Synthesis of phosphodiesterase IVb inhibitors 2. Stereoselective synthesis of hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one and tetrahydro-1H-pyrrolo[1,2-c][1, 3]oxazol-3-one derivatives

Article abstract of DOI:10.1007/s11172-011-0367-5

The total stereoselective synthesis of two highly potent phosphodiesterase IVb inhibitors from nitroethane, isovanillin, and ethyl vinyl ether was developed. The compounds obtained are the derivatives of hexahydro-3H-pyrrolo[1, 2-c]imidazol-3-one and tetr

Full text of DOI:10.1007/s11172-011-0367-5

Russian Chemical Bulletin, International Edition, Vol. 60, No. 11, pp. 2390—2395, November, 2011
2390
Synthesis of phosphodiesterase IVb inhibitors
2.* Stereoselective synthesis of
hexahydroꢀ3Hꢀpyrrolo[1,2ꢀc]imidazolꢀ3ꢀone
and tetrahydroꢀ1Hꢀpyrrolo[1,2ꢀc][1,3]oxazolꢀ3ꢀone derivatives**
P. A. Zhmurov,a A. A. Tabolin,a A. Yu. Sukhorukov,a A. V. Lesiv,b
M. S. Klenov,a Yu. A. Khomutova,a S. L. Ioffe,a and V. A. Tartakovskya
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: sukhorukov@server.ioc.ac.ru
bMoscow Chemical Lyceum No. 1303,
4 Tamozhennyi proezd, 111033 Moscow, Russian Federation
Fax: +7 (495) 362 3440
The total stereoselective synthesis of two highly potent phosphodiesterase IVb inhibitors
from nitroethane, isovanillin, and ethyl vinyl ether was developed. The compounds obtained
are the derivatives of hexahydroꢀ3Hꢀpyrrolo[1,2ꢀc]imidazolꢀ3ꢀone and tetrahydroꢀ1Hꢀpyrꢀ
rolo[1,2ꢀc][1,3]oxazolꢀ3ꢀone. The strategy proposed involves silylation of sixꢀmembered cyclic
nitronates as a key step leading to 5,6ꢀdihydroꢀ4Hꢀ1,2ꢀoxazines with the group CH2FG
(FG = N3 or OH) at the C(3) atom.
Key words: stereoselective synthesis, nitro compounds, cyclic nitronates, silylation, pyrrolꢀ
idines, rolipram, phosphodiesterase, pyrrolo[1,2ꢀc]imidazolꢀ3ꢀones, pyrrolo[1,2ꢀc][1,3]oxazolꢀ
3ꢀones.
Phosphodiesterase (PDE) IVb inhibitors are considꢀ
ered to be promising drugs for the treatment of disorders of
the central nervous system and respiratory diseases.1 The
wellꢀknown representatives are, e.g., rolipram (antidepresꢀ
sant)2 and cilomilast (antiasthmatic drug).3 Bicyclic deꢀ
rivatives 1—3 proposed by GlaxoSmithKline Co.4 are vastly
superior to rolipram and cilomilast in the PDE IVb inhibiꢀ
tion constants IC50.5 However, the syntheses of products
1—3 developed by GlaxoSmithKline Co. are nonstereoꢀ
selective, yielding mixtures of diastereomers in nearly
equimolar ratios.4
Recently,6 we have proposed a strategy for the stereoꢀ
selective synthesis of 2,3ꢀtransꢀdisubstituted pyrrolidines
from nitroethane, aldehydes, and vinyl ethers through inꢀ
* For Part 1, see Ref. 1a.
** Dedicated to Academician of the Russian Academy of
Sciences O. M. Nefedov on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2343—2348, November, 2011.
1066ꢀ5285/11/6011ꢀ2390 © 2011 Springer Science+Business Media, Inc.

Stereoselective synthesis of PDE inhibitors
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011 2391
Scheme 1
X = NH (1), O (2), CH2 (3)
LG stands for a leaving group; FG = N3, OH, CH(CO2Me)2
termediate formation of sixꢀmembered cyclic oxime ethers
with a functionalized methyl group at the C(3) atom. The
key step in this synthesis was silylation of sixꢀmembered
cyclic nitronates.7 Obviously, this strategy can be employed
for stereocontrolled synthesis of PDE IVb inhibitors 1—3
(Scheme 1). For instance, immediate precursors of prodꢀ
ucts 1—3 are pyrrolidines 4, which can be obtained by
reduction of cyclic oxime ethers 5. In turn, such oxime
ethers can be derived from cyclic nitronate 6 according to
our recent silylationꢀbased procedures. Cyclic nitronate 6
is assembled via a [4+2] cycloaddition8 of nitroalkene 7
(accessible from isovanillin) to ethyl vinyl ether.
