Synthesis of new enantiomerically pure β-amino alcohols of the pinane series

Article abstract of DOI:10.1134/S1070428017030046

A series of new β-amino alcohols with pinane structure, (+)- and (?)-3α-amino-10β-pinan-4β-ols, 4β-amino-10β-pinan-3α-ol, and 4α-amino-10β-pinan-3α-ol have been synthesized with the goal of using them as organocatalysts in the aldol reaction of isatin with acetone.

Full text of DOI:10.1134/S1070428017030046

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 3, pp. 335–343. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © L.L. Frolova, D.V. Sudarikov, I.N. Alekseev, O.A. Banina, P.A. Slepukhin, A.V. Kutchin, 2017, published in Zhurnal Organicheskoi
Khimii, 2017, Vol. 53, No. 3, pp. 338–345.
Synthesis of New Enantiomerically Pure β-Amino Alcohols
of the Pinane Series
a
a
a
a
L. L. Frolova ,* D. V. Sudarikov , I. N. Alekseev , O. A. Banina ,
b, c
a
P. A. Slepukhin , and A. V. Kutchin
a
Institute of Chemistry, Komi Scientific Center, Ural Branch, Russian Academy of Sciences,
ul. Pervomaiskaya 48, Syktyvkar, 167982 Russia
*
e-mail: frolova-ll@chemi.komisc.ru
b
Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences,
ul. S. Kovalevskoi/Akademicheskaya 22/20, Yekaterinburg, 620990 Russia
c
Yeltsin Ural Federal University, ul. Mira 19, Yekaterinburg, 620002 Russia
Received November 25, 2016
Abstract—A series of new β-amino alcohols with pinane structure, (+)- and (‒)-3α-amino-10β-pinan-4β-ols,
β-amino-10β-pinan-3α-ol, and 4α-amino-10β-pinan-3α-ol have been synthesized with the goal of using them
4
as organocatalysts in the aldol reaction of isatin with acetone.
DOI: 10.1134/S1070428017030046
Asymmetric organocatalysis is a rapidly developing
field of modern organic chemistry. Achiral compounds
can be converted into chiral structures in the presence
of a small amount of an enantiomerically pure organic
compound through fairly simple experimental proce-
dures. The main source of organocatalysts includes
natural compounds such as amino acids [1], alkaloids
(3), and 4β-amino-10β-pinan-3β-ol (4) [9], in this work
we synthesized new enantiomerically pure β-amino
alcohols with the pinane skeleton containing functional
groups in positions 3 and 4 with the goal of subse-
quently using them as chiral catalysts.
Compounds 1 and 2 were synthesized by nitrosa-
tion of cis-verbanone with isoamyl nitrite to the corre-
sponding ketone oxime and its subsequent reduction
[2], carbohydrates [3], and terpenes [4, 5]. New difunc-
tional organocatalysts successfully used in asymmetric
aldol reactions [6] and Michael additions [7] were syn-
thesized on the basis of isomeric 3-aminopinan-2-ols.
with LiAlH to 1 (the yield of crude 1 in two steps
4
starting from cis-verbanone was 24%). If the reduction
was carried out using first NaBH and then LiAlH ,
4
4
In addition to already known isomeric amino-
pinanols, 3α-amino-10β-pinan-4α-ol (1), 3β-amino-
compound 2 was obtained (the yield of crude 2 in three
steps was 34%) [8]. Amino alcohols 3 and 4 were
prepared by nitrosation of 2α-hydroxypinan-3-one,
followed by reduction of the resulting hydroxy ketone
oxime with sodium in pentan-1-ol, which was accom-
panied by elimination of the hydroxy group with
formation of a mixture of 3 (24%) and 4 (10%) [9].
There are no published data on applications of amino
alcohols 1–4.
1
0β-pinan-4β-ol (2) [8], 4α-amino-10β-pinan-3β-ol
Me
Me
NH2
NH2
Me
Me
Me
Me
OH
OH
1
2
With the goal of synthesizing enantiomers of
Me
Me
3
α-amino-10β-pinan-4β-ol (5), we preliminarily opti-
mized the procedure for the synthesis of cis-verbanone
6) via 1,4-conjugate reduction of verbenone (7); the
OH
OH
(
Me
Me
Me
Me
NH2
NH2
latter was prepared in turn by oxidation of α-pinene (8)
3
4
according to [10]. 1,4-Reduction of the C=C bond in
3
35

3
36
FROLOVA et al.
Scheme 1.
Me
Me
Me
Me
Me
i
ii
+
+
Me
Me
Me
Me
Me
Me
Me
Me
O
O
O
OH
Me
Me
8
7
6
9
10
Me
Me
+
+
Me
Me
Me
OH
OH
Me
1
1
12
i: Pb(OAc)
4
, KOH‒EtOH, Na
2
Cr
2
O
7
‒Et
2
O; ii: NaBH
4
‒Py.
α,β-enones can be accomlished using NaBH in pyri-
verbanones 6 and 9 at a ratio of 2:1 in an overall yield
of 72% (according to the GLC data); in addition, an al-
cohol fraction was isolated which contained (according
4
dine [11], NaBH –NiCl –B(OH) –H O [12], and
4
2
3
2
NaBH in the presence of Ni, Co, Fe(III), or Cu salt in
4
1
methanol [13]. The reduction of verbenone with
to the H NMR data) 67% of neoisoverbanol 10,
NaBH in pyridine gave a mixture of cis- and trans-
17% of neoverbanol 11, and ~3% of cis-verbenol 12
4
(
Scheme 1).
