Structural optimization of enantiopure 2-cyclialkylamino-2-aryl-1,1- diphenylethanols as catalytic ligands for enantioselective additions to aldehydes

Article abstract of DOI:10.1021/jo800615d

(Chemical Equation Presented) The structural optimization of a family of modular, enantiopure β-amino alcohol ligands with a common 2-amino-2-aryl-1,1-diphenylethanol skeleton, whose stereogenicity was introduced through the Jacobsen epoxidation of 1,1-diphenyl-2-arylethylenes, has led to the identification of a small set of optimal catalysts with enhanced activity and enantioselectivity in the addition of alkylzinc and arylzinc reagents to aldehydes. Criteria for the discrimination between apparently analogous, highly enantioselective ligands are proposed.

Full text of DOI:10.1021/jo800615d

Structural Optimization of Enantiopure
2-Cyclialkylamino-2-aryl-1,1-diphenylethanols as Catalytic Ligands
for Enantioselective Additions to Aldehydes
Sergi Rodr´ıguez-Escrich,† Katamreddy Subba Reddy,‡ Ciril Jimeno,† Gisela Colet,†
Carles Rodr´ıguez-Escrich,† Llu´ıs Sola`,† Anton Vidal-Ferran,†,§ and Miquel A. Perica`s*,†,‡
Institute of Chemical Research of Catalonia (ICIQ), AV. Pa¨ısos Catalans 16, E-43007 Tarragona, Spain,
Department of Organic Chemistry, UniVersity of Barcelona, E-08028 Barcelona, Spain, and Catalan
Institution for Research and AdVanced Studies (ICREA), E-08010 Barcelona, Spain
mapericas@iciq.es
ReceiVed March 26, 2008
The structural optimization of a family of modular, enantiopure ꢀ-amino alcohol ligands with a common
2-amino-2-aryl-1,1-diphenylethanol skeleton, whose stereogenicity was introduced through the Jacobsen
epoxidation of 1,1-diphenyl-2-arylethylenes, has led to the identification of a small set of optimal catalysts
with enhanced activity and enantioselectivity in the addition of alkylzinc and arylzinc reagents to aldehydes.
Criteria for the discrimination between apparently analogous, highly enantioselective ligands are proposed.
Introduction
Within this approach, exploration of diversity space by means
of small, focused ligand libraries becomes straightforward and
the subsequent, benchmark-guided structural optimization results
are accelerated.
Some years ago, we proposed the synthesis of modular
ꢀ-amino alcohol ligands from synthetic yet enantiopure epoxides
prepared through the Sharpless2 or Jacobsen3 epoxidations.
Work in this field has led to the preparation of four regioisomeric
families of ligands, as depicted in Figure 1. The absolute
stereochemistry of these molecules is fixed in the preparation
Amino alcohols are among the most useful ligands for
asymmetric catalysis because either on their own or in the form
of their derivatives (oxazaborolidines, bis(oxazolines), phos-
phinooxazolines) they can effectively act as catalysts for a great
variety of enantioselective reactions. However, many of them
are still obtained from natural products, and fine-tuning of their
structures for optimal catalytic behavior is not always easy.1
In response to this difficulty, the synthesis of new ligands
based on achiral precursors and involving processes amenable
to parallel synthesis appears as a most convenient alternative.
(2) For reviews, see: (a) Katsuki, T.; Mart´ın, V. S. Org. React. 1996, 48,
1–299. (b) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH Publishers: New York, 1993; pp 101-158. (c) Katsuki, T.
In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer-Verlag: Berlin, 1999; Vol. II, pp 621-648.
† Institute of Chemical Research of Catalonia.
‡ University of Barcelona.
§ ICREA.
(3) (a) Jacobsen E. N. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
VCH Publishers: New York, 1993; pp 1159-202. (b) Jacobsen, E. N.; Wu, M. H.
In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer-Verlag: Berlin, 1999; Vol. II, pp 649-677.
(1) (a) Chiral Auxiliaries and Ligands in Asymmetric Synthesis; Seyden-
Penne, J., Ed.; John Wiley & Sons: New York, 1995. (b) Blaser, H. U. Chem.
ReV. 1992, 92, 935.
5340 J. Org. Chem. 2008, 73, 5340–5353
10.1021/jo800615d CCC: $40.75 2008 American Chemical Society
Published on Web 06/13/2008

Catalytic Ligands for EnantioselectiVe Additions to Aldehydes
SCHEME 1. Preparation of 2-Piperidino-1,1,2-
triphenylethanol, 1a
triphenylethylene: Jacobsen epoxidation followed by regiose-
lective and stereospecific ring opening of the enantiopure
triphenyloxirane11 with piperidine yields the desired amino
alcohol in a straightforward manner. Initial efforts devoted to
the optimization of the amino moiety were circumscribed to
cyclic, six-membered amines using the enantioselective ethy-
lation of aldehydes7a as a benchmark reaction. Working on the
enantioselective methylation of aldehydes,7b it could also be
established that 1a was a far more active catalyst as compared
to structural analogs containing acyclic dialkylamino sub-
stituents.7b However, no systematic approach had been tackled so
far concerning an in-depth optimization of the structure of amino
alcohols analogous to 1a for catalytic applications.
Given the interest in 1a for catalytic enantioselective
arylation,9j we decided to undertake a systematic exploration
of variations in its structure that could lead to even more efficient
and enantioselective ligands. Bearing in mind the parallelism
recorded so far in the catalytic activity displayed by 1a in
ethylation, methylation, and arylation, we decided to use the
experimentally simpler ethylation reaction as a benchmark for
the optimization process.
The optimization procedure followed has been represented
in Figure 2. It is based in preserving the diphenylcarbinol
moiety, whose beneficial characteristics in catalysis are well-
known,12 while sequentially exploring the influence of the amino
and the skeletal aryl moieties. The best hits obtained by this
procedure will be eventually fine-tuned, focusing on the amino
moiety.
This project involved as a requisite the synthesis by Jacobsen
epoxidation of a full set of new 2-aryl-1,1-diphenylethylene
oxides with aryl groups covering a wide range of electronic
and steric diversity.
FIGURE 1. Structural types of ꢀ-amino alcohols developed at our
research group from enantiopure Sharpless (Types I and II) and
Jacobsen (Types III and IV) epoxides.
of the precursor epoxides and can be predictably selected. Then,
regioselective and stereospecific ring opening with amines yields
the enantiopure amino alcohols. In this way, type I4 and II5
ligands are prepared via Sharpless epoxidation, whereas type
III6 and IV7 ligands stem from Jacobsen epoxidation. All of
them are fully modular and possess the following common
features of structural diversity: the skeletal groups (Ar and R′),
coming from the starting olefins, the dialkylamino groups,
arising from epoxide ring-opening steps, and in the cases of
type I and II ligands, the O-protecting group R′′.
The role of the different modules in the control of catalytic
activity and enantioselectivity has been analyzed for type I and
type II ligands in detail, with the finding that important catalytic
characteristics can be traced to the nature of the dialkylamino
substituent and to the steric bulk of the alkoxy group.4,5,8
Second-generation ligands arising from type I amino alcohols,
such as bis(oxazolines), oxazaborolidines, amino thiols, and
imino alcohols (Schiff bases), have also been prepared in our
group and successfully submitted to structural optimization for
application in a variety of catalytic enantioselective reactions.9
2-Piperidino-1,1,2-triphenylethanol, 1a10 (Scheme 1), a type
IV ligand synthesized in our group, turned out to be one of the
most successful catalysts for the highly enantioselective addition
of alkylzinc7 and arylzinc9i reagents to aldehydes. It is, in fact,
one of the readily available ꢀ-amino alcohol structures, since it
can be prepared in two simple steps from commercially available
Herein we report on the different stages of this structural
optimization process and on analysis methods for the discrimi-
nation between ligands of similar, very high efficiency.
Results and Discussion
Jacobsen Epoxidation of 1,1-Diphenyl-2-arylethylenes. To
ensure that a maximum of electronic and steric diversity was
(9) (a) Puigjaner, C.; Vidal-Ferran, A.; Moyano, A.; Pericas, M. A.; Riera,
A. J. Org. Chem. 1999, 64, 7902. (b) Jimeno, C.; Vidal-Ferran, A.; Moyano,
A.; Perica`s, M. A.; Riera, A. Tetrahedron Lett. 1999, 40, 777. (c) Jimeno, C.;
Reddy, K. S.; Sola`, L.; Moyano, A.; Perica`s, M. A.; Riera, A. Org. Lett. 2000,
2, 3157. (d) Pasto´, M.; Riera, A.; Perica`s, M. A. Eur. J. Org. Chem. 2002, 2337.
(e) Jimeno, C.; Moyano, A.; Perica`s, M. A.; Riera, A. Synlett 2001, 1155. (f)
Perica`s, M. A.; Puigjaner, C.; Riera, A.; Vidal-Ferran, A.; Go´mez, M.; Jime´nez,
F.; Muller, G.; Rocamora, M. Chem. Eur. J. 2002, 8, 4164. (g) Fontes, M.;
Verdaguer, X.; Sola`, L.; Vidal-Ferran, A.; Reddy, K. S.; Riera, A.; Perica`s, M. A.
Org. Lett. 2002, 4, 2381. (h) Ferrer, S.; Pasto´, M.; Rodr´ıguez, B.; Riera, A.;
Perica`s, M. A. Tetrahedron: Asymmetry 2003, 14, 1747. (i) Rodr´ıguez, B.; Pasto´,
M.; Jimeno, C.; Perica`s, M. A. Tetrahedron: Asymmetry 2006, 17, 151. (j) Fontes,
M.; Verdaguer, X.; Sola`, L.; Perica`s, M. A.; Riera, A. J. Org. Chem. 2004, 69,
2532. (k) Popa, D.; Puigjaner, C.; Go´mez, M.; Benet-Buchholz, J.; Vidal-Ferran,
A.; Perica`s, M. A. AdV. Synth. Cat. 2007, 349, 2265.
(4) (a) Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera, A. J. Org. Chem.
1997, 62, 4970. (b) Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron Lett. 1997, 38, 8773.
(5) Jimeno, C.; Pasto´, M.; Riera, A.; Perica`s, M. A. J. Org. Chem. 2003, 68,
3130.
(6) (a) Reddy, K. S.; Sola`, L.; Moyano, A.; Perica`s, M. A.; Riera, A. J. Org.
Chem. 1999, 64, 3969. (b) Reddy, K. S.; Sola`, L.; Moyano, A.; Perica`s, M. A.;
Riera, A. Synthesis 2000, 165.
(7) (a) Sola`, L.; Reddy, K. S.; Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.;
´
Riera, A.; Alvarez-Larena, A.; Piniella, J.-F. J. Org. Chem. 1998, 63, 7078. (b)
Garc´ıa-Delgado, N.; Fontes, M.; Perica`s, M. A.; Riera, A.; Verdaguer, X.
Tetrahedron: Asymmetry 2004, 15, 2085. (c) Garc´ıa-Delgado, N.; Reddy, K. S.;
Sola`, K. S.; Riera, A.; Perica`s, M. A.; Verdaguer, X. J. Org. Chem. 2005, 70,
7426.
(10) Ligand 1a is now commercially available from Aldrich and Acros.
(11) Brandes, B. D.; Jacobsen, E. N. J. Org. Chem. 1994, 59, 4378.
(12) Braun, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 519–522.
(8) Jimeno, C.; Vidal-Ferran; A.; Perica`s, M. A. Org. Lett. 2006, 8, 3895.
J. Org. Chem. Vol. 73, No. 14, 2008 5341

