Application of deoxycholic acid-based copper-phosphite complexes as ligands in the enantioselective conjugate addition of diethylzinc to acyclic enones

Article abstract of DOI:10.1016/S0957-4166(03)00044-2

Four phosphites obtained by linking enantiomerically pure binaphthylchlorophosphite to the two different hydroxy groups of deoxycholic acid were synthesized and used as chiral ligands in the enantioselective copper-catalyzed 1,4-addition of diethylzinc to

Full text of DOI:10.1016/S0957-4166(03)00044-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 611–618
Application of deoxycholic acid-based copper–phosphite
complexes as ligands in the enantioselective conjugate addition of
diethylzinc to acyclic enones
Anna Iulianoa,* and Patrizia Scafatob,*
aDipartimento di Chimica e Chimica Industriale, Universita` di Pisa, via Risorgimento 35, 56126 Pisa, Italy
bDipartimento di Chimica, Universita` della Basilicata, via Nazario Sauro 85, 85100 Potenza, Italy
Received 29 November 2002; revised 3 January 2003; accepted 9 January 2003
Abstract—Four phosphites obtained by linking enantiomerically pure binaphthylchlorophosphite to the two different hydroxy
groups of deoxycholic acid were synthesized and used as chiral ligands in the enantioselective copper-catalyzed 1,4-addition of
diethylzinc to acyclic enones. The ligands were screened for activity and enantioselectivity using chalcone as the substrate 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 affording the best results was eventually used in the copper-catalyzed 1,4-addition to various
acyclic enones, affording the alkylation products in good yields and e.e.s up to 78%. © 2003 Elsevier Science Ltd. All rights
reserved.
1. Introduction
units so that chiral auxiliaries having properties which
depend on the nature of the moieties introduced have
been obtained.7 In addition, the use of arylcarba-
moyl derivatives of bile acids as chiral selectors
in enantioselective chromatography has demon-
strated that the enantiodiscriminating properties of
these compounds depend not only on the nature
of the introduced moieties but also on the posi-
tion where these units are located on the cholestanic
backbone.8
The requirement in modern organic synthesis for
highly enantioselective CꢀC bond-forming reactions
has directed scientists towards the development of
chiral complexes that can efficiently promote the
asymmetric conjugate addition of organozinc reagents
to enones.1 Good enantioselectivities have been real-
ized in the copper-catalyzed Michael addition of
diethylzinc to a,b-unsaturated carbonyl compounds
using phosphoramidites,2 amidophosphines,3 phos-
phite–oxazolines,4 diphosphites as chiral ligands.5
More recently, the use of phosphites prepared starting
from highly functionalized compounds with several
stereogenic centers has emerged as an important tool
for obtaining a series of chiral ligands that can be
screened for high activity and enantioselectivity.6
On this basis, deoxycholic acid, 1, possessing two
hydroxy groups that can be reacted selectively, seems
a good candidate for the preparation of enantiomeri-
cally pure phosphites. Since the two hydroxy groups
have different reactivity, derivatives bearing the phos-
phite moiety at positions 3 and 12 of the cholestanic
backbone can be obtained, which can exhibit different
enantioselectivity depending on the position of the
phosphite moiety. Herein we report the synthesis of
four different deoxycholic based phosphites (Fig. 1)
obtained by reacting suitable monohydroxy deriva-
tives of deoxycholic acid with (R)- and (S)-binaphthyl
chlorophosphites and their screening for activity and
enantioselectivity in the copper-catalyzed enantioselec-
tive conjugate addition of diethylzinc to acyclic
enones.
Bile acids are very attractive compounds for such a
purpose. In fact they possess a unique structure
endowed with several stereogenic centers and hydroxy
groups having different reactivity due to their differ-
ent steric environment. Thanks to these features bile
acids have been derivatized with different molecular
* Corresponding authors. Tel.: +39050918232; fax: +39050918260
(A.I.); Tel.: +390971202399; fax: +390971202223 (P.S.); e-mail:
iuliano@dcci.unipi.it; scafato@unibas.it
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00044-2

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A. Iuliano, P. Scafato / Tetrahedron: Asymmetry 14 (2003) 611–618
Figure 1. Structures of deoxycholic acid and phosphite derivatives.