Following Scheme 1, we have earlier9 succeeded in the
stereoselective synthesis of pyrrolizidinone 3. In the present
work, we pioneered in the total stereoselective synthesis of
pyrroloimidazolone 1 and pyrrolooxazolone 2.
The key intermediates in the synthesis of target prodꢀ
ucts 1 and 2 are sixꢀmembered cyclic oxime ethers 5a and
5b, respectively (Scheme 2). They were obtained in two
steps from nitronate 6 described earlier.9
For the synthesis of azide 5a, nitronate 6 was transꢀ
formed into bromomethyldihydrooxazine 8 according to
a known method7a using an excess of trimethylsilyl bromꢀ
ide and triethylamine. To replace the Br atom by azido
group, compound 8 was treated with NaN3 in aqueous
acetone in the presence of catalytic amounts of NaI.10
For the synthesis of hydroxymethyldihydrooxazine 5b,
we used our recent procedure for rearrangement of
Me3Siꢀprotected 1,2ꢀoxazines.11 To do this, nitronate 6
was initially transformed into cyclic compound 9 by
monosilylation with trimethylsilyl bromide in the presꢀ
ence of triethylamine.7b Treatment of compound 9 with
trifluoroacetic anhydride followed by methanolysis of the
reaction mixture gave product 5b in good yield.
For high stereoselectivity to be achieved, reductive
transformation6a of the dihydrooxazine ring into a pyrroꢀ
lidine one was carried out in two steps (Scheme 3): sucꢀ
cessive hydride reduction of the C=N bond and catalytic
hydrogenation of the N—O bond.6a
Reduction of dihydrooxazines 5a and 5b with sodium
cyanoborohydride in acetic acid stereoselectively gave only
tetrahydroꢀ2Hꢀ1,2ꢀoxazines 10a and 10b, respectively,
with the required 3,4ꢀtransꢀconfiguration of the substituꢀ
ents in the oxazine ring. Catalytic hydrogenation of comꢀ
pounds 10a and 10b on Raney nickel yielded, via the
1,2ꢀoxazine→pyrrolidine transformation, products 11a
and 11b, respectively (see Scheme 3). Oxazine 10a was
hydrogenated in the presence of diꢀtertꢀbutyl dicarbonate
(1 equiv.) for protection of the primary amino group in an
intermediate resulting from the firstꢀstep reduction of the
azido group. Pyrrolidine 11a was transformed without furꢀ
ther purification into the target product 1 in boiling DMSO
(see Scheme 3). Cyclization of pyrrolidine 11b into the
target product 2 was carried out under the action of
1,1´ꢀcarbonyldiimidazole12 in CH2Cl2.
The structures of novel intermediate products 5a,b, 9,
and 10a,b were confirmed by 1D (1H and 13C) and 2D
NMR spectroscopy (COSY and HSQC), highꢀresolution

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Zhmurov et al.
Scheme 2
Scheme 3

Stereoselective synthesis of PDE inhibitors
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011 2393
of NaN3 (0.249 g, 3.8 mmol) and NaI (0.035 g, 0.23 mmol) in
water (2.5 mL) was added to a solution of bromooxazine 8 (0.410 g,
1.0 mmol) in acetone (12 mL).9 The reaction mixture was stirred
at room temperature for 24 h and concentrated. The residue was
preadsorbed on silica gel (~2 g) and then chromatographed on
silica gel with gradient elution in hexane—EtOAc (10 : 1 → 5 : 1).
The resulting colorless oil crystallized on cooling, m.p. 38—41 °C.
The yield of compound 5a was 0.330 g (88%), Rf 0.68
(EtOAc—hexane, 1 : 1). Found (%): C, 60.76; H, 7.27; N, 14.86.
C19H26N4O4. Calculated (%): C, 60.95; H, 7.00; N, 14.96.
HRMS, m/z: 375.2030 [MH]+, calculated for [MH]+: 375.2027.
