Directed synthesis of compounds capable to spontaneous resolution

Article abstract of DOI:10.1070/MC2002v012n01ABEH001516

A qualitative conception for constructing conglomerates has been proposed; bis-lactam 1 has been synthesised by two methods, and it exhibited a priori predicted properties like formation in the optically active form under conditions of a routine crystallization.

Full text of DOI:10.1070/MC2002v012n01ABEH001516

Mendeleev Commun., 2002, 12(1), 4–6
Directed synthesis of compounds capable to spontaneous resolution
Remir G. Kostyanovsky,*a Irina A. Bronzovaa and Konstantin A. Lyssenkob
a N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax:+7 095 938 2156; e-mail: kost@center.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
10.1070/MC2002v012n01ABEH001516
A qualitative conception for constructing conglomerates has been proposed; bis-lactam 1 has been synthesised by two methods,
and it exhibited a priori predicted properties like formation in the optically active form under conditions of a routine crystallization.
Crystallization of a racemate as a mixture of homochiral crys-
(a)
tals (conglomerate) makes it possible to carry out a simple
spontaneous resolution into enantiomers.1 However, in most
cases, the racemates yield heterochiral crystals,1(a) the known
list of conglomerates is rather short, and for the most part they
have been found by a lucky chance. Naturally, it was a matter of
interest to elucidate possibilities for constructing conglomerates
on the basis of prediction of the crystal structure. However,
such a predictivity was entirely denied (‘…nothing can be said
a priori on the spontaneous resolution of racemic solutions by
crystallization, …there are at present no really predictive con-
cepts on this fascinating subject, which may be related to the
chirality of the chemistry of life’.2(a) ‘In crystal engineering…
design and control packing arrangements… are not routinely
possible from knowledge of the molecular structure alone’.2(b)).
Nevertheless, we have launched attempts to construct con-
glomerates of chiral bicyclic bis-lactams (BBL) starting from
our qualitative predictive concepts as a basis. The racemates
of BBL of types A3,4 and B5 seemed to be doomed for co-
crystallization of the enantiomers [Scheme 1(a),(b)]. In crystals,
they are combined in a strictly alternating sequence by H-bonds
of the lactam groups into tapes of either linear (A)3,4 or diagonal
(B)5 zigzag. These tapes are assembled into walls where the
BBL skeletons are tightly packed into columns. The same pattern
is observed for co-crystals of both quasi-racemate, (1R,4R)-(–)-A
(R = Et) with (1S,4S)-(+)-A (R = Pr),4(b) and diastereomers B
[R = (S)-Et(Me)CHCH2O].5(c) The latter cannot be separated by
chromatography, and enantiomers A' have been obtained only
after the chiral chromatographical resolution of a 2,5-bis-p-
methoxybenzyl derivative3,6 (where the lactam-type H-bonding is
absent). Comparison between the racemate4(a) and enantiomer4(b)
of A (R = Et) points out a significant difference in the homo-
chiral assembling of molecules in the crystal [Scheme 1(a),(c)]
and a greater stability of the less soluble racemic crystal (higher
density, and the melting point is higher by 37 °C).
R
R
H
O
H
O
N
N
N
N
120°
O
O
H
H
R
R
( )-A' (H instead of CO2R)3
( )-A (R = Me, Et, Pri)4
Heterochiral tapes of
the types of linear (a) and
diagonal (b) zigzags
RO2C
(b)
O
H
H
N
O
N H
RO2C
O
N
CO2R
H
N
O
CO2R
( )-B, R = Et [ref. 5(a)], n-C12H25 [ref. 5(b)],
RO = (S)-Et(Me)CHO [ref. 5(c)]
(c)
Homochiral six-membered
ring for BBL of the type of
[2.2.2]
Homochiral helix
for BBL of the type of
[3.3.1]
RO
CO2R
O
N
O
H
O
N
N
N
H
O
H
H
CO2R
As a first approximation to arranging a homochiral assembling
of BBL and its analogues there was the following assumption.