2. Results and discussion
To obtain such a derivative it is necessary to initially
protect the more reactive 3-OH group and afterwards
the 12-OH: of course, the 3-OH protecting group must
be cleaved selectively over the 12-OH protecting group.
This strategy can be accomplished by protecting the
3-OH as the acetate ester and subsequently protecting
the 12-OH as the benzoate ester, which is stable under
the mild acidic conditions used to cleave the 3-acetate
group.
2.1. Synthesis of phosphites
The synthesis of the four cholic acid-based phosphites
is summarized in Scheme 1. In order to obtain the
derivative bearing the binaphthylphosphite moiety at
position 12 of the cholestanic backbone, protection of
the 3-OH group is required. Of course, transformation
of the free carboxyl group into the corresponding
methyl ester before derivatization of the 12-OH group
is also mandatory. Protection of the two functional
groups was obtained in one step, by reacting deoxy-
cholic acid with methyl acetate9 in the presence of
p-toluenesulphonic acid and water, which afforded the
corresponding 3-acetoxy methylcholate 2 in very good
yield. Under these experimental conditions the axial
12-OH group does not react at all. The treatment of 2
with (S)- and (R)-binaphthyl chlorophosphite, pre-
pared starting from binaphthol and PCl3 according to
standard procedures,2b in the presence of triethylamine
and DMAP afforded, after chromatographic purifica-
tion, the enantiomerically pure phosphites 3 in 60%
yield.
As reported in Scheme 1, compound 2 was reacted with
CaH2 in the presence of benzyltriethylammonium chlo-
ride as phase transfer catalyst followed by addition of
benzoyl chloride, affording derivative 4 in excellent
yield after chromatographic purification. The reaction
of 4 with HCl in methanol gave derivative 5 in quanti-
tative yield, which was reacted with (R)- and (S)-
binaphthyl chlorophosphites affording the phosphites 6
in 60% yield after chromatographic purification.
2.2. Conjugate addition to acyclic enones
Chiral auxiliaries 3 and 6 were assayed in the copper-
catalyzed conjugate addition of diethylzinc to acyclic
enones. In a typical procedure the catalytic system was
generated in situ by stirring a solution containing the
ligand and the copper salt for 1 h at room temperature,
followed by addition of diethylzinc. The effect of differ-
ent reaction parameters was investigated using ligand
3a and chalcone as a substrate and the obtained results
are summarized in Table 1.
In order to obtain a deoxycholic acid derivative bearing
the phosphite moiety at the
3 position of the
cholestanic backbone, we needed a methylcholate
derivative with the 12-OH group protected. Since the
3-OH moiety is more reactive than the 12-OH group,
direct protection of the 12-OH group was unrealizable.

A. Iuliano, P. Scafato / Tetrahedron: Asymmetry 14 (2003) 611–618
613
Scheme 1. Reagents and conditions: (a) methyl acetate, TsOH, H2O, reflux, 24 h; (b) triethylamine, DMAP, binaphthylchlorophos-
phite, THF, −60 to rt, 20 h; (c) CaH2, benzyltriethylammonium chloride, benzoyl chloride, toluene, reflux, 24 h; (d) HCl,
methanol, rt, 20 h.
