Synthesis of 4-aryl-2-pyrrolidones and β-aryl-γ-amino-butyric acid (GABA) analogues by Heck arylation of 3-pyrrolines with arenediazonium tetrafluoroborates. Synthesis of (±)-rolipram on a multigram scale and chromatographic resolution by semipreparative chiral simulated moving bed chromatography

Article abstract of DOI:10.1021/jo0484880

(Chemical Equation Presented) We report herein a new, practical, and economic synthesis of the phosphodiesterase inhibitor Rolipram on a multigram scale as well as the synthesis of new 4-aryl pyrrolidones and β-aryl-γ-amino butyric acids (GABA derivatives) employing an efficient Heck-Matsuda arylation of 3-pyrroline with aryldiazonium tetrafluoroborates. Racemic Rolipram was resolved into its enantiomers using chiral simulated moving bed chromatography having the low-cost microcrystalline cellulose triacetate as a chiral stationary phase.

Full text of DOI:10.1021/jo0484880

Synthesis of 4-Aryl-2-pyrrolidones and
â-Aryl-γ-amino-butyric Acid (GABA)
Analogues by Heck Arylation of
3-Pyrrolines with Arenediazonium
Tetrafluoroborates. Synthesis of
(()-Rolipram on a Multigram Scale and
Chromatographic Resolution by
Semipreparative Chiral Simulated Moving
Bed Chromatography
FIGURE 1. Structures of Rolipram, Baclofen, and GABA
Ariel L. L. Garcia,† Marcos J. S. Carpes,†
Antonio C. B. M. de Oca,† Marco A. G. dos Santos,‡
Ce´sar C. Santana,‡ and Carlos Roque D. Correia*,†
adenosine-3′,5′-monophosphate (cAMP). Cleavage of the
phosphodiester bridge of cAMP blocks the action of this
secondary messenger and consequently the cascade of
biochemical events leading to inflammatory processes.4
The action of PDE4 is also related to a number of
pathological processes in the central nervous system
(CNS) such as multiple sclerosis, coronary failure, asthma,
pulmonary diseases, and diabetes, among others.5
Despite a number of synthetic approaches to Rolipram
in the literature,6 this compound is a very expensive one,
limiting its use in pharmacological studies.7 Both enan-
tiomers of Rolipram are active toward PDE4 with the (R)-
(-) isomer being the most active one.6c,k In view of the
importance of Rolipram as a potential drug and as a
pharmacological probe, a general approach to Rolipram
and new derivatives is highly desirable. Moreover, due
to the close chemical correlations of Rolipram to the
important neurotransmitter γ-amino butyric acid 3
(GABA) and, in particular, to GABAB receptor agonists
such as Baclofen 2 (used to treat spasms caused by spinal
cord injuries), a route designed for the preparation of
Rolipram could also be amenable to the preparation of
new GABA derivatives.
Herein, we report on a new route to the efficient
synthesis of Rolipram 1 on a multigram scale, as well as
the synthesis of new Rolipram and Baclofen analogues.
The route features a Heck-Matsuda arylation of a simple
3-pyrroline with a diazonium salt as the key step.8
The first stages of the synthesis were directed to the
preparation of the aryldiazonium salt 7 on a multigram
scale, from the cheap and commercially available 5-nitro-
2-methoxyphenol 4. Phenol 4 was readily converted into
the cyclopentyl ether 5 with cyclopentyl bromide in
acetone,6b in 98% yield (> 98% of purity by capillary GC).
Chemistry Institute, State University of
Campinas-UNICAMP, 13084-971, Campinas,
Sa˜o Paulo, Brazil, and Chemical Engineering Institute,
Department of Biotechnology, State University of
Campinas-UNICAMP, 13083-970, Campinas,
Sa˜o Paulo, Brazil
roque@iqm.unicamp.br
Received August 29, 2004
We report herein a new, practical, and economic synthesis
of the phosphodiesterase inhibitor Rolipram on a multigram
scale as well as the synthesis of new 4-aryl pyrrolidones and
â-aryl-γ-amino butyric acids (GABA derivatives) employing
an efficient Heck-Matsuda arylation of 3-pyrroline with
aryldiazonium tetrafluoroborates. Racemic Rolipram was
resolved into its enantiomers using chiral simulated moving
bed chromatography having the low-cost microcrystalline
cellulose triacetate as a chiral stationary phase.
