Synthesis of Yb complexes with amino-acid-armed ligands for direct asymmetric tandem aldol reduction reactions

Article abstract of DOI:10.1002/ejoc.200800726

A synthetic route to a series of C₂-symmetric chiral ligands armed with selectively protected amino acids have been developed with the aim to study the potential of the corresponding Yb(III) complexes for enantioselective direct aldol reactions

Full text of DOI:10.1002/ejoc.200800726

FULL PAPER
DOI: 10.1002/ejoc.200800726
Synthesis of Yb Complexes with Amino-Acid-Armed Ligands for Direct
Asymmetric Tandem Aldol Reduction Reactions
[a]
[a]
[a]
´ ´
Maciej Stodulski, Jarosław Jazwinski, and Jacek Mlynarski*
Keywords: Aldol reactions / Chiral ligands / Asymmetric catalysis / Yterbium / Amino acids
A synthetic route to a series of C2-symmetric chiral ligands
armed with selectively protected amino acids have been de-
veloped with the aim to study the potential of the corre-
sponding Yb(III) complexes for enantioselective direct aldol
reactions. These ligands, which contain chiral bis(ester) or
bis(amide) moieties, were readily prepared in enantiomer-
ically pure form by the reaction of (S,S)-hydrobenzoin or
(S,S)-diphenylethylenediamine with various chiral amino ac-
ids. In this article, the asymmetric aldol-reduction reaction
leading to 1,3-diols (known as the aldol–Tishchenko reac-
tion) has been performed with an elaborated family of li-
gands. This unique tandem reaction was catalysed by chiral
Yb complexes that promote both the aldol reaction of unacti-
vated carbonyl compounds and the Evans–Tishchenko re-
duction of the aldol intermediates. 1,3-anti-Diols with three
stereogenic centers have been isolated as a result of the con-
densation of aliphatic ketones with aromatic aldehydes with
up to 64% ee. Additional detailed investigations of the na-
ture of the binding of both class of ligands have also been
carried out with high-resolution 1H-, 13C-, and 14N-NMR
techniques.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
action. The aldol condensation is a key C–C bond-forming
reaction, creating the β-hydroxy carbonyl structural unit
found in many natural products and drugs.[6] From the sev-
eral methods available for the asymmetric aldol reaction,[7]
the direct condensation of an aldehyde with a ketone is a
most attractive approach since it does not require the isola-
tion of preformed enolates.[8] In particular, heterodimetallic
complexes have been found to be suitable catalysts for the
direct asymmetric aldol reaction.[9] These catalysts can be
regarded as enzyme mimics of metal-containing, type-II al-
dolases which, in turn, are built essentially from amino
acid-type elements. In this light, it is surprising that, despite
the increasing acceptance of chiral lanthanide complexes as
direct aldol reaction catalysts,[10] the application of modi-
fied amino acids as chiral ligands is limited mainly to zinc
complexes.[11] One example of a chiral lanthanide complex
application is the direct, asymmetric, aldol–Tishchenko re-
action promoted by chiral Yb complexes.[12]
Introduction
Lewis acid-catalyzed reactions are of great interest be-
cause of their unique reactivities and selectivities and mild
reaction conditions used.[1] In particular, Lewis acids having
chiral ligands are becoming more important as catalysts for
selective and asymmetric organic transformations. The in-
fluence of ligands coordinated to Lewis acid-type catalysts
on the rate and particularly the enantioselectivity of organic
reactions is one of the most extensively studied topics in
modern organic chemistry. Among the many Lewis acids
developed so far, lanthanide triflates have received growing
attention because of the combination of their strong Lewis
acidity with their mildness and usually high selectivity.[2]
The use of chiral lanthanide complexes as new catalysts in
asymmetric synthesis is currently of intense interest,[3] but
knowledge about their interaction with chiral ligands re-
mains narrow, and the number of tested structures is still
restricted.[4]
Our success in this field was the discovery of a selective
catalyst for the asymmetric aldol–Tishchenko reaction of
aliphatic ketones with aldehydes.[13] In this unique, one-
step, tandem process, aldehydes reacted with methylene
ketones to give 1,3-diols with three adjacent stereogenic
centers (Scheme 1).[14] Despite the enormous synthetic po-
tential of the aldol–Tishchenko reaction of unmodified
ketones with aldehydes leading directly to an important
class of 1,3-diols, its enantioselective variant needs further
exploration. Interestingly, in all the known procedures of
coupling unmodified ketones and aldehydes, only chiral
lanthanide complexes were used with any success.[15] From
Despite the vast current interest in the biological aspects
of lanthanide coordination chemistry, relatively few investi-
gations have been carried out with amino acid derivatives
as ligands. Considering the natural abundance of α-amino
acids, it is somewhat surprising that their use as ligands in
Lewis-acid catalysis remains largely unexplored.[5]
One of the promising fields of application of such amino
acid-lanthanide complexes is the direct asymmetric aldol re-
[a] Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01224 Warsaw, Poland
Fax: +48-22-6326681
E-mail: mlynar@icho.edu.pl
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M. Stodulski, J. Jaz´win´ski, J. Mlynarski
FULL PAPER
a practical perspective, however, there remains much room
for improvement in the available methodology. Some limita-
tions are still encountered including high catalyst loading
(15–20%), difficulties in obtaining high enantioselectivity,
and the substrate scope being limited to activated aromatic
aldehydes. Therefore, a new catalyst for the asymmetric al-
dol–Tishchenko reaction is needed especially in terms of
improved catalyst efficiency. Despite the creative efforts de-
scribed above, the design and synthesis of new catalysts re-
mains a considerable challenge. Herein, we report the syn-
thesis and application of new Yb-based catalysts, armed
with chiral amino acids, to enantioselective direct aldol re-
actions leading directly to 1,3-diols.
Scheme 2. Asymmetric aldol–Tishchenko reaction promoted by the
ligand 1–Yb complex.
accomplished.[12] In our preliminary experiments, we could
not achieve satisfactory enantioselectivity (20% ee,
Scheme 2). This finding motivated us to further tune the
catalyst and investigate the possible catalytic efficiency of a
more complex ligand composed of selectively blocked chiral
amino acids. We speculated that substitution of the amino-
acid arm at the C-2 position (Scheme 2, arrow A) would
lead to more enantioselective Yb catalysts on the basis of
an interaction with an additional stereogenic center in the
catalyst. Additionally, we modified the protecting groups
on the amino groups (Scheme 2, arrow B) and tested how
changes within the aromatic backbone influenced the reac-
Scheme 1. Condensation of ketones with aldehydes by means of a
catalytic aldol–Tishchenko reaction.
Results and Discussion
Previously, we reported our initial attempt at the asym- tivity and enantioselectivity of the resulting Yb complex
metric aldol–Tishchenko reaction with a glycine-based chi- (Scheme 2, arrow C).
ral ligand complexed with Yb salts, by which the direct
To realize this concept, we prepared a series of ligands
asymmetric aldol reaction of 3-pentanone was efficiently based on the chiral (S,S)-hydrobenzoin backbone (3-OH,
Scheme 3. Chiral ligands derived from (S,S)-hydrobenzoin.
