Chiral blocks for the synthesis of cyclopentanoids from [2+2]-cycloadduct of dichloroketene and dimethylfulvene

Article abstract of DOI:10.1134/S1070428012030190

Opening of the α,α-dichlorocyclobutanone ring in the [2 + 2]-cycloadduct of dichloroketene and dimethylfulvene with (+)-α- methylbenzylamine gave diastereoisomeric 2-dichloromethyl-5-isopropylidene- N-(α-methylbenzyl)cyclopent-3-ene-1-carboxamides, and hy

Full text of DOI:10.1134/S1070428012030190

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 3, pp. 442–450. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © N.A. Ivanova, N.P. Akhmetdinova, Z.R. Valiullina, V.A. Akhmet’yanova, O.V. Shitikova, A.N. Lobov, K.Yu. Suponitskii,
L.V. Spirikhin, M.S. Miftakhov, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 3, pp. 442–449.
Chiral Blocks for the Synthesis of Cyclopentanoids
from [2+2]-Cycloadduct of Dichloroketene and Dimethylfulvene
N. A. Ivanovaa, N. P. Akhmetdinovaa, Z. R. Valiullinaa, V. A. Akhmet’yanovab, O. V. Shitikovac,
A. N. Lobova, K. Yu. Suponitskiid, L. V. Spirikhina, and M. S. Miftakhova
a Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: bioreg@anrb.ru
b Bashkir State University, Ufa, Bashkortostan, Russia
c Ufa State Academy of Economics and Servises, Ufa, Bashkortostan, Russia
d Nesmeyanov Institute of Organometallic Compounds, Russian Academy of Sciences,
ul. Vavilova 28, Moscow, 119991 Russia
Received April 19, 2011
Abstract—Opening of the α,α-dichlorocyclobutanone ring in the [2+2]-cycloadduct of dichloroketene and
dimethylfulvene with (+)-α-methylbenzylamine gave diastereoisomeric 2-dichloromethyl-5-isopropylidene-
N-(α-methylbenzyl)cyclopent-3-ene-1-carboxamides, and hydrolysis of the latter at the dichloromethyl group
afforded the corresponding bicyclic aminals which can be readily separated by chromatography on silica gel.
The subsequent removal of the α-methylbenzylamine fragment via reduction and hydrolysis resulted in the
formation of enantiomerically pure (–)- and (+)-6-(1-methylethylidene)-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]-
furan-1-ones.
DOI: 10.1134/S1070428012030190
Chiral polyfunctionalized cyclopentane blocks are
used in the synthesis of biologically active cyclopen-
tanoids such as prostaglandins, cyclopentenone anti-
biotics, carbanucleosides, and their analogs [1–3].
Gimazetdinov et al. [4] recently synthesized individual
enantiomeric lactones II from racemic [2+2]-cyclo-
adduct I of dichloroketene and cyclopentadiene [5] by
the action of (+)- or (–)-α-methylbenzylamine and sub-
sequent chromatographic separation of diastereoiso-
mers and their transformation.
With a view to obtain new enantiomerically pure
vicinally substituted cyclopentenone blocks A we
performed analogous reaction sequence with racemic
bicyclic compound III. As might be expected, opening
of the strained dichlorocyclobutanone ring in III
readily occurred by the action of (+)-α-methylbenzyl-
amine with formation of a mixture of chromatographi-
cally indistinguishable (TLC) diastereoisomeric amides
IVa and IVb at a ratio of 1:1 (according to the 1H NMR
data). Hydrolysis of amides IVa and IVb at the di-
chloromethyl group on heating in a boiling 1.5:1 mix-
ture of acetonitrile with water containing barium oxide
gave 50% of lactams Va and Vb (Scheme 1). The yield
of compounds Va and Vb considerably increased
(87%; conversion 82%) when the reaction was carried
out using sodium hydrogen carbonate instead of
barium oxide. Unlike amides IVa and IVb, bicyclic
lactams Va and Vb were characterized by appreciably
different Rf values (TLC), and they were readily
separated by column chromatography on silica gel.
Thus the cyclization of the hydrolysis products of
amides IVa and IVb gave only two diastereoisomeric
O
O
O
O
O
+
Cl
Cl
(±)-I
(–)-II
(+)-II
Me
Me
O
R1
O
*
*
Cl
R2
Cl
(±)-III
A
442

CHIRAL BLOCKS FOR THE SYNTHESIS OF CYCLOPENTANOIDS
443
Scheme 1.
Me
Me
Me
Me
Me
O
O
Me
Me
Me
O
O
Ph
Ph
Me
Me
N
N
i
·
H
H
+
+
93%
Cl
CHCl2
CHCl2
IVb
Cl
Cl
Cl
(±)-III
IVa
Me
Me
Me
Me
O
O
Me
Ph
Me
Ph
ii or iii
+
N
N
50 or 87%
3a
3
OH
(–)-Va
OH
(+)-Vb
[α]D20 = –75.1°
[α]D20 = +87°
Me
Me
Me
Me
O
O
Me
iv
v
Ph
(–)-Va
N
O
75%
89%
H
CH2OH
(–)-VIa
(–)-VIIa
[α]D20 = –328.6°
[α]D20 = –309.2°
Me
Me
Me
O
Me
O
Me
iv
v
Ph
(+)-Vb
N
H
O
75%
89%
CH2OH
(+)-VIb
(+)-VIIb
[α]D20 = +207.1°
[α]D20 = +375.6°
i: (+)-α-PhCH(Me)NH2, anhydrous PhH, 24 h; ii: BaO, MeCN–H2O, 76°C, 5 h; iii: NaHCO3, MeCN–H2O, 76°C, 6 h (conversion
82%); iv: NaBH4, dioxane–H2O, Δ, 8 h (conversion 93%); v: 1 N H2SO4–THF, Δ, 5 h.
2'
Me
Me
Me
Me
1'
Me
Me
Me
Me
O
O
O
O
H
H
H
H
6
1
Me
1''R
Me
1''R
Me
Ph
Me
6aR
6aS
5
N2
N
N
N
3aR
3aS
3S
3R
Ph
Ph
Ph
4
H
H
H
H
OH
(–)-Va
OH
(+)-Vb
OH
(–)-Vc
OH
(+)-Vd
for the 3a-H and 6a-H protons in the bridgehead posi-
tions, J3a,6a = 6.8 and 6.7 Hz, respectively, indicated
lactams Va and Vb among four theoretically possible
structures Va–Vd.
