Deoxycholic acid-based phosphites as chiral ligands in the enantioselective conjugate addition of dialkylzincs to cyclic enones: Preparation of (-)-(R)-muscone

Article abstract of DOI:10.1016/j.tetasy.2004.07.009

Four phosphites, obtained by linking enantiomerically pure binaphthylchlorophosphite to the two different hydroxy substituted positions of deoxycholic acid, were used as chiral ligands in the enantioselective copper catalysed 1,4-addition of diethylzinc to 2-cyclohexenone and dimethylzinc to 2-cyclopentadecenone. Various reaction parameters were changed in order to select the experimental conditions that would maximise yield and ee. The four ligands were screened for activity and enantioselectivity under the optimised reaction conditions for comparative purposes, in order to establish the influence of the absolute configuration of the binaphthyl moiety as well as the position on the cholestanic backbone of the phosphite moiety. The ligand possessing a (R)-binaphthylphosphite moiety at position 12 of the cholestanic backbone proved to be the most enantioselective affording (-)-(R)-muscone in 63% ee.

Full text of DOI:10.1016/j.tetasy.2004.07.009

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2533–2538
Deoxycholic acid-based phosphites as chiral ligands in the
enantioselective conjugate addition of dialkylzincs to cyclic
enones: preparation of (–)-(R)-muscone
Anna Iuliano,a,* Patrizia Scafatob,* and Rita Torchiab
a
Dipartimento di Chimica e Chimica Industriale, Universit a` di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
b
Dipartimento di Chimica, Universit a` della Basilicata, via Nazario Sauro 85, 85100 Potenza, Italy
Received 8 June 2003; accepted 2 July 2004
Abstract—Four phosphites, obtained by linking enantiomerically pure binaphthylchlorophosphite to the two different hydroxy sub-
stituted positions of deoxycholic acid, were used as chiral ligands in the enantioselective copper catalysed 1,4-addition of diethylzinc
to 2-cyclohexenone and dimethylzinc to 2-cyclopentadecenone. Various reaction parameters were changed in order to select the
experimental conditions that would maximise yield and ee. The four ligands were screened for activity and enantioselectivity under
the optimised reaction conditions for comparative purposes, in order to establish the influence of the absolute configuration of the
binaphthyl moiety as well as the position on the cholestanic backbone of the phosphite moiety. The ligand possessing a (R)-binaph-
thylphosphite moiety at position 12 of the cholestanic backbone proved to be the most enantioselective affording (À)-(R)-muscone in
6
3% ee.
Ó 2004 Elsevier Ltd. All rights reserved.
2
3
4
5
1
. Introduction
phines, diphosphites, phosphoramidites, phosphites
6
and aminophosphines as copper ligands. More re-
cently, attention has been paid to the development of
tunable ligands, which allow the effects of changes in
conformational and stereochemical properties of the
chiral catalyst on activity and enantioselectivity to be
evaluated. Following this idea, we synthesised the four
chiral phosphites 1 and 2 (Fig. 1), by linking
The asymmetric copper catalysed 1,4-addition of or-
ganozinc reagents to conjugated enones is a useful syn-
thetic transformation that involves a carbon–carbon
bond formation together with the introduction of a
new stereogenic centre at the b-position. High levels
of enantioselectivity have been reached using diphos-
7
1
O
*
R
O
O
O
O
OCH
3
OCH3
O
*
R
H
3
C
O
O
1a and b
2
a and b
O
O
O
P
a: R* =
b: R* =
P
O
Figure 1. Structure of the phosphites.
*
Corresponding authors. Tel.: +39-0502219232; fax: +39-0502219260 (A.I.); tel./fax: +39-0971202223 (P.S.); e-mail addresses: iuliano@dcci.unipi.it;
scafato@unibas.it
0
957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.07.009

2534
A. Iuliano et al. / Tetrahedron: Asymmetry 15 (2004) 2533–2538
enantiomerically pure binaphthylchlorophosphite to the
two different hydroxy groups of deoxycholic acid, which
were used as copper ligands in the enantioselective con-
2. Results and discussion
2.1. Using ligands 1 and 2 in the copper catalysed
conjugate addition of diethylzinc to cyclohexenone
8
jugate addition of diethylzinc to acyclic enones. The ob-
tained results demonstrated that the copper complexes
of ligands 1 and 2 show high activity in the conjugate
addition of diethylzinc to acyclic enones, affording high
isolated yields (up to 88%) of the alkylated products at
The results obtained using chiral auxiliaries 1 and 2 in
the copper catalysed conjugate addition of diethylzinc
to cyclohexenone are listed in Table 1.