All the reactions were stopped when conversion of the
substrate was complete or did not proceed further, as
judged by TLC analysis. The conjugate addition of
diethylzinc in the presence of the catalytic species
obtained from 3a and Cu(OTf)2 in molar ratio 1.2:1 at
−20°C affords the alkylated product in 87% yield and
59% e.e. after 2 h (entry 1). Increasing the ligand/Cu
salt ratio did not affect the outcome of the reaction: in
fact, the alkylation product was obtained in compara-
ble yield and e.e (entry 2). On lowering the temperature
an improvement in the enantioselectivity was achieved
without loss of catalytic activity (entry 3). Worse results
in terms of both activity and enantioselectivity were
obtained on moving from toluene to dichloromethane
as the solvent (entry 4). Varying the copper salt showed
that the use of Cu(OTf)2 seems to be mandatory: its
replacement with CuOTf gave poorer results both in
terms of yield and enantioselectivity (entry 5). The
results were even worse using CuI (entry 6): the cata-
lytic activity of the system dropped dramatically and
the alkylation product was obtained in only 46% yield
after 24 h. The use of CuI was also detrimental to the
enantioselectivity of the process, the alkylation product
being obtained with 6% e.e.
On the basis of these results, for comparative purposes,
the other ligands were assayed under the experimental
conditions which afforded the best results, i.e. ligand to
copper ratio of 1:1.2, Cu(OTf)2 as copper salt, tempera-
ture of −70°C and toluene as solvent. The results are
listed in Table 2.
Perusal of Table 2 shows that all the deoxycholic
acid-based ligands form catalytic species, which were

614
A. Iuliano, P. Scafato / Tetrahedron: Asymmetry 14 (2003) 611–618
Table 1. Catalytic enantioselective conjugate addition to chalcone in the presence of 3a
Entry
Cu salt
3a (mol%)
Time (h)
Solvent
Temp. (°C)
Yield (%)a
E.e. (%)b
A.C.c
1
2
3
4
5
6
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuOTf
3.0
6.0
3.0
3.0
3.0
3.0
2
2
3
7
3.5
24
Toluene
Toluene
Toluene
CH2Cl2
Toluene
Toluene
−20
−20
−70
−70
−70
−70
87
81
86
58
58
46
59
58
76
60
60
6
S
S
S
S
S
S
CuI
a Isolated yield.
b Determined by HPLC analyses on Chiralcel OJ, 254 nm, 1.0 ml/min, hexane:2-propanol, 99.5:0.5.
c Determined by the sign of the specific rotation.
Table 2. Catalytic enantioselective conjugated addition to chalcone
Entry
Ligand
Time (h)
Yield (%)a
E.e. (%)b
A.C.c
1
2
3
4
5
6
3a
3b
6a
6b
7
3
3
3
3
20
20
86
88
88
85
46
54
76
40
58
6
32
34
S
R
S
R
S
S
7d
a Isolated yield.
b Determined by HPLC analyses on Chiralcel OJ, 254 nm, 1.0 ml/min, hexane:2-propanol, 99.5:0.5.
c Determined by the sign of the specific rotation.
d Performed with 6 mol% of ligand.
12-position gives rise to a more enantioselective ligand.
Additionally, in the case of ligands 6a–b the matched
couple is still that possessing the (R)-binaphthyl moi-
ety: when 6b, which has an (S)-binaphthyl moiety, was
used as the chiral ligand the alkylation product was
obtained with only 6% e.e. This result also indicates
that the difference between the e.e. obtained using the
matched or mismatched couple is strongly dependent
on the position of the binaphthylphosphite moiety on
the cholestanic backbone. The difference in e.e. is 76
versus 40% when the binaphthylphosphite moiety is
linked at the 12-position of the deoxycholic acid,
whereas it is 58 versus 6% when the binaphthylphos-
phite moiety is linked at the 3-position. However, the
deoxycholic moiety does not exert its influence on the
sense of the asymmetric induction and an (S)-configu-
rated product is always obtained when using ligands
possessing an (R)-binaphthyl moiety, as observed with
other phosphorous ligands.2b,4b In order to evaluate the
influence of the binaphthol moiety on the enantioselec-
tivity we tested (R)-(1,1%-binaphthyl-2,2%-diyl) cyclo-
hexyl phosphite 7, which is chiral only by virtue of the
very reactive in the conjugate addition of diethylzinc to
chalcone, affording the alkylation product in good yield
after 3 h (entries 1–4). The comparable yields indicate
that the catalytic activity of the formed species is
independent of the structure and stereochemistry of the
starting ligand. On the contrary, both the structure and
stereochemistry of the ligands strongly affect the enan-
tioselectivity of the reaction. As far as the absolute
configuration of the stereogenic binaphthyl moiety is
concerned, ligand 3a, which contains an R-configurated
binaphthylic moiety afforded the alkylation product
with 76% e.e., whereas its diastereoisomer 3b gave
1,3-diphenylpentan-1-one with 40% e.e.