3
cis-junction of the five-membered rings. Analysis of
signal multiplicity, specifically the lack of coupling
between 3-H and 3a-H (3J3a,3 ≈ 0 Hz) and the absence
of cross peak for these protons in the HH-COSY
spectrum, showed that the dihedral angle H3aC3aC3H3
approaches 90°; this means that the 3-H and 3a-H
protons are oriented trans with respect to each other.
The structure of lactams Va and Vb was determined
by 1H and 13C NMR spectroscopy with the use of two-
dimensional HH-COSY [6, 7] and HETCOR [8] cor-
relation techniques, as well as by quantum-chemical
calculations; in addition, the structure of lactam Va
1
was proved by X-ray analysis. In the H NMR spectra
of Va and Vb the vicinal spin–spin coupling constant
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

IVANOVA et al.
mate the contribution of each rotamer to the overall
444
E0, a.u.
–902.944
–902.946
–902.948
–902.950
–902.952
–902.954
–902.956
–902.958
chemical shifts. Two local energy minima were found
(a)
for each structure Va and Vb (Fig. 1), and the corre-
1
sponding H and 13C chemical shifts were calculated
by the gauge-invariant atomic orbital method (GIAO)
1
[9] in the same approximation. The calculated H and
13C chemical shifts averaged according to the Boltz-
mann distribution are given in Tables 1 and 2.
1
We also estimated differences Δδ in the H and 13C
chemical shifts of diastereoisomers Va and Vb and
found considerable Δδ values for some nuclei, in par-
ticular Δδ = 0.18 (5-H), 0.50 (3-H), –0.06 (6a-H), and
+sc
–60
–sc
1
–0.17 ppm (1″-Me) in the H NMR spectra (Table 1)
–180
–120
0
60
120
180
(b)
and ΔδC = 1.62 (Ci), –0.54 (C3), –0.83 (C3a), and
–1.66 ppm (1″-Me) in the 13C NMR spectra (Table 2).
Good agreement between the experimental and cal-
culated Δδ values in both sign and magnitude was
observed for 3-H, 5-H, and 6a-H (Table 1) and Ci and
1″-Me (Table 2), which confirmed the assignment of
structures of lactams Va and Vb.
φ(C1N2C1″Ci), deg
E0, a.u.
–902.944
–902.946
–902.948
–902.950
–902.952
–902.954
–902.956
–902.958
Finally, the absolute configurations of the chiral
centers in lactams Va and Vb was determined by X-ray
analysis of compound Va. Single crystals of Va suit-
able for X-ray analysis were obtained by slow crystal-
lization from petroleum ether–ethyl acetate (4 :1).
A unit cell of Va in crystal includes two molecules A
and A′ which slightly differ by orientation of the sub-
stituent on the nitrogen atom, the conformation of the
bicyclic fragment being the same (Figs. 2, 3). This
difference may be described by the torsion angle
C3N2C1''Ci which is close to 90° (80.7° in molecule A
and 85.4° in A′). The angle between the planes of the
five-membered rings in the bicyclic fragment is 65.12°
(A) and 64.61° (A′), indicating cis-junction of the
cyclopentene and pyrrolidine rings (analogous conclu-
sion was drawn on the basis of the 1H NMR spectra of
Va and Vb; see above). The cyclopentene ring
C3aC4C5C6C6a (C3a′C4′C5′C6′C6a′) is planar, whereas the
heteroring adopts a flattened half-chair conformation
with the C3 (C3′) and C3a (C3a′) atoms deviating by
0.125 (0.126) and 0.171 (0.137) Å, respectively, in the
opposite directions with respect to the plane formed by
the remaining atoms C6aC1N2 (C6a′C1′N2′); the C3 (C3′)
atom is oriented anti relative to the carbocycle. Mole-
cules A and A′ in a unit cell are linked through rela-
tively strong intermolecular hydrogen bonds between
the hydroxy group of one molecule and carbonyl group
of the other, O2–H2···O1 (O···O 2.866, H···O 2.03 Å,
∠OHO 166°); as a result, chains parallel to the b axis
are formed (Fig. 4).
+sc
–60
φ(C1N2C1″Ci), deg
–ac
120
–180
–120
0
60
180
Fig. 1. Dependence of the potential energy of conformers of
(a) Va and (b) Vb on the torsion angle C1N2C1″Ci
Therefore, both lactams Va and Vb have a structure
with anti orientation of the carbocycle and OH group
relative to the lactam ring plane.
Quantum-chemical calculations of the proposed
structures (PRIRODA 06 software [9]; PBE/3ζ approx-
imation [10, 11]) allowed us to estimate the energies of
most favorable conformations of each diastereoisomer
and calculate the corresponding H and 13C chemical
1
shifts. The phenyl group in the α-position with respect
to the nitrogen atom in lactams Va and Vb is magneti-
cally anisotropic and is therefore capable of differently
shielding (or deshielding) neighboring protons and
carbon nuclei [12]. Taking into account that orientation
of the phenyl group (and magnetic anisotropy cone)
is determined by the angle of its rotation about the
N2–C1″ bond, the potential energies of all possible rota-
mers were calculated in the PBE/3ζ approximation by
varying the dihedral angle C1N2C1″Ci in order to esti-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

CHIRAL BLOCKS FOR THE SYNTHESIS OF CYCLOPENTANOIDS
445
1
Table 1. Experimental and calculated H NMR chemical
shifts of lactams Va and Vb
Taking into account the X-ray diffraction data for
lactam Va and (R)-configuration of initial α-methyl-
benzylamine, the chiral centers in isomer Va were as-
signed (1″R,3S,3aR,6aR)-configuration. Correspond-
ingly, (1″R,3R,3aS,6aS)-configuration was assigned to
second diastereoisomer Vb.
δcalc,a ppm
δexp, ppm
Atom
no.
