Carane amino alcohol organocatalysts
Russ.Chem.Bull., Int.Ed., Vol. 66, No. 2, February, 2017
295
Table 1. Aldol reaction of isatin with acetone in
the presence of 20 mol.% amino alcohols 5, 6,
10, and 11 at 20 °C
direct statistical method and refined by the fullꢀmatrix least
squares method with respect to F2 using anisotropic approximaꢀ
tion parameters for all the nonhydrogen atoms, using the
SHELXL program.18 Hydrogen atoms of the C—H bonds were
placed in geometrically calculated position and refined in isoꢀ
tropic approximation. The effect of anomalous scattering was
neglected. The results of the Xꢀray diffraction experiments were
deposited with the Cambridge Crystallographic Data Center
(CCDC 1519876—1519877) and are available free of charge upon
Catalyst
τ∗/h
Y (%)**
ee (%)
11
10
10
6
5
5
120
121
196
100
150
124
74
77
95
60
95
95
0
39 (R)
49 (R)
15 (S)
77 (S)
84 (S)
(+)ꢀ(1S,3S,4R,6R)ꢀ3,4ꢀEpoxyꢀ3,7,7ꢀtrimethylbicyclo[4.1.0]ꢀ
heptane (2) ([α 20] = +12.0° (c 1.0; EtOH), Ref. 11: [α 20] =
D
D
= +13.9° (neat)) was obtained from 3ꢀcarene 1. The spectral
data are similar to those described in the literature.11
(1S,3S,4S,6R)ꢀ4ꢀAzidoꢀ3,7,7ꢀtrimethylbicyclo[4.1.0]heptanꢀ
3ꢀol (3) and (1R,3R,4R,6S)ꢀ4ꢀazidoꢀ4,7,7ꢀtrimethylbicycloꢀ
[4.1.0]heptanꢀ3ꢀol (4) were synthesized based on transꢀ3,4ꢀepꢀ
oxycarane 2. The spectral characteristics correspond to those
described in the literature.13
* τ is the reaction time.
** Y is the product yield.
nary carbon atom C(3)), catalyzes aldol coupling with
a minimum enantiomeric excess (5%). A racemate is
formed in the presence of compound 11. Note that when
the catalyst 10 is used, the required (R)ꢀisomer is formed,
but with moderate enantiomeric excesses (39% and 49%).
In order to increase enantioselectivity, we plan to continꢀ
ue our experiments on optimization of the reaction condiꢀ
tions (by variation of temperature, reaction time, solvents,
catalyst concentration).
The spectral data for (+)ꢀ4βꢀaminoꢀ3αꢀhydroxyꢀcisꢀcarane
(5) ([α 26] = +62.6° (c 1.0; CHCl3), Ref. 15: [α 25] = +35.0°
D
D
(c 1.8; CHCl3)) and (–)ꢀ3βꢀaminoꢀ4αꢀhydroxyꢀtransꢀcarane (6)
([α 26]= –9.0° (c 1.0; CHCl3), Ref. 15: [α 25] = –8.0° (c 1.0;
D
D
CHCl3)) agree with those described in the literature.15
(–)ꢀ(1S,3R,4S,6R)ꢀ3,4ꢀEpoxyꢀ3,7,7ꢀtrimethylbicyclo[4.1.0]ꢀ
heptane (7) was synthesized from 3ꢀcarene 1. The spectral data
correspond to those described in the literature.12
In conclusion, 3ꢀcarene was used as a basis for the
synthesis of a series of vicinal amino alcohols, their appliꢀ
cation as organocatalysts in the asymmetric aldol reaction
of isatin with acetone was studied for the first time. The
highest yield of the product and its enantiomeric excess
were obtained in the presence of (+)ꢀ4βꢀaminoꢀ3αꢀhydrꢀ
oxyꢀcisꢀcarane 5.
(1S,3R,4R,6R)ꢀ4ꢀAzidoꢀ3,7,7ꢀtrimethylbicyclo[4.1.0]heptanꢀ
3ꢀol (8) and (1R,3S,4S,6S)ꢀ4ꢀazidoꢀ3,7,7ꢀtrimethylbicycloꢀ
[4.1.0]heptanꢀ3ꢀol (9) were obtained from cisꢀ3,4ꢀepoxycarane 7.
