Synthesis of PDE IVb inhibitors. 3. Synthesis of (+)-, (-)-, and (±)-7-[3-(cyclopentyloxy)-4-methoxyphenyl]hexahydro-3 H -pyrrolizin-3-one via reductive domino transformations of 3-β-carbomethoxyethyl-substituted six-membered cyclic nitronates

Article abstract of DOI:10.1021/jo300955n

Simple three-step asymmetric and racemic syntheses of GlaxoSmithKline's highly potent PDE IVb inhibitor 1 were developed. The suggested approach is based on reductive domino transformations of 3-β-carbomethoxyethyl- substituted six-membered cyclic nitronates, which are easily accessed by a stereoselective [4 + 2] cycloaddition of an appropriate nitroalkene to vinyl ethers. In vitro studies of PDE IVb inhibition by enantiomeric pyrrolizidinones (+)-1 and (-)-1 were performed.

Full text of DOI:10.1021/jo300955n

Note
pubs.acs.org/joc
Synthesis of PDE IVb Inhibitors. 3. Synthesis of (+)-, (−)-, and ( )-7-[3-
(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one
via Reductive Domino Transformations of 3-β-Carbomethoxyethyl-
Substituted Six-Membered Cyclic Nitronates
Alexey Yu. Sukhorukov,*,† Yaroslav D. Boyko,† Yulia V. Nelyubina,‡ Stephane Gerard,§ Sema L. Ioffe,†
and Vladimir A. Tartakovsky†
†N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991, Leninsky prosp. 47, Moscow, Russia
‡A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991, Vavilov str., 28, Moscow, Russia
§Institut de Chimie Molec
ulaire de Reims, UMR CNRS 6229, Universite de Reims-Champagne-Ardenne, Faculte de Pharmacie, 51
́ ́ ́
rue Cognacq-Jay, F-51096 Reims Cedex, France
S
* Supporting Information
ABSTRACT: Simple three-step asymmetric and racemic
syntheses of GlaxoSmithKline’s highly potent PDE IVb
inhibitor 1 were developed. The suggested approach is based
on reductive domino transformations of 3-β-carbomethox-
yethyl-substituted six-membered cyclic nitronates, which are
easily accessed by a stereoselective [4 + 2] cycloaddition of an
appropriate nitroalkene to vinyl ethers. In vitro studies of PDE
IVb inhibition by enantiomeric pyrrolizidinones (+)-1 and
(−)-1 were performed.
7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrro-
lizin-3-one (1; Scheme 1) is a highly potent second-generation
phosphodiesterase (PDE) IVb inhibitor considered as a drug
candidate for the treatment of respiratory disorders such as
asthma and chronic obstructive pulmonary disease (COPD).1
Pyrrolizidinone 1 is several times more potent than the
standard PDE IVb inhibitor Rolipram and the recently
introduced anti-inflammatory drug Cilomilast.1a However, the
biological activity of the pyrrolizidinone’s 1 enantiomers still
remains unknown. To perform full-scale biological studies, an
efficient asymmetric synthesis of pyrrolizidinone 1 on a
preparative scale is needed.
Previously, several approaches to the total synthesis of
racemic1a,2b and enantiomerically pure2a,c pyrrolizidinone 1
were suggested. The major disadvantages of all these methods
are low overall yield and large number of synthetic steps
(minimum six steps for racemic 1 and seven steps for
enantiomers) as well as low stereoselectivity on key stages. In
the present work, a simple, scalable, three-step synthesis of the
racemate and both enantiomers of pyrrolizidinone 1 from
available precursors was developed.
lactamization of D to give pyrrolizidinone 1. Furthermore, in
order to get the desired diastereomer of product 1, the
reduction of the CN bond should occur trans stereoselective
with respect to the substituent at C-4 of nitronate 2.3
Cyclic nitronates 2 can be assembled by a Lewis acid
catalyzed [4 + 2] cycloaddition of nitroalkene 3 to the
corresponding vinyl ether according to Denmark’s procedure.4
Nitroalkene 3 in turn can be obtained by Henry condensation
of commercially available 3-(cyclopentyloxy)-4-methoxybenzal-
dehyde and methyl 4-nitrobutyrate (Scheme 2). To obtain the
target product 1 asymmetrically, it is necessary to incorporate a
chiral auxiliary in nitronate 2 by employing an optically pure
vinyl ether on the cycloaddition step. It is known that the vinyl
ether of trans-2-phenylcyclohexanol produces the correspond-
ing nitronates in [4 + 2] cycloaddition reactions with high
stereocontrol.2c,4a,c,5 Indeed, the reaction of nitroalkene 3 with
racemic trans-1-phenyl-2-(vinyloxy)cyclohexane in the presence
of SnCl4 gave the corresponding cyclic nitronate rac-2a in 63%
yield (Scheme 2). Only two of the four possible stereoisomers
were formed with predominance of isomer 2a (ratio 2a/2a′ =
8.3:1). The isomers can be easily separated by flash
chromatography or crystallization. The structure and stereo-
chemistry (4S*,6S*,7S*,8R*) of major isomer 2a was
established by X-ray crystallographic analysis (Figure 1,
We speculated that the target molecule 1 may result from a
reductive domino transformation of the C-3-functionalized six-
membered cyclic nitronate 2 shown in Scheme 1. This
multistage process should involve the reduction of the nitronate
fragment to an amino group, fragmentation of the resulting
semiacetal A into aldehyde B, cyclization of intermediate B to
pyrroline C, reduction of C to pyrrolidine D, and finally
Received: May 10, 2012
Published: May 30, 2012
© 2012 American Chemical Society
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Note
To explore the possibility of the transformation 2 → 1 and to
optimize this process, the reduction of nitronate 2a under
various conditions was studied (Scheme 3, Table 1).
