First highly regio- and diastereoselective [3+2] cycloaddition of chiral nonracemic Fischer carbene complexes with azomethine ylides: An enantioselective synthesis of (+)-Rolipram

Article abstract of DOI:10.1002/1521-3765(20010817)7:16<3533::AID-CHEM3533>3.0.CO;2-E

A new procedure for the synthesis of 1,3,4-trisubstituted and 1,4-di-substituted pyrrolidin-2-one derivatives in an enantioselective fashion is reported. The 1,3-dipolar cycloaddition of (±)-menthol and (-)-8-phenylmenthol derived Fischer alkoxy alkenyl carbene complexes with in situ generated functionalized azomethine ylides gives the corresponding cycloadducts as chelated tetracarbonyl Fischer carbene complexes. Only one regioisomer is detected in all cases, and the diastereoselectivity of the reaction is very high when (-)-8-phenylmenthol derived carbenes are employed. Oxidation and further transformation of the cycloadducts provide an easy access to pyrrolidin-2-ones. The anti-inflammatory and antidepressant drug (+)-Rolipram is readily prepared in four steps in a 20% overall yield by taking advantage of this newly developed methodology.

Full text of DOI:10.1002/1521-3765(20010817)7:16<3533::AID-CHEM3533>3.0.CO;2-E

FULL PAPER
First Highly Regio- and Diastereoselective [3‡2] Cycloaddition of Chiral
Nonracemic Fischer Carbene Complexes with Azomethine Ylides:
An Enantioselective Synthesis of (‡)-Rolipram
Jose Barluenga,*[a] Manuel A. FernaÂndez-Rodríguez,[a] Enrique Aguilar,[a]
FeÂlix FernaÂndez-Marí,[a, b] Alejandro Salinas,[a, c] and Bernardo Olano[a]
Abstract: A new procedure for the syn-
thesis of 1,3,4-trisubstituted and 1,4-di-
substituted pyrrolidin-2-one derivatives
in an enantioselective fashion is report-
ed. The 1,3-dipolar cycloaddition of (Æ)-
menthol and ( )-8-phenylmenthol de-
rived Fischer alkoxy alkenyl carbene
complexes with in situ generated func-
tionalized azomethine ylides gives the
corresponding cycloadducts as chelated
tetracarbonyl Fischer carbene com-
plexes. Only one regioisomer is detected
in all cases, and the diastereoselectivity
of the reaction is very high when ( )-8-
phenylmenthol derived carbenes are
employed. Oxidation and further trans-
formation of the cycloadducts provide
an easy access to pyrrolidin-2-ones. The
anti-inflammatory and antidepressant
drug (‡)-Rolipram is readily prepared
in four steps in a 20% overall yield by
taking advantage of this newly devel-
oped methodology.
Keywords: azomethine ylides
carbenes cycloaddition
pyrrolidinones ´ Rolipram
´
´
´
few examples of the latter can be found in the chemical
literature.[4] In these 1,3-dipolar cycloadditions, the presence
of the metal pentacarbonyl moiety results in an increase of the
reaction rate, as well as in an improvement in the regio- and
diastereoselectivity of the processes when carbenes are
employed instead of their ester analogues. This allows one
to prepare enantiopure cycloadducts when starting from ( )-
8-phenylmenthol derived carbenes.[5]
Pyrrolidin-2-ones possess varied biological and pharma-
ceutical activity and are also valuable and effective inter-
mediates for the synthesis of pyrrolidine alkaloids, g-amino
acids, and other biologically interesting nitrogen-containing
products.[6] The preparation of pyrrolidin-2-ones is mainly
based on two approaches: i) transformation of pyroglutamic
acid derivatives[7] and ii) Michael addition of glycine derived
enolates to activated olefins followed by cyclization,[8]
although other routes, including 1,3-dipolar cycloadditions,
have also been reported.[9]
Among the drugs bearing a pyrrolidin-2-one ring, Roli-
pram 1 is a potent and selective inhibitor of cyclic-AMP
specific phosphodiesterase (cAMP PDE) designated PDE IV,
and it is known to bind stereoselectively and with very high
affinity to binding sites in brain tissue. PDE IVappears also to
be the predominant functional enzyme in a variety of human
inflammatory cells. As a consequence Rolipram, which was
initially developed as a therapeutically interesting reagent for
the treatment of central nervous system (CNS) disorders
(mainly as an antidepressant),[10] has presented great potential
(as well as other selective PDE IV inhibitors) as an anti-
Introduction
Five- and six-membered rings are ubiquitous in both naturally
occurring compounds and synthetic products. The most
powerful tool to access six-membered rings is widely recog-
nized to be the Diels ± Alder reaction, while 1,3-dipolar
cycloadditions have proved to be extremely versatile for the
preparation of five-membered rings. We have been interested
in the role of Fischer carbene complexes[1] to create six- and
five-membered rings by means of [4‡2] and [3‡2] cyclo-
additions.[2] While the former have been widely developed,[3]
Â
[a] Prof. Dr. J. Barluenga, Lic. M. A. Fernandez-Rodríguez, Dr. E. Aguilar
Â
Dr. F. Fernandez-Marí, Lic. A. Salinas, Dr. B. Olano
Instituto Universitario
Â
de Química Organometalica
ªEnrique Molesº, Unidad Asociada al C.S.I.C.
Â
Universidad de Oviedo, C/Julian Clavería, 8
33006 Oviedo (Spain)
Fax : (‡34)985-103-450
E-mail: barluenga@sauron.quimica.uniovi.es
Â
[b] Dr. F. Fernandez-Marí
Current address
Asturpharma, Polígono Industrial Silvota
C/PenÄa Brava, 22-23, Silvota, Llanera
33192, Asturias (Spain)
[c] Lic. A. Salinas
Current address
Asturiana de Aleaciones (Aleastur)
Polígono Industrial de Maqua, s/n
apt.371, Aviles, 33400, Asturias (Spain)
Â
Chem. Eur. J. 2001, 7, No. 16 ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0716-3533 $ 17.50+.50/0
3533

J. Barluenga et al.
FULL PAPER
We disclose here a novel synthesis of pyrrolidin-2-ones with
2 as dipole precursors in [3‡2] dipolar cycloadditions with
chiral nonracemic alkoxy alkenyl Fischer carbenes and the
application of the developed methodology to an enantiose-
lective synthesis of (‡)-Rolipram.
OMe
O
O
N
H
1 (+)-Rolipram
Results and Discussion
inflammatory agent, of particular value in the treatment of
diseases such as asthma.[11] In fact, although both enantiomers
are active, the levorotatory isomer, for which several synthe-
ses have been recently reported,[12] has proved to be the most
active one.
The recently described functionalized azomethine ylide
precursor 2a[13] attracted our attention as it seemed to be a
suitable starting material to react with Fischer alkenyl carbene
complexes. In fact, treatment of iminium salt 2a with CsF
generates azomethine ylide 3a that behaves as a synthetic
equivalent of carbonyl-fused and thiocarbonyl-fused dipoles
4a and 5a (Scheme 1) and cycloadds in a 1,3-dipolar fashion
to alkenes, ketones, and thioketones; the addition allows the
preparation of interesting g-lactam alkaloids,[14] 1,3-oxazol-
idine,[15] and thiazolidine-2-thiones,[15] respectively.[16]
The cycloaddition reactions were initially performed by using
(Æ)-menthol derived carbene 6a as a model system at differ-
ent temperatures. Treatment of (Æ)-menthol derived car-
bene 6a with 2a in the presence of CsF at room temperature
yielded cycloadduct 7a as a single regioisomer, although a
mixture of two diastereomers with moderate diastereoselec-
tivity could be detected (Scheme 2). The reaction was
immediate when carried out at room temperature (see
Table 1, entry 1) and it only took 30 minutes to be completed
at 308C with a slight improvement in the diastereoselectiv-
ity (Table 1, entry 2), but it did not proceed at temperatures
lower than 508C. The reaction was extended to other
menthol derived Fischer alkenyl carbene complexes 6b ± d
and iminium salts 2a and 2b; in all these cases, 1:1 mixtures of
diastereomers were obtained at 508C (Table 1, entries 3 ±
5). However, when the reaction was performed using ( )-8-
phenylmenthol derived carbenes 6e ± h a great improvement
in the diastereoselectivity was achieved, and only one
diastereomer was detected by 1H NMR spectroscopy
(300 MHz) (Table 1, entries 6 ± 12).
TfO
S
S
≡
X
N
S
S
N
TMS
N
Carbenes 7 bear only four carbonyl ligands as supported by
the observation in the 13C NMR and FT-IR spectra of a
tetracarbonyl ligand pattern. This fact indicates that they are
chelated tetracarbonyl alkoxy Fischer carbenes stabilized by
coordination of S to the metal center.[17] This is one of the few
cases reported so far of this situation, although several
examples in which other heteroatoms (N, O),[5, 17a, 18] ole-
fins,[3k, 19] or alkynes[20] stabilize the metal have been de-
scribed. This result is particularly interesting as it allows us to
assign the proposed regiochemistry to carbenes 7; the other
R
R
R
3
4
X = O
X = S
a
R = H
2
5
b
R = Ph
Scheme 1. Iminium salts (2) as precursors of azomethine ylides (3) that
behave as synthetic equivalents of carbonyl-fused and thiocarbonyl-fused
dipoles.
Abstract in Spanish: En este artículo se describe un nuevo
procedimiento para la preparacion de derivados 1,3,4-trisusti-
Â
tuidos y 1,4-disustituidos de pirrolidin-2-ona de forma enan-
Â
tioselectiva. La cicloadicion 1,3-dipolar de complejos alcoxial-
quenilcarbeno de Fischer derivados de (Æ)-mentol y ( )-8-
fenilmentol con iluros de azometino funcionalizados, genera-
dos in situ, origina los correspondientes cicloaductos como
tetracarbonil complejos carbeno de Fischer quelados. En todos
Â
los casos se detecta solamente un regioisomero de los dos
Â
Â
posibles; ademas, la diastereoselectividad de la reaccion es muy
elevada cuando se utilizan complejos carbeno derivados de
Â
Â
( )-8-fenilmentol. La oxidacion y posterior transformacion de
los cicloaductos supone una ruta muy sencilla para acceder a
Â
pirrolidin-2-onas. Como una aplicacion de la nueva metodo-
Â
Â
logía desarrollada se llevo a cabo la síntesis del farmaco (‡)-
Rolipram, que presenta actividad anti-inflamatoria y anti-
depresiva, en cuatro pasos y con un rendimiento global del
20%.
Scheme 2. Reaction of in situ generated azomethine ylides (3) with
carbene complexes (6).
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Chem. Eur. J. 2001, 7, No. 16

Enantioselective Synthesis of (‡)-Rolipram
3533±3544
Table 1. Carbene cycloadducts 7 obtained by cycloaddition of alkenyl carbenes 6 Table 2. Esters 8 resulting from oxidation of carbene adducts 7 or by
with azomethine ylides 3 derived from iminium salts 2a and 2b. sequential cycloaddition ± oxidation from carbenes 6.
6
R*OH
R1
R
7
dr[a]
Yield
[%][b]
s.m.[a] R*OH
R1
R
8
Yield [%][b] (8/9/10)
1
2
3
4
5
6
7
7a
7a
7c
6c
7d
6d
7e
(Æ)-menthol Ph
(Æ)-menthol Ph
(Æ)-menthol Ph
(Æ)-menthol Ph
(Æ)-menthol 2-furyl
(Æ)-menthol 2-furyl
H
H
a
a
b
b
c
28[c] (28/-/-)
26[c,d] (26/-/-)
78[c] (45/33/-)
38[c,e] (38/-/-)
52[c] (20/32/-)
32[c,e] (32/-/-)
quantitative
(>99/-/-)
1
2
a
a
(Æ)-menthol
(Æ)-menthol
Ph
Ph
H
H
a
a
3:1[c] 28
4:1[d] 54
Ph
Ph
Ph
Ph
H
c
d
O
3
b
(Æ)-menthol
Ph
b
1:1
67
(
)-8-phenyl- Ph
menthol
)
MeO
8
7 f
(
)-8-phenyl- 2-furyl
H
e
f
25[c] (25/-/-)
menthol
4
5
6
7
c
d
e
f
(Æ)-menthol
(Æ)-menthol
Ph
2-furyl
Ph
Ph
H
c
d
e
f
1:1
1:1
> 95:5
> 95:5
45
69
29
57
(
(
)-8-phenylmenthol Ph
)-8-phenylmenthol 2-furyl
H
9
7g
(
)-8-phenyl-
H
93 (55/23/15)
77 (38/19/20)
O
menthol
)
MeO
O
8
g
(
)-8-phenylmenthol
H
g
> 95:5
60
)
MeO
10 7h
(
)-8-phenyl-
H
g
Fe
menthol
9
h
(
)-8-phenylmenthol
H
h
> 95:5
66
31[c,e] (31/-/-)
27[c,e] (27/-/-)
Fe
11 6e
12 6 f
(
)-8-phenyl- Ph
Ph
Ph
h
i
menthol
(
menthol
)-8-phenyl- 2-furyl
10
11
e
f
(
(
)-8-phenylmenthol Ph
)-8-phenylmenthol 2-furyl
Ph
Ph
i
j
> 95:5
> 95:5
60
68
13 7k
(
)-8-phenyl-
Ph
j
61 (37/8/16)
O
O
12
g
(
)-8-phenylmenthol
Ph
k
> 95:5
58
menthol
)
)
MeO
MeO
1
[a] Starting material. [b] Isolated and combined yields for the sunlight
promoted oxidation step, based on carbene adducts 7 unless otherwise
stated; in brackets, isolated yields of each compound. [c] Variable amounts
of 9 and/or 10 were also detected, although not isolated. [d] Oxidation
performed with PNO. [e] Isolated yields for a sequential cycloaddition ±
oxidation procedure based on alkenyl carbenes 6.
[a] Diastereomeric ratio (dr) determined by H NMR spectroscopy (300 MHz).
[b] Isolated yields based on alkenyl carbenes 6; all reactions were carried out at
508C unless otherwise stated. [c] Reaction performed at room temperature.
[d] Reaction performed at 308C.
regioisomer must be a pentacarbonyl derivative, as S coordi-
nation to chromium would not be feasible in this case.
Carbenes 7 could be readily oxidized to the corresponding
esters 8 by treatment with pyridine N-oxide (PNO) or, better,
just by sunlight exposure. However, the isolated yield of
esters 8 was low to moderate in most cases, as variable
amounts of thiopyrrolidinones 9 and pyrrolidinones 10 were
obtained (Table 2); the combined yield was quite high
(entries 3, 7, 9, and 10, Table 2). Other oxidants commonly
employed in carbene chemistry (such as cerium ammonium
nitrate, DMSO) gave less satisfactory results.
to a p-stacking interaction between that phenyl group and the
alkene double bond,[5] as depicted in Scheme 4.
