Cyclopenta[b]thiophene-alkyloxazolines: New nitrogen-sulfur hybrid ligands and their use in asymmetric palladium-catalyzed allylic alkylation

Article abstract of DOI:10.1016/j.tetasy.2004.01.036

New chiral nitrogen and sulfur containing hybrid ligands have been prepared and fully characterized. Their structure includes cyclopenta[b] tiophene and oxazoline moieties as sources of chirality. Their catalytic activity has been tested successfully in t

Full text of DOI:10.1016/j.tetasy.2004.01.036

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1043–1051
Cyclopenta[b]thiophene-alkyloxazolines: new nitrogen–sulfur
hybrid ligands and their use in asymmetric palladium-catalyzed
allylic alkylation
Bianca-Flavia Bonini,a Laurent Giordano,b Mariafrancesca Fochi,a
a
Mauro Comes-Franchini, Luca Bernardi, Elena Capito and Alfredo Ricci
a
a,
*
ꢀa
aDipartimento di Chimica Organica ‘A. Mangini’, Universitꢀa di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
bLaboratoire de Synthꢀese Asymꢁetrique, UMR-CNRS 6516, Facultꢁe des Sciences Saint-Jꢁer^ome, Av. Escadrille Normandie-Niemen,
13397 Marseille Cedex 20, France
Received 29 December 2003; accepted 29 January 2004
Abstract—New chiral nitrogen and sulfur containing hybrid ligands have been prepared and fully characterized. Their structure
includes cyclopenta[b]tiophene and oxazoline moieties as sources of chirality. Their catalytic activity has been tested successfully in
the Pd-allylic alkylation leading to enantioselectivities of up to 74% ee.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
*
The search for new ligands in asymmetric catalysis is
a field of continuing interest. To facilitate practical
S
O
N
applications, new ligands should be easy to prepare
from simple and easily accessible starting materials. In
this context the use of nitrogen and sulfur containing
ligands is growing. Recent reports have shown that these
compounds are suitable for many types of catalysis.1
Among chiral moieties containing nitrogen, oxazolines
have several advantages as sources of chirality, the
principal being that they are readily accessible from
homochiral amino alcohols and have proven to be
effective catalysts in a variety of reactions.2 The use of a
second different heteroatom binding site to induce elec-
tronic bias in the intermediate catalyst–substrate com-
plex has been reported so far, often with sulfur being
used for this purpose. Whereas the thioeter moiety has
been frequently used,3 thiophene has only occasionally
been employed,4 although there are reports of thiophene
functioning as either g1 or g5 ligands.5 High stability
and fairly good accessibility from the chiral pool,
highlight some beneficial aspects of ligands based on
sulfur and nitrogen when compared with phosphines.
Furthermore the thiophene–oxazoline combination in
*
R
CPTOX
Figure 1.
ligands for asymmetric catalysis has for the most part
been largely overlooked.6
Herein we report the synthesis of novel bidentate ligands
(Fig. 1) with two stereogenic centres with an oxazoline
moiety linked to a rigid cyclopenta[b]thiophene,5,6,-
dihydro backbone in which the sulfur atom is part of
a strong p-donor structure.
The first promising results with these chiral ligands for
the enantioselective palladium-catalyzed allylic substi-
tution are also described.
2. Synthesis of the ligands
The different cyclopenta[b]thiophene-alkyloxazolines
(CPTOxꢀs) have been synthesized following classical
* Corresponding author. Tel.: +39-051-2093635; fax: +39-051-20936-
54; e-mail: ricci@ms.fci.unibo.it
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.01.036

1044
B.-F. Bonini et al. / Tetrahedron: Asymmetry 15 (2004) 1043–1051
i) NaBH4, MeOH, r.t., 12h
ii) ClCOMe, Py, DMAP (cat)
MeI, KOH, 18-crown-6
Et2O, r.t., 12h
S
Toluene, 100°C, 12h
91%
O
S
S
OAc
O
81%
1
2
TMSCN, BF3 .Et2O
NaOH, OH-CH2-CH2-OH
CH2Cl2, r.t., 12h
90%
S
150°C, 3h
92%
S
CN
COOH
3
4
Scheme 1.
synthetic procedures for oxazolines. The 5-methyl-4,5-
dihydro-4H-cyclopenta[b]thiophen-6-one was prepared
using the one-pot reaction developed by Meth-Cohn
and Gronowitz.7 Under treatment of this ketone with
MeI and KOH in the presence of catalytic amounts of
18-crown-ether the 5,5 dimethyl derivative 1 was iso-
lated in 91% yield. For the synthesis of racemic car-
boxylic acid rac-4, 1 was readily converted as shown in
Scheme 1 via NaBH4 reduction into the corresponding
alcohol. At this stage the acetylated derivative 2 was
transformed into the nitrile 3 by treatment with
Me3SiCN under activation of BF3ÆEt2O.
Et2O after solvent evaporation, the enantiomerically
enriched free acid (+)-4 was obtained in 32% overall
yield from rac-4. Concentration under reduced pressure
of the mother liquor followed by treatment with 1 M
HCl, gave ())-enriched 4, which was converted into the
())-4-(R)-PEA salt by treatment with (R)-())-a-phen-
ethylamine [(R)-PEA]. Crystallization and successive
recrystallization from acetone gave the diastereomeri-
cally enriched salt in 60% yield, from which, upon
treatment with 1 M HCl, enantiomerically enriched
())-4 was obtained in 34% yield from rac-4. From the
filtrate, rac-4 was recovered with no chemical deterio-
ration nor significant loss and could thus be used in the
next resolution. The two enantiomerically enriched
compounds (+)-4 and ())-4 were then transformed into
the corresponding amides (+)-5 and ())-5 by a reaction
Hydrolysis with NaOH in ethylene glycol8 finally
afforded rac-4 in 67% overall yield from 1.
We next examined (Scheme 2) the resolution of rac-4
using phenethylamine as a chiral amine. Crystallization
and successive recrystallization of a diastereomeric salt
mixture of rac-4 with (S)-())-a-phenethylamine [(S)-
PEA] from acetone, afforded the (+)-4-(S)-PEA salt as a
white solid in 35% yield. By treatment with 1 M HCl
followed by dilution with water and extraction with
with (2S)-())-2-amino-2-isopropyl-ethan-1-ol
linol). On the same grounds the reaction of (+)-4 and
())-4 with (S)-())-2-amino-3-phenyl-1-propanol
(L-va-
(L-
phenylalaninol) led to hydroxyamides (+)-6 and ())-6.
In no one case did racemization occur during the reac-
tion using DCC in CH2Cl2 at rt. The diastereomeric
excesses detected on the crude amides were found to be
(+)-4-(S)-PEA
(-)-4-(S)-PEA
double crystallization
from acetone
HCl 1M
(+)-4-(S)-PEA
(+)-4
32%
35%
1) Concentration of
the mother liquor
(S)-PEA
2) HCl 1 M
(
)-4
3) (R)-PEA
HCl 1M
double crystallization
from acetone
(-)-4-(R)-PEA
(-)-4
34%
60%
L-valinol, DCC
70%
L-valinol, DCC
COOH
S
C
O
S
S
S
65%
C
O
HOOC
(-)-4
NH
(6R)-(+)-5
(+)-4
HN
(6S)-(-)-5
HO
d.e.
