Tropos deoxycholic acid-derived biphenylphosphites: synthesis, stereochemical characterization and use as chiral ligands in the copper catalyzed conjugate addition of diethylzinc to acyclic enones

Article abstract of DOI:10.1016/j.tetasy.2006.10.039

Three new deoxycholic acid-based 5,5′-substituted biphenylphosphites, 2-4, were synthesized and their stereochemical features were examined by CD and NMR spectroscopy, which allowed us to determine the sense of twist of the substituted biphenyl moiety as

Full text of DOI:10.1016/j.tetasy.2006.10.039

Tetrahedron: Asymmetry 17 (2006) 2993–3003
Tropos deoxycholic acid-derived biphenylphosphites: synthesis,
stereochemical characterization and use as chiral ligands
in the copper catalyzed conjugate addition of diethylzinc to
acyclic enones
Sarah Facchetti, Debora Losi and Anna Iuliano*
`
Dipartimento di Chimica e Chimica Industriale, Universita di Pisa, via Risorgimento 35, 56126 Pisa, Italy
Received 11 October 2006; accepted 27 October 2006
Available online 22 November 2006
Abstract—Three new deoxycholic acid-based 5,50 substituted biphenylphosphites, 2–4, were synthesized and their stereochemical features
were examined by CD and NMR spectroscopy, which allowed us to determine the sense of twist of the substituted biphenyl moiety as
well as the extent of its prevalence in different solvents. Phosphites 1–4 were used as chiral ligands in the copper catalyzed conjugate
addition of diethylzinc to acyclic enones, affording the alkylation products with ees up to 65%. The results obtained allowed a correlation
between asymmetric induction and the sense of twist of the biphenylphosphite moiety of the chiral inducers.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
lies in the capability of the configurationally stable unit
to induce a prevalent screw sense in the flexible moiety: this
guarantees the presence of a greatly prevalent diastereoiso-
mer, which must give rise to the formation of a very enan-
tioselective catalyst,3a and hence the achievement of high
ees.
The asymmetric copper catalyzed conjugate addition of
dialkylzinc reagents to unsaturated compounds represents
a straightforward methodology to form C–C bonds in an
enantioselective way.1 The success of this approach lies in
the good choice for chiral ligands of the copper salt, which
are able to afford high levels of asymmetric induction in
formation of the alkylated product. Once it was established
that the most efficient ligands for this reaction, both in
terms of activity and enantioselectivity, are phospho-
rus(III) species such as phosphites and phosphoramidites,
a great deal of efforts has been addressed towards the de-
sign of such ligands, especially those having the most suit-
able stereochemical features that allow a high level of
asymmetric induction to be reached.2 Recently, the diaste-
reoisomeric control of tropos ligands combined with a chi-
ral subunit which adopts a preferential conformation of a
diastereoisomeric complex,3 has allowed us to obtain phos-
phite and phosphoramidite ligands based on a chiral unit
and a tropos biphenol moiety that have proven able to
induce high enantioselectivities in the copper catalyzed
conjugate addition of dialkylzinc reagents.4 Their success
Very recently, we have demonstrated that the cholestanic
moiety represents a configurationally stable unit capable
of exerting an excellent diastereoisomeric control on the
tropos biphenylphosphite framework in the preparation
of bile acid derived biphenylphosphites.5 The diastereoiso-
meric control depends on the position of the cholestanic
backbone where the biphenylphosphite moiety is linked:
as a matter of fact, the biphenylphosphite moiety linked
at the 12-position, as in phosphite 1, shows a very high
prevalence of the
M
torsion.5 By contrast, the
biphenylphosphite unit adopts a prevalent P screw sense
when linked at the 7-position of cholic acid, and the phos-
phite bearing the same moiety at the 3-position of the cho-
lestanic skeleton exists as an equimolar mixture of two
rapidly interconverting M–P diastereoisomers.5 The good
asymmetric induction exerted by the cholestanic skeleton
on the tropos biphenylphosphite moiety linked at the 7-
and 12-positions suggests that they can be used as chiral
controllers in the asymmetric copper catalyzed conjugate
addition of diethylzinc to enones. In addition, given the
*
Corresponding author. Fax: +39 0509 18260; e-mail: iuliano@
dcci.unipi.it
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.10.039

2994
S. Facchetti et al. / Tetrahedron: Asymmetry 17 (2006) 2993–3003
tropos nature of the bile acid derived biphenylphosphites,
the ligand bearing the biphenylphosphite moiety at the 3-
position can give rise to the formation of a prevailing dia-
stereoisomeric species when the copper complex is formed.
However, preliminary results concerning the use of these
phosphites as chiral ligands in the copper catalyzed conju-
gate addition of diethylzinc to enones showed that only 1 is
able to afford asymmetric induction in this reaction.6 These
results prompted us to address our efforts only towards the
use, as chiral controllers, of 1 and other kind of deoxy-
cholic acid derived phosphites, bearing the phosphite moi-
ety at the 12-position. Since it is well known that
substitution on the biphenyl framework can affect the effi-
ciency of a tropos ligand,7 we were interested in checking
the effect of the presence of substituent groups at the
5,50-positions of the biphenyl system on the stereochemical
features of this type of ligands as well as on the outcome of
the alkylation reaction.
Herein we report the synthesis and stereochemical charac-
terization of phosphites 2–4 (Fig. 1), where a 5,50-substi-
tuted biphenylphosphite moiety is linked at the 12-
position of the cholestanic backbone, and the results ob-
tained using phosphites 1–4 as chiral ligands in the asym-
metric copper catalyzed conjugate addition of diethylzinc
to acyclic enones.
2. Results and discussion
2.1. Synthesis of phosphites 2–4
Biphenols 6 and 9, which constitute the flexible part of
phosphites 2 and 3, respectively, were prepared as reported
in Scheme 1, according to a modification of a synthetic
method used to prepare the analogous 3,30,5,50-tetrasubsti-
tuted biphenols.7
R
Bromination of the 5,50-positions was realized in 65% yield,
by reacting biphenol 5 with a slight excess of bromine in
dichloromethane solution at low temperature; reaction
conditions that promote the formation of the kinetic prod-
uct.8 Biphenol 6 was used as starting material for the prep-
aration of 9, which was obtained in 65% overall yield from
6 by the protection of the OH groups, Suzuki coupling9
with phenylboronic acid and acidolysis of the methoxy-
methyl protecting groups.
O
P
R
O
O
O
OCH3
12
3
7
1: R = H
H3COCO
2: R = Br
3: R = Ph
4: R = iPr
The synthetic route to biphenol 13, the precursor of phos-
phite 4, is outlined in Scheme 2 and follows a literature
method.10
Figure 1. Structures of the phosphites.
Br
Br
Br
Br2, CH2Cl2,
-78 °C
OH
OH
OMOM
OMOM
NaH, THF
MOMCl
OH
OH
Br
6
7
5
Ph
Ph
PhB(OH)2, Pd(PPh3)4
NaHCO3, DME
HCl, MeOH
OMOM
OMOM
OH
OH
Ph
Ph
8
9
Scheme 1. Synthesis of 5,50-diphenyl-2,20-dihydroxybiphenyl.