We then checked the [3‡2] cycloaddition reactions of
dipole 2 with the analogue esters, such as (1R,2S,3R)-8-
phenylmenthyl cinnamate and (Æ)-menthyl cinnamate, in
order to confirm the advantages of our carbene chemistry.
Those reactions did not proceed either at low or at room
temperature; in fact the mixture had to be refluxed in THF for
several days and was worked up before the starting esters
1
were totally consumed. The H NMR spectrum of the crude
The relative stereochemistry of the cycloadducts was
proposed to be trans as a result of the observation of
crosspeaks between H-3 and the hydrogen in position 3 in
the furyl group in NOESY experiments performed on
thiolactam 9e (Scheme 3). This was as expected if the facts
that 1,3-dipolar cycloadditions are suprafacial, and the stereo-
chemistry of the alkene is maintained are taken into account.
The absolute configuration of carbene complexes 7 was
assigned to be R for C-9 on the basis of the X-ray structure
of dithiolane derivative 8g[21] (Scheme 3). This should be the
result of a dipole approach to the olefin from the bottom face
because of an effective blocking of the upper face by the
phenyl group of the ( )-8-phenylmenthol chiral auxiliary due
residue showed the presence of compounds 8, 9, and 10 as a
complex mixture of regio- and diastereomers, the ratio of
which could not be determined (Scheme 5). This result was
O
OR*
OR*
Fe
O
O
R
9
H
H
3
H
S
S
N
N
S
9e
8g (X-ray)
Scheme 3. Structural assignments: NOESY crosspeaks for compound 9e
and absolute configuration for compound 8g determined by X-ray analysis.
Chem. Eur. J. 2001, 7, No. 16
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J. Barluenga et al.
FULL PAPER
variable amounts of N-benzylpyrrolidin-2-one carboxylic
acids 11 (Scheme 8). These compounds could be easily
separated by acid ± base extraction, and it is noteworthy that
( )-8-phenylmenthol, employed as a chiral auxiliary during
the cycloaddition process, was recovered in high yield and
purity after chromatographic purification. On the other hand,
treatment of 11 with copper(i) oxide in refluxing pyridine
allowed decarboxylation, which led to 12 in good yields.
The synthetic sequence from carbenes 6 to N-benzylpyrrol-
idin-2-ones 12 that involves five steps (cycloaddition ± car-
bene oxidation ± ester hydrolysis ± carbonyl deprotection ±
decarboxylation) resulted in an expedient and easy-to-work
transformation; it can be performed avoiding the isolation of
intermediates 7 ± 10 and with no more than two rapid filtra-
tions through Celite to remove cesium and chromium salts.
The reaction allows rapid access to N-benzylpyrrolidin-2-
ones 12. N-Benzyl pyrrolidin-2-ones 12 were analyzed by
HPLC using a chiral column in order to determine the
enantiomeric ratio, which was found to be 92:8 for 12a
(Table 3, entry 1), but this procedure was unsuccessful for
12b.
OR*
N
O
(CO)5Cr
H
(CO)4Cr
R1
R
R1
S
S
S
CH2
CH2R
N
S
Scheme 4. Mechanistic hypothesis: Postulated reactive conformation of 6,
in which the chiral auxiliary phenyl group shields the (Re,Re)-face of the
double bond, inducing selective attack from the (Si,Si)-face.
OR*
CsF, THF
O
+
2b
Complex mixtures
Ph
R*OH = (–)-8-Phenylmenthol, (±)-menthol
Scheme 5. Reaction of in situ generated azomethine ylides (3) with
cinnamates.
The final debenzylation step was accomplished by treat-
ment with lithium in liquid ammonia to give Rolipram 1 in
95% yield, while other classical hydrogenolysis methods (for
example, H2, Pd/C; H2, Pd(OH)2/C; cyclohexene, Pd(OH)2/
C; formic acid) failed. At this point, the sign of the specific
rotation {[a]2D6 ˆ ‡24.7 (c ˆ 0.23 in MeOH)} indicated that we
had prepared the dextrorotatory enantiomer, and this con-
firmed our model for the cycloaddition step. However, the
value of the specific rotation was smaller than the one
reported in the literature for the ( )-isomer {[a]D ˆ 31 (c ˆ
0.5 in MeOH)};[12d] a similar result had been previously
observed for the synthesis of Meyers and Snyder who
not surprising as we had previously observed that thiirane
extrusion and dithiolane hydrolysis could be achieved when
heating 8e in refluxing toluene to afford pyrrolidinone
derivatives 9e and 10e as a mixture in 63% and 14% isolated
yield, respectively (Scheme 6).
OR*
2-Furyl
OR*
2-Furyl
OR*
2-Furyl
O
O
O
Toluene
+
S
∆
O
N
S
N
N
S
10e
9e
8e
R*OH = (–)-8-Phenylmenthol
63 %
14 %
Scheme 6. Thermal decomposition of 8e in refluxing toluene.
OR*
HO2C
O
Ar
O
Ar
Ar
As an application of the methodology described above for
the synthesis of pharmaceutically interesting compounds, (‡)-
Rolipram 1 was chosen as a target. The retrosynthetic route to
1 is depicted in Scheme 7. As proposed therein, (‡)-Roli-
pram 1 should be easily prepared by a decarboxylation ± hy-
drogenolysis sequence from N-benzyl pyrrolidinone carbox-
ylic acid 11b, which, in turn, should be accessed by hydrolysis
of 10j. Pyrrolidin-2-one 10j can be obtained by transforma-
tion of the cycloadduct 7k that results from the reaction
between Fischer carbene 6g and azomethine ylide 3b, as
described earlier (Table 1, entry 12 and Table 2, entry 13).
As the oxidation of cycloadducts 7 led to a mixture of
products, several attempts to deprotect the carbonyl group
were unsuccessfully carried out on cycloadducts 7 and on
esters 8. We then decided to perform the hydrolysis of the
ester functionality prior to the carbonyl group deprotection.
To our surprise, when the crude residue from sunlight
oxidation of cycloadducts 7 was submitted to basic hydrolysis
(LiOH in 1,4-dioxane/H2O) N-benzylpyrrolidin-2-ones 12,
which resulted from an ester hydrolysis ± decarboxylation ±
carbonyl deprotection sequence, were obtained together with
N
O
N
O
N
H
Ph
Ph
11b
10j
1
OR*
S
TfO
(CO)4Cr
Ar
OR*
S
S
N
TMS
(CO)5Cr
+
N
Ph
S
Ar
Ph
6g
7k
2b
O
)
Ar = MeO
R*OH = (–)-8-Phenylmenthol
Scheme 7. Retrosynthetic analysis of (‡)-Rolipram (1).
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Chem. Eur. J. 2001, 7, No. 16

Enantioselective Synthesis of (‡)-Rolipram
3533±3544
Scheme 8. Synthesis of (‡)-Rolipram (1).
Table 3. Determination of the enantiomeric ratio by chiral HPLC analysis.
Column
Eluent
Flow Rate
Retention Time [min]
R isomer
Retention Time [min]
S isomer
er
1
[mLmin
]
12a
13
Chiralcel-OJ
Chiralcel-OD-H
HexH/IPA[a] 50:1
HexH/IPA 9:1
1.0
0.8
64.3
19.3
80.6
23.9
92:8 (R/S)
91:9 (S/R)
[a] HexH ˆ Hexane; IPA ˆ Isopropyl alcohol.
evacuated, and purged with nitrogen. All common reagents and solvents
were obtained from commercial suppliers and used without any further
purification unless otherwise indicated. CsF was dried by heating at 1208C
under vacuum (0.01 mmHg) for several hours (3 ± 10 h) immediately prior
to use. Fischer carbene complexes 6 were prepared following described
procedures,[5] except for 6h, which was obtained following a slightly
modified method; 6b and 6g have been synthesized for the first time, and
their spectroscopic data are reported below. The compound 3-cyclopentyl-
oxy-4-methoxybenzaldehyde, required for the synthesis of carbenes 6b and
6g, was prepared following literature procedures.[12b] Iminium salt 2a was
prepared as reported.[13] Solvents were dried by standard methods. Hexane,
ethyl acetate, and triethylamine were distilled before use. TLC was
performed on aluminum-backed plates coated with silica gel60 with F254
indicator; the chromatograms were visualized under ultraviolet light and/or
by staining with a Ce/Mo reagent, or anisaldehyde or phosphomolibdic acid
solutions and subsequent heating. Rf values are reported on silica gel. Flash
column chromatography was carried out on silica gel60 (230 ± 240 mesh).
For the determination of the enantiomeric ratio by HPLC, a ShimadzuLC-
10 and a WatersLC Module I Plus chromatograph were used, both of them
equipped with V-UV Diode-Array detectors; ChiralcelOJ and OD-H were
employed as chiral columns. Routine NMR measurements were recorded
on BrukerAC-200, AC-300, or DPX-300 spectrometers. 1H NMR: splitting
pattern abbreviations are: s, singlet; brs, broad singlet; d, doublet; t, triplet;
q, quartet; m, multiplet, ABq (AB quartet). 13C NMR: multiplicities were
determined by DEPT 90 and DEPT 135 experiments, abbreviations are: q,
CH3; t, CH2; d, CH; s, quaternary carbons. In the cases where a mixture of
diastereomers was observed, the abbreviation ªminº refers to the signals
assigned to the minor diastereomer, and the abbreviation ªmajº to the
signals belonging to the major one; in the cases where nothing is specified,
either it hasnꢁt been possible to assign the signal to any of the
diastereomers, or it belongs to both of them. NOESY experiments were
carried out on a BrukerAMX-400 spectrometer. Standard pulse sequences
were employed for the DEPT experiments. FT-IR measurements were
reported a specific rotation of [a]D ˆ 19.5 (c ˆ 1.15 in
MeOH)[12d] for a sample which proved to have ee > 99%. To
determine exactly the enantiomeric purity of our compound,
(‡)-Rolipram 1 was transformed into its Boc-protected
derivative 13 (Scheme 8). Chiral HPLC analysis of 13 indi-
cated an enantiomeric ratio of 91:9 (Table 3, entry 2). This
unexpected result is probably the consequence of the
undetected presence of the other diastereomer after the
cycloaddition reaction.[22]
Conclusion
In summary, we have established a new protocol to access 3,4-
disubstituted pyrrolidinone derivatives by a [3‡2] cycloaddi-
tion reaction; the employment of ( )-8-phenylmenthol derived
alkenyl Fischer carbenes allows us to obtain the cycloadducts
as a single regioisomer in a highly diastereoselective fashion.
The usefulness of this methodology for the synthesis of
pharmaceutically interesting compounds that contain a pyr-
rolidinone ring was proved by accomplishing the synthesis of
(‡)-Rolipram in 20% overall yield.
Experimental Section
General: All reactions involving air-sensitive compounds were carried out
under a N2 atmosphere (99.99%). All glassware was oven-dried (1208C),
Chem. Eur. J. 2001, 7, No. 16
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J. Barluenga et al.
FULL PAPER
performed with a Mattson 3000 FT-IR spectrometer. High-resolution mass
spectra (HRMS) were obtained with a Finnigan Mat95 Mass Spectrometer;
low-resolution mass spectra were obtained with a Hewlett-Packard 5880A
Spectrometer. In both cases, electron impact techniques (70 eV) were
employed. Melting points were determined on a Büchi ± Tottoli apparatus
and are uncorrected. For optical rotations, a Perkin-Elmer 241 polarimeter
was employed; values were determined using a sodium lamp, and the
concentration was reported in g/100 mL. Elemental analyses were carried
out with a Perkin-Elmer 240B microanalyzer.
Pentacarbonyl[1-((1R*,3R*,4S*)-menthyloxy)-trans-3-(3-cyclopentyloxy-
4-methoxyphenyl)-2-propenylidene]chromium(0) (6b): Red oil; yield:
94% (2.71 g); Rf ˆ 0.18 (hexane/CH2Cl2: 3:1); FT-IR (neat): nÄ ˆ 2052,
1
1977, 1928 (broad band), 1586 cm
;
1H NMR (300 MHz, CDCl3, 258C,
TMS): d ˆ 7.92 ± 7.70 (brs, 1H), 7.32 ± 6.85 (m, 4H), 5.19 ± 4.75 (m, 2H), 3.91
(s, 3H), 2.10 ± 0.70 (m, 26H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 224.2
(s), 217.0 (s), 152.9 (s), 147.9 (s), 127.1 (s), 124.1 (d), 114.0 (d), 111.6 (d), 80.5
(d), 67.8 (t), 55.9 (q), 48.1 (d), 33.9 (t), 32.7 (t), 31.0 (d), 26.4 (d), 25.4 (t),
24.0 (t), 21.8 (q), 21.4 (q), 16.9 (q); -the signals for the carbene carbon
(around d ˆ 323) and the menthyl CH O carbon (around d ˆ 91) were not
observed-; elemental analysis calcd (%) for C30H36CrO8 (576.61): C 62.49,
H 6.29; found C 62.25, H 6.20.
Synthesis of N-benzyl,1,3-dithiolanilidene,trimethylsilyl ammonium tri-
fluoromethanesulfonate 2b: It was prepared following a two-step proce-
dure similar to the one employed for the synthesis of 2a[13] (Scheme 9). In
the first step the yield was low (31%), but cheap reagents were employed;
in the second step, which required the more expensive trimethylsilylmethyl
trifluoromethanesulfonate the yield was quantitative.
Pentacarbonyl[1-((1R,3R,4S)-8-phenylmenthyloxy)-trans-3-(3-cyclopent-
yloxy-4-methoxyphenyl)-2-propenylidene]chromium(0) (6g): Red oil;
yield: 80% (2.61 g); Rf ˆ 0.57 (hexane/AcOEt, 5:1); FT-IR (neat): nÄ ˆ
1
2051, 1975, 1932 (broad band), 1587 cm
;
1H NMR (200 MHz, CDCl3,
258C, TMS): d ˆ 7.66 (brs, 1H), 7.42 ± 6.83 (m, 8H), 6.10 (brs, 1H), 5.26
(brs, 1H), 4.87 (brs, 1H), 3.92 (s, 3H), 2.60 (brs, 1H), 2.40 ± 0.70 (m, 24H);
13C NMR (75 MHz, CDCl3, 258C): d ˆ 324.4 (s), 223.9 (s), 217.1 (s), 152.6
(s), 151.0 (s), 147.7 (s), 139.4 (d), 128.9 (d), 127.9 (d), 127.0 (s), 125.3 (d),
124.9 (d), 124.4 (d), 114.5 (d), 111.4 (d), 91.3 (d), 80.5 (d), 55.9 (q), 52.5 (d),
43.5 (t), 39.5 (s), 34.5 (t), 32.7 (t), 31.1 (d), 28.0 (q), 26.5 (t), 25.1 (q), 24.1 (t),
21.6 (q); elemental analysis calcd (%) for C36H40CrO8 (652.70): C 66.25, H
6.18; found C 66.03, H 6.15.