L-phenylalaninol,
L-phenylalaninol,
85%
73%
OH
d.e. > 98%
98%
DCC
O
DCC
S
C
S
C
O
NH
HN
(6S)-(-)-6
(6R)-(+)-6
HO
OH
d.e. > 98%
Bn
d.e. > 98%
Bn
Scheme 2.

B.-F. Bonini et al. / Tetrahedron: Asymmetry 15 (2004) 1043–1051
1045
malonate, chiral ligands may lead to enantioselectivity.
The new ligands 7 and 8 shown in Scheme 3 were tested
in this catalytic system to see if they were able to bind to
a suitable palladium precursor and interact with the
allylic substrate. Allylic substitutions on acetate 9 were
carried out using [Pd(g3-C3H5)Cl]2, and a mixture
of dimethylmalonate N,O-bis(trimethylsilyl)acetamide
(BSA) and potassium acetate in methylene chloride at
40 ꢁC. The ligand and palladium procatalyst were pre-
mixed in CH2Cl2 at room temperature for 1 h prior to
the reaction. After a suitable reaction time, isolated
product 10 was essayed for enantiomeric excess by
employing HPLC analysis on a Daicel Chiralcel OD-
column with absolute configuration determined by
comparison with literature values.12
Figure 2. ORTEP drawing.
90% by H and 13C NMR spectra thus suggesting that
1
Table 1 summarizes the yields and the enantioselectivi-
ties reached. Ligands 7 and 8 gave effective palladium
catalysis affording the dimethyl 1,3-diphenylprop-2-
enylmalonate 10 in very high yields, with the only dif-
ference in reaction rates being detected in favour of the
(S)-configured ligands. When the influence of the ratio
of ligand versus palladium on the enantiomeric excess
was tested, no sizeable variation in activity was observed
between a 1:1 ratio (see entry 5) and a 2:1. This indicated
that these ligands could act as bidentate species towards
the metal centre and that the active catalytic species
formed is more rapidly obtained and stabilized in the
presence of an excess amount of ligand. The assumption
that the catalytic species is an ML1-type complex formed
between 1 mol of CPTOx per Pd atom and therefore that
these N,S-ligands are quite strongly bound to the metal
centre, is further supported by the ESI spectrum of the
Pd-ligands complex (see Experimental). Good levels of
enantioselectivity were observed throughout and sub-
stituents on the oxazoline ring did not appear to be
influential to ensure different enantiodiscrimination.
However a surprising result deals with the fact that
irrespective of the configuration of the ligands [(R) or
(S)] all the complexes induce an excess of the enantiomer
with an (S)-configuration as shown in Table 1. To
rationalize the direction of the enantioselectivity,
we assumed according to the accepted notion, that
enantiomeric excess of enriched (+)-4 and ())-4 was
90%. After column chromatography (see Experimental),
amides (+)-5, ())-5, (+)-6 and ())-6 were obtained as
single diastereoisomers with de >98%.
The absolute configuration of the carbon atom at the
6-position in (+)-5 was determined (Fig. 2) to be (R) by a
single-crystal X-ray structural analysis.9 Consequently,
an (R)-configuration at the 6-position of (+)-4 was
established. The absolute configuration of ())-4 would
thus follow to be (S). In an analogous way, the absolute
configuration at C-6 in (+)-6 and ())-6 could be deduced
to be (R) and (S), respectively (Fig. 2).
The synthetic plan revealed that the oxazoline core
could be synthesized via a ring-forming procedure
developed by Evans10 by treating the hydroxyamides
with p-toluensulfonyl chloride and TEA in the presence
of catalytic quantities of DMAP (Scheme 3).
CPTOxꢀs (i-Pr), (R)-7 and (S)-7 were thus obtained
according to this procedure from (+)-5 and ())-5 and
CPTOxꢀs (Bn). (R)-8 and (S)-8 were similarly synthe-
sized starting from (+)-6 and ())-6. After purification,
the average yields of isolated products for the whole
process starting from carboxylic acids (+)-4 and ())-4,
were around 50%.
Table 1. Allylic alkylation of rac-9 with CPTOxꢀs ligands
2.1. Pd-catalyzed allylic substitution
MeOOC
COOMe
Ph
OAc
Ph
Pd-cat. 2.5 mol% /Ligand 10 mol%
Palladium-catalyzed allylic alkylation with soft carbon
nucleophiles is a useful tool for C–C bond formation.11
In the reaction of 1,3-diphenylacetate with dimethyl
Ph
Ph
CH2(CO2Me)2
9
Pd-cat.= [PdCl(η3-(C3H5)]2
(S)-10
Entry Ligand
Solvent
CH2Cl2
Time
(h)
Yield of Ee
10 (%)
(%)
TsCl, Et3N, DMAP
*
*
1
2
3
4
5a
6
7
8
(R)-7
(S)-7
(R)-8
(S)-8
(S)-8
(S)-8
136
70
95
91
92
93
94
96
96
94
66 (S)
70 (S)
62 (S)
73 (S)
74 (S)
51 (S)
69 (S)
73 (S)
S
S
O
O
CH2Cl2, r.t., 12h
HN
N
96
30
*
OH
R
R
60
48
(R)-7, 80%
(S)-7, 74%
(R)-8, 73%
(S)-8, 85%
(+)-5, R= i-Pr
(-)-5, R= i-Pr
(+)-6, R=Bn
(-)-6, R=Bn
Toluene
(R)-7/(S)-7 1/1 CH2Cl2
(R)-8/(S)-8 1/3
112
96
Scheme 3.
a Reaction of the ligand (5 mol %) and Pd-cat (2.5 mol %).

1046
B.-F. Bonini et al. / Tetrahedron: Asymmetry 15 (2004) 1043–1051
useful in enantioselective catalysis. In the present con-
Ph
S
Ph
Nu
text it could allow, for instance, the synthesis of CTPOx
ligands starting directly from rac-4. Finally very pre-
liminary results obtained in the 1,4-conjugated addition
of diethylzinc to chalcone 11 (Table 2) suggest that this
peculiar behaviour of CTPOx ligands is only restricted
to the allylic alkylation.
Nu
S
Ph
N
Pd
Pd
Ph
O
O
N
A
B
Table 2. Asymmetric conjugate addition of trans-chalcone 11 with
CPTOxꢀs ligands
Figure 3.
