Asymmetric syn-aldol reaction of α-hydroxy ketones with tertiary amine catalysts

Article abstract of DOI:10.1002/ejoc.201300872

The tertiary amine-catalyzed direct asymmetric aldol reaction of 2-hydroxyacetophenones (2-hydroxy-1-arylethanones) with a variety of aliphatic aldehydes has been demonstrated. By using 20 mol-% of unmodified cinchonine as catalyst, the direct aldol reaction products were isolated in good yields and with remarkably high syn diastereocontrol and good asymmetric induction (40-78 % ee). This newly elaborated tertiary-amine-catalyzed direct asymmetric aldol reaction has extended the scope of organocatalytic processes to aromatic α-hydroxy ketones, which have hitherto been unreactive towards enamine catalysis. Unmodified cinchona alkaloids have been found to promote efficiently the direct aldol reaction of hydroxy ketones and various aldehydes in good yields and with remarkably high syn diastereocontrol and good asymmetric induction (40-78 % ee). Copyright

Full text of DOI:10.1002/ejoc.201300872

FULL PAPER
DOI: 10.1002/ejoc.201300872
Asymmetric syn-Aldol Reaction of α-Hydroxy Ketones with Tertiary Amine
Catalysts
[a]
[a]
[a]
[a,b]
Sebastian Ba s´ , Łukasz Wo z´ niak, Judyta Cygan, and Jacek Mlynarski*
Keywords: Asymmetric synthesis / Organocatalysis / Aldol reactions / Alkaloids
The tertiary amine-catalyzed direct asymmetric aldol reac-
tion of 2-hydroxyacetophenones (2-hydroxy-1-arylethan-
ones) with a variety of aliphatic aldehydes has been demon-
good asymmetric induction (40–78% ee). This newly elabo-
rated tertiary-amine-catalyzed direct asymmetric aldol reac-
tion has extended the scope of organocatalytic processes to
strated. By using 20 mol-% of unmodified cinchonine as cata- aromatic α-hydroxy ketones, which have hitherto been unre-
lyst, the direct aldol reaction products were isolated in good
active towards enamine catalysis.
yields and with remarkably high syn diastereocontrol and
Introduction
cance in total synthesis.[6] Since 2000, few initial reports
The asymmetric aldol reaction is undoubtedly one of the have addressed the direct aldol addition of hydroxy ketones
most powerful methods for the construction of carbon–car- to aldehydes by using both organometallic and proline cata-
bon bonds under asymmetric control.[ The recent rapid lysts (Scheme 1). In 2001, Trost et al. reported the use of
development in this area is related mainly to the direct cata- the dinuclear zinc ProPhenol catalyst in the syn-selective
lytic aldol reaction which combines high selectivity with a synthesis of 1,2-diols from 2-hydroxyacetophenone.[ The
1]
7]
[
2]
requirement for catalytic amounts of chiral promoters.
same syn selectivity for the reaction of 2-hydroxyacetophe-
[3]
Since the first reports of metal-complex- and proline-cata- none was achieved by Shibasaki and co-workers in the reac-
lysed direct asymmetric aldol reactions,[ numerous cata- tion promoted by a zinc-based catalyst with a BINOL li-
4]
[
8]
lysts have been designed that have further improved the cat- gand. Interestingly, with a catalyst based on lanthanum
alyst reactivity, enantioselectivity and most importantly ion with BINOL ligands (LLB), anti-configured diols have
substrate scope of this reaction.[
5]
been predominantly formed, thus giving access to the re-
Among the various substrate combinations, hydroxy- maining diastereoisomeric diols.[9]
ketone-based aldol reactions are of considerable impor-
Hydroxyacetone has also been activated by organo-
tance because they provide expedient access to the 1,2-diol catalysts. At the very beginning of the renaissance of
unit that frequently occurs in natural products, such as in organocatalysis (2000), Notz and List showed that proline
carbohydrates or polyhydroxylated molecules of signifi- is a remarkably effective catalyst for the direct asymmetric
Scheme 1. Aldol reactions between hydroxy ketones and aldehydes.
aldol reaction of hydroxyacetone to various aldehydes with
[
a] Faculty of Chemistry, Jagiellonian University,
ee values of the anti-aldol products ranging from 67 to
Ingardena 3, 30-060 Krakow, Poland
[10]
99%.
In spite of high catalyst (30 mol-%) and ketone
E-mail: jacek.mlynarski@gmail.com
www.jacekmlynarski.pl
(20 vol.-%) loadings, these authors demonstrated the first
successful application of unprotected acetone as a donor in
non-enzymatic asymmetric aldol reactions. Later, a number
of organocatalysts were tested to control the difficult
[b] Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300872.