OCH3
OCH3
Br
TMEDA, Et2O
BuLi, Br2,
hexane
BuLi, Et2O,
CuCl2
BBr3, CH2Cl2
OH
OH
OCH3
OCH3
10
11
12
13
Scheme 2. Synthesis of 5,50-diisopropyl-2,20-dihydroxybiphenyl.

S. Facchetti et al. / Tetrahedron: Asymmetry 17 (2006) 2993–3003
2995
Br
According to this procedure, commercial 4-isopropylani-
sole 10 was ortho-metallated by butyllithium and TMEDA
and the resulting lithium derivative was treated with bro-
mine, to afford 11, which was used without purification
in the coupling reaction. The copper promoted coupling
of 11 afforded 12 in 45% yield, after chromatographic puri-
fication. Deprotection of the OH groups with BBr3, gave
biphenol 13 in 50% yield.
O
P
O
O
COOMe
Br
AcO
40000
35000
30000
25000
20000
15000
10000
5000
2
Δε
ε
1
Phosphites 2–4 were obtained by reacting the deoxycholic
acid derivative 14 with the suitable biphenylchlorophosphite
in the presence of triethylamine and DMAP (Scheme 3). To
achieve satisfactory yields of these phosphites, a slight
modification of the previous preparation was mandatory:
the chlorophosphite prepared at room temperature, instead
of at ꢀ60 ꢁC, was reacted with 14 in the presence of a large
excess of triethylamine and a stoichiometric amount of
DMAP.11
0
-1
-2
-3
-4
-5
-6
0
220
240
260
280
300
320
340
λ (nm)
2.2. Stereochemical characterization
Figure 2. Absorption (bold line) and CD (solid line) spectra of 2 in ACN.
The stereochemical features of phosphites 2–4, that is, the
sense of twist of the substituted biphenyl moiety and the
extent of its prevalence and tropos nature, were assayed
by CD and NMR spectroscopy. CD spectroscopy is the
most suitable way to determine if the substituted biphenyl
moiety is twisted in a prevalent screw sense in phosphites
2–4. In fact, the only absorbing chromophore in the wave-
length region between 300 and 230 nm is the substituted
biphenyl moiety12 and Cotton effects in this region can be
present only if this moiety, linked to the bile acid system,
is twisted in a prevalent screw sense.12 In addition, a corre-
lation between the sign of the CD bands of 1 and the sense
of twist of the biphenyl moiety has been established,5 so
that a comparison of the CD spectra of these phosphites
with that of 1 can allow us to determine the prevalent sense
of twist of the biphenyl unit. The CD spectra of 2 and 4 can
be compared safely with the CD spectrum of 1, given that
the presence of bromine or isopropyl groups at the 5,50-
positions of the biphenylphosphite moiety does not modify
the nature of the chromophore to a significant extent.13
This is confirmed by the high similarity of the UV spectra
of 2, 4 (Figs. 2 and 3) and 1, as far as number, position and
sign of the bands are concerned.
iPr
O
P
O
O
iPr
COOMe
40000
35000
30000
25000
20000
15000
10000
5000
2
ε
Δε
AcO
1
0
-1
-2
-3
-4
0
220
240
260
280
300
320
340
λ (nm)
Figure 3. Absorption (bold line) and CD (solid line) spectra 4 in ACN.
R
O
O
P
OH
R
R
O
OCH3
O
O
OCH3
OH
OH
14
Et3N, DMAP
PCl3, Et3N
H3COCO
toluene, rt
2: R = Br
R
H3COCO
3
: R = Ph
4: R = iPr
R = Br, Ph, iPr
Scheme 3. Synthesis of phosphites 2–4.

2996
S. Facchetti et al. / Tetrahedron: Asymmetry 17 (2006) 2993–3003
The CD spectrum of 2 (Fig. 2), which shows two positive
Cotton effects at 290 nm (De 0.4) and at 255 nm (De 1.7),
and that of 4 (Fig. 3), showing two positive Cotton effects
at 285 nm (De 0.4) and at 252 nm (De 1.8), are similar to the
CD spectrum5 of 1, as far as the number and sign of the
Cotton effects are concerned. The presence of Cotton ef-
fects in the CD spectra of 2 and 4 suggests that the substi-
tuted biphenyl moiety of these phosphites is twisted in a
prevalent screw sense.12 By comparing the CD spectra of
2 and 4 to that of 1, based on the sign of the Cotton effects,
a prevalence of M torsion for the substituted biphenyl moi-
eties of 2 and 4 is inferred. The lower intensity of the CD
bands in both spectra with respect to that of the Cotton ef-
fects in the CD spectrum of 1, is attributable to a lower
prevalence of the M screw sense in the case of 2 and 4.
The extent of the prevalence can be evaluated as 39% in
the case of 2 and 42% in the case of 4, using a value of
4.3 (De of the CD band at 250 nm in the CD spectrum of
1)5 as Demax and assuming that the dihedral angle between
the aromatic rings of the biphenyl moieties of 1, 2 and 4 is
almost the same.
10
8
Δε
6
4
2
0
-2
-4
220
240
260
280
300
320
340
(nm)
λ
Figure 5. CD spectra of phosphites 2 (solid line) and 4 (bold line) in THF.
the presence of two negative Cotton effects, at 280 and
250 nm, symptomatic of the prevalence of a P screw sense.
As observed in the case of 1, the CD bands of 2 in THF are
less intense (De ꢀ0.9 at 250 nm) than the corresponding
CD bands in ACN solution, indicating a lower prevalence
of the P sense of twist. On the contrary, the intensity of the
Cotton effects in the CD spectrum of 4 in THF is higher
(De ꢀ3.0 at 250 nm) than in ACN, suggesting that in this
case, the prevalence of the P screw sense in THF solution
is higher than the prevalence of the M sense of twist in
ACN solution. In the case of 3, disappearance of the CD
signal is observed in passing from the ACN solution to
the THF solution.
All of these considerations cannot be applied to phosphite
3, where the two conjugated phenyl rings at the 5,50-posi-
tions make this substituted biphenylphosphite moiety a
completely different chromophore.13 As a matter of fact,
the UV spectrum of 3 (Fig. 4) only shows one absorbing
band, very large, centered at 250 nm (e 75,000), which is
very different with respect to the UV spectrum of 1. The
CD spectrum (Fig. 4) shows a negative Cotton effect at
270 nm (De ꢀ5), suggesting that the 5,50-diphen-
ylbiphenylphosphite unit also assumes a prevalent screw
sense. However, given that the chromophores of 1 and 3
are different, the comparison between their CD spectra
cannot be used to assess the sense of twist of the substituted
biphenyl moiety of 3, which must be determined otherwise.
The dependence of the sense of twist on the solvent points
at the tropos nature of the phosphites 2–4 and hence vari-
able temperature 31P NMR measurements were carried
out to determine the M–P interconversion barrier as well
as the ratio of the two diastereisomeric forms. The mea-
surements were performed in THF-d8 and toluene-d8.14
The variable temperature 31P NMR measurements show
a very similar behaviour of the three phosphites.
