Asymmetric induction by the cholestanic moiety on Tropos species: Synthesis and stereochemical characterization of bile acid-based biphenyl phosphites

Article abstract of DOI:10.1021/jo0606453

Three different bile acid-derived biphenyl phosphites were synthesized, starting from cholic and deoxycholic acids and biphenol, and their stereochemical features were checked by CD and NMR spectroscopies. On the basis of the spectroscopic results, the ca

Full text of DOI:10.1021/jo0606453

Asymmetric Induction by the Cholestanic Moiety on Tropos
Species: Synthesis and Stereochemical Characterization of Bile
Acid-Based Biphenyl Phosphites
A. Iuliano,* S. Facchetti, and G. Uccello-Barretta
Dipartimento di Chimica e Chimica Industriale, UniVersita` di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
iuliano@dcci.unipi.it
ReceiVed March 24, 2006
Three different bile acid-derived biphenyl phosphites were synthesized, starting from cholic and
deoxycholic acids and biphenol, and their stereochemical features were checked by CD and NMR
spectroscopies. On the basis of the spectroscopic results, the capability of the cholestanic system to induce
a prevalent sense of twist on the biphenyl moiety of the bile acid-derived phosphites as well as their
tropos nature was inferred.
Introduction
a prevalent screw sense in the flexible moiety: this guarantees
the presence of a largely prevailing diastereoisomer and hence
the achievement of high ee’s.
An elegant approach to asymmetric activation of tropos
catalysts1 is the diastereoisomeric control of tropos ligands
combined with a chiral subunit, which adopts a preferential
conformation of a diastereoisomeric complex.2 According to
such a concept, phosphite and phosphoramidite ligands based
on a chiral unit and a tropos biphenol moiety have been
employed in asymmetric hydrogenation3 and hydroformylation,4
in the rhodium-catalyzed conjugate addition of phenylboronic
acid,5 and in the copper-catalyzed conjugate addition of dialkyl-
zinc reagents6 to induce high enantioselectivities. Their success
lies in the capability of the configurationally stable unit to induce
Recently, we have demonstrated that good levels of asym-
metric induction can be reached in the copper-catalyzed
conjugate addition of dialkylzincs to enones using deoxycholic
acid-based binaphthyl phosphites.7 The enantioselectivity of the
reaction depended on the absolute configuration of the binaph-
thyl moiety as well as on its position on the cholestanic
backbone, suggesting that the cholestanic structure plays a
fundamental role in the asymmetric induction.7 Prompted by
these results, we became interested in investigating the capability
of the cholestanic moiety to induce a prevalent screw sense on
the tropos unit of biphenyl phosphite, to obtain bile acid-based
biphenyl phosphites to be used in asymmetric catalysis. Bile
(1) Mikami, K.; Aikawa, K.; Yusa, Y.; Jodry, J. J.; Yamanaka, M. Synlett
2002, 1561-1578.
(2) Mikami, K.; Yamanaka, M. Chem. ReV. 2003, 103, 3369-3400.
(3) Reetz, M. T.; Neugebeauer, T. Angew. Chem., Int. Ed. 1999, 38, 179-
181; Chen, W.; Xiao, J. Tetrahedron Lett. 2001, 42, 2897-2899. Chen,
W.; Xiao, J. Tetrahedron Lett. 2001, 42, 8737-8740.
(6) Alexakis, A.; Polet, D.; Benhaim, C.; Rosset, S. Tetrahedron:
Asymmetry 2004, 15, 2199-2203. Alexakis, A.; Benhaim, C.; Rosset, S.;
Humam, M. J. Am. Chem. Soc. 2002, 124, 5262-5263. Alexakis, A.; Rosset,
S.; Allamand, J.; March, S.; Guillen, F.; Benhaim, C. Synlett 2001, 9, 1375-
1378. Alexakis, A.; Polet, D.; Rosset, S.; March, S. J. Org. Chem. 2004,
69, 5660-5667. Alexakis, A.; Burton, J.; Vastra, J.; Benhaim, C.; Fournioux,
X.; van den Heuvel, A.; Leveˆque, J.; Maze´, F.; Rosset, S. Eur. J. Org.
Chem. 2000, 4011-4027. Scafato, P.; Cunsolo, G.; Labano, S.; Rosini, C.
Tetrahedron 2004, 60, 8801-8806.
(4) Buisman, G. J. H.; van der Veen, L. A.; Klotwijk, A.; de Lange, W.
G. J.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Vogt, D. Organometallics
1997, 16, 2929-2939. Die´guez, M.; Pa`mies, O.; Ruiz, A.; Castillo`n, S.;
Claver, C. Chem. Commun. 2000, 1607-1608. Die´guez, M.; Pa`mies, O.;
Ruiz, A.; Castillo`n, S.; Claver, C. Chem.-Eur. J. 2001, 7, 3086-3094.
Pa`mies, O.; Net, G.; Ruiz, A.; Claver, C. Tetrahedron: Asymmetry 2001,
12, 3441-3445.