Rodr´ıguez-Escrich et al.
FIGURE 2. Benchmark-guided synthesis of amino alcohol ligands.
FIGURE 3. Hammett plot of the Jacobsen epoxidation of para-
substituted 1,1-diphenyl-2-arylethylenes.
SCHEME 2. Jacobsen Epoxidation of Trisubstituted Olefins
with Different Stereoelectronic Modulation in One Aromatic
Ring (Ar) and a Fixed Diphenylmethylene Moietya
obtained in g99% ee, either after the reaction or (for
compounds 2, 3, 10, and 11) by simple recrystallization from
hexanes (Table 1).
When we analyzed the results obtained for the epoxidation
of a set of electronically diverse triarylethylenes, we realized
that we might be able to correlate the enantioselectivity of the
catalytic reaction (in the form of enantiomeric ratio of the
epoxides before recrystallization) with the structure of the tri-
substituted olefin/epoxide. A Hammett plot of the log of the
ratio of epoxide enantiomers against σp values of the para
substituents in epoxides 1, 4, 5, 6, and 9 gave a perfect linear
fit, with slope F ) 0.38 (Figure 3). Electron-withdrawing
substituents in the alkene favor the epoxidation and give higher
enantioselectivities than the electron-donating ones. The linearity
of the Hammett plot ultimately indicates that the variation of
the enantioselectivity throughout the considered series of olefins
reflects changes in the relative energies of the corresponding
transition states induced by the electronic nature of the para
substituent in the aryl group.
Previous studies of electronic effects on the Jacobsen epoxi-
dation were restricted to the catalyst itself.15 Jacobsen et al.
analyzed the effect of the substituents on the salicylaldehyde
moiety of the salen ligand and showed linear free-energy
correlations for several olefin substrates. For a given substrate,
the enantioselectivity achieved with the different catalysts
displayed a linear relationship with the Hammett parameter σp
of the substituent on the para position of the phenoxy group in
the salen moiety. Electron-donating substituents stabilize the
Mn(V) oxo complex, generating a relatively milder oxidant
which, according to the Hammond postulate, transfers oxygen
to the alkene via a more product-like transition state. Later
transition states favor a smaller separation between substrate
and catalyst and facilitate a better differentiation of the diaster-
eomeric transition states, thus leading to higher degrees of
enantioselectivity.15 A recent report has complemented those
studies by establishing quantitative correlations between modi-
fied Hammett parameters (σ+) with the electronic properties
of the catalyst and the transition state geometries,16 but to our
knowledge there are no previous quantitative correlations
between the enantioselectivity of the reaction and the electronic
properties of the substrate olefins.17,18
a See details in Table 1.
TABLE 1. Jacobsen Epoxidation of Trisubstituted Olefins
compound
Ar substituent
yield (%)a
ee (%)b
1c
2
3
Ph
97
77
95
>99
93
92
96
27
75
92 (>99)
88 (>99)
83 (>99)
96 (>99)
93 (>99)
90 (>99)
94 (>99)
95 (>99)
94 (>99)
84 (>99)
77 (>99)
m-ClC6H4
o-ClC6H4
p-NO2C6H4
p-FC6H4
p-MeOC6H4
2-Naphthyl
CH3
4
5d
6d
7
8
9
10
11
p-CH3C6H4
m-CH3C6H4
o-CH3C6H4
76
53
a Isolated yield. b Determined by HPLC with a chiral stationary phase.
In parentheses is the ee after recrystallization from hexanes. c See ref 7a.
d See ref 7c.
found in the triarylethylene skeleton of the target ligands, a
family of known olefins13 containing a diphenylmethylene
subunit and accommodating different electron-donating and
electron-withdrawing groups in the third aryl moiety were
selected. The presence in the starting olefins of a diphenylm-
ethylene moiety plays a double role for the purposes of this
investigation: Besides being the ultimate source of the diphe-
nylcarbinol moiety in the target amino alcohols, the symmetrical
substitution at one of the alkene termini suppresses stereochem-
ical problems at the olefination and epoxidation steps. After
submitting this set of trisubstituted alkenes to Jacobsen epoxi-
dation using standard conditions (Scheme 2),14 we were able
to isolate the corresponding oxiranes in excellent yields and
high enantioselectivities (Table 1) in a multigram scale. It is
important to point out that in all cases, the epoxide could be
(13) All olefins used as substrates in the present study are known compounds.
See Supporting Information for synthetic details and references.
(14) (a) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am.
Chem. Soc. 1990, 112, 2801. (b) Zhang, W.; Jacobsen, E. N. J. Org. Chem.
1991, 56, 2296. (c) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng,
L. J. Am. Chem. Soc. 1991, 113, 7063. (d) Jacobsen, E. N.; Wu, M. H. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer-Verlag: Berlin, 1999; Vol. II, pp 649-678.
As expected, the electronic effects described in the literature
for a series of catalysts (electron-donating substituents increase
the efficiency of the catalyst) are opposite to what we observe
in the triarylethylenes (electron-withdrawing substituents favor
5342 J. Org. Chem. Vol. 73, No. 14, 2008

Catalytic Ligands for EnantioselectiVe Additions to Aldehydes
SCHEME 3. Epoxide Opening with Secondary Amines To
Afford ꢀ-Amino Alcohols
CHART 1. Amino Alcohols Synthesized by Ring Opening
of Epoxides 1-11
FIGURE 4. Radical pathways for the formation of triarylethylene
oxides by Jacobsen epoxidation.
the epoxidation and lead to higher enantioselectivities). This is
in accordance with the reactivity-selectivity principle, since the
more electron-poor the oxidizing agent (or the more electron-
rich the alkene) the more reactive the system will be, with the
consequent erosion in the enantioselectivity of the process. As
far as the magnitude of these effects is concerned, the electronic
effects of the substituents on the alkene are less pronounced
than those produced by the substituents on the catalyst. A lower
F value is observed in our case (F ) 0.38) for the whole substrate
series with the standard Jacobsen catalyst compared with the F
value which is reported for isochromene with a series of catalysts
(F ) -1.37).15 This ultimately reflects that enantioselectivities
(ranging from 92% to >99% ee) are not so dramatically affected
along the alkene series, while the selectivity displayed by the
catalyst is much more strongly dependent on the nature of the
para substituent in the catalyst structure (22-96% ee for
isochromene15a).
As it has been mentioned already, the linearity in the Hammett
plot indicates that, in our case, the changes in enantioselectivity
should arise from changes in the electronic character of the
relevant transition states. Given the nonsymmetric substitution
of the olefin substrates in the present study, two possible
monoradicals, namely, A and B, may arise (see Figure 4). Our
working hypothesis was based in the assumption that the bis-
benzylic radical B would be preferentially formed, and therefore
the ee of the process would be governed by the first elementary
step, that is, the radical combination of the manganese oxide to
the monosubstituted end of the olefin. Considering that the
manganese atom suffers a global two-electron reduction, the
olefin has to contribute with one electron to this first step.
Consequently, electron-donating substituents will render more
reactive olefins which add to the manganese oxo complex in
earlier transition states, thus affording lower levels of enanti-
oselectivity. On the other hand, electron-withdrawing groups
attenuate the reactivity of the olefin, which as a result reacts
through later transition states affording higher enantioselectivi-
ties.
of epoxide with cyclic amines, was dictated by the progress of
the optimization process. Several cyclic secondary amines
(pyrrolidine, piperidine, 3,3-dimethylpiperidine, hexamethyl-
eneimine, and heptamethyleneimine) were used (Scheme 3). The
overrepresentation of piperidine-containing amino alcohols
reflects the results of the optimization process (see below), in
agreement with what is observed in the ꢀ-amino alcohol
catalysts previously designed by us.4,7 Despite its potential
interest,4b no R-substituted amines could be evaluated in the
optimization process because of their lack of reactivity in the
ring-opening reaction.
Preparation of Amino Alcohols. Ring opening of the ep-
oxides was carried out using Crotti’s conditions.19 The nature
of the prepared amino alcohols, i.e., the different combinations
(15) (a) Jacobsen, E. N.; Zhang, W.; Gu¨ler, M. L. J. Am. Chem. Soc. 1991,
113, 6703. (b) Palucki, M.; Finney, N. S.; Pospisil, P. J.; Gu¨ler, M. L.; Ishida,
T.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 948.
We have depicted the structures of the ꢀ-amino alcohols
synthesized in the course of this work in Chart 1 (amino alcohols
are designated by the same number as their parent epoxides
and a letter that indicates the cyclialkylamino fragment in their
structures).
The absolute configuration of the amino alcohols depicted
in Chart 1 was assigned as follows: For those derived from
triphenylethylene oxide (1a-e), the configuration is deduced
(16) Cavallo, L.; Jacobsen, H. J. Org. Chem. 2003, 68, 6202.
(17) For the Hammett correlation (σ+) to relative epoxidation rates of styrenes
by a chiral ruthenium-porphyrin catalyst, see: Zhang, R.; Yu, W.-Y.; Wong,
K.-Y.; Che, C.-M. J. Org. Chem. 2001, 66, 8145.
(18) For a qualitative correlation of enantioselectivity with the electronic
properties of the substrate in the epoxidation of styrenes catalyzed by a chiral
dioxirane, see: Hickey, M.; Goeddel, D.; Crane, Z.; Shi, Y. Proc. Nat. Acad.
Sci. U.S.A. 2004, 101, 5794.
J. Org. Chem. Vol. 73, No. 14, 2008 5343

Rodr´ıguez-Escrich et al.
TABLE 2. Preparation of Amino Alcohol by LiClO4-Mediated
Ring Opening of Triarylethylene Oxides with Secondary Amines
TABLE 3. Diethylzinc Additions to Benzaldehyde Catalyzed by
Amino Alcohols 1a-11a (Data for Optimal Ligands Appear Bold)
compound
amino group
yield (%)a
1ab
1b
1c
1d
1e
2a
2b
3a
4a
5a
6a
7a
8a
9a
10a
11a
piperidino
98
90
18
99
91
72
72
9
hexamethyleneimino
heptamethyleneimino
3,3-dimethylpiperidino
pyrrolidino
piperidino
hexamethyleneimino
piperidino
piperidino
piperidino
piperidino
piperidino
ligand
conversion (%)a
selectivity (%)a
ee (%)a
1ab
1b
1c
1d
1e
2a
2b
3a
5a
6a
7a
8a
9a
10a
11a
99
100
100
100
99
99
100
94
95
99
94
99
99
100
99
99
99
99
99
98
96
93
88
99
96
94
99
98
98
92
95
81
96
98
69
96
95
71
86
94
95
96
0
93
75
63
97
93
66
43
piperidino
piperidino
piperidino
piperidino
92
99
99
a Isolated yield. b See ref 7a.
a Determined by GC using a ꢀ-DEX capillary column. b See ref 7a.
from the known configuration (S) of the epoxide obtained with
the (S,S)-enantiomer of the Jacobsen catalyst and assuming that
the ring opening of the epoxide takes place with inversion of
configuration, as confirmed by X-ray diffraction of 1a.7a In all
other cases, configurations have been assigned by assuming that
the epoxidation of 2-aryl-1,1-diphenylethenes with the (S,S)-
enantiomer of the Jacobsen catalyst leads to the corresponding
S epoxides, as predicted by the empirical model developed by
Jacobsen,11 and that the ring opening of the epoxides with the
cyclic, secondary amines employed in this study takes place
with inversion of configuration. It is to be noted that the sign
of the enantioselectivity observed in carbonyl additions mediated
by amino alcohols 1a-f, 2a,b, and 3a-11a is fully consistent
with the assigned configurations.
Epoxide ring-opening reactions proceeded generally in good
to excellent yields (Table 2), except for epoxide 4, which proved
reluctant to react. In spite of harsh reaction conditions being
explored, the ring-opening product 4a could not be detected in
the reaction crudes. Lower yields were obtained when epoxides
with ortho substituents were used, and therefore amino alcohols
3a (o-Cl) and 11a (o-CH3) were isolated in only 9% and 43%
yield, respectively. When a specially hindered amine such as
heptamethyleneimine was used in combination with epoxide 1,
amino alcohol 1c was obtained in a low 18% as well. All other
examples, though, account for the usefulness of the ring-opening
process, which takes place with total regioselectivity and
inversion of the configuration at the stereocenter where the
amine attack takes place.
Benchmark-Guided Optimization of Ligands: Catalytic
Enantioselective Additions of ZnEt2. As already mentioned,
the choice of amino alcohol ligands in this study was driven by
the sequential optimization process that took place as outlined
in the Introduction (see Figure 2). In the first optimization step
triphenylethylene oxide was opened with several cyclic amines
to generate ligands 1a-1e, and the resulting amino alcohols
were benchmarked for enantioselectivity in the ethylation of
benzaldehyde. Since 1a turned out to be the optimal ligand in
this test, analogues of this structure where the nonphenyl aryl
group was systematically varied with respect to electronic and
steric effects (2a-11a) were prepared and evaluated. This
process converged again on 1a as the optimal combination of
triarylethylene skeleton and cyclialkylamino fragment. Finally,
the structural features of the second best hit in the first
optimization step (1b) were combined with those of the second
best hit in the second optimization step (2a), and amino alcohol
2b was prepared. The catalytic profile displayed by these ligands
in the diethylzinc addition to benzaldehyde (benchmark reaction)
is illustrated in Table 3. The conditions involved the use of 6
mol % of ligand in toluene at 0 °C.
As seen in the table, the first optimization step gave 1b
(containing a hexamethyleneimino group) as the second best
ligand, together with the reference ligand 1a. As for the second
step, the most promising results were provided by the introduc-
tion of a meta-chloro substituent (2a), which guided the third
and last step toward 2b, containing both the meta-chloro and
hexamethyleneimino moieties. Thus, a reduced set of optimal
ligands (1a, 1b, and 2b) arose from the optimization process
(with 2a as the fourth place candidate). However, the high
catalytic profile of all these ligands posed some problems for
the identification of the absolute best hit.
Although enantioselectivity is generally used as the most
important criteria for the selection of optimal ligands, differences
in catalytic activity between ligands with similar enantioselec-
tivity profiles have much deeper consequences on the practical
value and economical interest of the processes where they
participate. According to this idea, we decided to compare 1a,
1b, and 2a from the points of view of catalytic activity and of
enantioselectivity. Consequently, in order to gain a better insight
of the catalytic activity of the three best ligands, the diethylzinc
addition to benzaldehyde mediated by 1a, 1b and 2b was
monitored by in situ FTIR analysis. This technique uses an FTIR
probe based on attenuated total reflection (ATR) directly
immersed in the reaction media and records spectra of the
solution in contact with the probe at defined time intervals. It
has the advantages of being very simple to use and non invasive,
and allows following the process in real time. In the present
case, the addition reaction could be easily monitored following
the absorbance at 1710 cm-1, due to the characteristic stretching
vibration of the carbonyl group in benzaldehyde. Thus, the
decrease of the absorbance at this wavenumber is directly related
to the conversion of the starting aldehyde in the reaction media.
The plots of the normalized absorption of the CdO group of
benzaldehyde versus time are shown in Figure 5. Clear
differences in catalytic activity are found for the three ligands
5344 J. Org. Chem. Vol. 73, No. 14, 2008