The spectral characteristics are similar to those described in the
literature.13
Reduction of azido alcohols 8 and 9. A solution of azido alcoꢀ
hol (1.14 g, 5.8 mmol) in Et2O (15 mL) was added dropwise to
a suspension of LiAlH4 (0.22 g, 5.8 mmol) in Et2O (10 mL) cooled
to –5 °C, and the mixture was stirred for 2 h. Then, a 5% aqueous
NaOH (15 mL) was added, the resulting mixture was extracted
with Et2O, the extract was washed with brine, dried with Na2SO4,
and recrystallized from a mixture of hexane and diethyl ether to
obtain compounds 9 and 10.
Experimental
IR spectra were recorded on a Shimadzu IR Prestige 21
Fourierꢀtransform spectrometer. Melting points were determined
1
on a GallencampꢀSanyo heating stage. H and 13C NMR specꢀ
(1S,3R,4R,6R)ꢀ4ꢀAminoꢀ3,7,7ꢀtrimethylbicyclo[4.1.0]heptanꢀ
3ꢀol (4αꢀaminoꢀ3βꢀhydroxyꢀtransꢀcarane) (10). White needleꢀ
like crystals, the yield was 75%, Rf 0.30 (1 : 1, C6H6 : PriOH),
tra were recorded on a Bruker Avanceꢀ300 spectrometer (300.17
and 75.48 MHz, respectively) in CDCl3. Thinꢀlayer chromatoꢀ
graphy was carried out on Sorbfil plates, visualizing agents were
a 10% solution of phosphomolybdic acid in EtOH, a 3% solution
of vanillin in ethanol, iodine, UV light. Column chromatograꢀ
phy was carried out on Alfa Aesar silica gel (0.06—0.2 mm) and
neutral aluminum oxide from Acros. HPLC analysis was carried out
using Chiralpak ADꢀH chiral columns (hexane : 2ꢀpropanol =
= 8 : 2). Elemental analysis was carried out on a EA 1110 CHNSꢀO
automated analyzer. Optical rotation angles were determined on
a Kruss P3002RS automated polarimeter (Germany). (+)ꢀ3ꢀ
m.p. 61 °C, [α 26] = –34.3° (c 1.0, CHCl3). IR (KBr, ν/cm–1):
D
3356, 1597 (NH2), 3082, 1448 (OH). 1H NMR (300 MHz,
CDCl3), δ: 0.58 (t, 1 H, H(6), J = 8.3 Hz); 0.70 (td, 1 H, H(1),
J = 9.5 Hz, J = 5.0 Hz); 0.96 (s, 6 H, Me(8), Me(9)); 1.10 (s, 3 H,
Me(10)); 1.18 (dd, 1 H, H(2α), J = 14.1 Hz, J =5.0 Hz); 1.42
(dd, 1 H, H(5α), J = 14.5 Hz, J =11.1 Hz, J =8.3 Hz); 1.79 (br.s,
3 H, NH2, OH); 1.98 (dd, 1 H, H(2β), J = 14.1 Hz, J = 9.5 Hz);
2.05 (dd, 1 H, H(5β), J = 14.5 Hz, J = 7.2 Hz); 2.35 (dd, 1 H,
H(4), J = 11.1 Hz, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3), δ:
15.52 (C(8)), 17.56 (C(7)), 19.08 (C(10)), 20.23 (C(1)), 20.56
(C(6)), 28.85 (C(9)), 30.30 (C(5)), 34.29 (C(2)), 55.43 (C(4)),
71.94 (C(3)). Found (%): C, 70.56; H, 11.59; N, 8.74. C10H19NO.
Calculated (%): C, 70.96; H, 11.31; N, 8.27.
Carene ([α 20] = +17.1° (neat)) and commercial 98% isatin
D
purchased from SigmaꢀAldrich were used in the work.
Xꢀray diffraction study of compounds 10 and 11 was carried out
on a Xcalibur 3 automated fourꢀcircle diffractometer with a CCD
detector (MultiꢀUser Center of the IOC of the Ural Branch of
the Russian Academy of Sciences) according to the standard
procedure17 (ωꢀscan technique with a 1° step at monochromaꢀ
tized MoKα radiation and Т = 295(2) K). Empirical correction
for absorption was introduced. The structures were solved by
Xꢀray diffraction study of compound 10. A monoclinic crysꢀ
tal, space group P21, a = 9.7323(7) Å, b = 8.9751(5) Å,
c = 12.1117(6) Å, β = 97.720(5)°, V = 1048.35(11) Å3, for
a compound with molecular formula C10H19NO, M = 169.26,
Z = 2, μ(MoKα)= 0.068 mm–1. On the scattering angle