Table 1. 1,4-Conjugate reduction of verbenone 7 in water
We failed to achieve chemoselective formation of 6
(
reaction time 1–1.5 h)
following the procedure for 1,4-conjugate reduction
12] in water in the presence of boric acid. When
NaBH and B(OH) were used in considerable excess,
[
Run
no. 7–NiCl
Molar ratio
–NaBH –H
Conversion Selectivity
4
3
2
4
3
BO
3
of 7, %
for 6, %
the major product was neoisoverbanol 10 (Table 1).
1
2
3
4
5
1:1:8.6:7.3
1:1:4.3:3.65
1:1:3.2:2.73
1:1:3.2:0
100
088
097
098
063
046
058
072
080
100
096
Decrease of the amount of NaBH and B(OH) was
4
3
accompanied by increase of the yield of saturated
ketone 6, but the reaction was less selective, and
isoverbanol 13 (4–12%) was detected among the
products. High selectivity for compound 6 (96–100%)
was observed at incomplete conversion of initial
verbenone.
1:1:2.15:1.8
a
a
0
81
a
The reaction mixture from run no. 5 was left overnight.
Me
Table 2. 1,4-Reduction of verbenone 7 in methanol (reaction
time 1–2 h)
Me
OH
Me
Run
Molar ratio
Tempera- Conversion Selectivity
1
3
no. 7–NaBH
4
–NiCl
2
ture, °C
of 7, %
for 6, %
a
1
2
3
4
5
6
7
8
1:(1.0‒1.2):0.25 0 to 30
1:(2.0‒2.5) :0.25 0 to 30
80‒87
100
100
100
100
082
092
100
094‒100
22‒37
25
1,4-Conjugate reduction of 7 in the system NaBH ‒
4
a
NiCl –MeOH was carried out at different reactant
2
ratios, temperatures, and rates of addition of NaBH4
Table 2). Depending on the conditions, the major
1:1.5:0.1
1:2.0:0.25
1:2.0:0.25
1:1.5:0.5
1:1.75:0.5
1:2.0:0.5
‒2 to 8
18–22
‒5 to 5
‒2 to 6
‒5 to 5
‒5 to 6
(
58
product was cis-verbanone or neoisoverbanol. As in
the previous case, 94–100% selectivity for the forma-
tion of 6 was achieved at incomplete conversion of the
initial enone (80–87%). The optimal conditions were
reactant molar ratio 7–NaBH ‒NiCl 1:2:(0.25‒0.5),
69‒79
88
75
4
2
65‒78
temperature ~0°C, and reaction time 1.5‒2 h. The
a
Reaction time 0.5 h.
reaction mixture was then subjected to Beckmann
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017

SYNTHESIS OF NEW ENANTIOMERICALLY PURE β-AMINO ALCOHOLS
337
Scheme 2.
Me
Me
Me
N
O
NH2
O
NH ·HCl
2
i
ii
iii
OH
(
+)-6, (–)-6
Me
Me
Me
Me
Me
Me
O
(
+)-Z-14, (–)-Z-14
15
16
Me
Me
NH2
OH
NH2
v
+
Me
Me
Me
Me
OH
iv
1
5
5
17
vi
(
+)-5, (–)-5
–
i: i-AmONO, t-BuOK, THF; ii: Zn–NaOH; iii: HCl, Et
2
O; iv: OH ; v: LiAlH
4
2 3
, Et O; vi: LiBHEt , THF.
oxidation with sodium dichromate to obtain cis-ver-
banone in 83‒86% yield over two steps (purity 97–
cyclohexane fragment is essentially flattened, and it
appears in a sofa conformation. The amino group is
oriented pseudoequatorially, and the hydroxy group is
pseudoaxial. The crystal packing of 5 consists of layers
formed by infinite networks of tetramers linked to each
other through intermolecular hydrogen bonds.
9
8%, according to the GLC data). Column chromatog-
raphy afforded 100% pure ketones (+)-6 and (–)-6:
[
α] = +56.2° (CHCl ), 89% ee, and [α] = ‒50.2°
D 3 D
(
CHCl ), 85% ee (cf. [α] = +44.4°, 89% ee and [α] =
3 D D
‒
42.7°, 83% ee for the initial α-pinenes).
The (+)- and (–)-enantiomers of 6 were converted
to enantiomerically pure 3-aminopinan-4-ols
Scheme 2). Oximation of (+)-6 with i-AmONO–
We failed to synthesize in a similar way isomeric
4-aminopinan-3-ols from isopinocamphone 18
(Scheme 3). However, unlike [9, 15], the structure of
compound 19 thus formed was determined by not only
NMR spectroscopy but also X-ray analysis [16].
(
t-BuOK in THF at ‒70°C gave ketoxime 14 in 75%
yield [14]. The H NOESY spectrum of 14 showed no
correlation between the OH and C H protons, which
indirectly proved Z-configuration of the oxime group.