At the step of prenucleation, the self-association of the molecules
occurs solely by means of H-bonding each molecule with two
other ones [Scheme 1(a)–(c)]. Then, in case of BBL A a homo-
chiral association through the stable lactam–lactam H-bonding
is forbidden, since termination of the H-bond polymerization
chain is inevitable due to the formation of a cyclic hexamer.3,6(a)
At the same time, in case of BBL B and its analogues a homo-
chiral association to form helical tapes is possible; however,
some transformation to flatten these tape is necessary in order
to provide a tight packing. Motive of the structure (–)-A (R = Et)
displays a possibility for such a transformation of helix though
with the weakened H-bonding O–C=O…H–N [Scheme 1(c)]. A
perfect version of the desirable flattening may be seen in the struc-
ture of enantiomer (–)-A' [Scheme 1(d)].3(b) Each of its molecules
is connected with four other ones by the same strong H-bonds
similar to those in the structure of a racemate [Scheme 1(a)] and,
also, it is an element of two reciprocally perpendicular flattened
helices, which form corrugated layers. A tight packing of the
latter occurs in such a way that a skeleton of each molecule goes
into a well-shaped column. It is interesting that the racemate
O
O
OR
Homochiral tapes of
the type of double
zigzag (helices)
A
b
(–)- , R = Et [ref. 4( )]
( ) and
(–)-A', R = H dihydrates [ref. 4(c)]
(d)
H
H
H
H
N
N
O
O
O
O
O
O
H
N
N
H
H
H
N
N
H
H
O
O
O
Homochiral
corrugated
layer
H
H
N
H
H
H
N
N
H
O
O
H
N
N
H
H
H
H
H
O
N
H
H
(–)-A' [ref. 3(a)], confer with 1 (Figure 1)
Scheme 1
– 4 –

Mendeleev Commun., 2002, 12(1), 4–6
R
H
H
EtO2C
HN
HO2C
HN
O
O
O
N
N
N
N
i
ii
iii
HN
O
NH
O
O
NH
NH
52.3%
86%
78.7%
H
O
O
O
CO2Et
CO2H
R
EtO2C
RN
O
C6
D, R = Me,7(b) Et7(a),(c),8
HN
O
NH
NR
Scheme 2
and enantiomer structures do not differ in the parameters of
H-bonds and density.3(a) Moreover, the melting point of the homo-
chiral crystal (300–305 °C)3(a) is higher than that of the racemate
(275–277 °C).3(c) This suggests that for ensuring the homochiral
self-assembling of BBL like B and its analogues the substituents
CO2R, which hinder the self-assembling by Scheme 1(d), should
be removed.
H
O
CO2Et
HO2C
RN
H
H
O
O
1
iv
v
vi
NR
RN
O
NR
80.9%
61.4%
40.5%
O
CO2H
R = p-MeOC6H4CH2
Therefore, the synthesis of earlier unknown BBL 1,5(a) C6
has been worked out, and their analogues like chiral glycolurils
D7 (Scheme 2) have been studied. Indeed, it was found that 1 is
crystallised in the form of a conglomerate (space group P212121,
Z = 4), and as it was expected a priori its structure is very
similar to that of (–)-A' [Scheme 1(d), Figure 1].5(a)
Scheme 3 Reagents and conditions: i, Ce(NH4)2(NO3)6 in MeCN–H2O, 2 days
at 20 °C, then NaHCO3 and extraction of the product with MeCO2Et; ii,
KOH in EtOH–H2O, 2 days at 20 °C and 1–1.5 h at 4 °C, then with CF3CO2H
in H2O, 2 h at 20 °C and 5 days at 4 °C, then separation of the product
precipitate; iii, heating 2 h at 125–150 °C (2–3 mmHg) and sublimation, 10 h
at 230–250 °C (2–3 mmHg); iv, KOH in EtOH, 2 days at 20 °C, 1–1.5 h at
4 °C, then with CF3CO2H in wet EtOH 1 day at 20 °C and 3 h at 4 °C, then
separation of the product precipitate; v, heating 2 h at 145–150 °C (2–3 mmHg)
and sublimation of the residue, 10 h at 170–180 °C (2–3 mmHg), in contrast
to the earlier reported5(a) the product has been isolated in a crystal form,
mp 31–33 °C; vi, Ce(NH4)2(NO3)6 in MeCN–H2O, 2 days at 20 °C, then
NaHCO3, extraction of anisaldehyde with diethyl ether, heating 2 h at 145–
150 °C (2–3 mmHg), and sublimation of the residue, 10 h at 170–180 °C
(2–3 mmHg).