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Catalyzed Asymmetric Aldol Reduction Reaction
Scheme 3). To this backbone were added side arms com- mini turned out even more troublesome. Ligands 8 and 13,
posed of alkyl groups (4–5) or amino acids with dialk- having ethyl groups, were unselective, affording racemic diol
ylamino groups at the termini. To provide a better under- 2 (Table 1, Entries 5 and 10).
standing of the requirements for catalyst reactivity, we pre-
We speculated that para substitution of the backbone
pared both types of ligands. Ligands 4–17 were efficiently phenyl rings could change the catalyst reactivity and selec-
prepared by the DIC-promoted esterification of chiral tivity by altering the complexation properties of the ben-
(S,S)-hydrobenzoin. In addition, the analogous 1,2-dicyclo- zylic oxygens. Unfortunately, attaching electron-donating or
hexylethanediol derivative 6 was also prepared for compari- electron-withdrawing substituents at the para positions of
son with the hydrobenzoin derivatives.[16] para-Substituted ligands 14–16 yielded moderate enantioselectivities but low-
hydrobenzoins were prepared with the Sharpless hydroxyla- ered the reactivities of the catalysts. The application of li-
tion protocol.[17] All di-N-ethyl- and -methyl-protected gand 17, having naphthyl groups, was also not promising
amino acids (glycine, alanine, phenylalanine, valine, and (Table 1, Entry 17).
proline) were prepared under standard conditions.[18]
To improve the enantioselectivity in the tandem aldol re-
With a diverse range of ligands in hand, we then exam- action and provide a better understanding of the require-
ined each of them in the direct, asymmetric, aldol–Tish- ments for a good asymmetric induction, we changed ligand
chenko reaction. The results of the catalytic reaction of structure to tune the character of the binding atoms around
benzaldehyde with 3-pentanone in THF with a catalyst the catalytic center. Our means of limiting the number of
composed of Yb(OTf)3 and the prepared ligands (1:1, available transition states in the enantiodetermining step
20 mol-%) are collected in Table 1.
was to restrict the number of degrees of freedom in the
metal–ligand complex. One degree of freedom results from
rotation about the carbon–oxygen bond in the esters. This
may be rigidified by going to the analogous amide linkage.
Moreover, in the development of Yb-containing catalysts,
the use of N,N-donor ligands seemed attractive, as they
would allow for the systematic tuning of both steric and
electronic properties. In order to realize this concept, we
prepared amide ligands 18–26 from the corresponding,
Table 1. Asymmetric aldol–Tishchenko reaction of benzaldehyde
and 3-pentanone, promoted by Yb complexes with the ligands de-
picted in Scheme 3.
Entry
Ligand
% Yield[a]
% ee
1
2
3
4
5
6
7
8
4
5
n.d.
n.d.
15
95
68
98
97
70
98
66
55
35
13
92
–
–
5
6
7
40 (1S,2S,3R)[b]
[19]
readily available, enantiomerically pure diamine 3-NH2
(Scheme 4).
8
0
0
0
9
40
0
23
14
27
30
9
10
11
12
13
14
15
16
17
Optically pure 1,2-diaminocyclohexane and diphenyl-
ethylenediamine were acylated with the appropriately pro-
tected amino acids using DIC to give the corresponding
chiral ligands. (1S,2S)-N1,N2-Dimethyl-1,2-diphenylethane-
1,2-diamine, the substrate for ligand 20, was prepared ac-
cording to literature procedure.[20] N-Ethyl-, N-benzyl-, and
N-isopropyl-N-methyl alanine were also prepared by known
protocols.[21] Table 2 summarize the application of these li-
gands to the reaction of Scheme 2.
9
10
11
12
13
14
[a] Yield of isolated diol 2. [b] The absolute configuration was de-
termined by HPLC and CD techniques.[13c]
The ligands without a tertiary amine group were inferior
As we observed for the ester-type ligands, aromatic sub-
in this application (Table 1, Entries 1 and 2). Therefore, it stituents in the ligand backbone were essential for catalyst
appears that the presence of a basic coordination site in the reactivity. Diaminocyclohexane derivative 18 was not suit-
ligand is essential for catalyst reactivity. The ligand derived able as a ligand. The amide-based catalyst with glycine side
from glycine and 1,2-dicyclohexyloethanediol led to a small arms led to increased enantioselectivity (30% ee, Table 2
increase in reactivity and enantioselectivity and afforded Entry 2 vs. 20% ee, Scheme 2), albeit at the expense of the
diol 2 in 5% ee only. Thus, the aromatic substituents in yield. Additional N-methyl groups in the ligand backbone
the catalyst backbone were indispensable for reactivity. The adversely affected the catalyst reactivity (Table 2, Entry 3).
most promising levels of enantioselectivity (40% ee) and Further improvements in the selectivity were achieved for
yield were obtained with ligands composed of dimethylala- the chiral amino acids. Alanine-based ligand 21 afforded
nine (7, Table 1, Entry 4) and methylproline (12, Table 1, the product with a 30% ee, while the N-methyl-proline-
Entry 9). For both ligands, diols with a (1S,2S,3R) configu- based ligand 22 resulted in a 50% ee. To study the catalytic
ration predominated. The level of asymmetric induction effect of inverting stereocenters in the ligand, we prepared
was similar to that observed with ligands lacking ligand 23 from the (R,R)-amine, but the resulting ligand
stereogenic centers in the amino-acid arms.
was unreactive. This indicates that the diastereomeric cata-
Unfortunately, the further modification of the ligand lyst 22 with matched configurations (R,R) between the
structures at the α position in the amino-acid arms was not backbone and side-arm stereocenters was better than cata-
productive. The application of amino acids with bulkier lyst 23 with a mismatched configuration (R,S).
substituents like valine (9 and 10) and phenylalanine (11)
Additionally, various ligands with two different alkyl
was not promising. Surprisingly, tuning at the nitrogen ter- groups attached to the N termini were tested. Although the
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M. Stodulski, J. Jaz´win´ski, J. Mlynarski
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Scheme 4. Amine-derived chiral ligands.
Table 2. Asymmetric aldol–Tishchenko reaction of benzaldehyde (Table 3). For several substrates, a higher catalyst loading
and 3-pentanone promoted by Yb complexes with the ligands de-
picted in Scheme 4.
was necessary to obtain higher yields. All the aromatic alde-
hydes tested gave useful product yields. In addition to benz-
Entry
Ligand
% Yield[a]
% ee
aldehyde, other aromatic substrates reacted effectively to
give diols in good yields with high anti selectivities. A less
electrophilic anisaldehyde delivered diols in slightly lower
yields but with higher enantiocontrol of 64% ee (Table 3,
Entries 11–13). A number of aliphatic (K1–K3) and aro-
matic (K4–K6) ketones can be used as a donors without a
loss of efficiency or enantiocontrol. Moreover, the catalysts
exhibited similar efficiencies without considerable deterio-
ration of enantiocontrol for more demanding substrates (di-
butyl- and dipropylketone).
1
2
3
4
5
6
7
8
9
18
19
23
42
n.d.
46
51
50
n.d.
91
95
0
30
–
40
20
21
22
50 (1S,2S,3R)
48 (1R,2R,3S)
ent-22
23
–
24
46
10
10
25
10
26
55
[a] Yield of isolated diol 2.
To shed light on the possible structure of the catalysts
and the catalytic action of species formed in situ, we gained
insight into the NMR spectra of Yb complexes with repre-
sentative examples of both classes of tested ligands. We first
N-ethyl-N-methyl combination did not alter the enantio-
selectivity significantly, the yield was much better than that
observed for the other amide-type ligands (Table 2, Entry
8). For this ligand, as little as 5 mol-% of the catalyst was
sufficient to produce a high yield. Replacing the ethyl group
with a benzyl or isopropyl group resulted in the loss of
enantioselectivity (Table 2, Entries 9 and 10).
1
examined the H and 13C NMR spectra of a complex of
glycine-based (bis)ester 1 and Yb(OTf)3 in a 1:1 mole ratio.
To maintain the reaction conditions, all spectra were re-
corded in [D8]THF.