Oxime 14 was reduced to amino ketone 15 with zinc in
strongly alkaline solution; the configuration of hydro-
1
Amino alcohols 20 and 21 were synthesized as
follows. Hydroboration/oxidation of verbenone 7 gave
trans-pinane-3,4-diol (22) which was oxidized with
1
0
3
1
11
chloride 16 was determined by H NOESY. The reduc-
C
tion of 15 with LiAlH in Et O afforded a 1:1 mixture
4
2
of diastereoisomeric amino alcohols 5 and 17. The
1
reaction of 15 with 1‒1.5 equiv of LiBHEt produced
3
N
3
C
pure amino alcohol 5 in 60% yield; its configuration
2
C
1
was determined on the basis of the H NOESY data
4
and was confirmed by X-ray analysis (Fig. 1).
C
8
C
According to the X-ray diffraction data, compound
5
crystallized in a chiral space group belonging to the
7
1
1
O
C
C
orthorhombic crystal system. There are no heavy
atoms in the crystal structure of 5; therefore, it was
impossible to determine its absolute configuration by
the anomalous scattering effect. The absolute con-
figuration of 5 was determined on the basis of the con-
figuration of the initial compound. The bond lengths
and bond angles in molecule 5 approach the corre-
sponding standard values. Due to strong steric effect of
the methyl groups in the cyclobutane fragment, the
9
C
6
C
5
C
Fig. 1. Structure of the molecule of 3-amino-4,6,6-trimethyl-
bicyclo[3.1.1]heptan-2-ol (5) according to the X-ray diffrac-
tion data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017

3
38
FROLOVA et al.
Scheme 3.
Me
Me
Me
O
OH
O
i
ii
N
Me
Me
Me
Me
Me
Me
OH
8
18
19
6
+
i: BH
3
/Cr ; ii: i-AmONO, t-BuOK, THF.
Scheme 4.
Me
Me
Me
Me
OH
OH
O
OH
OH
i
ii
+
Me
Me
Me
Me
Me
OH
Me
Me
OH
N
N
Me
OH
2
2
23
Z-24
E-25
Me
Me
Me
OH
OH
OH
iv
v
iii
iii
Z-24
E-25
Me
Me
Me
Me
Me
NH2
NH ·HCl
NH2
2
Me
2
0
26
20
–
2 2 4 2 2
i: ClO , DMF; ii: NH OH·HCl, MeOH; iii: LiAlH , Et O; iv: HCl, Et O; v: OH .
chlorine dioxide in DMF with high selectivity and
good preparative yield of hydroxy ketone 23. The
oximation of 23 quantitatively afforded isomer mixture
Z -24/E-25 (Scheme 4). When the reaction time was
The reduction of 25 with LiAlH in anhydrous di-
4
ethyl ether also gave a mixture of epimers 20 and 21 at
a ratio of 1:5. By double recrystallization from diethyl
ether–ethanol we isolated pure 4α-amino-10β-pinan-
3α‑ol (21) in 45% yield (based on the initial E-oxime).
The structure of stereoisomer pairs 24/25 and 20/21
was proved by correlations observed in their NOESY
spectra (Fig. 2).
3
–4 h, the major product was Z-oxime 24 (60–70%),
whereas prolonged reaction (7 h) favored formation of
E-oxime 25 (60%); isomeric oximes 24 and 25 can
readily be separated by column chromatography on
silica gel. By reduction of 24 with 3 equiv of LiAlH4
we obtained a mixture of compounds 20 and 21 at
a ratio of 3.5:1 as a thick oily material; treatment of
the product mixture with a solution of HCl in diethyl
ether gave a mixture of crystalline hydrochlorides at
a ratio of 5:1. Pure hydrochloride 26 was isolated by
recrystallization from diethyl ether–ethanol, and alka-
line hydrolysis of 26 afforded 4β-amino-10β-pinan-3α-
ol (20) in an overall yield of 32% based on the initial
Z-oxime.
Amino alcohols (+)-5, (–)-5, 20, and 21 were tested
as chiral catalysts in the aldol reaction of acetone with
isatin 27 (Scheme 5) which is an important inter-
mediate product in the synthesis of a large number of
physiologically active compounds, including medicinal
agents [17]. The best results were obtained using
amino alcohol 21 as catalyst and toluene as solvent.
The yield of (R)-3-hydroxy-3-(2-oxopropyl)-1,3-dihy-
dro-1H-indole-2-one (28) was 95%, and the enantio-
selectivity was 82% (Table 3).
1
0
Me
Me
Me
Me
OH
H
OH
H
OH
H
OH
H
H
H
1
3
4
7
8
Me
H
H
Me
Me
OH
Me
H
Me
NH2
9
N
N
Me
Me
NH
2
Me
H
H
OH
2
5
24
21
20
Fig. 2. Nuclear Overhauser effects in molecules 20, 21, 24, and 25.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017

SYNTHESIS OF NEW ENANTIOMERICALLY PURE β-AMINO ALCOHOLS
339
Scheme 5.
O
O
O
HO
HO
O
Me
Me
+
+
O
O
O
Me
Me
N
N
N
H
H
H
2
7
R-28
S-28
In summary, new enantiomerically pure β-amino
alcohols have been synthesized on the basis of
α-pinene and shown to be promising as asymmetric
organocatalysts.
isatin (98%, Sigma–Aldrich), and LiBHEt (a 1 M so-
lution in THF, Alfa Aesar) were commercial products.