To verify if in the case of phosphites 2–4 dependence of the
sense of twist on the solvent exists as in the case of 1,5 CD
measurements in THF solutions were performed. The CD
spectra of 2 and 4 (Fig. 5) recorded in THF solution show
The variable temperature profile of the 31P NMR spectra in
toluene-d8 (Fig. 6) and THF-d8 (Fig. 7) of 4, chosen as an
example, confirms the hypothesis coming from the CD
measurements about the presence at room temperature of
two rapidly interconverting M–P diastereoisomeric species.
As a matter of fact, only one signal at 155.6 ppm is present
Ph
O
P
O
O
COOMeΔε
Ph
5
a
b
ε
100000
80000
60000
40000
20000
0
4
3
2
AcO
1
0
-1
-2
-3
-4
-5
-6
c
ppm
158.0
159.0
153.0
151.0
157.0 156.0 155.0 154.0
152.0
200
250
300
350
λ (nm)
Figure 6. 31P NMR (121 MHz, toluene-d8) spectra of phosphite 4 at 25 ꢁC
(a), ꢀ40 ꢁC (b) and ꢀ60 ꢁC (c).
Figure 4. Absorption (bold line) and CD (solid line) spectra 3 in ACN.

S. Facchetti et al. / Tetrahedron: Asymmetry 17 (2006) 2993–3003
2997
a
b
a
2
b
c
a
b
3
158.0
154.0
152.0
ppm
151.0
157.0 156.0 155.0
159.0
153.0
Figure 7. 31P NMR (121 MHz, THF-d8) spectra of phosphite 4 at 25 ꢁC
(a), ꢀ40 ꢁC (b) and ꢀ60 ꢁC (c).
a
b
in the spectrum recorded in toluene solution at room tem-
perature (Fig. 6), which broadens at ꢀ40 ꢁC and splits at
ꢀ60 ꢁC in two baseline separated signals at 155.8 and
156.8 ppm, the integrated areas of which give a diastereo-
meric ratio of 25% in favour of the M diastereoisomer15
that resonates at higher frequencies. The spectroscopic pat-
tern in THF solution (Fig. 7) is similar: the signal present at
room temperature at 154.0 ppm broadens at ꢀ40 ꢁC and
splits in two resonances (154.0 ppm and 155.4 ppm) at
ꢀ60 ꢁC. The integrated areas of the two signals give a dia-
stereomeric ratio of 48% in favour of the P diastereoisomer
that resonates at lower frequencies. These NMR data are in
keeping with the CD results discussed above, which
showed a higher prevalence of the P diastereoisomer in
THF solution than the M diastereoisomer in ACN
solution.
4
157.0
158.0
156.0 155.0
152.0
154.0 153.0 151.0
ppm
159.0
Figure 8. 31P NMR (121 MHz) spectra of phosphites 2–4 in toluene (a)
and THF (b) at the decoalescence temperature.
by the addition of diethylzinc. The effect of different
parameters on the outcome of the reaction was checked
using phosphite 1 as a chiral controller and chalcone as a
substrate: Table 1 reports on the obtained results.
All reactions were monitored by TLC and stopped when
the conversion of the substrate was complete or did not
proceed further. The catalytic system generated by mixing
Cu(OTf)2 and 1 in molar ratio of 1:1.2, affords, in toluene
solution at 0 ꢁC, the alkylated product in quantitative yield
and 26% ee, after 2 h (entry 1). Lowering the reaction tem-
perature to ꢀ20 ꢁC improves the enantioselectivity of the
conjugate addition (entry 2), without altering the reaction
rate. Higher asymmetric induction is reached by perform-
ing the reaction at ꢀ50 and ꢀ70 ꢁC (entries 3 and 4),
but, at these temperatures, longer reaction times are re-
quired to obtain a satisfactory yield of the alkylation prod-
uct. Increasing of the amount of chiral ligand accelerates
the reaction, which affords a quantitative yield of the prod-
uct at ꢀ50 ꢁC after 2 h (entry 5); by contrast, under these
conditions, the enantioselectivity decreases slightly. Chang-
ing the solvent gives rise to lower ees (entries 6–8) and, in
some cases (entries 7 and 8) also to lower yields, because
of the formation of a by-product coming from the attack
of the in situ formed enolate to another molecule of unre-
acted substrate.17 The prevailing enantiomer is (S)-config-
ured, except when THF is used as the reaction solvent. It
is known that in deoxycholic acid-based binaphthyl-
phosphites the absolute configuration of the alkylated
product depends only on the absolute configuration of
the binaphthyl moiety.18 Given that the sense of twist of
the biphenyl moiety of 1, which corresponds to the abso-
lute configuration of the binaphthyl moiety, changes in
passing from toluene to THF, the change of the sense of
asymmetric induction (entries 3 and 7) has to be attributed
to inversion of the screw sense. In addition, it is noteworthy
This variable temperature behaviour is the same for phos-
phites 2 and 3, the sole exception being the decoalescence
temperature of 2 in toluene solution, which is ꢀ80 ꢁC. It
is noteworthy that, at the decoalescence temperature, the
M diastereoisomer resonates at higher frequencies for both
2 and 4, and 3 shows the same spectroscopic pattern
(Fig. 8): on this basis, it is also possible to determine the
prevalent sense of twist for phosphite 3 that results, as in
the other cases, M in toluene and P in THF solution.
The integrated areas of the signals at the decoalescence
temperature show a prevalence of the M diastereoisomer
in toluene solution of 22% for 2, and a prevalence of the
P diastereoisomer in THF solution of 13% for 2 and 16%
for 3. The interconversion barriers, evaluated on the basis
of the variable temperature NMR measurements,16 are in
the range 10.70–10.85 kcal/mol for all the phosphites in
both the solvent: only phosphite 2 shows a lower barrier
(9.93 kcal/mol in toluene solution and 10.30 kcal/mol in
THF solution).
2.3. Conjugate addition of diethylzinc to acyclic enones
Phosphites 1–4 were assayed as chiral auxiliaries in the cop-
per catalyzed conjugate addition of diethylzinc to acyclic
enones. In a typical procedure, the catalytic system was
generated in situ by reacting a solution of the copper salt
and the chiral ligand for 1 h at room temperature, followed

2998
S. Facchetti et al. / Tetrahedron: Asymmetry 17 (2006) 2993–3003
Table 1. Catalytic enantioselective conjugate addition to chalcone in the presence of 1
O
O
Et
*
1, Cu salt (2.5 mol %)
Et2Zn (1.5 eq)
Entry
Cu Salt
1 (mol %)
Time (h)
Solvent
Temperature (ꢁC)
Yielda (%)
eeb (%)
ACc
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OAc)2ÆH2O
3.0
3.0
3.0
3.0
6.0
3.0
3.0
3.0
3.0
2
2
5
7
2
4
5
7
6
Toluene
Toluene
Toluene
Toluene
Toluene
Et2O
THF
CH2Cl2
Toluene
0
ꢀ20
ꢀ50
ꢀ70
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ70
100
100
72
89
100
85
55
25
24
26
34
43
44
39
26
35
—
17
S
S
S
S
S
S
R
—
S
a Determined by NMR.
b Determined by HPLC analyses on Chiralcel OJ, 254 nm, 1.0 mL/min, hexane–2-propanol 99.5:0.5.
c Determined by comparison with an enantiomerically enriched sample of known configuration.18
that the sense of asymmetric induction remains the same in
going from deoxycholic acid-based binaphthylphosphite to
1: in fact, the phosphite possessing the (R)-binaphthyl moi-
ety, corresponding to an M screw sense of the biphenyl
unit, afforded an (S)-configured alkylation product,18 as
observed in the case of 1. The use of a different copper salt
(entry 9) gives worse results both in terms of yield and
enantioselectivity of the reaction.
gate addition, in toluene as a solvent, proceed faster but
also the ees of the alkylation product are slightly higher
(entries 3, 5 and 8).