(7) Iuliano, A.; Scafato, P. Tetrahedron: Asymmetry 2003, 14, 611-
618. Iuliano, A.; Scafato, P.; Torchia, R. Tetrahedron: Asymmetry 2004,
15, 2533-2538.
(5) Monti, C.; Gennari, C.; Piarulli, U.; Chem. Commun. 2005, 5281-
5283
10.1021/jo0606453 CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/20/2006
J. Org. Chem. 2006, 71, 4943-4950
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Iuliano et al.
and DMAP.9 The synthesis of derivative 2 required protection
of 12-OH. Because this hydroxyl group is less reactive than
3-OH, its selective protection was not possible. However,
selective deprotection of the 3-OH group is obtained easily
because of its higher reactivity; therefore, compound 5 was
reacted with benzoyl chloride,10 to obtain 6, from which the
desired derivative 7, having protected 12-OH and free 3-OH,
was obtained after removing the acetyl group under mild acidic
conditions that does not hydrolyze the 12-benzoate.
Phosphite 2 was then obtained in 76% yield after chromato-
graphic purification, by reacting 7 with biphenylchlorophosphite
in the presence of triethylamine and DMAP.7
The synthetic route to the cholic acid-derived phosphite 3 is
outlined in Scheme 2. Selective introduction of the biphenyl
phosphite moiety at the position 7 of the cholestanic backbone
requires protection of both the 3- and 12-OH groups. Because
both 12- and 7-OH are axial, their reactivity is very similar,
and hence, direct selective protection of 12-OH was not possible.
However, selective protection of the 7-hydroxy group can be
accomplished by means of its regioselective oxidation with NBS:
11
in fact, it is well-known that the reduction with NaBH4 of
the carbonyl function takes place with complete stereoselectivity,
the stereogenic center being restored to the same absolute
configuration as that in cholic acid.10 Therefore, 9, obtained by
treating cholic acid with methyl acetate in the presence of
p-toluenesulfonic acid and water, was reacted with NBS in
acetone, giving 10, which was acetylated at the 12-position by
means of acetic anhydride in the presence of triethylamine. The
reaction of 11 with NaBH4 in THF-MeOH afforded in
quantitative yield the desired cholic acid derivative 12 having
protected both 3- and 12-OH. By reacting 12 with biphenyl-
chlorophosphite under the same conditions used for preparing
1 and 2, phosphite 3 was obtained in 40% yield after
chromatographic purification.
Stereochemical Characterization. A. Circular Dichroism
Measurements. The circular dichroism (CD) spectroscopy in
the UV region represents the most suitable way to determine
not only the capability of the cholestanic moiety to induce a
prevalent screw sense to the biphenyl unit but also its sense of
twist in the phosphites 1-3. In fact, the only absorbing
chromophore in the wavelength region between 300 and 230
nm is the substituted biphenyl moiety,12 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,
the sign of the Cotton effects will depend only on the sense of
twist of the biphenyl unit, given that the same biphenyl
phosphite chromophore is present in the three phosphites.
The UV spectrum of 1 (Figure 2) shows two absorption
bands, the first one at 280 nm (ꢀ 8000) and the second one at
250 nm (ꢀ 19000), attributable to the electrically dipole-allowed
transitions of the substituted biphenyl moiety.12 The CD
spectrum shows two positive Cotton effects corresponding to
the UV absorption bands, at 280 nm (∆ꢀ 1) and at 250 nm (∆ꢀ
4.3). The presence of these Cotton effects indicates that the
electrically dipole-allowed transitions of the biphenyl chro-
mophore are optically active, and hence, the biphenyl group is
twisted in a prevalent screw sense. This means that the
FIGURE 1. Structures of phosphites 1-3.
acids possess two (deoxycholic acid) or three (cholic acid)
different hydroxyl substituted positions, at which the biphenyl
phosphite moiety can be linked to obtain different phosphites.
Because these positions are in stereochemically different
environments, the asymmetric induction exerted by the choles-
tanic moiety upon the tropos unit could depend on the position
at which this unit is linked as far as both sense of twist of the
biphenyl moiety and extent of its prevalence are concerned.
Therefore, deoxycholic acid-derived phosphites 1 and 2 and
cholic acid-derived phosphite 3 (Figure 1) were synthesized and
their stereochemical features were assayed by circular dichroism
(CD) and NMR spectroscopies.
Results and Discussion
Synthesis of Phosphites. The synthesis of the deoxycholic
acid-derived phosphites 1 and 2, performed according to the
method used for synthesizing the analogous deoxycholic acid-
based binaphthyl phosphites,7 is summarized in Scheme 1.
To obtain 1, bearing the biphenyl phosphite moiety at the
position 12 of the cholestanic skeleton, protection of both
carboxylic and 3-OH functions was required. This double
protection was realized in one step by reacting deoxycholic acid
with methyl acetate in the presence of p-toluensulfonic acid and
water,8 obtaining the 3-acethoxymethylcholate in good yield
because under these experimental conditions 12-OH did not
react. Derivative 1 was obtained in 70% yield after chromato-
graphic purification, by reacting 5 with biphenylchlorophosphite,
obtained by standard procedures, in the presence of triethylamine
(9) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Nassz,
R.; Feringa, B. L. Tetrahedron 2000, 56, 2865-2878.