1
The H and 13C NMR spectra of this catalyst show un-
equivocal downfield shifts of all the signals (Figure 1). The
most interesting shift was that of the methylene signals at δ
= 3.18 ppm. These diastereotopic protons generated sepa-
rate NMR signals in an AB pattern at 4.15 and 4.61 ppm
(Figure 1).
In all cases, THF was the solvent of choice. Changing
the reaction medium to more or less polar or coordinating
solvents decreased the reactivity. In general, the reaction
was not temperature-dependent. Decreasing the reaction
temperature to 0 °C affected only the yield, since a reaction
at 40 °C was much faster. In both cases, the selectivity was
Such a change must have resulted from a restrained rota-
unchanged. Other metal sources tested in this reaction with tion in the amino-acid arms. This observation and the C2
ligand 22 gave either less satisfactory results [Sc(OTf)3, symmetry of the complex, deduced from the NMR spectra,
Er(OTf)3, and Eu(OTf)3] or failed to react altogether suggest coordination of the Yb to both nitrogens. To sup-
[Pr(OTf)3, La(OTf)3, Yb(O-iPr)3, and YbCl3].
port this speculation, we also recorded the 14N spectrum of
The combination of Yb(OTf)3 with the best ligands 12, the complex. The results of this experiment confirmed the
22, and 24 was subsequently employed in the tandem aldol- complexation of the Yb cation to the tertiary amines. In the
reduction reactions of various ketones and aldehydes measured complex, the nitrogens were shifted downfield by
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Catalyzed Asymmetric Aldol Reduction Reaction
Table 3. Asymmetric reaction of aldehydes with ketones, catalyzed by Yb(III) triflate and ligands 12, 22 and 24.
Entry
Ketone
Aldehyde R
Product
Ligand
Catalyst loading [mol-%]
Yield[a] [%]
e.r.
1
2
3
4
5
6
7
8
K1
K1
K1
K1
K1
K2
K3
K1
K2
K3
K1
K1
K1
K2
K1
K1
K4
K5
K6
K4
H
H
H
H
H
H
H
27
27
27
27
27
28
29
30
31
32
33
33
33
34
35
36
37
38
39
40
12
22
22
24
24
24
24
22
22
24
22
22
22
22
24
22
24
24
24
24
20
20
30
10
20
20
20
40
40
30
20
30
40
40
20
40
20
20
20
20
98
48
97
70:30
75:25
75:25
73:27
73:27
78:22
77:23
78:22
78:22
76:24
87:23
87:23
87:23
75:25
65:35
78:22
75:25
69:31
77:23
68:32
54 (72)[b]
92
74
95
98
69
54
26
75
98
44
84
96
79
87
44
53
CH3
CH3
CH3
OCH3
OCH3
OCH3
OCH3
Br
C(CH3)3
H
H
H
OCH3
9
10
11
12
13
14
15
16
17
18
19
20
[a] Yield of isolated diol 2. [b] The yield in parentheses was obtained at 40 °C.
which the same rule was observed for the Yb complex of
triethylamine. In the 14N NMR, the nitrogen of the
Yb(OTf)3–Et3N complex (1:1) was shifted downfield rela-
tive to that of triethylamine (Figure 2).
Figure 2. 14N NMR chemical shifts of measured Yb complexes.
We made further deductions of the complex architecture
1
based on the H NMR spectra of 1 and Yb(OTf)3 in vari-
ous stoichiometric ratios. The chemical shift of the methyl-
ene protons changed when 0.5 equiv. of Yb(OTf)3 was
added to ligand 1 (Figure 3), indicating the formation of
complexed chemical species among the uncomplexed ligand
when less than 1.0 equiv. of Yb salt was added. Saturation
was observed when 1.0 equiv. of Yb(OTf)3 was added, indi-
cating a 1:1 stoichiometric complexation of metal salt to
Figure 1. 1H NMR spectra of ligand 1 (a) and the 1–Yb(OTf)3 (1:1)
complex (b) in [D8]THF. The scheme illustrates the NMR chemical
shifts of ligand 1 and Yb complex (bold).
about 20 ppm relative to 1 (–344.2 and –364.3 ppm, respec- ligand.
tively, Figure 2). This rather unexpected change in the
The 1H NMR spectra of a complex composed of the
chemical shifts of the N–metal complex vs. the free amino structurally related amide ligand 19 showed similar features
group was further investigated with a model experiment, in to those observed for the ester-based complex. In the ti-
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M. Stodulski, J. Jaz´win´ski, J. Mlynarski
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1
Figure 4. H NMR spectra of complex 19–Yb(OTf)3 (1:1) in [D8]-
THF measured at 303 K and 263 K, compared with the spectrum
of ligand 19. The scheme illustrates the NMR chemical shifts of
ligand 19 and its Yb complex (bold).
amide proton and the lateral amino groups can also be as-
sumed, as shown in structure B in Figure 5. Unfortunately,
suitable crystals of the complex could not be obtained for
X-ray analysis.
Figure 3. 1H NMR titration of 1 with Yb(OTf)3 in [D8]THF (meth-
ylene region) at 25 °C.
tration experiment, saturation was observed for a 1:1 stoi-
chiometric complexation of metal salt to ligand 19. As a
result of complexation, both diastereotopic methylene pro-
tons showed different chemical shifts, and the groups be-
came magnetically non equivalent. This observation re-
quired a lower temperature NMR experiment (Figure 4).
At T Ͼ –10 °C, the N-methyl signals coalesced, which was
evidence for the fast inversion of the N-methyl nitrogen on
the NMR time scale. Interestingly, this inversion was slower
at around 0 °C.
The chemical shift of the NH proton changed upon com-
plexation with the Yb salt from 7.89 ppm to 8.58 ppm but
was still observed in the amide region. This suggested a
nitrogen–Yb complexation with the hydrogen still attached
to nitrogen. Such a complexation, although highly debat-
able, was previously postulated for Yb(III) triflate based on
NMR and MS experiments.[22] Thus, based on our observa-
tions of similar reactivity of the ester- and amide-type li-
gands, the structures of the catalysts were tentatively as-
sumed as shown in Figure 5. In both cases, the complex-
ation of four heteroatoms is possible and is postulated
based on NMR experiments (Figure 5, structure A). For
Figure 5. A plausible catalyst structure.
Conclusions
In conclusion, we have presented careful insight into a
new class of Yb complexes with chiral bis(ester) and (bis)-
amide ligands for a tandem asymmetric aldol reaction. A
modular design of the catalyst is possible by varying the
starting chiral backbone and amino-acid parts of the li-
gands. The most reactive ligand for this reaction was readily
prepared (in two steps) from commercially available starting
materials, and it can be obtained in both enantiomeric
forms. Catalyst YbIII-24 was the most active for aliphatic
ketone donors. Current studies are directed at further im-
proving the enantioselectivity of the reactions and the prac-
tical application of the asymmetric aldol–Tischenko meth-
odology to the synthesis more complex molecules.
Experimental Section
General: All reactions involving organometallic or other moisture-
the amide ligand, additional hydrogen bonding between the sensitive reagents were carried out under argon with standard vac-
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Catalyzed Asymmetric Aldol Reduction Reaction
uum line techniques and glassware that was flame dried and cooled
under Ar before use. Solvents were dried according to standard
procedures. All organic solutions were dried with Na2SO4. Thin-
layer chromatography was performed with aluminum plates coated
with 60 F254 silica (Merck). Plates were visualized with UV light
(254 nm) and ethanolic phosphomolybdic acid solution or etha-
nolic ninhydrin solution followed by heating. Reaction products
were purified by flash chromatography with silica gel 60 (240–
400 mesh, Merck). Optical rotations were measured with a JASCO
Dip-360 Digital Polarimeter at room temperature. Specific rota-
tions are reported in 10–1 degcm2 g–1 and in concentrations of
grams per 100 mL. 1H NMR spectra were recorded with a Varian-
200, Varian-400, or Bruker-500 spectrometer in [D8]THF or CDCl3
with Me4Si as an internal standard. High-resolution mass spectra
were recorded with a Mariner PerSeptive Biosystems mass spec-
trometer with a time-of-flight (TOF) detector. IR spectra were re-
corded with a Perkin–Elmer FT-IR-1600 spectrophotometer as
either a thin film on NaCl plates (film), as a KBr disc (KBr), or as
chloroform solutions in 0.1 mm cells (CHCl3), as stated.
