Asymmetric activation of tropos catalysts in the stereoselective catalytic conjugate additions of R2Zn to α,β-enones: An efficient synthesis of (-)-muscone

Article abstract of DOI:10.1016/j.tet.2004.07.034

The preparation of a new phosphoramidite starting from (R)-BINOL and a biphenylamine is presented. In such a compound the chirality is due only to atropisomerism and this molecule possesses a flexible biphenylamine residue. Therefore it can work as a tropos catalyst. The catalytic efficiency of this new phosphoramidite has been tested in some asymmetric conjugate additions of dialkylzinc reagents to α,β-enones and compared with that of an analogous already known non-tropos ligand. Interestingly, while comparable results were obtained in the addition of ZnEt₂ to chalcone and cyclohexenone, in the case of the addition of ZnMe₂ to (E)-cyclopentadec-2-en-1-one, the new ligand provides (-)-muscone, a valuable ingredient of the perfume industry, in 84% ee, while the non-tropos ligand gives a much lower (57%) ee value. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.07.034

Tetrahedron 60 (2004) 8801–8806
Asymmetric activation of tropos catalysts in the stereoselective
catalytic conjugate additions of R2Zn to a,b-enones: an efficient
synthesis of (K)-muscone
*
Patrizia Scafato, Giovanni Cunsolo, Stefania Labano and Carlo Rosini
`
Dipartimento di Chimica, Universita degli Studi della Basilicata, via N. Sauro 85, 85100 Potenza, Italy
Received 7 May 2004; revised 23 June 2004; accepted 15 July 2004
Available online 21 August 2004
Abstract—The preparation of a new phosphoramidite starting from (R)-BINOL and a biphenylamine is presented. In such a compound the
chirality is due only to atropisomerism and this molecule possesses a flexible biphenylamine residue. Therefore it can work as a tropos
catalyst. The catalytic efficiency of this new phosphoramidite has been tested in some asymmetric conjugate additions of dialkylzinc reagents
to a,b-enones and compared with that of an analogous already known non-tropos ligand. Interestingly, while comparable results were
obtained in the addition of ZnEt2 to chalcone and cyclohexenone, in the case of the addition of ZnMe2 to (E)-cyclopentadec-2-en-1-one, the
new ligand provides (K)-muscone, a valuable ingredient of the perfume industry, in 84% ee, while the non-tropos ligand gives a much lower
(57%) ee value.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
flexible biphenyl ketone, forms the corresponding ketal.
Herein, we want to show a further example of this concept in
which it becomes possible to carry out a highly enantiose-
lective synthesis of (K)-muscone,4 a valuable ingredient of
the perfume industry, by means of the asymmetric conjugate
addition of dimethylzinc to (E)-cyclopentadec-2-en-1-one.5
The last few years have witnessed significant progresses6 in
the field of the catalytic asymmetric conjugate addition of
organozinc compounds to a,b-unsaturated ketones, allow-
ing the construction of C–C bonds in high chemical yields
and efficient stereocontrol, thus providing the synthetic
organic chemist with a very powerful tool to assemble even
large and polyfunctional molecules.7 The success obtained
in such of process relies mainly in the development of
efficient catalytic precursors which are constituted by Cu(II)
or Cu(I) salts coordinated by enantiopure phosphorus
ligands. The family of phosphoramidites, the use of which
has been pioneered by Feringa and co-workers,6a,7a,b,8 has
been particularly successful in this respect. In these ligands
the chiral source is often derived from enantiopure 2,20-
dihydroxy-1,10-binaphthyl, BINOL, or modified
binaphthols, coupled to another achiral or chiral residue,
so the phenomenon of double asymmetric induction may
also result.9 Our attention was captured by a recent paper of
Feringa et al. where a systematic study of the relationship
between structure of the chiral ligand and asymmetric
induction was carried out:8a of the several ligands tested,
compound 1 (Scheme 1) seemed to us particularly attractive
because we immediately saw in it the possibility to make a
Configurationally stable biaryl compounds (i.e. 2,20,6,600-
tetrasubstituted biphenyls and 2,20-disubstituted-1,1 -
binaphthyls) have received a lot of attention as chiral1
ligands and catalysts in asymmetric synthesis. More
recently, even non-atropisomerically stable, flexible biaryl
compounds have been employed towards the same end.2
From this point of view, excellent results have been
obtained by Mikami and co-workers who introduced2 the
concept of ‘asymmetric activation of tropos catalysts’: here,
if a tropos species (say a flexible biphenyl compound) is
linked to a metal which, in turn, is linked to a stable
enantiopure ligand (the chiral activator) a single diaster-
eoisomeric compound can be formed, since a preferred
sense of twist is induced in the tropos moiety by the stable
chiral activator. This may cause an increase of the catalytic
activity and of the asymmetric induction: many examples of
highly enantioselective processes carried out within this
scheme have been described. Interestingly, the same
concept has also been applied3 in a related topic: the
assignment of the absolute configuration of aliphatic 1,n-
diols (nZ2–4) by exploiting the sense of twist induced in a
biphenyl moiety when a diol, reacting with a suitable
Keywords: (K)-Muscone; Asymmetric conjugate addition; Organozinc
compounds; Asymmetric copper catalysis; Asymmetric activation; Phos-
phoramidites; a,b-Enones.