Pyrrolidin-2-ones encompass a wide variety of physi-
ologically active compounds that also work as precursors
for the synthesis of γ-amino butyric acids (GABA ana-
logues).1 Several analogues of the neurotransmitter
GABA display important pharmacological and therapeu-
tic functions on the central nervous system.2
Rolipram 1, or (R,S)-4-(3-cyclopentyloxy-4-methoxyphen-
yl)-pyrrolidin-2-one, was initially developed as an anti-
depressant drug and commercialized in Europe by Scher-
ing AG.3 It is a potent and selective inhibitor of phos-
phodiesterase IV (PDE4), the main enzyme regulating
the concentration of the secondary messenger, cyclic
(3) (a) Seildelman, D.; Schmiechen, R.; Paschelke, G.; Muller, B.
(Schering A. G., Berlin). German Pat. 2413935/3, 1974; Chem. Abstr.
1976, 84, 30878u. (b) Schmiechen, R.; Horowski, R.; Palenschat, D.;
Paschelke, G.; Wachtel, H.; Kehr, W. (Schering A. G., Berlin). U.S.
Pat. 4193926, 1976.
(4) (a) Beavo, J. A.; Conti, M.; Heaslip, R. J. Mol. Pharmacol. 1994,
46, 399. (b) 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. (c) Sommer, N.;
Loeschmann, P. A.; Northoff, G. H.; Weller, M.; Steinbrecher, A.;
Steinbach, J. P.; Richtenfels, R.; Meyermann, R.; Reithmueller, A.;
Fontana, A.; Dichgans, J.; Martin, R. Nat. Med. 1995, 1, 244. (d) Seika,
M. Drugs Future 1998, 23, 108.
(5) (a) Marivet, M. C.; Bourguignon, J.-J.; Lugnier, C.; Mann, A.;
Stoclet, J.-C.; Wermuth, C.-G. J. Med. Chem. 1989, 32, 1450. (b)
Doherthy, A. M. Curr. Opin. Chem. Biol. 1999, 3, 466. (c) Burnouf, C.;
Pruniaux, M.-P.; Szilagyi, C. M. Annu. Rep. Med. Chem. 1998, 33, 91.
(d) For a recent application of Rolipram, see: Pearse, D. D.; Pereira,
F. C.; Marcillo, A. E.; Bates, M. L., Berrocal, Y. A.; Filbin, M. T.; Bunge,
M. B. Nat. Med. 2004, 10, 610.
† Chemistry Institute.
‡ Chemical Engineering Institute.
(1) Shorvon, S. Lancet 2001, 358, 1885.
(2) (a) Pearl, P. L.; Gibson, K. M. Curr. Opin. Neurol. 2004, 17, 107.
(b) Pacher, P.; Kecskemeti, V. Curr. Med. Chem. 2004, 11, 925. (c)
Tsang, S. Y.; Xue, H. Curr. Pharm. Des. 2004, 10, 1035.
10.1021/jo0484880 CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/06/2005
1050
J. Org. Chem. 2005, 70, 1050-1053

SCHEME 1. Synthesis of the Aryldiazonium
Tetrafluoroborate 7
into the aryldiazonium tetrafluoroborate 7 using a stan-
dard procedure, as indicated in Scheme 1, in 73% yield
after recrystallization.