Va
Vb
Δδ
Va
Vb
Δδ
1″-Me 1.66
1′-Me 1.89
C2″H3 2.12
1.63
0.03
1.51
1.68 –0.17–
1.84 –0.02–
2.06 –0.03–
The anti orientation of the hydroxy group and
carbocycle in molecules Va and Vb was indirectly
confirmed by the reaction of racemic compound
(±)-III with benzylamine. Opening of the cyclobutane
ring and subsequent cyclization gave no more than
20% of cis isomer IXa (3J3,3a = 7.0 Hz) (Scheme 2).
1.90 –0.01– 1.82
2.16 –0.04– 2.03
3a-H
6a-H
3-H
3.45
3.88
5.17
5.22
5.90
6.57
3.35
3.96 –0.08– 3.88
4.43 0.75 5.14
5.66 –0.44– 5.29
0.10
3.26
3.25
3.94 –0.06–
4.64 0.50
5.30 –0.01–
0.01
1″-H
4-H
5.60
6.52
0.30
0.05
6.38
5.78
6.36
5.60
0.02
0.18
Scheme 2.
5-H
Me
Me
O
Me
Me
a
δcalc = ∑ni·δi, where ni is the population according to the Boltz-
O
Ph
N
mann distribution.
i
H
87%
Table 2. Experimental and calculated 13C NMR chemical
shifts of lactams Va and Vb
Cl
CHCl2
Cl
(±)-III
(±)-VIII
Me
δC, calc,a ppm
δC, exp, ppm
Atom
no.
Me
Me
Me
Va
Vb
ΔδC
Va
Vb
ΔδC
O
O
1″-Me 019.02 019.53 –0.51– 017.05 018.71 –1.66–
ii
C6a
C1″
C3a
C3
C4
C5
C6
Ci
053.62 053.14 0.48 046.90 046.98 –0.08–
059.92 057.66 2.26 049.95 050.22 –0.27–
063.95 063.78 0.17 052.84 053.67 –0.83–
096.68 096.11 0.57 083.84 084.38 –0.54–
138.44 138.40 0.04 133.01 132.60 0.41
139.45 139.17 0.28 130.63 130.81 –0.18–
146.61 146.88 –0.27– 135.63 135.63 0.00
151.08 148.29 2.79 141.44 139.82 1.62
177.03 175.59 1.44 174.82 174.78 0.04
+
N
N
Ph
Ph
H
H
OH
OH
IXb, 66%
IXa, 16%
i: PhCH2NH2, anhydrous PhH, 24 h; ii: NaHCO3, MeCN–
H2O, 76°C, 6 h (conversion 85%).
Individual lactams Va and Vb turned out to be
resistant to hydrolysis under standard acidic or alkaline
conditions. Therefore, they were initially reduced with
sodium tetrahydridoborate, and subsequent acid hy-
drolysis [13] of hydroxymethyl amides VIa and VIb
gave expected lactones VIIa and VIIb.
C1
a
δcalc = ∑ni·δi, where ni is the population according to the Boltz-
mann distribution.
300.13 and 75.47 MHz, respectively, using CDCl3 as
solvent and reference (CHCl3, δ 7.27 ppm; CDCl3,
δC 77.00 ppm). The optical rotations were determined
on a Perkin Elmer 241 MC polarimeter. The mass
spectra (electron impact, 70 eV) were obtained on
a Thermo Finnigan MAT 95XP instrument (ion source
temperature 200°C). HPLC analysis was performed on
a Shimadzu LC-20 instrument equipped with a diode
array detector (λ 215 nm) and a Bondapak Phenyl col-
umn (300×3.9 mm, grain size 5 μm); eluent aceto-
nitrile–water (60:40). The progress of reactions was
monitored by thin-layer chromatography using Sorbfil
plates; spots were detected by treatment with a 10%
New enantiomerically pure bicyclic lactones VIIa
and VIIb can be used to obtain vicinally substituted
cyclopentenone blocks via oxidative cleavage of the
exocyclic double bond. The results of our studies on
building up enone fragment in lactones VIIa and VIIb
will be the subject of separate publication.
EXPERIMENTAL
The IR spectra were recorded on a Shimadzu IR
Prestige-21 spectrometer from films or samples dis-
1
persed in mineral oil. The H and 13C NMR spectra
were measured on a Bruker AM-300 spectrometer at
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

IVANOVA et al.
perature in an argon atmosphere to a solution of 5.42 g
446
′
C2
(25.0 mmol) of cycloadduct III in 140 ml of anhydrous
benzene. The mixture was stirred for 7 h, and the
precipitate was filtered off and washed with cold
petroleum ether to isolate 0.59 g of minor isomer IVa.
The filtrate was concentrated, and the precipitate was
filtered off and washed with cold petroleum ether to
isolate 7.26 g of a mixture of diastereoisomers IVa and
IVb. Overall yield 7.85 g (93%), colorless crystals,
mp 180–181°C, Rf 0.30 (petroleum ether–ethyl acetate,
8:2). IR spectrum, ν, cm–1: 3319 (NH), 3051, 3035,
1631 (C=O), 1452 (C=C), 1381, 749, 693.
O1
C1
′
C1
C6
C6a
C1″
C5
C4
N2
C3
Ci
C3a
O2
Fig. 2. Structure of the molecule of (3aR,6aR)-3-hydroxy-6-
(1-methylethylidene)-2-[(1R)-1-phenylethyl]-3,3a,6,6a-tetra-
hydrocyclopenta[c]pyrrol-1(2H)-one (Va) according to the
X-ray diffraction data.