TfO
1) CS2 / EtOH
S
S
TMS
OTf
Ph
NH2
2) ClCH2CH2Cl
NaOH
S
S
CH2Cl2
N
N
TMS
Ph
Ph
quant.
31 %
2b
Pentacarbonyl[1-((1R,3R,4S)-8-phenylmenthyloxy)-trans-3-ferrocenyl-2-
propenylidene]chromium(0) (6h): BuLi (4.37 mmol, 2.73 mL, 1.6m in
Scheme 9. Preparation of iminium salt (2b).
hexanes) was added dropwise to
a solution of pentacarbonyl[1-
((1R,3R,4S)-8-phenylmenthyloxy)ethenylidene]chromium(0)[5]
(3.64 mmol, 1.64 g) in dry Et2O (40 mL) at 808C. After 1 h, a solution of
ferrocenecarbaldehyde (7.28 mmol, 1.56 g) and BF3 ´ OEt2 (7.28 mmol,
0.92 mL) in dry Et2O (40 mL) was added dropwise at 808C, and the
reaction mixture was stirred and allowed to reach room temperature
overnight. Silica gel (5 g) was added, and solvents were evaporated under
vacuum. The residue was purified by column chromatography on silica gel
under nitrogen using hexane/CH2Cl2 (95:5) as eluent. Purple foam; yield:
65% (1.53 g).
N-Benzyl-1,3-dithiolane-2-imine: Thus, in this first step the compound was
prepared as follows. Benzylamine (200 mmol, 21.84 mL) was added
dropwise to a solution of CS2 (200 mmol, 12.03 mL) in EtOH (200 mL)
at 08C. A white suspension was formed and, once the addition of
benzylamine was completed, the reaction mixture was stirred for 30 min.
A solution of NaOH (400 mmol, 2 equiv, 16.0 g) in H2O (10 mL) was added
at 08C followed by the dropwise addition of 1,2-dichloroethane (500 mmol,
39.4 mL) at the same temperature. The white solid disappeared, and the
reaction mixture was heated at 608C for 3 h. The solution turned yellow,
and the reaction mixture was allowed to cool down to room temperature.
Solvents were evaporated under vacuum to give a yellow solid residue, that
was partitioned between AcOEt (50 mL) and HCl (2n, 50 mL). The layers
were separated, and the aqueous acidic layer was extracted twice more with
AcOEt (2 Â 30 mL). The organic layers were discarded. The aqueous layer
was neutralized with NaOH (3n) till pH > 10 and extracted with AcOEt
(3 Â 40 mL). The combined organic layer was dried over Na2SO4 and
filtered, and the solvents were removed at low pressure. The oily residue
was purified by column chromatography on silica gel using hexane/AcOEt
(3:1) as eluent, to give the desired compound, which presented the
following properties. Brown oil; yield: 31% (12.98 g).
Rf ˆ 0.39 (hexane/CH2Cl2, 95:5); FT-IR (neat): nÄ ˆ 2050, 1974, 1728 (broad
band), 1573 cm 1; 1H NMR (300 MHz, CDCl3, 258C, TMS): d ˆ 7.58 ± 7.10
(m, 6H), 6.51 (brs, 1H), 5.20 (brs, 1H), 4.58 (m, 4H), 4.15 (m, 5H), 2.65 ±
0.72 (m, 17H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 320.2 (s), 223.9 (s),
217.2 (s), 150.9 (s), 139.6 (d), 133.9 (d), 128.0 (d), 125.4 (d), 125.2 (d), 91.1
(d), 78.1 (s), 72.2 (d), 70.5 (d), 70.3 (d), 70.1 (d), 69.1 (d), 52.5 (d), 43.5 (t),
39.9 (s), 34.5 (t), 31.1 (d), 27.5 (q), 26.8 (t), 26.0 (q), 21.7 (q); elemental
analysis calcd (%) for C34H34CrFeO6 (646.48): C 63.17, H 5.30; found C
62.98, H 5.29.
Cycloaddition of dithiolane stabilized azomethine ylides 2 with Fischer
alkoxy alkenyl carbenes 6: A solution of the corresponding Fischer alkoxy
alkenyl carbene 6 (1 mmol) and the corresponding iminium salt 2
(1.5 equiv, 1.5 mmol) in dry THF (10 mL) was added dropwise to a white
suspension of anhydrous CsF (5 equiv, 5 mmol, 760 mg) in dry THF (5 mL)
under an inert atmosphere at 508C. The resulting suspension was stirred
at 508C till TLC analysis showed complete consumption of the starting
material (7 ± 10 h). Silica gel (0.5 g) was then added to the reaction mixture,
and solvents were evaporated under vacuum. The residue was purified by
column chromatography on silica gel under a nitrogen atmosphere using
hexane/AcOEt (100:1 to 9:1) mixtures as eluents. Cycloadducts 7 were
isolated as orange oils and as a mixture of diastereomers for (Æ)-menthol
derived carbenes or as only one diastereomer for ( )-8-phenylmenthol
derived carbenes.
1
Rf ˆ 0.46 (hexane/AcOEt, 3:1); FT-IR (neat): nÄ ˆ 1593 cm
;
1H NMR
(200 MHz, CDCl3, 258C, TMS): d ˆ 7.42 ± 7.28 (m, 5H), 4.57 (s, 2H), 3.63
(m, 2H), 3.45 (m, 2H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 168.9 (s),
138.7 (s), 128.2 (d), 127.6 (d), 126.7 (d), 62.7 (t), 37.7 (t), 34.5 (t); MS (70 eV,
‡
EI): m/z (%): 209 (42) [M] , 181 (18), 91 (100), 83 (18); HRMS for
C10H11NS2: calcd 209.0333; found 209.0337; elemental analysis calcd (%)
for C10H11NS2 (209.32): C 57.38, H 5.30, N 6.69; found C 57.22, H 5.18, N
6.59.
In the second step, trimethylsilylmethyl trifluoromethanesulfonate
(33.8 mmol, 6.76 mL) was added by syringe to a solution of N-benzyl-1,3-
dithiolane-2-imine (33.8 mmol, 7.08 g) in dry CH2Cl2 at 08C and stirred for
24 h at room temperature. Solvents were evaporated under vacuum to give
a quantitative yield of a brownish oil, which solidified on standing and was
used without further purification. A small amount was recrystallized in
hexane/CHCl3 (95:5) to be fully characterized. White solid; yield:
quantitative (15.06 g); m.p. 103 ± 1058C.
Tetracarbonyl{[6-methyl-8-phenyl-1,4-dithia-6-azaspiro[4,4]nonan-9-yl]-
[(1R*,3R*,4S*)-menthyloxy]methyliden}chromium(0) (7a): Orange oil;
mixture (4:1) of diastereomers; yield: 54% (314 mg); Rf ˆ 0.79 (hexane/
1
AcOEt, 9:1); FT-IR (neat): nÄ ˆ 2059, 2010, 1909 (broad band), 1864 cm
;
1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.41 ± 6.77 (m, 10H), 5.39 (m,
1H, min), 5.08 (m, 1H, maj), 4.16 ± 2.70 (m, 16H), 2.59 (s, 3H, maj), 2.52 (s,
3H, min), 2.39 ± 0.66 (m, 36H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ
353.2 (s), 230.7 (s), 228.9 (s), 218.3 (s), 217.2 (s), 142.8 (s, min), 141.9 (s, maj),
128.4 (d, min), 128.3 (d, maj), 127.8 (d, maj), 127.2 (d, min), 126.7 (d), 105.5
(s, min), 104.4 (s, maj), 92.7 (d, min), 91.4 (d, maj), 88.4 (d, maj), 87.3 (d,
min), 63.3 (t, min), 62.8 (t, maj), 48.3 (t, maj), 48.1 (t, min), 47.4 (d, maj), 47.1
1
FT-IR (neat): nÄ ˆ 1562, 1261 cm
;
1H NMR (200 MHz, CDCl3, 258C,
TMS): d ˆ 7.48 ± 7.36 (m, 5H), 5.09 (s, 2H), 4.05 (s, 4H), 3.70 (s, 2H), 0.17 (s,
9H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 192.9 (s), 132.0 (s), 129.2 (d),
129.0 (d), 128.0 (d), 64.3 (t), 54.0 (t), 41.7 (t), 41.3 (t), 1.3 (q); elemental
analysis calcd (%) for C15H22F3NO3S3Si (445.61): C 40.43, H 4.98, N 3.14;
found C 40.27, H 4.85, N 3.11.
3538
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0716-3538 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 16

Enantioselective Synthesis of (‡)-Rolipram
3533±3544
(d, min), 46.7 (d, maj), 45.9 (d, min), 41.5 (t, maj), 40.9 (t, min), 37.5 (t, maj),
37.4 (t, min), 34.1 (q), 33.9 (t, maj), 33.6 (t, min), 31.0 (d, min), 30.7 (d, maj),
26.3 (d, maj), 25.2 (d, min), 23.5 (t, maj), 22.3 (t, min), 22.0 (q, maj), 21.9 (q,
min), 21.0 (q, min), 20.5 (q, maj), 16.5 (q, maj), 15.4 (q, min); elemental
analysis calcd (%) for C28H35CrNO5S2 (581.70): C 57.81, H 6.06, N 2.41;
found C 57.60, H 6.00, N 2.42.
(7 f): Orange oil; yield: 57% (369 mg); Rf ˆ 0.37 (hexane/AcOEt, 9:1);
1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.45 ± 7.12 (m, 6H), 6.41 (dd,
3J(H,H) ˆ 3.0 and 1.8 Hz, 1H), 6.00 (d, 3J(H,H) ˆ 3.0 Hz, 1H), 5.38 (m,
1H), 3.58 (m, 1H), 3.40 (t, 3J(H,H) ˆ 5.4 Hz, 2H), 3.11 ± 2.84 (m, 4H), 2.51
(s, 3H), 2.35 (m, 1H), 2.22 ± 0.75 (m, 17H); 13C NMR (50 MHz, CDCl3,
258C): d ˆ 353.0 (s), 230.5 (s), 228.8 (s), 218.9 (s), 217.1 (s), 153.8 (s), 150.9
(s), 141.4 (d), 128.3 (d), 125.6 (d), 125.0 (d), 110.1 (d), 106.6 (d), 103.8 (s),
91.4 (d), 83.5 (d), 59.2 (t), 54.0 (d), 51.0 (d), 47.7 (t), 42.5 (t), 37.6 (t), 34.7 (t),
34.2 (q), 30.7 (d), 27.0 (q), 26.3 (t), 25.3 (q), 21.9 (q); elemental analysis
calcd (%) for C32H37CrNO6S2 (647.76): C 59.34, H 5.76, N 2.16; found C
59.30, H 5.70, N 2.15.
Tetracarbonyl{[6-benzyl-8-(3-cyclopentyloxy-4-methoxyphenyl)-1,4-di-
thia-6-azaspiro[4,4]nonan-9-yl][(1R*,3R*,4S*)-menthyloxy]methyliden}-
chromium(0) (7b): Orange oil; mixture (1:1) of diastereomers; yield: 67%
(517 mg); Rf ˆ 0.39 (hexane/AcOEt, 9:1); FT-IR (neat): nÄ ˆ 2059, 2011,
1
1909 (broad band), 1514 cm
;
1H NMR (200 MHz, CDCl3, 258C, TMS):
d ˆ 7.45 ± 7.10 (m, 10H), 6.88 ± 6.60 (m, 6H), 5.62 (m, 1H), 5.18 (m, 1H),
4.82 (m, 2H), 4.29 ± 3.60 (m, 12H), 3.58 ± 2.87 (m, 8H), 2.73 ± 0.70 (m,
58H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 354.7 (s), 353.2 (s), 230.4 (s),
228.8 (s), 228.5 (s), 219.8 (s), 218.2 (s), 217.1 (s), 216.8 (s), 148.6 (s), 147.5 (s),
147.3 (s), 137.5 (s), 137.4 (s), 135.1 (s), 134.1 (s), 128.7 (d), 128.3 (d), 128.1
(d), 127.0 (d), 126.6 (d), 119.6 (d), 114.1 (d), 113.9 (d), 111.5 (d), 111.0 (d),
105.1 (s), 103.9 (s), 92.7 (d), 91.2 (d), 88.7 (d), 87.6 (d), 80.0 (d), 60.1 (t), 59.7
(t), 55.7 (q), 55.5 (q), 52.1 (t), 47.6 (t), 47.3 (t), 47.0 (d), 46.7 (d), 46.5 (d), 45.7
(d), 41.4 (t), 40.8 (t), 37.2 (t), 37.0 (t), 33.5 (t), 32.5 (t), 31.0 (d), 30.5 (d), 26.4
(d), 25.1 (d), 23.8 (t), 21.8 (q), 21.6 (q), 21.4 (t), 21.3 (t), 20.8 (q), 20.4 (q),
16.6 (q), 15.2 (q); elemental analysis calcd (%) for C40H49CrNO7S2 (771.95):
C 62.24, H 6.40, N 1.81; found C 62.36, H 6.29, N 1.77.
Tetracarbonyl{[(8S,9R)-8-(3-cyclopentyloxy-4-methoxyphenyl)-6-methyl-
1,4-dithia-6-azaspiro[4,4]nonan-9-yl][(1R,3R,4S)-8-phenylmenthyloxy]-
methyliden}chromium(0) (7g): Orange oil; yield: 60% (463 mg); Rf ˆ 0.28
(hexane/AcOEt, 100:1); FT-IR (neat): nÄ ˆ 2010, 1905 (broad band),
1
1860 cm
;
[a]2D6 ˆ ‡351.4 (c ˆ 0.25 in CH2Cl2); 1H NMR (200 MHz,
CDCl3, 258C, TMS): d ˆ 7.29 ± 6.95 (m, 5H), 6.85 (m, 1H), 6.66 (m, 2H),
3
5.34 (m, 1H), 4.80 (m, 1H), 3.93 (s, 3H), 3.65 (m, 1H), 3.43 (t, J(H,H) ˆ
5.6 Hz, 2H), 3.07 (m, 2H), 2.72 (m, 2H), 2.53 (s, 3H), 2.34 (m, 3H), 2.08 ±
0.80 (m, 23H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 354.1 (s), 230.6 (s),
228.9 (s), 219.2 (s), 217.3 (s), 150.9 (s), 148.8 (s), 147.5 (s), 135.0 (s), 128.0 (d),
125.1 (d), 124.9 (d), 120.1 (d), 114.8 (d), 111.8 (d), 104.8 (s), 91.3 (d), 87.3 (d),
80.4 (d), 63.0 (t), 56.2 (q), 51.1 (d), 47.6 (t), 46.7 (d), 42.7 (t), 39.7 (s), 37.4 (t),
34.4 (q), 34.3 (t), 33.0 (t), 32.9 (t), 30.8 (d), 29.6 (q), 26.3 (t), 26.0 (q), 24.1 (t),
21.9 (q); elemental analysis calcd (%) for C40H49CrNO7S2 (771.95): C 62.24,
H 6.40, N 1.81; found C 62.01, H 6.31, N 1.77.