Next, the N-Boc-3-pyrroline 8 (prepared in 82% yield
according to the protocol of Grubbs)9 was submitted to a
Heck-Matsuda arylation with the aryldiazonium tet-
rafluoroborate salt 7 in the presence of 2 mol % Pd(OAc)2
in CH3CN/H2O (1:1, v/v).8b The reaction proceeded rapidly
(30-45 min) to furnish lactamol 10, which was isolated
and used in the next step without further purification
(Scheme 2). Under the Heck-Matsuda conditions, the
primary product of the Heck arylation was the endocyclic
enecarbamate 9, which quickly underwent hydrolysis due
to the acidity of the reaction medium, to provide lactamol
10.10
SCHEME 2. Heck-Matsuda Reaction Coupling
the Pyrrolidine Ring to the Aromatic Moiety
The crude lactamol 10 was then oxidized with catalytic
tetrapropylammonium perruthenate (TPAP), with N-
methylmorpholine-N-oxide (NMO) as a co-oxidant in CH2-
Cl2, to give lactam 11 (66% yield from 7).11 Oxidation
employing either pyridinium chlorochromate (PCC) in
CH2Cl2 or o-iodoxybenzoic acid (IBX) in EtOAc12 led to
lactam 11 in comparable yields (60-63%). Finally, acidic
hydrolysis of lactam 11 with 6 M HCl in ethyl acetate at
room temperature provided racemic Rolipram 1 in quan-
titative yield (Scheme 3). The physical and spectroscopic
data of Rolipram 1 were in excellent agreement with
those reported in the literature.6
SCHEME 3. Synthesis of Rolipram 1 from the
Heck-Matsuda Adduct 10
Following the protocol described above, racemic Rolip-
ram was synthesized in six steps from commercially
available 5-nitro-2-methoxyphenol 4 in an overall yield
of 45% (average of 87-88% yields per step).13
The Heck-Matsuda approach was flexible enough to
allow the synthesis of the unreported γ-amino butyric
acids (GABA) analogues 13 and 14. Thus, basic hydroly-
sis of lactam 11 with LiOH in THF using Grieco’s
conditions14 produced N-protected γ-amino acid 12 in 85%
yield. Removal of the Boc protecting group occurred
smoothly with 6 M HCl/EtOAc (1:1) at room temperature
to provide the desired γ-amino butyric acid hydrochloride
13 in quantitative yield. The temperature of acidic
hydrolysis significantly affects the type of product ob-
tained. Thus, lactam 11 was hydrolyzed at 95 °C with 6
M HCl for 12 h to cleanly furnish the hydrochloride 14
in 84% yield. On the other hand, when hydrolysis of
lactam 11 was carried out under acidic conditions at
reflux, a hard-to-separate mixture of the γ-amino butyric
Ether 5 was next subjected to catalytic hydrogenation
(H2, Pd-C, EtOAc, 10 h), followed by filtration through
Celite and acidification with 6 M HCl to provide the pure
aniline hydrochloride 6 in 95% yield. Acidification with
HCl caused precipitation of the ammonium salt, which
helped to improve the yields. Moreover, purification of
the hydrochloride 6 was unnecessary; washing the crude
hydrochloride 6 with CH2Cl2 resulted in a white solid of
high purity. The hydrochloride 6 was then transformed
(6) For previous synthesis of Rolipram, see: (a) Mulzer, J.; Zuhse,
R.; Schmiechen, R. Angew. Chem., Int. Ed. Engl. 1992, 31, 870-872.
(b) Meyers, A. I.; Snyder, L. J. Org. Chem. 1993, 58, 36-42. (c) Baures,
P. W.; Eggleston, D. S.; Erhard, K. F.; Cieslinski, L. B.; Thorphy, T.
J.; Christensen, S. B. J. Med. Chem. 1993, 36, 3274-3277. (d) Mulzer,
J. J. Prakt. Chem. 1994, 336, 287-291. (e) Braun, M.; Opdenbusch,
K.; Unger, C. Synlett 1995, 11, 1174-1176. (f) Honda, T.; Ishikawa,
F.; Kanai, K.; Sato, S.; Kato, D.; Tominaga, H. Heterocycles 1996, 42,
109-112. (g) Langlois, N.; Wang, H.-S. Synth. Commun. 1997, 27,
3133-3144. (h) Diaz, A.; Siro, J. G.; Garc´ıa-Nav´ıo, J. L.; Vaquero, J.
J.; Alvarez-Builla, J. Synthesis 1997, 559-562. (i) Demnitz, J.; LaVec-
chia, L.; Bacher, E.; Keller, T. H.; Mu¨ller, T.; Schu¨rch, F.; Weber, H.-
P.; Pombo-Villar, E. Molecules 1998, 3, 107-119. (j) Anada, M.; Mita,
O.; Watanabe, H.; Kitagaki, S.; Hashimoto, S. Synlett 1999, 1775-
1777. (k) Barluenga, J.; Ferna´ndez-Rodr´ıguez, M. A.; Aguilar, E.;
Ferna´ndez-Mar´ı, F.; Salinas, A.; Olano, B. Chem. Eur. J. 2001, 7,
3533-3544. (l) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124,
13394-13395. (m) Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald, M.