(1R,2R)-2-Dichloromethyl-5-(1-methylethyli-
dene)-N-[(1R)-1-phenylethyl]cyclopent-3-ene-1-car-
boxamide (IVa). Colorless crystals, mp 181–182°C,
[α]D20 = +201.3° (c = 0.97, CH2Cl2), Rf 0.30 (petroleum
ether–ethyl acetate, 8:2). IR spectrum, ν, cm–1: 3324
(NH), 3057, 3030, 1633 (C=O), 1544, 1452 (C=C),
O1
′
C2
Ci
1
C1″
C1
1377, 744, 692. H NMR spectrum, δ, ppm: 1.45 d
3
N2
′
(3H, 1″-Me, J = 6.8 Hz), 1.57 s and 1.81 s (3H each,
C1
C6a
3
C6
C5
Me), 3.74 d (1H, 1-H, J1,2 = 8.2 Hz), 3.87 d (1H, 2-H,
3
3J2,1 = 8.2 Hz), 5.09 q (1H, 1″-H, J = 6.8 Hz), 6.03 d
C3
C3a
3
3
(1H, NH, J = 7.1 Hz), 6.10 d (1H, 1′′′-H, J1′′′,2
=
O2
3
5.1 Hz), 6.31 d (1H, 4-H, J4,3 = 5.7 Hz), 6.62 d.d (1H,
C4
3
3
3-H, J3,2 = 2.6, J3,4 = 5.7 Hz), 7.27–7.37 m (5H, Ph).
13C NMR spectrum, δC, ppm: 20.99 (1″-Me), 21.22
(Me), 21.72 (Me), 48.98 (C1″), 51.15 (C1), 59.35 (C2),
73.24 (C1′′′), 126.25 (Cm), 126.39 (C1′), 127.46 (Co),
128.61 (Cp), 131.73 (C4), 133.50 (C3), 137.51 (C5),
142.35 (Ci), 168.59 (C=O). Found, %: C 63.98;
H 6.15; Cl 20.88; N 4.09. C18H21Cl2NO. Calculated,
%: C 63.91; H 6.26; Cl 20.96; N 4.14.
Fig. 3. Superposition of the structures of symmetry-inde-
pendent molecules A (solid lines) and A′ (dashed lines) of
compound Va in crystal.
a
c
(1S,2S)-2-Dichloromethyl-5-(1-methylethyli-
dene)-N-[(1R)-1-phenylethyl]cyclopent-3-ene-1-car-
0
′
H2
′
O1
′
O2
1
H2
O1
O2
boxamide (IVb). H NMR spectrum,* δ, ppm: 1.50 d
3
(3H, 1″-Me, J = 6.7 Hz), 1.62 s and 1.69 s (3H each,
3
b
Me), 3.72 d (1H, 1-H, J1,2 = 8.3 Hz), 3.86 br.s (1H,
2-H), 5.10 q (1H, 1″-H, 3J = 6.7 Hz), 6.05 m (1H, NH),
3
6.11 d (1H, 1′′′-H, J1′′′,2 = 5.0 Hz), 6.23 d (1H, 4-H,
3
3
3J4,3 = 5.3 Hz), 6.62 d.d (1H, 3-H, J3,2 = 2.4, J3,4
=
5.3 Hz), 7.20–7.50 m (5H, Ph). 13C NMR spectrum,*
δC, ppm: 21.07 (1″-Me), 21.23 (Me), 21.69 (Me),
48.96 (C1″), 51.20 (C1), 59.60 (C2), 73.22 (C1′′′), 126.95
(C1′), 127.53 (Cm), 128.60 (Co), 129.11 (Cp), 131.70
(C4), 133.47 (C3), 137.66 (C5), 142.39 (Ci), 168.67
(C=O).
Fig. 4. A fragment of crystal packing of (3aR,6aR)-3-hy-
droxy-6-(1-methylethylidene)-2-[(1R)-1-phenylethyl]-
3,3a,6,6a-tetrahydrocyclopenta[c]pyrrol-1(2H)-one (Va).
solution of 4-methoxybenzaldehyde in ethanol con-
taining sulfuric acid [14].
2-Dichloromethyl-5-(1-methylethylidene)-
N-[(1R)-1-phenylethyl]cyclopent-3-ene-1-carbox-
amide (IVa/IVb). A solution of 8.9 ml (70.0 mmol) of
(+)-α-methylbenzylamine in 50 ml of anhydrous ben-
zene was added dropwise under stirring at room tem-
Hydrolysis of amides IVa/IVb. a. A solution of
0.14 g (0.89 mmol) of barium oxide in 4 ml of water
was added under stirring to a solution of 0.30 g
* From the NMR spectrum of isomer mixture IVa/IVb.
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CHIRAL BLOCKS FOR THE SYNTHESIS OF CYCLOPENTANOIDS
447
(0.89 mmol) of amide mixture IVa/IVb in 12 ml of
acetonitrile. The mixture was stirred for 6 h on heating
under reflux, diluted with chloroform, washed with
10% hydrochloric acid to pH 7, and extracted with
chloroform (3×50 ml). The combined extracts were
washed with a saturated solution of sodium chloride,
dried over Na2SO4, and concentrated. The residue was
subjected to column chromatography on silica gel
using methylene chloride–methanol (150:1) as eluent.
Yield of lactams Va and Vb 0.14 g (50%), mixture of
two diastereoisomers at a ratio of 55:45 (HPLC).
133.01 (C4), 135.63 (C6), 141.44 (Ci), 174.82 (C1).
Mass spectrum, m/z (Irel, %): 265 (100) [M – H]+, 250
(61) [M – Me]+, 188 (9) [M – Ph]+, 161 (15), 146
(46), 145 (23), 105 (37). Found, %: C 76.32; H 7.44;
N 4.98. C18H21NO2. Calculated, %: C 76.29; H 7.47;
N 4.94.