Scheme 1. Proposed Reductive Domino Transformation of
Nitronates 2
As can be seen from Table 1, nitronate 2a did not react with
conventional N−O bond reducing agents such as zinc and
sodium dithionite (entries 1 and 2). However, under catalytic
hydrogenation conditions nitronate 2a usually produced
pyrrolizidinone 1 in good to high yields. The stereoselectivity
of the reduction process depended on the nature of the catalyst.
Thus, the hydrogenation of nitronate 2a with Raney nickel led
to a mixture of diastereomeric products 1 and 1′ with a slight
predominance of the second isomer (entry 3, Table 1).
Supported palladium and rhodium catalysts also afforded
mixtures of 1 and 1′ in a similar ratio (entries 4−6 and 8,
Table 1). The most efficient catalyst in terms of stereo-
selectivity and yield of target product proved to be the Adams
catalyst (entry 7, Table 1). Hydrogenation of nitronate 2a with
Wilkinson’s catalyst produced a multicomponent mixture of
products rather than the desired pyrrolizidinone 1 (entry 9,
Table 1).
To perform asymmetric synthesis of pyrrolizidinone 1,
optically pure cyclic nitronates (+)-2a and (−)-2a were
prepared from nitroalkene 3 and available (+)- and (−)-trans-
1-phenyl-2-(vinyloxy)cyclohexanes, respectively (Scheme 2).
The nitronates (+)-2a and (−)-2a were isolated by
crystallization with high diastereomeric purity (de > 99%).
The catalytic hydrogenation of each enantiomer (+)-2a or
(−)-2a in acetic acid with the Adams catalyst (entry 7, Table 1)
afforded pyrrolizidinones 1 + 1′ in high yield (75%) and
stereoselectivity (ca. 7:1).7 Diastereomerically pure products
(+)-1 and (−)-1 were isolated by flash chromatography of
reaction mixtures. As a result, pyrrolizidinone (−)-(7S,7aS)-1
was obtained from nitronate (+)-2a, and pyrrolizidinone
(+)-(7R,7aR)-1 was prepared from nitronate (−)-2a. All
physicochemical characteristics of products (+)-1 and (−)-1
were consistent with literature data.1a,2 It should be noted that
enantiopure (+)- and (−)-trans-2-phenylcyclohexanols were
recovered after hydrogenation in 90% yield (Scheme 3).
The developed process was employed for the synthesis of
racemic pyrrolizidinone 1 on a preparative scale (Scheme 4). In
this synthesis racemic cyclic nitronate 2b was prepared by
SnCl4-promoted [4 + 2] cycloaddition of nitroalkene 3 to ethyl
vinyl ether. Subsequent hydrogenation of nitronate 2b with
Adams catalyst provided a mixture of racemic pyrolizidinones 1
and 1′ in a 4.5:1 ratio and 81% yield (Scheme 4). The pure
diastereomer rac-1 could be isolated by flash chromatography
and crystallization. Hydrogenation of nitronate 2b with Adams
catalyst in MeOH led to pyrrolizidinone 1 with the same
stereoselectivity, but considerably less yield (57%).
Scheme 2. Synthesis of Nitronates 2a
The sequence shown in Scheme 4 was successfully tested on
12.5 g of nitroalkene 3 (ca. 15 grams of nitronate 2b was
hydrogenated at once). As a result, ca. 5.5 g of pure rac-1 (47%
yield from nitroalkene 3) was obtained. For the catalytic
hydrogenation only 2% mass of PtO2 was used, and 98% of the
platinum was recovered.