In this work, the synthesis of 15(a) has been optimised by
two methods providing total yields of 30 and 21% (Scheme 3).
Yields of compounds at the separate steps have been increased; at
the next to last step (in the second method) the product, 3,7-bis-
p-methoxybenzyl derivative of BBL 1, has been obtained in a
crystal form suitable for X-ray diffraction analysis (this product
has been isolated earlier as an oil5(a)). For the first time, the
spontaneous resolution of 1 has been accomplished by crystal-
lization from H2O. The separate well-formed crystals of 1 have
a noticeably higher melting point than that of the racemate, and
possess an optical activity† (Figure 2). A random crystal of 1
taken from the racemic mixture was used as a seed for crystal-
lization resolution of the racemate by an internal entrainment
procedure.6(b),(c) By analogy with (1R,4R)-(–)-A' [see ref. 3(a)]
the absolute configuration of (1R,5R)-(–)-1 can be accepted.
On the basis of the above conception, we succeeded in finding
one more conglomerate in the series of chiral glycolurils D
(R = Me)7(b) (Scheme 2). Spontaneous resolution of D (R = Me,
Et)7(a),(b) has been carried out, and enantiomers D (R = Et) have
been used in the synthesis of the chiral drug Albicar.7(b),(c) How-
ever, in these cases, though the molecular packing is similar to
those shown in Scheme 1(d) but it is complicated by H-bonding
between the layers to form three-dimensional nets.7(b),8 Note
that in case of the unsubstituted glycoluril two different patterns
of packing are observed for its two forms of crystals, one being
H-bonded corrugated layers according to Scheme 1(d), and another
being three-dimensional nets9 like D.
In conclusion, it may be said that the main feature for origi-
nating the proposed conception is a comparative analysis of
both enantiomer and racemate crystal structures of key com-
pounds in the series under study. Such an approach seems to be
universal.
0
–0.2
–0.4
–0.6
200 210
220
230
240
l/nm
Figure 2 CD Spectrum of BBL (–)-1.
This work was supported by the Russian Academy of Sciences,
the Russian Foundation for Basic Research (grant nos. 00-03-32738
and 00-15-97359) and INTAS (grant no. 99-00157).
O(1')
N(2')
H(2N')
H(1N')
N(1')
†
Characteristics and spectroscopic data. Compounds presented in Scheme 3,
have been characterised by H and 13C NMR spectra identical to those
1
O(2')
O(1)
described earlier.5(a)
(–)-1, upon crystallization from H2O with self-evaporation at 20 °C
H(2N)
N(2)
the crystals up to 14 mg in weight have been obtained; mp 364 °C
17
17
17
(decomp.), [a]1D7 = –3.0°; [a] = –3.2°; [a] = –4.2°; [a] = –8.2°;
H(1N)
N(1)
578
546
436
[a]14706 = –9.5° (c 1.3, H2O); CD spectrum (c 3.25×10–5 M in H2O),
∆e (lmax/nm): 0.75 (212). For grinded mixtures the melting point is
355–358 °C (decomp.) in case of the crystals of opposite signs of optical
rotation and to 350 °C (decomp.) in case of a non optically active mixture
[cf. ref. 5(a)]. Then, the mother liquor and precipitate were combined,
and crystallization from H2O with self-evaporation at 20 °C was repeated.
Solution of (–)-1 used for the measurement of the optical rotation angle
was evaporated entirely, the crystals were isolated, grinded and taken as
a seed. Using an internal entrainment procedure,6(b),(c) the precipitate of
(–)-1 has been obtained in 26% yield, [a]1D7 = –2.8° (c 1.5, H2O).
O(1'')
O(2)
N(2'')
H(2N'')
O(2'')
N(1'')
H(1N'')
Figure 1 Homochiral corrugated layer in the crystal structure of BBL 15(a)
[cf. Scheme 1(d)].
– 5 –

Mendeleev Commun., 2002, 12(1), 4–6
7 (a) R. G. Kostyanovsky, K. A. Lyssenko, G. K. Kadorkina, O. V. Lebedev,
References
A. N. Kravchenko, I. I. Chervin and V. R. Kostyanovsky, Mendeleev
Commun., 1998, 231; (b) R. G. Kostyanovsky, K. A. Lyssenko, A. N.