X-Ray analysis of compound Va. Colorless crys-
tals. C18H21NO2. M 283.36. Monoclinic crystal system;
unit cell parameters (100 K): a = 8.4161(8), b =
7.8851(7), c = 22.412(2) Å; β = 90.810(2)°; V =
1487.2(2) Å3; space group P21; Z = 4; dcalc = 1.266 g×
cm–3. Total of 17520 reflection intensities were meas-
ured on a Bruker SMART APEX II diffractometer at
100 K (λMoKα irradiation, θmax = 28.73°) and were
processed using SAINT and SADABS programs
(APEX2 software package) [15]. The structure was
solved by the direct method and was refined against
F2hkl by the full-matrix least-squares procedure in aniso-
tropic approximation for non-hydrogen atoms. Hydro-
gen atoms (except for OH hydrogen) were placed into
positions calculated on the basis of geometry con-
siderations. Hydrogen atom in the hydroxy group was
localized by difference synthesis of electron density,
and the O–H distance was then normalized to a value
of 0.85 Å. The positions of hydrogen atoms were
refined according to the riding model [Uiso(H) =
nUeq(C, O), where n = 1.5 for methyl carbon atoms and
oxygen atoms and n = 1.2 for other carbon atoms;
4116 independent reflections with Rint = 0.0925 were
involved]. The final divergence factors were wR2 =
0.1143 (all independent reflections), R1 = 0.0556
[2669 reflections with I > 2σ(I)]. All calculations were
performed on an IBM PC using SHELXTL software
package [16]. The complete set of crystallographic
data was deposited to the Cambridge Crystallographic
Data Centre (entry no. CCDC 810360) and is available
at www.ccdc.cam.ac.uk/data_request/cif.
b. A solution of 0.54 g (6.40 mmol) of sodium
hydrogen carbonate in 5 ml of water was added under
stirring to a solution of 0.72 g (2.13 mmol) of amide
mixture IVa/IVb in 55 ml of acetonitrile, heated to
60°C. The mixture was stirred for 30 min on heating
under reflux (until gaseous products no longer evolved),
a solution of 0.90 g (10.71 mmol) of NaHCO3 in 8 ml
of water was added in two portions in a 30-min inter-
val, and the mixture was heated for 2 h under reflux.
The mixture was then diluted with chloroform, washed
with 10% hydrochloric acid to pH 7, and extracted
with chloroform (3×100 ml). The combined extracts
were washed with a saturated solution of sodium
chloride, dried over Na2SO4, and concentrated, and the
residue was subjected to column chromatography on
silica gel using methylene chloride–methanol (150:1)
as eluent to isolate 0.53 g (87%; conversion 82%) of
a mixture of lactams Va and Vb at a ratio of 55:45
(HPLC). Pure diastereoisomers Va and Vb were
isolated by column chromatography on silica gel;
gradient elution with petroleum ether–ethyl acetate
(30:1 to 8:2).
(3aR,6aR)-3-Hydroxy-6-(1-methylethylidene)-2-
[(1R)-1-phenylethyl]-3,3a,6,6a-tetrahydrocyclo-
penta[c]pyrrol-1(2H)-one (Va). Colorless crystals,
mp 106–107°C, Rf 0.33 (petroleum ether–ethyl acetate,
8:2, double elution), [α]D20 = −75.1° (c = 1.0, CHCl3).
IR spectrum, ν, cm–1: 3402 (OH), 3064, 1668 (C=O),
1656 (C=C), 1480, 1375, 1280, 1082, 810, 758.
(3aS,6aS)-3-Hydroxy-6-(1-methylethylidene)-2-
[(1R)-1-phenylethyl)]-3,3a,6,6a-tetrahydrocyclo-
penta[c]pyrrol-1(2H)-one (Vb). Colorless crystals,
mp 106–107°C, Rf 0.20 (petroleum ether–ethyl acetate,
8:2, double elution), [α]D20 = +87.0° (c = 1.0, CHCl3).
IR spectrum, ν, cm–1: 3402 (OH), 3064, 1668, 1656
3
1H NMR spectrum, δ, ppm: 1.51 d (3H, 1″-Me, J =
7.1 Hz), 1.82 s (3H, 1′-Me), 2.03 s (3H, C2′H3),
3
2.23 br.s (1H, OH), 3.26 d.d.d (1H, 3a-H, J3a,5 = 2.1,
1
3
3
3J3a,4 = 2.3, J3a,6a = 6.8 Hz), 3.88 d (1H, 6a-H, J6a,3a
=
(C=O), 1480, 1375, 1280, 1082, 810, 758. H NMR
3
3
spectrum, δ, ppm: 1.68 d (3H, 1″-Me, J = 7.1 Hz),
6.8 Hz), 5.14 d (1H, 3-H, J3,OH = 4.1 Hz), 5.29 q (1H,
1.84 s (3H, 1′-Me), 2.06 s (3H, C2′H3), 2.33 br.m (1H,
3
4
1″-H, J = 7.1 Hz), 5.78 d.d (1H, 5-H, J5,3a = 2.1,
3
3
3J5,4 = 5.6 Hz), 6.38 d.d (1H, 4-H, J4,3a = 2.3, J4,5
=
3
3
OH), 3.25 d.d.d (1H, 3a-H, J3a,5 = 2.1, J3a,4 = 2.3,
3J3a,6a = 6.7 Hz), 3.94 d (1H, 6a-H, J6a,3a = 6.7 Hz),
3
5.6 Hz), 7.26–7.44 m (5H, Ph). 13C NMR spectrum, δC,
ppm: 17.05 (1″-Me), 21.31 (Me), 22.62 (Me), 46.90
(C6a), 49.95 (C1″), 52.85 (C3a), 83.84 (C3), 127.34 (Co),
127.84 (Cp), 128.51 (C1′), 128.89 (Cm), 130.63 (C5),
3
4.64 d (1H, 3-H, J3,OH = 7.3 Hz), 5.30 q (1H, 1″-H,
3J = 7.1 Hz), 5.60 d.d (1H, 5-H, J5,3a = 2.1, J5,4
=
4
3
3
3
6.7 Hz), 6.36 d.d (1H, 4-H, J4,3a = 2.3, J4,5 = 6.7 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

IVANOVA et al.
448
7.22–7.35 m (5H, Ph). 13C NMR spectrum, δC, ppm:
18.71 (1″-Me), 21.30 (Me), 22.59 (Me), 46.98 (C6a),
50.22 (C1″), 53.67 (C3a), 84.38 (C3), 127.39 (Co),
127.45 (Cp), 128.26 (C1′), 128.44 (Cm), 130.81 (C5),
132.60 (C4), 135.63 (C6), 139.82 (Ci), 174.84 (C1).
Mass spectrum, m/z (Irel, %): 265 (100) [M – H]+, 250
(61) [M – Me]+, 188 (9) [M – Ph]+, 161 (15), 146 (46),
145 (23), 105 (37). Found, %: C 76.32; H 7.44;
N 4.98. C18H21NO2. Calculated, %: C 76.29; H 7.47;
N 4.94.