Et2Zn (1.1 equiv),
2.5 mol % Cu(OTf)2
nucleophilic attack of the p-allyl complex occurs, trans
to the better p-acceptor end of the chelate ligand from
the most stable Pd-allyl intermediate. In ligands 7 and 8
the thiophene moiety would behave as a p-donor since it
is a p-excessive aromatic and also in agreement with
literature data6a;13 that the oxazoline N atom is the
better p-acceptor. The plausible key p-allyl palladium
intermediates A and B involved in the reaction of 1,3-
diphenylpropenyl acetate in the presence of ligands (S)-7
and (R)-7 are depicted in Figure 3.
O
O
5 mol % L*
*
Ph
Ph
Ph
Ph
Et2O, 0°C, 16h
11
12
Ligand
Yield of 12 (%)
Ee (%)
Configuration
(R)-8
(S)-8
35
33
44
7
R
S
Using CTPOx (S)-8, (though the addition product is
obtained in both cases in moderate yields) a marked
decrease in enantioselectivity was observed together
with an inversion of configuration of the addition
product 12 on going from the (R)- to the (S)-configured
ligand. Evidently the configuration at C-6 plays in this
case an important role in determining the reaction ste-
reoselectivity as the consequence of a different reaction
mechanism.
We infer that for the 1,3-diphenylallyl group used here
W configured (p-allyl)palladium complex intermediates
A and B (exo) are enforced rather than those M con-
figured (endo) in which the phenyl groups would be
oriented towards the steric bulk. Attack of the malonate
nucleophile should logically occur away from the
greatest steric bulk (Fig. 3) on the side of the thiophene
ring. This is also expected electronically14 as the soft
nucleophile attacks trans to the oxazoline nitrogen,
which is the better p-acceptor and would thus lead in
both cases to the observed (S)-configuration of 10.
3. Conclusions
Finally as shown in Table 1 (entries 7 and 8), mixtures of
diastereoisomers can be successfully applied in the
asymmetric allylic alkylation. Thus in the experiment
reported in entry 7, an enantiomeric excess of 69% in
favour of the (S)-configured product, which is compa-
rable to the 66% (entry 1) and 70% (entry 2) obtained in
the sole presence of (R)-7 or (S)-7, respectively, was
achieved with a catalyst that had 0% de. Similarly using
unequal mixtures of diastereomeric 9-CPTOxꢀs (entry 8)
led to almost the same results obtained with the pure
diastereomers. There are quite a few cases in the litera-
ture in which mixtures of diastereoisomers have been
employed.15 We feel that in our case these unexpected
results cannot be explained by drastically different
reaction rates of the two diastereoisomers16 and there-
fore by the predominance of one catalyst on the ste-
reochemical outcome, or by the occurrence of nonlinear
effects.17 Rather we assume that the previously men-
tioned capacity of the CPTOxꢀs ligands in the (R)- or
(S)-configuration to stabilize only the exo-palladium
complexes A and B, combined with the electronic bias
exerted by the two chelating centres, which dictates the
nucleophilic attack along the same trajectory, might
account for these results. It is important to realize that
such a phenomenon could be of preparative importance
in those cases where no complete stereoselectivity in a
ligand functionalization process is feasible since the
resulting diastereomeric mixture as such could be highly
We have prepared four new bidentate S–N ligands with
multiple stereogenic elements and with (S)-oxazoline
and (6R)- or (6S)-cyclopenta[b]thiophene moieties as
homochiral cores. The ligands, available in five simple
synthetic steps in good yields and fairly large amounts,
were stable and reusable. They were tested in Pd-cata-
lyzed asymmetric allylic alkylation, reaching in all cases
almost quantitative yields of the alkylation product and
up to 74% ee. With these ligands the observation that
the prevailing (S)-configuration obtained in the substi-
tution product is not connected with the configuration
at C-6, indicates that the catalysts provide a unique
chiral environment, which orientates the allyl fragment
into a predisposed conformation around the Pd-allyl
axis and dictates the reaction at one end of the allyl
fragment. This intriguing issue turns out to be of high
interest allowing, in several cases, the use of diastereo-
meric mixtures of new ligands in asymmetric catalysis.
4. Experimental
Melting points (uncorrected) were determined with a
Buchi melting point apparatus. H NMR and 13C NMR
1
€
spectra were recorded using CDCl3 solutions at 300, 400

B.-F. Bonini et al. / Tetrahedron: Asymmetry 15 (2004) 1043–1051
1047
and 600 MHz for 1H and 75.46, 100.6 and 150.92 MHz
for 13C. Chemical shifts (d) are reported in ppm relative
33.6 mmol) in dry methanol (150 mL). Stirring was
continued for 12 h at room temperature. The mixture
was then cooled in a ice bath, and water (60 mL) then
added. The methanol was removed and the aqueous
phase extracted with ether (3 · 50 mL). The combined
organic layers were washed with brine (50 mL), dried
over Na2SO4, filtered and concentrated. Chromatogra-
phy on silica gel of the crude (Et2O/light petroleum 1/2)
yielded 5.2 g (92%) of alcohol as a white solid, mp 69–
1
to CHCl3 (d ¼ 7:26 for H and d ¼ 77:0 for 13C or 7.24
1
and 128.0 ppm for C6D6). J values are given in Hz. H
NMR and 13C NMR spectral assignments were made by
DEPT, gCOSY and gHSQC experiments. IR spectra
were recorded on a Perkin–Elmer model 257 grating
spectrometer. Mass spectra were obtained using a VG
7070-E spectrometer at an ionizing voltage of 70 eV.
20
D
½aꢀ values were determined with a Perkin–Elmer
70 ꢁC. 1H NMR (CDCl3, 75.3 MHz)
d 7.31 (d,
Polarimeter 341. Reactions were conducted in oven-
dried (120 ꢁC) glassware under a positive Ar atmo-
sphere. Transfer of anhydrous solvents or mixtures was
accomplished with oven-dried syringes/septum tech-
niques. THF was distilled from sodium/benzophenone
just prior to use and stored under Ar. Toluene was
distilled from sodium. Et2O was distilled from phos-
phorus pentoxide. CH2Cl2 was passed through basic
alumina and distilled from CaH2 prior to use. Other
solvents were purified by standard procedures. Light
petroleum ether refers to the fraction with bp 40–60 ꢁC.
The reactions were monitored by TLC performed on
silica gel plates (Baker-flex IB2-F). Column chroma-
tography was performed with Merck silica gel 60 (70–
230 mesh). Preparative thick layer chromatography was
carried out on glass plates using a 1 mm layer of Merck
silica gel 60 Pf 254. All chemicals were used as obtained
or purified by distillation as needed. Lithium aluminium
hydride (1 M THF) was purchased by Aldrich. Ee
measured on a Daicel Chiralcel OD column at
k ¼ 254 nm; absolute configuration was determined by
comparison with known data.
