Asymmetric three-coordinated nitrogen compounds: Spontaneous resolution and absolute asymmetric synthesis

Article abstract of DOI:10.1070/MC2003v013n03ABEH001807

The spontaneous resolution of conglomerates of a dibenzo analogue of Tr?ger's base 1 and aziridine 2, as well as the second-order asymmetric transformation of (±)-1 into a single enantiomer were carried out for the first time.

Full text of DOI:10.1070/MC2003v013n03ABEH001807

,
2003, 13(3), 111–113
Asymmetric three-coordinated nitrogen compounds: spontaneous resolution and
†
absolute asymmetric synthesis
a
a
a
b
Remir G. Kostyanovsky,* Vasilii R. Kostyanovsky, Gul’nara K. Kadorkina and Konstantin A. Lyssenko
a
N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 938 2156; e-mail: kost@chph.ras.ru
b
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5085; e-mail: kostya@xrlab.ineos.ac.ru
1
0.1070/MC2003v013n03ABEH001807
The spontaneous resolution of conglomerates of a dibenzo analogue of Tröger’s base 1 and aziridine 2, as well as the second-order
asymmetric transformation of (±)-1 into a single enantiomer were carried out for the first time.
The Pasteur’s discovery stimulated the search for homochiral
systems with stereogenic heteroatoms. Even during Pasteur’s life-
time, questions were raised whether asymmetric four-coordinated
2,3,6,7-dibenzobicyclo[3.3.1]nona-2,6-diene-4,8-dione, which
also undergoes spontaneous resolution.5
It is known that (+)- and (–)-TBs racemise in acidic media,
2
3(f)
(
J. Wislicenus, 1877) or three-coordinated nitrogen (A. Hantzsch,
whereas a salt of (±)-TB with a chiral acid will undergo almost
complete asymmetric conversion into a single diastereomer.8
We succeeded in the almost complete conversion of (±)-1 into a
single enantiomer (absolute asymmetric synthesis ) by crystal-
lisation under conditions of acid-catalysed enantiomerisation in
solution (Scheme 1).
A. Werner, 1890) can exist. The positive answer for the former
was found by the Pasteur-like separation of racemates of chiral
ammonium salts both via diastereomeric salts and by spon-
2
2
taneous resolution. As for the three-coordinated asymmetric
nitrogen, the separation of numerous racemates was performed
only with the use of chiral agents.3
In this work, we aimed at the spontaneous resolution of racemic
compounds containing three-coordinated asymmetric nitrogen.
In the search for conglomerates, we paid special attention to
classical stereochemical objects, namely, the Tröger’s base (TB)
and its analogues, which were intensely studied in the last
Table 1 Spontaneous resolution of (±)-2 by stirred crystallisation from
water.
Crystal-
Precipitate lisation
mass/mg mass/mg tempera- rate/rpm
Concen-
tration in
MeOH,
c (%)
Sample
Stirring
2
5
ee (%)a
[
a]
decade.3 As far as we know (Cambridge Crystallographic
(f)
D
ture/°C
Database-2003), TB racemates studied by X-ray diffraction
3
(f)
crystallise in achiral space groups.