Thus, the target PDE IVb inhibitor 1 was synthesized in only
three steps in overall yields of 28% (for enantiomers (+)-1 and
(−)-1) and 38% (for racemate rac-1) starting from
commercially available precursors (methyl 4-nitrobutyrate and
3-(cyclopentyloxy)-4-methoxybenzaldehyde). The best pre-
vious syntheses afforded enantiopure 1 in 16% yield (seven
steps2c) and rac-1 in 23% yield (six steps2b).
Supporting Information).6 The minor nitronate 2a′ according
to NMR also has a 4,6-trans configuration of stereocenters in
the 1,2-oxazine ring, thus being a facial isomer of 2a.
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Note
Scheme 3. Reduction of Racemic and Chiral Nitronates 2a
Table 1. Optimization of Nitronate’s 2a Reduction
most rapid method for the construction of a pyrrolizine scaffold
which is present in many natural and bioactive molecules.
Pyrrolizidinone (−)-(7S,7aS)-1 was shown to be a more potent
PDE IVb inhibitor than its enantiomer (+)-(7R,7aR)-1.
yield of 1 +
1/1′
a
a
entry
cat.
reduction conditions
1′, %
ratio
b
1
2
Zn, EtOH, reflux
n.r.
b
Na2S2O4, EtOH, H2O,
reflux
n.r.
EXPERIMENTAL SECTION
■
3
4
5
6
7
8
9
Ra−Ni
20 bar H2, 50−60 °C,
65
58
92
55
77
52
1.0:1.5
1.4:1.0
1.0:2.3
1.7:1.0
7.0:1.0
1.8:1.0
1D and 2D NMR spectra were recorded at room temperature in
CDCl3. The chemical shifts (1H, 13C) are given in ppm (δ) relative to
the solvent signal.8 Multiplicities are indicated by s (singlet), d
(doublet), t (triplet), q (quadruplet), m (multiplet), and br (broad).
The numbering of atoms in products 2a,a′,b and 3 is given in the
Supporting Information. HRMS were measured on a electrospray
ionization (ESI) instrument with a time-of-flight (TOF) detector.
Concentrations c in the optical rotation angles are given in g/100 mL.
Analytical thin-layer chromatography was performed on silica gel
plates with QF-254. Visualization was accomplished with UV light, a
solution of FeCl3 in aqueous hydrochloric acid, or a solution of
anisaldehyde/H2SO4 in ethanol. Catalytic hydrogenations were carried
out in a steel autoclave with external stirring and heating. Flash
chromatography was performed using Kieselgel 40−60 μm 60A silica
gel. Glacial acetic acid was recrystallized two times. CH2Cl2 (technical
grade) and ethyl vinyl ether were redistilled from CaH2. Hexane, ethyl
acetate, diethyl ether, toluene, ethanol, and methanol were distilled
without drying agents. Racemic, (+)-trans-, and (−)-trans-1-phenyl-2-
(vinyloxy)cyclohexanes were synthesized from commercially available
racemic, (+)-trans-, and (−)-trans-2-phenylcyclohexanols (>98% ee)
according to known procedures.2c Adams catalyst (PtO2), Raney
nickel (50% slurry in water), palladium on activated carbon (5% Pd),
palladium on γ-Al2O3 (0.5% Pd), palladium on calcium carbonate (5%
Pd, 3.5% Pb), rhodium on activated alumina (5% Rh), and
Rh(PPh3)3Cl were purchased from commercial sources. PDE IVb
activity was monitored by using a PDE assay kit (Enzo) adapted to
human recombinant phosphodiesterase isoform PDE IVb expressed in
E. coli (for details see the Supporting Information).
CH3OH, 2 h
5% Pd/C
25 bar H2, 50−60 °C,
CH3OH, 6 h
0.5% Pd/Al2O3
20 bar H2, 60−70 °C,
EtOH, 2 h
5% Pd/CaCO3
(3.5% Pb)
20 bar H2, 50−60 °C,
CH3OH, 2 h
PtO2
20 bar H2, 50−60 °C,
AcOH, 2 h
5% Rh/Al2O3
20 bar H2, 50−60 °C,
CH3OH, 2 h
c
Rh(PPh3)3Cl
20 bar H2, 50−60 °C,
0
CH3OH, 2 h
a
b
1
Determined by H NMR analysis with external standard. n.r. = no
c
reaction. Complex mixture of unidentified products.