Eur. J. Org. Chem. 2013, 6917–6923
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6917

S. Ba s´ , Ł. Wo z´ niak, J. Cygan, J. Mlynarski
FULL PAPER
regio-[11] and stereoselective[12] addition of unprotected hy-
The use of 20 mol-% of tertiary amine in THF at room
droxyacetone. Only recently, various amine-based organo- temp. led to the preferential formation of syn-aldol 7a in
catalysts have been successfully used for the selective forma- low yields ranging from only 14% for cinchinodine (2) to
tion of syn diols from the unprotected hydroxyacetone do- 31% for cinchonine (1) and quinidine (4) catalysts (Table 1,
[
13]
nor. It was assumed that organocatalysts containing pri- entries 1–4). However, the observed enantioselectivity en-
mary and secondary amine functions activated hydroxy- couraged us to continue this research. The most promising
acetone by forming a (Z)- or (E)-enamine intermediate, catalyst in terms of ee was cinchonine (1). Further careful
[
14]
which attacked one face of the aldehyde stereoselectively.
optimization revealed that the reaction promoted by
It is striking that most organocatalysts have been applied 20 mol-% of catalyst 1 in CHCl at 0 °C resulted in the for-
3
to the reaction of hydroxyacetone and, in contrast to mation of aldol 7a with remarkably high syn selectivity
metalloorganic catalysts, not a single organocatalyst has (94% de) and good enantioselectivity (61% ee; Table 1, en-
been demonstrated to activate aromatic hydroxy ketones try 5). Although the reaction yield leaves much to be de-
(i.e., 2-hydroxyacetophenone). This deficiency in organocat- sired (ca. 35%), the selectivity was very good for commer-
alysis is not only a methodological problem, but also a con- cial and inexpensive catalyst 1. Note that the best reaction
[
15]
siderable limitation in the synthesis of natural products.
efficiency was observed for a 1:2 ratio of ketone to aldehyde,
Therefore we planned to address this issue and develop or- with no need to overload ketone as was the case previously.
ganocatalysts for direct asymmetric aldol reactions of 2-
hydroxyacetophenones. However, this task required signifi-
cant effort and was successful only by using tertiary amine
catalysts instead of secondary amine catalysts and catalytic
enamine formation. Herein we report the application of un-
modified cinchona alkaloid-type organocatalysts for use in
enantioselective syn-selective direct aldol reactions.
Table 1. Screening for an efficient catalyst and conditions for the
asymmetric aldol reaction of 2-hydroxyacetophenone with prop-
anal.
Entry
Catalyst
amount [mol-%])
Solvent Yield
syn/anti
ee
(syn)
[a]
[b]
(
[%]
[
c]
1
1 (20)
2 (20)
3 (20)
4 (20)
THF
THF
THF
THF
31
14
16
31
86:14
70:30
74:26
72:28
35 (2S,3R)
24 (2R,3S)
19 (2R,3S)
14 (2S,3R)
[c]
2
[
c]
3
[
c]
4
Results and Discussion
5[
6
7
8
d]
1 (20)
2 (20)
3 (20)
4 (20)
CHCl
CHCl
CHCl
CHCl
34
35
18
25
97:3
88:22
95:5
61
51
41
43
3
To select promising organocatalysts, we first examined
the direct aldol reaction of 2-hydroxyacetophenone (5a)
with pentanal (6), which was selected as a more demanding
enolizable aldehyde partner. Interestingly, not one of the
known enamine-containing organocatalysts described pre-
[d]
3
3
3
[d]
[d]
95:5
9[e]
10
1 (5)
1 (10)
1 (20)
1 (30)
CHCl
CHCl
CHCl3
CHCl
3
n.d.
8
37
59
–
–
–
–
40
40
3
[e]
[e]
3
[13]
viously for the aldol reaction of hydroxyacetone was able 11
77:23
86:14
[16]
2[e]
1
to deliver the desired product from 5a. However, our pre-
[
17]
vious studies
have shown that the direct aldol reaction [a] Isolated yield. [b] The enantiomeric excess was determined by
using a hydroxyacetone donor with various aldehydes cata- HPLC analysis on a chiral phase column (Chiralpak AD-H). [c]
Reagents and conditions: 5a (1 mmol), 6 (2 mmol), catalyst (see
lysed by quinidine provided syn-selective aldol adducts al-
beit in moderate ee values. Following this discovery, we
table), THF (0.5 mL), room temp., 60 h. [d] Reagents and condi-
tions: 5a (1 mmol), 6 (2 mmol), catalyst (see table), CHCl
2.5 mL), 0 °C, 60 h. [e] Reagents and conditions: 5 (1 mmol), 6
(2 mmol), catalyst (see table), CHCl (2.5 mL), room temp., 60 h.