However, according to
50.1
50.2
16.1
16.6
15.6
16.3
15.5
15.0
16.0
16.3
12
14
14
8
20
40
60
80
500
600
850
1000
1000
1000
1000
1000
–4.8 1.2
–7.0 1.3
10.1
14.8
50.0
38.0
52.9
61.0
72.5
96.0
4
Tálas et al., the melting point of the enantiomer of TB dibenzo
analogue 1 (Scheme 1) is 45 °C higher than that of the
racemate. This is an indication of conglomerate formation;
50.0
+23.6 1.3
–17.3 1.2
+25.1 1.3
–28.9 1.3
–34.3 1.2
+45.5 1.3
5
50.1
5
5
5
0.0
0.3
0.2
‡
therefore, we synthesised and studied compound (±)-1. In fact,
the crystal grown from MeOH was found to have a chiral space
§
group (P2 2 2 , Z = 4), similarly to that for previously studied
1
1
1
50.1
4
authentic (S,S)-(+)-1. It should be noted that a similar bis-
aAssuming [a] D2 5 47.4° (c 1.0, MeOH) for enantiomerically pure (R)-(+)-2.10(b)
acridine TB analogue crystallises in an achiral space group
6
(
Pna2 , Z = 4). Analysis of the crystal structure showed that
1
§
Crystallographic data: crystals of 1 (C H N , M = 322.39) are ortho-
2
3
18
2
molecules of 1 are united into helices directed along the
rhombic, space group P2 2 2 , at 110 K a = 6.384(1) Å, b = 9.411(1) Å,
1
1 1
7
crystallographic axis a (Figure 1) by C–H···π contacts. We
3
–3
c = 26.866(5) Å, V = 1614.1(5) Å , Z = 4 (Z' = 1), d = 1.327 g cm ,
m(MoKα) = 0.78 cm , F(000) = 680. Intensities of 15298 reflections were
calc
have recently found the similar crystallographic packing for
–1
measured with a Smart 1000 CCD diffractometer [λ(MoKα) = 0.71072 Å,
w-scans with a 0.3° step in w and 10 s per frame exposure, 2q < 60°].
4643 independent reflections (Rint = 0.0371) were used in a further re-
finement.
†
Asymmetric nitrogen. Part 88, previous communication see ref. 1.
‡
6
4
(
±)-1 was obtained from β-napthylamine [a strong carcinogene (!)]
and hexamethylene tetramine in MeOH in the presence of CF CO H;
yield 76.5%; the H and C NMR spectra coincided with reported data
and are similar to those reported for the TB bis-quinoline analogue.
Crystallisation from MeOH with slow self-evaporation gave single crys-
tals of 1.1, 1.5 and 2.3 mg. It was found that the melting point of the
former is 258 °C, which is equal to that of (+)-1 [mp 257–259 °C, in
3
2
1
13
4
2
Crystals of 2 (C H N O , M = 159.15) are orthorhombic, space group
5
9
3
3
1
P2 2 2 , at 190 K a = 7.439(2) Å, b = 7.522(2) Å, c = 13.369(4) Å,
1 1 1
3
–3
–1
V = 748.0(4) Å , Z = 4 (Z' = 1), d = 1.413 g cm , m(MoKα) = 1.17 cm ,
F(000) = 336. Intensities of 1409 reflections were measured with a
calc
Syntex P2 diffractometer [l(MoKα) = 0.71072 Å, q/2q-scans, 2q < 60°]
1
4
contrast to 213–215 °C for (±)-1]. The third crystal was found to have
and 1107 independent reflections were used in a further refinement.
Both structures were solved by a direct method and refined by the full-
optical activity, [a]2 +1100° (c 0.05, CHCl ) {cf. for (+)-1 [a]
0
4
24
D
(a)
D
3
5
2
+
1166° (c 0.1, CHCl ); for the similar bis-acridine analogue,
matrix least-squares technique against F in the anisotropic–isotropic
3
[
a] +2600° (c 0.09, CHCl )}. The second crystal was studied by X-ray
approximation. Hydrogen atoms were located from the Fourier synthesis
and refined in the isotropic approximation. The refinement converged to
wR = 0.1197 and GOF = 1.045 for all independent reflections [R =
D
3
§
diffraction.