Lowering of the temperature to ꢀ70 ꢁC caused a slight
improvement of the ee of the alkylation product only in
the case of phosphite 3 (entry 6); by contrast, under these
reaction conditions, the catalytic system generated by 4,
which at ꢀ50 ꢁC affords the best asymmetric induction,
gives lower enantioselectivity (entry 9). The prevailing
enantiomer is (S)-configured when the reaction is carried
out in toluene solution (entries 1, 3, 5, 6, 8 and 9) and
(R)-configured for the reactions performed in THF (entries
2, 4, 7 and 10). Given that the prevalent sense of twist of
the biphenyl moiety of phosphites 2–4 is opposite in these
two solvents, again the absolute configuration of the alkyl-
ated product depends only on the configuration of the bia-
ryl unit of the phosphites. THF is a worse reaction solvent
with respect to toluene, affording lower yields in longer
reaction times (entries 2, 4 and 7), except when 4 is used
as chiral ligand (entry 10). The trend of the ees in THF
Taking into account these results, for comparative pur-
poses, the other phosphites were checked as chiral ligands
in the copper catalyzed conjugate addition of diethylzinc
to chalcone under the optimal reaction conditions, that
is, ligand to copper salt ratio 1.2:1, Cu(OTF)2 as copper
salt, temperature of ꢀ50 ꢁC and toluene and THF as
solvents. Table 2 lists the results obtained.
A study of Table 2 shows that substitution at the 5,50-posi-
tion of the biphenyl moiety affords 12-deoxycholic acid de-
rived biphenylphosphites able to give a more efficient
catalytic system with respect to 1: not only does the conju-
Table 2. Catalytic enantioselective conjugate addition to chalcone
O
O
Et
*
Cu(OTf)2 (2.5 mol %)
Ligand (3.0 mol %)
Temperature (ꢁC)
Entry
Ligand
Timea (h)
Solvent
Yielda (%)
eeb (%)
ACc
1
2
3
4
5
6
7
8
9
1
1
2
2
3
3
3
4
4
4
5
5
3
3
2.5
4
7
6
6.5
6
Toluene
THF
Toluene
THF
Toluene
Toluene
THF
Toluene
Toluene
THF
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ70
ꢀ50
ꢀ50
ꢀ70
ꢀ50
72
55
100
35
100
94
28
100
100
70
43
35
45
10
47
50
12
51
38
65
S
R
S
R
S
S
R
S
S
R
10
a Determined by NMR.
b Determined by HPLC analyses on Chiralcel OJ, 254 nm, 1.0 mL/min, hexane–2-propanol 99.5:0.5.
c Determined by comparison with an enantiomerically enriched sample of known configuration.18

S. Facchetti et al. / Tetrahedron: Asymmetry 17 (2006) 2993–3003
2999
vs toluene reflects the extent of the prevalence of the screw
sense of biphenylphosphite unit, which is higher in toluene
than in THF for 2 and 3, but lower for 4. As a matter of
fact, very low asymmetric induction was obtained when
using 2 and 3 as ligands in THF solution (entries 4 and
7), whereas performing the reaction with 4 in THF gave
the highest ee (entry 10). The results obtained in toluene
and in THF seem conflicting, given the complete preva-
lence, in toluene, of the M sense of twist in the case of 1
and a lower prevalence for the other phosphites, which in
spite of this give better enantioselectivity. This behaviour
can be explained19 allowing for the formation of a highly
prevalent diastereisomeric species, in toluene solution, once
the catalytically active copper complex is formed, in the
case of phosphites 2–4.
the contrary, the asymmetric induction exerted by 3 in-
creases with a substrate possessing an electron rich aro-
matic ring linked to the olefinic carbon atom (entry 3).
This result is perfectly in keeping with the lower ee ob-
tained in the conjugate addition of diethylzinc to the enone
bearing an electron poor p-chlorophenyl group linked to
the olefinic carbon (entry 4). As far as phosphite 4 is con-
cerned, electronic factors seem to have less importance
than structural factors: as a matter of fact, the two sub-
strates having an electron rich aromatic ring linked to the
carbonyl group afford different ees (entries 7 and 10). In
contrast, chalcone and the two enones bearing the electron
rich aromatic ring linked at the carbonyl group or at the
olefinic carbon atom are alkylated with comparable ees
(entries 6–8). The presence of an electron poor aromatic
ring is detrimental to the reaction promoted by 4, which
affords the alkylation product in only 32% ee (entry 9).
This should be possible as the alkylation reactions are car-
ried out near the decoalescence temperature,20 where the
equilibrium between the two species is still rapid: this mech-
anism seems operating specially in the case of 4, which gives
a decrease in the ee of the alkylation product when lowering
the reaction temperature under ꢀ50 ꢁC. Alternatively, it is
also conceivable that one of the two diastereomeric
complexes has higher activity and, hence, determines the
outcome of the reaction.3a
3. Conclusions
The synthesis of deoxycholic acid derived phosphites bear-
ing a 5,50 substituted biphenylphosphite moiety linked at
the 12-position of the cholestanic backbone has allowed
us to obtain tropos systems, showing stereochemical prop-
erties that depend on the type of substituent. CD analysis
showed that the substitution at the 5,50-position of the
biphenyl unit does not prevent the capability of the choles-
tanic moiety to induce a prevalent sense of twist to the
biphenylphosphite framework linked at its 12-position.
However, the presence of substituents at these positions af-
fects the extent of the prevalence of the screw sense, which
is lower than in the case of the analogous biphenylphosph-
ite devoid of substituents. The tropos nature of phosphites
2–4 joined to a low interconversion barrier of their biphe-
nyl moiety engenders the change of the sense of twist in
passing from toluene and ACN to THF. The nature of
the substituents at the 5,50-position affects the M–P diaste-
reoisomeric ratio, whereas the kinetics of the interconver-
Screening of phosphites 1–4 as chiral ligands in the copper
catalyzed conjugate addition of diethylzinc to chalcone has
showed that phosphites 3 and 4 are the best ligands at
temperatures of ꢀ70 and ꢀ50 ꢁC, respectively. To check
the effect of the substrate structure on the outcome of the
reactions promoted by 3 and 4, different acyclic enones
were screened with the results reported in Table 3.