3
tested four native cinchona alkaloids 1–4 in the reaction of
a and 6 (Scheme 2).
(
5
3
Scheme 2. Asymmetric reaction of 2-hydroxyacetophenone (5a) promoted by cinchona alkaloid catalysts 1–4.
918 Eur. J. Org. Chem. 2013, 6917–6923
6
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Asymmetric syn-Aldol Reaction of α-Hydroxy Ketones
It was possible to considerably increase the reaction effi- Table 3. Substrate scope of direct catalytic asymmetric aldol reac-
tions catalyzed by 1 (20–30 mol-%).
ciency (59%, Table 1, entry 12) by using 30 mol-% of cin-
chona catalyst at room temp., but only at the expense of
selectivity. Commenting on the correlation between the
structure of the catalyst and the resulting aldol, application
of 1/4 and pseudo-enantiomeric couple 2/3 delivers the ex-
pected enantiomeric aldol (Table 1, entries 1–4).
Because it is known that hydrogen bonds play an impor-
tant role in the stabilization of the transition states of reac-
tions involving cinchona catalysts,[ we synthesized and
tested various known modified derivatives of 1. Unfortu-
nately, unmodified catalyst 1 showed the best selectivity and
18]
[19]
for this reason was used for further studies. The next step
was to test our assumption that a change in the electronic
structure of ketones can greatly affect the reactivity. We
confirmed our suspicions by testing the reactions of p-chlo-
ro- and p-methoxy-substituted ketones. The reaction of 2-
hydroxy-p-chloroacetophenone delivered the aldol in 74%
yield, whereas the analogous ketone with an electron-releas-
ing group was far less reactive under the same reaction con-
ditions, even after a prolonged reaction time (Table 2, en-
tries 1–3). Further examination of the reaction of 2-hy-
droxy-p-chloroacetophenone indicated that lowering the
temperature is beneficial for enantioselectivity and that the
use of 30 mol-% of the catalyst gave optimal results in terms
of both the yield and selectivity (entry 5).
Table 2. Effect of donor substituents on the asymmetric aldol reac-
tion of 2-hydroxyacetophenones with propanal catalyzed by 1.
Entry
R
Temp. Yield [%][a] syn/anti
ee (syn)[b]
1
2
H (7a)
r.t.
r.t.
r.t.
0 °C
0 °C
37
74
12
17
55
77:23
81:19
91:9
92:8
95:5
40
28
45
65
72
Cl (7b)
OMe (7c)
Cl (7b)
Cl (7b)
[
c]
3
4
5
[
d]
[
a] Isolated yield. Reagents and conditions: ketone (1 mmol), 6
2 mmol), 1 (20 mol-%), CHCl (2.5 mL), room temp. or 0 °C, 60 h.
b] The enantiomeric excess was determined by HPLC analysis on
a chiral phase column (Chiralpak AD-H, AS-H). [c] Reaction time:
(
3
[
72 h. [d] 30 mol-% of catalyst was used.
Finally, to explore the scope and limitation of the elabo-
rated methodology in depth, the reactions of various
ketones and aldehydes were investigated with 1 as the cata-
lyst (Table 3). The reactions were performed with 20 or
30 mol-% of cinchonine under the standard reaction condi-
tions for 60 h. Entries 1–6 in Table 3 show the results for
less reactive ketones, whereas entries 7–16 present the data
for synthetically useful ketones with electron-withdrawing
substituents.
In accord with previous observations, the reaction of 2-
hydroxyacetophenone resulted in the selective formation of
syn-aldols in low-to-good yields (Table 2 and Table 3, en-
tries 1–4). Interestingly, the reaction of 2-hydroxyaceto-
Eur. J. Org. Chem. 2013, 6917–6923
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Ba s´ , Ł. Wo z´ niak, J. Cygan, J. Mlynarski
FULL PAPER
Table 3. (Continued)
tries 5 and 6), but the observed ee of aldol 7i was lower,
reaching only 31% (entry 6). The absolute configurations
of the syn-aldol products 7d, 7e and 7h were determined to
be 2S,3R by comparison of the optical rotation values and
HPLC analysis with the known compounds prepared by
[
8,15]
asymmetric Sharpless dihydroxylation.