Compound (±)-2 was obtained by the amidation of diethyl 1-methoxy-
2
1
1
0(a)
1
aziridine-2,2-dicarboxylate,
yield 80%, mp 158 °C (EtOH). H NMR
= 0.0505 was calculated against F for 3750 observed reflections with
2
(
400.13 MHz, CDCl ) d: 2.66 (d, 1H, H , J –2.7 Hz), 3.11 (br. d, 1H,
I > 2s(I)] for 1 and to wR = 0.1126 and GOF = 1.098 for all independent
3
b
2
2
H , J –2.7 Hz), 3.66 (s, 3H, MeO), 5.45, 5.69, 6.86 and 6.94 (br. s, 4H,
reflections [R = 0.0423 was calculated against F for 2810 observed
a
1
13
2
HN). C NMR (100.61 MHz, [ H ]methanol/D O, 5:1) d: 41.92 (dd,
CH , J 178.0 Hz, J 170.8 Hz), 52.58 (t, CN, J 2.9 Hz), 61.23 (q,
reflections with I > 2s(I)] for 2. All calculations were performed using
SHELXTL PLUS 5.0.
4
2
1
1
2
2
CHa
CHb
1
3
3
MeO, J 143.9 Hz), 167.41 (dd, A-CO, J 4.4 Hz, J 3.6 Hz), 171.44
Atomic coordinates, bond lengths, bond angles and thermal param-
eters have been deposited at the Cambridge Crystallographic Data Centre
(CCDC). These data can be obtained free of charge via www.ccdc.cam.uk/
conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336 033; or deposit@ccdc.cam.ac.uk).
Any request to the CCDC for data should quote the full literature citation
and CCDC reference numbers 213980 and 213981. For details, see ‘Notice
to Authors’, Mendeleev Commun., Issue 1, 2003.
CHa
CHb
(
t, B-CO, 3J 3.6 Hz). A portion of (±)-2 (100 mg) was dissolved on
i
heating in 2 ml of an Pr OH–H O mixture (1:1); the solution was cooled
to 20 °C and kept for three days at 0 °C. The intergrown crystal (48.5 mg)
was divided by the cleavages. For one of the parts (26.5 mg), [a]
–
ee 48.2%. Crystallisation of (±)-2 from 2 ml of H O was carried out at
different temperatures and stirring rates; the results are shown in Table 1.
2
2
5
D
14.6° (c 2.2, MeOH), ee 30.8%; for the other part (22 mg), [a]2 +22.8°,
5
D
2
–
111 –

,
2003, 13(3), 111–113
H(6C)
C(6)
O(3)
H(3A) C(4)
H(3NA)
O(1)
N(3)
H(3NB)
C(3)
H(6B) H(6A)
N(1)
C(2)
C(14)
H(14)
H(3B)
N(5)
O(2)
N(1)
C(5)
N(2)
H(2NB)
H(2NA)
Figure 2 General view of 2. Selected bond lengths (Å): O(1)–N(1)
.443(2), N(1)–C(3) 1.468(3), N(1)–C(2) 1.502(2), C(2)–C(3) 1.490(3); bond
1
angles (º): O(1)–N(1)–C(3) 107.1(1), O(1)–N(1)–C(2) 109.1(1), C(3)–N(1)–
C(2) 60.2(1), C(3)–C(2)–N(1) 58.8(1), N(1)–C(3)–C(2) 61.0(1), N(1)–C(2)–
C(4) 117.6(1), N(1)–C(2)–C(5) 116.3(1). The parameters of intramolecular
H-bond: N(1)···H(2NA) 2.32 Å, N(1)···N(2) 2.764(2) Å, N(1)H(2NA)N(2) 114º.
‡
of the entire portion of crystals (Table 1) obtained in 30–33%
yields (Scheme 2).
Figure 1 C–H···(π-system) contacts in the crystal structure of 1. The
C(14)–H(14)···X contact parameters are: H(14)···X 2.59 Å, C(14)···X
H
N
H
N
3.71(2) Å, C(14)H(14)X 172º.