Tetracarbonyl{[6-benzyl-8-phenyl-1,4-dithia-6-azaspiro[4,4]nonan-9-yl]-
[(1R*,3R*,4S*)menthyloxy]methyliden}chromium(0) (7c): Orange oil;
mixture (1:1) of diastereomers; yield: 45% (296 mg); Rf ˆ 0.45 (hexane);
FT-IR (neat): nÄ ˆ 2011, 1909 (broad band), 1863 cm 1; 1H NMR (200 MHz,
CDCl3, 258C, TMS): d ˆ 7.40 ± 6.95 (m, 20H), 5.46 (m, 1H), 5.15 (m, 1H),
4.42 ± 3.62 (m, 6H), 3.58 ± 3.37 (m, 4H), 3.32 ± 2.80 (m, 6H), 2.69 ± 2.20 (m,
4H), 2.00 ± 0.59 (m, 36H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 355.0 (s),
353.4 (s), 230.7 (s), 229.1 (s), 228.8 (s), 219.8 (s), 218.3 (s), 217.1 (s), 216.8 (s),
142.5 (s), 141.6 (s), 137.7 (s), 137.6 (s), 128.45 (d), 128.37 (d), 128.30 (d),
127.8 (d), 127.3 (d), 127.2 (d), 126.7 (d), 105.0 (s), 103.8 (s), 92.9 (d), 91.4 (d),
88.8 (d), 87.6 (d), 60.4 (t), 59.8 (t), 52.2 (t), 48.2 (t), 47.9 (t), 47.5 (d), 47.2 (d),
46.9 (d), 46.1 (d), 41.6 (t), 41.0 (t), 37.6 (t), 37.4 (t), 33.9 (t), 33.7 (t), 31.2 (d),
30.7 (d), 26.5 (d), 25.3 (d), 23.6 (t), 22.3 (t), 22.0 (q), 21.0 (q), 20.6 (q), 16.6
(q), 15.4 (q); elemental analysis calcd (%) for C34H39CrNO5S2 (657.80): C
62.08, H 5.98, N 2.13; found C 61.99, H 5.95, N 2.08.
Tetracarbonyl{[(8S,9R)-8-ferrocenyl-6-methyl-1,4-dithia-6-azaspiro[4,4]-
nonan-9-yl][(1R,3R,4S)-8-phenylmenthyloxy]methyliden}chromium(0)
(7h): Orange oil; yield: 66% (505 mg); Rf ˆ 0.49 (hexane/AcOEt, 9:1); FT-
IR (neat): nÄ ˆ 2009, 1908 (broad band), 1858 cm 1; [a]D31 ˆ ‡471.1 (c ˆ 0.45
in CH2Cl2); 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.40 ± 6.98 (m,
5H), 5.35 (m, 1H), 4.28 ± 3.92 (m, 8H), 3.56 (m, 1H), 3.38 (t, 3J(H,H) ˆ
5.5 Hz, 2H), 3.18 ± 2.95 (m, 2H), 2.61 ± 2.18 (m, 3H), 2.56 (s, 3H), 1.95 ±
0.72 (m, 17H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 354.5 (s), 230.6 (s),
228.7 (s), 219.3 (s), 217.2 (s), 150.9 (s), 128.1 (d), 125.2 (d), 124.8 (d), 105.1
(s), 91.5 (d), 90.3 (s), 87.1 (d), 69.5 (d), 68.3 (d), 68.1 (d), 66.8 (d), 65.7 (d),
61.2 (t), 51.1 (d), 47.0 (t), 42.7 (t), 40.7 (d), 39.7 (s), 37.3 (t), 34.5 (q), 34.3 (t),
30.8 (d), 26.8 (q), 26.4 (t), 25.8 (q), 21.9 (q); elemental analysis calcd (%) for
C38H43CrFeNO5S2 (765.72): C 59.61, H 5.66, N 1.83; found C 59.52, H 5.60,
N 1.83.
Tetracarbonyl{[6-benzyl-8-(2-furyl)-1,4-dithia-6-azaspiro[4,4]nonan-9-yl]-
[(1R*,3R*,4S*)menthyloxy]methyliden}chromium(0) (7d): Orange oil;
mixture (1:1) of diastereomers; yield: 69% (447 mg); Rf ˆ 0.45 (hexane);
Tetracarbonyl{[(8S,9R)-6-benzyl-8-phenyl-1,4-dithia-6-azaspiro[4,4]non-
an-9-yl][(1R,3R,4S)-8-phenylmenthyloxy]methyliden}chromium(0) (7i):
Orange oil; yield: 60% (440 mg); Rf ˆ 0.62 (hexane/AcOEt, 20:1); FT-IR
(neat): nÄ ˆ 2010, 1909 (broad band), 1859 cm 1; [a]D33 ˆ ‡432.2 (c ˆ 0.32 in
CH2Cl2); 1H NMR (300 MHz, CDCl3, 258C, TMS): d ˆ 7.57 ± 6.92 (m,
15H), 5.43 (m, 1H), 4.06 (m, 2H), 3.75 (m, 1H), 3.53 (m, 2H), 3.28 ± 3.03
(m, 3H), 2.83 (m, 1H), 2.62 (t, 3J(H,H) ˆ 7.5 Hz, 1H), 2.44 (m, 1H), 2.05 ±
0.72 (m, 16H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 354.0 (s), 230.6 (s),
228.8 (s), 219.0 (s), 217.2 (s), 150.9 (s), 141.7 (s), 137.7 (s), 128.5 (d), 128.3
(d), 128.0 (d), 127.2 (d), 126.7 (d), 125.2 (d), 124.9 (d), 104.0 (s), 91.4 (d), 87.4
(d), 59.7 (t), 52.5 (t), 51.0 (d), 47.6 (t), 47.1 (d), 42.8 (t), 39.6 (s), 37.5 (t), 34.3
(t), 30.7 (d), 26.4 (q), 26.3 (t), 25.9 (q), 21.9 (q); elemental analysis calcd
(%) for C40H43CrNO5S2 (733.90): C 65.46, H 5.91, N 1.91; found C 65.22, H
5.86, N 1.90.
1
FT-IR (neat): nÄ ˆ 2060, 2011, 1906 (broad band), 1454 cm
;
1H NMR
(200 MHz, CDCl3, 258C, TMS): d ˆ 7.75 ± 6.95 (m, 12H), 6.40 (m, 2H), 6.06
(m, 2H), 5.47 (m, 1H), 5.20 (m, 1H), 4.28 (d, 3J(H,H) ˆ 13.4 Hz, 1H),
4.15 ± 3.61 (m, 6H), 3.57 ± 2.98 (m, 9H), 2.71 (m, 2H), 2.37 (m, 2H), 2.00 ±
0.68 (m, 36H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 353.6 (s), 352.6 (s),
230.7 (s), 229.0 (s), 228.7 (s), 219.3 (s), 217.9 (s), 217.0 (s), 216.6 (s), 154.6 (s),
153.5 (s), 141.45 (d), 141.40 (d), 137.6 (d), 137.5 (d), 128.3 (d), 128.2 (d), 127.2
(d), 110.1 (d), 106.4 (d), 105.6 (d), 103.8 (d), 102.8 (d), 92.9 (d), 91.5 (d), 85.5
(d), 84.9 (d), 56.9 (t), 56.3 (t), 52.0 (t), 48.5 (t), 48.2 (t), 47.6 (d), 47.3 (d), 41.4
(t), 41.0 (t), 39.8 (d), 38.9 (d), 37.8 (t), 37.6 (t), 33.9 (t), 33.7 (t), 31.2 (d), 30.7
(d), 26.4 (d), 25.3 (d), 23.6 (t), 22.5 (t), 22.0 (q), 21.0 (q), 20.8 (q), 16.6 (q),
15.4 (q); elemental analysis calcd (%) for C32H37CrNO6S2 (647.76): C 59.34,
H 5.76, N 2.16; found C 59.15, H 5.69, N 2.14.
Tetracarbonyl{[(8S,9R)-6-methyl-8-phenyl-1,4-dithia-6-azaspiro[4,4]non-
an-9-yl][(1R,3R,4S)-8-phenylmenthyloxy]methyliden}chromium(0) (7e):
Orange oil; yield: 29% (191 mg); Rf ˆ 0.56 (hexane/AcOEt, 9:1); FT-IR
(neat): nÄ ˆ 2005, 1943, 1886 (broad band), 1842 cm 1; [a]D26 ˆ ‡409.0 (c ˆ
0.35 in CH2Cl2); 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.42 ± 6.90
(m, 10H), 5.32 (m, 1H), 3.64 (m, 1H), 3.44 (t, 3J(H,H) ˆ 5.8 Hz, 2H), 3.14 ±
2.98 (m, 2H), 2.78 (ABq, 3J(H,H) ˆ 6.1 Hz, 2H), 2.54 (s, 3H), 2.33 (m, 1H),
2.00 ± 0.72 (m, 17H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 353.9 (s), 230.7
(s), 228.9 (s), 219.2 (s), 217.3 (s), 151.0 (s), 142.1 (s), 128.3 (d), 128.2 (d),
128.1 (d), 126.7 (d), 125.1 (d), 124.8 (d), 104.9 (s), 91.4 (d), 86.4 (d), 62.6 (t),
50.9 (d), 47.5 (t), 46.8 (d), 42.7 (t), 39.4 (s), 37.4 (t), 34.34 (q), 34.28 (t), 30.8
(d), 27.1 (q), 26.3 (t), 25.1 (q), 21.9 (q); elemental analysis calcd (%) for
C34H39CrNO5S2 (657.80): C 62.08, H 5.98, N 2.13; found C 61.89, H 5.99, N
2.12.
Tetracarbonyl{[(8S,9R)-6-benzyl-8-(2-furyl)-1,4-dithia-6-azaspiro[4,4]non-
an-9-yl][(1R,3R,4S)-8-phenylmenthyloxy]methyliden}chromium(0) (7j):
Orange oil; yield: 68% (492 mg); Rf ˆ 0.61 (hexane/AcOEt, 9:1); FT-IR
(neat): nÄ ˆ 2011, 1908 (broad band), 1861 cm 1; [a]D26 ˆ ‡469.3 (c ˆ 0.51 in
CH2Cl2); 1H NMR (300 MHz, CDCl3, 258C, TMS): d ˆ 7.49 ± 6.94 (m,
11H), 6.38 (m, 1H), 5.98 (m, 1H), 5.38 (m, 1H), 4.14 (m, 1H), 3.83 ± 3.52
(m, 2H), 3.43 (m, 2H), 3.20 (m, 1H), 3.09 ± 2.75 (m, 3H), 2.61 (m, 1H), 2.35
(m, 1H), 2.11 ± 0.68 (m, 16H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 353.3
(s), 230.5 (s), 228.8 (s), 218.7 (s), 217.0 (s), 153.6 (s), 150.9 (s), 141.4 (d), 137.7
(s), 128.4 (d), 128.3 (d), 127.9 (d), 127.2 (d), 125.6 (d), 125.3 (d), 110.2 (d),
106.7 (d), 102.9 (s), 91.5 (d), 84.7 (d), 56.3 (t), 52.3 (t), 51.1 (d), 47.9 (t), 42.7
(t), 40.0 (d), 39.8 (s), 37.8 (t), 34.3 (t), 30.7 (d), 26.5 (t), 26.4 (q), 26.0 (q), 21.9
(q); elemental analysis calcd (%) for C38H41CrNO6S2 (723.86): C 63.05, H
5.71, N 1.94; found C 62.89, H 5.71, N 1.93.
Tetracarbonyl{[(8R,9R)-8-(2-furyl)-6-methyl-1,4-dithia-6-azaspiro[4,4]-
nonan-9-yl][(1R,3R,4S)-8-phenylmenthyloxy]methyliden}chromium(0)
Tetracarbonyl{[(8S,9R)-6-benzyl-8-(3-cyclopentyloxy-4-methoxyphenyl)-
1,4-dithia-6-azaspiro[4,4]nonan-9-yl][(1R,3R,4S)-8-phenylmenthyloxy]-
Chem. Eur. J. 2001, 7, No. 16
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0716-3539 $ 17.50+.50/0
3539

J. Barluenga et al.
FULL PAPER
1
methyliden}chromium(0) (7k): Orange oil; yield: 58% (492 mg); Rf ˆ 0.50
(509 mg); Rf ˆ 0.54 (hexane/AcOEt, 5:1); FT-IR (neat): nÄ ˆ 1728 cm
;
1
(hexane/AcOEt, 9:1); FT-IR (neat): nÄ ˆ 2058, 2010, 1980 cm (broad
[a]2D5
ˆ
25.6 (c ˆ 1.08 in CH2Cl2); 1H NMR (200 MHz, CDCl3, 258C,
band); [a]3D0 ˆ ‡398.3 (c ˆ 0.35 in CH2Cl2); 1H NMR (300 MHz, CDCl3,
258C, TMS): d ˆ 7.50 ± 6.99 (m, 10H), 6.93 (d, 3J(H,H) ˆ 6.8 Hz, 1H),
TMS): d ˆ 7.45 ± 7.09 (m, 10H), 4.93 (m, 1H), 3.60 (m, 2H), 3.38 ± 3.17 (m,
5H), 2.83 (m, 1H), 2.50 (s, 3H), 2.07 ± 0.82 (m, 17H); 13C NMR (75 MHz,
CDCl3, 258C): d ˆ 171.2 (s), 150.7 (s), 141.8 (s), 128.5 (d), 127.8 (d), 127.6
(d), 126.7 (d), 125.6 (d), 125.1 (d), 99.3 (s), 75.7 (d), 66.9 (d), 60.9 (t), 50.2
(d), 44.7 (d), 41.6 (t), 40.3 (s), 40.0 (t), 39.3 (t), 34.3 (t), 33.8 (q), 31.2 (d), 29.7
(q), 27.1 (t), 23.0 (q), 21.7 (q); MS (70 eV, EI): m/z (%): 449 (<5) [M
3
6.74 ± 6.67 (s ‡ d, J(H,H) ˆ 8.3 Hz, 2H), 5.46 (m, 1H), 4.82 (m, 1H), 4.06
(m, 2H), 3.98 (s, 3H), 3.73 (m, 1H), 3.53 (m, 2H), 3.25 ± 3.00 (m, 3H),
2.76 ± 2.62 (m, 2H), 2.50 (m, 1H), 2.01 ± 0.70 (m, 24H); 13C NMR (75 MHz,
CDCl3, 258C): d ˆ 354.1 (s), 230.5 (s), 228.7 (s), 218.9 (s), 217.1 (s), 150.7 (s),
148.7 (s), 147.6 (s), 137.7 (s), 134.8 (s), 128.5 (d), 128.2 (d), 127.9 (d), 127.2
(d), 125.0 (d), 124.9 (d), 120.0 (d), 114.5 (d), 111.6 (d), 104.1 (s), 91.2 (d),
88.1 (d), 80.2 (d), 59.8 (t), 56.1 (q), 52.6 (t), 51.0 (d), 47.5 (t), 46.7 (d), 42.7
(t), 39.6 (s), 37.1 (t), 34.2 (t), 32.9 (t), 32.8 (t), 30.6 (d), 26.3 (t), 26.2 (q), 25.9
(q), 24.0 (t), 23.9 (t), 21.8 (q); elemental analysis calcd (%) for
C46H53CrNO7S2 (848.04): C 65.15, H 6.30, N 1.65; found C 65.01, H 6.25,
N 1.66.