Changing of the substrate requires longer reaction times to
obtain satisfactory yields of the alkylation products with
both the phosphites. The presence of an electron rich aro-
matic ring linked to the carbonyl group reduces the enantio-
selectivity of the reaction promoted by 3, independent of
the structure of the aromatic unit (entries 2 and 5). On
Table 3. Catalytic enantioselective conjugate addition to acyclic enones
Entry
Ligand
R1
R2
Temperature (ꢁC)
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
3
3
3
3
3
4
4
4
4
4
Ph
Ph
Ph
ꢀ70
ꢀ70
ꢀ70
ꢀ70
ꢀ70
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ50
3
6
6
6
6
6
7
7
7
7
75
51
59
55
22
100
80
52
29
50
50
40
60
41
40c
51
50
46
32
40c
p-OMe(C6H4)
Ph
Ph
2-Thienyl
Ph
p-OMe(C6H4)
Ph
Ph
p-OMe(C6H4)
p-Cl(C6H4)
Ph
Ph
Ph
p-OMe(C6H4)
p-Cl(C6H4)
Ph
10
2-Thienyl
a Determined by NMR.
b Determined by HPLC analyses on Chiralcel OJ, 254 nm, 1.0 mL/min, hexane–2-propanol 99.5:0.5.
c Determined by HPLC analyses on Chiralcel OD-H, 254 nm, 1.0 mL/min, hexane–2-propanol 99.75:0.25.

3000
S. Facchetti et al. / Tetrahedron: Asymmetry 17 (2006) 2993–3003
sion is very similar for the three phosphites. Only 2 exhibits
a slightly faster interconversion kinetics.
were recorded in toluene-d8 or THF-d8 at 121 MHz: ppm
are referred to H3PO4 as external standard. IR stretches
are given in cmꢀ1. Circular dichroic (CD) spectra were ob-
tained using a 0.1-cm path length cell and spectropolari-
metric grade acetonitrile or THF as solvents, at 25 ꢁC,
unless otherwise specified. Sample concentration for CD
analyses was typically (6–9) · 10ꢀ4 M. UV–vis absorption
spectra were obtained using a 0.1-cm path length cell
and spectrophotometric grade acetonitrile or THF as sol-
vents, at 25 ꢁC. Sample concentration of UV–vis analyses
was typically (6–9) · 10ꢀ4 M. Optical rotations were mea-
sured with a digital polarimeter. Melting points are
uncorrected.
The use of phosphites 1–4 as chiral ligands in the copper
catalyzed conjugate addition of diethylzinc to acyclic en-
ones gives rise to catalysts able to promote the alkylation
reaction in an enantioselective fashion. The extent of the
asymmetric induction depends on the structure of the phos-
phite as well as the reaction conditions. Because of their
tropos nature, the enantioselection, in toluene solution,
does not depend on the extent of the prevalence of the
screw sense of the substituted biphenyl unit of 2–4. In con-
trast, when THF is used as a reaction solvent, the extent of
the enantioselectivity can be related to the prevalence of the
sense of twist in this solvent. The sense of asymmetric
induction depends only on the sense of twist of the biphe-
nyl moiety of phosphites 1–4: actually, the inversion of the
sense of twist in THF corresponds to the achievement of an
alkylation product having an opposite absolute configura-
tion. This is an interesting result, especially as far as the use
of 4 as a chiral ligand is concerned. In fact, given that a sat-
isfactory yield of the alkylation product is obtained using
this ligand in THF as a solvent, it is possible to obtain both
enantiomers of the alkylation product starting from the
same chiral ligand, by only changing the reaction solvent.
Finally, considering that the substitution on the biphenyl
moiety of 12-substituted deoxycholic acid based biphenyl-
phosphites affects the outcome of the copper catalyzed
conjugate addition of diethylzinc to acyclic enones, it is
conceivable that even better results could be obtained by
changing both the nature and position of the substituents:
studies are currently in progress to this end.
4.2.1. 5,50-Dibromo-2,20-dihydroxybiphenyl 6. Bromine
(2.8 mL, 56.04 mmol) was slowly added to a solution of 5
(3.91 g, 20.98 mmol) in CH2Cl2 (120 mL) at ꢀ75 ꢁC. The
solution was stirred at room temperature and a solution
of 10% NaHSO3 was added after 3 h; the precipitate was
filtered and dissolved in ethyl acetate. The organic layer
was washed with a solution of 10% NaHSO3, brine and
dried over anhydrous Na2SO4. After removing the solvent
in vacuo, 6 was obtained as a brown solid (4.5 g, 63%). 1H
NMR (300 MHz, DMSO-d6, d): 6.93 (d, J = 8 Hz, 1H);
7.33–7.39 (dd, J1 = 8 Hz, J2 = 2.4 Hz, 2-H). 13C NMR
(75 MHz, DMSO-d6, d): 110.2; 118.4; 127.2; 131.7; 134.1;
154.7. Anal. Calcd for C12H8Br2O2: C, 41.90; H, 2.34; Br,
46.46; O, 9.30. Found: C, 41.85; H, 2.36; Br, 46.49.
4.2.2.
5,50-Dibromo-2,20-bis(methoxymethyloxy)biphenyl
7. A solution of 6 (4 g, 11.6 mmol) in dry THF (40 mL)
was slowly added, under nitrogen, to a suspension of
NaH (0.835 g, 34.88 mmol) in dry THF (150 mL). A solu-
tion of methoxymethyl chloride (2.7 mL, 34.88 mmol) in
dry THF (20 mL) was added to the mixture after 2 h.
The resulting suspension was stirred overnight under nitro-
gen, and water was then added to quench the reaction. The
organic layer was washed with an aqueous solution of 10%
NaHCO3, brine and dried over anhydrous Na2SO4. After
removing the solvent in vacuo and recrystallization from
CH2Cl2, pure 7 was obtained (4.06 g, 81%) mp = 122–
123 ꢁC. 1H NMR (300 MHz, CDCl3, d): 3.35 (s, 3H);
5.06 (s, 2H); 7.1 (d, J = 9 Hz, 1H); 7.35 (d, J = 2.4 Hz,
1H); 7.42 (dd, J1 = 8.7 Hz, J2 = 2.4 Hz, 1H). 13C NMR
(75 MHz, CDCl3, d): 53.2; 98.0; 115.9; 116.8; 124.4;
131.7; 133.9; 159.9. IR (KBr, cmꢀ1): 2957; 2361; 2343;
1772; 1734; 1718; 1700; 1684; 1670; 1654; 1647; 1636;
1576; 1560; 1540; 1507; 1490; 1448; 1399; 1309; 1261;
1224; 1199; 1165; 1135; 1089; 990; 922; 874; 820. Anal.
Calcd for C16H16Br2O4: C, 44.47; H, 3.73; Br, 36.98; O,
14.81. Found: C, 44.51; H, 3.72; Br, 37.01.
4. Experimental
4.1. General procedures and material
TLC analyses were performed on silica gel 60 sheets; flash
chromatography separations were carried out on columns
using silica gel 60 (230–400 mesh). Toluene and was re-
fluxed over sodium and distilled before the use. THF and
diethylether were refluxed over Na/K alloy and distilled
before use. Triethylamine and TMEDA were refluxed over
CaH2 and distilled before use. Methoxymethyl chloride,
1,2-dimethoxyethane and PCl3 were distilled before the
use. Unless otherwise specified, the reagents were used
without any purification. Methyl 3a-acetyloxy-12a-hydr-
oxy-5b-cholan-24-oate 1421 and the substituted unsaturated
ketones22 were obtained as previously described and
matched the reported characteristics.18
4.2. Instrumentation
4.2.3.