J ¼ 4:8 Hz, 1H), 6.79 (d, J ¼ 4:8 Hz, 1H), 4.64 (s, 1H),
2.70 (d, J ¼ 15:3 Hz, 1H), 2.48 (d, J ¼ 15:3 Hz, 1H),
1.65 (m, 1H, OH), 1.22 (s, 3H), 1.19 (s, 3H); 13C NMR
(CDCl3, 300 MHz) d 146.7 (s), 142.9 (s), 130.0 (d), 122.6
(d), 80.2 (d), 49.5 (s), 41.6 (t), 28.5 (q), 23.2 (q); IR mmax
(thin film, NaCl plate) 3599.6, 3465.5 cmꢁ1; GC–MS m=z
(relative intensity) 168 (8), 150 (43); TLC: Rf ¼ 0:47
(light petroleum/EtOAc 85/15). Acetyl chloride (3.7 g,
3.4 mL, 47.6 mmol) was slowly added to a stirred ice
cooled solution of alcohol (4.0 g, 23.8 mmol), DMAP
(586 mg, 4.8 mmol) and pyridine (9.4 g, 9.6 mL,
119 mmol) in anhydrous diethyl ether (120 mL) under
N2. After 12 h at room temperature, to the mixture
cooled in an ice bath, water (30 mL) and ether (50 mL)
were added. The organic phase was separated and
washed with
a copper sulfate saturated solution
(3 · 30 mL) and brine (30 mL). After drying over
Na2SO4, and ether removal, rapid chromatography on
silica gel of the crude (Et2O/light petroleum 1/9) affor-
1
ded 4.5 g (21.4 mmol, 90%) of 2 as a colourless oil. H
NMR (CDCl3, 300 MHz) d 7.33 (d, J ¼ 4:8 Hz, 1H),
6.78 (d, J ¼ 4:8 Hz, 1H), 5.54 (s, 1H), 2.77 (d,
J ¼ 15:3 Hz, 1H), 2.50 (d, J ¼ 15:3 Hz, 1H), 2.06 (s,
3H), 1.23 (s, 3H), 1.22 (s, 3H); 13C NMR (CDCl3,
75.3 MHz) d 171.0 (s), 148.6 (s), 138.9 (s), 131.3 (d),
122.2 (d), 81.2 (d), 48.5 (s), 42.1 (t), 28.8 (q), 23.5 (q),
4.1. 5,5-Dimethyl-4,5-dihydro-6H-cyclopenta[b]thiophen-
6-one 1
21.0 (q); IR mmax (thin film, NaCl plate) 1733.4 cmꢁ1
;
Powdered KOH (13.5 g, 240.6 mmol) was mixed with
toluene (70 mL) and 18-crown-6 (18.5 mg, 0.07 mmol).
The starting ketone (5.6 g, 36.8 mmol) was added and
the obtained mixture heated to 70 ꢁC. Iodomethane
(32 g, 225.4 mmol) was then added and after 12 h of
refluxing, the mixture was cooled and quenched by the
addition of water (50 mL). The two layers were sepa-
rated, and the aqueous layer was extracted twice with
ether (2 · 50 mL). The combined organic extracts were
dried over Na2SO4, filtered and concentrated. Purifica-
tion by distillation under vacuum (bp 114–116 ꢁC/
1.8 mmHg) afforded 5.58 g (91%) of 1 as a colourless oil.
1H NMR (CDCl3, 300 MHz) d 7.91 (d, J ¼ 4:8 Hz, 1H),
7.01 (d, J ¼ 4:8 Hz, 1H), 2.87 (s, 2H), 1.28 (s, 6H); 13C
NMR (CDCl3, 200 MHz) d 201.9 (s), 164.9 (s), 140.5 (d),
138.6 (s), 123.9 (d), 51.6 (s), 40.3 (t), 25.4 (q); IR mmax
(thin film, NaCl plate) 1704.8 cmꢁ1; GC–MS m=z (rela-
tive intensity) 166 (65); TLC: Rf ¼ 0:56 (light petroleum/
EtOAc 85/15).
ESIMS m=z 233 (M+Na); TLC: Rf ¼ 0:85 (light petro-
leum/EtOAc 85/15).
4.3. 5,5-Dimethyl-5,6-dihydro-4H-cyclopenta[b]thio-
phene-6-carbonitrile 3
To a stirred solution of acetate 2 (4.5 g, 21.4 mmol) and
TMSCN (2.5 g, 3.2 mL, 25.7 mmol) in dry CH2Cl2
(150 mL), cooled to 0 ꢁC under N2, BF3–Et2O (3.6 g,
3.2 mL, 25.7 mmol) was slowly added. After stirring at
room temperature for 2 h, to the mixture cooled in an ice
bath, water (50 mL) was added. The organic phase was
separated off, and the aqueous phase extracted with
CH2Cl2 (2 · 30 mL). The combined organic layers were
washed with 10% solution of Na2CO3 (2 · 30 mL), and
dried over Na2SO4. Evaporation of the solvent gave
3.8 g (100%) of the crude product as a dark oil. This was
purified by means of a bulb to bulb distillation (120–
130 ꢁC/1 mmHg) yielding 3.4 g (19.3 mmol, 90%) of 3 as
1
a light-yellow oil. H NMR (CDCl3, 300 MHz) d 7.28
4.2. 5,5-Dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophen-
6-yl acetate 2
(dd, J ¼ 1:2, 5.1 Hz, 1H), 6.79 (d, J ¼ 5:1 Hz, 1H), 3.83
(s, 1H), 2.74 (dd, J ¼ 1:2, 15.3 Hz, 1H), 2.63 (dd,
J ¼ 1:2, 15.3 Hz, 1H), 1.43 (s, 3H), 1.35 (s, 3H); 13C
NMR (CDCl3, 75.3 MHz) d 146.6 (s), 134.5 (s), 129.9
(d), 122.6 (d), 118.3 (s), 50.4 (s), 43.7 (d), 42.6 (t), 28.9
NaBH4 (1.6 g, 42.3 mmol) was added portionwise to
a stirred ice cooled solution of ketone 1 (5.58 g,

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B.-F. Bonini et al. / Tetrahedron: Asymmetry 15 (2004) 1043–1051
(q), 26.6 (q); IR mmax (thin film, NaCl plate) 2240.0 cmꢁ1
;
4.6. (6R)-(+)-N-[(1S)-1-(Hydroxymethyl)-2-methylpro-
pyl]-5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-
6-carboxamide (+)-5
ESIMS m=z 200 (M+Na); TLC: Rf ¼ 0:58 (light petro-
leum/EtOAc 85/15).
N,N-dicyclohexylcarbodiimide
(DCC)
(200 mg,
4.4. 5,5-Dimethyl-5,6-dihydro-4H-cyclopenta[b]thio-
phene-6-carboxylic acid 4
0.97 mmol) was added to a stirred cooled solution (0 ꢁC)
of (+)-carboxylic acid (+)-4 (180 mg, 0.92 mmol) in
CH2Cl2 (7 mL). After 20 min, (2S)-())-2-amino-2-iso-
propyl-ethan-1-ol (100 mg, 0.97 mmol) was added in one
portion. The reaction mixture was stirred at room
temperature for 2 h, and the urea then filtered. The
organic layer was diluted with Et2O (30 mL) and washed
successively with sodium carbonate solution 10%
(10 mL), HCl (1 M, 10 mL) and then brine (10 mL).