161°C, Rf 0.35 (petroleum ether–ethyl acetate, 1:1,
double elution), [α]D20 = +207.1° (c = 1.0, CHCl3). IR
spectrum, ν, cm–1: 3251, 3244 (NH, OH), 3057, 3030,
1
1633 (C=O), 1544, 1454, 1377, 743, 790. H NMR
3
spectrum, δ, ppm: 1.46 d (3H, 1″-Me, J = 7.0 Hz),
1.51 s (3H, 1′-Me), 1.79 s (3H, C2′H3), 3.49–3.62 m
3
(2H, 2-CH2), 3.74 d (1H, 1-H, J1,2 = 9.8 Hz), 3.84 d
3
(1H, OH, J = 7.8 Hz), 4.02 d (1H, 2-H, J2,1 = 9.8 Hz),
3
5.18 q (1H, 1″-H, J = 7.2 Hz), 5.69 d (1H, 4-H, 3J4,3
=
5.7 Hz), 6.27 d (1H, NH, J = 7.5 Hz), 6.46 d.d (1H,
3
3
3-H, J3,2 = 2.1, J3,4 = 5.7 Hz), 7.24–7.37 m (5H, Ph).
13C NMR spectrum, δC, ppm: 20.99 (1″-Me), 21.41
(Me), 21.57 (Me), 48.67 (C2), 51.28 (C1″), 52.68 (C1),
63.37 (2-CH2), 126.01 (Cp), 127.54 (C4, C1′), 128.71
(Cm), 131.34 (Co), 134.84 (C3), 138.42 (C5), 142.72 (Ci),
172.00 (C=O). Found, %: C 75.80; H 8.09; N 4.95.
C18H23NO2. Calculated, %: C 75.76; H 8.12; N 4.91.
(1R,2R)-2-Hydroxymethyl-5-(1-methylethyli-
dene)-N-[(1R)-(1-phenylethyl)]cyclopent-3-ene-
1-carboxamide (VIa). A solution of 0.68 g
(17.28 mmol) of sodium tetrahydridoborate in 8 ml of
water was added in four portions under stirring to
a solution of 0.18 g (0.64 mmol) of lactam Va in 18 ml
of dioxane–water (12:1), heated to 65°C, and the
mixture was heated for 5 h under reflux. The mixture
was diluted with chloroform, washed with 10% hydro-
chloric acid to pH 7, and extracted with chloroform
(3×40 ml). The combined extracts were washed with
a saturated solution of sodium chloride, dried over
Na2SO4, and concentrated. The residue was purified by
column chromatography on silica gel using petroleum
ether–ethyl acetate (9:1) as eluent. Yield 0.13 g (75%),
conversion 93%. Colorless crystals, mp 159–161°C,
Rf 0.40 (petroleum ether–ethyl acetate, 1:1, double
elution), [α]D20 = −328.6° (c = 1.0, CHCl3). IR spec-
trum, ν, cm–1: 3251, 3244 (NH, OH), 3057, 3030, 1633
(3aR,6aR)-6-(1-Methylethylidene)-3,3a,6,6a-
tetrahydro-1H-cyclopenta[c]furan-1-one (VIIa).
Compound VIa, 0.31 g (1.09 mmol), was dissolved in
5 ml of tetrahydrofuran, 4.5 ml of 1 N H2SO4 was
added dropwise under stirring, and the mixture was
stirred for 1 h on heating under reflux. The mixture
was diluted with chloroform, washed with a saturated
solution of sodium hydrogen carbonate to pH 5, and
extracted with chloroform (3×50 ml). The combined
extracts were washed with a saturated solution of
sodium chloride, dried over Na2SO4, and concentrated,
and the residue was purified by chromatography on
silica gel using petroleum ether–ethyl acetate (9:1) as
eluent. Yield 0.16 g (89%), colorless crystals, mp 79–
81°C, Rf 0.60 (petroleum ether–ethyl acetate, 1:1,
double elution), [α]D20 = −309.2° (c = 1.0, CHCl3). IR
spectrum, ν, cm–1: 1753 (C=O), 1462, 1377, 1168, 991,
800. 1H NMR spectrum, δ, ppm: 1.83 s and 1.99 s (3H
each, Me), 3.70–3.79 m (2H, 3a-H, 6a-H), 4.21 d.d
1
(C=O), 1544, 1454, 1377, 743, 790. H NMR spec-
3
trum, δ, ppm: 1.46 d (3H, 1″-Me, J = 7.0 Hz), 1.72 s
(3H, 1′-Me), 1.87 s (3H, C2′H3), 3.33 d (1H, 1-H,
3J1,2 = 9.8 Hz), 3.48 m (1H, 2-H), 3.62 d.t (1H, 2-CH2,
2
3J1′′′, 2 = 3.3, J = 10.8 Hz), 3.88 d (1H, OH, J =
8.8 Hz), 3.95 d (1H, 2-CH2, 2J = 10.1 Hz), 5.19 q (1H,
3
3
1″-H, J = 7.2 Hz), 5.72 d (1H, 4-H, J4,3 = 5.4 Hz),
3
3
2
6.34 d (1H, NH, J = 8.0 Hz), 6.44 d.d (1H, 3-H, J3,2
=
(1H, 3-HA, J3A,3a = 1.8, J = 9.1 Hz), 4.44 d.d (1H,
2.6, J3,4 = 5.4 Hz), 7.22–7.35 m (5H, Ph). 13C NMR
spectrum, δC, ppm: 21.10 (1″-Me), 21.62 (Me), 21.62
(Me), 48.49 (C2), 51.27 (C1″), 52.70 (C1), 63.14 (C1′′′),
125.98 (C4, C1′), 127.37 (Cp), 127.45 (Cm), 128.69 (Co),
131.25 (C4), 134.97 (C3), 138.65 (C5), 142.67 (Ci),
172.01 (C=O). Mass spectrum, m/z (Irel, %): 267 (100)
[M − H]+, 163 (25), 148 (18), 119 (62), 105 (82), 91
(26). Found, %: C 75.80; H 8.09; N 4.95. C18H23NO2.
Calculated, %: C 75.76; H 8.12; N 4.91.
