Circular dichroism of R- and S-enantiomers of Ugi′s amine and their conjugates with l-tartaric acid

Article abstract of DOI:10.1007/s11172-017-1891-8

Circular dichroism spectra of the optically active (R)- and (S)-enantiomers of N,N-(dimethylamino)ethylferrocene (Ugi′s amine) were studied for a free form and for their diastereomeric salts with с l(+)-tartaric acid.

Full text of DOI:10.1007/s11172-017-1891-8

Russian Chemical Bulletin, International Edition, Vol. 66, No. 7, pp. 1314—1317, July, 2017
1314
Brief Communications
Circular dichroism of Rꢀ and Sꢀenantiomers of Ugi´s amine
and their conjugates with Lꢀtartaric acid
K. K. Babievskii, T. R. Kachura, E. Yu. Osipova, A. A. Simenel, and L. V. Snegur
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 6549. Eꢀmail: snegur@ineos.ac.ru
Circular dichroism spectra of the optically active (R)ꢀ and (S)ꢀenantiomers of N,Nꢀ(diꢀ
methylamino)ethylferrocene (Ugi´s amine) were studied for a free form and for their
diastereomeric salts with с L(+)ꢀtartaric acid.
Keywords: enantiomers, Ugi´s amine, Lꢀtartaric acid, ferrocene.
Combination of an organometallic ferrocenyl fragꢀ
ment and biologically active compounds leads to the deꢀ
velopment of a wide range of physiologically active subꢀ
stances with low toxicity.1—5 The opportunity for designꢀ
ing drugs with antianemic, antitumor, tuberculostatic,
and antimalarial activities2,3,5,6 draws attention of chemꢀ
ists,7—9 biochemists, and biologists.
Active investigations of enantiomerically enriched ferꢀ
roceneꢀcontaining compounds have already started in the
1970s, when Gokel and Ugi proposed universal apꢀ
proaches to their synthesis based on ferrocene.10,11 These
syntheses unsurpassed in chemical logic and simplicity
are still in practice. Meanwhile, works on the stereoꢀ
selective reduction of unsymmetrically substituted ketones
with oxaborolidines as catalysts are well known.12—14
More recently, this approach was applied to enantioꢀ
selective reduction of ferrocenyl alkyl ketones (FcC(O)R)
to alcohols with the boraneꢀtetrahydrofuran complex in
the presence of methyl oxazaboralidine,15 resulting in the
formation of Rꢀseries of the ferrocenyl alcohols with enanꢀ
tiomeric excess greater than 95%. Such examples of the
enantioselective syntheses of simple ferrocene compounds
are quite common,16 but they all allow synthesis of mainly
one of the two possible enantiomers and their use for
subsequent transformations.
The biologically active compounds studied by our
group usually contain a chiral carbon atom in the alpha
position to the cyclopentadienyl ring, and therefore they
are not individual compounds but a racemic mixture of
two enantiomers.17,18 A need for investigation of biologiꢀ
cal effects of each of the stereoisomers arises in accorꢀ
dance with current regulations of the Russian pharmaꢀ
ceutical committee on the enantiomeric purity of potenꢀ
tial drugs.19
Results and Discussion
(R,S)ꢀ1ꢀN,Nꢀ(Dimethylamino)ethylferrocene (Ugi´s
amine) is widely utilized as a key starting compound for
the synthesis of planar chiral enantioselective catalysts.20
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1314—1317, July, 2017.
1066ꢀ5285/17/6607ꢀ1314 © 2017 Springer Science+Business Media, Inc.