1H NMR (CDCl3, COSY, HSQC), δ: 1.27 (t, 3 H, H3C(9),
J = 7.0 Hz); 1.57—1.66 (m, 2 H, HC(19)); 1.81—1.97 (m, 6 H,
H2C(18), HC(19)); 2.14 (ddd, 1 H, HaxC(5), J = 13.9 Hz,
J = 12.5 Hz, J = 2.2 Hz); 2.31 (ddd, 1 H, HeqC(5), J =13.9 Hz,
J = 7.3 Hz, J = 1.8 Hz); 3.48 (d, 1 H, HC(7), J = 13.2 Hz); 3.65
(m, 1 H, HC(8)); 3.7 (dd, 1 H, HC(4), J = 12.5 Hz, J = 7.3 Hz);
3.82 (d, 1 H, HC(7), J = 13.2 Hz); 3.93 (s, 3 H, H3C(16)); 3.91
(m, 1 H, HC(8)); 4.76 (m, 1 H, HC(17)); 5.20 (dd, 1 H, HC(6),
J = 2.2 Hz, J = 1.8 Hz); 6.70 (d, 1 H, HC(11), J = 1.5 Hz); 6.75
(dd, 1 H, HC(15), J = 8.1 Hz, J = 1.5 Hz); 6.85 (d, 1 H, HC(14),
J = 8.1 Hz). 13C NMR (CDCl3, HSQC), δ: 15.0 (C(9)); 24.0
(C(19)); 32.8 (C(5), C(18)); 34.4 (C(4)); 52.5 (C(7)); 56.1
(C(16)); 63.8 (C(8)); 80.5 (C(17)); 95.9 (C(6)); 112.6, 114.9,
120.5 (C(11), C(14), C(15)); 131.1 (C(10)); 148.2, 149.6 (C(12),
C(13)); 157.2 (C(3)).
mass spectrometry, and elemental analysis. The spectroꢀ
scopic characteristics of the target products 1 and 2 agree
well with the literature data.4
To sum up, starting from nitroethane and isovanillin,
we performed the stereoselective sevenꢀstep syntheses of
the known PDE IVb inhibitors 1 and 2 in overall 18 and
22% yields, respectively. The previously described schemes
for their syntheses are nonstereoselective4 and inferior in
yields: 2% over nine steps for product 1 and 5% over six
steps for product 2.
Experimental
Catalytic hydrogenation was carried out in a steel autoclave
(Parr) with external heating and stirring. Column chromatoꢀ
graphy was carried out on silica gel (Merck Kieselgel 40—60 μm
60A). 1D and 2D NMR spectra were recorded on a Bruker
AMꢀ300 spectrometer (300.13 MHz). Chemical shifts are referꢀ
enced to the residual signal of the solvent.13 Highꢀresolution
mass spectra were recorded on a MicroTOFF instrument. Eleꢀ
mental analysis was performed at the analytical laboratory of the
N. D. Zelinsky Institute of Organic Chemistry (Russian Acadeꢀ
my of Sciences). Melting points were measured on a Kofler hot
stage and are given uncorrected.
Acetic acid was recrystallized twice. Dichloromethane,
MeCN, Et3N, ethyl vinyl ether, and Me3SiBr were distilled over
CaH2; DMSO (SigmaꢀAldrich), SnCl4 (Aldrich), NaBH3CN
(Acros), NaN3 (Aldrich), (CF3CO)2O (Aldrich), (ButOCO)2O
(Aldrich), Raney nickel (Acros, 50% suspension in water), and
1,1´ꢀcarbonyldiimidazole (Acros) were used as purchased.
Nitronate 6, nitroalkene 7, and bromooxazine 8 were prepared
as described earlier.9
(4S*,6S*)ꢀ4ꢀ(3ꢀCyclopentyloxyꢀ4ꢀmethoxyphenyl)ꢀ6ꢀethꢀ
oxyꢀ3ꢀhydroxymethylꢀ5,6ꢀdihydroꢀ4Hꢀ1,2ꢀoxazine (5b). Triꢀ
fluoroacetic anhydride (0.105 mL, 0.74 mmol) was added under
argon at –78 °C to a stirred solution of nitroso acetal 9 (0.312 g,
0.74 mmol) in CH2Cl2 (3.7 mL). The reaction mixture was stirred
at –78 °C for 1 h. Then K2CO3 (0.19 g) and MeOH (0.8 mL)
were successively added. The reaction mixture was stirred withꢀ
out cooling for 2.5 h and poured into the twoꢀphase system EtOAc
(60 mL)—brine (20 mL). The organic layer was washed with
brine (20 mL), dried over Na2SO4, and concentrated in vacuo.