Catalytic Ligands for EnantioselectiVe Additions to Aldehydes
FIGURE 5. Comparison of the catalytic activity of ligands 1a, 1b, and 2b in the addition of diethylzinc to benzaldehyde.
TABLE 4.
and 2b
Addition of Diethylzinc to Aldehydes Catalyzed by 1b
entries 1 and 6-10 for 1b and 1, 4, and 8 for 2b the results
obtained are comparable or superior to the ones displayed by
ligand 1a.7a
At first sight differences between both ligands are minimal,
but as illustrated in Table 4, they behave in a slightly different
manner depending on the substrate. Therefore, 1b gives
consistently high levels of stereoinduction (98% ee) in meta-
and para-substituted aromatic aldehydes (entries 6-10), whereas
2b is extremely enantioselective (99% ee, entry 4) in the
diethylzinc addition to o-methoxybenzaldehyde. For example,
enantiopure 1-aryl-1-propanols and, in particular, 1-(o-meth-
oxyphenyl)-1-propanol, are basic building blocks of a recently
discovered family of calcium receptor agonists.20
From a global perspective, the catalytic behavior of 1b and
2b in the enantioselective ethylation of aldehydes is very similar
to that of 1a, so that the results obtained using standard amounts
of ligand do not allow drawing definitive conclusions on the
existence of an optimal ligand within the considered set.
Therefore, we decided to push the catalytic profile of these
molecules to the limit by decreasing the catalyst loading to 0.5
mol %. Noteworthy, this is 1 order of magnitude below the
usual amount of chiral ligand normally employed in this type
of reaction. Under these conditions, a selection of aldehydes
was reacted with Et2Zn, and the results are summarized in
Table 5.
In general, ligand 1a proved superior in terms of conversion,
while the differences observed in enantioselectivity were not
significant in most of the cases studied. It is interesting to realize
that the more reactive, electron-poor substrates like p-trifluo-
romethylbenzaldehyde (entry 2) are completely converted
despite the very low amount of catalytic ligand used. As a
general trend, the differences between ligands are accentuated
when poorly reactive, electron-rich aldehydes are used as
substrates (entries 1 and 4-7). Thus, although these reactions
were not optimized for complete conversion, it is clear that
ligand 1b
conv ee
(%)a (%)a (%)a (%)a
ligand 2b
conv ee
entry
aldehyde (product)
1
2
3
4
5
6
7
8
benzaldehyde (12a)
o-fluorobenzaldehyde (12b)
o-tolualdehyde (12c)
o-methoxybenzaldehyde (12d)
m-fluorobenzaldehyde (12e)
m-tolualdehyde (12f)
m-methoxybenzaldehyde (12g)
p-fluorobenzaldehyde (12h)
p-tolualdehyde (12i)
p-methoxybenzaldehyde (12j)
cinnamaldehyde (12k)
heptanal (12 l)
3-phenylpropanal (12m)
2-ethylbutiraldehyde (12n)
(E)-R-methylcinnamaldehyde (12o)
>99
nd
>99
99
>99
99
>99
>99
>99
96
98
nd
97
97
97
98
98
98
98
98
nd
92
93
97
97
>99
>99
99
98
>99
97
>99
>99
>99
96
99
>99
99
98
95
96
99
97
97
97
98
97
96
85
84
86
96
94
9
10
11
12
13
14
15
nd
99
99
99
91
62
96
a Determined by GC using a ꢀ-DEX capillary column.
studied. Amino alcohol 1a exhibits the highest catalytic activity;
thus, when the addition reaction is catalyzed by ligand 1a,
benzaldehyde is completely consumed within 1 h. On the other
side, amino alcohol 2b is the less active ligand in the group; it
takes up to 3 h for total consumption of benzaldehyde when 2b
is used in the reaction. Ligand 1b, in turn, possesses an
intermediate activity, requiring 2 h for total benzaldehyde con-
sumption.
For comparison of the enantioselectivity induced by the three
ligands, 1b and 2b were tested in the ethylation of a representa-
tive family of aldehydes (the corresponding results for 1a have
been previously reported7a).
We have collected in Table 4 the conversions and enanti-
oselectivities recorded for the diethylzinc addition to the selected
family of aldehydes using ligands 1b and 2b. Remarkably, in
(19) (a) Chini, M.; Crotti, P.; Macchia, F. J. Org. Chem. 1991, 56, 5939. (b)
Chini, M.; Crotti, P.; Flippin, L. A.; Gardelli, C.; Giovanni, E.; Macchia, F.;
Pinesci, M. J. Org. Chem. 1993, 58, 1221.
(20) Shinagawa, Y.; Katsushima, T.; Nakagawa, T. PCT Int. Appl. WO
2002014259, 2002.
J. Org. Chem. Vol. 73, No. 14, 2008 5345

Rodr´ıguez-Escrich et al.
TABLE 5. Addition of Diethylzinc to Aldehydes Catalyzed by 1a,
1b, and 2b in the Presence of 0.5 mol % Ligand
addition to benzaldehyde was monitored by in situ FTIR for
the three ligands (Figure 6). Since the catalytic addition of
dimethylzinc is much slower than the addition of other alkyl
or aryl zinc reagents and the background, noncatalytic
reaction does not take place at a measurable rate, the reaction
represents an optimal test to compare the catalytic perfor-
mance of similar ligands. The addition reaction performed
at 0 °C mediated by ligand 1a proceeds with nearly total
conversion after 24 h, whereas for ligands 1b and 2b full
conversions are far from being achieved within the same
reaction time (64% for 1b and 39% for 2b respectively). It
is thus evident that ligand 1a presents a much higher catalytic
activity in comparison with ligands 1b and 2b.
Catalytic Enantioselective Arylation Reactions. Since the
asymmetric reduction of diaryl ketones to afford enantiopure
diarylmethanols is a difficult task due to the steric and
electronic similarities between the re and si faces of the
substrate,22 the catalytic enantioselective addition of aryl
fragments to aldehydes arises as the best method for the
preparation of this class of compounds.23 Although several
new reagents, additives, and catalysts have been developed
recently to substitute expensive diphenylzinc as a source of
phenyl groups,24–29 the formation and asymmetric addition
of the mixed species EtPhZn (prepared from ZnEt2 and
ZnPh2) introduced by Bolm is still a fast and simple way to
perform this particular transformation.27,9j Key to the success
of this methodology is the avoidance of highly reactive
diphenylzinc in the reaction medium. In this way, the
competitive, fast background addition of ZnPh2 and its
deletereous effects on enantioselectivity are efficiently sup-
pressed. Therefore, it is still of great interest to develop and
study new catalysts that can efficiently carry out this reaction
for particular substrates.
ligand 1a
ligand 1b
ligand 2b
conv
ee
conv
ee
conv
ee
entry
R
(%)a
(%)a
(%)a
(%)a
(%)a
(%)a
1
2
3
4
5
6
7
CH3
CF3
F
CH3O
H
63.9
99.1
69.1
44.5
85.7
49.7
77.0
94.9
95.8
94.6
94.6
95.4
94.9
94.7
56.3
99.0
60.1
23.0
81.6
50.1
71.7
94.2
94.5
93.8
94.3
95.1
94.7
93.7
44.4
97.8
53.0
23.1
60.0
39.1
61.0
93.0
93.9
93.6
92.6
93.7
93.7
92.9
t-Bu
Ph
a Determined by GC using a ꢀ-DEX capillary column.
electron-rich substrates represent the most stringent test for the
discrimination between highly active ligands.
Catalytic Enantioselective Additions of ZnMe2. Although
chiral 1-aryl ethanols are more important building blocks than
1-aryl propanols, they are usually prepared by asymmetric
ketone reduction rather than by enantioselective methyl addition.
This is basically due to the low reactivity of ZnMe2 as compared
to ZnEt2, and thus improving the performance of such a reaction
is of great practical interest.21 In a recent paper, we established
that the presence of cyclic amino groups in triarylethylene
derived amino alcohol ligands was crucial for the achievement
of high conversions and enantioselectivities in this reaction. In
particular, we found that ligand 1a was very useful for this
transformation, although methylations induced by this ligand
were still slow if compared with the corresponding ZnEt2
addition.7b According to this characteristic, the amino alcohol
promoted methylation of aldehydes appeared as an appropriate
benchmark for the systematic evaluation of the optimal ligands
1a, 1b, and 2b. In addition, the identification of new ligands
able to efficiently mediate the enantioselective methylation of
aldehydes is a matter of considerable interest. Thus, 1a, 1b,
and 2b were evaluated in the methylation of a representative
group of aldehydes, results being summarized in Table 6. These
reactions were carried out with a 10 mol % of catalyst loading
at room temperature to drive the reaction at a reasonable rate.
Still, 24 h were required to attain good conversions.
As it is readily seen, the behavior exhibited by 1a, 1b, and
2b in the methylation of aldehydes almost exactly reproduces
what is observed with the same ligands in the corresponding
ethylation reactions. Thus, the use of ligand 1a consistently leads
to higher conversions and enantioselectivities, and only ligand
1b shows comparable activity and enantioselectivity for the most
reactive p-trifluoromethylbenzaldehyde (entry 7). On the other
hand, ligand 2b turned out to be clearly inferior for the
asymmetric addition of ZnMe2 to aldehydes. This shows that
this particular addition reaction, characterized by higher activa-
tion energies, is more sensitive to structural variations in the
ligand than the corresponding ZnEt2 additions.
(22) Ohkuma, T.; Koizumi, M.; Ikehira, H.; Yokozawa, T.; Noyori, R. Org.
Lett. 2000, 2, 659, and references therein.
(23) For reviews on this topic, see: (a) Bolm, C.; Hildebrand, J. P.; Mun˜iz,
K.; Hermanns, N. Angew. Chem., Int. Ed. 2001, 40, 3284. (b) Schmidt, F.;
Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem. Soc. ReV. 2006, 35, 454.
(24) Arylboronic acids/ZnEt2: (a) Schmidt, F.; Rudolph. J.; Bolm, C. AdV.
Synth. Catal. 2007, 349, 703. (b) Wu, P.-Y.; Wu, H.-L.; Uang, B.-J. J. Org.
Chem. 2006, 71, 833. (c) Ito, K.; Tomita, Y.; Katsuki, T. Tetrahedron Lett. 2005,
46, 6083. (d) Ji, J.-X.; Wu, J.; Au-Yeung, T. T.-L.; Yip, C.-W.; Haynes, R. K.;
Chan, A. S. C. J. Org. Chem. 2005, 70, 1093. (e) Braga, A. L.; Lu¨dtke, D. S.;
Schneider, P. H.; Vargas, F.; Schneider, A.; Wessjohann, L. A.; Paixaˆo, M. W.
Tetrahedron Lett. 2005, 46, 7827. (f) Rudolph, J.; Hermanns, N.; Bolm, C. J.
Org. Chem. 2004, 69, 3997. (g) Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002,
124, 14850.
(25) Triarylboranes/ZnEt2: (a) Dahmen, S.; Lormann, M. Org. Lett. 2005,
7, 4597. (b) Rudolph, J.; Lormann, M.; Bolm, C.; Dahmen, S. AdV. Synth. Catal.
2005, 347, 1361. (c) Bolm, C.; Schmidt, F.; Zani, L. Tetrahedron: Asymmetry
2005, 16, 1367. (d) Bolm, C.; Zani, L.; Rudolph, J.; Schiffers, I. Synthesis 2004,
2173. (e) Rudolph, J.; Schmidt, F.; Bolm, C. AdV. Synth. Catal. 2004, 346, 867.
(26) Triarylboroxines/ZnEt2: (a) Wu, X.; Liu, X.; Zhao, G. Tetrahedron:
Asymmetry 2005, 16, 2299. (b) Jimeno, C.; Sayalero, S.; Fjermestad, T.; Colet,
G.; Maseras, F.; Perica`s, M. A. Angew. Chem., Int. Ed. 2008, 47, 1098.
(27) ZnPh2/ZnEt2: (a) Park, J. K.; Lee, H. G.; Bolm, C.; Kim, B. M. Chem.
¨
Eur. J. 2005, 11, 945. (b) Ozc¸ubukc¸u, S.; Schmidt, F.; Bolm, C. Org. Lett. 2005,
7, 1407. (c) Bolm, C.; Kesselgruber, M.; Hermanns, N.; Hildebrand, J. P.; Raabe,
G. Angew. Chem., Int. Ed. 2001, 40, 1488. (d) Bolm, C.; Hermanns, N.;
Kesselgruber, M.; Hildebrand, J. P. J. Organomet. Chem. 2001, 624, 157. (e)
Bolm, C.; Kesselgruber, M.; Grenz, A.; Hermanns, N.; Hildebrand, J. P. New.
J. Chem. 2001, 25, 13. (f) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Mun˜iz,
K. Angew. Chem., Int. Ed. 2000, 39, 3465.
The trends of catalytic activity for the optimal ligands
shown in Table 6 were made evident when the dimethylzinc
(28) ZnPh2: (a) Qin, Y.-C.; Pu, L. Angew. Chem., Int. Ed. 2006, 45, 273. (b)
Ko, D.-H.; Kim, K.-H.; Ha, D.-C. Org. Lett. 2002, 4, 3759. (c) Zhao, G.; Li,
X.-G.; Wang, X.-R. Tetrahedron: Asymmetry 2001, 12, 399. (d) Huang, W.-S.;
Pu, L. Tetrahedron Lett. 2000, 41, 145. (e) Bolm, C.; Mun˜iz, K. Chem. Commun.
1999, 1295. (f) Huang, W.-S.; Pu, L. J. Org. Chem. 1999, 64, 4222. (g) Dosa,
P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62, 444.
(21) An interesting alternative has been developed by Cozzi, using a
ClCr(salen) catalyst: (a) Cozzi, P. G.; Kotrusz, P. J. Am. Chem. Soc. 2006, 128,
4940. For recent examples of catalytic additions of Me2Zn to aldehydes, see:
(b) Blay, G.; Ferna´ndez, I.; Herna´ndez-Olmos, V.; Marco-Aleixandre, A.; Pedro,
J. R. Tetahedron: Asymmetry 2005, 16, 1953. (c) Hatano, M.; Miyamoto, T.;
Ishihara, K. Synlett 2006, 1762.
(29) Arylmetallic species/Zn salt: (a) Kim, J. G.; Walsh, P. J. Angew. Chem.,
Int. Ed. 2006, 45, 4175. (b) Coˆte´, A.; Charette, A. B. J. Am. Chem. Soc. 2008,
130, 2771.
5346 J. Org. Chem. Vol. 73, No. 14, 2008