* Corresponding author. Tel.: C39-0971-202241; fax: C39-0971-202223;
e-mail: rosini@unibas.it
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.034

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P. Scafato et al. / Tetrahedron 60 (2004) 8801–8806
Scheme 1.
comparison with the properties of the structurally related
ligand 2 (Scheme 1).
measured the CD spectrum of 1 and 2: the difference
spectrum, CD(2)–CD(1), could afford a reasonable esti-
mate14 of the CD coming from a distorted biphenyl group.
Interestingly, in the spectrum (Fig. 1) two Cotton effects can
be recorded below 280 nm (i.e. in the region where the
biphenyl chromophore absorbs): a broad positive one (220–
260 nm), which clearly results from the contribution of two
bands of the same positive sign at about 220 and 240 nm,
and a negative one at about 215 nm. The Cotton effect at
240 nm is reasonable due to the A transition of the biphenyl
chromophore which is a probe of the sense of twist of the
biphenyl group: a positive Cotton effect from the A band
indicates3,12 a negative (M) torsion of the biphenyl.
The possibility of asymmetric activation exists in compound
2 and this is not possible in 1.2,5e Previous examples of
phosphoramidite catalysts based on the principle of
asymmetric activation made use5e of a centrochiral amine
residue and phenolic part derived from flexible biphenol.
Interestingly, ligand 2 derives from a part coming from
enantiopure BINOL and an achiral, flexible biphenyl amine;
in other words 2 shows a completely new design: chiral
phenol, flexible biphenyl amine and overall chirality only
due to atropisomerism.
Asymmetric conjugate additions of dialkylzinc reagents to
the enones 4–6 (Scheme 3) were carried out in toluene
(at K40 8C for 4 and 5 and at 0 8C for 6) with a catalytic
precursor deriving from Cu(OTf)2/1 or 2 (ratio substrate/Cu/
chiral ligandZ1/0.03/0.06). The results are collected in
Table 1. In the presence of 1 diethyl zinc adds quickly (4 h)
and smoothly to both 4 (run 1) and 5 (run 2) affording the
corresponding ketones in high yields and moderate
enantiomeric excesses. It is noteworthy that the same
results have been obtained8a by Feringa et al. who used
slightly different experimental conditions (CuOTf instead of
Cu(OTf)2, K10 8C for 16 h instead of K40 8C for 4 h). A
moderate value of enantiomeric excess has also been
obtained with the same ligand for ketone 615 (run 3): (K)-
muscone is prepared in 57% ee, i.e. a value which is not of
practical interest for the perfume industry. Then the same
reactions were repeated (under the same experimental
conditions) using phosphoramidite 2. Also, ligand 2 gives
rise to an efficient catalytic system: in the cases of 4 (run 4)
and 5 (run 5) the addition products are obtained in good
yields and short reaction times (2 h ca.), but we could not
observe a substantial ‘asymmetric activation’ effect. In fact,
while in the case of chalcone (Table 1, run 1 vs run 4) we
had an increase from 52 to 65%, in the case of
cyclohexenone (Table 1, run 2 vs run 5) we had a slight
reduction of stereoselectivity (from 54% with 1 to 45% with
2). However, much to our delight, significant increase of ee
was observed just in the case of ketone 6: in fact, (run 6)
with 2 derived from (R)-BINOL, (K)-muscone having 84%
ee was obtained. Of course, using (S)-BINOL for the
preparation of 2, the (C) antipode is obtained with the same
2. Results and discussion
We synthesized the phosphoramidites 1 and 2 simply by
adding a solution of (R)-BINOL in THF to a solution of
dichloroamidite of dibenzylamine or amine 3 respectively,
prepared in situ by treating the suitable amine with PCl3 and