The product was isolated by column chromatography with
gradient elution in hexane—EtOAc (3 : 1 → 1 : 1). The resultꢀ
ing faintly yellow oil solidified upon storage, m.p. 97—99 °C.
The yield of the target oxazine 5b was 0.179 g (69%), Rf 0.39
(EtOAc—hexane, 1 : 1). HRMS, m/z: 350.1962 [MH]+, calcuꢀ
(4S*,6S*)ꢀ4ꢀ(3ꢀCyclopentyloxyꢀ4ꢀmethoxyphenyl)ꢀ6ꢀethꢀ
oxyꢀ3ꢀmethylideneꢀ2ꢀtrimethylsilyloxyꢀ1,2ꢀoxazinane (9). Triꢀ
ethylamine (0.19 mL, 1.3 mmol) and TMSBr (0.16 mL,
1.2 mmol) were successively added under argon at –78 °C to
a stirred solution of oxazine Nꢀoxide 6 (0.389 g, 1.11 mmol) in
CH2Cl2 (2.2 mL). The reaction mixture was kept at –78 °C for
48 h, diluted with hexane (5 mL), and poured into the twoꢀphase
system hexane (40 mL)—H2O (20 mL). The organic layer was
washed with a solution of NaHSO4 (0.12 g) in water (20 mL) and
with brine (2×20 mL), dried over Na2SO4, and concentrated
in vacuo. The resulting labile nitroso acetal 9 (0.449 g, 96%) as
1
lated for [MH]+: 350.1962. H NMR (CDCl3), δ: 1.26 (t, 3 H,
H3C(9), J = 7.3 Hz); 1.53—1.68 (m, 2 H, HC(19)); 1.73—1.95
(m, 6 H, H2C(18), HC(19)); 2.11 (ddd, 1 H, HCax(5), J = 13.9 Hz,
J = 12.5 Hz, J = 2.9 Hz); 2.26 (ddd, 1 H, Heq(5), J = 13.9 Hz,
J = 7.3 Hz, J = 2.2 Hz); 2.56 (br.s, 1 H, HO); 3.59 (dd, 1 H,
HC(4), J = 12.5 Hz, J = 7.3 Hz); 3.66 (dq, 1 H, HC(8), J = 9.5 Hz,
J = 7.3 Hz); 3.84 (s, 3 H, H3C(16)); 3.91 (dq, 1 H, HC(8),
J = 9.5 Hz, J = 7.3 Hz); 3.98 (s, 2 H, HC(7)); 4.76 (m, 1 H,
HC(17)); 5.20 (br.s, 1 H, HC(6)); 6.68 (d, 1 H, HC(11), J = 1.9 Hz);
6.73 (dd, 1 H, HC(15), J = 8.1 Hz, J = 1.9 Hz); 6.83 (d, 1 H,
HC(14), J = 8.1 Hz). 13C NMR (CDCl3), δ: 15.0 (C(9)); 24.0
(C(19)); 32.6, 32.7 (C(5), C(18)); 34.2 (C(4)); 56.1 (C(16)); 62.6,
63.9 (C(7), C(8)); 80.5 (C(17)); 96.1 (C(6)); 112.4, 114.8, 120.6
(C(11), C(14), C(15)); 131.0 (C(10)); 148.1, 149.6 (C(12),
C(13)); 159.0 (C(3)).
1
a colorless oil was further used without purification. H NMR
(CDCl3), δ: 0.26 (s, 9 H, H3C(20)); 1.27 (t, 3 H, H3C(9),
J = 7.3 Hz); 1.57—1.67 (m, 2 H) and 1.78—1.97 (m, 6 H)
(H2C(18) and H2C(19)); 2.10 (ddd, 1 H, HeqC(5), J = 13.2 Hz,
J = 5.5 Hz, J = 5.5 Hz); 2.23 (ddd, 1 H, Hax(5), J = 13.2 Hz,
J = 9.5 Hz, J = 4.4 Hz); 3.59 (dq, 1 H, HC(8), J = 9.5 Hz,
J = 7.3 Hz); 3.85 (s, 3 H, H3C(16)); 3.89—4.14 (m, 3 H, HC(4),
HC(7), HC(8)); 4.74—4.79 (m, 1 H, HC(17)); 4.95 (br.s, 1 H,
HC(7)); 5.10 (t, 1 H, HC(6), J = 4.4 Hz); 6.83 (br.s, 3 H,
HC(11), HC(14), HC(15)). 13C NMR (CDCl3), δ: –0.8 (C(20));
15.0 (C(9)); 24.0 (C(19)); 32.8, 36.6 (C(5), C(18)); 40.5 (br,
C(4)); 56.1 (C(16)); 64.1 (C(8)); 80.4 (C(17)); 97.4 (br, C(7));
99.3 (C(6)); 111.9, 115.9, 120.6 (C(11), C(14), C(15)); 133.0
(br, C(10)); 147.5, 149.0 (C(12), C(13)); 158.4 (br, C(3)).