Catalytic Ligands for EnantioselectiVe Additions to Aldehydes
TABLE 6. Addition of Dimethylzinc to Aldehydes Catalyzed by 1a, 1b, and 2b
ligand 1a
conv (%)a
ligand 1b
conv (%)a
ligand 2b
conv (%)a
entry
aldehyde (product)
ee (%)a
ee (%)a
ee (%)a
1
2
3
4
5
6
7
8
heptanal (13a)
88
45
93
80
96
63
>99
93
65
89
84
84
90
88
91
91
88
26
80
53
79
39
98
76
61
88
86
83
90
84
91
90
84
15
56
32
57
32
94
57
60
79
81
79
89
79
88
88
(E)-R-methylcinnamaldehyde (13b)
cyclohexylcarbaldehyde (13c)
p-methoxybenzaldehyde (13d)
benzaldehyde(13e)
o-tolualdehyde(13f)
p-trifluoromethylbenzaldehyde (13g)
m-tolualdehyde (13h)
a Determined by GC using a ꢀ-DEX capillary column.
FIGURE 6. Comparison of the catalytic activity of ligands 1a, 1b, and 2b in the addition of dimethylzinc to benzaldehyde at 0 °C.
We applied our catalysts set to this reaction under the
conditions previously optimized for ligand 1a.9j As anticipated,
the reactions were fast at 10 °C and were complete within 1 h.
High conversions and enantioselectivities were recorded for fully
R-substituted aldehydes (aromatic and R,ꢀ-unsaturated), even
though only 5 mol % of amino alcohol was used (see Table 7,
entries 3-8). For aliphatic aldehydes, although conversions were
essentially complete with the three studied ligands, ee’s were
below 70% (Table 7, entries 1 and 2).
It is worth mentioning that, for this particular reaction, the
three considered ligands behave almost equally with all of the
studied substrates. Accordingly, it is evident that a fast reaction
such as the arylation of aldehydes, when performed at a fixed,
nonoptimized reaction time, is not suitable for the discrimination
between similar ligands.
Turning our attention to kinetic behavior, monitoring of the
phenylation reaction of p-tolualdehyde by in situ FTIR shows
that the three considered ligands present in this reaction the same
catalytic activity trend already observed for the ethylation and
the methylation of benzaldehyde (Figure 7). That is, 1a is the
most active ligand, followed by 1b, while 2a is substantially
less active. The reactions used for kinetic analysis were
performed at 0 °C, using only 2.5 mol % of ligand with the
aim of slowing down the process in order to be able to detect
differences in activity. Even under these demanding experi-
mental conditions, the reaction is completed for all three ligands
in a 60-70 min reaction time. Thus, if reaction progress was
only inspected after such a period, the three ligands would
appear as practically equivalent.
On the other hand, if the reactions were quenched after only
3 min, conversions would be 75% with 1a, 50% with 1b, and
22% with 2b. From the perspective of a potential practical
application, where TON was important for economic reasons
(energy cost, reactor occupation, etc.), the three ligands would
appear as markedly different, 1a being clearly preferred.
Conclusions
In summary, we have shown that amino alcohol ligands
belonging to a common structural type (2-aryl-2-cyclialky-
lamino-1,1-diphenylethanols) exhibit marked differences in their
catalytic behavior when used as ligands for the enantioselective
C-C bond formation by addition to aldehydes. We have also
shown that a benchmark-guided, structural fine-tuning of the
considered ligands can be easily performed through a short,
iterative process when the ligands (as it is the case here) have
a modular design.
Very interestingly, the best hit ligand in the benchmark-guided
process (1a) has been shown to be also optimal for mechanisti-
J. Org. Chem. Vol. 73, No. 14, 2008 5347

Rodr´ıguez-Escrich et al.
TABLE 7. Addition of a Mixed Phenylzinc Species to Aldehydes Catalyzed by 1a, 1b, and 2b
ligand 1a
conv (%)a
ligand 1b
conv (%)a
ligand 2b
conv (%)a
entry
aldehyde (product)
heptanal (14a)
cyclohexylcarbaldehyde (14b)
(E)-R-methylcinnamaldehyde (14c)
p-methoxybenzaldehyde (14d)
p-phenylbenzaldehyde (14e)
o-tolualdehyde (14f)
ee (%)b
ee (%)b
ee (%)b
1
2
3
4
5
6
7
8
96
97
96
99
97
99
99
96
67
66
94
96
96
97
94
97
96
97
95
97
98
97
98
97
63
63
93
96
96
95
94
97
96
>99
95
98
97
97
98
99
62
62
92
94
95
94
93
96
p-trifluoromethylbenzaldehyde (14g)
p-tolualdehyde (14h)
a
Determined by H NMR. b Determined by HPLC using a chiral stationary phase.
1
FIGURE 7. Comparison of the catalytic activity of ligands 1a, 1b, and 2b in the addition of PhZnEt to p-tolualdehyde at 10 °C.
cally related chemistries not explicitly included in the bench-
marking process. This behavior, that underlies the existence of
priVileged ligands, allows keeping the toolkit of catalytic ligands
for a given type of process within a reasonable size.
Experimental Section
General Procedure for the Enantioselective Epoxidation of
Olefins 1-11 (GP1). A solution of olefin (5 mmol) in CH2Cl2 (10
mL), (S,S)-Jacobsen catalyst (0.25 mmol) and 4-phenylpyridine
N-oxide (0.3 mmol) was cooled to 0 °C. Buffered bleach (7.5 mL,
pH ) 11.3) precooled to 0 °C was added dropwise in such a way
that the internal temperature of the reaction mixture was maintained
at 0-5 °C, and the reaction was stirred at 0 °C. When the complete
disappearance (ca. 3-6 h) of starting material was ascertained by
TLC, the two phases were separated. The aqueous phase was
extracted with CH2Cl2 (2 × 25 mL), and the combined organic
phases were washed with water and dried over anhydrous Na2SO4
before concentration in vacuo to furnish the crude reaction mixture.
Purification was effected by flash column chromatography on silica
gel (pretreated with Et3N 2.5% v/v) and n-hexanes/EtOAc mixtures
as eluent to afford analytically pure products.
From a methodological point of view, an important conse-
quence of this study concerns the possible ways to discriminate
between highly efficient, apparently equivalent ligands (1a, 1b,
and 2b, in the present case). Thus, we have shown that important
differences in catalytic activity exist even between ligands
depicting very similar enantioselectivity profiles. We have also
shown that these differences, which can have a deep impact on
the economy of catalytic processes, are only detected when the
considered ligands are submitted to stringent tests, i.e., poorly
reactive substrates, low ligand loading, and/or short reaction
times.
(3S)-2,2,3-Triphenyloxirane (1).11 Following the general pro-
cedure GP1, compound 1, a white crystalline solid, was isolated in
97% yield (264 g) and 92% ee. The enantiomeric purity was
enhanced to >99% ee by a single recrystallization from hexanes.
The ee was determined by HPLC (Chiralcel-ODR column; eluent,
As an additional bonus, the preparation by Jacobsen epoxi-
dation of a family of 2-aryl-1,1-diphenylethene oxides has led
to the identification of a linear free-energy relationship between
the electronic character of the aryl substituent in the starting
olefin and the enantiomeric ratio of the corresponding epoxide.
5348 J. Org. Chem. Vol. 73, No. 14, 2008