3
3
2
3-HB, J3B,3a = 7.1, J = 9.1 Hz), 5.81 d (1H, 4-H,
3J4,5 = 5.6 Hz), 6.42 d.d (1H, 5-H, J5,6a = 1.7, J5,4
=
4
3
5.6 Hz). 13C NMR spectrum, δC, ppm: 22.19 (Me),
22.33 (Me), 45.01 (C6a), 45.74 (C3a), 70.95 (C3),
129.10 (C6), 132.42 (C4), 132.69 (C5), 134.66 (C1′),
177.45 (C1). Mass spectrum, m/z (Irel, %): 164 (78)
[M − H]+, 149 (13), 119 (100), 105 (95), 91 (75).
Found, %: C 73.19; H 7.33. C10H12O2. Calculated, %:
C 73.15; H 7.37.
(1S,2S)-2-Hydroxymethyl-5-(1-methylethyli-
dene)-N-[(1R)-(1-phenylethyl)]cyclopent-3-ene-1-
carboxamide (VIb) was synthesized in a similar way
from 0.30 g (1.06 mmol) of lactam Vb. Yield 0.17 g
(70%), conversion 89%. Colorless crystals, mp 159–
(3aS,6aS)-6-(1-Methylethylidene)-3,3a,6,6a-
tetrahydro-1H-cyclopenta[c]furan-1-one (VIIb) was
synthesized in a similar way from 0.30 g (1.09 mmol)
of compound VIb. Yield 0.16 g (88%), colorless crys-
tals, mp 79–81°C, Rf 0.58 (petroleum ether–ethyl
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

CHIRAL BLOCKS FOR THE SYNTHESIS OF CYCLOPENTANOIDS
449
acetate, 1:1, double elution), [α]D20 = +375.6° (c = 1.0,
CHCl3). IR spectrum, ν, cm–1: 1753 (C=O), 1462,
1377, 1168, 991, 800. H NMR spectrum, δ, ppm:
jected to column chromatography on silica gel using
methylene chloride–methanol (150:1) as eluent to
isolate 0.23 g (82%) of a mixture of diastereoisomeric
lactams IXa and IXb at a ratio of 1:4 (1H NMR);
conversion 85%. Pure diastereoisomers IXa and IXb
were isolated by column chromatography on silica gel;
gradient elution with petroleum ether–ethyl acetate
(30:1 to 8:2).
1
1.84 s and 2.01 s (3H each, Me), 3.71–3.80 m (2H,
3
2
3a-H, 6a-H), 4.23 d.d (1H, 3-HA, J3A,3a = 1.8, J =
3
2
9.3 Hz), 4.43 d.d (1H, 3-HB, J3B,3a = 7.2, J = 9.3 Hz),
3
5.82 d (1H, 4-H, J4,5 = 5.6 Hz), 6.43 d.d (1H, 5-H,
3J5,6a = 1.7, J5,4 = 5.6 Hz). 13C NMR spectrum, δC,
3
ppm: 21.20 (Me), 22.35 (Me), 45.02 (C6a), 45.74 (C3a),
70.95 (C3), 129.07 (C6), 132.42 (C4), 132.72 (C5),
134.67 (C1′), 177.45 (C1). Mass spectrum, m/z (Irel, %):
164 (78) [M − H]+, 149 (13), 119 (100), 105 (95), 91
(75). Found, %: C 73.19; H 7.33. C10H12O2. Calculat-
ed, %: C 73.15; H 7.37.
(3S,3aS)-2-Benzyl-3-hydroxy-6-(1-methylethyli-
dene)-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrol-
1(2H)-one (IXa). Colorless crystals, mp 111–113°C,
Rf 0.24 (petroleum ether–ethyl acetate, 8:2, triple
elution). IR spectrum, ν, cm–1: 3400 (OH), 3053, 1663,
1
1665, 1480, 1377, 1278, 1080, 809. H NMR spec-
trum, δ, ppm: 1.85 s (3H, C2′H3), 1.95 d (1H, OH, 3J =
11.6 Hz), 2.08 s (3H, 1′-Me), 3.71–3.79 m (2H, 3a-H,
N-Benzyl-2-dichloromethyl-5-(1-methylethyli-
dene)cyclopent-3-ene-1-carboxamide (VIII). A solu-
tion of 0.75 ml (3.32 mmol) of benzylamine in 4 ml of
anhydrous benzene was added dropwise under stirring
at room temperature in an argon atmosphere to a solu-
tion of 0.33 g (1.52 mmol) of racemic adduct (±)-III in
7 ml of anhydrous benzene. The mixture was stirred
for 5 h, and the precipitate was filtered off and washed
with cold pentane. Yield 0.43 g (87%). Colorless crys-
tals, mp 138–140°C, Rf 0.49 (petroleum ether–ethyl
acetate, 8:2, double elution). IR spectrum, ν, cm–1:
3324 (NH), 3057, 3030, 1645 (C=O), 1620, 1551, 749,
2
6a-H), 4.10 d and 4.82 d (1H each, PhCH2, J =
3
3
14.6 Hz), 5.08 d.d (1H, 3-H, J3,3a = 7.0, J3,OH
=
=
4
3
11.6 Hz), 5.81 d.d (1H, 4-H, J4,6a = 1.7, J4,5
3
3
5.6 Hz), 6.58 d.d (1H, 5-H, J5,3a = 1.9, J5,4 = 5.6 Hz),
7.28–7.35 m (5H, Ph). 13C NMR spectrum, δC, ppm:
21.47 (Me), 22.79 (Me), 43.19 (C1″), 47.76 (C6a), 48.10
(C3a), 81.95 (C3), 127.50 (C5), 127.61 (Cp), 128.59 (Cm,
Co), 129.72 (C1′), 135.48 (C4), 136.01 (Ci), 136.49
(C6), 172.70 (C1). Found, %: C 75.85; H 7.07; N 5.25.
C17H19NO2. Calculated, %: C 75.81; H 7.11; N 5.20.