NEt3, according to the Alexakis procedure.10 Amine 3 was
prepared (Scheme 2) starting from 2,20-bis(bromomethyl)-
biphenyl,11a,b obtained from diphenic acid, by transforming
it in the corresponding hydroxylamine and successive
reduction with In/Zn in boiling ethanol.l1c
It is well known3,12 that biphenyl compounds like 3 present
an M–P equilibrium and that the activation energy for this
transformation is about 14–15 kcal/mol, so the inversion of
the biphenyl sense of twist is really fast at room temperature
and the two enantiomers of 3 cannot be isolated. In
principle, starting from (R)-BINOL two diastereoisomeric
phosphoramidites could be obtained, taking into account
that the biphenyl group could be P or M twisted, i.e. (R,P)-2
and (R,M)-2. However, also in compounds where the
biphenyl moiety is linked to a chiral group, a fast P–M
interconversion still occurs:3,12 thus, this fact ensures that
the stereoisomeric ratio between (R,P)-2 and (R,M)-2 is only
determined by their thermodynamic stability. The 31P NMR
spectrum of 2 showed the presence of only one peak (dZ
146.38). Taking into account that diastereoisomeric phos-
phoramidites8a (and phosphites13) show different 31P
signals, it is tempting to assume that in the case of 2 a
single diastereoisomer is present in solution. We also
Scheme 2.

P. Scafato et al. / Tetrahedron 60 (2004) 8801–8806
8803
Figure 1. Difference spectrum (CD-2)–(CD-1) in THF.
antipode of (K)-muscone having high enantiomeric purity
and this certainly constitutes an economic access to this
valuable fine chemical. From a more theoretical point of
view, this result demonstrates the importance of the concept
of asymmetric activation: here the (R)-chirality of BINOL
imposes the biphenyl moiety of the ligand 2 to assume a
preferred M sense of twist. The pair (R,M) obtained in this
way allows an efficient enantioselective conjugate addition
of dimethylzinc to (E)-cyclopentadec-2-en-1-one. On the
other hand, the same ligand 2 does not work with the same
efficiency in the cases of 4 and 5, indicating that the
asymmetric activation effect is strongly dependent on the
substrate employed. However, it is interesting to note that, if
the results provided by 2 are compared with those obtained
in the case of 1, an increase of the ee is observable for
addition to 4 and 6 (13 and 27%, respectively) whilst a small
Scheme 3.
enantiomeric excess (run 7). Another interesting obser-
vation is the result with a different amount of Cu(OTf)2.
Using enone/Cu(OTf)2/L*Z1/0.01/0.02 (i.e. with only 1%
of metal) the ee goes to 61% ee (run 8). These results are
very important from a practical point of view: the use of (R)-
2 guarantees a truly catalytic synthesis of the natural
Table 1. Asymmetric conjugated addition of R2Zn to a,b-enones in the presence of ligands 1 and 2
Run
Enone
Ligand
R2Zn
Yielda
ee (a.c.)b
1
2
3
4
5
6
7
8
4
5
6
4
5
6
6
6
1
1
1
2
2
Et2Zn
Et2Zn
Me2Zn
Et2Zn
Et2Zn
Me2Zn
Me2Zn
Me2Zn
68
95
52c (S)
54d (R)
57f (R)
65c (S)
45d (R)
84f (R)
84f (S)
61f (R)
60e
70
98
2
72e
68e
50g
2g
2h
a
Carried out at K40 8C in toluene; enone/Cu(OTf)2/L*Z1/0.03/0.06; yield calculated on the isolated and purified product.
Determined by the sign of optical rotatory power.
Determined by HPLC on chiral column Chiralcel OJ, hexane/isopropanol 99.5: 0.5, 1.0 ml/min, 254 nm.
b
c
d
Determined by HPLC on chiral column Chiralcel OD, hexane/isopropanol 99.7: 0.3, 0.5 ml/min, 254 nm, on the corresponding dioxolane obtained with
(R,R)-1,2-diphenylethane-1,2-diol.
e
f
Carried out at 0 8C in toluene; enone/Cu(OTf)2/L*Z1/0.03/0.06; yield calculated on isolated and purified product.