(10) D’Souza, L.; Maitra, U. J.Org. Chem. 1996, 61, 9494-9502.
(11) Fieser, R.; Rajagopalan J. Am. Chem. Soc. 1949, 71, 3935-3938.
(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.
(8) Kuhaida, K.; Kandrac, J.; Cirin-Novta, V.; Milkovic, D. Collect.
Czech. Chem. Commun. 1996, 61, 1073-1076.
4944 J. Org. Chem., Vol. 71, No. 13, 2006

Synthesis of Bile Acid-Based Biphenyl Phosphites
SCHEME 1. Synthesis of Phosphites 1 and 2
SCHEME 2. Synthesis of Phosphite 3
cholestanic system is able to induce a prevalent sense of twist
to the biphenyl unit when the biphenyl phosphite moiety is
linked at the 12-position of the deoxycholic acid.
-5), attributable to the transition of the benzoate chromophore,13
which is optically active because this group is linked to a
stereogenic center. The lack of CD bands in the 300-240 nm
region means that the transitions of the biphenyl chromophore
are not optically active, and hence, the biphenyl moiety of 2 is
not twisted in a prevalent screw sense.
The UV spectrum of phosphite 2 (Figure 3) is very similar
to the UV spectrum of 1, as far as number, position, and intensity
of the absorption bands are concerned in the 300-240 nm
wavelength region; by contrast, the CD spectrum (Figure 3) is
very different with respect to the CD spectrum of 1 because it
is lacking of any Cotton effect in the wavelength region between
300 and 240 nm. A negative CD band is present at 230 nm (∆ꢀ
(13) Jaffe´, A.; Orchin, M. Theory and Application of UV Spectroscopy;
Wiley: New York, 1962. Harada, N.; Nakanishi, K. Circular Dichroic
Spectroscopy, Exciton coupling in Organic Stereochemistry; University
Science Books: Oxford, 1983.
J. Org. Chem, Vol. 71, No. 13, 2006 4945

Iuliano et al.
FIGURE 4. Absorption (dotted line) and CD (solid line) spectra of 3.
FIGURE 2. Absorption (dotted line) and CD (solid line) spectra of 1.
using the MMFF94s force field by the Spartan 02 package15
and was fully optimized at the DFT/B3LYP/631G* level.
The rotatory strengths for the lowest-energy 30 excited states
were calculated using the time-dependent density functional
theory (TDDFT) with the B3LYP hybrid functional and the
6-31G* basis set. The rotatory strengths were obtained using
the dipole-length formalism as well as the dipole-velocity
formalism. The calculated CD spectra in de units were obtained
using overlapping Gaussian functions.16
It is noteworthy that the CD spectra calculated with the two
formalisms are almost coincident: this guarantees that the
molecular wave functions used are of good quality. The
calculated CD spectra show, in the region 300-240 nm
wavelength, a large negative band, which is likely originated
by the superimposition of two negative CD bands, corresponding
to those observed in the experimental spectrum of 3, which is
qualitatively reproduced. By comparing the calculated CD
spectra for the methylbiphenyl phosphite having P-torsion
(Figure 5) with the experimental CD spectra of phosphites 1
and 3 (Figures 2 and 4), we can infer a prevalent M-torsion for
the biphenyl unit of 1 and a prevalent P-torsion for the biphenyl
unit of 3.
FIGURE 3. Absorption (solid line) and CD (dotted line) spectra of 2.
The UV spectrum of 3 (Figure 4), as expected, is very similar
to the UV spectrum of phosphite 1, as far as number, position,
and intensity of the absorption bands are concerned. The CD
spectrum (Figure 4) shows two negative Cotton effects at 280
(∆ꢀ -1) and 250 nm (∆ꢀ -4.3) and is in an enantiomeric
relationship with the CD spectrum of 1. Therefore, the biphenyl
unit of phosphite 3 is twisted in a prevalent screw sense, which
is opposite to the sense of twist of the biphenyl moiety of 1, as
the opposite sign of the Cotton effects suggests; furthermore,
the extent of the prevalence must be similar to that of phosphite
1, as indicated by the similar intensity of the CD bands.
B. NMR Measurements. Once we determined the sense of
twist of the biphenyl unit of both phosphites 1 and 3, two
questions remained open, one concerning the extent of the
prevalence of the screw sense, and the other concerning the
(14) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, revision B.01; Gaussian, Inc.: Pittsburgh, PA, 2003.
This means that the cholestanic moiety is able to induce a
prevalent sense of twist to the biphenyl unit also when the
biphenyl phosphite system is linked at the 7-position of cholic
acid.
The sense of twist of the biphenyl unit of phosphites 1 and
3 was determined by comparison of the experimental CD spectra
of 1 and 3 with theoretical CD spectra generated by Gaussian
0314 for the methylbiphenyl phosphite having P-torsion, assumed
as the model compound. The molecular geometry adopted for
these calculations was obtained from the geometry optimization
(15) SPARTAN 02; Wave Function Inc.: Irvine, CA, 2002.