A.; King, S. A.; Morton, H. E.; Plagge, F. A.; Preskill, M.; Wagaw, S.
H.; Wittenberger, S. J.; Zhang, J. J. Am. Chem. Soc. 2002, 124, 13097-
13105. (n) Yoon, C. H.; Nagle, A.; Chen, C.; Gandhi, D.; Jung, K. W.
Org. Lett. 2003, 5, 2259-2262. (o) Chang, M.-Y.; Sun, P.-P.; Chen, S.-
T.; Chang, N.-C. Heterocycles 2003, 60, 1865-1872. (p) Becht, J.-M.;
Meyer, O.; Helmchen, G. Synthesis 2003, 2805-2810.
(7) Rolipram is a very expensive tool for pharmacological investiga-
tions: (()-Rolipram: 10 mg, US$ 55; 50 mg, US$ 245; 10 mg of (R)-
(-)-Rolipram or (S)-(+)-Rolipram: US$ 129. TOCRIS online catalogue
(http://www.tocris.com).
(8) (a) Carpes, M. J. S.; Correia, C. R. D. Synlett 2000, 1037. (b)
Carpes, M. J. S.; Correia, C. R. D. Tetrahedron Lett. 2002, 43, 741. (c)
Severino, E. A.; Costenaro, E. R.; Garc´ıa, A. L. L.; Correia, C. R. D.
Org. Lett. 2003, 5, 305. (d) Garc´ıa, A. L. L.; Correia, C. R. D.
Tetrahedron Lett. 2003, 44, 1553.
(9) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426-
5427.
(10) For recent results on the mechanism of the Heck-Matsuda
reaction: Sabino, A. A.; Machado, A. H. L.; Correia, C. R. D.; Eberlin,
M. N. Angew. Chem., Int. Ed. 2004, 43, 2514-2518.
(11) For a review on oxidation with TPAP, see: Ley, S. V.; Norman,
J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 640.
(12) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001-3003.
(13) Correia, C. R. D.; Garc´ıa, A. L. L. Brazilian Patent BR 204007,
2004.
(14) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48,
2424.
J. Org. Chem, Vol. 70, No. 3, 2005 1051

SCHEME 4. Conversion of the 4-Arylpyrrolidin-2-one 11 into New GABA Derivatives
SCHEME 5. Synthesis of 4-(9,10-Dioxo-9,10-di-
hydro-anthracenyl)-pyrrolidin-2-ones 18 and 20a
SCHEME 6. Hydrolysis of Pyrrolidinones 17 and
19 to the Anthracenyl GABA Derivatives
a Reagents and Conditions: (a) (1) Pd(OAc)2, 8, CH3CN/H2O;
(2) PCC, CH2Cl2, rt, 3 h. (b) 6 N HCl/EtOAc (1:1), rt, 2 h.
Recently, there has been increasing interest in the
pharmaceutical sector in the synthesis of single enanti-
omers of chiral drugs.17 As part of an ongoing project to
associate continuous simulated moving bed chromatog-
raphy (SMBC) to organic synthesis, the racemic Rolipram
(1 g scale) prepared as described herein was resolved into
its enantiomers by means of a semipreparative chiral
simulated moving bed chromatographic unit composed
of eight semipreparative columns having microcrystalline
cellulose triacetate (MCTA)6c as a chiral stationary phase.
The SMBC was performed with ethanol as an eluent and
with a feed concentration of 4.0 g/L to provide enantio-
merically enriched (R)-(-)-1 (>88% ee) as determined by
analytical HPLC analysis on a Kromasil Chiral TBB
column and (S)-(+)-1 (>68% ee), with good recoveries.
After a single recrystallization of the compound obtained
in the raffinate stream in EtOAc/Hex, the enantiomer
(R)-(-)-1 was obtained with more than 96% enantiomeric
excess (Fig. 1 in Supporting Information).