(2S,2ЈS)-[(1S,2S)-1,2-Diphenylethane-1,2-diyl] Bis[2-(diethylamino)-
propanoate] (8): Yield 176 mg, 75%. [α]2D0 = –15.0 (c = 0.53 in
CHCl3); Rf = 0.50 (Hex/AcOEt, 1:1). 1H NMR (CDCl3, 200 MHz):
δ = 0.99 (t, J = 7.0 Hz, 12 H), 1.24 (d, J = 7.2 Hz, 6 H), 2.30–2.70
(m, 8 H), 3.58 (q, J = 7.2 Hz, 2 H), 6.09 (s, 2 H), 7.00–7.20 (m, 10
H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 14.1, 15.3, 44.4, 58.0,
77.1, 127.4, 128.0, 128.2, 136.3, 172.9 ppm. IR (CHCl ): ν = 2971,
˜
3
2935, 1736, 1454, 1375, 1199, 1154, 1106, 1077, 698 cm–1. HRMS
(ESI): calcd. for C28H41N2O4 [M + H]+ 469.3061; found 469.3081.
(2S,2ЈS)-[(1S,2S)-1,2-Diphenylethane-1,2-diyl]
Bis[2-(dimethyl-
amino)-3-methylbutanoate] (9): Yield 164 mg, 70%. [α]2D0 = +14.9 (c
1
= 0.52 in CHCl3); Rf = 0.50 (Hex/AcOEt, 7:3). H NMR (CDCl3,
200 MHz): δ = 0.77 (d, J = 6.4 Hz, 6 H), 0.94 (d, J = 6.6 Hz, 6 H),
1.80–2.10 (m, 2 H), 2.17 (s, 6 H), 2.73 (d, J = 10.6 Hz, 2 H), 6.12
(s, 2 H), 7.15–7.25 (m, 10 H) ppm. 13C NMR (CDCl3, 50 MHz): δ
= 19.2, 19.9, 27.4, 41.4, 73.9, 77.1, 127.9, 128.0, 128.2, 136.6, 171.1
ppm. IR (CHCl ): ν = 2971, 2935, 1720, 1454, 1199, 1154, 1106,
˜
3
1077, 698, 611 cm–1. HRMS (EI): calcd. for C20H40N2O4 [M]+
468.2988; found 468.2999.
General Procedure for the Preparation of Ester Ligands 4–17: A
mixture of (1S,2S)-1,2-diarylethane-1,2-diol [for (S,S)-hydroben-
zoin: 107 mg, 0.5 mmol, FLUKA], N,N-dimethylamino acid
(2 mmol), 1,3-dicyclohexylcarbodiimide (412 mg, 2 mmol), and
DMAP (6 mg, 0.05 mmol) in dry DCM (5 mL) was stirred magnet-
ically under argon for 24 h. The precipitate was removed by fil-
tration, and the residue was washed with DCM (5 mL). The solvent
was evaporated, and the residue was purified by flash column
chromatography to afford esters 4–17.
(S)-{(1S,2S)-2-[(R)-2-(Dimethylamino)-3-methylbutanoyloxy]-1,2-
diphenylethyl} 2-(Dimethylamino)-3-methylbutanoate (10): Yield
176 mg, 75%. [α]2D0 = +46.2 (c = 0.54 in CHCl3); Rf = 0.50 (Hex/
AcOEt, 7:3). 1H NMR (CDCl3, 200 MHz): δ = 0.67 (d, J = 6.6 Hz,
6 H), 0.94 (d, J = 6.8 Hz, 6 H), 1.80–2.00 (m, 2 H), 2.21 (s, 6 H),
2.80 (d, J = 10.2 Hz, 2 H), 6.06 (s, 2 H), 7.10–7.25 (m, 10 H) ppm.
13C NMR (CDCl3, 50 MHz): δ = 19.7, 19.9, 28.1, 41.2, 73.9, 77.6,
127.6, 128.0, 128.1, 136.5, 171.2 ppm. IR (CHCl ): ν = 2963, 2937,
˜
3
2792, 1723, 1456, 1145, 1121, 988, 700, 598 cm–1. HRMS (ESI):
calcd. for C28H41N2O4 [M + H]+ 469.3061; found 469.3062.
(1S,2S)-1,2-Diphenylethane-1,2-diyl Dipropionate (4): Yield 160 mg,
98%. [α]2D0 = +21.5 (c = 1.03 in CHCl3); Rf = 0.60 (Hex/AcOEt,
(2S,2ЈS)-[(1S,2S)-1,2-Diphenylethane-1,2-diyl]
Bis[2-(dimeth-
1
4:1). H NMR (CDCl3, 200 MHz): δ = 1.12 (t, J = 7.4 Hz, 6 H),
ylamino)-2-phenylacetate] (11): Yield 81 mg, 30%. [α]2D0 = +48.6 (c
2.36 (q, J = 7.4 Hz, 4 H), 6.07 (s, 2 H), 7.10–7.25 (m, 10 H) ppm.
1
= 0.52 in CHCl3); Rf = 0.35 (Hex/AcOEt, 1:1). H NMR (CDCl3,
13C NMR (CDCl3, 50 MHz): δ = 9.1, 27.8, 77.0, 127.5, 128.1,
200 MHz): δ = 2.07 (s, 12 H), 3.87 (s, 2 H), 5.98 (s, 2 H), 6.85–6.95
(m, 4 H), 7.00–7.15 (m, 6 H), 7.20–7.35 (m, 10 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 43.1, 74.7, 76.9, 127.1, 127.8, 128.0, 128.2,
128.3, 136.3, 173.1 ppm. IR (CHCl ): ν = 3033, 2982, 2947, 1724,
˜
3
1280, 1212, 1067, 1009, 701, 550 cm–1. HRMS (ESI): calcd. for
C20H22O4, [M + Na]+ 349.1410; found 349.1398.
128.4, 128.7, 135.8, 136.2, 170.4 ppm. IR (CHCl ): ν = 2939, 2830,
˜
3
(1S,2S)-1,2-Diphenylethane-1,2-diyl Bis(2-methoxyacetate) (5):
Yield 173 mg, 97%. [α]2D0 = +30.1 (c = 1.04 in CHCl3); Rf = 0.60
(Hex/AcOEt, 1:1). 1H NMR (CDCl3, 200 MHz): δ = 3.40 (s, 6 H),
4.04 (s, 4 H), 6.18 (s, 2 H), 7.05–7.25 (m, 10 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 59.4, 69.7, 77.3, 127.5, 128.3, 128.6, 135.4
2792, 1752, 1738, 1450, 1204, 1131, 1041, 699 cm–1. HRMS (EI):
calcd. for C34H36N2O4 [M]+ 536.2675; found 536.2685.