The effect of the structure of the ligand on the enan-
tioselectivity can be established by comparing the
results obtained using ligands 3a and 6a (entries 1 and
3), which have a R configurated binaphthylphosphite
moiety linked at the two different hydroxy-substituted
positions of the cholestanic backbone. The higher e.e.
obtained using 3a, suggests that linking the binaph-
thylphosphite moiety to the more sterically demanding

A. Iuliano, P. Scafato / Tetrahedron: Asymmetry 14 (2003) 611–618
615
diethylzinc to chalcone. In order to evaluate the influ-
ence of the substrate structure on the activity and
enantioselectivity of the catalytic species formed from
3a, screening of differently substituted acyclic enones
was performed and the results are reported in Table 3.
The presence of an arylketone moiety, as already
observed with phosphoramidite ligands,2a seems to be
important for a satisfactory degree of asymmetric
induction: in passing from chalcone to benzylideneace-
tone (entry 2) the enantioselectivity dropped to 40%.
The effect of electronic factors on the outcome of the
reaction can be investigated using para-substituted
chalcones. The presence of an electron-donating group
effects a slight lowering of asymmetric induction (entry
3), whereas a chlorine substituent does not significantly
affect the enantioselectivity of the process. On the
contrary, differences in the activity of the catalytic
species depending on the substrate structure were not
observed and comparable yields were obtained with the
four different substrates (entries 1–4). Different consid-
erations have to be made when the chalcone possesses a
strong electron-withdrawing substituent, such as the
CF3 group (entry 5). In this case both activity and
enantioselectivity of the catalytic system fell dramati-
cally and the alkylation product was obtained in 22%
yield and 16% e.e. after 20 h. The very low yield was
due to partial conversion of the substrate and the
formation of by-products. Again, formation of the
dimeric compound generated by conjugate addition of
the in situ formed zinc enolate to the unreacted sub-
strate was observed, suggesting that this reaction
becomes competitive when the 1,4 addition of diethyl-
zinc is slow.
Figure 2. Structure of (R)-(1,1%-binaphthyl-2,2%-diyl)cyclo-
hexyl phosphite 7 and side-product 8.
binaphthol moiety. This ligand shows lower activity
and enantioselectivity with respect to the deoxycholic
ligands. Under the experimental conditions used with
the other ligands the conversion of the substrate was
complete after 20 h, as judged by TLC, and the isolated
yield was only 46%. The lower yield is due to the
formation of the side-product 8, generated by attack of
the enolate formed in situ on another molecule of
unreacted substrate, as already observed with other
ligands.10 Side product 8 was isolated and characterized
by NMR.
Both the yield and e.e. did not improve significantly
even after increasing the ligand to copper ratio (entry
6). The obtained e.e. suggests that the chirality of the
binaphthol alone is sufficient to induce enantioselectiv-
ity, but the asymmetric induction is helped by the
presence of the deoxycholic acid moiety when it is in a
matched relationship with the binaphthyl moiety. In
addition, the deoxycholic acid moiety deeply affects the
activity of the formed catalytic species: Using 7 longer
reaction time is required to observe complete conver-
sion of the substrate and the product is obtained in
lower yield (Fig. 2).