Circular dichroism of Ugi´s amine
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 7, July, 2017
1315
ΔA•10–6
We chose the classical approach of Ugi and Gokel for its
synthesis,10,11 which allowed preparation of both enantiꢀ
omers with high chemical yields and enantiomeric purity
of more than 95% from commercially available ferrocene
using simple reagents instead of expensive catalysts. We
utilized a modified procedure,10 based on the interaction
of 1ꢀferrocenylethanol (FcCH(OH)Me) with acetic anꢀ
hydride and the subsequent reaction of ferrocenyl ethyl
acetate with a dimethylamine aqueous solution (Scheme 1).
We found that the acylation reaction proceeds equally
well using either acetic or propionic anhydrides.
S
400
200
0
–200
R
300
400
500
600
λ/nm
Scheme 1
Fig. 1. CD spectra for (S)ꢀ and (R)ꢀ1ꢀN,Nꢀ(dimethylamino)ꢀ
ethylferrocene in methanol (10−2 mol L–1).
In this communication, a circular dichroism (CD)
method was used as yet another efficient approach for the
determination of the enantiomeric composition of (R,S)ꢀ
1ꢀ(dimethylamino)ethylferrocene and its analogues.
As can be seen in the CD spectra of Rꢀ and Sꢀenantiꢀ
omers of Ugi´s amine depicted in Fig. 1, both compounds
demonstrate intense extreme points (Cotton effect, CE)
at 452.4 nm, which correspond to the electronic transiꢀ
tion 1A1g → a1E1g in the ferrocene system.23,24
The spectra of this pair of enantiomers were, as it
would be expected, mirror identical. In this case, CE is
positive for the Sꢀenantiomer and negative for the Rꢀenanꢀ
tiomer. Both enantiomers have high enantiomeric purity
according to the CD spectra. A peak at 294.6 nm indiꢀ
cates the insignificant content of the impurity of the
(L)ꢀtartrate in Rꢀenantiomer (see Fig. 1).
Of a special interest is a comparison of the spectra of
neutral ferrocenylamine molecules and their diastereoꢀ
meric salts with Lꢀtartric acid. It appeared that an almost
perfect mirror image is observed: a positive CE at 295.8 nm
for Sꢀtartrate and a negative CE at 294.6 nm for Rꢀtarꢀ
trate. A simultaneous shift of the CE extreme points to
shorter wavelengths in circular dichroism spectra characꢀ
terizes changes in the electronic transition energies of the
organometallic ferrocene systems upon quaternization of
Ugi´s amines.
In conclusion, we synthesized a pair of stereoisomers of
Ugi´s amine, the enantiomeric purity of which was deterꢀ
mined by the optical circular dichroism method. The Rꢀ and
Sꢀazoleꢀcontaining ferrocene compounds were syntheꢀ
sized by further transformations of the Rꢀ and Sꢀenanꢀ
tiomers. Results of their biological trials demonstrate the
significant difference in biological activity of the either
enantiomer as well as the racemic product, respectively.
R = H, Me
Reagents and conditions: i. Ac2O or propionic angydride, Py,
50 °C, 10 h; ii. HNMe2/H2O—MeOH, 48 h.
The obtained racemic (R,S)ꢀ1ꢀ(dimethylamino)ꢀ
ethylferrocene was almost quantitively resolved into
Rꢀ and Sꢀenantiomers by a classical method, viz., by crystalꢀ
lization of their diastereomeric salts with Lꢀtartaric acid.
It is known,21 that (S)ꢀ(−)ꢀ1ꢀN,Nꢀ(dimethylamino)ꢀ
ethylferrocene and its Rꢀstereoisomer are convenient
chiral precursors for the preparation of various ferrocene
derivatives and ligands. The enantiomeric purity of these
compounds is usually determined by HPLC as well as by
polarimetry and 1H NMR spectroscopy. Noteworthy, the
enantiomeric excess of the prepared amines was 98% for
(R)ꢀ(+)ꢀ1ꢀN,Nꢀ(dimethylamino)ethylferrocene and 97%
for the Sꢀenantiomer according to HPLC .
Experimental
CD spectra were collected on an SKDꢀ2 automatic recording
dichrograph (joint development of the Engelhardt Institute of
Rꢀenantiomer
Sꢀenantiomer