(2S,2ЈS)-[(1S,2S)-1,2-Diphenylethane-1,2-diyl] Bis(1-methylpyrrol-
idine-2-carboxylate) (12): Yield 160 mg, 79%. [α]2D0 = –45.5 (c =
0.51 in CHCl3); Rf = 0.35 (AcOEt/MeOH, 4:1). 1H NMR (CDCl3,
400 MHz): δ = 1.75–1.90 (m, 6 H), 2.00–2.15 (m, 2 H), 2.20–2.35
(m, 10 H), 3.00–3.15 (m, 2 H), 7.10–7.20 (m, 10 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 23.1, 29.4, 40.6, 56.1, 67.1, 77.0, 127.3,
ppm. IR (CHCl ): ν = 2992, 2937, 2823, 1755, 1193, 1176, 1126,
˜
3
778, 702, 594 cm–1. HRMS (ESI): calcd. for C20H22O6 [M + Na]+
381.1309; found 381.1326.
(1S,2S)-1,2-Dicyclohexylethane-1,2-diyl Bis[2-(dimethylamino)ace-
tate] (6): From (1S,2S)-1,2-dicyclohexyl-1,2-ethanediol.[16] Yield
149 mg, 75%. [α]2D0 = –18.3 (c = 0.52 in CHCl3); Rf = 0.30 (AcOEt/
MeOH, 9:1). 1H NMR (CDCl3, 200 MHz): δ = 0.80–1.70 (m, 22
H), 2.37 (s, 12 H), 3.22 (s, 4 H), 5.04 (d, J = 6.8 Hz, 2 H) ppm.
13C NMR (CDCl3, 50 MHz): δ = 25.8, 26.1, 28.3, 29.1, 29.6, 38.4,
128.1, 128.2, 136.2, 172.5 ppm. IR (CHCl ): ν = 3409, 2957, 2538,
˜
3
1748, 1455, 1233, 1196, 997, 756, 700 cm–1. HRMS (ESI): calcd.
for C26H33N2O4 [M + H]+ 437.2434; found 437.2448.
(2S,2ЈS)-[(1S,2S)-1,2-Diphenylethane-1,2-diyl]
Bis(1-ethylpyrrol-
idine-2-carboxylate) (13): Yield 174 mg, 75%. [α]2D0 = –52.9 (c =
0.10 in CHCl3); Rf = 0.35 (Hex/acetone, 3:2). 1H NMR (CDCl3,
500 MHz): δ = 0.98 (t, J = 7.2 Hz, 6 H), 1.75–1.95 (m, 6 H), 2.00–
2.10 (m, 2 H), 2.30–2.39 (m, 4 H), 2.58–2.66 (m, 2 H), 3.05–3.15
(m, 2 H), 3.20–3.26 (m, 2 H), 6.14 (s, 2 H), 7.15–7.25 (m, 10 H)
ppm. 13C NMR (CDCl3, 125 MHz): δ = 13.6, 23.1, 29.1, 48.3, 52.7,
45.1, 59.9, 75.6, 170.2 ppm. IR (CHCl ): ν = 2924, 2852, 2817,
˜
3
1751, 1450, 1187, 1158, 1058, 984, 854 cm–1. HRMS (ESI): calcd.
for C22H41N2O4 [M + H]+ 397.3061; found 397.3072.
(2S,2ЈS)-[(1S,2S)-1,2-Diphenylethane-1,2-diyl]
Bis[2-(dimethyl-
amino)propanoate] (7): Yield 166 mg, 86%. [α]2D0 = +6.5 (c = 1.02
in CHCl3); Rf = 0.25 (DCM/MeOH, 95:5). 1H NMR (CDCl3,
200 MHz): δ = 1.24 (d, J = 7.2 Hz, 6 H), 2.25 (s, 12 H), 3.30 (q, J
= 7.2 Hz, 2 H), 6.13 (s, 2 H), 7.05–7.30 (m, 10 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 15.3, 41.4, 62.5, 77.1, 127.4, 128.1, 128.3,
65.3, 76.9, 127.2, 128.1, 128.2, 136.3, 173.0 ppm. IR (KBr): ν =
˜
2988, 2806, 1735, 1455, 1244, 1175, 1067, 706, 593, 494 cm–1.
HRMS (ESI): calcd. for C28H37N2O4 [M + H]+ 465.2748; found
465.2738.
136.2, 172.0 ppm. IR (CHCl ): ν = 2979, 2937, 2834, 1730, 1456,
(2S,2ЈS)-[(1S,2S)-1,2-Bis(4-fluorophenyl)ethane-1,2-diyl]
methylpyrrolidine-2-carboxylate) (14): Yield 185 mg, 78%. [α]2D0
–54.3 (c = 0.52 in CHCl3); Rf = 0.15 (AcOEt/MeOH, 9:1). 1H
Bis(1-
˜
3
1173, 1149, 1109, 698, 598 cm–1. HRMS (ESI): calcd. for
C24H32N2O4 [M + Na]+ 435.2254; found 435.2237.
=
Eur. J. Org. Chem. 2008, 5553–5562
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5559

M. Stodulski, J. Jaz´win´ski, J. Mlynarski
FULL PAPER
NMR (CDCl3, 200 MHz): δ = 1.80–2.05 (m, 9 H), 2.15–2.40 (m, 9
H), 2.95–3.15 (m, 2 H), 6.09 (s, 2 H), 6.85–6.98 (m, 4 H), 7.05–7.15
(m, 4 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 23.2, 29.5, 40.7,
CHCl3); Rf = 0.20 (AcOEt/MeOH, 4:1). 1H NMR (CDCl3,
200 MHz): δ = 2.24 (s, 12 H), 2.92 (s, 4 H), 5.20–5.40 (m, 2 H),
7.05–7.30 (m, 10 H), 7.95–8.05 (m, 2 H) ppm. 13C NMR (CDCl3,
56.2, 67.1, 76.3, 115.2 (d, J = 21.5 Hz), 129.1 (d, J = 8.4 Hz), 131.9, 50 MHz): δ = 45.9, 57.8, 63.1, 127.4, 127.5, 128.3, 138.8, 170.5
162.5 (d, J = 246.2 Hz) ppm. IR (CHCl ): ν = 2956, 2843, 2802, ppm. IR (CHCl ): IR (KBr): ν = 3295, 2942, 2818, 1645, 1512,
˜
˜
3
3
1736, 1514, 1352, 1252, 1008, 847, 552 cm–1. HRMS (ESI): calcd.
for C26H31N2O4F2 [M + H]+ 473.2246; found 473.2268.
1271, 1046, 865, 698, 553 cm–1. HRMS (ESI): calcd. for
C22H31N4O2 [M + H]+ 383.2442; found 383.2437.
(2S,2ЈS)-[(1S,2S)-1,2-Bis(4-methoxyphenyl)ethane-1,2-diyl] Bis(1-
N,NЈ-[(1S,2S)-1,2-Diphenylethane-1,2-diyl]bis[2-(dimethylamino)-N-
methylacetamide] (20): Yield 406 mg, 97%. [α]2D0 = +396.4 (c = 0.29
in CHCl3); Rf = 0.30 (AcOEt/MeOH, 4:1). 1H NMR (CDCl3,
200 MHz): δ = 2.32 (s, 12 H), 2.76 (s, 6 H), 3.09 (s, 4 H), 6.75 (s,
methylpyrrolidine-2-carboxylate) (15): Yield 163 mg, 66%. [α]2D0
=
–60.1 (c = 0.27 in CHCl3); Rf = 0.25 (AcOEt/MeOH, 9:1). 1H
NMR (CDCl3, 200 MHz): δ = 1.75–1.98 (m, 6 H), 2.00–2.10 (m, 2
H), 2.20–2.40 (m, 10 H), 2.95–3.15 (m, 2 H), 3.75 (s, 6 H), 6.08 (s,
2 H), 6.65–6.80 (m, 2 H), 7.00–7.10 (m, 2 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 23.2, 29.4, 40.7, 55.1, 56.1, 67.2, 76.7, 113.5,
2 H), 7.10–7.35 (m, 10 H) ppm. IR (CHCl ): ν = 2944, 2825, 1639,
˜
3
1454, 1404, 1320, 1038, 750, 701, 532 cm–1. HRMS (ESI): calcd.
for C24H35N4O2 [M + H]+ 411.2755; found 411.2775.