3
(+)-Verbenone (7, [α] = +228°, c = 1.0, EtOH),
D
(–)-verbenone (7, [α] = ‒210°, c = 1.0, EtOH) [10],
D
isopinocamphone (18) ([α] = –14.1, c = 1.2, EtOH)
D
EXPERIMENTAL
[18], trans-pinane-3,4-diol {22, [α] = +6°, c = 0.5,
D
EtOH, mp 149‒150°C; from (–)-verbenone} [19], and
GLC analyses were obtained on a Shimadzu GC-
010AF chromatograph using an HP1 column. The ee
3α-hydroxy-10β-pinan-4-one (23, [α] = +73.6°, c =
D
2
0.6, EtOH, mp 57‒58°C) [20] were synthesized ac-
values were determined with the aid of an HP-
CHIRAL-20B column (flame ionization detector,
carrier gas helium). The IR spectra were recorded from
thin films or KBr discs on a Shimadzu IR Prestige 21
instrument. The H and C NMR spectra were
measured on a Bruker Avance II 300 spectrometer at
cording to known methods.
X-Ray analysis was performed on an Xcalibur 3
automated four-circle diffractometer with a CCD
detector (Joint Center, Postovskii Institute of Organic
Synthesis, Ural Branch, Russian Academy of Sciences)
according to standard procedure [ω-scanning with
1
13
3
00 and 75 MHz, respectively, according to Bruker
a step of 1°; monochromatized Mo K radiation;
α
standard pulse sequences for one- and two-dimensional
experiments. The melting points were determined on
a Gallenkamp Sanyo melting point apparatus. The
optical rotations were measured with an PolAAr-
2
95(2) K]. A correction for absorption was applied
empirically. The structure was solved and refined using
OLEX2 [21]. The structure was determined by the
direct statistical method (SHELXS) and was refined
2
3
001Optical Activity automated polarimeter (UK).
against F by the full-matrix least-squares method in
HPLC analysis was performed using a chiral Chiralpak
AD-H column. The elemental analyses were obtained
on a EA 1110 CHNS-O automated analyzer.
anisotropic approximation for all non-hydrogen atoms
(
SHELXL) [22]. Hydrogen atoms attached to carbons
were placed in geometrically calculated positions and
refined in isotropic approximation. Anomalous scat-
tering effect was neglected.
Silica gel 60 (70–230 mesh, Alfa Aesar) was used
for column chromatography. Analytical TLC was per-
formed on Sorbfil plates; hexane and petroleum ether–
diethyl ether were used as eluents; spots were visual-
ized by treatment with a 10% phosphomolybdic acid in
ethanol, a 3% solution of vanillin in ethanol, or iodine
1,4-Conjugate reduction of verbenone (7) in the
system NaBH ‒NiCl ‒H O‒H BO . An emulsion of
4
2
2
3
3
verbenone (7) in an aqueous solution of NiCl ·6H O
2
2
was cooled to 0°C, sodium tetrahydridoborate was
added in portions with stirring over a period of 5‒
10 min (foaming!), and boric acid was then added in
vapor. (–)-α-Pinene (Acros, [α] = ‒42.7°, ee 83%),
D
(
+)-α-pinene (Alfa Aesar, [α] = +44.4°, ee 89%),
D
Table 3. Aldol condensation of isatin with acetone catalyzed by amino alcohols (+)-5, (−)-5, 20, and 21 (20 mol % of the
catalyst, 30 equiv of acetone, 2 equiv of water)
Catalyst
Solvent
Reaction time, h
Temperature, °C
Yield of 28, %
ee, %
Configuration
(
(
+)-5
−)-5
CH
CH
CH
CH
2
2
2
2
Cl
Cl
Cl
Cl
2
2
2
2
096
120
067
090
072
180
20
20
20
20
50
40
67
80
88
72
39
95
37
35
34
49
46
82
S
R
R
R
R
R
2
2
2
2
0
1
1
1
PhMe
PhMe
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017

3
40
FROLOVA et al.
portions. The mixture was stirred on cooling, and the
progress of the reaction was monitored by TLC. When
the reaction was complete, the mixture was saturated
with sodium chloride at room temperature and ex-
tracted with diethyl ether. The extract was washed with
residue was treated with 50 mL of water and extracted
with diethyl ether (3×15 mL). The aqueous phase was
diluted with 150 mL of water and adjusted to pH by
adding acetic acid. The precipitate was filtered off,
washed with water, and dried first in air and then in
a desiccator over anhydrous calcium chloride. Yield of
pure Z-oxime 14 70–75%, white powder, mp 135°C,
brine and dried over MgSO , the solvent was removed,
4
and the product mixture (yield 86–87%) was analyzed
by GLC and NMR (Table 1).