Catalytic Ligands for EnantioselectiVe Additions to Aldehydes
MeOH; flow rate, 0.5 mL/min; λ ) 254nm). Peaks appeared at tS
) 10.6 min for the S isomer (major), and tR ) 16.2 min for the R
isomer.
1H), 3.73 (s, 3H). 13C NMR (50.3 MHz, CDCl3) δ 159.5, 141.5,
136.3, 133.0, 130.5, 129.7, 128.8, 128.5, 128.3, 128.1, 128.0, 126.7,
113.6, 69.0, 68.5, 55.5. IR (KBr) 3028, 3020, 2980, 2860, 1611,
1516, 1447, 1248, 1173, 1030, 835, 760, 746, 696 cm-1. MS (EI,
70 eV) m/z 302 (M+, 22). 165 (M - C8H8O2+, 100). Anal. Calcd
for C21H18O2: C, 83.42, H, 5.99. Found: C, 83.32, H, 5.99.
(3S)-2,2-Diphenyl-3-naphthalen-2-yl-oxirane (7). Following the
general procedure GP1, compound 7 (1.55 g, 96% yield, 94% ee)
was obtained as a white crystalline solid. Upon one recrystallization
from hexanes the enantiomeric purity was increased to >99% ee.
The ee was determined by HPLC (Chiralcel-ODR column); eluent
MeOH; flow rate 0.5 mL/ min, R isomer, tR ) 16.5 min, and S
isomer, tS ) 18.8 min (major); mp 115 °C. [R]23D: +49 (c 0.76,
CHCl3). 1H NMR (200 MHz, CDCl3) δ 7.76-7.66 (m, 2H),
7.62-7.57 (m, 2H), 7.45-7.30 (m, 7H), 7.27-7.05 (m, 6H), 4.48
(s, 1H). 13C NMR (50.3 MHz, CDCl3) δ 140.9, 135.6, 133.1, 132.9,
132.7, 129.2, 128.4, 127.9, 127.8, 127.6, 127.3, 126.3, 126.0, 125.9,
(3S)-2,2-Diphenyl-3-m-chlorophenyl-oxirane (2). Following the
general procedure GP1 a white crystalline solid (2.5 g, 77% yield)
was obtained with 88% ee, which upon recrystallization from
hexanes afforded enantiomerically pure (>99% ee) 2. The ee was
determined by HPLC (Chiralcel-OD column); eluent, n-hexane/2-
propanol (19:1); flow rate 0.5 mL/ min, S isomer, tS ) 10.1 min
(major), and R isomer, tR ) 11.5 min; mp 100 °C. [R]23D: +46.7
(c 1.79, CHCl3). 1H NMR (200 MHz, CDCl3) δ 7.38-6.87 (series
of m, 14H); 4.29 (s, 1H). 13C NMR (50.3 MHz, CDCl3) δ 140.5,
137.6, 135.3, 133.8, 129.0, 128.9, 128.4, 127.9,127.8, 126.9, 126.3,
125.8, 124.8, 68.8, 67.1. IR (KBr) 3075, 3035, 2985, 1597, 1479,
1449, 897, 877, 785, 767, 758, 715, 698, 684, 629, 590 cm-1. MS
(CI, NH3) m/z 307 (C20H15ClO, 7), 324 (100). Anal. Calcd for
C20H15ClO: C, 78.30; H, 4.93. Found: C, 78.34; H, 4.94.
(3S)-2,2-Diphenyl-3-o-chlorophenyloxirane (3). Following the
general procedure GP1, compound 3 (1.46 g, 95% yield, 83% ee)
was obtained as a white crystalline solid. Upon one recrystallization
from hexanes the enantiomeric purity was increased to >99% ee.
The ee was determined by HPLC (Chiralcel-ODR); eluent, MeOH/
NaClO4 (0.5 M) 9:1; flow rate 0.5 mL/min, R isomer, tR ) 38.1
min, and S isomer, tS ) 43.7 min (major); mp 76 °C. [R]23D: +97.2
(c 1.83, CHCl3). 1H NMR (200 MHz, CDCl3) δ 7.24-6.66 (series
of m, 14H); 4.36 (s, 1H). 13C NMR (50.3 MHz, CDCl3) δ 140.5,
136.2, 133.6, 132.6, 128.6, 128.5, 128.4, 128.1, 128.0, 127.7, 127.4,
126.9, 68.7, 64.9. IR (KBr) 3082, 3053, 3018, 2989, 1493, 1476,
1449, 1263, 1053, 1028, 901, 754, 706, 644, 615, 588 cm-1. MS
(CI, NH3) m/z 307 (C20H15ClO, 11), 324 (100); Anal. Calcd for
C20H15ClO: C, 78.30; H, 4.93; Cl, 11.56. Found: C, 78.53; H, 4.92;
Cl, 11.76.
(3S)-2,2-Diphenyl-3-p-nitrophenyloxirane (4). Following the
general procedure GP1 compound 4 (1.59 g, >99% yield) was
obtained with 96% ee as a white crystalline solid, which upon one
recrystallization from hexane gave enantiomerically pure (>99%
ee) 4. The ee was determined by HPLC (Chiralcel-ODR); eluent
MeOH; flow rate 0.5 mL/ min, R isomer, tR ) 13.8 min, and S
isomer, tS ) 19.3 min (major); mp 84 °C. [R]23D: +66.3 (c 1.23,
CHCl3). 1H NMR (200 MHz, CDCl3) δ 8.03-8.00 (m, 2H),
7.36-7.19 (m, 12H), 4.42 (s, 1H). 13C NMR (50.3 MHz, CDCl3)
δ 47.2, 142.8, 139.8, 134.7, 128.9, 128.4, 128.2, 127.4, 126.2, 69.3,
66.8. MS (EI,70 eV) m/z 317 (M+, 23), 165 (M - C7H5NO3+, 100).
Anal. Calcd for C20H15NO3: C, 75.71; H, 4.88; N, 4.42. Found:
C,75.79; H, 4.77; N, 4.42.
124.3, 68.9, 68.3. IR (KBr) 3023, 3000, 2941, 1493, 1447, 825,
+
756, 696, 663, 623, 584, cm-1. MS (CI, NH3) m/z 306.5 (C24H18
,
6), 340 (100). Anal. Calcd for C24H18O: C, 89.41; H, 5.63. Found:
C, 89.47; H, 5.62.
(3S)-3-Methyl-2,2-diphenyloxirane (8).30 Following the general
procedure GP1, compound 8 (0.284 g, 27% yield, 95% ee) was
obtained as a white crystalline compound. Upon one recrystalli-
zation from hexanes the enantiomeric purity was increased to >99%
ee.
(3S)-2,2-Diphenyl-3-p-tolyloxirane (9). Following the general
procedure GP1, compound 9 (1.07 g, 75% yield, 91% ee) was
obtained as a white crystalline solid. Upon one recrystallization
from hexanes the enantiomeric purity was increased to >99% ee.
The ee was determined by HPLC (Chiralcel-ODR column); eluent
MeOH/NaClO4 (0.5 M) in a 9:1 ratio; flow rate 0.5 mL/min; R
isomer, tR ) 24.9 min, and S isomer, tR ) 27.6 min (major); mp
80 °C. [R]23D: +66.3 (c 1.23, CHCl3). 1H NMR (200 MHz, CDCl3)
δ 7.36-7.21 (m, 10H), 6.93-6.92 (m, 4H), 4.28 (s,1H), 2.24 (s,
CH3). 13C NMR (75 MHz, CDCl3) δ 141.0, 137.2, 135.9, 132.3,
129.1, 128.3, 128.2, 128.0, 127.8, 127.6, 127.4, 126.0, 126.2, 68.5,
68.1, 21.1. IR (KBr) 3035, 3015, 2902, 1518, 1493, 14449, 816,
760, 744, 698 cm-1. MS (EI, 70 eV) m/z 286 (M+, 27), 165 (M -
C8H80+, 100). Anal. Calcd for C21H18O: C, 88.08; H, 6.39. Found:
C, 88.15; H, 6.35.
(3S)-2,2-Diphenyl-3-m-tolyloxirane (10). Following the general
procedure GP1, compound 10 (2.17 g, 76% yield, 84% ee) was
obtained as a white crystalline solid. Upon one recrystallization
from hexanes the enantiomeric purity was increased to >99% ee.
The ee was determined by HPLC analysis (Chiralcel-OD column);
eluent, n-hexanes/2-propanol (19:1); flow rate 0.5 mL/min, S isomer,
tS ) 8.5 min (major), and R isomer, tR ) 17.6 min; mp 111 °C.
(3S)-2,2-Diphenyl-3-p-fluorophenyloxirane (5). Following the
general procedure GP1, compound 5 (1.35 g, 93% yield, 93% ee)
was obtained as a white crystalline solid. Upon one recrystallization
from hexanes the enantiomeric purity was increased to >99% ee.
The ee was determined by HPLC (Chiralcel-ODR column); eluent
MeOH/NaClO4 (0.5M) in 9:1 ratio; flow rate 0.5 mL/min, R isomer,
tR ) 21.1 min, and S isomer, tS ) 23.6 min (major); mp 125 °C.
1
[R]23D: +56.7 (c 1.86, CHCl3). H NMR (200 MHz, CDCl3) δ
7.41-6.79 (series of m, 14H), 4.29 (s, 1H), 2.19 (s, 3H). 13C NMR
(50.3 MHz, CDCl3) δ 141.1, 137.2, 135.9, 135.3, 129.2, 128.4,
128.3, 127.7, 127.5, 127.4, 126.3, 123.8, 68.6, 68.0, 21.2. IR (KBr)
3027, 3000, 2950, 2802, 1601, 1491, 1449, 1333, 914, 879, 837,
764, 750, 704, 652, 632, 588 cm-1. MS (CI, NH3) m/z 286
(C21H18O, 0), 304 (100). Anal. Calcd for C21H18 O: C, 88.07; H,
6.35. Found: C, 88.30; H, 6.40.
[R]23D: + 66.8 (c ) 1.07 in CHCl3). H NMR (200 MHz, CDCl3)
1
δ 7.37-7.19 (m,10H), 7.03-6.90 (m, 2H), 6.88-6.79 (m, 2H),
4.30 (s,1H). 13C NMR (50.3 MHz, CDCl3) δ 163.8, 160.6, 140.6,
135.5, 131.2, 129.1, 128.4, 128.3, 127.9, 127.8, 127.6, 126.2, 114.8,
114.5, 68.6, 67.3. IR (KBr) 3085, 3062, 3000, 2989, 1599, 1508,
1447, 1221, 1155, 835, 752, 702, 582, 565 cm-1. MS (EI, 70 eV)
m/z 290 (M+, 11), 165 (M - C7H5FO+, 100); Anal. Calcd for
C20H16FO: C, 82.74; H, 5.21. Found: C, 82.81; H, 5.21.
(3S)-2,2-Diphenyl-3-o-tolyloxirane (11). Following the general
procedure GP1, compound 11 (0.750 g, 53% yield, 77% ee) was
obtained as a white crystalline solid. Upon one recrystallization
from hexanes the enantiomeric purity was increased to >99% ee.
The ee was determined by HPLC (Chiralcel-OD column); eluent,
n-hexanes/2-propanol (19:1); flow rate 0.5 mL/min, S isomer, tS )
(3S)-2,2-Diphenyl-3-p-methoxyphenyloxirane (6). Following
the general procedure GP1, compound 6 (1.39 g, 92% yield, 90%
ee) was obtained as a white crystalline solid. Upon one recrystal-
lization from hexanes the enantiomeric purity was increased to
>99% ee. The ee was determined by HPLC (Chiralcel-ODR
column); eluent MeOH; flow rate 0.5 mL/ min, S isomer, tS ) 14.9
min (major), and R isomer, tR ) 17.9 min; mp 96 °C. [R]23D: +69.8
8.9 min (major), and R isomer, tR ) 9.8 min; mp 95 °C. [R]23
:
D
1
+76 (c 1.38, CHCl3). H NMR (200 MHz, CDCl3) δ 7.49-6.90
(series of m, 14H); 4.47 (s, 1H), 2.42 (s, 3H). 13C NMR (50.3 MHz,
(30) (a) Chini, M.; Crotti, P.; Macchia, F. J. Org. Chem. 1991, 56, 5939. (b)
Chini, M.; Crotti, P.; Flippin, L. A.; Gardelli, C.; Giovanni, E.; Macchia, F.;
Pinesci, M. J. Org. Chem. 1993, 58, 1221.
1
(c 1.04, CHCl3). H NMR (200 MHz, CDCl3) δ 7.35-7.22 (m,
10H), 6.93 (d, J ) 8.8 Hz, 2H), 6.68 (d, J ) 8.8 Hz, 2H), 4.26 (s,
J. Org. Chem. Vol. 73, No. 14, 2008 5349