(16) Diedrich, C.; Grimme, S. J. Phys. Chem. A 2003, 107, 2524-2539.
4946 J. Org. Chem., Vol. 71, No. 13, 2006

Synthesis of Bile Acid-Based Biphenyl Phosphites
FIGURE 5. Calculated CD spectra from the dipole-length formalism
(dotted line) and dipole-velocity formalism (solid line) of methyl-
biphenyl phosphite having P torsion.
FIGURE 7. 31P NMR (121.4 MHz, DMSO) spectra of 3 at: (a) 25
°C, (b) 40 °C, (c) 60 °C, and (d) 70 °C.
FIGURE 8. 1D NOE spectra (600 MHz, C6D6, 25 °C) of 3
corresponding to the selective excitation at: (a) 7.23 ppm and (b) 7.18
ppm.
in keeping with the presence of two interconverting M-P
stereoisomers, which are equally populated at room temperature.
At -80 °C, the two slowly interconverting species give rise to
a 30% prevalence of one on the other.
FIGURE 6. 31P NMR (121.4 MHz, CD2Cl2) spectra of 2 at: (a) 25
°C, (b) 0 °C, (c) -10 °C, (d) -40 °C, (e) -60 °C, and (f) -80 °C.
Derivative 3 showed a completely different spectral pattern
of 31P NMR resonances: two well-separated resonances were
detected between 25 and -80 °C (Figure S1, Supporting
Information). The ratio of their integrated areas was 90:10,
which did not undergo any change within the above said
temperature range. These two signals were attributed to slowly
interconverting M-P diastereomeric species on the basis of the
variable-temperature profile within the range 25-70°C. The
resonances approach each other on rising of the temperature
and coalesce at 70 °C (Figure 7).
Therefore, the presence of a largely prevalent stereoisomeric
form of 3 is confirmed, the structure of which was ascertained
by 1D NOE measurements in C6D6 at room temperature. Very
useful in this regard was the comparison between NOE patterns
of the two aromatic protons of biphenyl rings, which are adjacent
to phosphite oxygens.
The two protons gave well-separated doublets centered at 7.23
ppm (Ha) and 7.18 ppm (Hb). The higher-frequency shifted
aromatic proton Ha originated dipolar interactions with both
acetyl moieties at 1.68 and 1.64 ppm (Figure 8a), at the C12
and C3 sites, respectively, whereas the aromatic proton centered
at 7.18 ppm (Figure 8b) selectively produced NOEs at the
frequency of the acetyl methyl at 1.68 ppm, which is directly
bound to the C12 carbon atom.
Therefore, the biphenyl plane lies almost perpendicular to
the cholestanic skeleton (Figure 9) on the same side of the two
acetyl moieties and in a well-defined conformation with respect
to them: proton Ha points at the spatial region between the
tropos nature of phosphites 1-3. In fact, the asymmetric
induction of the cholestanic system on the flexible biphenyl unit
could result either in the formation of two diastereoisomeric
stable species or in the existence of rapidly interconverting M-P
diastereoisomers.
Satisfactory answers to these questions came from NMR
investigations, involving variable-temperature 31P NMR and
NOE measurements. 31P NMR analyses were carried out in CD2-
Cl2 and in DMSO-d6, allowing us to perform low- and high-
temperature measurements, respectively; dipolar interactions
were detected by NOE measurements in C6D6 as solvent, in
which a good spectral resolution was obtained. On the hypoth-
esis that only diastereoisomeric species could be distinguished
in the NMR spectra, the three derivatives were expected to
produce very simple 31P NMR spectra, containing one to two
signals due to the two possible M and P forms.
The presence of two species of 2 was clearly established on
the basis of the variable-temperature profile of its 31P NMR
spectra (Figure 6). As a matter of fact, already, at 0 °C, two
partially superimposed broad resonances were detected at 147.9
and 147.8 ppm, the integrated areas of which were very similar.
At -40 °C, the two resonances were completely superimposed,
and at -80 ° C, two well-separated signals were detected at
154.4 and 150.3 ppm, the integrated areas of which, respectively,
were in the ratio 65:35. The above-described spectral pattern is
J. Org. Chem, Vol. 71, No. 13, 2006 4947

Iuliano et al.
FIGURE 9. Representation of 3 corresponding to NOE data.
FIGURE 11. Representation of 1 corresponding to NOE data.
mol for 3. The equilibrium is strongly shifted toward one
diastereoisomer in the case of 3, whereas a 1:1 ratio of the two
forms is found for 2.
Dependence of the Screw Sense on the Solvent. The NMR
data did not allow us to gain any insight into the tropos nature
of 1, which was ascertained in a different way.
Preliminary results showed that the use of 1 as a chiral ligand
in the copper-catalyzed addition of diethylzinc to chalcone gave
moderate ee’s of the product having an S absolute configura-
tion.19 In an attempt to improve the extent of the asymmetric
induction, different reaction conditions were screened. As far
as the reaction solvent was concerned, we observed a reverse
asymmetric induction in passing from toluene, Et2O, and CH2-
Cl2 to THF.19
FIGURE 10. 1D NOE spectra (600 MHz, C6D6, 25 °C) of 1
corresponding to the excitation at: (a) 7.37 ppm and (b) 7.31 ppm.
two acetyl functions, whereas Hb is directed toward the C12
site and partially directed at the external of the cholestanic plane.