1
Determined by H NMR spectroscopy in the presence of Eu(hfc)3 as described by Yamamoto.16 When the same measurament has been carried out by
polarimetry [for (K)-muscone: [a]DZK12.7 (cZ0.9, MeOH), lit. 4g] the slightly higher value of 89% is obtained.
2 has been prepared from (S)-BINOL.
g
h
Carried out at 0 8C in toluene; enone/Cu(OTf)2/L*Z1/0.01/0.02.

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P. Scafato et al. / Tetrahedron 60 (2004) 8801–8806
reduction (9% ca.) is observed in the case of 5. Therefore,
(R,M)-2 behaves like a matched pair of the BINOL and
biphenyl chiralities in the cases of chalcone and (E)-
cyclopentadec-2-en-1-one, while it looks like a mismatched
pair in the case of cyclohexenone. This different outcome
could be related to a different conformational behavior6c of
the a,b-unsaturated ketones. In fact, whilst 4 and 6 are
flexible compounds, 5 is fixed in a pure s-trans situation. In
other words, a pure s-trans system is not a very good
substrate for the Cu/2 catalyst since the enantioselectivity is
only moderate, on the contrary flexible a,b-unsaturated
ketones afford higher values of asymmetric induction, the
macrocyclic ketone 6 providing the highest ee. It is
noteworthy that the present results are at variance with
those reported by Alexakis et al.5e who employed a
phosphoramidite ligand where the amine part was centro
chiral and the phenolic part derived from the flexible
biphenol. Here, in fact, ketone 5 is a good substrate whilst 4
and 6 are not, giving rise only to moderate enantioselec-
tivities (27 and 49%, respectively).
polarimeter. Melting points were taken using a Kofler
Reichert–Jung Thermovar apparatus and are uncorrected.
Mixture compositions were determined by GC–MS on a
Hewlett Packard 6890 chromatograph equipped with a HP-
5973 mass detector. IR spectra were performed with a
Perkin–Elmer 883 spectrometer. Toluene and dichloro-
methane were refluxed over sodium–benzophenone and
calcium hydride respectively and distilled before the use.
Unless otherwise specified the reagents were used without
any purification.
4.1.1. Synthesis of 2,20-(2-azapropane0-1,3-diyl)-1,10-
biphenyl (3). 2,20-Bis(bromomethyl)-1,1 -biphenyl was
prepared by PBr3 bromination of 2,20-bis(hydroxymethyl)-
1,10-biphenyl, in turn obtained by Red-Al reduction of
dimethyl ester of commercially available diphenic acid.
To a solution of Et3N (53 ml) and hydroxylamine
hydrochloride (3.7 g, 54 mmol), under nitrogen atmosphere,
2,20-bis(bromomethyl)-1,10-biphenyl (5.4 g, 16 mmol) was
added and the mixture was heated to reflux for 2 h. The
mixture was filtered under vacuum and the resulting
solution was distilled to remove the Et3N. The crude
product was purified on silica gel (petroleum ether/ethyl
ether 4:1–petroleum ether/ethyl ether 2:1) affording the pure
2,20-(2-azapropane-1,3-diyl)-1,10-biphenyl-N-hydroxide
3. Conclusions
This work describes some important results in the field of
the asymmetric conjugate addition to a,b-unsaturated
ketones: first, the completely new designed phosphorami-
dite ligand 2, where the chirality is due only to
atropisomerism and where the amine residue constitutes
the tropos part, has been prepared and tested. In this way, a
protocol has been set up by which a valuable fine chemical,
(K)-muscone, can be easily prepared. Second, it has been
possible to make a comparison between the previously
reported (‘asymmetrically activated’) phosphoramidites
(where the amine moiety was centrochiral and the phenolic
counterpart a flexible biphenol) and 2 (without stereogenic
centers, deriving from enantiopure BINOL and showing the
flexible biphenyl amine 3). This comparison shows that the
two kinds of phosphoramidites have opposite behavior
versus rigid or flexible ketones. Understanding the origin of
this correlation could be an extremely useful key to
understand the reaction stereochemistry and thus to reliably
predict the enantioselectivity of this reaction.