Rodr´ıguez-Escrich et al.
CDCl3) δ 141.0, 136.7,135.1, 133.7, 129.3, 128.4, 128.3, 127.9,
127.6, 127.4, 127.3, 126.8, 126.2, 125.3, 68.3, 65.8, 19.2. IR (KBr)
3060, 2956, 1491, 1460, 1447, 901, 764, 748, 721,702, 648, 623,
586 cm-1. MS (CI, NH3) m/z 286 (C21H18O, 0), 304 (100). Anal.
Calcd for C21H18O: C, 88.07; H, 6.35. Found: C, 88.16; H, 6.34.
Epoxide Ring-Opening Reactions.30 General Procedure 2
(GP2). A mixture of the oxirane (1.0 mmol), LiClO4 (214 mg, 2.0
mmol), and amine (10.0 mmol) was heated at 100 °C under N2.
After the complete disappearance of the oxirane, the excess of amine
was distilled under reduced pressure. The residue was dissolved in
CH2Cl2 (10 mL), washed with water (2 × 100 mL), dried (Na2SO4),
and concentrated under reduced pressure to give the crude product,
which was purified by chromatography on silica gel pretreated with
Et3N (2.5% v/v) using hexanes/EtOAc as eluent. General Proce-
dure 3 (GP3). A solution of the oxirane (1.0 mmol) in anhydrous
acetonitrile (2 mL) was treated with LiClO4 (1.07 g, 10.0 mmol)
and the cyclic amine (10.0 mmol), and the reaction mixture was
stirred at 80 °C under nitrogen atmosphere until the complete
disappearance of the starting oxirane (ca. 24-96 h). The reaction
mixture was diluted with water (25 mL) and extracted with
dichloromethane (3 × 25 mL). The organic layer was washed with
water, dried over anhydrous Na2SO4, and concentrated in vacuo to
give a crude product. Purification by column chromatography on
silicagel pretreated with Et3N (2.5% v/v) and hexane/EtOAc as
eluent afforded analytically pure compounds.
(CI, NH3) m/z 385 (C27H31NO.H+, 100). Anal. Calcd for C27H31NO:
C, 84.11; H, 8.10; N, 3.63. Found: C, 84.32; H, 8.16; N, 3.64.
(R)-1,1,2-Triphenyl-2-pyrrolidine-yl-ethanol (1e). Following
the general procedure GP3 for oxirane 1 (1.0 mmol, 272 mg), and
pyrrolidine (0.82 mL, 10.0 mmol) for 48 h, compound 1e was
isolated (312 mg, 91%) as a white solid; mp 155 °C. [R]23D: +7.3
1
(c 0.96, CHCl3). H NMR (200 MHz, CDCl3): δ 7.86-7.83 (2H,
m), 7.33-6.77 (13H, m), 4.52 (1H, s), 2.28-2.16 (4H, m),
1.57-1.51 (4H, m). 13C NMR (50.3 MHz, CDCl3): δ 149.8, 146.1,
139.9, 130.1, 128.0, 127.3, 127.1, 126.8, 126.2, 125.9, 125.3, 125.2,
78.2, 76.4, 54.3, 23.3. IR (KBr): 3388, 3025, 2967, 2811, 1491,
1449, 1034, 746, 698, 636 cm-1. MS (CI, NH3) m/z 343
(C24H25NO.H+, 100). Anal. Calcd for C24H25NO: C, 83.93; H, 7.34;
N, 4.08. Found: C, 84.11; H, 7.36; N, 3.93.
(R)-2-(3-Clorophenyl)-1,1-diphenyl-2-piperidine-1-yl-etha-
nol (2a). Following the general procedure GP3 for oxirane 2 (1.0
mmol, 307 mg), and piperidine (1.0 mL, 10.0 mmol) for 48 h,
compound 2a was isolated (284 mg, 72%) as a white solid; mp
167 °C. [R]23D: -106.0 (c 1.12, CHCl3). 1H NMR (200 MHz,
CDCl3): δ 7.67-7.63 (2H, m), 7.36-6.92 (12H, m), 5.59 (1H, br
s), 4.49 (1H, s), 2.46-2.34 (2H, m), 2.06-1.96 (2H, m), 1.45-1.26
(6H, m). 13C NMR (50.3 MHz, CDCl3): δ 148.9, 145.4, 139.7,
133.3, 131.1, 129.4, 128.7, 128.0, 127.4, 127.0, 126.6, 126.4, 125.9,
125.6, 78.9, 77.0, 54.6, 26.8, 24.1. IR (KBr): 3290, 3060, 2934,
2851, 1597, 1493, 1476, 1449, 1084, 1055, 1034, 793, 146, 696,
665 cm-1. MS (CI, NH3) m/z 392 (C25H26ClNO.H+, 100). Anal.
Calcd for C25H26ClNO: C, 76.61; H, 6.69; N, 3.57; Cl, 9.05. Found:
C, 76.89; H, 6.70; N, 3.61; Cl, 9.30.
(R)-2-Piperidino-1,1,2-triphenylethanol (1a).7a Following the
general procedure GP2 for oxirane 1 (1.0 mmol, 272 mg), and
piperidine (1.0 mL, 10.0 mmol) for 24 h, compound 1a was isolated
(351 mg, 98%) as white crystals. All spectroscopic data matched
those reported in the literature.
(2R)-2-Azepan-1-yl-2-(3-chlorophenyl)-1,1-diphenyl-ethanol
(2b). Following the general procedure GP3 for oxirane 2 (1.0 mmol,
307 mg), and hexamethyleneimine (1.13 mL, 10.0 mmol) for 48 h,
compound 2b was isolated (290 mg, 72%) as a white solid; mp
161 °C. [R]23D: -55.3 (c 1.13, CHCl3). 1H NMR (200 MHz,
CDCl3): δ 7.66-7.63 (2H, m), 7.33-6.97 (12H, series of m), 5.08
(1H, br s), 4.76 (1H, s), 2.75-2.67 (2H, m), 2.42-2.36 (2H, m),
1.48-1.33 (8H, m). 13C NMR (50.3 MHz, CDCl3): δ 148.5, 145.3,
140.3, 133.3, 130.8, 129.1, 128.6, 127.9, 127.4, 126.9, 126.4, 126.3,
125.9, 125.8, 79.5, 77.2, 55.4, 29.2, 26.5). IR (KBr): 3573-3274
(2R)-2-Azepan-1-yl-1,1,2-triphenylethanol (1b). Following the
general procedure GP3 for oxirane 1 (1.0 mmol, 272 mg), and
hexamethyleneimine (1.13 mL, 10.0 mmol) for 24 h, compound
1b was isolated (334 mg, 90%) as a white solid; mp 160 °C. [R]23
:
D
1
-8.1 (c 1.99, CHCl3). H NMR (200 MHz, CDCl3): δ 7.75-7.57
(2H, m), 7.39-6.90 (13H, m), 5.51 (1H, br s), 4.78 (1H, s),
2.76-2.59 (2H, m), 2.48-2.31 (2H, m), 1.45-1.26 (8H, m). 13C
NMR (50 MHz, CDCl3): δ 149.1, 145.8, 138.2, 131.0, 127.8, 127.5,
127.2, 127.0, 126.8, 126.7, 126.2, 125.9, 125.7, 79.3, 78.0, 55.4,
29.2, 26.2. IR (KBr): 3402, 3084, 3059, 3023, 2918, 2843, 1493,
1449, 1317, 1148, 1055, 760, 748, 700 cm-1. MS (CI, NH3) m/z
371 (C26H29NO.H+, 100). Anal. Calcd for C26H29NO: C, 84.06; H,
7.87; N, 3.77. Found: C, 84.05; H, 7.96; N, 3.71.
(br), 3060, 3027, 2927, 2853, 1659, 1449, 1279, 762, 702, 638 cm-1
.
MS (CI, NH3) m/z 406 (C26H28ClNO.H+, 100). Anal. Calcd for
C26H28ClNO: C, 76.93; H, 6.95; N, 3.45; Cl, 8.73. Found: C, 76.98;
H, 6.91; N, 3.34 Cl, 8.51.
(R)-2-(2-Chlorophenyl)-1,1-diphenyl-2-piperidine-1-yl-etha-
nol (3a). Following the general procedure GP3 for oxirane 3 (1.0
mmol, 307 mg), and piperidine (1.0 mL, 10.0 mmol) for 72 h,
compound 3a was isolated (36 mg, 9%) as a white solid; mp 169
°C. [R]23D: -216.2 (c 1.39, CHCl3). 1H NMR (200 MHz, CDCl3):
δ 7.74-7.70 (2H, m), 7.60-6.55 (1H, series of m), 7.34-6.33
(11H, m), 5.81 (1H, br s), 5.33 (1H, s), 2.50-2.42 (2H, m),
2.06-2.0 (2H, m), 1.42-1.26 (6H, m). 13C NMR (50.3 MHz,
CDCl3): δ 149.3, 145.8, 136.1, 135.4, 133.2, 128.8, 128.1, 127.4,
126.2, 125.8, 125.6, 125.4, 78.9, 71.5, 54.0, 27.0, 24.2. IR (KBr):
3395, 3060, 3025, 2923, 2844, 2833, 2819, 1449, 1173, 1057, 1034,
748, 708, 665 cm-1. MS (CI, NH3) m/z 392 (C25H26ClNO.H+, 100).
(R)-2-(4-Fluorophenyl)-1,1-diphenyl-2-piperidine-1-yl-etha-
nol (5a). Following the general procedure GP3 for oxirane 5 (1.0
mmol, 290 mg), and piperidine (1.0 mL, 10.0 mmol) for 24 h,
compound 5a was isolated (350 mg, 93%) as a white solid; mp
151 °C. [R]23D: -123.0 (c 0.67, CHCl3). 1H NMR (300 MHz,
CDCl3): δ 7.67-7.64 (2H, m), 7.32-6.94 (10H, m), 6.83-6.78
(2H, m), 5.69 (1H, br s), 4.53 (1H, s), 2.39-2.35 (2H, m),
2.00-1.97 (2H, m), 1.42-1.37 (4H, m), 1.29-1.27 (2H, m). 13C
NMR (75 MHz, CDCl3): δ 163.2, 159.9, 149.0, 145.5, 132.6, 132.5,
127.9, 127.3, 126.7, 126.2, 125.7, 125.5, 114.4, 114.1, 78.7, 76.7,
54.5, 26.7, 24.1. IR (KBr): 3455, 3030, 3000, 2944, 2841, 1607,
1508, 1449, 1227, 1165, 1055, 748, 696, 550 cm-1. MS (CI, NH3)
m/z 371 (C25H26FNO.H+, 100). Anal. Calcd for C25H26FNO: C,
79.97; H, 6.98; N, 3.73. Found: C, 79.83; H, 6.94; N, 3.74.
(R)-2-Azocan-1-yl-1,1,2-triphenylethanol (1c). Following the
general procedure GP3 for oxirane 1 (1.0 mmol, 272 mg), and
heptamethyleneimine (1.26 mL, 10.0 mmol) for 48 h, compound
1c was isolated (72 mg, 18%) as a white solid; mp 149 °C. [R]23
:
D
-78.1 (c 1.21, CHCl3). 1H NMR (200 MHz, CDCl3): δ 7.73-7.69
(2H, m), 7.35-6.90 (13H, series of m), 5.38 (1H, br s), 4.80 (1H,
s), 2.74-2.59 (2H, m), 2.43-2.30 (2H, m), 1.50-1.21 (10H, m).
13C NMR (50.3 MHz, CDCl3): δ 149.1, 146.1, 138.1, 131.2, 127.9,
127.4, 127.2, 126.8, 126.5, 126.2, 125.8, 125.6, 79.6, 78.9, 54.8,
28.0, 27.3, 25.2. IR (KBr): 3416, 3075, 3046, 3021, 2927, 2855,
1493, 1449, 1319, 1175, 1121, 993, 972, 762, 746, 702 cm-1. MS
(CI, NH3) m/z 385 (C27H31NO.H+, 100). Anal. Calcd for C27H31NO:
C, 84.11; H, 8.11; N, 3.63. Found: C, 84.16; H, 8.11; N, 3.63.
(R)-2-(3,3-Dimethylpiperidine-yl)-1,1,2-triphenylethanol (1d). Fol-
lowing the general procedure GP3 for oxirane 1 (1.0 mmol, 272
mg), and 3,3-dimethylpiperidine (1.41 mL, 10.0 mmol) for 48 h,
compound 1d was isolated (380 mg, 99%) as a white solid; mp
147 °C. [R]23D: -131.5 (c 1.11, CHCl3). 1H NMR (200 MHz,
CDCl3): δ 7.69-7.65 (2H, m), 7.33-6.90 (13H, m), 5.56 (1H, s),
4.55 (1H, s), 2.47-2.36 (1H, m), 2.13 (1H, d, J ) 11.1 Hz),
1.93-1.78 (2H, m), 1.43-1.34 (2H, m), 1.07-0.98 (2H, m), 0.83
(3H, s), 0.69 (3H, s). 13C NMR (50 MHz, CDCl3): δ 149.2, 145.7,
137.1, 131.3, 127.9, 127.3, 127.2, 126.8, 126.6, 126.1, 125.6, 79.4,
77.1, 65.9, 54.2, 37.0, 31.5, 27.2, 26.8, 23.0. IR (KBr): 3417, 3064,
3025, 2938, 2817, 1495, 1449, 976, 750, 700, 654, 636 cm-1. MS
5350 J. Org. Chem. Vol. 73, No. 14, 2008