‡
C2H4S] , 236 (85), 191 (67), 119 (100), 91 (78); HRMS for C28H35NO2S
[M C2H4S] : calcd 449.2389; found 449.2378; elemental analysis calcd
(%) for C30H39NO2S2 (509.76): C 70.69, H 7.71, N 2.75; found C 70.50, H
7.64, N 2.74.
‡
(1R,3R,4S)-8-Phenylmenthyl (8R,9R)-8-(2-furyl)-6-methyl-1,4-dithia-6-
azaspiro[4,4]nonan-9-carboxylate (8e): Yellow oil; yield: 25% (125 mg);
Rf ˆ 0.29 (hexane/AcOEt, 9:1); FT-IR (neat): nÄ ˆ 1722 cm 1; [a]D23
ˆ
31.2
Oxidation of the cycloadducts 7: A solution of chromium carbene cyclo-
adducts 7 (1 mmol) in hexane/AcOEt (3:1, 100 mL) was exposed to
sunlight till the solution turned almost colorless (two to five hours on a
sunny day). The reaction mixture was filtered through Celite, and solvents
were evaporated under vacuum. The residue was purified by column
chromatography on silica gel using hexane/AcOEt mixtures (50:1 to 1:1) as
sequential eluents to isolate compounds 8, 9, and 10 in the yields reported
in Table 2.
(c ˆ 0.86 in CH2Cl2); 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.39 ±
7.12 (m, 6H), 6.30 (dd, 3J(H,H) ˆ 2.2 and 3.1 Hz, 1H), 6.09 (d, J(H,H) ˆ
3
3.1 Hz, 1H), 4.95 (m, 1H), 3.70 (m, 2H), 3.39 ± 3.18 (m, 5H), 2.86 (m, 1H),
2.48 (s, 3H), 2.18 ± 0.84 (m, 17H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ
170.6 (s), 154.5 (s), 150.6 (s), 141.5 (d), 127.8 (d), 125.6 (d), 125.1 (d), 110.1
(d), 105.4 (d), 98.8 (s), 76.2 (d), 64.2 (d), 57.9 (t), 50.3 (d), 41.5 (t), 40.3 (s),
39.9 (t), 39.3 (t), 37.7 (d), 34.3 (t), 33.7 (q), 31.2 (d), 30.0 (q), 27.2 (t), 23.0 (q),
21.7 (q); elemental analysis calcd (%) for C28H37NO3S2 (499.73): C 67.30, H
7.46, N 2.80; found C 67.12, H 7.40, N 2.79.
(1R*,3R*,4S*)-Menthyl (8S*,9R*)-6-methyl-8-phenyl-1,4-dithia-6-azaspiro-
[4,4]nonan-9-carboxylate (8a): Yellow oil; mixture (4:1) of diastereomers;
(1R,3R,4S)-8-Phenylmenthyl
(8S,9R)-8-(3-cyclopentyloxy-4-methoxy-
yield: 28% (121 mg); Rf ˆ 0.37 (hexane/AcOEt, 9:1); FT-IR (neat): nÄ ˆ
phenyl)-6-methyl-1,4-dithia-6-azaspiro[4,4]nonan-9-carboxylate (8 f): Yel-
low oil; yield: 55% (343 mg); Rf ˆ 0.59 (hexane/AcOEt, 5:1); FT-IR (neat):
nÄ ˆ 1726 cm 1; [a]D31 ˆ ‡22.4 (c ˆ 0.84 in CH2Cl2); 1H NMR (200 MHz,
CDCl3, 258C, TMS): d ˆ 7.38 ± 7.10 (m, 6H), 6.82 (m, 2H), 4.93 (m, 1H),
4.80 (m, 1H), 3.85 (s, 3H), 3.54 (m, 1H), 3.39 ± 3.14 (m, 5H), 2.79 (m, 1H),
2.51 (s, 3H), 2.29 (m, 1H), 2.02 ± 0.61 (m, 25H); 13C NMR (75 MHz, CDCl3,
258C): d ˆ 171.5 (s), 150.6 (s), 148.7 (s), 147.6 (s), 134.1 (s), 127.7 (d), 125.5
(d), 125.0 (d), 119.6 (d), 114.2 (d), 111.8 (d), 99.2 (s), 80.2 (d), 75.6 (d), 67.4
(d), 61.0 (t), 56.0 (q), 50.2 (d), 44.6 (d), 41.6 (t), 40.3 (s), 39.8 (t), 39.2 (t), 34.3
(t), 33.8 (q), 32.7 (t), 31.1 (d), 29.7 (q), 27.1 (t), 24.0 (t), 22.9 (q), 21.7 (q); MS
1
1727 cm
;
1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.38 ± 7.16 (m,
10H), 4.75 (m, 2H), 3.76 (m, 4H), 3.40 ± 3.10 (m, 10H), 3.00 ± 2.85 (m, 2H),
2.51 (s, 6H), 2.03 (m, 2H), 1.79 ± 0.62 (m, 34H); 13C NMR (50 MHz, CDCl3,
258C): d ˆ 170.1 (s, min), 170.0 (s, maj), 141.9 (s, maj), 141.8 (s, min), 128.4
(d), 127.4 (d), 127.3 (d), 126.6 (d), 99.5 (s, maj), 99.3 (s, min), 74.9 (d, maj),
74.8 (d, min), 68.3 (d, min), 67.8 (d, maj), 60.6 (t, maj), 59.9 (t, min), 46.9 (d),
43.7 (d, maj), 43.5 (d, min), 40.71 (t, maj), 40.66 (t, min), 40.0 (t), 39.4 (t,
min), 39.3 (t, maj), 34.2 (t, min), 34.1 (t, maj), 33.8 (q), 31.3 (d), 26.0 (q,
min), 25.2 (q, maj), 23.3 (t, min), 22.7 (t, maj), 22.0 (d), 20.9 (q, maj), 20.6 (q,
‡
min), 16.0 (q, min), 15.6 (q, maj); MS (70 eV, EI): m/z (%): 433 (<5) [M] ,
‡
(70 eV, EI): m/z (%): 563 (<5) [M C2H4S] , 349 (92), 236 (100), 119 (80),
91 (21); HRMS for C34H45NO4S [M C2H4S] : calcd 563.3069; found
563.3090; elemental analysis calcd (%) for C36H49NO4S2 (623.91): C 69.31,
H 7.92, N 2.25; found C 69.26, H 7.83, N 2.21.
373 (9), 236 (100), 218 (51), 190 (63); HRMS for C24H35NO2S2: calcd
433.2109; found 433.2130; elemental analysis calcd (%) for C24H35NO2S2
(433.67): C 66.47, H 8.13, N 3.23; found C 66.52, H 8.01, N 3.20.
‡
(1R*,3R*,4S*)-Menthyl (8S*,9R*)-6-benzyl-8-phenyl-1,4-dithia-6-azaspiro-
[4,4]nonan-9-carboxylate (8b): Yellow oil; mixture (1:1) of diastereomers;
(1R,3R,4S)-8-Phenylmenthyl (8S,9R)-8-ferrocenyl-6-methyl-1,4-dithia-6-
azaspiro[4,4]nonan-9-carboxylate (8g): Yellow solid; yield: 38%
(235 mg); m.p. 120 ± 1228C; Rf ˆ 0.27 (hexane/AcOEt, 9:1); FT-IR (neat):
yield: 45% (229 mg); Rf ˆ 0.60 (hexane/AcOEt, 5:1); FT-IR (neat): nÄ ˆ
1
1726 cm
;
1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.45 ± 7.05 (m,
nÄ ˆ 1724 cm 1; [a]D30
ˆ
62.9 (c ˆ 1.09 in CH2Cl2); 1H NMR (200 MHz,
20H), 4.79 (m, 2H), 4.26 ± 3.55 (m, 8H), 3.41 ± 3.12 (m, 8H), 3.03 (m, 2H),
2.73 (m, 2H), 2.16 ± 0.51 (m, 36H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ
169.7 (s), 141.8 (s), 141.7 (s), 138.8 (s), 128.4 (d), 128.3 (d), 128.1 (d), 127.3
(d), 127.2 (d), 126.8 (d), 126.5 (d), 99.2 (s), 99.0 (s), 74.8 (d), 68.3 (d), 67.6
(d), 57.5 (t), 56.9 (t), 51.7 (t), 46.9 (d), 46.7 (d), 43.5 (d), 43.3 (d), 40.7 (t),
40.6 (t), 39.9 (t), 39.3 (t), 39.2 (t), 34.2 (t), 34.1 (t), 31.3 (d), 25.9 (d), 25.1 (d),
23.2 (t), 22.6 (t), 22.0 (q), 20.9 (q), 20.6 (q), 16.0 (q), 15.5 (q); MS (70 eV,
CDCl3, 258C, TMS): d ˆ 7.40 ± 7.12 (m, 5H), 4.90 (m, 1H), 4.18 ± 4.03 (m,
9H), 3.43 ± 3.16 (m, 7H), 2.74 (m, 1H), 2.50 (s, 3H), 2.20 ± 0.86 (m, 17H);
13C NMR (75 MHz, CDCl3, 258C): d ˆ 150.9 (s), 127.9 (d), 125.7 (d), 125.1
(d), 99.1 (s), 89.3 (s), 76.4 (d), 68.4 (d), 67.6 (d), 67.5 (d), 66.1 (d), 59.8 (t),
50.5 (d), 41.4 (t), 40.4 (t), 39.7 (t), 39.3 (d), 34.4 (t), 33.9 (q), 31.3 (d), 30.0
(q), 27.3 (t), 23.2 (q), 21.8 (q), the quaternary carbon from the chiral
auxiliary (around d ˆ 40) and the ester carbonyl carbon (around d ˆ 170)
‡
EI): m/z (%): 509 (<5) [M] , 449 (10), 311 (100), 266 (49), 91 (83); HRMS
‡
for C30H39NO2S2: calcd 509.2422; found 509.2453; elemental analysis calcd
(%) for C30H39NO2S2 (509.76): C 70.69, H 7.71, N 2.75; found C 70.55, H
7.67, N 2.77.
were not observed; MS (70 eV, EI): m/z (%): 557 (16) [M C2H4S] , 299
‡
(24), 143 (30), 119 (100), 91 (62); HRMS for C32H39FeNO2S [M C2H4S] :
calcd 557.2052; found 557.2054; elemental analysis calcd (%) for C34H43Fe-
NO2S2 (617.69): C 66.11, H 7.02, N 2.27; found C 65.99, H 6.99, N 2.29.
(1R*,3R*,4S*)-Menthyl (8S*,9R*)-6-benzyl-8-(2-furyl)-1,4-dithia-6-aza-
spiro[4,4]nonan-9-carboxylate (8c): Yellow oil; mixture (1:1) of diaste-
reomers; yield: 20% (100 mg); Rf ˆ 0.40 (hexane/AcOEt, 9:1); FT-IR
(1R,3R,4S)-8-Phenylmenthyl (8S,9R)-6-benzyl-8-phenyl-1,4-dithia-6-aza-
spiro[4,4]nonan-9-carboxylate (8h): Yellow oil; yield: 31% (182 mg);
1
(neat): nÄ ˆ 1729 cm 1; H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.49 ±
Rf ˆ 0.37 (hexane/AcOEt, 9:1); FT-IR (neat): nÄ ˆ 1730 cm 1; [a]D22
ˆ
19.7
7.15 (m, 12H), 6.23 (m, 2H), 6.02 (m, 2H), 4.81 (m, 2H), 4.09 ± 3.73 (m,
8H), 3.41 ± 3.11 (m, 8H), 3.04 (m, 2H), 2.74 (m, 2H), 2.19 ± 0.61 (m, 36H);
13C NMR (75 MHz, CDCl3, 258C): d ˆ 169.7 (s), 169.5 (s), 154.2 (s), 154.1
(s), 141.4 (d), 141.3 (d), 138.6 (s), 128.4 (d), 128.2 (d), 126.8 (d), 109.9 (d),
105.1 (d), 98.6 (s), 98.4 (s), 75.1 (d), 75.0 (d), 65.1 (d), 64.8 (d), 54.3 (t), 53.9
(t), 51.5 (t), 51.4 (t), 46.95 (d), 46.89 (d), 40.6 (t), 39.9 (t), 39.8 (t), 39.5 (t),
39.3 (t), 37.35 (d), 37.26 (d), 34.2 (t), 34.1 (t), 31.3 (d), 26.0 (d), 25.2 (d), 23.3
(t), 22.7 (t), 22.0 (q), 20.9 (q), 20.6 (q), 16.2 (q), 15.6 (q); elemental analysis
calcd (%) for C28H37NO3S2 (499.73): C 67.30, H 7.46, N 2.80; found C 67.18,
H 7.45, N 2.77.