Scheme 4. Synthesis of Racemic Pyrrolizidinone rac-1
Methyl (4E)-5-[3-(Cyclopentyloxy)-4-methoxyphenyl]-4-ni-
tropent-4-enoate (3). To a solution of 3-(cyclopentyloxy)-4-
methoxybenzaldehyde9 (15.0 g, 68.0 mmol) in toluene (40 mL) was
added methyl 4-nitrobutyrate (10.0 g, 68.0 mmol) and n-butylamine
(1.0 mL, 0.74 g, 10.0 mmol). The mixture was refluxed with a Dean−
Stark water trap. After the theoretical amount of water was collected
(ca. 14 h), the reaction mixture was concentrated under vacuum. The
residue was crystallized from EtOH to give 17.5 g (74%) of
nitroalkene 3 as yellow crystals. Mp: 75−77 °C. HRMS: m/z
372.1419 (positive ions), calcd for [C18H23NO6Na+] 372.1418. Anal.
Calcd for C18H23NO6: C, 61.88; H, 6.64; N, 4.01. Found: C, 61.84; H,
6.94; N, 4.16. 1H NMR (300 MHz, HSQC): 1.56−1.60 and 1.75−2.03
(2 m, 2 and 6 H, 15-CH2 and 16-CH2), 2.69 and 3.24 (dd, J = 8.7, 8.0
Hz and dd, J = 8.7, 8.0 Hz, 2 and 2 H, 3-CH2 and 4-CH2), 3.69 (s, 3 H,
6-CH3), 3.89 (s, 3 H, 13-CH3), 4.79 (m, 1 H, 14-CH), 6.93 (d, J = 8.4
Hz, 1 H, 12-CH), 7.01 (s, 1 H, 8-CH), 7.07 (d, J = 8.4 Hz, 1 H, 11-
CH), 8.07 (s, 1 H, 1-CH). 13C NMR (75.47 MHz, HSQC, DEPT):
23.2 and 31.8 (3-C and 4-C), 24.0 and 32.8 (15-C and 16-C), 51.8 (6-
C), 56.0 (13-C), 80.7 (14-C), 112.0 (11-C), 116.0 (8-C), 124.1 (7-C),
The enantiomers (−)-(7S,7aS)-1 and (+)-(7R,7aR)-1 were
both tested for their ability to inhibit cAMP hydrolysis
catalyzed by PDE IVb. The (−)-1 enantiomer inhibited PDE
IVb with an IC50 of 84 nM, and the (+)-1 enantiomer had an
IC50 of 161 nM, thus being 2 times less active.
In conclusion, a simple three-step synthesis of racemic and
enantiopure PDE IVb inhibitor 1 was developed. The suggested
approach is based on a novel reductive domino transformation
of C-3-functionalized six-membered cyclic nitronates, which are
available by [4 + 2] cycloaddition of nitroalkenes to vinyl
ethers. This strategy involves only two C−C bond formation
steps and one ring formation step and can be considered as the
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Note
124.2 (12-C), 135.4 (1-C), 147.6 and 148.0 (9-C and 10-C), 152.4 (2-
C), 172.3 (5-C).
82.5 (7-C), 101.6 (6-C), 112.3 (21-C), 114.5 (18-C), 120.5 (22-C),
125.7 (3-C), 126.6 (16-C), 127.9 (14-C), 128.3 (15-C), 132.0 (17-C),
143.7 (13-C), 145.7 and 148.1 (19-C and 20-C), 173.6 (29-C).
Methyl 3-{4-[3-(Cyclopentyloxy)-4-methoxyphenyl]-6-
ethoxy-2-oxo-5,6-dihydro-4H-1,2-oxazin-3-yl}propanoate
(2b). SnCl4 (0.143 mL, 0.299 g, 1.15 mmol) was added to a solution
of nitroalkene 3 (0.400 g, 1.15 mmol) in CH2Cl2 (7.5 mL) at −94 °C
under an argon atmosphere. Ethyl vinyl ether (0.27 mL, 0.203 g, 2.82
mmol) was added dropwise to the reaction mixture with intensive
stirring. The resulting solution was warmed to −40 °C within 30 min
and then poured into a mixture of EtOAc (200 mL) and a saturated
solution of K2CO3 (200 mL). The aqueous layer was back-extracted
with EtOAc (2 × 50 mL). The combined organic layers were then
washed with a saturated solution of K2CO3 (100 mL), water (100
mL), and brine (100 mL), dried with Na2SO4, and evaporated under
vacuum. The residue was subjected to flash chromatography on silica
gel (eluent EtOAc/hexane 10/1 → 5/1 → 3/1 → 1/1) to give 0.378 g
(78%) of nitronate 2b. Colorless oil. Rf = 0.21 (hexane/EtOAc = 1:1).