After filtration and evaporation of the solvents, the
crude product was purified by flash chromatography
(MeOH/CHCl3 0.5/99.5), affording 181 mg (70%) of (+)-
To a stirred solution of nitrile 3 (3.4 g, 19.2 mmol) in
ethylene glycol (150 mL), NaOH was added (24 g, 0.6
mol) in one portion. The resulting mixture was heated to
140–150 ꢁC for 3 h, then the solution cooled to 0 ꢁC and
water (100 mL) and Et2O (100 mL) added followed by
HCl 3 M (pH ꢂ 1). The two layers were separated and
the aqueous layer extracted twice with ether (2 · 30 mL).
The combined organic layers were extracted three times
with sodium carbonate solution 10% (3 · 35 mL). The
aqueous phases were combined and the carboxylic acid
liberated from its salt by cautious addition of HCl 3 M
(pH ꢂ 1). The aqueous layer was extracted three times
with ether (3 · 40 mL). The organic phases were dried
over Na2SO4, filtered and concentrated under vacuum.
The yellow solid was purified by chromatography (silica
gel, Et2O/light petroleum 1/1) to give 3.46 g (17.7 mmol,
92%) of 4 as a colourless solid, mp 107–108 ꢁC. 1H
NMR (CDCl3, 300 MHz) d 8.97 (br m, 1H), 7.27 (dd,
J ¼ 1:2, 5.1 Hz, 1H), 6.80 (d, J ¼ 5:1 Hz, 1H), 3.78 (s,
1H), 2.71 (dd, J ¼ 1:2, 15.3 Hz, 1H), 2.64 (dd, J ¼ 1:2,
15.3 Hz, 1H), 1.42 (s, 3H), 1.22 (s, 3H); 13C NMR
(CDCl3, 75.3 MHz) d 179.1 (s), 145.8 (s), 137.4 (s), 129.1
(d), 122.2 (d), 57.7 (d), 50.6 (s), 43.6 (t), 29.5 (q), 24.9
(q); IR mmax (thin film, NaCl plate) 3526.6, 3253.4,
1705.8 cmꢁ1; ESIMS m=z 195 (M)H); TLC: Rf ¼ 0:23
(light petroleum/EtOAc 85/15).
1
5 as a white solid: mp 106–108 ꢁC. H NMR (CDCl3,
300 MHz)
d
7.31 (d, J ¼ 5:1 Hz, 1H), 6.85 (d,
J ¼ 5:1 Hz, 1H), 5.66 (br m, 1H), 3.76 (m, 1H), 3.67 (dd,
J ¼ 3:0, 10.8 Hz, 1H), 3.59 (s, 1H), 3.56 (dd, J ¼ 6:6,
10.8 Hz, 1H), 2.70 (d, J ¼ 14:7 Hz, 1H), 2.59 (d,
J ¼ 14:7 Hz, 1H), 1.81 (m, 2H, OH), 1.37 (s, 3H), 1.23
(s, 3H), 0.91 (d, J ¼ 6:9 Hz, 3H), 0.82 (d, J ¼ 6:9 Hz,
3H); 13C NMR (CDCl3, 100 MHz) d 172.6 (s), 147.1 (s),
138.4 (s), 129.8 (d), 122.9 (d), 64.0 (t), 60.0 (d), 56.9 (d),
50.2 (s), 43.1 (t), 30.8 (q), 28.7 (d), 25.2 (q), 19.6 (q), 18.1
(q); IR mmax (thin film, NaCl plate) 3378.7, 1650.9,
1509.6 cmꢁ1; ESIMS m=z 280 (M)H), 304 (M+Na);
20
½aꢀ +55.7 (c 0.5, CHCl3); TLC: Rf ¼ 0:75 (CHCl3/
D
MeOH 9/1), 0.48 (CHCl3/MeOH 95/5).
For a single-crystal X-ray analysis, the amide (+)-5 was
recrystallized from hexane/Et2O giving the product as
white crystals. The absolute configuration of the asym-
metric carbon atom at the 6-position of diastereoisomer
(+)-5 was established as (R). Consequently, an (R)-con-
figuration at the 6-position of (+)-4 was also established.
4.5. Resolution of the (R)-(+)-4 and (S)-())-4 enantiomers
of 5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-6-
carboxylic acid 4
( )-Carboxylic acid ( )-4 (3.36 g, 17.1 mmol) was dis-
solved in acetone (100 mL) and (S)-())-a-phenethyl-
amine [(S)-PEA] (2.1 g, 2.2 mL, 17.1 mmol) was added.
After 1.5 h, the obtained salt [(+)-4-(S)-PEA] was
filtered and dried under vacuum. The salt was recry-
stallized twice from acetone to give (S)-())-a-phene-
4.7. (6S)-())-N-[(1S)-1-(Hydroxymethyl)-2-methylpro-
pyl]-5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-
6-carboxamide ())-5
Following the same procedure as for (+)-5, but starting
from ())-4, ())-5 was obtained in 65% yield as a col-
ourless oil. 1H NMR (CDCl3, 300 MHz) d 7.28 (dd,
J ¼ 0:9, 4.8 Hz, 1H), 6.82 (d, J ¼ 4:8 Hz, 1H), 5.79 (br
m, 1H), 3.62 (m, 1H), 3.60 (m, 1H), 3.54 (s, 1H), 3.40
(m, 1H), 2.67 (dd, J ¼ 0:9, 15.3 Hz, 1H), 2.56 (d,
J ¼ 15:3 Hz, 1H), 2.28 (m, 1H, OH), 1.85 (m, 1H), 1.33
(s, 3H), 1.19 (s, 3H), 0.87 (d, J ¼ 6:9 Hz, 3H), 0.81 (d,
J ¼ 6:9 Hz, 3H); 13C NMR (CDCl3, 75.3 MHz) d 172.7
(s), 147.1 (s), 138.4 (s), 129.8 (d), 122.9 (d), 63.9 (t), 60.1
thylammonium-(+)-carboxylate as a white solid (1.9 g,
20
D
6.0 mmol, 35%), ½aꢀ +22.2 (c 0.75, CHCl3). The salt
was suspended in Et2O (50 mL) and treated first with
HCl (1 M, 3 · 15 mL) and then with water (15 mL). The
free acid dissolved in Et2O was dried over Na2SO4 and
concentrated under reduced pressure to give (+)-4
20
D
(1.07 g, 5.47 mmol, 32%) ½aꢀ +46 (c 0.5, CHCl3). From
the mother liquor it was possible to recover 2 g
(10.2 mmol) of the racemic (enriched) carboxylic acid
( )-4, which was resolved following exactly the same
procedure, but using (R)-(+)-a-phenethylamine (1.23 g,
1.29 mL, 10.2 mmol) [(R)-PEA]. After two crystalliza-
(d), 57.5 (d), 50.2 (s), 43.2 (t), 30.8 (q), 28.5 (d), 25.3 (q),
20
D
19.5 (q), 18.4 (q); ½aꢀ )86.7 (c 0.5, CHCl3).
tions from acetone, 1.94 g (6.12 mmol, 60% yield) of ())-
4.8. (6R)-(+)-N-[(1S)-1-Benzyl-2-hydroxyethyl]-5,5-dimethyl-
5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxamide (+)-6
20
4-(R)-PEA were recovered, ½aꢀ )23.3 (c 0.75, CHCl3).