[α]
= ‒12.0° (c = 1.0, CHCl
), [α]−
= +11.9° (c = 1.0,
D
3
D
1
CHCl ). IR spectrum (KBr), ν, cm : 3235 (OH), 1719
3
Reduction of verbenone (7) in the system
1
(
C=O), 1690 (C=N). H NMR spectrum (DMSO-d ),
6
NaBH –NiCl –MeOH. Sodium tetrahydridoborate
4
2
δ, ppm: 0.95 s (3H, 8-Me), 1.31 d (3H, 10-Me, J =
was added in portions to a solution of verbenone (7)
and NiCl ·6H O in 40‒100 mL of methanol cooled to
7
9
5
3
.8 Hz), 1.34 d (1H, 7-H , J = 9.6 Hz), 1.36 s (3H,
-Me), 2.15 t.d (1H, 1-H, J = 5.9, 2.9 Hz), 2.53 t (1H,
ax
2
2
0
°C. The progress of the reaction was monitored by
-H, J = 5.4 Hz), 2.65 d.t (1H, 7-H , J = 11.6, 5.8 Hz),
eq
TLC. When the initial compound disappeared, the
mixture was filtered, the solvent was distilled off, the
residue was diluted with a small amount of water, and
the products were thoroughly extracted with diethyl
ether (one or two drops of concentrated aqueous HCl
was added to decompose the emulsion). The extract
.09 q.d (1H, 2-H, J = 7.1, 2.9 Hz), 12.33 br.s (1H,
1
3
NOH). C NMR spectrum (DMSO-d ), δ , ppm: 16.4
6
C
1
0
8
9
7
2
(
(
C ), 24.1 (C ), 27.4 (C ), 28.0 (C ), 36.2 (C ), 42.1
C ), 45.6 (C ), 56.5 (C ), 155.9 (C ), 198.8 (C ).
6
1
5
3
4
Found, %: C 66.35; H 8.39; N 7.68. C H NO . Cal-
10
15
2
culated, %: C 66.27; H 8.34; N 7.73.
1R,3S,4R,5R)- and (1S,3R,4S,5S)-3-Amino-
,6,6-trimethylbicyclo[3.1.1]heptan-2-one hydro-
was washed with brine and dried over MgSO , the
4
(
solvent was removed, and the residue (yield 88–94%)
was analyzed by GLC and NMR (Table 2).
4
chloride (16). Zinc dust, 5.89 g (90 mmol, 10 μm),
was added to a suspension of 5.44 g (30 mmol) of
oxime 14 in 25 mL of 30% aqueous sodium hydroxide.
When the exothermic reaction ceased (5 min), 70 mL
of diethyl ether was added, and the mixture was stirred
for 5 min. The organic phase was separated, and
the aqueous phase was extracted with diethyl ether
Oxidation of a mixture of cis-verbanone (6) and
neoisoverbanol (10) to cis-verbanone (6). Beck-
mann’s mixture (sodium dichromate in sulfuric acid),
1
5 mL, was added dropwise with stirring to 5 g of
mixture 6/10 in 50 mL of diethyl ether. The mixture
was refluxed for 2–3 h with stirring until alcohol 10
disappeared (TLC) and cooled, the organic layer was
separated, and the aqueous layer was extracted with
two portions of diethyl ether. The extracts were com-
bined with the organic phase, washed with a 5% solu-
tion of sodium hydrogen carbonate and with brine, and
(
2 ×30 mL). The extracts were combined with the
organic phase, washed with 20 mL of water and with
brine, dried over Na SO for 5 min, and filtered, and
2
4
7
.34 mL (33 mmol) of a 4.5 M solution of HCl in
diethyl ether was added to the filtrate. The precipitate
was filtered off, washed with diethyl ether (2×30 mL),
and dried under reduced pressure. Yield of trans-amino
ketone hydrochloride 87–93%, light red powder, de-
dried over MgSO , and the solvent was removed. Yield
4
9
0–92%, fraction of 6 97–98% (GLC). The product
was subjected to chromatography on silica gel;
(
(
+)-verbanone: [α] = +56.2 (c = 1.3, CHCl );
D 3
composition point 225‒230°C, [α] = ‒34.3° (c = 0.9,
D
–)-verbanone: [α] = ‒50.2 (c = 1.1, CHCl ). The
D
3
CHCl ), [α] = +33.7° (c = 1.2, CHCl ). IR spectrum
3
D
3
spectral data coincided with those reported in [23].
1R,4R,5R,Z)- and (1S,4S,5S,Z)-3-(Hydroxy-
imino)-4,6,6-trimethylbicyclo[3.1.1]heptan-2-one
14). A solution of 7.61 g (50 mmol) of verbanone in
0 mL of anhydrous THF was slowly added to a sus-
−1
+
3
(
KBr), ν, cm : 2877, 2924 (NH ), 1724 (C=O).
1
(
H NMR spectrum (DMSO-d ), δ, ppm: 1.04 s (3H,
6
8-Me), 1.30 d (3H, 10-Me, J = 7.6 Hz), 1.34 s (3H,
(
1
9-Me), 1.78 d (1H, 7H , J = 11.2 Hz), 2.11 t (1H, 1-H,
ax
J = 5.0 Hz), 2.25 quint (1H, 2-H, J = 6.8 Hz), 2.66 t
pension of 6.73 g (60 mmol) of potassium tert-but-
oxide in 20 mL of anhydrous THF, cooled to ‒80°C.
The mixture was stirred for 10 min, 7.03 g (60 mmol)
of isoamyl nitrite was added over a period of 20 min,
and the mixture was stirred, allowed to slowly warm
up to room temperature, and left overnight. The sol-
vent was distilled off under reduced pressure, and the
(1H, 5-H, J = 5.6 Hz), 2.65 d.d.d (1H, 7-H , J = 11.5,
eq
+
5.6, 5.0 Hz), 3.93 br.s (1H, 3-H), 8.74 br.s (3H, NH ).