Remarkably different NOE dipolar interactions of Ha and Hb
are in keeping with a strong degree of conformational prefer-
ence, as expected on the basis of the presence of a largely
prevalent stereoisomeric form.
This was judged a very unusual result, perhaps due to a
change of screw sense of the biphenyl moiety in passing from
toluene, acetonitrile (ACN), etc. to THF because the sense of
asymmetric induction in the reaction promoted by bile acid-
based biaryl phosphite depended on the absolute configuration
of the biaryl moiety. To verify this hypothesis, a CD spectrum
of 1 in THF solution was measured. This CD spectrum (Figure
12) shows in the wavelength region of the biphenyl absorptions
two negative Cotton effects at 280 nm (∆ꢀ -0.4) and at 240
nm (∆ꢀ -1.5), suggesting a prevalent P-torsion for the biphenyl
unit of 1. The lower intensity of these CD bands with respect
to those observed in the spectrum measured on the ACN solution
can be attributed both to a lower prevalence of one sense of
twist, which should explain the lower ee obtained using THF
as reaction solvent,19 and to a different dihedral angle between
the two aromatic rings in passing from ACN to THF solution.
Anyway, the dependence of the screw sense of the biphenyl
unit of 1 on the solvent points out its tropos nature and
represents an unusual behavior, found, to the best of our
knowledge, only in very few cases20 and never observed with
biphenyl phosphites.21 In addition, this happens only in the case
of phosphite 1: in fact, the sense of twist of the biphenyl unit
The 31P NMR spectrum of 1 showed only one resonance
between 25 and -80 °C (Figure S2, Supporting Information),
the presence of which could be interpreted as being due to a
single diastereoisomer or two rapidly interconverting stereo-
isomeric forms, with a very high prevalence of one of them.
Dipolar interaction patterns detected by 1D NOE measurements
unequivocally pointed out the presence of a largely prevalent
1
conformation. As a matter of fact, in the H NMR spectrum,
the two aromatic protons of 1, adjacent to the phosphite oxygen
atoms, showed well-separated doublets centered at 7.31 ppm,
named Hb, and at 7.37 ppm, named Ha. The proton at 7.31
ppm produced NOE effects (Figure 10b) only with the side-
chain protons H22 and H23, in addition to a relevant effect on
H17. A very low dipolar interaction is also detected at the H12
frequency. The other aromatic proton centered at 7.37 ppm
(Figure 10a) originated dipolar interactions with completely
different cholestanic protons. As a matter of fact, relevant effects
were measured at the protons H2 and H4, which are in
pseudoaxial position; a dipolar interaction was also detected at
the H9 frequency and on the acetyl group. Therefore, a largely
prevailing conformation of 1 was detected in solution, in which
the biphenyl plane and the cholestanic skeleton are almost
perpendicular, as depicted in Figure 11.
(18) Binsch, G. In Band-Shape Analysis in Dynamic Nuclear Magnetic
Resonance Spectroscopy; Jackman, L. M., Cotton, F. A., Eds.; Academic
Press: New York, 1975; pp 45-81.
(19) The reactions were performed under the following conditions:7
1
These results definitively point out the tropos nature17 of
phosphites 2 and 3. They exist in solution as interconverting
M-P diastereoisomeric mixtures, and the interconversion barrier
has been evaluated on the basis of the variable-temperature
NMR measurements,18 at about 15 kcal/mol for 2 and 18 kcal/
mol of chalcone, 1.5 mol of ZnEt2, ligand-to-copper ratio of 1.2, Cu(OTf)2
as copper salt (2.5% mol), temperature of -50 °C. Using toluene as solvent,
(S)-1,3-diphenylpentan-1-one was obtained in 89% yield and 44% ee. Using
THF as reaction solvent, (R)-1,3-diphenylpentan-1-one was obtained in 55%
yield and 35% ee. Work, aimed at optimizing reaction conditions, is in
progress. These results together with some others concerning the use of
different biphenyl phosphites of bile acids as chiral ligands will be reported
in due course.
(17) Oki, M.; Yamamoto, G. Bull. Chem. Soc. Jpn. 1971, 44, 266-270.
Oki, M. Top. Stereochem. 1983, 14, 1-81.
(20) Eguchi, T.; Kondo, K.; i Kakinuma, K.; Uekusa, H.; Ohashi, Y.;
Mizoue, K.; Qiao, Y.-F. J. Org. Chem. 1999, 64, 5371-5376.
4948 J. Org. Chem., Vol. 71, No. 13, 2006

Synthesis of Bile Acid-Based Biphenyl Phosphites
THF. The achievement of a bile acid-based biphenyl phosphite
having opposite screw sense depending on the solvent represents
an important result, as far as its use as a chiral ligand in the
copper-catalyzed conjugate addition of diethylzinc to enones.