Kravchenko, O. V. Lebedev, G. K. Kadorkina and V. R. Kostyanovsky,
Mendeleev Commun., 2001, 134; (c) R. G. Kostyanovsky, G. K. Kadorkina,
K. A. Lyssenko, V. Yu. Torbeev, A. N. Kravchenko, O. V. Lebedev, G. V.
Grintselev-Knyazev and V. R. Kostyanovsky, Mendeleev Commun.,
2002, 6.
8 E. B. Shamuratov, A. S. Batsanov, Yu. T. Struchkov, A. Yu. Tsivadze, M. G.
Tsitsadze, L. I. Khmel’nitskii, Yu. A. Simonov, A. A Dvorkin, O. V. Lebedev
and T. B. Markova, Khim. Geterotsikl. Soedin., 1991, 937 [Chem. Heterocycl.
Compd. (Engl. Transl.), 1991, 27, 745].
1 (a) J. Jacques, A. Collet and S. H. Wilen, Enantiomers, Racemates, and
Resolutions, Krieger Publishing Company, Malabar, Florida, 1994; (b)
A. Collet, in Comprehensive Supramolecular Chemistry, ed. D. N. Reinhoudt,
Pergamon, Oxford, 1996, vol. 10, ch. 5, pp. 113–149; (c) A. Collet, Enantio-
mer, 1999, 4, 157.
2 (a) A. Gavezzotti, Acc. Chem. Res., 1994, 27, 309; (b) G. R. Desiraju,
Nature, 2001, 412, 397.
3
(a) M.-J. Brienne, J. Gabard, M. Lecklercq, J.-M. Lehn, M. Cesario, C. Pascard,
M. Heve and G. Dutruc-Rosset, Tetrahedron Lett., 1994, 35, 8157; ( ) J.-M.
b
Lehn, Supramolecular Chemistry, VCH, Weinheim, 1995; (c) P. A. Sturm,
and D. V. Henry, J. Med. Chem., 1974, 17, 481.
4 (a) R. G. Kostyanovsky, Yu. I. El’natanov, O. N. Krutius, I. I. Chervin, and
K. A. Lyssenko, Mendeleev Commun., 1998, 228; (b) R. G. Kostyanovsky,
K. A. Lyssenko and D. A. Lenev, Mendeleev Commun., 1999, 154; (c)
R. G. Kostyanovsky, Yu. I. El’natanov, O. N. Krutius, K. A. Lyssenko, I. I.
Chervin and D. A. Lenev, Mendeleev Commun., 1999, 109.
9 N. Li, S. Maluendes, R. H. Blessing, M. Dupuis, G. R. Moss and G. T.
DeTitta, J. Am. Chem. Soc., 1994, 116, 6494.
5 (a) R. G. Kostyanovsky, K. A. Lyssenko, D. A. Lenev, Yu. I. El’natanov,
O. N. Krutius, I. A. Bronzova, Yu. A. Strelenko and V. R. Kostyanovsky,
Mendeleev Commun., 1999, 106; (b) R. G. Kostyanovsky, K. A. Lyssenko,
I. A. Bronzova, O. N. Krutius, Yu. A. Strelenko and A. A. Korlyukov,
Mendeleev Commun., 2000, 106; (c) R. G. Kostyanovsky, O. N. Krutius,
I. A. Bronzova, D. A. Lenev, K. A. Lyssenko and B. B. Averkiev, Mendeleev
Commun., 2001, 6.
6 (a) R. G. Kostyanovsky, Yu. I. El’natanov, O. N. Krutius, K. A. Lyssenko
and Yu. A. Strelenko, Mendeleev Commun., 1999, 70; (b) R. G. Kostyanovsky,
V. R. Kostyanovsky, G. K. Kadorkina and V. Yu. Torbeev, Mendeleev Commun.,
2000, 83; (c) R. G. Kostyanovsky, V. Yu. Torbeev and K. A. Lyssenko,
Tetrahedron Asymmetry, 2001, 12, 2721.
Received: 13th September 2001; Com. 01/1842
– 6 –