Methyl 3-{4-[3-(Cyclopentyloxy)-4-methoxyphenyl]-2-oxo-
6-[(2-phenylcyclohexyl)oxy]-5,6-dihydro-4H-1,2-oxazin-3-yl}-
propanoate (2a). A solution of nitroalkene 3 (0.790 g, 2.26 mmol)
and enantiopure or racemic trans-1-phenyl-2-(vinyloxy)cyclohexane
(0.750 g, 3.71 mmol) in CH2Cl2 (37.5 mL) was cooled to −94 °C
(acetone/liquid nitrogen), and SnCl4 (0.334 mL, 0.745 g, 2.85 mmol)
was added under argon with intensive stirring. The resulting dark
solution was stirred at the same temperature for 15 min and poured
into a mixture of EtOAc (150 mL) and a saturated solution of K2CO3
(150 mL). The aqueous layer was back-extracted with EtOAc (2 × 50
mL). The combined organic layers were then washed with a saturated
solution of K2CO3 (100 mL), water (100 mL), and brine (100 mL),
dried with Na2SO4, and evaporated under vacuum. The residue was
preadsorbed on silica gel and subjected to flash chromatography on
silica gel (eluent EtOAc/hexane 10/1 → 5/1 → 3/1 → 1/1). Three
fractions were collected. The first fraction contained 0.233 g of
unreacted nitroalkene 3 (30% recovered), the second fraction
contained 0.084 g of nitronate 2a′ (7%), and the third fraction
contained 0.702 g of nitronate 2a (56%). The major nitronate 2a was
crystallized from MeOH to give analytically pure material with de >
+
HRMS: m/z = 422.2187 (positive ions); calcd for [C22H32NO7 ]:
422.2184. Anal. Calcd for C22H31NO7: C, 62.69; H, 7.41; N, 3.32.
Found: C, 62.67; H, 7.45; N, 3.36. 1H NMR (300 MHz, COSY,
HSQC): 1.27 (t, J = 7.0 Hz, 3 H, 8-CH3), 1.53−1.67 (m, 2 H, 18-CH),
1.76−1.98 (m, 6 H, 17-CH2 and 18-CH), 2.12 (ddd, J = 13.8, 11.1, 2.5
Hz, 1 H, 5-CHax), 2.26 (ddd, J = 13.8, 7.9, 1.6 Hz, 1 H, 5-CHeq), 2.36
(ddd, J = 15.0, 7.1, 3.6 Hz, 1 H, 20-CH), 2.40 (ddd, J = 14.6, 7.1, 3.0
Hz, 1 H, 19-CH), 2.53 (ddd, J = 14.6, 11.5, 3.6 Hz, 1 H, 19-CH), 2.84
(ddd, J = 15.0, 11.5, 3.0 Hz, 1 H, 20-CH), 3.56 (s, 3 H, 22-CH3), 3.72
(m, 1 H, 7-CH), 3.84 (s, 3 H, 15-CH3), 3.94 (dd, J = 11.1, 7.9 Hz, 1 H,
4-CHax), 4.02 (m, 1 H, 7-CH), 4.76 (m, 1 H, 16-CH), 5.36 (dd, J =
2.5, 1.6 Hz, 1 H, 6-CHeq), 6.70 (d, J = 1.4 Hz, 1 H, 10-CH), 6.77 (dd, J
= 8.1, 1.4 Hz, 1 H, 14-CH), 6.83 (d, J = 8.1 Hz, 1 H, 13-CH). 13C
NMR (75.47 MHz, HSQC, DEPT): 15.0 (8-C), 24.0 (18-C), 26.3
(19-C), 27.7 (20-C), 32.7 (17-C), 34.4 (5-C), 39.8 (4-C), 51.6 (22-
C), 56.1 (15-C), 64.8 (7-C), 80.5 (16-C), 101.2 (6-C), 112.5 (13-C),
114.7 (10-C), 120.5 (14-C), 125.7 (3-C), 131.9 (9-C), 148.2 and
149.7 (11-C and 12-C), 172.8 (21-C).
1
99% (determined by H 500 MHz NMR spectroscopy analysis).
Data for Major Isomer 2a. Rf = 0.30 (hexane/EtOAc 1/1). HRMS
+
(for rac-2a): m/z 552.2953 (positive ions), calcd for [C32H42NO7 ]