8
À70°C in 3h. The enantioselectivity of the reaction de-
pended on the absolute configuration of the binaphthyl
moiety as well as on its position on the cholestanic back-
bone; the best combination of these two parameters was
found in ligand 1a, which afforded the highest enantio-
The catalytic system was generated in situ by stirring a
solution containing the ligand and the copper salt for
1h at room temperature. All the reactions were stopped
when the conversion of the substrate was complete or
did not proceed further, as judged by GC–MS analysis.
To determine the enantiomeric excess of the alkylation
product, 3-ethylcyclohexanone was reacted with (R,R)-
1,2-diphenylethane-1,2-diol and the diastereomeric com-
position of the dioxolane derivative was obtained by
HPLC. The influence of different reaction parameters,
such as temperature, solvent and copper salt were eval-
uated using ligand 1a. The catalytic species obtained
8
selectivity levels (up to 78%).
It is well known that the catalytic efficiency of phospho-
rus ligands depends strongly on the nature of the sub-
1
a,9
strate.
In fact, at present, only a few ligands afford
copper catalysts showing uniformly good enantioselec-
tivity against a wide range of substrates, such as acyclic
and cyclic enones or differently sized cyclic enones:
among these, there are the phosphoramidites from Fer-
starting from 1a and Cu(OTf) was very active affording
2
4
a
inga and the BINOL based phosphites from Pfaltz and
5
complete substrate conversion in 15min at room tem-
perature (entry 1); the alkylation product was isolated
in 96% yield and 25% ee. On lowering the temperature
to 0°C, no improvement in stereoselectivity was ob-
served (entry 2). Better results were obtained by reacting
cyclohexenone at À20°C; the alkylation product was
obtained in 89% yield and 50% ee (entry 3). No improve-
ment was observed at lower temperatures. In fact at
À40°C, the same enantioselectivity was obtained,
whereas at À70°C both activity and enantioselectivity
dropped with the alkylation product obtained after
b,10
co-workers.
Therefore, we became interested in
checking the possibility of extending the use of deoxy-
cholic based phosphites 1 and 2 to the asymmetric con-
jugate addition of dialkylzincs to cyclic enones. Herein
we report on the screening of the four chiral ligands in
the conjugate addition of diethylzinc to cyclohexenone,
1
as a model of cyclic enones, as well as in the addition
of dimethylzinc to 2-cyclopentadecenone, a model of
macrocyclic enone, which affords (À)-muscone, a com-
1
1,12
pound having high commercial value.
Table 1. Catalytic enantioselective conjugate addition of diethylzinc to 2-cyclohexen-1-one
O
O
Cu salt (2.5 mol%)
Et Zn (1.5 eq), L* (3 mol%)
*
2
*
a
Conv. (%)
b
Yield (%)
c,d
Ee (%)
Entry
L
Solvent
Cu salt
T (°C)
Time (h)
e
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
2a
2b
Toluene
Toluene
Toluene
Toluene
Toluene
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
2
2
2
2
2
2
2
2
rt
15min
30min
30min
100
96
96
62
89
61
73
89
75
88
75
82
74
85
80
71
91
25 (R)
24 (R)
50 (R)
50 (R)
20 (R)
30 (R)
6 (R)
0
e
À20
À40
À70
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
100
100
83
e
1
17
1
Et
THF
CH Cl
2
O
90
e
3
100
100
100
50
e
2
2
1
3 (R)
e
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Cu(OAc)
2
ÆH
2
O
1
20 (R)
2 (S)
10
11
12
13
14
15
CuBrÆSMe
2
6
f
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
2
2
2
2
2
1.5
1
88
85
35 (R)
41 (R)
12 (S)
5 (R)
g
e
1
100
100
100
e
1
e
1
20 (S)
a
b
c
Determined by GC/MS.
Isolated product.
Determined by HPLC analyses after derivatisation with (R,R)-1,2-diphenylethane-1,2-diol: Daicel Chiralcel OD, hexane/2-propanol 99.7:0.3,
.5mL/min, k = 254nm.
0
d
e
f
Absolute configuration assigned by the sign of the specific rotation.
Optimised time.
*
L (6.0mol%) were used.
g
Double the amount of solvent was used.