5,50-Diphenyl-2,20-bis(methoxymethyloxy)biphenyl
8. Pd(PPh3)4 (0.27 g, 0.23 mmol) was added under nitro-
gen to a solution of 7 (1 g, 2.13 mmol) in 1,2-dimethoxy-
ethane (70 mL). The mixture was stirred at room
temperature until the palladium complex was dissolved,
and then of a NaHCO3 1 M solution (20 mL) was added.
After 30 min of stirring, phenylboronic acid (1.13 g,
9.24 mmol) was added. The mixture was stirred over 70 h
under nitrogen at room temperature and was then heated
to 100 ꢁC over 24 h. The resulting brown mixture was
1H NMR spectra were recorded in CDCl3, benzene-d6 or
DMSO-d6 on a 200 MHz NMR spectrometer or a
300 MHz NMR spectrometer. The following abbreviation
are used: s = singlet, d = doublet, dd = double doublet,
t = triplet, hept = heptet, m = multiplet, br = broad. 13C
NMR were recorded at 50 MHz. The temperature was con-
1
trolled to 0.1 ꢁC. H and 13C NMR chemical shifts are
referenced to TMS as external standard. 31P NMR spectra

S. Facchetti et al. / Tetrahedron: Asymmetry 17 (2006) 2993–3003
3001
allowed to cool to room temperature and then was filtered
through a Celite pad. The solvent was evaporated in vacuo,
and the product was dissolved in ethyl acetate. The organic
layer was washed with water, 10% NaOH, 10% HCl, 10%
NaHCO3 and brine in that order then dried over anhy-
drous Na2SO4. Evaporation of the solvent in vacuo fol-
lowed by chromatographic purification (CH2Cl2/acetone,
80:20) yielded 0.73 g (1.71 mmol, 80%) of pure 8. 1H
NMR (300 MHz, CDCl3, d): 3.39 (s, 3H); 5.15 (s, 2H);
7.29–7.45 (m, 4H); 7.57–7.63 (m, 4H). 13C NMR
(75 MHz, CDCl3, d): 56.2; 95.5; 116.1; 127.1; 127.6;
129.0; 129.6; 130.5; 135.1; 140.9; 154.8. IR (KBr, cmꢀ1):
3030; 2954; 2899; 2847; 2824; 2786; 1602; 1508; 1479;
1449; 1398; 1307; 1270; 1233; 1198; 1155; 1143; 1131;
1078; 1050; 1001; 921; 893; 872; 822. Anal. Calcd for
C28H26O4: C, 78.85; H, 6.14; O, 15.01. Found: C, 78.79;
H, 6.18.
an oily residue. The crude product was purified by flash
chromatography (CH2Cl2–hexane 30:70), affording pure
12 as an oil (8.4 g, 28.3 mmol, 45%). 1H NMR
(300 MHz, CDCl3, d): 1.29 (d, J = 6.9 Hz, 6H); 2.93 (hept,
J = 6.9 Hz, 2H); 3.79 (s, 6H); 6.94 (d, J = 8.4 Hz, 2H); 7.16
(d, J = 2.1 Hz, 2H); 7.20 (dd, J1 = 8.4 Hz, J2 = 2.1 Hz,
2H). 13C NMR (75 MHz, CDCl3, d): 24.4; 33.5; 56.1;
111.2; 126.4; 128.0; 130.0; 140.7; 155.4. Anal. Calcd for
C20H26O2: C, 80.50; H, 8.78; O, 10.72. Found: C, 80.44;
H, 8.80.
4.2.7. 2,20-Dihydroxy-5,50-diisopropyldiphenyl 13. BBr3
(2.1 g, 8.4 mmol) was added at 0 ꢁC to a solution of 12
(1.32 g, 4.43 mmol) in CH2Cl2 (15 mL) and stirred at room
temperature overnight. The excess of BBr3 was decom-
posed by the dropwise addition of H2O (15 mL) and the
aqueous layer was extracted with CH2Cl2. The combined
organic layers were dried over anhydrous Na2SO4 and con-
centrated under vacuum to 10 mL. Crystals of 13 deposited
on cooling. The precipitate was washed with hexane then
dried under vacuum to give pure 13 (0.61 g, 2.26 mmol,
51%). 1H NMR (300 MHz, CDCl3, d): 1.25 (d,
J = 6.6 Hz, 6H); 2.90 (hept, J = 6.9 Hz, 2H); 5.60 (br s,
2H); 6.95 (d, J = 8.4 Hz, 2H); 7.12 (d, J = 2.1 Hz, 2H);
7.17 (dd, J1 = 8.4 Hz, J2 = 2.1 Hz, 2H). 13C NMR (CDCl3,
delta): 24.4; 33.5; 116.6; 123.8; 127.9; 129.2; 142.2; 151.0.
Anal. Calcd for C18H22O2: C, 79.96; H, 8.20; O, 11.84.
Found: C, 79.91; H, 8.23.
4.2.4. 5,50-Diphenyl-2,20-dihydroxybiphenyl 9. A suspen-
sion of 8 (670 mg, 1.57 mmol) in methanol (95 mL) was
heated to 65 ꢁC under a nitrogen atmosphere and concen-
trated hydrochloric acid (0.63 mL) was then added. After
2 h of stirring under these conditions, the mixture was
cooled to room temperature and a solution of 10% NaH-
CO3 was added until CO2 evolution ceased. The methanol
was evaporated in vacuo and the residue was dissolved in
ethyl acetate, washed with a solution of NaHCO3 and dried
over anhydrous Na2SO4. Evaporation of the solvent under
reduced pressure gave pure 9 as a white solid (0.5 g,
1
1.48 mmol, 94%). Mp = 182–184 ꢁC. H NMR (300 MHz,
4.2.8. Preparation of the phosphites: representative proce-
dure. A warm solution (60 ꢁC) of biphenol (1 mmol) in
dry toluene (25 mL) was slowly added to a solution of
PCl3 (1 mmol) and Et3N (2 mmol), in dry toluene (5 mL).
After 2 h of stirring, the reaction mixture was filtered under
an argon atmosphere. The solution was dropwise added to
a solution of DMAP (1 mmol) and Et3N (8.2 mmol) in dry
toluene (15 mL) at ꢀ60 ꢁC over 2 h then 14 (1.1 mmol) was
added, and the mixture allowed to warm to room temper-
ature and stirred over 20 h. The solids were removed by fil-
tration and the filtrate was evaporated to dryness under
reduced pressure. The crude product was purified by col-
umn chromatography (SiO2, CH2Cl2–acetone, 97:3),
affording the pure phosphite.
CDCl3, d): 7.15 (d, J = 8.1 Hz, 1H); 7.33 (t, J = 7.2 Hz,
1H); 7.43 (t, J = 7.1 Hz, 2H); 7.58–7.63 (m, 4H). 13C
NMR (75 MHz, CDCl3, d): 117.4; 124.1; 127.0; 127.3;
129.0; 129.1; 130.2; 135.2; 140.5; 152.7. Anal. Calcd for
C24H18O2: C, 85.18; H, 5.36; O, 9.46. Found: C, 85.22;
H, 5.33.