(4S*,6S*)ꢀ3ꢀAzidomethylꢀ4ꢀ(3ꢀcyclopentyloxyꢀ4ꢀmethoxyꢀ
phenyl)ꢀ6ꢀethoxyꢀ5,6ꢀdihydroꢀ4Hꢀ1,2ꢀoxazine (5a). A solution
(3R*,4S*,6S*)ꢀ3ꢀAzidomethylꢀ4ꢀ(3ꢀcyclopentyloxyꢀ4ꢀmethꢀ
oxyphenyl)ꢀ6ꢀethoxyꢀ1,2ꢀoxazinane (10a). Sodium cyanoboroꢀ
hydride (0.127 g, 2.05 mmol) was added to a stirred solution of
azidomethyloxazine 5a (0.250 g, 0.67 mmol) in acetic acid
(3 mL). The reaction mixture was vigorously stirred at room

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Zhmurov et al.
temperature for 1 h and poured into the system EtOAc
(150 mL)—K2CO3 (150 mL). The aqueous layer was washed
with EtOAc (50 mL). The combined organic layer was succesꢀ
sively washed with a saturated aqueous solution of K2CO3
(70 mL), water (100 mL), and brine (100 mL), dried over Na2SO4,
and concentrated in vacuo. The residue was preadsorbed on silica
gel (~2 g) and then chromatographed on silica gel with gradient
elution in hexane—EtOAc (10 : 1 → 5 : 1 → 3 : 1). The yield
of compound 10a was 0.207 g (82%), colorless oil, Rf 0.71
(EtOAc—hexane, 1 : 1). Found (%): C, 60.74; H, 7.56; N, 14.18.
C19H28N4O4. Calculated (%): C, 60.62; H, 7.50; N, 14.88.
HRMS, m/z: 377.2169 [MH]+, calculated for [MH]+: 377.2183.
1H NMR (CDCl3, COSY, HSQC), δ: 1.30 (t, 3 H, H3C(9),
J = 7.0 Hz); 1.55—1.67 (s, 2 H, HC(19)); 1.78—1.97 (m, 6 H,
H2C(18), HC(19)); 1.94 (ddd, 1 H, HeqC(5), J = 13.2 Hz,
J = 5.9 Hz, J = 1.4 Hz); 2.04 (ddd, 1 H, HaxC(5), J = 13.2 Hz,
J = 10.3 Hz, J = 2.9 Hz); 3.02 (ddd, 1 H, HaxC(4), J = 11.0 Hz,
J = 10.3 Hz, J = 5.9 Hz); 3.16 (dd, 1 H, HC(7), J = 12.5 Hz,
J = 5.1 Hz); 3.27 (ddd, 1 H, HaxC(3), J = 11.0 Hz, J = 5.1 Hz,
J = 2.2 Hz); 3.33 (dd, 1 H, HC(7), J = 12.5 Hz, J = 2.2 Hz); 3.58
(dq, 1 H, HC(8), J = 9.5 Hz, J = 7.3 Hz); 3.83 (s, 3 H, H3C(16));
3.85 (dq, 1 H, HC(8), J = 9.5 Hz, J = 7.3 Hz); 4.75 (m, 1 H,
HC(17)); 4.89 (dd, 1 H, HC(6), J = 2.9 Hz, J = 1.4 Hz); 5.39
(br.s, 1 H, HN(2)); 6.69—6.75 (m, 2 H, HC(11), HC(15)); 6.83
(d, 1 H, HC(14), J = 8.1 Hz). 13C NMR (CDCl3, HSQC), δ:
15.2 (C(9)); 24.0 (C(19)); 32.8 (C(18)); 36.3 (C(5)); 37.3 (C(4));
51.0 (C(7)); 56.1 (C(16)); 61.5 (C(3)); 63.6 (C(8)); 80.4 (C(17));
98.0 (C(6)); 112.5, 114.5, 119.3 (C(11), C(14), C(15)); 133.7
(C(10)); 147.9, 149.1 (C(12), C(13)).