(c ˆ 0.35 in CH2Cl2); 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.42 ±
7.07 (m, 15H), 4.97 (m, 1H), 4.07 ± 3.90 (ABq, 2J(H,H) ˆ 13.3 Hz, 2H), 3.73
(d, 3J(H,H) ˆ 8.7 Hz, 1H), 3.56 (m, 1H), 3.44 ± 3.32 (m, 4H), 3.08 (dd,
3J(H,H) ˆ 8.7 and 9.5 Hz, 1H), 2.70 (dd, 3J(H,H) ˆ 7.9 and 9.2 Hz, 1H), 2.07±
0.68 (m, 17H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 170.9 (s), 150.6 (s),
142.0 (s), 138.8 (s), 128.5 (d), 128.4 (d), 128.2 (d), 127.8 (d), 127.6 (d), 126.8
(d), 126.7 (d), 125.6 (d), 125.1 (d), 99.3 (s), 75.7 (d), 67.0 (d), 58.0 (t), 51.6 (t),
50.2 (d), 44.5 (d), 41.8 (t), 40.3 (s), 40.0 (t), 39.2 (t), 34.3 (t), 31.3 (d), 29.9 (q),
‡
27.2 (t), 22.8 (q), 21.7 (q); MS (70 eV, EI): m/z (%): 525 (11) [M C2H4S] ,
‡
311 (100), 266 (57), 119 (38), 91 (83); HRMS for C34H39NO2S [M C2H4S] :
(1R,3R,4S)-8-Phenylmenthyl (8S,9R)-6-methyl-8-phenyl-1,4-dithia-6-aza-
spiro[4,4]nonan-9-carboxylate (8d): Yellow oil; yield: quantitative
calcd 525.2702; found 525.2699; elemental analysis calcd (%) for C36H43-
NO2S2 (585.86): C 73.81, H 7.40, N 2.39; found C 72.98, H 7.30, N 2.42.
3540
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0716-3540 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 16

Enantioselective Synthesis of (‡)-Rolipram
3533±3544
(1R,3R,4S)-8-Phenylmenthyl
(8S,9R)-6-benzyl-8-(2-furyl)-1,4-dithia-6-
3.85 (s, 3H), 3.30 (s, 3H), 1.96 ± 0.83 (m, 25H); 13C NMR (75 MHz, CDCl3,
258C): d ˆ 196.0 (s), 169.4 (s), 151.2 (s), 149.3 (s), 147.8 (s), 132.0 (s), 127.8
(d), 125.7 (d), 124.9 (d), 118.7 (d), 113.4 (d), 112.0 (d), 80.4 (d), 76.8 (d), 67.4
(d), 62.6 (t), 56.0 (q), 50.1 (d), 43.0 (d), 40.9 (t), 40.0 (s), 35.3 (q), 34.4 (t),
32.8 (t), 31.2 (d), 27.5 (q), 26.9 (t), 25.9 (q), 24.0 (t), 21.6 (q); MS (70 eV, EI):
azaspiro[4,4]nonan-9-carboxylate (8i): Yellow oil; yield: 27% (155 mg);
Rf ˆ 0.38 (hexane/AcOEt, 9:1); FT-IR (neat): nÄ ˆ 1726 cm 1; [a]D25
ˆ
49.1
(c ˆ 0.81 in CH2Cl2); 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.41 ±
3
7.12 (m, 11H), 6.27 (dd, J(H,H) ˆ 1.8 and 3.2 Hz, 1H), 6.06 (d, 3J(H,H) ˆ
3.2 Hz, 1H), 4.96 (m, 1H), 4.12 (d, 2J(H,H) ˆ 13.3 Hz, 1H), 3.79 (d ‡ m,
2J(H,H) ˆ 13.3 Hz, 2H), 3.64 (m, 1H), 3.43 ± 3.22 (m, 4H), 3.05 (dd,
3J(H,H) ˆ 8.5 and 9.1 Hz, 1H), 2.69 (dd, 3J(H,H) ˆ 8.0 and 9.1 Hz, 1H),
2.46 ± 0.73 (m, 17H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 170.4 (s), 154.5
(s), 150.7 (s), 141.5 (d), 138.8 (s), 128.5 (d), 128.2 (d), 127.9 (d), 126.9 (d),
125.7 (d), 125.2 (d), 110.1 (d), 105.5 (d), 98.9 (s), 76.3 (d), 64.6 (d), 54.9 (t),
51.5 (t), 50.3 (d), 41.6 (t), 40.4 (s), 39.9 (t), 39.3 (t), 37.6 (d), 34.4 (t), 31.4 (d),
29.9 (q), 27.3 (t), 23.1 (q), 21.8 (q); MS (70 eV, EI): m/z (%): 515 (13) [M
m/z (%): 563 (18) [M] , 350 (45), 236 (90), 119 (100); HRMS for
‡
C34H45NO4S: calcd 536.3069; found 536.3071; elemental analysis calcd (%)
for C34H45NO4S (563.79): C 72.43, H 8.05, N 2.48; found C 72.25, H 7.97, N
2.47.
(1R,3R,4S)-8-Phenylmenthyl (3R,4S)-4-ferrocenyl-1-methylpyrrolidin-2-
thione-3-carboxylate (9g): Yellow oil; yield: 19% (106 mg); Rf ˆ 0.16
(hexane/AcOEt, 5:1); FT-IR (neat): nÄ ˆ 1727, 1261 cm 1; [a]D28 ˆ ‡3.17
(c ˆ 0.31 in CH2Cl2); 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.41 ±
7.16 (m, 5H), 4.87 (m, 1H), 4.17 (m, 7H), 4.02 ± 3.95 (m, 2H), 3.82 (d,
3J(H,H) ˆ 4.8 Hz, 1H), 3.54 (m, 1H), 3.28 (s, 3H), 3.11 (m, 2H), 2.34 (m,
1H), 2.06 (m, 3H), 1.75 ± 0.80 (m, 14H); 13C NMR (75 MHz, CDCl3, 258C):
d ˆ 195.8 (s), 169.7 (s), 151.2 (s), 128.0 (d), 125.8 (d), 125.0 (d), 89.2 (s), 76.8
(d), 68.6 (d), 68.1 (d), 67.9 (d), 66.5 (d), 62.9 (t), 50.3 (d), 41.1 (t), 40.0 (s),
37.4 (d), 35.4 (q), 34.5 (t), 31.3 (d), 27.4 (q), 27.0 (t), 26.3 (q), 21.7 (q); MS
‡
C2H4S] , 301 (100), 256 (70), 91 (73); HRMS for C32H37NO3S [M
‡
C2H4S] : calcd 515.2494; found 515.2504; elemental analysis calcd (%)
for C34H41NO3S2 (575.82): C 70.92, H 7.18, N 2.43; found C 70.90, H 7.28, N
2.45.
(1R,3R,4S)-8-Phenylmenthyl
(8S,9R)-6-benzyl-8-(3-cyclopentyloxy-4-
methoxyphenyl)-1,4-dithia-6-azaspiro[4,4]nonan-9-carboxylate (8j): Yel-
low oil; yield: 37% (259 mg); Rf ˆ 0.31 (hexane/AcOEt, 9:1); FT-IR (neat):
‡
(70 eV, EI): m/z (%): 557 (66) [M] , 299 (100), 119 (42); HRMS for
nÄ ˆ 1727 cm 1; [a]D33
ˆ
18.7 (c ˆ 1.82 in CH2Cl2); 1H NMR (300 MHz,
C32H39FeNO2S: calcd 557.2052; found 557.2072; elemental analysis calcd
(%) for C32H39FeNO2S (557.57): C 68.93, H 7.05, N 2.51; found C 68.70, H
7.00, N 2.54.
3
CDCl3, 258C, TMS): d ˆ 7.42 ± 7.14 (m, 11H), 6.82 ± 6.78 (d ‡ s, J(H,H) ˆ
2
8.3 Hz, 2H), 4.98 (m, 1H), 4.75 (m, 1H), 4.07 (d, J(H,H) ˆ 13.1 Hz, 1H),
3.90 (d, 2J(H,H) ˆ 13.1 Hz, 1H), 3.82 (s, 3H), 3.67 (d, 3J(H,H) ˆ 8.3 Hz,
1H), 3.50 ± 3.32 (m, 5H), 3.08 (t, 3J(H,H) ˆ 9.1 Hz, 1H), 2.69 (dd,
3J(H,H) ˆ 8.1 and 9.0 Hz, 1H), 2.06 ± 0.85 (m, 25H); 13C NMR (75 MHz,
CDCl3, 258C): d ˆ 171.2 (s), 150.5 (s), 148.6 (s), 147.6 (s), 138.8 (s), 134.6 (s),
128.4 (d), 128.1 (d), 127.7 (d), 126.8 (d), 125.5 (d), 125.0 (d), 119.6 (d), 114.1
(d), 111.7 (d), 99.2 (s), 80.1 (d), 75.6 (d), 67.6 (d), 58.2 (t), 55.9 (q), 51.5 (t),
50.2 (d), 44.2 (d), 41.7 (t), 40.3 (s), 39.8 (t), 39.1 (t), 34.2 (t), 32.7 (t), 31.2 (d),
30.0 (q), 27.1 (t), 24.0 (t), 22.7 (q), 21.7 (q); MS (70 eV, EI): m/z (%): 639
(1R,3R,4S)-8-Phenylmenthyl
(3R,4S)-1-benzyl-4(3-cyclopentyloxy-4-
methoxyphenyl)pyrrolidin-2-thione-3-carboxylate (9j): Yellow oil; yield:
8% (51 mg); Rf ˆ 0.45 (hexane/AcOEt, 3:1); FT-IR (neat): nÄ ˆ 1726,
1263 cm 1; [a]D33 ˆ ‡30.9 (c ˆ 0.79 in CH2Cl2); 1H NMR (200 MHz, CDCl3,
258C, TMS): d ˆ 7.40 ± 7.09 (m, 10H), 6.76 (m, 1H), 6.56 (m, 2H), 5.17 (d,
2
2J(H,H) ˆ 14.3 Hz, 1H), 4.88 ± 4.42 (d ‡ m, J(H,H) ˆ 14.3 Hz, 3H), 3.84 ±
3.73 (m, 2H), 3.81 (s, 3H), 3.54 (m, 2H), 2.29 ± 0.74 (m, 25H); 13C NMR
(75 MHz, CDCl3, 258C): d ˆ 196.4 (s), 169.3 (s), 151.3 (s), 149.2 (s), 147.8
(s), 134.6 (s), 132.5 (s), 128.8 (d), 128.3 (d), 127.9 (d), 125.7 (d), 125.0 (d),
118.6 (d), 113.2 (d), 111.9 (d), 80.4 (d), 76.8 (d), 67.9 (d), 60.0 (t), 56.0 (q),
51.5 (t), 50.1 (d), 42.5 (d), 41.0 (t), 40.0 (s), 34.5 (t), 32.8 (t), 31.2 (d), 27.2 (q),
‡
(<5) [M C2H4S] , 194 (20), 119 (100), 91 (56); HRMS for C40H49NO4S
‡
[M C2H4S] : calcd 639.3382; found 639.3376; elemental analysis calcd
(%) for C42H53NO4S2 (700.01): C 72.07, H 7.63, N 2.00; found C 71.90, H
7.71, N 1.97.
‡
26.9 (t), 26.3 (q), 24.0 (t), 21.7 (q); MS (70 eV, EI): m/z (%): 639 (10) [M] ,
214 (30), 119 (100), 91 (78); HRMS for C40H49NO4S: calcd 639.3382; found
639.3384; elemental analysis calcd (%) for C40H49NO4S (639.89): C 75.08, H
7.72, N 2.19; found C 74.82, H 7.68, N 2.22.
(1R*,3R*,4S*)-Menthyl (3R*,4S*)-1-benzyl-4-phenylpyrrolidin-2-thione-
3-carboxylate (9b): Mixture (1:1) of diastereomers; yellow oil; yield:
33% (148 mg); Rf ˆ 0.43 (hexane/AcOEt, 5:1); FT-IR (neat): nÄ ˆ 1728,
1
1261 cm
;
1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.40 ± 7.11 (m,
(1R,3R,4S)-8-Phenylmenthyl
(3R,4S)-4-(3-cyclopentyloxy-4-methoxy-
20H), 5.23 ± 4.89 (m, 4H), 4.78 (m, 2H), 4.10 ± 3.99 (m, 4H), 3.95 ± 3.80 (m,
2H), 3.68 ± 3.59 (m, 2H), 2.17 ± 0.63 (m, 36H); 13C NMR (50 MHz, CDCl3,
258C): d ˆ 196.3 (s), 169.4 (s), 169.1 (s), 139.8 (s), 139.1 (s), 134.7 (s), 134.5
(s), 128.95 (d), 128.90 (d), 128.8 (d), 128.7 (d), 128.2 (d), 128.1 (d), 127.6 (d),
126.7 (d), 126.6 (d), 75.8 (d), 75.7 (d), 68.1 (d), 67.8 (d), 59.6 (t), 59.0 (t), 51.6
(t), 51.5 (t), 46.83 (d), 46.77 (d), 43.6 (d), 43.2 (d), 40.6 (t), 40.3 (t), 34.1 (t),
31.4 (d), 31.3 (d), 25.9 (d), 25.7 (d), 23.2 (t), 22.9 (t), 21.9 (q), 20.8 (q), 20.5
phenyl)-1-methylpyrrolidin-2-one-3-carboxylate (10 f): Yellow oil; yield:
15% (82 mg); Rf ˆ 0.10 (hexane/AcOEt, 3:1); FT-IR (neat): nÄ ˆ 1737,
1698 cm 1; [a]D31 ˆ ‡33.3 (c ˆ 0.42 in CH2Cl2); 1H NMR (200 MHz, CDCl3,
258C, TMS): d ˆ 7.39 ± 7.10 (m, 5H), 6.82 (d, 3J(H,H) ˆ 8.0 Hz, 1H), 6.69 ±
3
6.64 (d ‡ s, J(H,H) ˆ 8.0 Hz, 2H), 4.87 ± 4.76 (m, 2H), 3.85 (s, 3H), 3.71 ±
3.53 (m, 2H), 3.39 ± 3.12 (m, 2H), 2.94 (s, 3H), 2.40 ± 2.15 (m, 1H), 2.09 ±
0.70 (m, 24H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 169.7 (s), 169.3 (s),
151.1 (s), 149.2 (s), 147.7 (s), 132.3 (s), 127.8 (d), 125.7 (d), 124.9 (d), 118.7
(d), 113.7 (d), 112.0 (d), 80.4 (d), 76.6 (d), 56.1 (d), 56.0 (q), 54.8 (t), 50.3 (d),
41.7 (d), 41.2 (t), 40.0 (s), 34.4 (t), 32.8 (t), 31.2 (q), 29.8 (d), 27.7 (q), 26.9 (t),
‡
(q), 16.0 (q), 15.8 (q); MS (70 eV, EI): m/z (%): 449 (<5) [M] , 311 (28),
149 (43), 119 (68), 91 (70), 84 (100); HRMS for C28H35NO2S: calcd
449.2389; found 449.2378; elemental analysis calcd (%) for C28H35NO2S
(449.65): C 74.79, H 7.85, N 3.12; found C 75.02, H 7.75, N 3.11.
‡
25.3 (q), 24.0 (t), 21.6 (q); MS (70 eV, EI): m/z (%): 547 (<5) [M] , 546
(20), 289 (21), 265 (48), 220 (69), 119 (100); HRMS for C34H45NO5: calcd
547.3298; found 547.3305; elemental analysis calcd (%) for C34H45NO5
(547.73): C 74.56, H 8.28, N 2.56; found C 74.30, H 8.15, N 2.60.