552.2956. Anal. Calcd for C32H41NO7: C, 69.67; H, 7.49; N, 2.54.
Found: C, 69.50; H, 7.70; N, 2.58. 1H NMR (500 MHz, COSY,
HSQC): 1.29 (ddd, J = 12.6, 11.0, 10.4, 3.0 Hz, 1 H, 12-CHax), 1.37
(m, 1 H, 11-CH), 1.40−1.57 (2 m, 2 H, 9-CH and 10-CH), 1.58−1.64
(m, 2 H, 26-CH), 1.67 (ddd, J = 16.6, 11.5, 4.3 Hz, 1 H, 28-CH),
1.75−1.95 (2 m, 10 H, 9-CH, 10-CH, 11-CH, 25-CH2, 26-CH and 27-
CH), 2.03 (m, 3 H, 5-CH2 and 27-CH), 2.22 (ddd, J = 16.6, 11.4, 4.9
Hz, 1 H, 28-CH), 2.35 (ddd, J = 12.6, 3.7, 2.9 Hz, 1 H, 12-CHeq), 2.61
(ddd, J = 12.8, 10.4, 3.1 Hz, 1 H, 8-CHax), 3.24 (dd, J = 9.8, 9.2 Hz, 1
H, 4-CHax), 3.58 (s, 3 H, 30-CH3), 3.81 (s, 3 H, 23-CH3), 4.18 (ddd, J
= 10.4, 10.4, 3.7 Hz, 1 H, 7-CHax), 4.70 (m, 1 H, 24-CH), 5.57 (dd, J =
2.3, 1.7 Hz, 1 H, 6-CHeq), 6.52 (d, J = 1.5 Hz, 1 H, 18-CH), 6.59 (dd, J
= 8.6, 1.5 Hz, 1 H, 22-CH), 6.75 (d, J = 8.6 Hz, 1 H, 21-CH), 7.20 (t, J
= 7.0 Hz, 1 H, 16-CH), 7.27 (d, J = 7.6 Hz, 2 H, 14-CH), 7.34 (dd, J =
7.6, 7.0 Hz, 2 H, 15-CH). 13C NMR (75.47 MHz, HSQC, DEPT):
24.1 (9-C), 24.5 (26-C), 26.0 and 26.3 (10-C and 27-C), 28.0 (28-C),
30.2 (12-C), 32.7 and 32.8 (25-C), 33.5 and 34.5 (5-C and 11-C), 38.9
(4-C), 50.7 (8-C), 51.6 (30-C), 56.0 (23-C), 76.5 (7-C), 80.3 (24-C),
95.5 (6-C), 111.8 (21-C), 114.2 (18-C), 120.6 (22-C), 124.4 (3-C),
126.3 (16-C), 127.4 (14-C), 129.0 (15-C), 131.0 (17-C), 144.1 (13-
C), 147.8 and 149.4 (19-C and 20-C), 172.8 (29-C).
The reaction was performed on 12.5 g of nitroalkene 3. Instead of
flash chromatography a simple filtration through a short pad of silica
gel (h = 3 cm, d = 6 cm) was used to remove ethyl vinyl ether
polymer. C.a. Fifteen g of crude nitronate 2b was obtained, which was
subjected to hydrogenation without special purification.
(+) and (−)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]-
hexahydro-3H-pyrrolizin-3-ones (1). PtO2 (0.0145 g) was added
to a solution of nitronate (+)-2a or (−)-2a (0.25 g, 0.45 mmol) in
AcOH (5.0 mL). The mixture was hydrogenated at 20 bar H2 and 60
°C for 4 h in a steel autoclave with external stirring. Then autoclave
was slowly depressurized and the catalyst was filtered off. The solvent
was evaporated in vacuum, the residue was dissolved in toluene (8
mL) and the solution was gently refluxed for 30 min. The solvent was
evaporated in vacuum and the residue was preadsorbed on silica gel.
Flash chromatography (eluent EtOAc/hexane 1/10 → 1/5 → 1/1
then MeOH/EtOAc 0/1 → 1/10) provided three fractions: the
EtOAc/hexane fraction contained trans-2-phenylcyclohexanol (0.072
g, 90%), the EtOAc fraction contained 0.013 g (9%) of the minor
isomer 1′, and the EtOAc/MeOH fraction contained 0.094 g (66%) of
rac-2a (obtained from racemic trans-1-phenyl-2-(vinyloxy)-
cyclohexane): mp 63−69 °C.
(+)-(4S,6S,7S,8R)-2a (obtained from (+)-trans-1-phenyl-2-
(vinyloxy)cyclohexane): mp 115 −118 °C; [α]D = +224.5° (MeOH,
c = 1, 26 °C).
(−)-(4R,6R,7R,8S)-2a (obtained from (−)-trans-1-phenyl-2-
(vinyloxy)cyclohexane): mp 114 −117 °C; [α]D = −213.8° (MeOH,
c = 1, 28 °C).