1
710. H NMR spectrum, δ, ppm: 1.62 s (3H, 1′-Me),
1.75 s (3H, C2′H3), 3.73 m (1H, 1-H), 3.82 m (1H,
(3R,3aS)-2-Benzyl-3-hydroxy-6-(1-methylethyli-
dene)-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrol-
1(2H)-one (IXb). Colorless crystals, mp 123–124°C,
Rf 0.15 (petroleum ether–ethyl acetate, 8:2, triple
elution). IR spectrum, ν, cm–1: 3400 (OH), 3053, 1663,
2-H), 4.21 d.d (1H, 1″-HA, 3J1″A,NH = 3.8, 2J = 14.8 Hz),
3
2
4.47 d.d (1H, 1″-HB, J1″B,NH = 5.3, J = 14.8 Hz),
3
6.03 d (1H, CHCl2, J = 5.1 Hz), 6.20 d (1H, 4-H,
3J4,3 = 6.0 Hz), 6.42 m (1H, NH), 6.56 d.d (1H, 3-H,
1
3J3,2 = 1.6, J3,4 = 6.0 Hz), 7.19–7.34 m (5H, Ph).
3
1665, 1480, 1377, 1278, 1080, 809. H NMR spec-
trum, δ, ppm: 1.63 s (3H, 1′-Me), 1.85 s (3H, C2′H3),
13C NMR spectrum, δC, ppm: 20.62 (2C, Me), 43.23
(C1″), 50.40 (C1), 59.69 (C2), 73.93 (CHCl2), 126.40
(C1′), 126.72 (Cp), 127.54 (Co), 128.35 (Cm), 131.72
(C4), 133.53 (C3), 137.24 (C5), 137.44 (Ci), 170.52
(C=O). Found, %: C 63.03; H 5.87; Cl 21.93; N 4.27.
C17H19Cl2NO. Calculated, %: C 62.97; H 5.91;
Cl 21.87; N 4.32.
3
2.68 d (1H, OH, J = 5.5), 3.37 d.d.d (1H, 6a-H,
4
3
4J6a,5 = 2.1, J6a,4 = 2.2, J6a,3a = 7.0 Hz), 3.95 d (1H,
3
3a-H, J3a,6a = 7.0 Hz), 4.26 d and 4.81 d (1H each,
PhCH2, J = 15.1 Hz), 4.83 d (1H, 3-H, J3,OH
5.5 Hz), 5.75 d.d (1H, 4-H, J4,6a = 2.2, J4,5 = 5.6 Hz),
2
3
=
4
3
4
3
6.41 d.d (1H, 5-H, J5,6a = 2.1, J5,4 = 5.6 Hz), 7.17–
7.32 m (5H, Ph). 13C NMR spectrum, δC, ppm: 21.17
(Me), 22.46 (Me), 42.98 (C1″), 46.72 (C6a), 52.76
(C3a), 84.61 (C3), 127.15 (C5), 127.45 (Cm), 128.13
(C1′), 128.38 (Co), 131.02 (Cp), 132.31 (C4), 135.42
(Ci), 136.14 (C6), 175.09 (C1). Found, %: C 75.85;
H 7.07; N 5.25. C17H19NO2. Calculated, %: C 75.81;
H 7.11; N 5.20.
Hydrolysis of amide VIII. A solution of 1.03 g
(4.29 mmol) of NaHCO3 in 12 ml of water was added
in three portions in 30-min intervals under stirring to
a solution of 0.40 g (1.23 mmol) of amide VIII in
30 ml of acetonitrile, heated to 60°C, and the mixture
was heated for 2 h under reflux. The mixture was
diluted with chloroform, washed with 10% hydro-
chloric acid to pH 7, and extracted with chloroform
(3×50 ml). The combined extracts were washed with
a saturated solution of sodium chloride, dried over
Na2SO4, and concentrated, and the residue was sub-
This study was performed under financial support
by the Ministry of Education and Science of the Rus-
sian Federation (state contract no. 4.740.11.0367) and
by the Bashkir State University .
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IVANOVA et al.
9. Laikov, D.N. and Ustynyuk, Yu.A., Izv. Ross. Akad.
450
REFERENCES
Nauk, Ser. Khim., 2004, p. 804.
1. Johnson, C.R. and Chen, Y.F., J. Org. Chem., 1991,
10. Perdew, J.P., Burke, K., and Ernzerhof, M., Phys. Rev.
Lett., 1996, vol. 77, p. 3865.
vol. 56, p. 3344.
2. Ferrier, R.Y., Chem. Rev., 1993, vol. 93, p. 2779.
11. Laikov, D.N., Chem. Phys. Lett., 1997, vol. 281, p. 151.
3. Moon, H.R., Choi, W.J., and Kim, H.O., Tetrahedron:
Asymmetry, 2002, vol. 13, p. 1189.
12. Seco, J.M., Quinoa, E., and Riguera, R., Chem. Rev.,
2004, vol. 104, p. 17.
4. Gimazetdinov, A.M., Vostrikov, N.S., and Miftakhov, M.S.,
13. Edwards, M.P., Ley, S.V., Lister, S.G., Palmer, B.D., and
Tetrahedron: Asymmetry, 2008, vol. 19, p. 1094.
Williams, D.J., J. Org. Chem., 1984, vol. 49, p. 3503.
5. Ghosez, L., Montaigne, R., and Roussel, A., Tetrahedron,
1971, vol. 27, p. 615.
6. Nagayama, K., Kumar, A., Wuthrich, K., and Ernst, R.R.,
14. Kirchner, J.G., Thin-Layer Chromatography, Perry, E.S.,
Ed., New York: Wiley, 1978, 2nd ed. Translated under
the title Tonkosloinaya khromatografiya, Moscow: Mir,
1981, vol. 1, p. 228.
J. Magn. Reson., 1980, vol. 40, p. 321.
15. APEX2, SAINT, Madison, Wisconsin, USA: Bruker
7. Aue, W.P., Bartholdi, E., and Ernst, R.R., J. Chem. Phys.,
AXS, 2005.
1976, vol. 64, p. 2229.
8. Bax, A. and Morris, G.A., J. Magn. Reson., 1981, vol. 42,
16. Sheldrick, G.M., Acta Crystallogr., Sect. A, 2008,
p. 501.
vol. 64, p. 112.
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