128.4, 128.8, 159.3, 172.5 ppm. IR (CHCl ): ν = 2960, 2839, 2785,
˜
3
(2S,2ЈS)-N,NЈ-[(1S,2S)-1,2-Diphenylethane-1,2-diyl]bis[2-(dimeth-
ylamino)propanamide] (21): Yield 368 mg, 90%. [α]2D0 = +47.6 (c =
1.00 in CHCl3); Rf = 0.25 (AcOEt/MeOH, 4:1). 1H NMR (CDCl3,
200 MHz): δ = 1.11 (d, J = 7.0 Hz, 6 H), 2.18 (s, 12 H), 2.97 (q, J
= 7.0 Hz, 2 H), 5.15–5.30 (m, 2 H), 7.00–7.25 (m, 10 H), 8.05–8.20
(m, 2 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 10.9, 41.9, 58.2,
1739, 1516, 1255, 1200, 1174, 1029, 822 cm–1. HRMS (ESI): calcd.
for C28H38N2O6 [M + H]+ 497.2646; found 497.2658.
(2S,2ЈS)-[(1S,2S)-1,2-Bis(4-tert-butylphenyl)ethane-1,2-diyl] Bis(1-
methylpyrrolidine-2-carboxylate) (16): Yield 214 mg, 78%. [α]2D0
=
–50.0 (c = 0.15 in CHCl3); Rf = 0.25 (AcOEt/MeOH, 9:1). 1H
NMR (CDCl3, 200 MHz): δ = 1.25 (s, 18 H), 1.55–2.10 (m, 9 H),
2.15–2.35 (m, 9 H), 2.97–3.15 (m, 2 H), 6.21 (s, 2 H), 7.05–7.25 (m,
8 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 23.1, 29.4, 31.2, 34.4,
40.6, 56.1, 67.1, 77.6, 124.9, 126.5, 133.3, 150.9, 172.4 ppm. IR
64.4, 127.3, 127.4, 128.2, 139.2, 174.0 ppm. IR (KBr): ν = 3310,
˜
2937, 1646, 1508, 1454, 1204, 1158, 1099, 701, 580 cm–1. HRMS
(ESI): calcd. for C24H35N4O2 [M + H]+ 411.2755; found 411.2737.
(2S,2ЈS)-N,NЈ-[(1S,2S)-1,2-Diphenylethane-1,2-diyl]bis(1-methyl-
pyrrolidine-2-carboxamide) (22): Yield 401 mg, 92%. [α]2D0 = –73.3
(c = 0.51 in CHCl3); Rf = 0.30 (AcOEt/MeOH, 4:1). 1H NMR
(CDCl3, 200 MHz): δ = 1.55–1.75 (m, 6 H), 2.05–2.18 (m, 2 H),
2.20–2.40 (m, 8 H), 2.82–2.94 (m, 2 H), 3.05–3.18 (m, 2 H), 5.20–
5.35 (m, 2 H), 7.00–7.20 (m, 10 H), 8.10–8.25 (m, 2 H) ppm. 13C
NMR (CDCl3, 50 MHz): δ = 24.3, 30.9, 41.9, 56.6, 57.7, 68.9,
(CHCl ): ν = 2966, 2790, 1753, 1461, 1269, 1155, 1057, 833, 727,
˜
3
569 cm–1. HRMS (ESI): calcd. for C34H49N2O4 [M + H]+ 549.3687;
found 549.3679.
(2S,2ЈS)-[(1S,2S)-1,2-Bis(naphthalen-1-yl)ethane-1,2-diyl] Bis[2-(di-
methylamino)propanoate] (17): Yield 207 mg, 81%. [α]2D0 = –58.0 (c
= 0.50 in CHCl3); Rf = 0.20 (AcOEt/MeOH, 9:1). 1H NMR
(CDCl3, 200 MHz): δ = 1.26 (d, J = 7.0 Hz, 6 H), 2.21 (s, 6 H),
3.36 (q, J = 7.0 Hz, 2 H), 7.12 (s, 2 H), 7.18–7.28 (m, 2 H), 7.31–
7.50 (m, 6 H), 7.55–7.75 (m, 4 H), 8.15–8.25 (m, 2 H) ppm. 13C
NMR (CDCl3, 50 MHz): δ = 15.3, 41.4, 62.5, 74.3, 123.3, 124.5,
125.5, 126.2, 126.4, 128.6, 129.1, 130.5, 132.3, 133.5, 172.1 ppm.
127.2, 127.3, 128.2, 139.0, 174.3 ppm. IR (CHCl ): ν = 3298, 2943,
˜
3
2733, 1648, 1504, 1314, 1255, 1048, 699, 550 cm–1. HRMS (ESI):
calcd. for C26H35N4O2 [M + H]+ 435.2755; found 435.2770.
(2R,2ЈR)-N,NЈ-[(1R,2R)-1,2-Diphenylethane-1,2-diyl]bis(1-methyl-
pyrrolidine-2-carboxamide) (ent-22): Yield 404 mg, 93%. [α]2D0
=
IR (CHCl ): ν = 2934, 2869, 2791, 1740, 1451, 121, 1175, 1106,
˜
3
+75.0 (c = 0.50 in CHCl3); Rf = 0.30 (AcOEt/MeOH, 4:1). 1H
NMR (CDCl3, 200 MHz): δ = 1.55–1.75 (m, 6 H), 2.05–2.18 (m, 2
H), 2.20–2.40 (m, 8 H), 2.82–2.94 (m, 2 H), 3.05–3.18 (m, 2 H),
5.20–5.35 (m, 2 H), 7.00–7.20 (m, 10 H), 8.10–8.25 (m, 2 H) ppm.
13C NMR (CDCl3, 50 MHz): δ = 24.3, 30.9, 41.9, 56.6, 57.7, 68.9,
969, 776 cm–1. HRMS (ESI): calcd. for C32H37N2O4 [M + H]+
513.2748; found 513.2738.
General Procedure for the Preparation of Amide Ligands 18–26: To
a cooled solution of the N,N-dimethylamino acid (2 mmol) in dry
DCM (4 mL), triethylamine (306 µL, 2.2 mmol) and ethyl chloro-
formate (192 µL, 2 mmol) were added at 0 °C. After 30 min, a solu-
tion of (1S,2S)-1,2-diphenylethane-1,2-diamine[19] (213 mg,
1 mmol) in dry DCM (4 mL) was added. The mixture was stirred
magnetically for 12 h under argon. The reaction mixture was
washed with water (5 mL). The layers were separated, and the
aqueous layer was extracted with DCM (3ϫ5 mL). The combined
organic layers were dried with anhydrous sodium sulfate, concen-
trated with a rotary evaporator, and the residue was purified by
flash column chromatography (AcOEt/MeOH, 4:1) to afford
amides 18–26.
127.2, 127.3, 128.2, 139.0, 174.3 ppm. IR (KBr): ν = 3298, 2943,
˜
2733, 1648, 1504, 1314, 1225, 1048, 699, 550 cm–1. HRMS (ESI):
calcd. for C26H35N4O2 [M + H]+ 435.2755; found 435.2770.