3. Conclusions
Four phosphite ligands, derived from inexpensive
deoxycholic acid, were screened in the enantioselective
conjugate addition of diethylzinc to chalcone. Changing
the absolute configuration at the stereogenic binaphthyl
Screening of the deoxycholic based ligands 3a–b and
6a–b has shown that phosphite 3a is the best ligand to
promote the enantioselective conjugate addition of
Table 3. Catalytic enantioselective conjugate addition to acyclic enones
Entry
R1
R2
Time (h)
Yield (%)a
E.e. (%)
1
2
3
4
5
Ph
Me
Ph
Ph
Ph
Ph
Ph
3
3
3
3
20
82
80
78
84
22
76b
40c
60d
78b
16e
p-OMe(C6H4)
p-Cl(C6H4)
p-CF3(C6H4)
a Isolated yield.
b Determined by HPLC analyses on Chiralcel OJ, 254 nm, 1.0 ml/min, hexane:2-propanol, 99.5:0.5.
c Chiralcel OJ, 254 nm, 0.5 ml/min, hexane:2-propanol, 99.5:0.5.
d Chiralcel OJ, 254 nm; 1.0 ml/min, hexane:2-propanol, 99:1.
e Chiralcel OJ, 254 nm, 1.0 ml/min, hexane.

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A. Iuliano, P. Scafato / Tetrahedron: Asymmetry 14 (2003) 611–618
moiety has allowed us to find the matched couples of
the ligands. The nature of the deoxycholic moiety,
possessing two hydroxy groups having different reactiv-
ity due to their different steric environment has allowed
us to vary the position of binaphthylphosphite moiety
on the steroidal skeleton and hence to find the best
substitution pattern for high levels of activity and enan-
tioselectivity. In fact, although the binaphthyl moiety
governs the sense of asymmetric induction and the
matched couple is always that possessing an (R)-
binaphthylphosphite, the position of the phosphite moi-
ety on the cholestanic backbone has a strong influence
on the enantioselectivity of the reaction. The best com-
bination of position on the cholestanic backbone–
binaphthol absolute configuration was found and
ligand 3a has emerged as the most suitable to obtain
high yields as well as good asymmetric induction. Thus,
3a was used in the catalytic conjugate addition of
diethylzinc to structurally different acyclic enones,
affording high yields and satisfactory enantioselectivi-
ties in most of the cases examined.
treated with a 10% solution of HCl, a 5% solution of
NaHCO3 and water in that order, then dried over
anhydrous Na2SO4. Evaporation of the solvent under
vacuum afforded the crude product, which was purified
by flash chromatography (CH2Cl2:acetone, 97:3) giving
pure 3 (1 g, 1.75 mmol, 82%). Mp 48–50°C; [h]2D0 65.9 (c
1
0.9; CH2Cl2); H NMR (200 MHz, CDCl3, l): 8.03 (d,
2H, aromatics), 7.55 (m, 3H, aromatics), 5.31 (s, 1H,
12CH), 3.59 (s, 3H, OCH3
6 ), 4.61 (m, 1H, 3CH), 1.91 (s,
3H, CH3CO) 2.27–0.97 (m, 23H, steroidal CH and
6
CH2), 0.91 (s, 3H, CH3), 0.81 (s, 3H, CH3), 0.82 (d, 3H,
CH3); 13C NMR (50 MHz, CDCl3, l): 12.8, 17.7, 21.6,
23.3, 23.8, 26.1, 26.3, 26.6, 27.1, 27.6, 31.1, 31.2, 32.5,
34.3, 34.9, 35.0, 36.0, 42.0, 45.8, 48.2, 50.3, 51.7, 74.3,
76.8, 128.7, 129.7, 131.1, 133.1, 166.1, 170.8, 174.8.