4.2.5. 2-Bromo-4-isopropylanisole 11. A 2.5 M solution of
BuLi in hexane (53.5 mL) was added dropwise to a solution
of 10 (10 g, 66.6 mmol) and 20 mL (0.13 mol) of TMEDA
in ethyl ether (75 mL). After 2 h, the mixture was cooled
to ꢀ78 ꢁC and a solution of bromine (7 mL, 0.14 mol) in
hexane (15 mL) added dropwise. The reaction mixture
was allowed to warm to room temperature, then 50 mL
of 3 M HCl were added and the aqueous phase extracted
with CH2Cl2. The combined organic layers were dried over
anhydrous Na2SO4. After removing the solvent in vacuo,
crude 11 was obtained as a colourless oil (14.4 g) and used
without further purification.
4.2.9. Methyl 3a-acetyloxy-12a-(5,50-dibromobiphenyl-2,20-
diyl)phosphite-5b-cholan-24-oate 2. Yield 0.39 g (0.47
22
mmol, 41%). Mp = 63–65 ꢁC; ½aꢁD ¼ 24:3 (c 1.00, CH2Cl2).
1H NMR (300 MHz, benzene-d6, d): 0.44 (s, 3H); 0.67 (s,
3H); 0.98 (d, J = 6.0 Hz, 3H); 1–2.4 (m, 31H); 1.71 (s,
3H); 3.34 (s, 3H); 4.51 (m, 1H); 4.79 (m, 1H); 6.95 (d,
J = 8.4 Hz, 1H); 7.00 (d, J = 8.4 Hz, 1H); 7.07 (d,
J = 2.4 Hz, 1H); 7.08 (d, J = 2.4 Hz, 1H); 7.17–7.07 (dd,
J1 = 8.4 Hz, J2 = 2.4 Hz, 1H); 7.25 (dd, J1 = 8.4 Hz,
J2 = 2.4 Hz, 1H). 13C NMR (50 MHz, benzene-d6, d):
12.2; 17.7; 17.8; 21.0; 22.9; 23.6; 26.0; 26.8; 27.0; 27.7;
28.7; 28.8; 31.0; 31.1; 32.4; 33.6; 34.2; 35.0; 35.8; 41.7;
4.2.6. 2,20-Dimethoxy-5,50-diisopropylbiphenyl 12. A solu-
tion of 2.5 M BuLi in hexane (30 mL) was cooled to
ꢀ78 ꢁC and a solution of 14.4 g (62.8 mmol) 11 in dry ethyl
ether (68.3 mL) was slowly added. After the addition was
complete, the reaction mixture was allowed to warm to rt
over 1 h, then cooled again to ꢀ78 ꢁC. Under intensive stir-
ring, 17 g of CuCl2 was added portionwise. The resultant
mixture was stirred at this temperature for 2 h and then al-
lowed to warm to rt. The reaction mixture was quenched
with H2O (30 mL) and extracted with CH2Cl2. The com-
bined organic layers were dried over anhydrous Na2SO4
and the solvent was evaporated at reduced pressure to give
2
46.6; 46.7; 47.8; 50.9; 73.8; 79.1 (d, J = 17.1 Hz); 118.1;
118.2; 123.9; 127.6; 128.2; 132.1 (d, 3J = 2.6 Hz); 132.2
(d, 3J = 2.6 Hz); 132.4; 132.7; 132.8; 148.9 (d,
2J = 5.6 Hz); 149.2 (d, 2J = 6.1 Hz); 169.5; 173.6. 31P
NMR (121 MHz, benzene-d6, d): 154.1. IR (KBr, cmꢀ1):
2961.9; 1732.8; 1472.0; 1393.4; 1261.0; 1190.7; 1110.8;

3002
S. Facchetti et al. / Tetrahedron: Asymmetry 17 (2006) 2993–3003
1027.5; 895.6; 799.1; 738.8; 714.0; 526.8. Anal. Calcd for
C39H49Br2O7P: C, 57.08; H, 6.02; Br, 19.47; O, 13.65; P,
3.77. Found: C, 57.12; H, 6.00; Br, 19.45; P, 3.78.
Acknowledgement
This work was supported by the University of Pisa, MIUR
(Project ‘High performance separation systems based on
chemo- and stereoselective molecular recognition’ Grant
2005037725).
4.2.10. Methyl 3a-acetyloxy-12a-(5,50-diphenylbiphenyl-
2,20-diyl)phosphite-5b-cholan-24-oate
3. Yield
0.49 g
24
(0.6 mmol, 68%). Mp = 71–73 ꢁC; ½aꢁD ¼ þ28:6 (c 0.95,
1
CH2Cl2). H NMR (300 MHz, benzene-d6, d): 0.50–2.09
References
(m, 37H); 0.5 (s, 3H); 0.72 (s, 3H); 1.12 (d, J = 6.6 Hz,
3H); 1.62 (s, 3H); 2.24–2.34 (m, 1H); 3.33 (s, 3H); 4.64–
4.66 (m, 1H); 4.8–4.9 (m, 1H); 7.3–7.58 (m, 16H). 13C
NMR (75 MHz, benzene-d6, d): 12.3; 17.8; 17.9; 20.9;
23.0; 23.7; 26.0; 27.0; 27.2; 27.8; 28.9 (d, 3J = 5.5 Hz);
31.1; 31.2; 32.5; 33.6; 34.3; 35.2; 25.9; 36.0; 41.9; 46.5;
46.7 (d, 3J = 4.0 Hz); 47.7; 50.9; 74.0; 78.8 (d,
2J = 17.5 Hz); 122.8; 127.3; 127.4; 127.5; 128.8; 128.9;
129.2; 129.3; 132.1; 138.8; 138.9; 140.7; 149.6 (d, 2J =
5.5 Hz); 149.9 (d, 2J = 6.0 Hz); 169.6; 173.7. 31P NMR
(121 MHz, benzene-d6, d): 153.1. IR (KBr, cmꢀ1): 2962.3;
1735.6; 1601.4; 1478.2; 1448.3; 1363.2; 1261.3; 1192.9;
1097.6; 1020.7; 900.0; 859.4; 799.9; 760.2; 696.0;
644.2; 600.3; 561.4. Anal. Calcd for C51H59O7P: C, 75.16;
H, 7.30; O, 13.74; P, 3.80. Found: C, 75.20; H, 7.29;
P, 3.82.
1. (a) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171–196;
(b) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221–
3236.
2. (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353; (b)
Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.;
Nassz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865–2878;
(c) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew.
Chem., Int. Ed. 1996, 35, 2374–2376; (d) Zhang, F. Y.; Chan,
A. S. C. Tetrahedron: Asymmetry 1998, 9, 1179–1182; (e)
Huttenloch, O.; Spieler, J.; Waldmann, H. Chem. Eur. J.