In fact, the tropos nature of phosphite 1, joined to a low
interconversion M-P barrier of its biphenyl moiety, which
determines the dependence of its sense of twist on the solvent,
will allow the different enantiomers of the same product to be
obtained using the same chiral inducer, simply by changing the
reaction solvent.
Experimental Section
General experimental details can be found in the Supporting
Information.
Methyl 3r-Acetyloxy-7-oxo-12r-hydroxy-5â-cholan-24-oate,
10. A solution of 6 (5.2 g, 11.2 mmol), NBS (1.25 equiv), and
water (70 mL) in acetone (100 mL) was stirred overnight at room
temperature. The solvent was evaporated in vacuo, and the product
was dissolved in CH2Cl2. The organic layer was washed with brine
and dried over anhydrous Na2SO4. Evaporation of the solvent in
vacuo followed by purification by flash chromatography (SiO2, CH2-
Cl2-acetone, 95:5) gave 3.2 g (60% yield) of pure product.
Mp: 166-168°C; [R]26D) +14.0 (c ) 1.05, CH2Cl2). 1H NMR
(200 MHz, CDCl3, δ): 0.69 (s, 3H), 0.98 (d, J ) 6.0 Hz), 1.18 (S,
3H), 2.04 (s, 3H), 0.8-2.5 (m, 24H), 2.85 (dd, J1 ) 7 Hz, J2 ) 6
Hz, 1H), 3.67 (s, 3H), 4.02 (m, 1H), 4.68 (m, 1H). 13C NMR (50
MHz, CDCl3, δ): 13.1, 17.7, 21.5, 23.1, 24.5, 26.2, 27.8, 29.5,
31.1, 31.3, 33.4, 34.0, 34.9, 35.1, 36.2, 41.0, 45.4, 46.0, 46.8, 46.9,
49.7, 51.7, 72.3, 73.1, 170.8, 174.8, 211.3. IR (KBr, cm-1): 3552,
2950, 2871, 2358, 2343, 1738, 1721, 1700, 1436, 1380, 1365, 1260,
1170, 1025. Anal. Calcd for C27H42O6: C, 70.10; H, 9.15; O, 20.75.
Found: C, 69.85; H, 9.20.
Methyl 3r,12r-Diacetyloxy-7-oxo-5â-cholan-24-oate, 11. A
solution of 10 (2.2 g, 4.75 mmol), acetic anhydride (3 equiv), Et3N
(1.5 equiv), and catalytic DMAP in dry THF was stirred at room
temperature overnight. The solvent was evaporated in vacuo, and
the product was dissolved in CH2Cl2. The organic layer was washed
with a 10% HCl solution, saturated NaHCO3 solution, and water
in that order, then dried over anhydrous Na2SO4. Evaporation of
the solvent gave 11 as a white solid (2.25 g, 4.46 mmol, 94% yield).
[R]26D ) +33.8 (c ) 1.47, CH2Cl2). 1H NMR (200 MHz, CDCl3,
δ): 0.71 (s, 3H), 0.79 (d, J ) 5.8 Hz, 3H), 1.15 (s, 3H), 1.96 (s,
3H), 2.19 (s, 3H), 1.0-2.5 (m, 23H), 2.84 (dd, J1 ) 6.6 Hz, J2 )
6.3 Hz, 1H), 3.64 (s, 3H), 4.65 (m, 1H), 5.08 (m, 1H). 13C NMR
(50 MHz, CDCl3, δ): 12.7, 17.8, 21.4, 21.5, 22.4, 23.0, 24.3, 26.3,
26.6, 27.7, 31.1, 31.2, 33.4, 33.8, 34.8, 34.9, 37.1, 42.2, 45.2, 45.3,
46.0, 47.0, 49.4, 51.7, 73.0, 74.9, 170.6, 170.7, 174.7, 211.3. IR
(KBr, cm-1): 2964.0, 2877.5, 1826.0, 1735.6, 1711.6. Anal. Calcd
for C29H44O7: C, 69.02; H, 8.79; O, 22.19. Found: C, 68.92; H,
8.85.
FIGURE 12. Absorption (dotted line) and CD (solid line) spectra of
1 in THF solution.
does not depend on the solvent in the case of phosphite 3, which
shows the same CD spectrum both in ACN and in THF, due to
the higher interconversion barrier.