O
A
O
In the series of three-membered nitrogen-containing hetero-
i
H
and
H
(±)-2
Ha
Hb
cycles, examples of crystallisation in chiral space groups are
known only for compounds that cannot be separated under
N
O
N
O
ii
9
(a)
OMe MeO
ordinary conditions: 1-H-
and 1-phenyl-2,2-dicarbamoyl-
H N
B
NH2
2
aziridines9 (two polymorphs have been found in each case)
and two 3,3-dialkyldiaziridine complexes.
(b)
¹
CONH2
9
(c)
(R)-(+)-2
(S)-(–)-2
It is also known
that enantiomeric enrichment is observed for 1-methoxy-2,2-
N
OMe
1
0(a)
dicarbamoylaziridine (±)-2
upon crystallisation from an
(
R)-(+)-2 or (S)-(–)-2
CONH2
1
0(b)
optically active solvent (l-methyl lactate),
which is used as a
test for conglomerate formation. However, it was shown that
noticeable enantiomeric enrichment of (±)-2 also occurs upon
simple heating in l-methyl lactate; this results from the asym-
metric inversion of nitrogen, i.e., a shift of inversion equilibrium
Scheme 2 Reagents and conditions:† i, routine crystallisation; ii, stirred
crystallisation at ∆.
On increasing the stirring rates and temperatures, the degree
towards the enantiomer that is more solvated by the chiral
of enrichment increased up to ee 96%.‡ Despite the rather
solvent.1
0(b)
Thus, here we deal with a non-racemic separable
#
–1
high inversion barrier of nitrogen in 2 (∆G = 31 kcal mol at
sample; hence, the above test for conglomerate formation is
ambiguous. In fact, although (±)-2-methoxy-3,3,5,5-tetracarba-
moyl-1,2-oxazolidine is enriched, similarly to (±)-2, upon crys-
0(a)
9
0 °C),1
these results can be explained by an autocatalytic
11
effect upon formation of the solid phase.
Thus, we found the conglomerates of racemic compounds
containing stereogenic centres only at three-coordinated nitrogen
atoms and performed their spontaneous crystallisation resolution.
1
0(c)
tallisation from l-methyl lactate,
it crystallises in an achiral
space group.1
0(d)
Conglomerate formation in the case of (±)-2 was unambigu-
ously confirmed using X-ray diffraction (space group P2 2 2 ,
1
1 1
We are grateful to Dr. V. V. Rozhkov for his help at the initial
stage of studying 2.
This work was supported by the President of the Russian
Federation (grant ‘Scientific Schools’ no. 1060.2003.3), INTAS
§
Z = 4). The trans-amide group forms an intramolecular H-bond
with the aziridine nitrogen, which results in a decrease in the
C(5)C(2)N(1) angle in comparison with the C(4)C(2)N(1) angle
(
3
Figure 2). In a crystal, the molecules of 2 are combined into a
D framework (3)N–H···O=C [N···O 2.881–2.906(2) Å], whereas
(
(
grant no. 99-00157), the Russian Foundation for Basic Research
grant nos. 03-03-32019 and 00-03-81187Bel) and the Russian
the (2)NH(2NB) group participates in the weaker intermolecular
H-bond with O(1) (N···O 3.086 Å), thus uniting molecules into
helices directed along the crystallographic axis c.
Routine crystallisation gave crystals of (–)- and (+)-2, whereas
stirred crystallisation resulted in the enantiomeric enrichment
Academy of Sciences.
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i
(
R,R)-(–)-1
N
ii
H C
2
N
(
S,S)-(+)-1
4
N
H
5
†
Scheme 1 Reagents and conditions: i, routine crystallisation; ii, CF CO H
in MeOH (10%), total evaporation with stirring (500 rpm), 5 h; dissolution
of the residue in methanolic NH , evaporation in vacuo, extraction with
6
3
2
3
CHCl and crystallisation from MeOH, (+)-1 yield of 80%, ee 94.3%.
3
–
112 –

,
2003, 13(3), 111–113
7
8
9
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Received: 27th May 2003; Com. 03/2133
–
113 –