a 50% suspension in water (~0.2 mL) was washed with MeOH
(4×2 mL) and added in MeOH (0.5 mL) to a solution of oxazine
10a (0.058 g, 0.154 mmol) and diꢀtertꢀbutyl dicarbonate (0.033 mL,
0.154 mmol) in MeOH (2.0 mL). The mixture was hydrogenated
in an autoclave (65—75 °C, H2, p = 40 atm) for 4.5 h, filtered
through a short pad of Celite to remove the catalyst, and conꢀ
centrated in vacuo. The residue was dissolved in DMSO (3.0 mL).
The resulting solution was gently refluxed under argon for
30 min. Then the solvent was removed in vacuo (100 °C, 1 Torr)
and the residue was chromatographed on silica gel with gradient
elution from hexane—EtOAc (10 : 1 → 5 : 1 → 3 : 1 → 1 : 1) to
EtOAc. The resulting oily product was recrystallized from Et2O.
The yield of the target compound 1 was 0.029 g (60%),
m.p. 139—141 °C (cf. Ref. 4: m.p. 118—120 °C), Rf 0.54
(EtOAc—MeOH, 3 : 1). Found (%): C, 68.39; H, 7.73; N, 8.67.
C18H24N2O3. Calculated (%): C, 68.33; H, 7.65; N, 8.85.
HRMS, m/z: 317.1866 [MH]+, calculated for [MH]+: 317.1860.
1H NMR (CDCl3), δ: 1.56—1.71 (m, 2 H, HC(19)); 1.79—1.94
(m, 6 H, H2C(18), HC(19)); 2.05 (dddd, 1 H, HC(4), J = 12.8 Hz,
J = 11.9 Hz, J = 10.1 Hz, J = 9.2 Hz); 2.38 (dddd, 1 H, HC(4),
J = 12.8 Hz, J = 10.1 Hz, J = 8.2 Hz, J = 4.6 Hz); 2.74 (ddd, 1 H,
HC(3), J = 11.0 Hz, J = 10.1 Hz, J = 9.2 Hz); 3.33 (dd, 1 H,
HC(1); J = 9.9 Hz, J = 9.9 Hz); 3.51 (dd, 1 H, HC(1), J = 9.9 Hz,
J = 7.7 Hz); 3.26—3.31 (m, 1 H) and 3.64—3.75 (m, 2 H) (HC(2),
H2C(5)); 3.82 (s, 3 H, H3C(16)); 4.76 (m, 1 H, HC(17)); 5.55
(br.s, 1 H, HN(8)); 6.72 (s, 1 H, HC(11)), 6.73 (d, 1 H, J = 7.3 Hz)
and 6.83 (d, 1 H, J = 7.3 Hz) (HC(14), HC(15)). 13C NMR
(CDCl3, JMOD), δ: 24.0, 32.7, 34.4, 41.3, 45.2 (C(1), C(4),
C(5), C(18), C(19)); 48.5, 56.2, 66.1 (C(2), C(3), C(16)); 80.6
(C(17)), 112.4, 114.7, 119.6 (C(11), C(14), C(15)); 131.7 (C(10));
147.9, 149.3 (C(12), C(13)); 165.8 (C(7)). The spectroscopic
characteristics are in full agreement with the literature data4 for
compound 1.
(7S*,7aR*)ꢀ7ꢀ(3ꢀCyclopentyloxyꢀ4ꢀmethoxyphenyl)tetraꢀ
hydroꢀ1Hꢀpyrrolo[1,2ꢀc][1,3]oxazolꢀ3ꢀone (2). Raney nickel as
a 50% suspension in water (~1 mL) was washed with MeOH
(4×2 mL) and added, under a layer of MeOH (1.5 mL), to
a solution of tetrahydrooxazine 10b (0.15 g, 0.43 mmol) in MeOH
(2.5 mL). The mixture was hydrogenated in a steel autoclave
(24 °C, H2, p = 40 atm) for 6 h and filtered through a short pad of
Celite. The Celite filter was washed with MeOH (50 mL). The
filtrate was concentrated in vacuo. The residue (0.104 g) was
dissolved in CH2Cl2 (3.0 mL) and 1,1´ꢀcarbonyldiimidazole
(0.063 g, 0.39 mmol) was added with stirring under argon. The
reaction mixture was kept for 72 h and poured into the twoꢀ
phase system EtOAc (50 mL)—0.07 M aqueous HCl (20 mL).