A. Iuliano et al. / Tetrahedron: Asymmetry 15 (2004) 2533–2538
2535
17h in only 20% ee (entry 5). Toluene proved to be the
best reaction solvent. When Et O was used, complete
lective ligands are obtained. In fact both diastereoiso-
mers 2a and 2b afforded lower ees of the alkylation
product (entries 14 and 15). These results are similar
2
substrate conversion was reached in 1h and 3-ethylcy-
clohexanone obtained in 30% ee (entry 6). THF and di-
chloromethane gave even worse results, mainly as far as
enantioselectivity was concerned (entries 7 and 8). The
copper salt had a remarkable influence on the outcome
8
to those obtained in the alkylation of chalcone and
can be explained by considering that the presence of
the binaphthylphosphite moiety on the more stereo-
chemically demanding position 12 results in the achieve-
ment of a more enantioselective ligand. When the
binaphthylphosphite moiety is linked at position 3, the
matched stereochemical relationship is obtained with a
(S)-binaphthyl system. In fact, the use of ligand 2b, pos-
sessing a (S)-configured binaphthyl unit, afforded the al-
kylation product in 20% ee (entry 15), whereas only 5%
ee was obtained with diastereoisomer 2a (entry 14).
These results are contrary to those obtained in the alkyl-
ation of chalcone, where the matched couple was always
the one possessing the (R)-configured binaphthyl
of the reaction. The alkylation product was obtained
in lower ee by replacing Cu(OTf) with a different Cu
II
2
I
salt (entry 9), whereas the use of Cu was detrimental
both for activity and enantioselectivity (entry 10).
Increasing the ligand to copper salt ratio had a negative
influence on the outcome of the reaction, affording the
alkylation product in lower yield and lower ee (entry
1
1). Dilution of the reaction mixture did not improve
the yield, but only lowered the enantioselectivity (entry
2), indicating that the concentration used in the previ-
1
8
ous runs is the most favourable. Once the optimal reac-
tion conditions were found, that is, ligand to copper
ratio 1:1.2, toluene as solvent, Cu(OTf) as the copper
moiety. As already observed, using chalcone as the
8
substrate, the deoxycholic moiety does not exert its
influence on the sense of the asymmetric induction:
a (R)-configured product was always obtained using
ligands possessing a (R)-binaphthyl moiety.
2
salt and a temperature of À20°C, the other chiral auxil-
iaries were tested under these experimental conditions,
for comparative purposes. All the ligands showed com-
parable activity, affording complete conversion of the
substrate after 1h and high yield of the alkylation prod-
uct. Changing the absolute configuration of the binaph-
thyl moiety, as well as the substitution position on the
cholestanic backbone, strongly affected the enantioselec-
tivity. Ligand 1b, possessing a (S)-binaphthylphosphite
moiety linked at position 12 of the cholestanic skeleton
afforded the alkylation product in 12% ee (entry 13).
Therefore, as previously observed in the alkylation of
2.2. Using ligands 1 and 2 in the copper catalysed
conjugate addition of dimethylzinc to cyclopentadecenone
Table 2 reports on the results obtained in the copper cat-
alysed addition of dimethylzinc to cyclopentadecenone
using 1 and 2 as ligands.
The reaction performed at room temperature using 1a as
the ligand with Cu(OTf) , in toluene as the solvent, af-
2
8
chalcone, when the binaphthylphosphite moiety is
forded complete conversion of the substrate in 15min
(entry 1); the alkylation product was obtained in 59%
yield and 34% ee. The yield is lower than that observed
in the alkylation of cyclohexenone (59 vs 96) because of
the formation of a by-product, generated by the attack
linked at position 12 of the cholestanic backbone, the
matched couple is that possessing the (R)-binaphthyl
system. When the binaphthylphosphite moiety is linked
to position 3 of the cholestanic backbone, less enantiose-
Table 2. Catalytic enantioselective conjugate addition of dimethylzinc to E-cyclopentadec-2-enone
O
O
Cu salt (2.5 mol%)
Me Zn (1.5 eq), L* (3 mol%)
*
2
*
L
a
Conv. (%)
b
Yield (%)
c
Ee (%)
Entry
Cu salt
T (°C)
Time (h)
d
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1b
2a
2b
2a
2b
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
2
2
2
2
25
0
15min
d
100
100
100
60
59
30
66
33
41
16
47
34
39
47
50
34 (R)
41 (R)
29 (R)
32 (R)
63 (R)
19 (S)
41 (S)
53 (R)
52 (S)
41 (R)
37 (S)
1
d
1
À10
À40
0
7
7
7
Cu(OAc)
Cu(OAc)
2
ÆH
ÆH
2
O
O
65
68
2
2
0
d
Cu(OTf)
Cu(OAc)
Cu(OAc)
2
0
15min
100
58
2
2
ÆH
ÆH
2
O
O
0
7
7
2
0
65
d
10
1
Cu(OTf)
Cu(OTf)
2
0
1
1.5
100
100
d
1
2
0
a
b
c
Determined by GC/MS.