1
(1.7 g, 50%). H NMR (300 MHz, CDCl3): d 3.15 (d, JZ
12.1 Hz, 2H), 3.95 (d, JZ12.1 Hz, 2H), 7.5 (m, 9H); 13C
NMR (75 Mz, CDCl3): d 60.44, 127.81, 129.51, 130.15,
133.92, 149.50.
To a 1:1 solution of EtOH/satd. NH4Cl (40 ml, pHy6) 2,20-
(2-azapropane-1,3-diyl)-1,10-biphenyl-N-hydroxide (1.7 g,
8 mmol) was added. Indium (5%, 46 mg, 0.4 mmol) and
zinc (1.04 g, 16 mmol) were then added and the mixture was
refluxed for 7 h. After cooling, the mixture was filtered on
Celite and concentrated. A satd. Na2CO3 solution was added
and the mixture was extracted with ethyl acetate. The
collected organic phases were dried over anhydrous Na2SO4
and the solvent evaporated in vacuo to afford the
biphenylazepine 3 (1.5 g, 7.6 mmol, 95%) as a white
solid. MpZ229–231 8C; IR (neat): nmax 3310, 3140, 2910,
1450, 1380, 1200, 760 cmK1; 1H NMR (500 MHz, CDCl3):
d 4.04 (s, 5H), 7.47–7.49 (m, 2H), 7.55–7.60 (m, 4H), 7.64
(d, 2H, JZ7.5 Hz); 13C NMR (125 Mz, CDCl3): d 45.90,
128.61, 129.22, 129.54, 130.50, 131.27, 140.81.
4. Experimental
4.1. General
4.1.2. Synthesis of O,O0-(R)-(1,10-dinaphthyl-2,20-diyl)-
N,N0-dibenzylphosphoramidite (1). Under nitrogen
atmosphere, at 0 8C, to a stirred mixture of freshly distilled
PCl3 (174 mL, 20 mmol) and Et3N (3.9 mL, 28 mmol) in dry
THF (4 mL) freshly distilled dibenzylamine (384 mL,
2.0 mmol) was added and the mixture was stirred for 3 h
at room temperature. Slowly, a solution of enantiopure
(R)-BINOL (572 mg, 2.0 mmol) in dry THF (6 mL) was
added at 0 8C. After stirring (19 h) at room temperature, the
resulting mixture was diluted with toluene and filtered on
neutral aluminum oxide. The solution was concentrated and
purified by flash chromatography on neutral aluminum
oxide using CH2Cl2 as eluent obtaining 417 mg (0.81 mmol,
41%) of the pure ligand as a foamy white solid. Stripping
with petroleum ether gave the product as white solid.
1H and 13C NMR spectra were recorded in CDCl3 on Bruker
Aspect300 300 MHz NMR and Varian AS500 500 MHz
NMR spectrometers, using TMS as external standard. The
31P NMR spectrum was recorded at the frequency of
242.88 MHz with an Inova 600 instrument. The sample was
dissolved in CD2Cl2 and the chemical shift of the signals
were calculated with respect to H3PO3 85% (0 ppm) by
replacement. TLC analyses were performed on silica gel 60
Macherey–Nagel sheets; flash chromatography separations
were carried out on suitable columns using silica gel 60
(230–400 mesh) or neutral aluminum oxide. 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

P. Scafato et al. / Tetrahedron 60 (2004) 8801–8806
8805
MpZ132–134 8C. Spectroscopic data (NMR and [a]2D0)
(104 mg, 0.5 mmol) was added and, after cooling to K40 8C,
diethylzinc (1.0 M in hexane, 1.0 mL, 2 equiv) was added
dropwise. The reaction was monitored by TLC. After
stirring for 2 h at K40 8C the reaction mixture was poured
in 10 mL of 1.0 M HCl solution and extracted three times
with ethyl ether. The combined organic phases were washed
with brine, dried with anhydrous Na2SO4 and the solvent
evaporated in vacuo. The crude product was purified by
column chromatography (SiO2, petroleum ether/ethyl ether
8:2), affording pure 1,3-diphenyl-pentanone (70%). The ee
was determined by HPLC analyses: Daicel Chiralcel OJ,
hexane/2-propanol 99.5:0.5, 1.0 mL/min, lZ254 nm, trZ
18.63 min (S); trZ28.29 min (R).