3
1
3
10
C NMR spectrum (DMSO-d ), δ , ppm: 19.2 (C ),
6
C
8
9
7
2
6
24.8 (C ), 27.2 (C ), 29.7 (C ), 38.1 (C ), 41.3 (C ),
1
3
5
4
47.5 (C ), 57.6 (C ), 57.9 (C ), 207.0 (C ). Found, %:
C 58.91; H 8.97; N 6.82. C H ClNO. Calculated, %:
1
0
18
C 58.96; H 8.91; N 6.88.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017

SYNTHESIS OF NEW ENANTIOMERICALLY PURE β-AMINO ALCOHOLS
341
(
1R,2S,3S,4R,5R)- and (1S,2R,3R,4S,5S)-3-
(1S,3R,4S,5S,Z)-3-Hydroxy-4,6,6-trimethylbi-
cyclo[3.1.1]heptan-2-one oxime (24) and
(1S,3R,4S,5S,E)-oxime 25. A mixture of 2.75 g
(16 mmol) of hydroxy ketone 23, 2.51 g (23 mmol) of
sodium hydrogen carbonate, and 1.59 g (23 mmol) of
hydroxylamine hydrochloride, 20 mL of methanol, and
Amino-4,6,6-trimethylbicyclo[3.1.1]heptan-2-ol (5).
A solution of 1 g (9 mmol) of sodium carbonate in
mL of water was added to a solution of 0.611 g
3 mmol) of hydrochloride 16 in 15 mL of water, and
the mixture was extracted with diethyl ether
3×20 mL). The extract was dried over Na SO for
min and filtered, and the solvent was distilled off
under reduced pressure. The residue was dissolved in
mL of anhydrous THF, the solution was cooled to
80°C, and 3.3 mL (3.3 mmol) of a 1 M solution of
5
(
1
.5 mL of water was stirred for 7 h at 65‒67°C. The
(
5
2 4
mixture was cooled, 20 mL of water was added, and
the mixture was extracted with diethyl ether. The ex-
tract was washed with a 5% solution of NaHCO and
5
–
3
with brine and dried over MgSO . Yield quantitative,
4
Z/E-isomer ratio 42:58 (NMR). Column chromatog-
raphy on silica gel (petroleum ether–diethyl ether)
gave 1.18 g (39%) of Z isomer 24 and 1.64 g (54%) of
E isomer 25.
LiBHEt in THF was slowly added under argon. The
3
mixture was stirred for 3‒5 h, allowing it to warm up
to ‒20°C, 2 mL of 10% aqueous sodium hydroxide
was added, the mixture was heated to room tempera-
ture, 20 mL of water was added, and the mixture was
extracted with ethyl acetate (3×20 mL). The combined
extracts were washed with 20 mL of water and with
brine, dried over Na SO , filtered, and evaporated
under reduced pressure, and the residue was recrys-
tallized from diethyl ether–hexane at ‒20°C. Yield 60–
5%, white powder, mp 148‒149°C, [α] = +7.2° (c =
.9, CHCl ), [α] ‒7.0° (c = 1.1, CHCl ). IR spectrum
KBr), ν, cm : 3445, 3260 (NH ), 1605 (δNH ), 1344,
041 (C‒OH). H NMR spectrum (CDCl ), δ, ppm:
.73 d (1H, 7-H , J = 10.1 Hz), 1.11 s (3H, 8-Me),
.12 d (3H, 10-Me, J = 7.4 Hz), 1.24 s (3H, 9-Me),
.61 quint (1H, 2-H, J = 7.0 Hz), 1.81 t (1H, 1-H, J =
.4 Hz), 2.06 m (1H, 5-H), 2.35 d.t (1H, 7-H , J =
0.1, 6.3 Hz), 2.64 br.s (3H, NH , OH), 3.03 d.d (1H,
-H, J = 6.9, 5.7 Hz), 3.78 d.d (1H, 4-H, J = 5.2,
Z-Oxime 24. Thick oily material, R 0.64 (Et O),
f
2
–
1
[
3
α] = +9.1° (c = 0.5, EtOH). IR spectrum, ν, cm :
259 (OH), 1653 (C=N), 1037, 947. H NMR spec-
D
1
trum (DMSO-d ), δ, ppm: 0.77 s (3H, 8-Me), 1.14 d
6
2
4
(
(
3H, 10-Me, J = 7.4 Hz), 1.28 s (3H, 9-Me), 1.32 d
1H, 7-H, J = 9.1 Hz), 1.93 m (1H, 1-H), 1.99 m (1H,
2
-H), 2.49 m (1H, 5-H), 2.52 m (1H, 7-H), 4.45 d.d
6
0
(
D
(
1H, 3-H, J = 3.3, 3.1 Hz), 4.58 d (OH, J = 2.9 Hz),
3
D
3
1
3
−
1
10.62 s (1H, =NOH). C NMR spectrum (DMSO-d ),
δ , ppm: 20.3 (C ), 25.0 (C ), 26.8 (C ), 29.5 (C ), 40
C
(
(
6
2 2
1
0
8
9
7
1
1
0
1
1
5
1
3
2
3
6
2
1
5
3
C ), 43.2 (C ), 46.9 (C ), 48.0 (C ), 68.4 (C ), 163.1
ax
4
C ). Found, %: C 65.51; H 9.32; N 7.55.C H NO .
1
0
17
2
Calculated, %: C 65.54; H 9.35; N 7.64.