The organic layer was washed with brine (2×15 mL), dried over
Na2SO4, and concentrated in vacuo. The product was isolated by
column chromatography with gradient elution in hexane—EtOAc
(2 : 1 → 1 : 1). The yield of the target compound 2 was 0.061 g
(45%), colorless oil. For analytical purposes, the product was
recrystallized from hexane—EtOAc (2 : 1), m.p. 99—101 °C
(cf. Ref. 4: m.p. 97—98 °C), Rf 0.37 (hexane—EtOAc, 1 : 1). HRMS,
m/z: 340.1517 [MNa]+, calculated for [MNa]+: 340.1519.
1H NMR (CDCl3, COSY), δ: 1.55—1.72 (m, 2 H) and 1.79—1.98
(m, 6 H) (H2C(18), H2C(19)); 2.15 (dddd, 1 H, HC(4), J = 12.7 Hz,
J = 11.7 Hz, J = 9.5 Hz, J = 8.8 Hz); 2.49 (dddd, 1 H, HC(4),
J = 12.7 Hz, J = 10.3 Hz, J = 8.1 Hz, J = 2.2 Hz); 2.79 (ddd, 1 H,
HC(3), J = 10.3 Hz, J = 9.5 Hz, J = 7.3 Hz); 3.48 (ddd, 1 H,
HC(5), J = 11.0 Hz, J = 9.5 Hz, J = 2.2 Hz); 3.74 (ddd, 1 H,
HC(5), J = 11.0 Hz, J = 8.8 Hz, J = 8.1 Hz); 3.82—3.88 (m, 1 H,
(3R*,4S*,6S*)ꢀ4ꢀ(3ꢀCyclopentyloxyꢀ4ꢀmethoxyphenyl)ꢀ6ꢀ
ethoxyꢀ3ꢀhydroxymethylꢀ1,2ꢀoxazinane (10b). Sodium cyanoꢀ
borohydride (0.109 g, 1.73 mmol) was added under argon to
a stirred solution of oxazine 5b (0.170 g, 0.49 mmol) in acetic
acid (3.1 mL). The reaction mixture was stirred at room temperꢀ
ature for 80 min and poured into the twoꢀphase system EtOAc
(60 mL)—saturated aqueous Na2CO3 (30 mL). The aqueous layꢀ
er was washed with EtOAc (2×20 mL). The combined organic
layer was washed with saturated aqueous Na2CO3 (20 mL),
water (20 mL), and brine (2×20 mL), dried over Na2SO4,
and concentrated in vacuo. The product was isolated by column
chromatography with gradient elution from CHCl3 to
CHCl3—MeOH (20 : 1). The yield of the target tetrahydrooxꢀ
azine 10b was 0.165 g (96%), faintly yellow oil. For analytical
purposes, the product was recrystallized from hexane—EtOAc
(2 : 1), m.p. 87—89 °C, Rf 0.49 (CHCl3—MeOH, 10 : 1). Found (%):
C, 64.59; H, 8.37; N, 3.99. C19H29NO5. Calculated (%):
1
C, 64.93; H, 8.32; N, 3.99. H NMR (CDCl3), δ: 1.30 (t, 3 H,
H3C(9), J = 7.0 Hz); 1.52—1.67 (m, 2 H, HC(19)); 1.72—2.12
(m, 8 H, H2C(18), H2C(19), H2C(5)); 2.95 (ddd, 1 H, HaxC(4),
J = 11.3 Hz, J = 11.3 Hz, J = 4.4 Hz); 3.21—3.35 (m, 2 H) and
3.45—3.55 (m, 1 H) (HC(3) and HC(7)); 3.58 (dq, 1 H, HC(8),
J = 9.5 Hz, J = 7.0 Hz); 3.81 (s, 3 H, H3C(16)); 3.85 (dq, 1 H,
HC(8), J = 9.5 Hz, J = 7.0 Hz); 4.76 (m, 1 H, HC(17)); 4.90
(br.s, 1 H, HC(6)); 6.68—6.75 (m, 2 H) and 6.81 (d, 1 H, J = 8.8 Hz)
(HC(11), HC(14), HC(15)). 13C NMR (CDCl3), δ: 15.2 (C(9));
24.0 (C(19)); 32.8, 36.5, 37.0 (C(4), C(5), C(18)); 56.2 (C(16));
61.5, 63.7, 77.3 (C(3), C(7), C(8)); 80.5 (C(17)); 98.3 (C(6));
112.5, 114.6, 119.4 (C(11), C(14), C(15)); 134.2 (C(10)); 147.8,
149.1 (C(12), C(13)).