4.3. Methyl 3a-hydroxy-12a-benzoyloxy-5b-cholan-24-
oate, 5
Concentrated HCl (1.07 ml) was added to a solution of
2 (1g, 1.75 mmol) in CH3OH (43 ml). The reaction
mixture was stirred overnight at rt, then poured into
water. The mixture was extracted with CH2Cl2, and the
organic phase was treated with a 10% solution of HCl,
a 5% solution of NaHCO3 and water in that order, then
dried over anhydrous Na2SO4. After removing the sol-
vent at reduced pressure, pure 5 was obtained in quan-
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded in CDCl3 on a
Varian Gemini-200 200 MHz NMR spectrometer, using
TMS as external standard. 31P NMR spectra were
recorded in benzene-D6: ppm are referred to H3PO4 as
external standard. The following abbreviation are used:
s=singlet, d=doublet, dd=double doublet, t=triplet,
m=multiplet, br=broad. TLC analyses 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 (230–400
mesh). HPLC analyses were performed on a JASCO
PU-980 intelligent HPLC pump equipped with a
JASCO UV-975 detector. Optical rotations were mea-
sured with a JASCO DIP-360 digital polarimeter. Melt-
ing points were obtained using a Kofler Reichert–Jung
apparatus and are uncorrected. The IR spectra were
recorded on a Perkin–Elmer 1710 spectrofotometer.
Toluene and THF were heated under reflux over
sodium–benzophenone and distilled before the use.
Unless otherwise specified the reagents were used with-
out any purification. Methyl 3a-acetyloxy-12a-hydroxy-
5b-cholan-24-oate9 2, (R)- and (S)-binaphthyl
chlorophosphite2a and the substituted unsaturated
ketones11 were obtained according to literature
procedures.
titative yield. H NMR (200 MHz, CDCl3, l): 8.03 (d,
1
2H, aromatics), 7.50 (m, 3H, aromatics), 5.31 (s, 1H,
12CH), 3.59 (s, 3H, OCH6 3), 3.51 (m, 1H, 3CH), 2.32–
0.85 (m, 23H, steroidal CH and CH2), 0.91 (s, 3H,
CH3), 0.81 (s, 3H, CH3), 0.82 (d, 3H, CH3); 13C NMR
(50 MHz, CDCl3, l): 12.8, 17.7, 23.4, 23.8, 26.0, 26.4,
27.3, 27.6, 30.7, 30.8, 31.1, 31.2, 34.3, 34.9, 35.3, 36.1,
36.6, 42.2, 45.8, 48.2, 50.2, 51.7, 71.9, 76.8, 128.8, 129.7,
131.0, 133.2, 166.2, 174.8.
4.4. Preparation of the phosphites: representative
procedure
A solution of freshly prepared binaphthyl chlorophos-
phite (3 mmol) in dry toluene (30 ml) was added
dropwise to a solution of DMAP (3.27 mmol) and Et3N
(31 mmol) in dry toluene (50 ml) at −60°C over 2 h.
The deoxycholic acid derivative (or cyclohexanol) was
then added and the mixture was allowed to warm to rt
and stirred for 20 h. After removing the solvent at
reduced pressure the crude product was purified by
column chromatography (SiO2, CH2Cl2–aceton, 95–5),
affording the pure phosphites as white foamy solids.