(2S,2ЈS)-N,NЈ-[(1R,2R)-1,2-Diphenylethane-1,2-diyl]bis(1-methyl-
pyrrolidine-2-carboxamide) (23): Yield 399 mg, 92%. [α]2D0 = –96.5
(c = 0.59 in CHCl3); Rf = 0.30 (AcOEt/MeOH, 4:1). 1H NMR
(CDCl3, 200 MHz): δ = 1.73–1.90 (m, 6 H), 2.5–2.40 (m, 10 H),
2.75–2.85 (m, 2 H), 3.05–3.18 (m, 2 H), 5.15–5.35 (m, 2 H), 7.00–
7.20 (m, 10 H), 8.05–8.15 (m, 2 H) ppm. 13C NMR (CDCl3,
50 MHz): δ = 24.2, 30.9, 41.5, 56.5, 57.6, 68.9, 127.2, 127.4, 128.2,
139.2, 174.4 ppm. IR (CHCl ): ν = 3298, 2943, 2733, 1648, 1504,
˜
3
N,NЈ-[(1S,2S)-Cyclohexane-1,2-diyl]bis[2-(dimethylamino)acet-
amide] (18): Yield 94 mg, 33%. [α]2D0 = –57.2 (c = 0.49 in CHCl3);
Rf = 0.10 (AcOEt/MeOH, 4:1). H NMR (CDCl3, 200 MHz): δ =
1314, 1225, 1048, 699, 550 cm–1. HRMS (ESI): calcd. for
C26H35N4O2 [M + H]+ 435.2755; found 435.2771.
1
1.15–1.40 (m, 4 H), 1.68–1.85 (m, 2 H), 1.95–2.15 (m, 2 H), 2.24
(s, 12 H), 2.87 (ABm, 2 H), 3.60–3.80 (m, 2 H), 7.20–7.40 (m, 2 H)
ppm. 13C NMR (CDCl3, 50 MHz): δ = 24.7, 32.6, 45.8, 52.2, 63.0,
(2S,2ЈS)-N,NЈ-[(1S,2S)-1,2-Diphenylethane-1,2-diyl]bis{2-[ethyl-
(methyl)amino]propanamide} (24): Yield 420 mg, 96%. [α]2D0 = +69.1
(c = 0.52 in CHCl3); Rf = 0.30 (AcOEt/MeOH, 4:1). 1H NMR
(CDCl3, 200 MHz): δ = 1.00 (t, J = 7.1 Hz, 6 H), 1.11 (d, J =
6.9 Hz, 6 H), 2.13 (s, 6 H), 2.36 (q, J = 7.1 Hz, 4 H), 3.19 (q, J =
6.9 Hz, 2 H), 5.15–5.25 (m, 2 H), 6.95–7.20 (m, 10 H), 8.05–8.25
(m, 2 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 9.1, 13.1, 37.7,
170.5 ppm. IR (CHCl ): IR (KBr): ν = 3281, 2939, 1640, 1519,
˜
3
1453, 1269, 1155, 1048, 866, 599 cm–1. HRMS (ESI): calcd. for
C14H29N4O2 [M + H]+ 285.2285; found 285.2282.
N,NЈ-[(1S,2S)-1,2-Diphenylethane-1,2-diyl]bis[2-(dimethylamino)-
acetamide] (19): Yield 344 mg, 90%. [α]2D0 = +37.3 (c = 0.65 in
47.9, 58.1, 62.2, 127.3, 127.3, 128.2, 139.2, 174.0 ppm. IR (KBr): ν
˜
5560
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5553–5562

Catalyzed Asymmetric Aldol Reduction Reaction
= 3313, 2974, 2795, 1645, 1514, 1454, 1233, 1107, 701, 584 cm–1.
HRMS (ESI): calcd. for C26H39N4O2 [M + H]+ 439.3068; found
439.3078.
[M + Na]+ 259.1668; found 259.1674; HPLC [Chiralpak AD-H,
Hex/iPrOH (9:1), flow rate = 1 mL/min, λ = 254 nm]: t1 = 6.4 min
(major peak), t2 = 7.4 min.
(1S,2S,3R)-2-Propyl-1-(4-methylphenyl)heptane-1,3-diol (32): Yield
71 mg, 54%. 1H NMR (CDCl3, 400 MHz): δ = 0.85–0.89 (m, 6 H),
1.15–1.40 (m, 8 H), 1.48–1.56 (m, 2 H), 1.69–1.74 (m, 1 H), 2.34
(s, 3 H), 3.12 (s, 2 H), 3.72 (d, J = 7.2 Hz, 1 H), 4.82 (d, J = 6 Hz,
1 H), 7.14–7.26 (m, 2 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
14.0, 14.2, 20.9, 21.1, 22.7, 27.7, 28.4, 33.2, 48.2, 7.2, 76.0, 126.0,
(2S,2ЈS)-N,NЈ-[(1S,2S)-1,2-Diphenylethane-1,2-diyl]bis{2-[benzyl-
(methyl)amino]propanamide} (25): Yield 535 mg, 95%. [α]2D0 = +11.5
(c = 0.56 in CHCl3); Rf = 0.30 (AcOEt/MeOH, 4:1). 1H NMR
(CDCl3, 200 MHz): δ = 1.17 (d, J = 7.0 Hz, 6 H), 2.05 (s, 6 H),
3.20 (q, J = 7.0 Hz, 2 H), 3.44 (ABm, 4 H), 5.20–5.35 (m, 2 H),
7.00–7.40 (m, 20 H), 8.05–8.20 (m, 2 H) ppm. 13C NMR (CDCl3,
50 MHz): δ = 8.2, 37.9, 58.2, 58.4, 61.6, 127.1, 127.4, 128.3, 128.4,
128.9, 136.7, 140.9 ppm. IR (CHCl ): ν = 3309, 2956, 2932, 2872,
˜
3
1513, 1466, 1457, 1037, 1010, 815 cm–1. HRMS (ESI): calcd. for
C17H28O2 [M + Na]+ 287.1981; found 287.1985; HPLC [Chiralpak
AD-H, Hex/iPrOH (9:1), flow rate = 1 mL/min, λ = 254 nm]: t1 =
6.1 min (major peak), t2 = 6.8 min.
128.6, 138.3, 139.0, 173.6 ppm. IR (KBr): ν = 3310, 3030, 2969,
˜
2796, 1644, 1495, 1243, 1028, 739, 699 cm–1. HRMS (ESI): calcd.
for C36H43N4O2 [M + H]+ 563.3381; found 563.3389.
(2S,2ЈS)-N,NЈ-[(1S,2S)-1,2-Diphenylethane-1,2-diyl]bis{2-[isopropyl-
(methyl)amino]propanamide} (26): Yield 444 mg, 95%. [α]2D0 = +50.3
(c = 0.53 in CHCl3); Rf = 0.30 (AcOEt/MeOH, 4:1). 1H NMR
(CDCl3, 200 MHz): δ = 1.04 (d, J = 6.5 Hz, 12 H), 1.15 (d, J =
7.1 Hz, 6 H), 2.06 (s, 6 H), 2.84 (spt, J = 6.5 Hz, 2 H), 3.29 (q, J
= 7.1 Hz, 2 H), 5.15–5.25 (m, 2 H), 6.98–7.20 (m, 10 H), 8.20–8.40
(m, 2 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 12.3, 19.3, 19.9,
32.5, 52.01, 57.86, 59.62, 127.26, 127.31, 128.17, 139.17, 174.70
(1S,2S,3R)-2-Ethyl-1-(4-methoxyphenyl)hex-1,3-diol (34): Yield
55 mg, 44%. 1H NMR (CDCl3, 400 MHz): δ = 0.86–0.93 (m, 6 H),
1.20–1.60 (m, 6 H), 1.62–1.68 (m, 1 H), 3.81 (s, 3 H), 4.83 (d, J =
6.3 Hz, 1 H), 6.87–6.91 (m, 2 H), 7.25–7.30 (m, 2 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 12.5, 14.0, 18.8, 19.5, 35.4, 50.5,
55.2, 71.9, 75.6, 113.7, 127.3, 136.0, 158.8 ppm. IR (CHCl ): ν =
˜
3
3381, 3130, 2961, 2934, 2878, 1513, 1250, 1036, 842, 777 cm–1
.