In summary, we report a new, practical, and economic
synthesis of the phosphodiesterase inhibitor Rolipram on
a multigram scale as well as the synthesis of new 4-aryl
pyrrolidones and â-aryl-γ-amino butyric acids (GABA
derivatives) employing an efficient Heck-Matsuda aryl-
ation of 3-pyrroline with aryldiazonium tetrafluorobo-
rates. We successfully separated racemic Rolipram into
its enantiomers using a “locally built” Chiral SMB
chromatographic unit composed of eight semipreparative
columns containing the low-cost MCTA as a chiral
acid hydrochlorides 14/15 was obtained in 60% yield, in
a ratio of ∼2:1, as determined by 1H NMR in D2O
(Scheme 4).
Due to our interest in new 4-arylpyrrolidones we
additionally obtained the unreported 4-(9,10-dioxo-9,10-
dihydro-anthracenyl)-pyrrolidin-2-ones 18 and 20 in
excellent overall yields (67 and 60% yields, respectively)
from the 9,10-dioxo-9,10-dihydro anthracenyl diazonium
salts 16a and 16b, as shown in Scheme 5. The corre-
sponding anthracenyl diazonium salts were obtained
following Milner’s procedure.15
Acidic hydrolysis of lactams 17 and 19 produced the
expected γ-amino butyric acid hydrochlorides 21 (90%)
and 22 (89%), respectively (Scheme 6).
Semipreparative Simulated Moving Bed Chro-
matography. The SMB Chromatography is an auto-
mated, continuous, and multicolumn chromatographic
system, which has reduced solvent consumption, time-
consumption, and purification costs.16 This technique
simulates movement of the chromatographic packing
material, or bed, against the liquid phase and allows a
continuous recovery of the desired compound. In this
process, the solvent and the binary mixture of compounds
(racemate) to be resolved are injected into and withdrawn
from a ring of chromatographic columns, at periodic and
simultaneous switching points between the columns in
the direction of the desorbent flow.
(15) Milner, D. J. Synth. Commun. 1992, 22, 73.
(16) McCoy, M. Chem. Eng. News 2000, 78 (June 19), 17.
(17) Rouhi, M. A. Chem. Eng. News 2004, 82 (June 14), 47.
1052 J. Org. Chem., Vol. 70, No. 3, 2005

MHz, CDCl3, rt): δ ) 172.8, 149.7, 149.1, 147.7, 132.7, 118.5,
113.5, 112.1, 82.9, 80.5, 56.0, 53.3, 40.5, 36.0, 32.8, 28.0, 24.0.
MS: m/z (rel intensity) ) 375 (17) [M]+• , 207 (100), 150 (83),
135 (15), 57 (52). Anal. Calcd for C21H29NO5: C, 67.18; H, 7.79;
N, 3.73. Found: C, 67.05; H, 7.70; N, 3.78. HRMS m/z calcd for
C21H29NO5, 375.20457; found, 375.20451.
stationary phase. (R)-(-)-Rolipram was obtained in >96%
ee after a single recrystallization of the material sepa-
rated in the raffinate stream.
Experimental Section
4-(3-Cyclopentyloxy-4-methoxyphenyl)-pyrrolidin-2-
one (Rolipram, 1). Lactam 11 (4.85 g, 12.92 mmol) was
dissolved in 50 mL of 6 M HCl/EtOAc (1:1). After stirring at
room temperature for 2 h, the solution was diluted with 80 mL
of EtOAc/H2O (3:1) and transferred to a separatory funnel and
the layers were separated. The organic layer was washed with
water, saturated Na2CO3 solution, and brine and then dried over
anhydrous Na2SO4. After filtration, the solvent was evaporated
in vacuum to give 3.55 g (100% yield) of Rolipram 1 as a white
solid. Mp: 130.5-131.5 °C (lit.3 130-132 °C). TLC: Rf ) 0.21
(EtOAc) phosphomolybdic acid. IR (film, NaCl) ν (cm-1): 3201,
3093, 2958, 2873, 1678, 1585, 1516, 1265, 1238, 1165, 1138,
1030, 818. IR (KBr) ν (cm-1): 3437, 3201, 3097, 2943, 2912, 2831,
1-(tert-butoxycarbonyl)-4-(3-cyclopentyloxy-4-methox-
yphenyl)-pyrrolidin-2-ol (10). To a solution of N-tert-butoxy-
carbonyl-3-pyrroline 8 (6.0 g, 35.46 mmol) in 160 mL of CH3CN/
H2O (1:1) was added the diazonium salt 7 (7.23 g, 23.62 mmol),
followed by addition of Pd(OAc)2 (110 mg, 2 mol %). The reaction
medium was stirred for 45 min at 30 °C. The reaction was
monitored by nitrogen evolution and by the precipitation of Pd-
(0). The mixture was diluted with EtOAc (∼250 mL), transferred
to a separatory funnel, and extracted with saturated NaHCO3
solution and brine. The organic layer was dried over anhydrous
Na2SO4 and filtered, and the solvent was removed under vacuum
to give 10 as a dark colored oil, which was used in the next step
without further purification. TLC: Rf ) 0.38 and 0.66 (EtOAc/
Hex ) 1:1) phosphomolybdic acid; IR (film, NaCl, crude oil) ν
(cm-1): 3452, 2966, 2870, 2835, 1693, 1516, 1392, 1257, 1165,
1126, 1011, 879.