Isolated product.
12
Determined by specific rotation; for (R)-(À)-muscone [a]
D
= À12.7 (c 0.9, MeOH).
d
Optimised time.

2536
A. Iuliano et al. / Tetrahedron: Asymmetry 15 (2004) 2533–2538
of the in situ formed enolate on another molecule of un-
8
ation products. The results obtained in the asymmetric
conjugate addition of Zn(CH ) to cyclopentadecenone
,13
reacted substrate.
Lowering the temperature to 0°C
3
2
causes an improvement in enantioselectivity (entry 2),
flanked by a lower yield of the alkylation product, due
to the formation of a greater amount of the dimeric
by-product. This most likely happens because when
the alkylation reaction is slower the formation of the
show the different behaviour of the deoxycholic based
chiral phosphites 1 and 2, with respect to that observed
in the conjugate addition of diethylzinc not only to
8
acyclic enones but also to cyclohexenone. The best cop-
per salt for obtaining the most enantioselective catalysts
8
dimeric product becomes competitive. On lowering
was Cu(OAc) ÆH O in three cases, instead of Cu(OTf)
2
2
2
the reaction temperature until À10°C, a lower ee was
obtained (entry 3). By contrast, the yield of the alkylated
product is higher, suggesting that, at this temperature,
the formation of the dimeric product is slower with
respect to the alkylation reaction. By lowering the tem-
perature until À40°C, we obtained worse results. Com-
plete conversion of the substrate was not reached in 7h
and, in addition, no improvement in either yield or
enantio- selectivity was observed (entry 3). Better results
were obtained by changing the copper salt. The use of
Cu(OAc) ÆH O at 0°C afforded in 7h only 65% sub-
as usually observed. Activity and enantioselectivity of
the chiral catalysts did not proceed in step. The more
active catalysts were obtained using Cu(OTf) as the
2
copper salt, whereas the use of Cu(OAc) ÆH O guaran-
2
2
teed the formation of a more enantioselective catalytic
species. The entity of the asymmetric induction still
seemed affected by the cholestanic backbone, but not
by the stereochemistry of the binaphthyl moiety. In fact
the introduction of the binaphthylphosphite unit at
position 12 of the cholestanic backbone still afforded
more efficient ligands. In contrast by changing the abso-
lute configuration of the binaphthyl moiety we obtained
ligands affording comparable ee values. However, the
binaphthyl moiety still determines the sense of the asym-
metric induction: ligands possessing the (R)-binaphthyl
unit afford the (À)-(R)-muscone, whereas the (+)-(S)-
muscone is obtained using ligands having the (S)-bi-
naphthyl fragment.
2
2
strate conversion (entry 5), but a higher yield of the
alkylation product and greater enantioselectivity (ee
6
3%) were obtained. This result suggests that using this
copper salt not only gives the (À)-muscone in higher ee
but also the formation of the dimeric product is slowed
to a greater extent with respect to the alkylation reac-
tion. The best reaction conditions for obtaining both
the highest yield and enantioselectivity (i.e., Cu(OAc)2Æ
H O as the copper salt at 0°C in toluene as the solvent)
2
were used to check the activity and enantioselectivity of
the catalyst obtained from 1b. Both yield and ee were
remarkably lower (entry 6), suggesting that changing
the absolute configuration of the binaphthyl moiety
gives rise to a less efficient chiral ligand. However, the
3. Conclusion
The results obtained using the four deoxycholic acid
based phosphites 1a and 1b and 2a and 2b as copper
ligands in the enantioselective conjugate addition of
diethylzinc to 2-cyclohexenone and dimethylzinc to 2-
cyclopentadecenone allowed us to reach the following
conclusions. Although these ligands give more enantio-
selective catalysts for the conjugate addition of diethyl-
use of Cu(OTf) as the copper salt, under the reaction
2
conditions that had afforded the best ee using 1a as lig-
and (entry 2), provided significantly better results (entry
7
), both in terms of yield and ee. In addition, under these
8
reaction conditions, 1b gave a more active catalyst than
that obtained using 1a. In fact, complete conversion of
the substrate was achieved in only 15min along with a
higher yield (47 vs 30) of the alkylation product. The
two chiral ligands afford the same enantioselectivity
but an opposite sense of asymmetric induction, giving
the same ee of products having opposite absolute config-
urations. Taking into account this result, chiral ligands
zinc to acyclic enones, the accurate screening of
various reaction parameters, aimed at maximising the
yields and ees, allowed us to obtain acceptable levels
of asymmetric induction also in the 1,4-addition of dial-
kylzinc to cyclic substrates and to obtain (À)-(R)-
muscone in 63% ee. The phosphite structure affects
differently the activity and enantioselectivity of the cata-
lyst depending on the nature of the substrate. As far as
the substitution pattern on the deoxycholic moiety is
concerned, catalysts obtained from the ligand possessing
the binaphthylphosphite unit on the 12 position of the
cholestanic backbone are still the most enantioselective.