2001, 7, 671–675; (f) Alexakis, A.; Benhaim, C.; Rosset, S.;
Humam, M. J. Am. Chem. Soc. 2002, 124, 5262–5263; (g)
Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen, F.;
Benhaim, C. Synlett 2001, 1375–1378; (h) Pamies, O.;
Dieguez, M.; Net, G.; Ruiz, A.; Claver, C. Tetrahedron:
Asymmetry 2000, 11, 4377–4383; (i) Alexakis, A.; Burton, J.;
Vastra, J.; Benhaim, C.; Fournioux, X.; van den Heuvel, A.;
´
Leveque, J. M.; Maze, F.; Rosset, S. Eur. J. Org. Chem. 2000,
4.2.11. Methyl 3a-acetyloxy-12a-(5,50-diisopropylbiphenyl-
4011–4027; (j) Liang, L.; Au-Yeung, T. L.; Chan, A. S. C.
Org. Lett. 2002, 4, 3799–3801.
3. (a) Mikami, K.; Yamanaka, M. Chem. Rev. 2003, 103,
3369–3400; (b) Reetz, M. T.; Neugebeauer, T. Angew.
2,20-diyl)phosphite-5b-cholan-24-oate
4. Yield
1.39 g
25
(1.87 mmol, 76%). Mp = 55–60 ꢁC; ½aꢁD ¼ 52:0 (c 1.03,
1
CH2Cl2). H NMR (300 MHz, CDCl3, d): 0.74 .5 (s, 3H);
´
`
Chem., Int. Ed. 1999, 38, 179–181; (c) Dieguez, M.; Pamies,
0.94–2.4 m, 31H); 0.94 (s, 3H); 1.03 (d, J = 6.0 Hz, 3H);
1.31 (d, J = 3.9 Hz, 3H); 1.32 (d, J = 3.9 Hz, 3H); 2.96–
3.02 (m, 2H); 3.67 (s, 3H); 4.6–4.8 (m, 2H); 7.09–7.33 (m,
6H). 13C NMR (75 MHz, CDCl3, d): 12.7; 17.8; 17.9;
21.7; 23.3; 23.9; 24.3; 24.4; 24.5; 26.3; 26.7; 27.3; 27.8;
28.7; 31.1; 31.4; 32.5; 33.8; 33.9; 34.0; 34.6; 35.3; 35.9;
36.1; 42.1; 46.5; 46.8; 46.9; 47.9; 51.7; 74.5; 78.4 (d,
2J = 15.5 Hz); 122.1; 122.2; 126.8; 126.9; 128.5; 129.3;
131.2 (d, 3J = 3.1 Hz); 131.4 (d, 3J = 3.5 Hz); 145.4;
`
O.; Ruiz, A.; Castillon, S.; Claver, C. Chem. Eur. J. 2001, 7,
3086–3094.
4. (a) Alexakis, A.; Polet, D.; Benhaim, C.; Rosset, S. Tetra-
hedron: Asymmetry 2004, 15, 2199–2203; (b) Alexakis, A.;
Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc.
2002, 124, 5262–5263; (c) Alexakis, A.; Rosset, S.; Allamand,
J.; March, S.; Guillen, F.; Benhaim, C. Synlett 2001, 9, 1375–
1378; (d) Alexakis, A.; Burton, J.; Vastra, J.; Benhaim, C.;
´
Fournioux, X.; van den Heuvel, A.; Leveˆque, J.; Maze, F.;
2
2
Rosset, S. Eur. J. Org. Chem. 2000, 4011–4027; (e) Scafato,
P.; Cunsolo, G.; Labano, S.; Rosini, C. Tetrahedron 2004, 60,
8801–8806.
145.6; 147.7 (d, J = 5.6 Hz); 148.2 (d, J = 6 Hz); 170.9;
174.9. 31P NMR (121 MHz, benzene-d6, d): 154.3. IR
(KBr, cmꢀ1): 2950.6; 2867.5; 1737.9; 1493.9; 1358.9;
1260.2; 1094.0; 1021.3; 927.9; 881.1; 798.0. Anal. Calcd
for C45H63O7P: C, 72.36; H, 8.50; O, 14.99; P, 4.15. Found:
C, 72.41; H, 8.48; P, 4.16.
5. Iuliano, A.; Facchetti, S.; Uccello-Barretta, G. J. Org. Chem.
2006, 71, 4943–4950.
6. Facchetti, S. Tesi di Laurea, University of Pisa, 2006.
7. Alexakis, A.; Polet, D.; Rosset, S.; March, S. J. Org. Chem.
2004, 69, 5660–5667.
8. Sogah, G. D. Y.; Cram, D. J. J. Am. Chem. Soc. 1979, 101,
3035–3042.
9. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981,
11, 513–519.
10. Kadyrov, R.; Heller, D.; Selke, R. Tetrahedron: Asymmetry
1998, 9, 329–340.
11. Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879–2888.
12. Mislow, K.; Glass, M. A. W.; O’Brien, R. E.; Rutkin, F.;
Steinberg, D. H.; Weiss, J.; Djerassi, C. J. Am. Chem. Soc.
1962, 84, 1455–1478.
4.2.12. Enantioselective conjugate addition of diethylzinc to
acyclic enones: general procedure. A solution of Cu(OTf)2
(0.025 mmol) and phosphite (0.03 mmol) in freshly distilled
solvent (5 mL) was stirred under a nitrogen atmosphere at
rt for 1 h. The solution was cooled to the reaction temper-
ature (see Tables 1–3) and diethylzinc (1.0 M in hexane,
1.5 mmol) was added. The enone was added slowly and
stirring was continued at that temperature and the reaction
was monitored by TLC. After complete conversion, the
mixture was poured into 1 M HCl (25 mL) and extracted
three times with diethyl ether. The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, fil-
tered and evaporated to yield the crude 1,4-products. The
yields were determined by NMR analysis and the ees were
determined by HPLC analyses.
´
13. Jaffe, A.; Orchin, M. Theory and Application of UV
Spectroscopy; Wiley: New York, 1962; Harada, N.; Nakani-
shi, K. Circular Dichroic Spectroscopy, Exciton Coupling in
Organic Stereochemistry; University Science Books: Oxford,
1983.
14. Toluene was used instead of ACN as this last has a freezing
point too high for low temperature measurements and

S. Facchetti et al. / Tetrahedron: Asymmetry 17 (2006) 2993–3003
3003
toluene behaves as ACN with respect the M–P equilibrium
position.5
18. Iuliano, A.; Scafato, P. Tetrahedron: Asymmetry 2003, 14,
611–618.
15. The calculated values of the ee using the CD spectra are
different than those obtained from the NMR data. This
should be attributed to the different solvents (ACN vs
toluene) used that afford the prevalence of the same sense
of twist but to a different extent.
19. This point deserves further experimental evidence for
a complete elucidation: studies are in progress on this
topic.
20. Monti, C.; Gennari, C.; Piarulli, U. Chem. Commun. 2005,
5281–5283.
16. Oki, M.; Yamamoto, G. Bull. Chem. Soc. Jpn. 1971, 44, 266–
270; Oki, M. Top. Stereochem. 1983, 14, 1–81.
17. Delapierre, G.; Constantieux, T.; Brunel, J. M.; Buono, G.
Eur. J. Org. Chem. 2000, 2507–2511.
21. Kuhaida, K.; Kandrac, J.; Cirin-Novta, V.; Milkovic, D.
Collect. Czech. Chem. Commun. 1996, 61, 1073–1076.
22. Hassner, A.; Cromwell, N. H. J. Am. Chem. Soc. 1958, 80,
893–900.