were in good agreement with data reported in literature.8a
4.1.3. Synthesis of O,O0-(R)-(K)-(1,10-dinaphthyl-2,20-
diyl)-N-2-[2,20-(2-azapropane-1,3-diyl)-1,10-biphenylyl]
phosphoramidite (2). Under nitrogen atmosphere, at 0 8C,
to a stirred solution of PCl3 (174 mL, 20 mmol) and Et3N
(3.9 mL, 28 mmol) in dry THF (4 mL) the biphenylazepine
3 (390 mg, 2.0 mmol) was added and the mixture was stirred
for 3 h at room temperature. Slowly, a solution of
enantiopure (R)-BINOL (572 mg, 2.0 mmol) in dry THF
(6 mL) was added at 0 8C. After 18 h of stirring at room
temperature, the resulting mixture was diluted with toluene
and filtered on neutral aluminum oxide. The solution was
concentrated and purified by flash chromatography on
neutral aluminum oxide using CH2Cl2 as eluent obtaining
630 mg (1.24 mmol, 62%) of the pure ligand as a foamy
solid. Stripping with petroleum ether gave the phosphor-
amidite 2 as a white solid. MpZ152–154 8C; [a]2D0ZK246
(cZ0.45; CH2Cl2); IR (neat): nmax 3080, 2860, 1580, 1460,
4.1.6. Enantioselective conjugate addition of diethylzinc
to 2-cyclohexen-1-one (5). A solution of Cu(OTf)2 (5 mg,
0.014 mmol) and chiral ligand (0.03 mmol) in toluene
(4 mL) was stirred for 1 h at room temperature under
nitrogen atmosphere. The solution was cooled to K40 8C
and 2-cyclohexen-1-one (48 mg, 0.5 mmol) followed by
Et2Zn (1.0 M in hexane, 1.0 mL, 2 equiv) were added
slowly. The reaction was monitored by GC–MS. After
stirring for 2 h at K40 8C the reaction mixture was poured
in 10 mL of 1 M HCl solution and extracted three times with
ethyl ether. The combined organic phases were washed with
brine, dried with anhydrous Na2SO4 and filtered. Removal
of ethyl ether under reduced pressure, 700–350 mbar, at
room temperature yielded the crude product in toluene
which was purified by flash column chromatography (SiO2,
pentane/ethyl ether 5:1) to afford 3-ethylcyclohexanone
(98%) as a colorless liquid. The ee was determined by
HPLC analyses after derivatization with (R,R)-1,2-diphenyl-
ethan-1,2-diol: to a solution of 3-ethylcyclohexanone
1230, 1050, 930, 820, 750 cmK1 1H NMR (500 MHz,
;
CDCl3): d 3.67 (dd, 2H, J1Z13.0 Hz, J2Z9.5 Hz), 4.00 (dd,
2H, J1Z13.0 Hz, J2Z6.5 Hz), 7.08 (d, 1H, JZ8.5 Hz),
7.19–7.21 (m, 1H), 7.27–7.30 (m, 4H), 7.35 (d, 1H, JZ
9.0 Hz), 7.39–7.48 (m, 8H), 7.57 (d, 1H, JZ8.5 Hz), 7.80
(d, 1H, JZ8.5 Hz), 7.88 (d, 1H, JZ7.5 Hz), 7.95 (d, 1H,
JZ8.5 Hz), 8.01 (d, 1H, JZ9.0 Hz); 13C NMR (125 MHz,
CDCl3): d 47.65, 47.82, 122.21, 122.31, 124.83, 125.06,
126.32, 127.18, 127.30, 128.06, 128.43, 128.50, 128.59,
129.51, 130.25, 130.56, 131.05, 131.67, 133.20, 135.20,
141.25, 149.29, 149.90; 31P NMR (242.88 MHz, CD2Cl2) d
146.38. Anal. calcd for C34H24NO2P: C 80.14; H 4.75; N
2.74; P 6.08. Found: C, 80.85; H, 5.10; N 2.90; P 6.30.