(7S*,7aR*)ꢀ7ꢀ(3ꢀCyclopentyloxyꢀ4ꢀmethoxyphenyl)hexaꢀ
hydroꢀ3Hꢀpyrrolo[1,2ꢀc]imidazolꢀ3ꢀone (1). Raney nickel as

Stereoselective synthesis of PDE inhibitors
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011 2395
HC(2)); 3.84 (s, 3 H, H3C(16)); 4.22 (dd, 1 H, HC(1), J = 9.5 Hz,
J = 2.9 Hz); 4.43 (dd, 1 H, HC(1), J = 9.5 Hz, J = 8.1 Hz);
4.73—4.81 (m, 1 H, HC(17)); 6.70—6.77 (m, 2 H) and 6.85 (d, 1 H,
J = 8.1 Hz) (HC(11), HC(14), HC(15)). 13C NMR (CDCl3,
HSQC), δ: 24.0 (C(19)); 32.8 (C(18)); 34.5 (C(4)); 45.8 (C(5));
49.2 (C(3)); 56.2 (C(16)); 65.8 (C(2)); 66.2 (C(1)); 80.7 (C(17));
112.5, 114.5, 119.4 (C(11), C(14), C(15)); 130.4 (C(10)); 148.1,
149.7 (C(12), C(13)); 161.7 (C(7)). The spectroscopic characꢀ
teristics are in full agreement with the literature data4 for comꢀ
pound 2.
5. E. E. Polymeropoulos, N. Hofgen, Quant. Struct.ꢀAct. Relat.,
1997, 16, 231.
6. (a) A. Yu. Sukhorukov, S. L. Ioffe, Chem. Rev., 2011, 111,
5004; (b) S. L. Ioffe, in Nitrile Oxides, Nitrones, and Nitroꢀ
nates in Organic Synthesis: Novel Strategies in Synthesis, 2nd
ed., Ed. H. Feuer, Wiley, Hoboken, 2008, p. 704; (c) A. Yu.
Sukhorukov, M. S. Klenov, P. E. Ivashkin, A. V. Lesiv, Y. A.
Khomutova, S. L. Ioffe, Synthesis, 2007, 97; (d) A. Yu.
Sukhorukov, A. V. Lesiv, Yu. A. Khomutova, S. L. Ioffe,
Synthesis, 2009, 741; (e) A. Yu. Sukhorukov, A. V. Lesiv,
O. L. Eliseev, Yu. A. Khomutova, S. L. Ioffe, A. O. Borisꢀ
sova, Eur. J. Org. Chem., 2008, 4025; (f) A. Yu. Sukhorukov,
A. V. Lesiv, O. L. Eliseev, Yu. A. Khomutova, S. L. Ioffe,
Synthesis, 2009, 2570.
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Nesterov, S. L. Ioffe, Synthesis, 2004, 1159; (b) A. A. Tishꢀ
kov, A. V. Lesiv, Yu. A. Khomutova, Yu. A. Strelenko, I. D.
Nesterov, M. Yu. Antipin, S. L. Ioffe, S. E. Denmark, J. Org.
Chem., 2003, 68, 9477.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 11ꢀ03ꢀ00737ꢀa),
the Council on Grants at the President of the Russian
Federation (State Support Program for Leading Scientific
Schools and Young Ph.D. Scientists of the Russian
Federation, Grant MKꢀ1361.2011.3), and the Federal
Agency on Science and Innovations (State Contract
No. 02.740.11.0258).
8. S. E. Denmark, A. Thorarensen, Chem. Rev., 1996, 96, 137.
9. A. Yu. Sukhorukov, A. V. Lesiv, Yu. A. Khomutova, S. L.
Ioffe, V. A. Tartakovsky, Synthesis, 2009, 1999.
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Received June 9, 2011