D
20
After the acidic work-up, ())-4 ½aꢀ )46.6 (c 0.5,
D
CHCl3), was isolated in 34% yield (1.14 g, 5.81 mmol),
from the starting rac-4.
Following the same procedure as for (+)-5, (+)-6 was
obtained in 73% yield as a white solid: mp 95–96 ꢁC. 1H

B.-F. Bonini et al. / Tetrahedron: Asymmetry 15 (2004) 1043–1051
1049
NMR (CDCl3, 400 MHz) d 7.25 (m, 4H), 7.09 (dd,
4.11. (6S)-())-2-(5,5-Dimethyl-5,6-dihydro-4H-cyclo-
penta[b]thiophen-6-yl)-(4S)-4-isopropyl-4,5-dihydro-1,3-
oxazole (S)-7
J ¼ 1:6, 8.0 Hz, 2H), 6.80 (d, J ¼ 4:4 Hz, 1H), 5.76 (d,
J ¼ 7:2 Hz, 1H), 4.20 (m, 1H), 3.61 (dd, J ¼ 4:0,
11.2 Hz, 1H), 3.53 (dd, J ¼ 5:2, 11.2 Hz, 1H), 3.46 (s,
1H), 3.18 (m, 1H, OH), 2.85 (dd, J ¼ 6:8, 14.0 Hz, 1H),
2.72 (dd, J ¼ 8:0, 14.0 Hz, 1H), 2.61 (dd, J ¼ 1:2,
15.0 Hz, 1H), 2.52 (d, J ¼ 15:0 Hz, 1H), 1.28 (s, 3H),
1.14 (s, 3H); 13C NMR (CDCl3, 100 MHz) d 172.4 (s),
147.0 (s), 138.3 (s), 137.0 (s), 129.8 (d), 129.1 (d), 128.6
(d), 126.6 (d), 122.8 (d), 64.6 (t), 59.9 (d), 52.8 (d), 50.3
(s), 43.0 (t), 36.8 (t), 30.8 (q), 25.1 (q); IR mmax (thin film,
Following the procedure used for (R)-7, (S)-7 was
1
obtained in 74% yield as a pale yellow oil. H NMR
(C6D6, 300 MHz) d 6.97 (dd, J ¼ 0:9, 5.1 Hz, 1H), 6.62
(d, J ¼ 5:1 Hz, 1H), 3.84 (m, 2H), 3.60 (m, 2H), 2.53
(dd, J ¼ 0:9, 14.4 Hz, 1H), 2.40 (dd, J ¼ 1:5, 14.4 Hz,
1H), 1.52 (m, 1H), 1.25 (s, 3H), 1.15 (s, 3H), 0.96 (d,
J ¼ 6:9 Hz, 3H), 0.77 (d, J ¼ 6:9 Hz, 3H); 13C NMR
(C6D6, 75.3 MHz) d 165.7 (s), 145.0 (s), 140.3 (s), 128.9
NaCl plate) 3408.3, 1664.6, 1501.1 cmꢁ1; ESIMS m=z
20
328 (M)H); ½aꢀ +38.9 (c 0.5, CHCl3); TLC: Rf ¼ 0:77
(d), 122.2 (d), 72.5 (d), 70.3 (t), 52.5 (d), 50.0 (s), 43.9 (t),
D
(CHCl3/MeOH 9/1), 0.51 (CHCl3/MeOH 95/5).
20
D
33.5 (d), 29.5 (q), 25.0 (q), 18.9 (q · 2); ½aꢀ )71.6 (c 0.5,
CHCl3).
4.9. (6S)-())-N-[(1S)-1-Benzyl-2-hydroxyethyl]-5,5-dimethyl-
5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxamide ())-6
4.12. (6R)-())-(4S)-4-Benzyl-2-(5,5-dimethyl-5,6-dihy-
dro-4H-cyclopenta[b]thiophen-6-yl)-4,5-dihydro-1,3-oxa-
zole (R)-8
Following the procedure used for (+)-5, ())-6 was
obtained in 85% yield as a colourless oil. 1H NMR
(CDCl3, 300 MHz) d 7.30 (d, J ¼ 4:8 Hz, 1H), 7.25 (m,
3H), 7.06 (dd, J ¼ 1:8, 8.1 Hz, 2H), 6.81 (d, J ¼ 4:8 Hz,
1H), 5.57 (br m, 1H), 4.09 (m, 1H), 3.70 (dd, J ¼ 3:3,
11.4 Hz, 1H), 3.59 (dd, J ¼ 5:4, 11.4 Hz, 1H), 3.46 (s,
1H), 2.88 (dd, J ¼ 6:3, 13.8 Hz, 1H), 2.74 (m, 1H, OH),
2.60 (dd, J ¼ 9:3, 13.8 Hz, 1H), 2.39 (d, J ¼ 15:0 Hz,
1H), 2.19 (d, J ¼ 15:0 Hz, 1H), 1.25 (s, 3H), 0.88 (s, 3H);
13C NMR (CDCl3, 75.3 MHz) d 172.4 (s), 147.1 (s),
138.0 (s), 137.4 (s), 129.8 (d), 128.9 (d), 128.5 (d), 126.5
Following the procedure used for (R)-7, (R)-8 was
1
obtained in 73% yield as a pale yellow oil. H NMR
(C6D6, 300 MHz) d 7.12–6.96 (m, 6H), 6.63 (d,
J ¼ 4:8 Hz, 1H), 4.18 (m, 1H), 3.75 (s, 1H), 3.69 (dd,
J ¼ 8:4, 9.3 Hz, 1H), 3.60 (dd, J ¼ 7:8, 8.4 Hz, 1H), 2.96
(dd, J ¼ 5:4, 13.5 Hz, 1H), 2.54 (dd, J ¼ 0:6, 14.7 Hz,
1H), 2.45 (dd, J ¼ 8:1, 13.5 Hz, 1H), 2.40 (dd, J ¼ 1:5,
14.7 Hz, 1H), 1.25 (s, 3H), 1.11 (s, 3H); 13C NMR
(C6D6, 75.3 MHz) d 166.4 (s), 145.0 (s), 140.0 (s), 138.6
(s), 129.7 (d), 129.1 (d), 128.6 (d), 126.6 (d), 122.2 (d),
71.5 (t), 67.7 (d), 52.4 (d), 50.0 (s), 43.9 (t), 42.1 (t), 29.5
(d), 122.7 (d), 64.3 (t), 59.8 (d), 53.1 (d), 50.1 (s), 42.6 (t),
20
D
36.7 (t), 30.8 (q), 24.8 (q); ½aꢀ )61.7 (c 0.5, CHCl3).