˚
(62 mg, 0.49 mmol) in CH2Cl2 (5 mL) actived 4 A molecu-
lar sieves were added at room temperature followed by
(R,R)-1,2-diphenylethan-1,2-diol (128 mg, 0.6 mmol) and
by traces of p-toluensulfonic acid. After stirring for 2 h the
4.1.4. Synthesis of cyclopentadec-2-en-1-one (6). To a
solution of 30% H2O2 (2.0 mL, 18 mmol) and 1,1,1-
trifluoromethylacetone (0.3 mL, 3.3 mmol) a solution of
2-phenylthiocyclopentadecanone (obtained from 2-cyclo-
pentadecanone as reported)15 (5.0 g, 15 mmol) in CHCl3
(15 ml) was added at 0 8C. After 1 h of stirring at 0 8C, the
mixture was diluted with CHCl3 and the organic layer was
separated, dried with anhydrous Na2SO4 and the solvent
evaporated in vacuo. The crude sulfoxide was purified by
column chromatography (SiO2, petroleum ether/ethyl
acetate 3/1) obtaining the pure product (4.2 g, 12 mmol,
80%) and the starting sulfide (300 mg, 6%).
˚
4 A molecular sieves were removed by filtration and the
reaction mixture was dried with anhydrous Na2SO4, and the
solvent removed under reduced pressure. The crude product
was purified by column chromatography (petroleum ether/
ethyl ether 98:2) to afford the desired ketal as a colorless
liquid. The ee was determined by HPLC analyses: Daicel
Chiralcel OD, hexane/2-propanol 99.7:0.3, 0.5 mL/min, lZ
254 nm, trZ8.0 min (R,R,R), trZ10.0 min (S,R,R).
4.1.7. Enantioselective conjugate addition of dimethyl-
zinc to 2-cyclopentadecen-1-one (6). A solution of
Cu(OTf)2 (5.6 mg, 0.015 mmol) and chiral ligand
(0.03 mmol) in toluene (4 mL) was stirred for 1 h at room
temperature under nitrogen atmosphere. After cooling to
0 8C, Me2Zn (2.0 M in toluene, 0.38 mL, 1.5 equiv) was
added followed by 2-cyclopentadecenone (111 mg,
0.5 mmol). The reaction was monitored by GC–MS
analysis. After stirring for 1.5 h at 0 8C 1 M HCl solution
(10 mL) and ethyl ether (5 mL) were added and stirred for a
few minutes. Then, the solution was extracted three times
with ethyl ether. The combined organic phases were washed
with brine, dried with anhydrous Na2SO4 and the solvent
removed in vacuo. The crude product was purified by flash
column chromatography (SiO2, petroleum ether/ethyl ether
95:5), affording (K)-muscone (70%) as colorless oil.
[a]DZK11.3 (cZ0.85, MeOH). The ee was determined
Under nitrogen atmosphere, the sulfoxide (4.2 g, 12 mmol)
was dissolved in anhydrous toluene (100 mL) and calcium
carbonate (160 mg, 1.6 mmol) was added. The mixture was
stirred 12 h at room temperature and refluxed for 2 h. After
cooling at room temperature, water (50 mL) was added and
the organic layer was separated, washed with brine, dried
with anhydrous Na2SO4 and the solvent evaporated in
vacuo. The crude product was purified by column
chromatography (SiO2, petroleum ether/ethyl acetate 3/1)
affording 2.38 g (89%) of 2-cyclopentadecenone.
4.1.5. Enantioselective conjugate addition of diethylzinc
to chalcone (4). A solution of Cu(OTf)2 (5 mg,
0.014 mmol) and chiral ligand (0.030 mmol) in toluene
(4 mL) was stirred for 1 h at room temperature under
nitrogen atmosphere. To this catalyst solution, chalcone

8806
P. Scafato et al. / Tetrahedron 60 (2004) 8801–8806
by the following NMR method:16 a solution of Eu(hfc)3
(107 mg) and (C) or (K)-muscone (3.6 mg) in 0.5 ml of
CDCl3 was subjected to analysis by NMR. The peak
(doublet) caused by methyl group of the (R) enantiomer
shifted to 3.72 ppm, while that of the (S) shifted to
3.59 ppm. The ee were calculated from the area peak ratio.
7. (a) Naasz, R.; Arnold, L. A.; Pineschi, M.; Keller, E.; Feringa,
B. L. J. Am. Chem. Soc 1999, 121, 1104. (b) Arnold, L. A.;
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Acknowledgements
`
The authors thank Universita degli Studi della Basilicata
and MIUR-COFIN 2002 ‘Sintesi di aromi e fragranze’ for
their financial support. The authors thank the NMR
`
laboratory of the Universita di Bologna for recording the
31P NMR spectrum.
8. (a) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries,
A. H. M.; Naasz, R.; Feringa, B. L. Tetrahedron 2000,
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