1316
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 7, July, 2017
Babievskii et al.
Molecular Biology and the Institute of Spectroscopy RAS).
The intensities of extreme points in the CD spectra were
calibrated against an aqueous solution of Dꢀ10ꢀcamphorsulfonic
acid, on the basis that Δε = 2.2 L mol–1 cm–1 at 291 nm. All
measurements were carried out in 1 cm quartz cells with
a spectral resolution of 3 nm, accumulation of 2.4 nm, at a scan
cool down to room temperature during 12 h. The precipitated
crystals of one of the enantiomers were filtered and twice
recrystallized from methanol. The resulting salt was dissolved
in water, then aqueous KOH solution was added, and the oily
mass was extracted with diethyl ether. After evaporation of the
solvent, (S)ꢀ1ꢀ(−)ꢀ(dimethylamino)ethylferrocene was obtainꢀ
1
rate of 35 nm min− in the range from 300 to 750 nm. The
ed, yield 4.3 g (67%), [α]20 –13.4 (c, 1.5; methanol), Ref.11
:
D
solvent is methanol. The CD values in a Fig. 1 are given as
a difference between the absorbance (ΔA), corresponding to
the right and left polarizarion. Optical rotation angles were
measured on a "PerkinꢀElmer 141" polarimeter.
The ferrocene compounds were obtained according to
known procedures10,11 with some modifications. The purity of
the obtained products was controlled by TLC on a largeꢀpore
silica gel after Pitra with Silufol UV 254 luminicent indicator
by "Kavalier".
[α]20D –14.1 (c, 1.6; ethanol).
After the separation of the Sꢀenantiomer, the mother liquor
was concentrated to 1/4 of the initial volume and diluted with
diethyl ether. The precipitated tartrate of the Rꢀenantiomer
was twice crystallized from aqueous acetone (10 : 1). The
crystals were dissolved in water, then aqueous solution of KOH
was added, and the oily mass was extracted with diethyl ether.
After evaporation of the solvent, (R)ꢀ1ꢀ(−)ꢀ(dimethylamino)ꢀ
ethylferrocene was obtained. Yield 4.5 g (70%), [α]20 +13.5
D
1ꢀFerrocenyl(ethyl)acetate.11 To a solution of 1ꢀferrocenylꢀ
ethanol (20.1 g, 0.087 mol) in 70 mL of anhydrous pyridine
freshly distilled acetic anhydride (26.2 mL, 0.22 mmol) was
added. The reaction mixture was stirred until a solution formed
and then left for one day in the dark, thereafter the solvent was
evaporated in vacuum of a water jet pump to a minimal volume.
The residue was dissolved in diethyl ether. The resulting solution
was washed with a cold NaCl solution (3×100 mL) and dried
over anhydrous MgSO4. The solvent was evaporated in vacuum
of a water jet pump vacuum. The product was sublimed at 85 °C
in oil pump. Yield 18 g (76%), yellow cristalline compound,
m.p. 65 °С. IR (KBr pellet), ν/cm−1: 3100, 3020—2920, 1730
(CO), 1380, 1240, 1080—1010, 950, 850—820, 520, 480.
1Н NMR (CDCl3), δ: 1.52 (d, 3 Н, СН3, J = 7.8 Hz); 2.00 (s, 3 Н,
Ме); 4.11—4.18 (m, 9 Н, (С5Н5)FeС5Н4)); 5.82 (q, 1 Н, СН,
J = 6.6 Hz). MS, m/z (Irel (%)): 272 [M]+ (21). Found (%):
С, 61.52; H, 5.90. Calculated for C14H16FeO2 (%): C, 61.79;
H, 5.93.
(c, 1.5; methanol).
This work was partially financially supported by
the Russian Foundation for Basic Research (Projects
Nos 16ꢀ03ꢀ00881 and 16ꢀ33ꢀ60163).
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Received February 1, 2017;
in revised form April 17, 2017