4.4.1. Methyl 3a-acetoxy-12a [(R)-(1,1%-binaphthyl-2,2%-
diyl)phosphite]-5b-cholan-24-oate, 3a. Yield 1.4 g (1.83
mmol, 61%). Mp 100–102°C; [h]2D5 −159.2 (c 1.0,
4.2. Methyl 3a-acetyloxy-12a-benzoyloxy-5b-cholan-24-
oate, 4
1
CHCl3); H NMR (300 MHz, C6D6, l): 0.47 (s, 3H,
CH3), 0.69 (s, 3H, CH3), 1.09 (d, J 6.6 Hz, 3H, CH3),
1.60 (s, 3H, CH3CO), 0.51–2.42 (m, 25H, steroidal CH
and CH2), 3.41 (s, 3H, OCH3), 4.58 (dd, J1 2 Hz, J2 5.5
Hz, 1H, H12), 4.79 (m, J 5 Hz, 1H, H3), 6.83 (m, 2H,
aromatics), 7.00 (m, 2H, aromatics), 7.08 (m, 2H, aro-
matics), 7.34 (d, J 8.5 Hz, 1H, aromatic), 7.41 (d, J 8.5
Hz, 1H, aromatic), 7.59 (m, 2H, aromatics), 7.67 (d, J
8.5 Hz, 1H, aromatic), 7.81 (d, J 8.5 Hz, 1H, aromatic);
CaH2 (0.15 g), Et3BnN+Cl− (0.08 g) and benzoyl chlo-
ride (0.3 ml) were added to a solution of 2 (1 g, 2.15
mmol) in dry toluene (15 ml) and the mixture was
heated under reflux for 24 h. The reaction mixture was
cooled to rt then water and CH2Cl2 were added. The
organic layer was separated and the aqueous phase was
extracted twice with CH2Cl2. The organic extracts were

A. Iuliano, P. Scafato / Tetrahedron: Asymmetry 14 (2003) 611–618
617
13C NMR (75 MHz, C6D6, l): 12.8, 18.1, 21.4, 23.4,
24.1, 26.1, 27.3, 27.5, 28.3, 29.4 (d, JCꢀP 7.5 Hz), 31.8,
31.9, 32.9, 33.7, 34.7, 35.8, 35.9, 36.3, 36.7, 42.3, 47.1
(d, JCꢀP 6 Hz), 47.4, 48.1, 51.4, 74.5, 79.4 (d, JCꢀP 16.6
Hz), 122.5, 123.0, 125.3, 126.7, 127.1, 127.7, 127.9,
128.9 (d, JCꢀP 4.5 Hz), 130.3, 130.9, 131.9, 132.3, 133.7,
133.9, 148.9, 149.2 (d, JCꢀP 6 Hz), 170.1, 174.2; 31P
NMR (121 MHz, C6D6, l): 155.9.
4.4.5. (R)-(1,1%-binaphthyl-2,2%-diyl) cyclohexyl phos-
phite, 7. 0.74 g (1.8 mmol, 60% yield). Mp 78–80°C
1
(dec.); [h]2D5 −303 (c 1.0, CHCl3); H NMR (300 MHz,
C6D6, l): 0.93 (m, 4H, cyclohexyl), 1.47 (m, 4H, cyclo-
hexyl), 1.75 (br s, 2H, cyclohexyl), 4.13 (br s, 1H, CH),
6.89 (q, J 8 Hz, 2H, aromatics), 7.10 (q, J 7.5 Hz, 2H,
aromatics), 7.42 (d, J 8.5 Hz, 2H, aromatics), 7.46 (d, J
9 Hz, 2H, aromatics), 7.54 (d, J 9 Hz, 1H, aromatic),
7.58 (d, J 8 Hz, 1H, aromatic), 7.61 (d, J 8.5 Hz, 2H
aromatics); 13C NMR (75 MHz, C6D6, l): 23.5, 25.2,
34.3, 34.6, 74.5, 122.1, 122.2, 123.3, 124.9 125.0, 126.4,
126.5, 128.1, 128.2, 128.4, 128.6, 129.8, 130.7, 131.3,
131.9, 133.2, 133.4, 148.3, 149.3.