Conclusions
The cholestanic moiety of cholic and deoxycholic acids was
capable of inducing a prevalent sense of twist to the biphenyl
phosphite moiety linked at the 3, 7, and 12 positions of the
steroidal backbone. The asymmetric induction exerted by the
bile acid system deeply depends on the position of the appended
biphenyl phosphite moiety. As a matter of fact, the CD analysis
showed that at room temperature a prevalent sense of twist of
the biphenyl unit is present in the case of 1 and 3, where the
biphenyl phosphite appendage is located at the more stereo-
chemically demanding 7 and 12 positions. In addition, the sense
of twist is opposite, being M for the biphenyl unit of 1 and P
for that of 3, as assayed by comparison of the experimental
CD spectra of 1 and 3 with the calculated CD spectrum for the
biphenyl phosphite fragment having P-torsion. By contrast, no
prevalence of one screw sense is observed, at room temperature,
in the case of phosphite 2, where the biphenyl phosphite moiety
is linked at the position 3 of the cholestanic backbone. The bile
acid moiety is capable of exerting asymmetric induction on the
sense of twist of the biphenyl unit of the biphenyl phosphite
appendage linked at the position 3 at low temperature (-80
°C), affording a prevalence (65:35) of one diastereoisomer on
the other. NMR analysis showed a high prevalence (90:10) of
the P diastereoisomer in the case of phosphite 3 and a very
large prevalence (>99%) of the M diastereoisomer in the case
of phosphite 1. The three bile acid-derived biphenyl phosphites
1-3 are all tropos species. The tropos nature of 2 and 3, which
show an interconversion M-P barrier of 15 and 18 kcal/mol,
respectively, was ascertained by variable-temperature NMR
measurements. Phosphite 1 showed an unusual dependence of
the sense of twist of the biphenyl moiety on the solvent that
definitively pointed out its tropos nature: the equilibrium M-P
is shifted toward the M form in ACN and toward the P form in
Methyl 3r,12r-Diacetyloxy-7r-hydroxy-5â-cholan-24-oate,
12. A solution of 11 (1.89 g, 3.75 mmol), NaBH4 (0.22 g, 5.25
mmol), and dry THF (4 mL) in 20 mL of methanol was stirred at
room temperature, and the reaction was followed by TLC. After
disappearance of the starting material, the solvent was evaporated
in vacuo, and the product was dissolved in CH2Cl2. The organic
layer was washed with NaHCO3, brine, and dried over anhydrous
Na2SO4. Evaporation of the solvent followed by chromatographic
purification (SiO2, CH2Cl2-acetone, 96:4) gave 12 as a white solid
(1.24 g, 2.45 mmol, 65% yield).
Mp: 145-146°C. [R]24D ) +71.9 (c ) 1.01; CH2Cl2). 1H NMR
(200 MHz, DCl3, δ): 0.72 (s, 3H), 0.79 (d, J ) 5.8 Hz, 3H), 0.87
(s, 3H), 1.97 (s, 3H), 2.06 (s, 3H), 0.9-2.34 (m, 25H), 3.64 (s,
3H), 3.85 (m, 1H), 4.54 (m, 1H), 5.07 (m, 1H). 13C NMR (50 MHz,
CDCl3, δ): 12.2, 17.4, 21.4, 21.4, 22.5, 22.9, 25.4, 26.7, 27.2, 27.6,
30.7, 30.9, 34.3, 34.5, 34.6, 35.2, 39.2, 41.1, 43.4, 45.0, 47.4, 51.5,
68.0, 74.2, 75.4, 170.5, 170.6, 174.5. IR (KBr, cm-1): 3545.8,
(21) A dependence of the tropo-inversion kinetics on the solvent has
been found in the case of the DABN-BIPHEP-Rh complex: Mikami,
K.; Kataoka, S.; Yusa, Y.; Aikawa, K. Org. Lett. 2004, 6, 3699-3701.
J. Org. Chem, Vol. 71, No. 13, 2006 4949

Iuliano et al.
2941.7, 2874.3, 1747.8, 1782.7, 1715.8. Anal. Calcd for
C29H46O7: C, 68.74; H, 9.15; O, 22.10. Found: C, 68.85; H, 9.07.
Preparation of the Phosphites: Representative Procedure.
A warm solution (60°C) of 2,2′-biphenol (382 mg, 2.05 mmol) in
dry toluene (25 mL) was added in 5 min to a cooled solution
(-60°C) of PCl3 (184.5 µL, 2.05 mmol) and Et3N (587.6 µL, 4.1
mmol), in dry toluene (5 mL). After 2 h of stirring, the reaction
mixture was warmed to room temperature and filtered under argon
atmosphere. The solution was dropwise added to a solution of
DMAP (0.095 g, 0.78 mmol) and Et3N (1.05 mL, 7.29 mmol) in
dry toluene (50 mL) at -60 °C over 2 h. The bile acid derivative
(2.05 mmol) was then added, and the mixture was allowed to warm
to room temperature and stirred for 20 h. After removing the solvent
at reduced pressure, the crude product was purified by column
chromatography (SiO2, CH2Cl2-acetone, 96:4), affording the pure
phosphite.
129.6, 130.2, 131.5, 131.6, 131.6, 131.7, 131.8, 133.0, 150.4, 150.5,
150.7, 150.8, 165.8, 173.6. 31P NMR (121 MHz, benzene-d6, δ):
142.3. IR (KBr, cm-1): 2946, 2866.3, 1738.1, 1712.6, 1601.4,
1583.8, 1567.7, 1498.8, 1476.0, 1499.9, 1435.7, 1370.3, 1328.4,
1272.3, 1248.3, 1186.6, 1112.1, 1010.0, 992.0, 894.7, 764.0, 712.0.
Anal. Calcd for C45H56O7P: C, 73.05; H, 7.63; O, 15.14; P, 4.19.
Found: C, 73.12; H, 7.61; P, 4.18.