E-Oxime 25. Crystalline solid, R 0.41 (Et O),
f
2
eq
–
1
[
3
α] = ‒58.8° (c = 0.9, EtOH). IR spectrum, ν, cm :
D
2
1
296 (OH), 1653 (C=N), 974 (C‒OH). H NMR spec-
1
3
trum (DMSO-d ), δ, ppm: 0.79 s (3H, 8-Me), 1.12 d
6
.1 Hz). C NMR spectrum (CDCl ), δ , ppm: 19.8
3
C
1
0
8
9
7
6
(3H, 10-Me, J = 7.5 Hz), 1.30 s (3H, 9-Me), 1.42 d
(1H, 7-H, J = 9.7 Hz), 1.90 d.d (1H, 1-H, J = 5.9,
(
(
%
C ), 24.0 (C ), 28.8 (C ), 32.4 (C ), 38.2 (C ), 46.5
2
1
5
3
4
C ), 48.5 (C ), 56.5 (C ), 61.0 (C ), 82.2 (C ). Found,
5
(
5
.5 Hz), 1.97 d.q (1H, 2-H, J = 7.5, 2.8 Hz), 2.38 d.d.d
1H, 7-H, J = 9.7, 5.9, 5.6 Hz), 3.38 d.d (1H, 5-H, J =
.6, 5.5 Hz), 4.01 d.d (1H, 3-H, J = 3.5, 2.8 Hz), 5.07 d
: C 70.95; H 11.33; N 8.25. C H NO. Calculated,
: C 70.96; H 11.31; N 8.28.
X-Ray diffraction data: C H NO, M 169.26;
orthorhombic crystal system, space group P2 22 ; unit
cell parameters: a = 8.5417(9), b = 11.1175(14), c =
10 19
%
13
1
0
19
(OH, J = 3.5 Hz), 10.2 s (=NOH). C NMR spectrum
10
8
9
1
1
(
DMSO-d ), δ , ppm: 20.2 (C ), 24.8 (C ), 27.2 (C ),
6 C
7
6
5
2
1
2
8.2 (C ), 40.7 (C ), 41.6 (C ), 44.6 (C ), 47.1 (C ),
3
3
4
1
0
1.1386(8) Å; V = 1057.75(19) Å ; Z = 4; μ(MoK ) =
α
71.7 (C ), 162.9 (C ).
–
1
.068 mm . Total of 2992 reflection intensities were
measured, including 1506 independent reflections
Rint = 0.0439). Final divergence factors: R = 0.1160,
Hydrochloride 26. A solution of 1.08 g (5.9 mmol)
of compound 24 in 15 mL of anhydrous diethyl ether
was added dropwise with stirring in an inert atmo-
sphere to a suspension of 0.672 g (17.6 mmol) of
(
1
wR = 0.2070 (all reflections); R = 0.0620, wR =
2
1
2
0
1
.1544 [reflections with I > 2σ(I)]; goodness of fit
.003; Δρ 0.19/‒0.19 ēÅ .
LiAlH in 50 mL of anhydrous diethyl ether. The
–3
4
ē
mixture was stirred for 6 h at 32‒34°C, cooled, and left
overnight. The mixture was then treated dropwise with
5% aqueous sodium hydroxide until it divided into
layers, the organic layer was separated, and the aque-
ous layer was extracted with diethyl ether (3×25 mL).
2
-{(1S,3S)-3-[(E)-1-(Hydroxyimino)ethyl]-2,2-di-
methylcyclobutyl}acetic acid (19). Physicochemical
and crystallographic characteristics of 19 were in
agreement with published data [16].
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017

3
42
FROLOVA et al.
The extracts were combined with the organic phase,
left overnight. It was then treated with 5% aqueous
sodium hydroxide until it divided into layers, the ether
layer was separated, and the aqueous layer was extract-
ed with diethyl ether (3×25 mL). The extracts were
combined with the organic phase, washed with brine,
washed with brine, and dried over MgSO , and the
4
solvent was removed to leave 0.858 g (87%) of an oily
material which contained compounds 20 and 21 at
a ratio of 7:2 (according to the NMR data). The prod-
uct was dissolved in 5 mL of diethyl ether, 1.25 mL
and dried over MgSO . After removal of the solvent,
4
(
5.6 mmol) of a 4.5 M solution of HCl in Et O was
the crystalline residue, 1.024 g (90%) contained com-
pounds 20 and 21 at a ratio of 1:5 (according to the
NMR data). The product was recrystallized twice from
diethyl ether–ethanol. Yield of pure (NMR) amino
alcohol 21 0.511 g (45% based on initial oxime 25),
[α] = +41.3° (c = 0.5, CHCl ), mp 78–80°C. IR spec-
2
added, and the precipitate was filtered off under
reduced pressure, and recrystallized from diethyl
ether–ethanol. Yield of pure (according to the NMR
data) hydrochloride 26 0.576 g (68%), mp 220°C
(
decomp.), [α] = +7.9° (c = 0.5, EtOH). IR spectrum,
D
D
3
–
1
+
3
–1
ν, cm : 3232, 2964, 1525 (NH ), 1053 (C‒OH).