The sense of the asymmetric induction is still governed
by the absolute configuration of the binaphthylphos-
phite moiety. Conversely, the best enantioselectivities
were not always obtained with ligands possessing a
(R)-binaphthyl moiety, as found previously. When the
binaphthylphosphite unit was linked at position 3 of
the cholestanic backbone, the highest ee in the conjugate
addition of diethylzinc to 2-cyclohexenone was obtained
using ligand 2b, which possesses a (S)-configured
binaphthyl system. On the contrary, the diastereoiso-
meric couples show the same enantioselectivity in the
conjugate addition of dimethylzinc to 2-cyclopentadece-
none, suggesting that the different stereochemical rela-
tionship between binaphthylphosphite and cholestanic
2
a and 2b were checked not only under the best condi-
tions found for the use of ligand 1a, but also under those
that afforded the best results with ligand 1b. By using
Cu(OAc) ÆH O as copper salt, both 2a and 2b afforded
2
2
in 7h similar substrate conversions and yields with re-
spect to 1a (entries 8 and 9). The ee obtained using the
two diastereomeric ligands are almost identical (52 vs
5
The use of Cu(OTf) as the copper salt, afforded analo-
3) but lower with respect to that obtained using 1a.
2
gous results to those observed in the case of 1a. The
activity of the chiral catalysts is better, providing com-
plete conversion of the substrate and higher yields of
alkylation product in shorter reaction times. In contrast,
the enantioselectivity was inferior, even if very similar
values of ee were obtained for the diastereoisomeric lig-
ands. As observed with ligands 1a and 1b, the two dia-
stereoisomers 2a and 2b also showed an opposite sense
of asymmetric induction, affording enantiomeric alkyl-

A. Iuliano et al. / Tetrahedron: Asymmetry 15 (2004) 2533–2538
2537
backbone does not affect the extent of the asymmetric
induction.
3H, J = 4.5Hz), 1.32–1.48 (m, 4H), 1.65–1.89 (m, 5H),
2.09 (d, 1H, J = 14.5Hz), 2.18 (d, 1H, J = 14.5Hz),
4
(
.76 (d, 1H, J = 9.0Hz), 4.84 (d, 1H, J = 9.0Hz), 7.26
m, 4H), 7.34 (m, 6H); (R,R,S): 0.96 (t, 3H,
J = 4.5Hz), 1.32–1.48 (m, 4H), 1.65–1.89 (m, 5H), 2.12
d, 1H, J = 15.5Hz), 2.15 (d, 1H, J = 15.5Hz), 4.78 (s,
4. Experimental
(
1
3
4
.1. General
2H), 7.26 (m, 4H), 7.34 (m, 6H); C NMR (75MHz,
CDCl , d): 11.69, 23.20, 23.60, 29.96, 31.74, 36.35,
3
1
13
H and C NMR spectra were recorded in CDCl on a
37.06, 43.54, 85.64, 110.73, 127.03, 128.47, 128.69,
137.36; MS(EI): m/z 322 (M , 2), 293 (5), 279 (6), 216
(100), 180 (36), 167 (22), 105 (12), 91 (47), 55 (14);
HPLC analyses: Chiralcel OD, hexane/2-propanol
99.7/0.3, 0.5mL/min, 254nm, t = 8.0 (R,R,R), t = 10.0
(R,R,S).