1-(tert-Butoxycarbonyl)-4-(3-cyclopentyloxy-4-methoxy-
phenyl)-pyrrolidin-2-one (11). To a solution of 8.916 g of the
crude lactamol 10 (∼23.6 mmol) in 180 mL of CH2Cl2 were added
830 mg (2.36 mmol, 10 mol %) of tetrapropylammonium perru-
thenate and 5.44 g (47.25 mmol) of N-methyl-morpholine-N-
oxide. The reaction mixture was vigorously stirred at room
temperature. After 3 h, the crude mixture was filtered through
a pad of silica gel (approximately 6 cm of SiO2 in a 5 cm i.d.
column) and washed with CH2Cl2. The solvent was evaporated
in vacuum, and the residue was flash chromatographed on silica
gel (EtOAc/hexane 10-20%) to provide 5.86 g (66% yield over
two steps) of lactam 11 as a white solid. Mp: 81-83 °C. TLC:
Rf ) 0.64 (EtOAc/Hex ) 1:1) phosphomolybdic acid. IR (film,
NaCl) ν (cm-1): 2962, 2873, 1786, 1751, 1712, 1516, 1365, 1315,
1261, 1153, 1018. 1H NMR (300 MHz, CDCl3, rt): δ ) 6.86-
6.73 (m, 3H), 4.76 (m, 1H), 4.13 (dd, J ) 8.1 and 10.2 Hz, 1H),
3.83 (s, 3H), 3.65 (dd, J ) 8.8 and 10.2 Hz, 1H), 3.46 (m, 1H),
2.87 (dd, J ) 8.8 and 17.6 Hz, 1H), 2.67 (dd, J ) 9.5 and 17.6
Hz, 1H), 2.04-1.74 (m, 6H), 1.70-1.43 (m, 11H). 13C NMR (75
1
1701, 1516, 1250, 1146, 1003, 814. H NMR (300 MHz, CDCl3,
rt): δ ) 6.91-6.65 (m, 4H), 4.78 (m, 1H), 3.83 (s, 3H), 3.76
(apparent t, J ) 8.8 Hz, 1H), 3.62 (apparent m, 1H), 3.39 (dd, J
) 7.3 and 8.8 Hz, 1H), 2.72 (dd, J ) 8.8 and 16.8 Hz, 1H), 2.48
(dd, J ) 8.8 and 16.8 Hz, 1H), 2.01-1.74 (m, 6H), 1.72-1.53
(m, 2H). 13C NMR (75 MHz, CDCl3, rt): δ ) 177.6, 148.9, 147.7,
134.4, 118.6, 113.7, 112.0, 80.5, 56.1, 49.8, 40.0, 38.2, 32.8, 24.0.
MS: m/z (rel intensity) ) 275 (25) [M]+•, 207 (87), 150 (100),
135 (24). HRMS m/z calcd for C16H21NO3, 275.15214; found,
275.15212.
Acknowledgment. We thank the Research Sup-
porting Foundation of the State of Sa˜o Paulo (FAPESP)
for financial support. We also thank FAPESP, CNPq,
and CAPES for fellowships.
Supporting Information Available: Chromatographic
analysis of (R)-(-)-Rolipram, experimental details and spec-
troscopic characterization for compounds 1, 5-7, 10-14, 14/
15, and 7-22. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0484880
J. Org. Chem, Vol. 70, No. 3, 2005 1053