Catalytic Ligands for EnantioselectiVe Additions to Aldehydes
1
(R)-2-(4-Methoxyphenyl)-1,1-diphenyl-2-piperidine-1-yl-etha-
nol (6a). Following the general procedure GP3 for oxirane 6 (1.0
mmol, 302 mg), and piperidine (1.0 mL, 10.0 mmol) for 24 h,
compound 6a was isolated (392 mg, 75% yield) as a white solid;
[R]23D: -171.4 (c 1.95, CHCl3). H NMR (200 MHz, CDCl3): δ
7.83-6.77 (14H, series of m), 4.92 (1H, s), 2.54-2.39 (2H, m),
2.46 (3H, s), 2.0-1.92 (2H, m), 1.38.1.26 (6H, m). 13C NMR (50.3
MHz, CDCl3): δ 149.8, 146.1, 136.7, 136.5, 132.3, 131.7, 130.0,
129.8, 128.2, 128.0, 127.2, 126.6, 126.2, 126.1, 125.4, 125.1, 78.7,
71.7, 54.1, 27.0, 24.3, 21.4. IR (KBr): 3366, 3082, 3065, 3058,
3033, 3018, 2923, 2820, 1491, 1449, 1315, 1055, 742, 696, 669,
638 cm-1. MS (CI, NH3) m/z 371 (C26H29NO.H+, 100). Anal. Calcd
for C26H29NO: C, 84.06; H, 7.87; N, 3.77. Found: C, 84.01; H,
7.74; N, 3.74.
1
mp 119 °C. [R]23D: -98.1 (c 0.38, CHCl3). H NMR (200 MHz,
CDCl3): δ 7.74-7.60 (2H, m), 7.38-6.92 (10H, m), 6.68-6.63
(2H, m), 6.05 (1H, s), 4.46 (1H, s), 3.72 (3H, s), 2.43-2.32 (2H,
m), 2.05-1.92 (2H, m), 1.50-1.20 (6H, m).13C NMR (50.3 MHz,
CDCl3): δ 158.5, 149.5, 147.8, 132.3, 129.6, 127.8, 127.2, 126.9,
126.1, 125.7, 112.7, 78.5, 77.1, 55.0, 54.3, 26.8, 24.1. IR (KBr):
3492, 3024, 2930, 2801, 1609, 1512, 1449, 1250, 1180, 1034, 754,
704 cm-1. HRMS (ESI+): m/z Calcd for C26H30NO2 [M+H]+:
388.2271, found: 388.2280.
General Procedure for the Enantioselective Amino Alcohol-
Catalyzed Addition of Diethylzinc to Aldehydes (GP4). (a) With
6 mol % of the ligand. To a solution of the amino alcohol ligand
(0.03 mmol, 6 mol %) in toluene (1 mL) under argon was added
diethylzinc (1.1 mL of a 1 M in hexanes solution, 1.1 mmol) at
room temperature. The mixture was stirred for 20 min and then
cooled to 0 °C. The aldehyde (0.50 mmol) was added dropwise.
The mixture was stirred for the corresponding reaction time. The
reaction was quenched by addition of a saturated NH4Cl solution
(5 mL). The mixture was then extracted with CH2Cl2 (3 × 10 mL),
and the combined organic extracts were dried and concentrated in
vacuo. The enantiomeric purity of the resulting alcohols was
determined from the crude mixture by GC analysis. When neces-
sary, in the case that the peaks corresponding to the enantiomeric
alcohols were not properly resolved by GC, another aliquot was
taken and the alcohols transformed into their acetyl derivatives.
Therefore, to 0.5 mL of the organic layer diluted with 0.5 mL of
CH2Cl2 were added Ac2O (0.1 mL, 1.06 mmol), Et3N (0.1 mL, 0.7
mmol), and DMAP (catalytic amount) successively. After 5 h at
room temperature, the mixture was extracted with Et2O, and the
organic layers were washed with 1 M NaCl saturated solution.
Enantiomeric purity of the resulting derivatives was determined
from the organic extract by GC analysis. (b) With 0.5 mol % of
the ligand. To a solution of the amino alcohol ligand (0.005 mmol,
0.5 mol %) in toluene (2 mL) under argon was added diethylzinc
(2.2 mL of a 1 M in hexanes solution, 2.2 mmol) at room
temperature. The mixture was stirred for 20 min and then cooled
to 0 °C. The aldehyde (1.0 mmol) was added dropwise. The mixture
was stirred for 4 h under Ar. The reaction was quenched by the
addition of a saturated NH4Cl solution (3 mL). The mixture was
then extracted with CH2Cl2 (3 × 5 mL), and the combined organic
extracts were dried and concentrated in vacuo. Conversion and ee
were determined as above.
(R)-2-Naphthlen-2-yl-1,1-diphenyl-2-piperidine-1-yl-ethanol
(7a). Following the general procedure GP3 for oxirane 7 (1.0 mmol,
322 mg), and piperidine (1.0 mL, 10.0 mmol) for 48 h, compound
7a was isolated (258 mg, 63%) as a white solid; mp 174 °C. [R]23
:
D
-161.8 (c 0.61, CHCl3). 1H NMR (200 MHz, CDCl3): δ 7.74-6.86
(17H, series of m), 6.04 (1H, br s), 4.70 (1H, s), 2.57- 2.40 (2H,
m), 2.16-1.99 (2H, m), 1.44-1.40 (4H, m), 1.26-1.20 (2H, m).
13C NMR (50 MHz, CDCl3): δ 149.3, 145.5, 135.1, 132.7, 132.3,
130.3, 129.2, 127.9, 127.4, 127.2, 126.9, 126.8, 126.2, 125.7, 78.6,
77.8, 54.5, 26.8, 24.1. IR (KBr): 3465, 3040, 2925, 2915, 2780,
1493, 1447, 1314, 1059, 746, 694, 663, 478 cm-1. MS (CI, NH3)
m/z 407 (C29H29NO.H+, 100). Anal. Calcd for C29H29NO: C, 85.47;
H, 7.17; N, 3.44. Found: C, 85.35; H, 7.17; N, 3.18.
(R)-1,1-Diphenyl-2-piperidine-1-yl-propan-1-ol (8a). Following
the general procedure GP3 for oxirane 8 (1.0 mmol, 286 mg), and
piperidine (1.0 mL, 10.0 mmol) for 48 h, compound 8a was isolated
(287 mg, 97%) as an oil. [R]23D: -56.9 (c 1.40, CHCl3). 1H NMR
(200 MHz, CDCl3): δ 7.43-7.17 (10H, series of m), 3.47 (1H, q,
J ) 7.7 Hz), 2.38-2.24 (4H, m), 1.68-137 (6H, m), 1.41 (3H, d,
J ) 7.7 Hz). 13C NMR (50.3 MHz, CDCl3): δ 146.4, 144.8, 128.0,
127.9, 127.4, 127.1, 126.9, 126.4, 77.3, 67.0, 52.3, 26.6, 24.4, 10.7.
IR (KBr): 3652-3058 (br), 2934, 2853, 2809, 1493, 1447, 1165,
1034, 769, 698, 611 cm-1. MS (CI, NH3) m/z 296 (C20H25NO.H+,
100). Anal. Calcd for: C20H25NO: C, 81.31; H, 8.53; N, 4.74. Found:
C, 81.08; H, 8.31; N, 4.70.
(R)-1,1-Diphenyl-2-piperidine-1-yl-2-p-tolylethanol (9a). Fol-
lowing the general procedure GP3 for oxirane 9 (1.0 mmol, 286
mg), and piperidine (1.0 mL, 10.0 mmol) for 24 h, compound 9a
was isolated (346 mg, 93% yield) as a white solid; mp 175 °C.
1
[R]23D: -34.1 (c 1.03, CHCl3). H NMR (200 MHz, CDCl3): δ
(S)-1-Phenylpropanol31 (12a). Following the general procedure
GP4 for benzaldehyde (51 µL, 0.50 mmol) the title compound was
obtained. The ee and the conversion were determined by GC. The
enantiomers were not separable by gas chromatography but as their
corresponding acetates. GC (acetate deriv): ꢀ-DEX 120 column,
115 °C, tS ) 13.8 min, tR ) 14.5 min.
7.66-7.62 (2H, m), 7.34-7.23 (4H, m), 7.17-6.91 (8H, m), 4.48
(1H, s), 2.44-2.36 (2H, m), 2.23 (3H, s), 2.00-1.96 (2H, m),
1.43-1.38 (4H, m), 1.30-1.26 (4H, m). 13C NMR (50.3 MHz,
CDCl3): δ 149.4, 145.8, 136.4, 134.0, 131.2, 128.1, 127.8, 127.2,
126.9, 126.1, 125.7, 125.6, 78.5, 77.5, 54.3, 26.8, 24.1, 21.0. IR
(KBr): 3495, 2936, 1514, 1493, 1447, 1315, 1171, 1055, 970, 744,
696, 617 cm-1. MS (CI, NH3) m/z 357 (C26H29NO.H+, 1), 372
(100). Anal. Calcd for C26H29NO: C, 84.06; H, 7.87; N, 3.77. Found:
C, 84.21; H, 7.80; N, 3.66.
(S)-1-(2-Fluorophenyl)-propanol32 (12b). Following the general
procedure GP4 for o-fluorobenzaldehyde (52 µL, 0.50 mmol), the
title compound was obtained. The ee and the conversion were
determined by GC: ꢀ-DEX 120 column, 110 °C, tR ) 17.1 min, tS
) 18.4 min.
(R)-1,1-Diphenyl-2-piperidine-1-yl-2-m-tolyl-ethanol (10a). Fol-
lowing the general procedure GP3 for oxirane 10 (1.0 mmol, 286
mg), and piperidine (1.0 mL, 10.0 mmol) for 72 h, compound 10a
(S)-1-(2-Tolyl)-propanol33 (12c). Following the general proce-
dure GP4 for o-methylbenzaldehyde (58 µL, 0.50 mmol), the title
compound was obtained. The ee and the conversion were deter-
mined by GC: ꢀ-DEX 120 column, 120 °C, tR ) 17.5 min, tS )
18.9 min.
was isolated (244 mg, 66%) as a white solid; mp 157 °C. [R]23
:
D
-67.2 (c 1.07, CHCl3). 1H NMR (200 MHz, CDCl3): δ 7.66-7.63
(2H, m), 7.33-6.91 (12H, m), 4.46 (1H, s), 2.46-2.31 (2H, m),
2.19 (3H, s), 2.05-1.94 (2H, m), 1.46-1.26 (6H, m). 13C NMR
(50.3 MHz, CDCl3): δ 149.4, 145.9, 137.1, 136.7, 132.1, 128.4,
127.8, 127.5, 127.2, 127.1, 126.9, 126.1, 125.7, 125.8, 125.7, 125.6,
78.5, 77.8, 54.3, 26.8, 24.1, 21.4. IR (KBr): 3400, 3058, 2934, 2853,
1605, 1493, 1449, 1153, 1055, 1034, 796, 740, 704 cm-1. MS (CI,
NH3) m/z 371 (C26H29NO.H+, 100). Anal. Calcd for C26H29NO: C,
84.06; H, 7.87; N, 3.77. Found: C, 84.04; H, 7.83; N, 3.66.
(R)-1,1-Diphenyl-2-piperidine-1-yl-2-o-tolylethanol (11a). Fol-
lowing the general procedure GP3 for oxirane 11 (1.0 mmol, 286
mg), and piperidine (1.0 mL, 10.0 mmol) for 72 h, compound 11a
was isolated (160 mg, 42% yield) as a white solid; mp 154 °C.
(S)-1-(2-Methoxyphenyl)-propanol34 (12d). Following the gen-
eral procedure GP4 for o-methoxybenzaldehyde (60 µL, 0.50
mmol), the title compound was obtained. The ee and the conversion
(31) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986,
108, 6071.
(32) Seebach, D.; Beck, A. K.; Schmidt, B.; Wang, Y. M. Tetrahedron 1993,
58, 1221.
(33) Chelucci, G.; Conti, S.; Falorni, M.; Giacomelli, G. Tetrahedron 1991,
47, 8251.
(34) Smaardijk, A. A.; Wynberg, H. J. Org. Chem. 1987, 52, 135.
J. Org. Chem. Vol. 73, No. 14, 2008 5351