(q), 24.9 (q); IR mmax (thin film, NaCl plate) 1656.6 (O–
20
D
C@N) cmꢁ1; ESIMS m=z 312 (M+H), 334 (M+Na); ½aꢀ
)0.5 (c 0.5, CHCl3); TLC: Rf ¼ 0:40 (light petroleum/
4.10. (6R)-())-2-(5,5-Dimethyl-5,6-dihydro-4H-cyclo-
penta[b]thiophen-6-yl)-(4S)-4-isopropyl-4,5-dihydro-1,3-
oxazole (R)-7
EtOAc 85/15).
4.13. (6S)-())-(4S)-4-Benzyl-2-(5,5-dimethyl-5,6-dihydro-
4H-cyclopenta[b]thiophen-6-yl)-4,5-dihydro-1,3-oxazole
(S)-8
To a solution of (+)-5 (160 mg, 0.57 mmol) in CH2Cl2
(4 mL) were added successively at room temperature p-
TsCl (163 mg, 0.85 mmol), DMAP (3.5 mg, 5 mol %) and
dry triethylamine (173 mg, 0.240 mL, 1.7 mmol). After
12 h, sodium carbonate solution 10% (5 mL) was added
and the solution stirred for 30 min and then extracted
once with CH2Cl2 (2 mL). The organic layer was dried
over Na2SO4, filtered and the filtrate purified by chro-
matography (silica gel, AcOEt/light petroleum 1/9)
without any reduction in volume of the crude. After
purification, compound (R)-7 was obtained in 80%
(120 mg) yield as a pale yellow oil.
Following the procedure used for (R)-7, compound (S)-
1
8 was obtained in 85% yield as a pale yellow oil. H
NMR (C6D6, 300 MHz) d 7.18–7.02 (m, 5H), 6.99 (dd,
J ¼ 1:2, 4.8 Hz, 1H), 6.63 (d, J ¼ 4:8 Hz, 1H), 4.14 (m,
1H), 3.73 (s, 1H), 3.70 (dd, J ¼ 8:4, 9.3 Hz, 1H), 3.62
(dd, J ¼ 7:8, 8.4 Hz, 1H), 2.85 (dd, J ¼ 6:0, 13.8 Hz,
1H), 2.55 (dd, J ¼ 0:9, 14.4 Hz, 1H), 2.53 (dd, J ¼ 7:5,
13.8 Hz, 1H), 2.40 (dd, J ¼ 1:2, 14.4 Hz, 1H), 1.24 (s,
3H), 1.11 (s, 3H); 13C NMR (C6D6, 75.3 MHz) d 166.3
(s), 145.1 (s), 140.1 (s), 138.5 (s), 129.9 (d), 129.0 (d),
1H NMR (C6D6, 300 MHz) d 6.96 (dd, J ¼ 1:2, 4.8 Hz,
1H), 6.62 (d, J ¼ 4:8 Hz, 1H), 3.80 (dd, J ¼ 7:8, 9.6 Hz,
1H), 3.79 (s, 1H), 3.69 (m, 1H), 3.53 (dd, J ¼ 7:5, 7.8 Hz,
1H), 2.56 (d, J ¼ 14:4 Hz, 1H), 2.41 (dd, J ¼ 1:2,
14.4 Hz, 1H), 1.53 (m, 1H), 1.27 (s, 3H), 1.15 (s, 3H),
0.88 (d, J ¼ 6:9 Hz, 3H), 0.74 (d, J ¼ 6:9 Hz, 3H); 13C
NMR (C6D6, 75.3 MHz) d 165.8 (s), 145.0 (s), 140.2 (s),
129.0 (d), 122.2 (d), 72.4 (d), 70.0 (t), 52.6 (d), 49.9 (s),
44.0 (t), 33.1 (d), 29.6 (q), 25.0 (q), 19.0 (q), 18.7 (q); IR
128.6 (d), 126.6 (d), 122.2 (d), 71.5 (t), 67.5 (d), 52.4 (d),
20
D
50.1 (s), 43.9 (t), 42.0 (t), 29.5 (q), 24.9 (q); ½aꢀ )41.3
(c 0.5, CHCl3).
4.14. General procedure for palladium-catalyzed allylic
alkylation
In a 10 mL flame-dried Schlenk tube [Pd(g3-C3H5)Cl]2
(4.6 mg, 0.0125 mmol, 2.5 mol %) and the chiral ligand
(0.05 mmol, 10 mol %) were dissolved under argon in dry
and degassed CH2Cl2 (1 mL) and the resulting solution
mmax (thin film, NaCl plate) 1656.1 (O–C@N) cmꢁ1
;
20
ESIMS m=z 264 (M+H), 286 (M+Na); ½aꢀ )68.0 (c 0.5,
D
CHCl3); TLC: Rf ¼ 0:53 (light petroleum/EtOAc 85/15).

1050
B.-F. Bonini et al. / Tetrahedron: Asymmetry 15 (2004) 1043–1051
stirred at room temperature. After 1 h, were added
successively solutions of 1,3-diphenylprop-3-en-1-yl
acetate (126 mg, 0.5 mmol) and dimethyl malonate
(198 mg, 1.5 mmol) respectively in 1 and 0.5 mL of dry
and degassed CH2Cl2, followed by N,O-(trimethyl-
silyl)acetamide (BSA, 304 mg, 1.5 mmol, 0.366 mL) and
a catalytic amount of potassium acetate (1 mol %). The
resulting mixture was stirred at 40 ꢁC for 30–136 h and
the solvent concentrated in vacuo to afford a dark crude
product. The excess of dimethyl malonate was removed
by means of a bulb to bulb distillation (65–75 ꢁC/
2 mmHg) and the dark crude mixture was purified by
flash chromatography (AcOEt/light petroleum 1/9),
affording 91–96% of product as a colourless oil that
solidified on standing. The enantiomeric excesses were
determined by HPLC analysis on a Daicel Chiralcel OD
column at k ¼ 254 nm; flow rate 0.3 mL/min; eluent:
hexane/i-PrOH 95/5, tR ¼ 68 min, tS ¼ 72 min.
gie ed Applicazioniꢀ 2002–2003 and by the RTN project
ꢁDesign, Analysis and Computation for Catalytic
Organic Reactionsꢀ (contract HPRN-CT-2001-00172).
References and notes
1. Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M.
Chem. Rev. 2000, 100, 2159–2232.
2. For reviews see: (a) Reuman, M.; Meyers, A. I. Tetrahe-
dron 1985, 41, 837–860; (b) Pfaltz, A. Acc. Chem. Res.
1993, 26, 339–345; (c) Togni, A.; Venanzi, L. Angew.
Chem., Int. Ed. Engl. 1994, 33, 497–526; (d) Gosh, A. K.;
Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry
1998, 9, 1–45; (e) Johnson, J. S.; Evans, D. A. Acc. Chem.