3
+
Bruker Aspect 300 300MHz NMR spectrometer, using
TMS as the external standard. TLC analysis were per-
formed on silica gel 60 Macherey–Nagel sheets; flash
chromatography separations were carried out on ade-
quate dimension columns using silica gel 60 (70–230 or
2
30–400mesh). HPLC analyses were performed on a
JASCO PU-1580 intelligent HPLC pump equipped with
a Varian 2550 UV detector. Optical rotations were
measured with a JASCO DIP-370 digital polarimeter.
Gas chromatographic analyses were carried out on
GC/MS Hewlett–Packard 6890, mass selective detector
HP 5973, capillary column HP-5MS (5% phenyl methyl
siloxane). Unless otherwise indicated, all experiments
4.3. Enantioselective conjugate addition of dimethylzinc to
2-cyclopentadecenone: general procedure
A solution of Cu(OTf) (4.5mg, 0.013mmol) and chiral
2
ligand (0.015mmol) in solvent (6mL) was stirred at
room temperature for 1h. The solution was cooled to
the suitable temperature and 2-cyclopentadecenone
(111mg, 0.5mmol) added followed by dimethylzinc
(2.0M in toluene, 1.5equiv). The reaction was moni-
tored by GC–MS analyses. 10mL of 1M HCl and
5mL of diethyl ether were added to the reaction mix-
ture, which was stirred for a few minutes and then
extracted with diethyl ether. The combined organic
layers were washed with brine, dried over anhydrous
Na SO , filtered and concentrated under reduced pres-
were carried out under a dry N atmosphere. Toluene,
2
diethyl ether and THF were dried over sodium/benzo-
phenone and distilled before use. Dichloromethane
was dried and distilled over CaH before use. Commer-
2
cially available 2-cyclohexenone was distilled before use.
Cyclopentadec-2-en-1-one was synthesised from com-
1
4
mercially available cyclopentadecanone. Ligands 1
and 2 were synthesised according to previously reported
2
4
8
methods.
sure. The crude product was purified by flash column
chromatography (SiO , light petroleum/diethyl ether
95/5), affording muscone as colourless oil.
2
4
2
.2. Enantioselective conjugate addition of diethylzinc to
-cyclohexen-1-one: general procedure
A solution of Cu(OTf) (9.0mg, 0.025mmol) and phos-
2
Acknowledgements
phite (0.03mmol) in toluene (or other solvent) (6mL)
was stirred at room temperature for 1h. The solution
was cooled to a suitable temperature and 2-cyclohexe-
none (97lL, 1.0mmol) added. After a few minutes,
diethylzinc (1.0M in hexane, 1.5mmol) was slowly
added and the reaction monitored by GC–MS analyses.
After complete conversion, the reaction mixture was
poured into 25mL of 1M HCl and extracted three times
with diethyl ether. The combined organic layers were
washed with brine, dried over anhydrous Na SO and
Financial support from MIUR-COFIN 2002, Univer-
sit a` degli Studi della Basilicata (Potenza) and Universit a`
di Pisa is gratefully acknowledged.
References
1
2
3
. (a) Alexakis, A.; Benhaim, C. Eur J. Org. Chem. 2002,
3
2
2
4
221; (b) Krause, N.; Hoffmann-Roeder, A. Synthesis
001, 171.
filtered. Removal of diethyl ether under reduced pres-
sure (500–350mbar) at room temperature yielded the
crude product in toluene, which was purified by column
. (a) Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1999, 64,
988; (b) Taira, S.; Crepy, K. V. L.; Imamoto, T. Chirality
2002, 14, 386.
2
chromatography (SiO , pentane/diethyl ether 5/1) to af-
2
ford 3-ethylcyclohexanone as a colourless liquid. The ee
was determined by HPLC analyses after derivatisation
with (R,R)-1,2-diphenylethan-1,2 diol. 3-Ethylcyclo-
. (a) Reetz, M. T.; Gosberg, A.; Moulin, D. Tetrahedron
Lett. 2002, 43, 1189; (b) Liang, L.; Au-Yeung, T. T.-L.;
Chan, A. S. C. Org. Lett. 2002, 4, 3799; (c) Su, L.; Li, X.;
Chan, W. L.; Jia, X.; Chan, A. S. C. Tetrahedron:
Asymmetry 2003, 14, 1865; (d) Alexakis, A.; Burton, J.;
Vastra, J.; Benhaim, C.; Fournioux, X.; van den Heuvel,
A.; Leveque, J. M.; Maze a´ , F.; Rosset, S. Eur. J. Org.