Rodr´ıguez-Escrich et al.
were determined by GC: ꢀ-DEX 120 column, 125 °C, tR ) 28.7
min, tS ) 29.6 min.
chromatography but as their corresponding acetates. GC (acetate
deriv): Column ꢀ-DEX 120 Isoterm 65 °C, tS ) 8.3 min, tR ) 8.7
min.
(S)-1-(3-Fluoro-phenyl)-propanol35 (12e). Following the gen-
eral procedure GP4 for m-fluorobenzaldehyde (53 µL, 0.50 mmol),
the title compound was obtained. The ee and the conversion were
determined by GC: ꢀ-DEX 120 column, 110 °C, tR ) 18.0 min, tS
) 19.2 min.
(S)-(E)-2-Methyl-1-phenyl-1-penten-3-ol44 (12o). Following the
general procedure GP4 for (E)-R-methylcinnamaldehyde (70 µL,
0.50 mmol), the title compound was obtained. The ee and the
conversion were determined by GC. The enantiomers were not
separable by gas chromatography but as their corresponding
acetates. GC (acetate deriv): Column ꢀ-DEX 120 Isoterm 140 °C:
tS ) 17.0 min, tR ) 17.7 min.
(S)-1-(3-Tolyl)-propanol36 (12f). Following the general proce-
dure GP4 for m-methylbenzaldehyde (59 µL, 0.50 mmol), the title
compound was obtained. The ee and the conversion were deter-
mined by GC: ꢀ-DEX 120 column, 120 °C, tR ) 16.6 min, tS )
18.0 min.
General Procedure for the Enantioselective Amino Alcohol-
Catalyzed Addition of Dimethylzinc to Aldehydes (GP5). To a
solution of the chiral ligand (0.05 mmol, 10 mol %) in toluene (2
mL) under argon was added 2 M dimethylzinc (0.5 mL, 1.0 mmol)
in toluene via syringe, and the reaction mixture was stirred at room
temperature for 30 min. The reaction was then cooled to 0 °C, and
the aldehyde (0.5 mmol) was added dropwise. After 24 h at the
same temperature, the reaction was quenched by careful addition
of HCl (1 M, 3 mL). An aliquot was taken from the organic layer
and analyzed by gas chromatography.
(S)-1-(3-Methoxyphenyl)-propanol37 (12g). Following the gen-
eral procedure GP4 for m-methoxybenzaldehyde (61 µL, 0.50
mmol), the title compound was obtained. The ee and the conversion
were determined by GC: ꢀ-DEX 120 column, 125 °C, tR ) 29.5
min, tS ) 30.6 min.
(S)-1-(4-Fluorophenyl)-propanol38 (12h). Following the general
procedure GP4 for p-fluorobenzaldehyde (53 µL, 0.50 mmol) the
title compound was obtained. The ee and the conversion were
determined by GC: ꢀ-DEX 120 column, 110 °C, tR ) 19.3 min, tS
) 21.2 min.
When necessary, in the case that the peaks corresponding to the
enantiomeric alcohols were not properly resolved by GC, another
aliquot was taken and the alcohols were transformed in their acetyl
derivatives. Therefore, to 0.5 mL of the organic layer diluted with
0.5 mL of CH2Cl2 were added Ac2O (0.1 mL, 1.06 mmol), Et3N
(0.1 mL, 0.7 mmol), and DMAP (catalytic amount) successively.
After 5 h at room temperature, the mixture was extracted with Et2O,
and the organic layers were washed with 1 M NaCl saturated
solution. Enantiomeric purity of the resulting derivatives was
determined from the organic extract by GC analysis.
(S)-1-(4-Tolyl)-propanol39 (12i). Following the general proce-
dure GP4 for p-methylbenzaldehyde (59 µL, 0.50 mmol) the title
compound was obtained. The ee and the conversion were deter-
mined by GC: ꢀ-DEX 120 column, 120 °C, tR ) 14.8 min, tS )
16.1 min.
(S)-1-(3-Methoxyphenyl)-propanol39(12j). Following the gen-
eral procedure GP4 for p-methoxybenzaldehyde (61 µL, 0.50
mmol), the title compound was obtained. The ee and the conversion
were determined by GC. The enantiomers were not completely
separable by gas chromatography but as their corresponding
acetates. GC (acetate deriv): ꢀ-DEX 120 column, 125 °C, tS ) 31.0
min, tR ) 32.9 min.
(S)-2-Octanol45 (13a). Following the general procedure GP5 for
heptanal (70 µL, 0.50 mmol), the desired product was obtained.
The ee and the conversion were determined by GC. The enantiomers
were not separable by gas chromatography but as their correspond-
ing acetates. GC (acetate deriv): ꢀ-DEX 120 column, 100 °C, tS )
8.5 min, tR ) 9.5 min.
(S)-(E)-1-Phenyl-1-penten-3-ol40 (12k). Following the general
procedure GP4 for trans-cinnamaldehyde (63 µL, 0.50 mmol), the
title compound was obtained. The ee and the conversion were
determined by GC. The enantiomers were not completely separable
by gas chromatography but as their corresponding acetates. GC
(acetate deriv): ꢀ-DEX 120 column, 140 °C, tS ) 16.7 min, tR )
17.4 min.
(S)-(E)-3-Methyl-4-phenyl-3-buten-2-ol35 (13b). Following the
general procedure GP5 for (E)-R-methylcinnamaldehyde (70 µL,
0.50 mmol), the desired product was obtained. The ee and the
conversion were determined by GC. The enantiomers were not
completely separable by gas chromatography but as their corre-
sponding acetates. GC (acetate deriv): ꢀ-DEX 120 Isoterm 140 °C:
tS ) 16.9 min, tR ) 17.5 min.
(S)-3-Nonanol41 (12l). Following the general procedure GP4 for
heptanal (70 µL, 0.50 mmol), the title compound was obtained.
The ee and the conversion were determined by GC. The enantiomers
were not separable by gas chromatography but as their correspond-
ing acetates. GC (acetate deriv): ꢀ-DEX 120 column, 100 °C, tS )
9.3 min, tR ) 10.6 min.
(S)-1-Cyclohexyl-ethanol46 (13c). Following the general pro-
cedure GP5 for cyclohexanecarbaldehyde (61 µL, 0.50 mmol), the
desired product was obtained. The ee and the conversion were
determined by GC: ꢀ-DEX 120 Isoterm 100 °C: tR ) 16.6 min, tS
) 17.9 min.
(S)-1-Phenyl-3-pentanol42 (12m). Following the general pro-
cedure GP4 for 3-phenylpropanal (66 µL, 0.50 mmol), the title
compound was obtained. The ee and the conversion were deter-
mined by GC. The enantiomers were not separable by gas
chromatography but as their corresponding acetates. GC (acetate
deriv): Column ꢀ-DEX 120 Isoterm 140 °C: tS ) 16.3 min, tR )
17.4 min.
(S)-1-(4-Methoxyphenyl)-ethanol21(13d). Following the general
procedure GP5 for p-methoxybenzaldehyde (61 µL, 0.50 mmol),
the desired product was obtained. The ee and the conversion were
determined by GC: ꢀ-DEX 120 Isoterm 125 °C: tR ) 30.1 min, tS
) 31.5 min.
(S)-1-Phenyl-ethanol47 (13e). Following the general procedure
GP5 for benzaldehyde (51 µL, 0.50 mmol), the desired product
was obtained. The ee and the conversion were determined by GC.
The enantiomers were not completely separable by gas chroma-
tography but as their corresponding acetates. GC (acetate deriv):
ꢀ-DEX 120 Isoterm 115 °C, tS ) 13.2 min, tR ) 13.9 min.
(S)-1-o-Tolyl-ethanol48 (13f). Following the general procedure
GP5 for o-tolualdehyde (58 µL, 0.50 mmol), the desired product
(S)-4-Ethyl-3-hexanol43 (12n). Following the general procedure
GP4 for 2-ethylbutyraldehyde (62 µL, 0.50 mmol), the title
compound was obtained. The ee and the conversion were deter-
mined by GC. The enantiomers were not separable by gas
(35) Chen, T.; Jiang, J.-J.; Xu, Q.; Shi, M. Org. Lett. 2007, 9, 865.
(36) Chaloner, P. A.; Perera, S. A. R. Tetrahedron Lett. 1987, 28, 3013.
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(38) Hatano, M.; Takashi, M.; Kazuaki, I. J. Org. Chem. 2006, 71, 6474.
(39) Capillon, J.; Gue´tte´, J. P. Tetrahedron 1979, 35, 1817.
(40) Soeta, T.; Kuriyama, M.; Tomioka, K. J. Org. Chem. 2005, 70, 297.
(41) Soai, K.; Niwa, S.; Watanabe, M. J. Org. Chem. 1988, 53, 927.
(42) Sato, T.; Gotoh, T.; Wakabayashi, Y.; Fujisawa, T. Tetrahedron Lett.
1983, 24, 4123.
(44) Huang, W. S.; Hu, Q. S.; Pu, L. J. Org. Chem. 1998, 63, 1364.
(45) Normant, J. F.; Alexakis, A.; Ghribi, A.; Mangeney, P. Tetrahedron
1989, 45, 507.
(46) Matharu, D. S.; Morris, D. J.; Clarkson, G. J.; Wills, M. Chem. Commun.
2006, 30, 3232.
(43) Watanabe, M.; Araki, S.; Butsugan, Y. J. Org. Chem. 1991, 56, 2218.
(47) Huang, W. S.; Hu, Q-S.; Pu, L. J. Org. Chem. 1999, 64, 7940.
5352 J. Org. Chem. Vol. 73, No. 14, 2008

Catalytic Ligands for EnantioselectiVe Additions to Aldehydes
was obtained. The ee and the conversion were determined by GC:
ꢀ-DEX 120 Isoterm 115 °C: tR ) 22.5 min, tS ) 26.6 min.
(S)-1-(4-Trifluoromethylphenyl)-ethanol48 (13g). Following the
general procedure GP5 for p-methoxybenzaldehyde (68 µL, 0.50
mmol), the desired product was obtained. The ee and the conversion
were determined by GC: ꢀ-DEX 120 Isoterm 115 °C: tR ) 14.2
min, tS ) 16.6 min.
nitrobenzoate derivative): Daicel CHIRALCEL-ADH. Hexane/2-
propanol 99:1, 0.5 mL/min, λ) 254 nm, tS ) 87.7 min, tR ) 92.8
min.
(S)-(4-Methoxy-phenyl)-phenyl-methanol27f (14d). Following
the general procedure GP6 for p-methoxybenzaldehyde (61 µL, 0.50
mmol), the title compound was obtained. HPLC: Daicel CHIRAL-
CEL-ADH. Hexane/2-propanol 95:5, 0.5 mL/min, λ ) 254 nm, tR
) 40.0 min, tS ) 43.5 min.
(S)-1-m-Tolyl-ethanol48(13h). Following the general procedure
GP5 for m-tolualdehyde (59 µL, 0.50 mmol), the desired product
was obtained. The ee and the conversion were determined by GC:
ꢀ-DEX 120 Isoterm 115 °C: tR ) 17.3 min, tS ) 18.7 min.
(S)-4-Biphenylphenylmethanol27f (14e). Following the general
procedure GP6 for 4-biphenylcarbaldehyde (130 mg, 0.50 mmol),
the title compound was obtained. HPLC: Daicel CHIRALCEL-
ODH. Hexane/2-propanol 95:5, 0.5 mL/min, λ ) 254 nm, tR
)
General Procedure for the Enantioselective Amino Alcohol-
Catalyzed Addition of a Mixed Phenylzinc Species to Alde-
hydes (GP6). A 6.4 mL aliquot of a mother solution containing
Ph2Zn (234 mg, 1.07 mmol) and Et2Zn (266 mg, 2.16 mmol) in
anhydrous toluene (20 mL) was added to the amino alcohol ligand
(0.025 mmol, 5 mol %), under argon. After stirring for 20 min at
room temperature, the reaction mixture was cooled to 10 °C before
the corresponding aldehyde (0.50 mmol) was added dropwise. After
1 h at that temperature, the reaction was quenched by careful
addition of 5 mL of 1 M HCl. It was extracted with Et2O (3 × 10
mL) and dried over MgSO4, and the solvent was removed under
vacuum. The conversion of the reaction was determined by 1H NMR
and the ee by HPLC using the chiral column indicated.
(R)-1-Phenyl-1-heptanol27c (14a). Following the general pro-
cedure GP6 for heptanal (70 µL, 0.50 mmol), the title compound
was obtained. HPLC: Daicel CHIRALCEL-ODH. Hexane/2-
propanol 95:5, 0.5 mL/min, λ) 254 nm, tR) 13.3 min, tS) 14.3
min.
56.3 min, tS ) 59.4 min.
(S)-Phenyl-o-tolyl-methanol51 (14f). Following the general
procedure GP6 for o-tolualdehyde (58 µL, 0.50 mmol), the title
compound was obtained. HPLC: Daicel CHIRALPACK-ODH.
Hexane/2-propanol 95:5, 1.0 mL/min, λ ) 254 nm, tS ) 21.4 min,
tR ) 23.4 min.
(S)-Phenyl-(4-trifluoromethyl-phenyl)-methanol52 (14g). Fol-
lowing the general procedure GP6 for p-trifluoromethyl-benzalde-
hyde (68 µL, 0.50 mmol), the title compound was obtained. HPLC:
Daicel CHIRALPACK-ODH. Hexane/2-propanol 95:5, 0.5 mL/min,
λ ) 254 nm, tR ) 31.1 min, tS ) 34.0 min.
(S)-Phenyl-p-tolyl-methanol27f (14h). Following the general
procedure GP6 for p-tolualdehyde (59 µL, 0.50 mmol), the title
compound was obtained. HPLC: Daicel CHIRALCEL-ODH. Hex-
ane/2-propanol 95:5, 0.5 mL/min, λ ) 254 nm, tS ) 28.0 min, tR
) 31.2 min.
Acknowledgment. This work was funded by MEC (Grant
CTQ2005-02193/BQU), DIUE (Grant 2005SGR225), Con-
solider Ingenio 2010 (Grant CSD2006-0003), and ICIQ
Foundation.
(R)-Cyclohexyl-phenyl-methanol49 (14b). Following the general
procedure GP6 for cyclohexanecarbaldehyde (61 µL, 0.50 mmol),
the title compound was obtained. HPLC: Daicel CHIRALCEL-
ADH. Hexane/2-propanol 90:10, 0.5 mL/min, λ) 254 nm, tS )
23.9 min, tR ) 25.6 min.
1
Supporting Information Available: Copies of H and 13C
NMR spectra of compounds 2-11, 1b-1e, 2a-2b, and
3a-11a. Experimental procedures and spectroscopic data of the
starting olefins. This material is available free of charge via the
Internet at http://pubs.acs.org.
(R)-(E)-2-Methyl-1,3-diphenyl-2-propen-1-ol50 (14c). Follow-
ing the general procedure GP6 for (E)-R-methyl-cinnamaldehyde
(70 µL, 0.50 mmol), the title compound was obtained. HPLC (p-
(48) Shimizu, H.; Igarashi, D.; Kuriyama, W.; Yusa, Y.; Sayo, N.; Saito, T.
Org. Lett. 2007, 9, 1655.
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J. Org. Chem. Vol. 73, No. 14, 2008 5353