(1R*,3R*,4S*)-Menthyl
one-3-carboxylate (9c): Mixture (1:1) of diastereomers; yellow oil; yield:
(3R*,4S*)-1-benzyl-4-(2-furyl)pyrrolidin-2-thi-
32% (141 mg); Rf ˆ 0.41 (hexane/AcOEt, 3:1); FT-IR (neat): nÄ ˆ 1725,
1
1262 cm
;
1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.51 ± 7.20 (m,
(1R,3R,4S)-8-Phenylmenthyl (3R,4S)-4-ferrocenyl-1-methylpyrrolidin-2-
one-3-carboxylate (10g): Yellow oil; yield: 20% (108 mg); Rf ˆ 0.11
(hexane/AcOEt, 5:1); FT-IR (neat): nÄ ˆ 1728, 1698 cm 1; [a]D28 ˆ ‡25.6
(c ˆ 0.39 in CH2Cl2); 1H NMR (300 MHz, CDCl3, 258C, TMS): d ˆ 7.46 ±
7.17 (m, 5H), 4.91 (m, 1H), 4.18 (brs, 9H), 4.03 ± 3.98 (m, 2H), 3.35 ± 3.23
(m, 2H), 2.96 (s, 3H), 2.06 (m, 2H), 1.65 ± 0.80 (m, 15H); 13C NMR
(75 MHz, CDCl3, 258C): d ˆ 170.1 (s), 169.5 (s), 151.3 (s), 127.9 (d), 125.7
(d), 125.0 (d), 89.3 (s), 76.7 (d), 68.4 (d), 68.1 (d), 67.9 (d), 66.5 (d), 66.3 (d),
56.4 (d), 54.6 (t), 50.4 (d), 41.3 (t), 39.9 (s), 35.9 (q), 34.4 (t), 31.2 (d), 29.8
(d), 27.2 (q), 26.9 (t), 25.8 (q), 21.7 (q); MS (70 eV, EI): m/z (%): 541 (59)
12H), 6.27 (m, 2H), 6.06 (m, 2H), 5.15 ± 4.72 (m, 6H), 4.29 ± 3.85 (m, 6H),
3.80 ± 3.52 (m, 2H), 2.19 ± 0.70 (m, 36H); 13C NMR (50 MHz, CDCl3,
258C): d ˆ 195.8 (s), 168.9 (s), 168.6 (s), 151.9 (s), 151.5 (s), 142.2 (d), 134.3
(s), 128.7 (d), 128.0 (d), 125.6 (d), 110.2 (d), 106.3 (d), 106.1 (d), 75.8 (d),
65.5 (d), 65.1 (d), 56.7 (t), 56.2 (t), 51.4 (t), 51.3 (t), 46.7 (d), 40.4 (t), 40.2 (t),
37.2 (d), 37.0 (d), 34.0 (t), 31.2 (d), 25.9 (d), 25.6 (d), 23.2 (t), 22.8 (t), 21.9
(q), 20.7 (q), 20.5 (q), 16.1 (q), 15.8 (q); MS (70 eV, EI): m/z (%): 439 (10)
‡
[M] , 302 (68), 256 (100), 91 (92); HRMS for C26H33NO3S: calcd 439.2181;
found 439.2187; elemental analysis calcd (%) for C26H33NO3S (439.61): C
71.04, H 7.57, N 3.19; found C 71.25, H 7.62, N 3.16.
‡
[M] , 283 (100), 119 (52), 91 (20); HRMS for C32H39FeNO3: calcd 541.2279;
found 541.2290; elemental analysis calcd (%) for C32H39FeNO3 (541.51): C
70.98, H 7.26, N 2.59; found C 70.79, H 7.27, N 2.57.
(1R,3R,4S)-8-Phenylmenthyl
(3R,4S)-4-(3-cyclopentyloxy-4-methoxy-
phenyl)-1-methylpyrrolidin-2-thione-3-carboxylate (9 f): Yellow oil; yield:
23% (130 mg); Rf ˆ 0.30 (hexane/AcOEt, 3:1); FT-IR (neat): nÄ ˆ 1727,
1262 cm 1; [a]D31 ˆ ‡69.2 (c ˆ 0.52 in CH2Cl2); 1H NMR (200 MHz, CDCl3,
258C, TMS): d ˆ 7.40 ± 7.11 (m, 5H), 6.81 (d, 3J(H,H) ˆ 8.2 Hz, 1H), 6.66 ±
6.61 (d ‡ s, 3J(H,H) ˆ 8.2 Hz, 2H), 4.90 ± 4.76 (m, 2H), 3.97 ± 3.37 (m, 4H),
(1R,3R,4S)-8-Phenylmenthyl
(3R,4S)-1-benzyl-4-(3-cyclopentyloxy-4-
methoxyphenyl)pyrrolidin-2-one-3-carboxylate (10j): Yellow oil; yield:
16% (100 mg); Rf ˆ 0.32 (hexane/AcOEt, 3:1); FT-IR (neat): nÄ ˆ 1730,
1697 cm 1; [a]D33 ˆ ‡35.4 (c ˆ 0.92 in CH2Cl2); 1H NMR (200 MHz, CDCl3,
Chem. Eur. J. 2001, 7, No. 16
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0716-3541 $ 17.50+.50/0
3541

J. Barluenga et al.
FULL PAPER
258C, TMS): d ˆ 7.40 ± 7.10 (m, 10H), 6.78 (d, 3J(H,H) ˆ 7.9 Hz, 1H), 6.62 ±
6.58 (d ‡ s, 3J(H,H) ˆ 7.9 Hz, 2H), 4.86 (m, 1H), 4.70 (m, 1H), 4.54 (ABq,
2J(H,H) ˆ 14.8 Hz, 2H), 3.83 (s, 3H), 3.57 ± 3.41 (m, 2H), 3.24 ± 3.18 (m,
2H), 1.97 ± 0.82 (m, 25H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 169.6 (s),
169.3 (s), 151.2 (s), 149.1 (s), 147.6 (s), 135.8 (s), 132.5 (s), 128.7 (d), 128.1
(d), 127.8 (d), 127.7 (d), 125.6 (d), 124.9 (d), 118.6 (d), 113.6 (d), 111.9 (d),
80.4 (d), 76.6 (d), 56.2 (d), 56.0 (q), 52.1 (t), 50.2 (d), 46.7 (t), 41.4 (d), 41.2
(t), 39.9 (s), 34.4 (t), 32.7 (t), 31.2 (d), 27.2 (q), 26.8 (t), 25.8 (q), 24.0 (t), 21.6
(3R,4R)-1-Benzyl-4-(2-furyl)-pyrrolidin-2-one-3-carboxylic acid (11a):
Yield 15 ± 20% (43 ± 57 mg) from 7j; Rf ˆ 0.30 (hexane/AcOEt/HCOOH,
1
20:12:1); FT-IR (neat): nÄ ˆ 3429 (broad band), 1728, 1678 cm 1; H NMR
(200 MHz, CDCl3, 258C, TMS): d ˆ 8.32 (brs, 1H), 7.39 ± 7.11 (m, 6H), 6.25
(m, 1H), 6.11 (m, 1H), 4.52 (s, 2H), 4.07 (m, 1H), 3.79 (d, J ˆ 8.2 Hz, 1H),
3.62 (m, 1H), 3.43 (m, 1H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 170.8
(s), 169.7 (s), 151.8 (s), 142.1 (d), 134.7 (s), 128.8 (d), 128.0 (d), 127.9 (d),
110.3 (d), 106.6 (d), 52.6 (d), 49.4 (t), 47.0 (t), 34.5 (d); MS (70 eV, EI): m/z
‡
‡
(q); MS (70 eV, EI): m/z (%): 623 (7) [M] , 297 (58), 119 (82), 91 (100);
(%): 285 (17) [M] , 241 (54), 91 (100); HRMS for C16H15NO4: calcd
HRMS for C40H49NO5: calcd 623.3611; found 623.3608; elemental analysis
calcd (%) for C40H49NO5 (623.83): C 77.01, H 7.92, N 2.25; found C 76.78, H
7.95, N 2.21.
285.1001; found 285.1005; elemental analysis calcd (%) for C16H15NO4
(285.30): C 67.36, H 5.30, N 4.91; found C 67.49, H 5.35, N 4.88.
(3R,4S)-1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-pyrrolidin-2-
one-3-carboxylic acid (11b): Yield 20 ± 25% (82 ± 102 mg) from 7k; Rf ˆ
0.42 (hexane/AcOEt/HCOOH, 20:12:1); FT-IR (neat): nÄ ˆ 3503 (broad
band), 1732, 1689 cm 1; 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 8.22
(brs, 1H), 7.39 ± 6.92 (m, 5H), 6.84 ± 6.46 (m, 3H), 4.82 ± 4.25 (m, 3H),
4.09 ± 3.12 (m, 4H), 3.83 (s, 3H), 1.95 ± 1.40 (m, 8H); 13C NMR (75 MHz,
CDCl3, 258C): d ˆ 171.1 (s), 170.2 (s), 149.0 (s), 147.6 (s), 135.0 (s), 132.4 (s),
128.6 (d), 127.7 (d), 118.6 (d), 113.6 (d), 111.9 (d), 80.2 (d), 55.8 (q), 55.5 (d),
52.1 (t), 46.9 (t), 40.2 (d), 34.5 (t), 23.8 (t); MS (70 eV, EI): m/z (%): 365 (46)
Preparation of 9e and 10e by thiirane extrusion and dithiolane hydrolysis:
A solution of 8e (1 mmol, 500 mg) was heated to reflux in toluene (10 mL)
for 48 hours. Solvents were evaporated under vacuum, and the residue was
purified by chromatography on silica gel with hexane/AcOEt (100:1 to 5:1)
as sequential eluents to give compounds 9e and 10e in 63% and 14% yield,
respectively.
(1R,3R,4S)-8-Phenylmenthyl
(3R,4R)-4-(2-furyl)-1-methylpyrrolidin-2-
‡
[M CO2] , 297 (100), 150 (88), 91 (40); HRMS for C23H27NO3 [M
thione-3-carboxylate (9e): Yellow oil; yield: 63% (277 mg); Rf ˆ 0.14
(hexane/AcOEt, 5:1); FT-IR (neat): nÄ ˆ 1728, 1261 cm 1; [a]D33 ˆ ‡16.1
(c ˆ 1.15 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 258C, TMS): d ˆ 7.37 ±
7.12 (m, 6H), 6.30 (d, 3J(H,H) ˆ 2.1 Hz, 1H), 6.06 (d, 3J(H,H) ˆ 3.0 Hz,
1H), 4.86 (m, 1H), 3.92 (dd, 3J(H,H) ˆ 8.6 and 10.7 Hz, 1H), 3.78 ± 3.68 (m,
2H), 3.45 (m, 1H), 3.28 (s, 3H), 2.06 ± 0.78 (m, 17H); 13C NMR (50 MHz,
CDCl3, 258C): d ˆ 195.3 (s), 168.6 (s), 152.1 (s), 151.3 (s), 142.2 (d), 127.9
(d), 125.6 (d), 125.0 (d), 110.2 (d), 106.2 (d), 76.9 (d), 64.9 (d), 59.6 (t), 50.0
(d), 40.9 (t), 39.9 (s), 36.6 (d), 35.3 (q), 34.5 (t), 31.2 (d), 27.0 (q), 26.9 (t),
‡
CO2] : calcd 365.1991; found 365.1992; elemental analysis calcd (%) for
C24H27NO5 (409.48): C 70.40, H 6.65, N 3.42; found C 70.48, H 6.59, N 3.38.
(R)-1-Benzyl-4-(2-furyl)-pyrrolidin-2-one (12a): Colorless oil; yield: 30%
(72 mg) from 7j [(Æ)-12a was obtained in 25% yield (60 mg) from 7d];
Rf ˆ 0.10 (hexane/AcOEt, 3:1); FT-IR (neat): nÄ ˆ 1671 cm 1; [a]D29
ˆ
18.5
(c ˆ 0.88 in CH2Cl2); 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.49 ±
7.08 (m, 6H), 6.28 (m, 1H), 6.05 (m, 1H), 4.49 (s, 2H), 3.67 ± 3.50 (m, 2H),
3.44 ± 3.21 (m, 1H), 2.94 ± 2.56 (m, 2H); 13C NMR (75 MHz, CDCl3, 258C):
d ˆ 173.1 (s), 154.5 (s), 141.7 (d), 135.9 (s), 128.5 (d), 127.9 (d), 127.5 (d),
110.0 (d), 105.1 (d), 50.9 (t), 46.3 (t), 36.2 (t), 30.8 (d); MS (70 eV, EI): m/z
‡
26.5 (q), 21.7 (q); MS (70 eV, EI): m/z (%): 439 (5) [M] , 226 (100), 180
(41), 119 (40), 91 (20); HRMS for C26H33NO3S: calcd 439.2181; found
439.2160; elemental analysis calcd (%) for C26H33NO3S (439.61): C 71.04, H
7.57, N 3.19; found C 71.08, H 7.51, N 3.22.
‡
(%): 241 (19) [M] , 149 (38), 91 (42), 85 (62), 83 (100); HRMS for
C15H15NO2: calcd 241.1103; found 241.1096; elemental analysis calcd (%)
for C15H15NO2 (241.29): C 74.67, H 6.27, N 5.81; found C 74.81, H 6.22, N
5.79.