Data for Minor Isomer rac-2a′. Colorless oil. Rf = 0.43 (hexane/
EtOAc 1/1). HRMS: m/z 552.2956 (positive ions), calcd for
1
+
1
target pyrrolizidinone (−)-1 or (+)-1 (de > 95%). H NMR (CDCl3,
[C32H42NO7 ] 552.2956. H NMR (300 MHz, COSY, HSQC): 1.33
(dddd, J = 13.5, 11.6, 8.3, 3.6 Hz, 1 H, 12-CHax), 1.40−1.52 (m, 2 H,
10-CH and 11-CH), 1.52−1.63 (m, 3 H, 9-CH, 26-CH), 1.64−1.80
(m, 3 H, 5-CH2, 11-CH), 1.80−1.96 (m, 8 H, 9-CH, 10-CH, 25-CH2,
26-CH), 2.14 (ddd, J = 13.5, 8.1, 3.0 Hz, 1 H, 12-CHeq), 2.21−2.47
(m, 3 H, 27-CH2, 28-CH), 2.53 (ddd, J = 12.2, 9.0, 4.5 Hz, 1 H, 8-
CHax), 2.81 (ddd, J = 14.9, 8.2, 6.7 Hz, 1 H, 28-CH), 3.66 (s, 3 H, 30-
CH3), 3.77−3.87 (s and m, 5 H, 4-CH, 7-CH and 23-CH3), 4.41 (dd, J
= 2.6, 2.3 Hz, 1 H, 6-CHeq), 4.71 (m, 1 H, 24-CH), 6.59 (d, 1.7 Hz, 1
H, 18-CH), 6.68 (dd, J = 8.2, 1.7 Hz, 1 H, 22-CH), 6.77 (d, J = 8.2 Hz,
1 H, 21-CH), 7.11−7.34 (m, 5 H, 14-CH, 15-CH and 16-CH). 13C
NMR (75.47 MHz): 24.0 (26-C), 25.1 (9-C), 25.7 (10-C), 26.2 (27-
C), 27.6 (28-C), 32.4 (11-C), 32.7 (25-C), 33.9 and 34.0 (5-C and 12-
C), 39.6 (4-C), 51.5 (8-C), 51.6 (30-C), 56.1 (23-C), 80.5 (24-C),
300 MHz): 1.55−1.68 and 1.75−1.97 (2 m, 2 and 7 H), 2.17−2.32
(m, 2 H), 2.45−2.53 (m, 2 H), 2.63−2.80 (m, 2 H), 3.33 (dd, J = 10.8,
10.3 Hz, 1 H), 3.63 (ddd, J = 10.6, 9.6, 8.7 Hz, 1 H), 3.82 (s, 3 H),
3.91 (ddd, J = 9.4, 7.2, 7.1 Hz, 1 H), 4.77 (m, 1 H), 6.72 (s, 1 H), 6.73
(d, J = 8.1 Hz, 1 H), 6.83 (d, J = 8.1 Hz, 1 H). NMR data of obtained
pyrrolizidinones 1 are consistent with those previously reported in the
literature.1a,2
(−)-(7S,7aS)-1 (Obtained from (+)-2a): colorless oil; [α]D
=
−63.2° (CHCl3, c = 0.3, 25 °C) (lit.2c [α]D = −65.9° (CHCl3, c = 0.35,
24 °C)).
(+)-(7R,7aR)-1 (Obtained from (−)-2a): colorless oil; [α]D
=
+64.9° (CHCl3, c = 0.3, 29 °C) (lit.2c [α]D = +64.2° (CHCl3, c = 0.35,
23 °C), lit.2a [α]D = +62.6 (CHCl3, c = 0.35, 20 °C)).
5468
dx.doi.org/10.1021/jo300955n | J. Org. Chem. 2012, 77, 5465−5469

The Journal of Organic Chemistry
Note
(+)-trans-2-Phenylcyclohexanol (Obtained from (+)-2a): mp 60−
61 °C (lit. 63−66 °C, Aldrich); [α]D = +54.6° (MeOH, c = 1.83, 26
°C) (lit. 10 [α]D = +57.3° (MeOH, c = 5, 20 °C)). 1H NMR spectra is
in accordance with literature data.11
(−)-trans-2-Phenylcyclohexanol (Obtained from (−)-2a): mp 60−
64 °C (lit. 63−66 °C, Aldrich); [α]D = −55.1° (MeOH, c = 1.83, 25
°C) (lit. 11 [α]D = −56.8° (MeOH, c = 1.42)). The 1H NMR spectrum
is in accordance with literature data.11
3868. (c) Denmark, S. E.; Marcin, L. R. J. Org. Chem. 1995, 60, 3221−
3235. (d) Denmark, S. E.; Gomez, L. Org. Lett. 2001, 3, 2907−2910.
(e) Denmark, S. E.; Baiazitov, R. Y. Org. Lett. 2005, 7, 5617−5620.
(5) Denmark, S. E.; Schnute, M. E.; Marcin, L. R.; Thorarensen, A. J.
Org. Chem. 1995, 60, 3205−3220.
(6) CCDC 872699 contains supplementary crystallographic data for
2a. These data can be obtained free of charge via http://www.ccdc.
cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road,
Cambridge CB2 1EZ, U.K. or deposit@ccdc.cam.ac.uk).