4.4.2. Methyl 3a-acetoxy-12a [(S)-(1,1%-binaphthyl-2,2%-
diyl)phosphite]-5b-cholan-24-oate, 3b. Yield 1.4 g (1.83
mmol, 61%). Mp 128–130°C. [h]2D5 240.4 (c 1.0, CHCl3);
1H NMR (300 MHz, C6D6, l): 0.54 (s, 3H, CH3), 0.76
(s, 3H, CH3), 1.16 (d, J 9 Hz, 3H, CH3), 1.68 (s, 3H,
CH3CO), 0.57–2.51 (m, 25H, steroidal CH and CH2),
3.48 (s, 3H, OCH3), 4.65 (dd, J1 3 Hz, J2 6 Hz, 1H,
H12), 4.87 (m, J 6 Hz, 1H, H3), 6.90 (m, 2H, aromatics),
7.06 (dd, J 6 Hz, 2H, aromatics), 7.14 (m, 2H, aromat-
ics), 7.41 (d, J 9 Hz, 1H, aromatic), 7.49 (d, J 9 Hz, 1H,
aromatic), 7.71 (m, 2H, aromatics), 7.75 (d, J 9 Hz, 1H,
aromatic), 7.89 (d, J 9 Hz, 1H, aromatic); 13C NMR
(75 MHz, C6D6, l): 12.4, 17.7, 21.0, 23.0, 23.7, 25.8,
26.9, 27.2, 27.9, 29.1 (d, JCꢀP 8 Hz), 31.4, 31.5, 32.5,
33.4, 34.3, 35.3, 35.9, 36.3, 41.9, 46,7(d, JCꢀP 4.5 Hz),
47.0, 47.7, 51.0, 74.1, 79.0 (d, JCꢀP 17.2 Hz), 122.1,
122.6, 124.9, 125.1, 126.3, 126.5, 127.3, 128.5 (d, JCꢀP
3.5 Hz), 129.8, 130.5, 131.6, 131.9, 133.3, 133.5, 148.5
(d, JCꢀP 3 Hz), 148.8 (d, JCꢀP 5.5 Hz), 169.6, 173.8; 31P
NMR (121 MHz, C6D6, l): 155.2.
4.5. 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 toluene (5 ml) was
stirred under nitrogen atmosphere at rt for 1 h. The
solution was cooled to −70°C and diethylzinc (1.0 M in
hexane, 1.5 mmol) was added. The enone was added
slowly and stirring was continued at −70°C and the
reaction was monitored by TLC. After complete con-
version the mixture was poured in 1 M HCl (25 ml) and
extracted three times with diethyl ether. The combined
organic layers were washed with brine, dried over anhy-
drous Na2SO4, filtered and evaporated to yield the
crude 1,4-products. After purification by column chro-
matography (SiO2 and hexane/diethyl ether 80/20), the
e.e.s were determined by HPLC analyses.
4.4.3.
Methyl
3a
[(R)-(1,1%-binaphthyl-2,2%-diyl)-
phosphite]-12a-benzoyloxy-5b-cholan-24-oate, 6a. Yield
1.5 g (1.95 mmol, 60%). Mp 110–112; [h]2D5 −172 (c 0.7,
CH2Cl2); H NMR (300 MHz, C6D6, l): 0.59 (s, 3H,
1
Acknowledgements
CH3), 065 (s, 3H, CH3) 0.90 (d, J 6 Hz, 3H, CH3),
0.44–2.22 (m, 25H, steroidal CH and CH2), 3.36 (s, 3H,
OCH3), 4.12 (m, J 6 Hz, 1H, H3), 5.56 (br s, 1H, H12),
6.74–7.26 (m, 8H, aromatics), 7.33 (d, J 8.7 Hz, 1H,
aromatic), 7.48 (m, 3H, aromatics), 7.64 (m, 3H, aro-
matics) 8.30 (dd, J1 2.1 Hz, J2 8.4 Hz, 2H, aromatics),
13C NMR (75 MHz, C6D6, l): 12.6, 17.7, 22.8, 23.8,
26.2, 26.3, 26.8, 27.6, 29.8, 31.0, 33.8, 34.9, 35.0, 35.5,
35.9, 42.0, 45.8, 48.3, 50.4, 50.9, 76.2, 78.0, 122.2, 123.8,
125.1, 125.6,126.6, 128.3, 128.8, 129.6, 129.8, 131.4 (d,
JCꢀP 4.2 Hz), 131.9, 133.1, 133.2, 133.4,148.4, 149.2 (d,
JCꢀP 4.9 Hz), 165.8, 173.6; 31P NMR (121 MHz, C6D6,
l): 147.3.
Financial support from MIUR (COFIN 2002), Univer-
sita` di Pisa and Universita` della Basilicata (Potenza) is
gratefully acknowledged.
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