Chem. 2000, 4011.
hexanone (63mg, 0.5mmol) was then dissolved in
˚
1
2mL of dichloromethane and 4A molecular sieves
added, followed by (R,R)-1,2-diphenylethan-1,2-diol
126mg, 0.6mmol) and traces of p-toluenesulfonic acid.
(
The mixture was stirred at room temperature and the
reaction monitored by GC–MS analyses. After complete
conversion (2h), molecular sieves were removed by fil-
tration and the crude dioxolane purified by column
4
. (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346; (b)
Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H.
M.; Nassz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865;
(
c) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew.
chromatography (SiO , light petroleum/diethyl ether
2
Chem., Int. Ed. 1996, 35, 2374; (d) Alexakis, A.; Rosset, S.;
Allamand, J.; March, S.; Guillen, F.; Benhaim, C. Synlett
1
9
8/2). H NMR (300MHz, CDCl , d) (R,R,R): 0.99 (t,
3

2538
A. Iuliano et al. / Tetrahedron: Asymmetry 15 (2004) 2533–2538
001, 1375; (e) Alexakis, A.; Benhaim, C.; Rosset, S.; 10. Knobel, A. K. H.; Escher, I. H.; Pfaltz, A. Synlett 1997,
1429.
2
Humam, M. J. Am. Chem. Soc. 2002, 124, 5262.
5
. (a) Alexakis, A.; Vastra, J.; Burton, J.; Benhaim, C.;
Mangeney, P. Tetrahedron Lett. 1998, 39, 7869; (b) Escher,
I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879; (c) Scafato, P.;
Labano, S.; Cunsolo, G.; Rosini, C. Tetrahedron: Asym-
metry 2003, 14, 3873.
11. (a) Brenna, E.; Fuganti, C.; Serra, S. Tetrahedron:
Asymmetry 2003, 14, 1; (b) Fujimoto, S.; Yoshikawa, K.;
Itoh, M.; Kitahara, T. Biosci. Biotechnol. Biochem 2002,
66, 1389; (c) Kraft, V. P.; Bajgrowitz, J. A.; Denis, C.;
Frater, G. Angew. Chem., Int. Ed. 2000, 39, 2980.
12. Oppolzer, W.; Radinov, R. N. J. Am. Chem. Soc. 1993,
115, 1593.
6
. (a) Mori, T.; Kosaka, K.; Nakagawa, Y.; Nagaoka, Y.;
Tomioka, K. Tetrahedron: Asymmetry 1998, 9, 3175; (b)
Hu, X.; Chen, H.; Zhang, X. Angew. Chem., Int. Ed. 1999,
13. Delapierre, G.; Constantieux, T.; Brunel, J. M.; Buono, G.
Eur. J. Org. Chem., 2000, 2507.
38, 3518.
7
. (a) Dieguez, M.; Net, G.; Ruiz, A.; Claver, C. Tetrahe-
dron: Asymmetry 2001, 12, 2895; (b) Dieguez, M.; P a` mies,
O.; Claver, C. Chem. Rev., 2004; (c) Wan, H.; Hu, Y.;
Liang, Y.; Gao, S.; Wang, J.; Zheng, Z.; Hu, X. J. Org.
Chem. 2003, 68, 8277.
14. (a) To prepare (E)-cyclopentadec-2-en1-one, the
procedure of Tanaka, K.; Ushio, H.; Kawabata, Y.;
Suzuki, H. J. Chem. Soc., Perkin Trans.1 1991, 1445, was
followed, except for the oxidation of the 2-phenylthio-
cyclopentadecanone intermediate. In this case, using the
8
. Iuliano, A.; Scafato, P. Tetrahedron: Asymmetry 2003, 14,
2 2 3 3
method of H O /CF COCH , as described by: (b)
6
11.
Lupattelli, P.; Ruzziconi, R.; Scafato, P.; DeglꢀInnocenti,
A.; Paolobelli, A. Synth. Commun. 1997, 27, 441, no
sulfone was formed with the desired sulfoxide obtained in
higher yield.
9
. Alexakis, A.; Benhaim, C.; Fournioux, X.; van den
Heuvel, A.; Leveque, J. M.; March, S.; Rosset, S. Synlett
1999, 1811.