trum, ν, cm : 3354, 3280 (NH ), 1577 (NH ), 1053
2 2
1
1
H NMR spectrum (DMSO-d ), δ, ppm: 0.94 d (7-H,
(C‒OH). H NMR spectrum (DMSO-d ), δ, ppm:
6
6
J = 9.8 Hz), 1.05 s (3H, 8-Me), 1.09 d (3H, 10-Me, J =
0.94 s (3H, 8-Me), 1.06 d (3H, 10-Me, J = 7 Hz),
1.04 d (1H, 7-H, J = 10 Hz), 1.22 s (3H, 9-Me), 1.67‒
1.75 m (2H, 1-H, 2-H), 1.97 m (1H, 5-H), 2.08 m (1H,
7-H), 3.30 d.d.d (1H, 4-H, J = 8.2, 4.8, 3.5 Hz),
7
5
5
6
.2 Hz), 1.22 s (3H, 9-Me), 1.78 d.d (1H, 1-H, J = 5.6,
.3 Hz), 1.85 m (1H, 2-H, J = 7.2 Hz), 1.83 d.d (1H,
-H, J = 6.7, 5.3 Hz), 2.45 d.d.d (1H, 7-H, J = 9.8, 6.7,
.3 Hz), 3.28 d.d (1H, 4-H, J = 5.4, 4.9 Hz), 3.91 d.d
1
3
3.63 d.d (1H, 3-H, J = 8.2, 5.3 Hz). C NMR spectrum
1
0
8
(
1H, 3-H, J = 6.3, 6.2 Hz), 8.30 br.s (3H, NH ).
(DMSO-d ), δ , ppm: 21.37 (C ), 23.52 (C ), 28.29
3
10
6 C
1
3
9
7
6
2
1
C NMR spectrum (DMSO-d ), δ , ppm: 19.87 (C ),
(C ), 28.67 (C ), 39.4 (C ), 46.76 (C ), 47.55 (C ),
49.45 (C ), 51.19 (C ), 70.5 (C ).
6
C
8
9
7
6
5
4
3
2
(
4.97 (C ), 28.48 (C ), 33.75 (C ), 38.20 (C ), 44.67
C ), 45.51 (C ), 47.73 (C ), 62.25 (C ), 74.16 (C ).
2
5
1
4
3
Aldol reaction of isatin with acetone catalyzed
by amino alcohols (+)-5, (–)-5, 20, and 21. Isatin (27),
0.018 g (0.122 mmol), was mixed with amino alcohol
catalyst, 0.0041 g (0.0242 mmol), 2 equiv of water was
added, and a solution of 0.3 mL of acetone in 1.2 mL
of appropriate solvent was then added. The progress of
the reaction was monitored by TLC. When the reaction
was complete, the solvent was distilled off, and the
residue was subjected to chromatography on neutral
aluminum oxide using petroleum ether (decreasing
amount), ethyl acetate, and methanol as eluents. The
enantiomeric purity of 3-hydroxy-3-(2-oxopropyl)-1,3-
dihydro-1H-indol-2-one (28) was analyzed by HPLC.
Its spectral characteristics coincided with those given
in [24].
(
1S,2R,3R,4S,5S)-2-Amino-4,6,6-trimethylbi-
cyclo[3.1.1]heptan-3-ol (20). Hydrochloride 26, was
dissolved in 5 mL of water, 3 mL of 10% aqueous
potassium hydroxide was added, and the mixture was
stirred and extracted with diethyl ether (3×25 mL).
The combined extracts were washed with brine, dried
over MgSO , and evaporated. Yield 0.32 g (32% based
on initial oxime 24), [α] = +4.6° (c = 0.4, CHCl ),
mp 92‒93°C. IR spectrum, ν, cm : 3323, 3251 (NH ),
593 (NH ), 1072 (OH). H NMR spectrum
4
D
3
–
1
2
1
1
(
1
1
1
2
DMSO-d ), δ, ppm: 0.82 d (1H, 7-H, J = 9.6 Hz),
6
.05 s (3H, 8-Me), 1.06 d (3H, 10-Me, J = 7.0 Hz),
.21 s (3H, 9-Me), 1.70‒1.80 m (2H, 1-H, 2-H),
.83 d.d.d (1H, 5-H, J = 6.8, 6.3, 1.8 Hz), 2.29 d.d.d
(
1H, 7-H, J = 9.6, 6.5, 6.3 Hz), 2.95 d.d (1H, 4-H, J =
This study was performed under financial support
by the Russian Foundation for Basic Research
(project no. 15-03-09352A) using the equipment of the
Chemistry Joint Center (Institute of Chemistry, Komi
Scientific Center, Ural Branch, Russian Academy of
Sciences) and Spectroscopy and Analysis of Organic
Compounds Center (Postovskii Institute of Organic
Synthesis, Ural Branch, Russian Academy of
Sciences).
5
.3, 1.8 Hz), 3.57 d.d (1H, 3-H, J = 6.3, 5.3 Hz).
1
3
10
C NMR spectrum (DMSO-d ), δ , ppm: 20.46 (C ),
6
C
8
9
7
6
2
5.05 (C ), 29.35 (C ), 33.96 (C ), 38.75 (C ), 45.33
2
1
5
4
3
(
C ), 48.57 (C ), 49.52 (C ), 63.83 (C ), 80.45 (C ).
Found, %: C 70.90; H 11.37; N 8.95. C H NO.
1
0
19
Calculated, %: C 70.95; H 11.35; N 8.27.
1S,2S,3R,4S,5S)-2-Amino-4,6,6-trimethylbi-
cyclo[3.1.1]heptan-3-ol (21). A solution of 1.23 g
6.7 mmol) of compound 25 in 15 mL of anhydrous
(
(
diethyl ether was added dropwise with stirring in
an inert atmosphere to a suspension of 0.766 g
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017

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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017