–212 ꢁC. EA for C31H32N4O4:
calcd C, 70.97; H, 6.15; N, 10.68. Found C, 70.16; H,
6.11; N, 10.64. MS (FAB) m/z: 525 (M+H)+.
20
D
½aꢂ ¼ þ192 (c 1.049, CH2Cl2). NMR spectra of 3b
˚
Mo Ka radiation (k = 0.71073 A). Data collection was
and 2a were identical as well as NMR spectra of 2b
and 3a.
performed at 123 K within the
h
range of
1.41ꢁ < h < 25.37ꢁ. A total of 29,297 reflections were
integrated. Raw data were corrected for Lorentz, and
polarization, and arising from the scaling procedure,
for latent decay and absorption effects. After merging
(Rint = 0.037), 4947 (4777 with Io > 2r(Io)) independent
reflections remained, and all were used to refine 481
parameters. The structure was solved by a combination
of direct methods and difference Fourier syntheses. All
nonhydrogen atoms were refined with anisotropic dis-
placement parameters. All hydrogen atoms were found
and refined with individual isotropic displacement
Acknowledgements
Grant by the Ministry of Education of the Czech
Republic MSM 6046137307, and grants 203/03/0900,
203/03/0716 from Grant Agency of the Czech Republic
and EU grant ÔCIDNAÕ NMP4-CT-2003-505669 sup-
ported the work. We also thank Dr D. Sy´kora, MS for
the help in preparation of the manuscript.
parameters. Full-matrix least-squares refinements were
carried out by minimizing
P
2
wðF 2o ꢀ F 2cÞ and con-
References
verged with R1 = 0.0274 (Io > 2r(Io)), wR2 = 0.0667
(all data), GOF = 1.032, and a shift/error of <0.001.
The final difference Fourier map shows no striking fea-
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´
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Compound 3a: 1H NMR (CDCl3): d 1.59 (6H, d,
J = 6.6 Hz, CHCH3); 3.62 (6H, s, NCH3); 3.92 (2H, d,
J = 16.2 Hz, endo CHHN); 4.09 (2H, s, NCH2N); 4.36
(2H, d, J = 16.0 Hz, exo CHHN); 5.97 (2H, q,
J = 6.6 Hz, CHCH3); 6.77 (2H, s, CHCN); 7.22–7.42
(10H, m, CH–Ph). 13C NMR (CDCl3): d 22.48
(CHCH3), 32.59 (NCH3), 52.18 (CCH2N), 68.96
(NCH2N), 71.59 (CHCH3), 110.10 (CHCN), 120.13
(CCO), 125.90 (o-CH of Ph), 126.97 (CCH2N), 127.64
(p-CH of Ph), 128.43 (m-CH of Ph), 131.14 (CNCH2),
142.14 (ipso-C of Ph), 160.42 (CO).
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b:30,20-f][1,5]diazocin-2,7-dicarboxylate 2b/3b
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hyde (9 mL) under similar conditions as 2a. Unlike 2a,
the crude product was treated with dichloromethane
(1 mL), methanol (30 mL), and concd aqueous HCl
(three drops) to give crude 3b (2.80 g), which gave with
the next crystallization (dichloromethane/methanol)
pure 3b (2.31 g, de >99%, 53% yield). Diastereoisomer-
ization of 3b in methanol with HCl gave a 1:1 mixture
of 2b and 3b.
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