Res. 2000, 33, 325–335.
3. (a) Dawson, G. J.; Frost, C. G.; Williams, J. M. J.; Coote,
S. J. Tetrahedron Lett. 1993, 34, 7793–7796; (b) Allen, J.
V.; Coote, S. J.; Dawson, G. J.; Frost, C. G.; Martin, C. J.;
Williams, J. M. J. J. Chem. Soc., Perkin Trans. 1 1994,
2065–2072; (c) Allen, J. V.; Dawson, G. J.; Frost, C. G.;
Williams, J. M. J.; Coote, S. J. Tetrahedron 1994, 50, 799–
808; (d) Allen, J. V.; Bower, J. F.; Williams, J. M. J.
Tetrahedron: Asymmetry 1994, 5, 1895–1898; (e) Newman,
L. M.; Williams, J. M. J.; McCague, R.; Potter, G. A.
Tetrahedron: Asymmetry 1996, 7, 1597–1598.
4.15. (R)-8/Pd-allyl complex
To a solution of ligand (R)-8 (34 mg, 0.11 mmol) dis-
solved in MeOH (1.5 mL), [Pd(g3-C3H5)Cl]2 (20 mg,
0.055 mmol) was added. After stirring the resulting
solution at room temperature for 30 min, LiClO4 (60 mg,
0.55 mmol) in 1 mL MeOH was added. Stirring was
continued at room temperature for 1 h, followed by
aqueous work-up and extraction with CH2Cl2. Filtra-
tion through a Celite pad and solvent evaporation
afforded the Pd complex as a yellow powder. ESIMS
m=z 458 (M), 312.
ꢀ
4. Benincori, T.; Cesarotti, T.; Piccolo, O.; Sannicolo, F.
J. Org. Chem. 2000, 65, 2043–2047.
5. (a) Russel, M. J. H.; White, C.; Yates, A.; Maitlis, P. J.
Chem. Soc., Dalton Trans. 1978, 857–861; (b) Loft, M. S.;
Widdowson, D. A.; Mowlen, T. J. Synlett 1992, 135–136.
6. (a) Frost, C. G.; Williams, J. M. J. Tetrahedron Lett. 1993,
34, 2015–2018; (b) Voituriez, A.; Fiaud, J.-C.; Schulz, E.
Tetrahedron Lett. 2002, 43, 4907–4909; (c) Voituriez, A.;
Schulz, E. Tetrahedron: Asymmetry 2003, 14, 339–346.
7. Meth-Cohn, O.; Gronowitz, S. Acta Chim. Scand. 1966,
20, 1577–1587.
4.16. General procedure for copper catalyzed conjugate
addition of Et2Zn to chalcone
8. Mc Guire, M. A.; Sorensen, E.; Owings, F. W.; Resnick,
T. M.; Fox, M.; Baine, N. H. J. Org. Chem. 1994, 59,
6683–6686.
In a 10 mL flame-dried flask, a solution of Cu(OTf)2
(9 mg, 0.025 mmol, 2.5 mol %) and the chiral ligand
(0.05 mmol, 5 mol %) in dry toluene (5 mL) was stirred at
room temperature under argon. After 1 h, chalcone
(208 mg, 1 mmol) was added. The solution was then
cooled to )20 ꢁC and ZnEt2 (1.1 mmol, 1.1 mL of a 1 M
solution of diethylzinc in hexane) was added dropwise.
The mixture was stirred at 0 ꢁC for 5 or 16 h. The reaction
was quenched with HCl (1 M, 5 mL) and the aqueous
layer extracted twice with ether (2 · 5 mL). The combined
organic extracts were washed with brine (10 mL), dried
over Na2SO4, filtered and evaporated. Purification by
chromatography on silica gel (AcOEt/light petroleum 2/
98), yielded 35% of product as a colourless oil that
solidified on standing. The enantiomeric excesses were
determined by HPLC analysis on a Daicel Chiralcel
OD column at k ¼ 254 nm; flow rate 1 mL/min; eluent:
hexane/i-PrOH 95/5, tS ¼ 12:4 min, tR ¼ 14:1 min.
9. CCDC 227371 contains the supplementary crystallographic
data for (+)-5. This data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
10. Evans, D. E.; Peterson, G. S.; Johnson, J. S.; Barnes,
D. M.; Campos, K. R.; Woerpel, K. A. J. Org. Chem.
1998, 63, 4541–4544.
11. (a) Hayashi, T. J. Organomet. Chem. 1999, 576, 195–202;
(b) Helmchen, G. J. Organomet. Chem. 1999, 576, 203–
214; (c) Trost, B. M.; Lee, C. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 2000;
p 593.
12. Widhalm, M.; Wimmer, P.; Klintschar, G. J. Organomet.
Chem. 1996, 523, 167–168.
€
13. Muller, A.; Dieman, E. In Comprehensive Coordination
Chemistry; Wilkinson, G., Ed.; Pergamon: Oxford, UK,
1987; Vol. 2, pp 515–558.
14. (a) Sprinz, J.; Kiefer, M.; Helmchen, G.; Reggelin, M.;
Huttner, G.; Walter, O.; Zsolnai, L. Tetrahedron Lett.
1994, 35, 1523–1526; (b) Brown, J. M.; Hulmes, D. I.;
Guiry, P. J. Tetrahedron 1994, 50, 4493–4506; (c) Adams,
H.; Anderson, J. C.; Cubbon, R.; James, D. S.; Mathias,
J. P. J. Org. Chem. 1999, 64, 8256–8262.
Acknowledgements
We acknowledge financial support by the National
Project ꢁStereoselezione in Sintesi Organica. Metodolo-
ꢂ
15. Muniz, K.; Bolm, C. Chem. Eur. J. 2000, 13, 2309–2316,
and references cited therein.

B.-F. Bonini et al. / Tetrahedron: Asymmetry 15 (2004) 1043–1051
1051
ꢂ
16. (a) Bolm, C.; Muniz, K.; Hildebrand, J. P. Org. Lett. 1999,
Int. Ed. 2000, 39, 495–499; (b) Kagan, H. B. Adv. Synth.
Catal. 2001, 343, 227–233; (c) Kagan, H. B. Synlett 2001,
888; (d) Todd, M. H. Chem. Soc. Rev. 2002, 31, 211–222;
(e) Buono, F.; Walsh, P. J.; Blackmond, D. G. J. Am.
Chem. Soc. 2002, 124, 13652–13653; (f) Hu, Y.; Liang, X.;
Zheng, Z.; Hu, X. Tetrahedron: Asymmetry 2003, 14,
2771–2774.
3, 491–494; (b) Blackmond, D. G.; Rosner, T.; Neu-
gebauer, T.; Reetz, M. Angew. Chem., Int. Ed. 1999, 38,
2196–2199.
17. Many examples of nonlinear effects have been reported in
recent years: (a) Heller, D.; Drexler, H.-J.; Fischer, C.;
Buschmann, H.; Baumann, W.; Heller, B. Angew. Chem.,