Methyl 3r,12r-Diacetyloxy-7r-(biphenyl-2,2′-diyl)phosphite-
5â-cholan-24-oate, 3. 0.49 g (0.68 mmol, 35%).
1
Mp: 65-67°C. [R]25 ) +35.5 (c ) 1.09, CH2Cl2). H NMR
D
(200 MHz, benzene-d6, δ): 0.58 (s, 3H), 0.62 (s, 3H), 0.96 (d, J )
5.9 Hz, 3H), 1.78 (s, 3H), 1.83 (s, 3H), 0.54-2.27 (m, 24H), 3.41
(s, 3H), 4.37 (m, 1H), 4.70 (m, 1H), 5.23 (m, 1H), 6.99-7.35 (m,
8H). 13C NMR (50 MHz, benzene-d6, δ): 12.4, 17.7, 20.7, 21.2,
22.4, 23.2, 23.3, 25.5, 27.1, 27.5, 27.8, 31.1, 31.2, 34.0, 34.5, 34.9,
35.0, 35.4, 37.3, 39.7, 41.2, 43.0, 45.3, 47.7, 50.9, 73.1, 73.5, 74.0,
75.1, 122.5, 122.6, 125.0, 125.2, 126.3, 129.2, 130.2, 131.8, 150.1,
169.5, 169.6, 173.7. 31P NMR (121 MHz, benzene-d6, δ): 153.8
(major diastereoisomer), 154.7 (minor diastereoisomer). IR (KBr,
cm-1): 2945.5, 1733.9, 1498.9, 1475.9, 1436.1, 1377.9, 1249.6,
1097.2, 1024.3, 892.1, 851.5, 770.6, 702.1, 602.2, 518.4. Anal.
Calcd for C42H56O9P: C, 68.55; H, 7.67; O, 19.57; P, 4.21.
Found: C, 68.42; H, 7.69; P, 4.19.
Methyl 3R-Acetyloxy-12R-(biphenyl-2,2′-diyl)phosphite-5â-
cholan-24-oate, 1. 1.1 g (1.66 mmol, 76%).
Mp: 42-43°C. [R]25D ) +47.22 (c ) 1.025, CH2Cl2). 1H NMR
(200 MHz, benzene-d6, δ): 0.55 (s, 3H), 0.82 (s, 3H), 1.18 (d, J )
6.1 Hz, 3H), 1.80 (s, 3H), 0.78-2.33 (m, 26H), 3.42 (s, 3H), 4.66
(m, 1H), 4.92 (m, 1H), 7.0-7.5 (m, 8H). 13C NMR (50 MHz,
benzene-d6, δ): 12.4, 17.8, 17.8, 21.0, 23.0, 23.8, 26.2, 26.9, 27.3,
27.8, 28.9, 29.0, 31.2, 31.3, 32.6, 33.6, 34.3, 35.2, 36.0, 36.0, 41.9,
46.6, 46.7, 46.8, 47.8, 51.0, 74.1, 78.5, 78.9, 122.5, 125.2, 125.3,
125.6, 128.3, 129.2, 130.4, 131.9, 133.9, 150.2, 150.3, 150.5, 150.6,
169.6, 173.8. 31P NMR (121 MHz, benzene-d6, δ): 154.8. IR (KBr,
cm-1): 2934.3, 1734.3, 1247.7, 1027.6, 895.5. Anal. Calcd for
C40H54O7P: C, 70.88; H, 8.03; O, 16.52; P, 4.57. Found: C, 71.02;
H, 8.01; P, 4.55.
Acknowledgment. This work was supported by the Uni-
versity of Pisa, MIUR (Project “High performance separation
systems based on chemo- and stereoselective molecular recogni-
tion” grant 2005037725). We thank Dr. Federica Balzano for
skillful execution of NMR spectra. A.I. is grateful to Dr. Michele
Claps (Universita` della Basilicata) for the TDDFT CD calcula-
tions.
Methyl 3r-(Biphenyl-2,2′-diyl)phosphite-12r-benzoyloxy-5â-
cholan-24-oate, 2. 1.13 g (1.56 mmol, 70%).
Mp: 43-45°C. [R]18D ) -69.58 (c ) 1.075, CH2Cl2). 1H NMR
(200 MHz, benzene-d6, δ): 0.65 (s, 3H), 0.74 (s, 3H), 1.05 (d, J )
5.8 Hz, 3H), 0.62-2.12 (m, 26H), 3.36 (s, 3H), 4.21 (m, 1H), 5.59
(m, 1H), 6.97-7.27 (m, 11H), 8.34 (m, 2H). 13C NMR (50 MHz,
benzene-d6, δ): 12.7, 17.7, 22.9, 22.9, 23.7, 26.2, 26.3, 27.0, 27.6,
29.6, 31.0, 33.8, 34.8, 35.1, 35.6, 35.9, 42.0, 45.7, 48.3, 50.5, 50.9,
75.7, 75.8, 76.2, 122.2, 122.3, 125.0, 125.6, 128.3, 128.9, 129.3,
Supporting Information Available: General experimental
details and 31P NMR spectra of 1 and 3 at variable temperature.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0606453
4950 J. Org. Chem., Vol. 71, No. 13, 2006