HRMS (ESI): calcd. for C15H24O3 [M + Na]+ 275.16177; found.
274.1612; HPLC [Chiralpak AD-H, Hex/iPrOH (9:1), flow rate =
1 mL/min, λ = 254 nm]: t1 = 8.1 min (major peak), t2 = 9.7 min.
ppm. IR (KBr): ν = 3300, 2968, 2937, 1645, 1515, 1245, 1132, 1105,
˜
701, 557 cm–1. HRMS (ESI): calcd. for C26H43N4O2 [M + H]+
467.3381; found 467.3358.
(1S,2S,3R)-1-(4-tert-Butylphenyl)-2-methylpentane-1,3-diol (36):
Yield 120 mg, 96%. H NMR (CDCl3, 400 MHz): δ = 0.82 (d, J =
General Procedure for the Aldol–Tishchenko Reaction: Yb(III) trifl-
ate (125 mg 0.20 mmol, 20 mol-%) was placed in an oven-dried
flask with a magnetic stirring bar, and the flask was heated at
200 °C for 10 min in vacuo and then flushed with argon. After the
flask was cooled to room temp., a solution of the appropriate li-
gand (0.20 mmol, 20 mol-%) in THF (2 mL) was added. The re-
sulting solution was stirred for 30 min at room temp. under argon.
To a solution of the catalyst, 3-pentanone (100 µL, 0.95 mmol) and
benzaldehyde (101 µL, 1.00 mmol) were added successively. The re-
sulting solution was stirred for 20 h at room temp. and then dis-
solved with MTBE and washed with water and brine. The organic
layer was dried with Na2SO4, concentrated, and submitted to short
column chromatography (Hex/AcOEt, 9:1) to afford a mixture of
Tishchenko esters as an oil. The obtained esters were dissolved in
MeOH (2 mL) and treated with NaOMe (5–10 mol-%) overnight.
The resulting mixture was purified by column chromatography on
silica gel (Hex/AcOEt, 3:2) to afford diol 2 and, with an analogous
procedure, diols 27–40.
1
7.1 Hz, 3 H), 0.90 (t, J = 7.3 Hz, 3 H), 1.31 (s, 9 H), 1.36–1.48 (m,
2 H), 1.50–1.60 (m, 1 H), 1.91 (qd, J = 7.1, 2.2 Hz, 1 H), 3.15 (s,
1 H), 3.68–3.75 (m, 1 H), 4.64 (d, J = 7.1 Hz, 1 H), 7.20–7.27 (m,
2 H), 7.33–7.38 (m, 2 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
10.7, 11.5, 26.5, 31.3, 34.4, 43.2, 74.0, 77.8, 125.1, 125.9, 140.7,
150.2 ppm. IR (CHCl ): ν = 3327, 2964, 2903, 2876, 1461, 1040,
˜
3
1025, 965, 841, 773 cm–1. HRMS (ESI): calcd. for C16H26O2 [M +
Na]+ 273.1825; found 273.1825; HPLC [Chiralpak AS-H, Hex/iP-
rOH (9:1), flow rate = 1 mL/min, λ = 254 nm]: t1 = 4.5 min, t2 =
5.52 min (major peak).
(1S,2R,3S)-1-(4-Methoxyphenyl)-2-methyl-3-phenylpropane-1,3-diol
1
(39): Yield 60 mg, 44%. H NMR (200 MHz, CDCl3): δ = 0.71 (d,
J = 7.1 Hz, 3 H), 2.10–2.25 (m, 1 H), 3.33 (dd, J = 14.2, 3.3 Hz, 2
H), 3.80 (s, 3 H), 4.60–4.70 (m, 1 H), 4.95 (br. s, 1 H), 6.86 (d, J =
8.7 Hz, 2 H), 7.20 (d, J = 8.5 Hz, 2 H), 7.25–7.40 (m, 5 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 13.5, 45.8, 55.2, 74.5, 77.8, 113.4,
126.3, 127.2, 127.5, 128.4, 134.6, 143.5, 158.6 ppm. IR (KBr): ν =
˜
Analytical data for diols 27, 28, 30, 33, 35, 37, 38, and 40 were
3560, 3351, 2979, 2903, 1511, 1246, 1006, 990, 704, 566 cm–1
.
previously published.[13c]
HRMS (ESI): calcd. for C17H20O3Na [M + Na]+ 295.1305; found
295.1293; HPLC [Chiralpak AD-H, Hex/iPrOH (4:1), flow rate =
1 mL/min, λ = 254 nm]: t1 = 7.9 min, t2 = 11.9 min (major peak).
(1S,2S,3R)-1-Phenyl-2-propylheptane-1,3-diol (29): Yield 119 mg,
1
95%. H NMR (CDCl3, 200 MHz): δ = 0.80–0.95 (m, 6 H), 1.15–
1.50 (m, 10 H), 1.60–1.71 (m, 1 H), 3.12 (d, J = 4.7 Hz, 1 H), 3.70–
3.77 (m, 2 H), 4.86 (t, J = 4.9 Hz, 1 H), 7.20–7.40 (m, 5 H) ppm.
13C NMR (CDCl3, 50 MHz): δ = 14.0, 14.2, 20.9, 22.6, 27.5, 28.4,
33.3, 48.1, 72.1, 76.0, 126.0, 127.1, 128.2, 143.9 ppm; HPLC [Chi-
ralpak AS-H, Hex/iPrOH (9:1), flow rate = 1 mL/min, λ = 254 nm]:
t1 = 4.9 min, t2 = 5.3 min (major peak).
Acknowledgments
Financial support by the Polish State Committee for Scientific Re-
search (KBN Grant N N204 4094 33) is gratefully acknowledged.
(1S,2S,3R)-2-Ethyl-1-(4-methylphenyl)hex-1,3-diol (31): Yield
81 mg, 69%. 1H NMR (CDCl3, 400 MHz): δ = 0.87 (t, J = 7.2 Hz,
3 H), 0.92 (t, J = 7.5 Hz, 3 H), 1.20–1.30 (m, 2 H), 1.32–1.46 (m,
2 H), 1.50–1.60 (m, 2 H), 1.61–1.67 (m, 2 H), 2.35 (s, 3 H), 2.70 (s,
2 H), 3.76–3.81 (m, 1 H), 4.86 (d, J = 6.1 Hz, 1 H), 7.14–7.18 (m,
2 H), 7.21–7.26 (m, 2 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
12.5, 14.0, 18.6, 19.5, 21.1, 35.6, 50.4, 71.8, 75.8, 126.1, 129.0,
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3
1049, 1011, 844, 816, 773 cm–1. HRMS (ESI): calcd. for C15H24O2 [4] H. C. Aspinall, Chem. Rev. 2002, 102, 1807–1850.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5561

M. Stodulski, J. Jaz´win´ski, J. Mlynarski
FULL PAPER
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6.8 Hz, 3 H), 1.42 (d, J = 7.0 Hz, 3 H), 1.58 (d, J = 7.1 Hz, 3
H), 2.73 (s, 3 H), 3.60–3.80 (m, 2 H) ppm. 13C NMR (CD3OD,
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˜
3
1019, 539 cm–1. HRMS (EI): calcd. for C7H15NO2, [M]+:
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Received: July 22, 2008
Published Online: October 10, 2008
5562
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5553–5562