(1R,3R,4S)-8-Phenylmenthyl
(3R,4R)-4-(2-furyl)-1-methylpyrrolidin-2-
one-3-carboxylate (10e): Yellow oil; yield: 14% (59 mg); Rf ˆ 0.10
(hexane/AcOEt, 5:1); FT-IR (neat): nÄ ˆ 1731, 1698 cm 1; [a]D33 ˆ ‡17.4
(c ˆ 1.05 in CH2Cl2); 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.40 ±
(S)-1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-pyrrolidin-2-one
(12b): Yellow oil; yield: 30 ± 35% (110 ± 128 mg) from 7k [(Æ)-12b was
obtained in 28% yield (102 mg) from 7b]; Rf ˆ 0.26 (hexane/AcOEt, 1:1);
3
7.05 (m, 6H), 6.32 (dd, 3J(H,H) ˆ 2.0 and 3.3 Hz, 1H), 6.06 (d, J(H,H) ˆ
FT-IR (neat): nÄ ˆ 1687 cm 1; [a]D26
ˆ
26.14 (c ˆ 1.32 in CH2Cl2); 1H NMR
3.3 Hz, 1H), 4.86 (m, 1H), 3.71 ± 3.53 (m, 2H), 3.48 ± 3.25 (m, 2H), 2.91 (s,
3H), 2.36 ± 2.24 (m, 1H), 2.06 ± 0.71 (m, 16H); 13C NMR (75 MHz, CDCl3,
258C): d ˆ 168.9 (s), 168.7 (s), 152.7 (s), 151.1 (s), 142.1 (d), 127.9 (d), 125.6
(d), 125.0 (d), 110.2 (d), 105.9 (d), 76.8 (d), 53.7 (d), 51.9 (t), 50.2 (d), 41.1
(t), 40.0 (s), 35.4 (q), 34.4 (t), 31.2 (d), 29.8 (d), 27.5 (q), 26.9 (t), 25.6 (q),
(300 MHz, CDCl3, 258C, TMS): d ˆ 7.27 ± 7.20 (m, 5H), 6.72 (d, 3J(H,H) ˆ
3
8.0 Hz, 1H), 6.64 ± 6.62 (d ‡ s, J(H,H) ˆ 8.0 Hz, 1H), 4.64 (m, 1H), 4.51 ±
4.38 (ABq, 2J(H,H) ˆ 14.5 Hz, 2H), 3.74 (s, 3H), 3.56 (m, 1H), 3.41 (m,
1H), 3.20 (m, 1H), 2.81 (dd, 3J(H,H) ˆ 9.0 and 2J(H,H) ˆ 17.0 Hz, 1H), 2.53
(dd, 3J(H,H) ˆ 8.0 and 2J(H,H) ˆ 17.0 Hz, 1H), 1.80 (m, 6H), 1.55 (m, 2H);
13C NMR (75 MHz, CDCl3, 258C): d ˆ 173.5 (s), 148.7 (s), 147.4 (s), 135.9
(s), 134.5 (s), 128.3 (d), 127.8 (d), 127.3 (d), 118.3 (d), 113.3 (d), 111.8 (d),
80.1 (d), 55.7 (q), 53.7 (t), 46.2 (t), 38.8 (t), 36.2 (d), 32.4 (t), 23.7 (t); MS
‡
21.7 (q); MS (70 eV, EI): m/z (%): 423 (<5) [M] , 210 (75), 119 (100), 91
(41); HRMS for C26H33NO4: calcd 423.2410; found 423.2427; elemental
analysis calcd (%) for C26H33NO4 (423.55): C 73.73, H 7.85, N 3.31; found C
73.80, H 7.79, N 3.28.
‡
(70 eV, EI): m/z (%): 365 (20) [M] , 297 (80), 150 (63), 91 (52), 85 (60), 83
Synthesis of N-benzylpyrrolidin-2-ones (12): A solution of the correspond-
ing cycloadduct 7 (1 mmol) in hexane/AcOEt (3:1, 100 mL) was exposed to
sunlight till it turned almost colorless. The reaction mixture was then
filtered through Celite, and solvents were evaporated under vacuum. The
crude residue was dissolved in a 1,4-dioxane/water (3:1, 32 mL) mixture;
LiOH ´ H2O (10 equiv, 0.42 g, 10 mmol) was added, and the reaction
mixture was heated to reflux for 48 h. After cooling down to room
temperature, solvents were evaporated, and the residue was partitioned
between water (20 mL) and AcOEt (20 mL); the organic layer was
separated, and the aqueous layer was extracted twice more with AcOEt
(2 Â 15 mL). The combined organic layer was dried over Na2SO4 and
filtered, and the solvents were evaporated under vacuum. The residue was
purified by column chromatography using hexane/AcOEt (20:1 to 1:2) as
sequential eluents to give N-benzylpyrrolidin-2-ones 12 in the yields
described in the text; the chiral auxiliary was recovered almost quantita-
tively after the chromatographic separation. The aqueous layer was
acidified with HCl (2n), and AcOEt (20 mL) was added. The organic
layer was separated, and the aqueous layer was extracted again with
AcOEt (2 Â 15 mL) and discarded. The combined organic layer was treated
with Na2SO4 and filtered, and solvents were removed under vacuum. The
residue was purified by column chromatography using sequential elution
with hexane/AcOEt (9:1 to 2:1) and hexane/AcOEt/HCOOH (20:12:1) to
give compounds 11.
(100); HRMS for C23H27NO3: calcd 365.1991; found 365.1993; elemental
analysis calcd (%) for C23H27NO3 (365.47): C 75.59, H 7.45, N 3.83; found C
75.43, H 7.44, N 3.80.
Decarboxylation of compounds 11: Copper(i) oxide (0.1 equiv, 0.05 mmol,
7 mg) was added to a solution of the corresponding carboxylic acid 11
(0.5 mmol) in pyridine (10 mL), and the mixture was refluxed under a
continuous flow of nitrogen till TLC monitoring showed complete
disappearance of the starting material. The reaction mixture was filtered
through Celite and extracted with water and diethyl ether (3 Â 15 mL). The
combined organic layer was dried over Na2SO4 and filtered, and solvents
were evaporated. Finally the crude residue was purified by column
chromatography on silica gel using hexane/AcOEt (20:1 to 4:1) as eluents
to give N-benzylpyrrolidin-2-ones 12 in 70 ± 75% yield.
Synthesis of (‡)-Rolipram 1: N-benzylpyrrolidin-2-one 12b (0.5 mmol)
was dissolved in the minimum amount of dry THF under an inert
atmosphere and cooled to 788C; NH3 was then bubbled through the flask
till approximately 25 mL were collected, and the reaction flask was allowed
to warm to 408C. Excess lithium (bars) was added, and the resulting deep
blue solution was stirred for 10 min. Solid NH4Cl was added to quench the
reaction; NH3 was evaporated by allowing the reaction mixture to warm till
room temperature, and the residue was extracted with water and CH2Cl2
(3 Â 15 mL). The organic layer was dried with Na2SO4, filtered, and
3542
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0947-6539/01/0716-3542 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 16

Enantioselective Synthesis of (‡)-Rolipram
3533±3544
evaporated, and the residue was purified by flash chromatography using
hexane/AcOEt (1:5) and AcOEt as sequential eluents to give (‡)-
Rolipram 1. White solid; yield: 95% (131 mg).
[2] For reviews about Fischer carbene complexes in cycloaddition
processes see: a) H.-W. Frühauf, Chem. Rev. 1997, 97, 523 ± 596;
b) W. D. Wulff in Comprehensive Organic Synthesis, Vol. 5 (Eds.: I.
Fleming, B. M. Trost), Pergamon, New York, 1991, pp. 1065 ± 1113.
Rf ˆ 0.16 (hexane/AcOEt, 1:5); FT-IR (neat): nÄ ˆ 1686 cm 1; [a]D26 ˆ ‡24.7
Â
[3] a) J. Barluenga, F. Aznar, S. Barluenga, M. Fernandez, A. Martín, S.
(c ˆ 0.23 in MeOH) {ref. [12d] [a]D
ˆ
31 (c ˆ 0.5 in MeOH) for the
Ä
Â
García-Granda, A. Pinera-Nicolas, Chem. Eur. J. 1998, 4, 2280 ± 2298;
1
levorotatory isomer}; H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 6.90 ±
6.70 (m, 3H), 6.60 (brs, 1H), 4.77 (m, 1H), 3.84 (s, 3H), 3.83 ± 3.59 (m, 2H),
3.39 (m, 1H), 2.72 (dd, 3J(H,H) ˆ 8.4 and 2J(H,H) ˆ 16.9 Hz, 1H), 2.48 (dd,
3J(H,H) ˆ 8.7 and 2J(H,H) ˆ 16.9 Hz, 1H), 1.90 ± 1.85 (m, 6H), 1.62 (m,
2H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 177.8 (s), 149.1 (s), 147.8 (s),
134.4 (s), 118.7 (d), 113.7 (d), 112.1 (d), 80.5 (d), 56.0 (q), 49.7 (t), 39.9 (d),
Â
b) J. Barluenga, F. Aznar, M. Fernandez, Chem. Eur. J. 1997, 3, 1629 ±
Â
1637; c) J. Barluenga, M. Tomas, A. Ballesteros, J. Santamaría, A.
Â
Suarez-Sobrino, J. Org. Chem. 1997, 62, 9229 ± 9235; d) J. Barluenga,
Â
Â
M. Tomas, J. A. Lopez-Pelegrín, E. Rubio, Tetrahedron Lett. 1997, 38,
3981 ± 3984; e) J. Barluenga, F. Aznar, A. Martín, S. Barluenga,
Tetrahedron 1997, 53, 843 ± 844; f) J. Barluenga, F. Aznar, A. Martín, S.
Barluenga, S. García-Granda, A. A. Paneque-Quevedo, J. Chem. Soc.
Chem. Commun. 1994, 843 ± 844; g) J. Barluenga, R. M. Canteli, J.
‡
38.1 (t), 32.7 (t), 23.9 (t); MS (70 eV, EI): m/z (%): 275 (12) [M] , 207 (78),
150 (100), 57 (66); HRMS for C16H21NO3: calcd 275.1521; found 275.1515.
The reaction performed with a racemic sample of 12b gave (Æ)-Rolipram
Â
Â
Florez, S. García-Granda, A. Gutierrez-Rodríguez, J. Am. Chem. Soc.
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in 95% yield (131 mg).
tert-Butyl (S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-pyrrolidin-2-one-1-
carboxylate (13): Triethylamine (0.1 mmol, 14 mL), DMAP (0.1 mmol,
12 mg), and t(Boc)2O (0.2 mmol, 44 mg) were added successively to a
solution of (‡)-Rolipram 1 (0.1 mmol, 27.5 mg) in dry dichloromethane
(5 mL) under nitrogen at room temperature, and the resulting solution was
stirred till disappearance of 12 was detected by TLC. Solvents were then
evaporated, and the obtained residue was purified by flash chromatography
on silica gel using hexane/AcOEt (20:1 to 1:1 mixtures) to give 13, which
has the following data: yellow oil, yield: 76% (29 mg) [73% yield (27 mg)
for the racemic compound from (Æ)-1).
Rf ˆ 0.50 (hexane/AcOEt, 1:1); FT-IR (neat): nÄ ˆ 1784, 1751, 1713,
[4] a) For an excellent review see: B. Alcaide, L. Casarrubias, G.
Domínguez, M. A. Sierra, Curr. Org. Chem. 1998, 2, 551 ± 574; see
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Chan, J. Org. Chem. 1998, 63, 7670 ± 7673.
1
1516 cm
;
1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 6.86 ± 6.74 (m,
3
3H), 4.77 (m, 1H), 4.13 (dd, J(H,H) ˆ 7.8 and 10.6 Hz, 1H), 3.84 (s, 3H),
3.65 (dd, 3J(H,H) ˆ 7.5 and 10.5 Hz, 1H), 3.46 (m, 1H), 2.88 (dd, 3J(H,H) ˆ
8.5 and 2J(H,H) ˆ 17.3 Hz, 1H), 2.67 (dd, 3J(H,H) ˆ 9.7 and 2J(H,H) ˆ
17.3 Hz, 1H), 2.00 ± 1.71 (m, 4H), 1.68 ± 1.43 (m, 13H); 13C NMR
(75 MHz, CDCl3, 258C): d ˆ 173.1 (s), 149.9 (s), 149.3 (s), 147.9 (s), 132.8
(s), 118.7 (d), 113.6 (d), 112.1 (d), 83.0 (s), 80.5 (d), 56.1 (q), 53.3 (t), 40.5 (t),
Â
Â
[5] a) J. Barluenga, F. Fernandez-Marí, R. Gonzalez, E. Aguilar, G. A.
Ä
Â
Revelli, A. L. Viado, F. J. Fananas, B. Olano, Eur. J. Org. Chem. 2000,
Â
1773 ± 1783; b) J. Barluenga, F. Fernandez-Marí, A. L. Viado, E.
‡
36.0 (d), 32.7 (t), 27.9 (q), 23.9 (t); MS (70 eV, EI): m/z (%): 375 (<5) [M] ,
Aguilar, B. Olano, S. García-Granda, C. Moya-Rubiera, Chem. Eur. J.
207 (95), 150 (100); HRMS for C21H29NO5: calcd 375.2046; found 375.2057.
Â
1999, 5, 883 ± 896; c) J. Barluenga, F. Fernandez-Marí, E. Aguilar,
A. L. Viado, B. Olano, Tetrahedron Lett. 1998, 39, 4887 ± 4890; d) J.
Â
Barluenga, F. Fernandez-Marí, A. L. Viado, E. Aguilar, B. Olano, J.
Chem. Soc. Perkin Trans. 1 1997, 2267 ± 2268.
Acknowledgements
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We acknowledge the financial support received from DGICYT (PB92-
1005). F.F.-M. is indebted to the Ministerio de Educacion y Ciencia (Spain)
for a predoctoral fellowship. A.S. thanks the Universidad de Oviedo for an
undergraduate fellowship.
Â
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Chem. Eur. J. 2001, 7, No. 16
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0947-6539/01/0716-3543 $ 17.50+.50/0
3543

J. Barluenga et al.
FULL PAPER
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Â
[21] S. García-Granda, J. Vallaure, M. A. Fernandez-Rodríguez, E. Agui-
Â
lar, F. Fernandez-Marí, Acta Crystallogr. Sect. E, in press.
[22] Several assays were performed in an attempt to rule out one of the two
options: the undetected presence of the other diastereomer after the
cycloaddition reaction or a partial racemization of the cycloadduct
during the basic hydrolysis step. Thus, a sample of 12a with an erˆ
92:8 was treated with LiOH under the same hydrolysis conditions
described before. After three days, an erˆ 91:9 was observed using
chiral HPLC analysis; this turned into an erˆ 85:15 after fifteen days
of reaction. Also, the whole sequence that leads to (‡)-Rolipram 1
was repeated, but this time the crude mixture after the cycloaddition
step was purified by column chromatography, and three sequential
fractions in approximately 1:1:1 ratio were taken. Solvents were
evaporated, and NMR experiments (1H NMR: 300 MHz; 13C NMR:
75 MHz) did not detect the presence of the other diastereomer in any
of the fractions. The three fractions were then transformed into (‡)-
Rolipram 1 {[a]2D0 ˆ ‡26.7 (c ˆ 0.55 in MeOH), [a]2D0 ˆ ‡19.3 (c ˆ 0.72
in MeOH), and [a]2D0 ˆ ‡21.5 (c ˆ 0.97 in MeOH) for the first, second,
and third fraction, respectively} and into the BOC-protected com-
pound 13 to be purified by chiral HPLC analysis. The er values
observed in these analyses were 97:3 for the first fraction, 95:5 for the
second fraction, and 90:10 for the third fraction. From these results,
the presence of the NMR-undetected diastereomer after the cyclo-
addition step is evident.
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Â
211; e) A. Padwa, G. Haffmanns, M. Tomas, Tetrahedron Lett. 1983,
24, 4303 ± 4306.
Received: November 16, 2000 [F2874]
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