(7) According to HRMS analysis the major component in the
reaction mixture after hydrogenation is pyrrolidine D, indicating that
the lactamization step occurs upon the evaporation of solvent. To
ensure that intermediate D is fully converted to pyrrolizidinone 1, the
crude product obtained after evaporation of acetic acid is refluxed in
toluene for 30 min; see the Experimental Section.
rac-7-[3-(Cyclopentyloxy)-4-(methyloxy)phenyl]hexahydro-
3H-pyrrolizin-3-one (1). PtO2 (0.050 g) was added to a solution of
nitronate 2b (1.0 g, 2.37 mmol) in AcOH (20.0 mL). The mixture was
hydrogenated at 20 bar of H2 and 50−60 °C for 5 h in a steel autoclave
with external stirring. Then the autoclave was slowly depressurized and
the catalyst was filtered off. The solvent was evaporated under vacuum,
and the residue was dissolved in toluene (40 mL). The solution was
gently refluxed for 30 min, and then the solvent was evaporated under
vacuum. Flash chromatography of the residue and subsequent
crystallization from Et2O provided 0.110 g (15%) of rac-1′ as an oil
and 0.496 g of rac-1 (66%) as white crystals (mp 66−70 °C, lit.1a mp
(8) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62,
7512−7515.
(9) Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.; King, S. A.;
Morton, H. E.; Plagge, A. M.; Preskill, F.; Wagaw, S. H.; Wittenberger,
S. J.; Zhang, J. J. Am. Chem. Soc. 2002, 124, 13097−13105.
(10) Cravotto, G.; Giovenzana, G. B.; Pilati, T.; Sisti, M.; Palmisano,
G. J. Org. Chem. 2001, 66, 8447−8453.
64−66 °C, lit.2c mp 67−68 °C). H NMR spectra of rac-1 and rac-1′
1
are in accordance with literature data.1a,2
Hydrogenation was performed on ca. 15 g of nitronate 2b with 0.35
g of PtO2 in 190 mL of AcOH (10 h). As a result, 5.35 g of rac-1 (47%
from nitroalkene 3) was isolated by dry column vacuum chromatog-
raphy12 and subsequent crystallization from Et2O. 0.296 g (98%) of
platinum black was recovered.
(11) King, S. B.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 5611−
5612.
(12) Pedersen, D. S.; Rosenbohm, C. Synthesis 2001, 2431−2434.
ASSOCIATED CONTENT
* Supporting Information
■
S
Figures giving NMR spectra of new compounds, a CIF file
giving crystallographic data for compound 2a, and text and
figures giving details of the PDE assay. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sukhorukov@ioc.ac.ru.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support from the Russian Foundation for Basic Research
(Grant No. 11-03-00737-a) and the Russian President’s
Council for Grants (Grant No. MK-1361.2011.3) is greatly
acknowledged.
REFERENCES
■
(1) (a) Brackeen, M. F.; Cowan, D. J.; Stafford, J. A.; Schoenen, F. J.;
Veal, J. M.; Domanico, P. L.; Rose, D.; Strickland, A. B.; Verghese, M.;
Feldman, P. L. J. Med. Chem. 1995, 38, 4848−4854. (b) Jackson, E. K.;
Carcillo, J. A. (University of Pittsburgh) U.S. Patent 5,849,774, Dec.
15, 1998. (c) Karlson, J.-A.; Aldous, D. Exp. Opin. Ther. Patents 1997,
7, 989−1003. For a recent review on PDE IV inhibitors and their
application see: (d) Michalski, J. M.; Golden, G.; Ikari, J.; Renard, S. I.
Clin. Pharm. Ther. 2012, 91, 134−142.
(2) (a) Feng, X.; Cui, H.-L.; Xu, S.; Wu, L.; Chen, Y.-C. Chem. Eur. J.
2010, 16, 10309−10312. (b) Sukhorukov, A. Yu.; Lesiv, A. V.;
Khomutova, Yu. A.; Ioffe, S. L.; Tartakovsky, V. A. Synthesis 2009,
1999−2008. (c) Sukhorukov, A. Yu.; Boyko, Y. D.; Khomutova, Yu.
A.; Nelyubina, Yu. V.; Ioffe, S. L.; Tartakovsky, V. A. J. Org. Chem.
2011, 76, 7893−7900.
(3) The reduction of 4,5-disubstituted six-membered cyclic nitronates
to pyrrolidines was reported by Denmark (see refs 4b and c); however,
the reduction of 3,4-disubstituted nitronates is unknown and the
stereochemistry of this process is not evident.
(4) (a) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137−
166. (b) Denmark, S. E.; Marcin, L. R. J. Org. Chem. 1993, 58, 3857−
5469
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