To show the synthetic potential of the developed method,
selected reactive ketones were prepared and used as donor
in the syn-selective aldol reaction with various aldehydes. 2-
Hydroxyacetophenones equipped with 4-chloro- (entry 7),
4-trifluoromethyl- (entry 8–10) and 3,5-bis(trifluoromethyl)
substituents (entry 11) were converted into the expected
syn-aldols in good yields (45–91%) and with good enantio-
selectivity (up to 56% ee). The tetrafluoro-substituted 2-
hydroxyacetophenones are better substrates in terms of re-
activity and selectivity (entries 12–16); for this donor sub-
strate syn-aldols were isolated in ee values of up to 78%.
To explain the stereochemistry of the reaction, we as-
sumed that the tertiary amine catalyst acts through the for-
mation of a tight ion pair with the ketone enolate followed
by stereocontrolled aldehyde addition (Scheme 3). Al-
though the reaction of the ketone involves an initial depro-
tonation by the cinchona catalyst 1 and subsequent attack
on the aldehyde, the catalyst also provides an asymmetric
[
a] Yield refers to the combined yield of isolated diastereomers.
Reagents and conditions: ketone (1 mmol), aldehyde (2 mmol), 1
20–30 mol-%), CHCl (2.5 mL), room temp. or 0 °C, 60 h. [b] The
(
3
enantiomeric excess was determined by HPLC analysis on a chiral environment for the reaction centre through a network of
phase column (Chiralpak AD-H, OD-H). [c] In this reaction the
catalyst seems to lead to the selective formation of the 2S,3R prod-
uct. The stereochemistry of the resulting aldols was determined
hydrogen bonds. The high syn selectivity can be explained
by (Z)-enol formation from the hydroxy ketone, which then
attacks the Si face of the aldehyde. Reaction at the Re face
based on a comparison of the optical rotation and HPLC analysis
of authentic samples with previously published data.[
tion time: 12 h.
8,15]
[d] Reac- of the aldehyde is more difficult due to steric repulsion be-
tween the two larger substituents.
phenone with α-branched 2-methylpropanal led to a low
yield but relatively high enantioselectivity (66% ee, Table 3,
entry 2). In the cases of 2-methylpropanal (entry 2) and
Conclusions
We have found a class of tertiary amine catalysts that
benzyloxyacetaldehyde (entry 3), it is likely that substrate are effective as highly syn-selective catalysts in the direct
self-condensation affected the yield, the best reaction effi- asymmetric aldol reaction of aromatic hydroxy ketones.
ciency being observed in a shorter reaction time. Unfortu- Simple commercial and unmodified cinchona alkaloids
nately, a remarkably efficient reaction with chloral delivered were found to efficiently promote the direct aldol reaction
the corresponding racemic aldol (entry 4). The reaction also of hydroxy ketones with various aldehydes in good yields
worked well when 2-acetylfuran was used as donor (en- and with good enantioselectivities of up to 78%. This is a
Scheme 3. Potential mechanism for the asymmetric aldol reaction catalyzed by chiral cinchona amine and a possible structure of the
transition state.
6920
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6917–6923

Asymmetric syn-Aldol Reaction of α-Hydroxy Ketones
valuable synthetic strategy not only because of the ready 7.55–7.47 (m, 2 H), 5.00 (d, J = 3.3 Hz, 1 H), 4.00–3.87 (m, 2 H),
1
.78–1.66 (m, 5 H), 1.58–1.30 (m, 3 H), 0.93 (t, J = 7.1 Hz) ppm.
availability of the catalysts, but also because of the lack of
other organocatalysts activating 2-hydroxyacetophenone
derivatives. Moreover, the reaction protocol developed may
be useful for the synthesis of fluoro- and trifluoromethyl-
derived chiral diols, which may be desired targets because
1
3
C NMR (75 MHz, CDCl
3.1, 34.6, 28.1, 22.8, 14.1 ppm. HPLC (Chiralpak AD-H, hexane/
= 8.3 (anti),
3
): δ = 200.5, 134.1, 129.1, 128.6, 75.6,
7
iPrOH = 80:20, flow rate: 1.0 mL/min, λ = 254 nm): t
9
R
.5 (anti), 11.7 (syn, major), 13.7 min (syn, minor).
(2S,3R)-1-(4-Chlorophenyl)-2,3-dihydroxyheptan-1-one (7b):[22] 1H
NMR (300 MHz, CDCl ): δ = 7.87–7.78 (m, 2 H), 7.52–7.45 (m, 2
H), 4.95 (d, J = 1.6 Hz, 1 H), 3.89 (td, J = 7.1, 1.5 Hz, 1 H), 1.77–
of their pharmacological properties.[
20]
As a result of the
3
simplicity of the concept presented, we believe that this pro-
cedure will influence the development of asymmetric syn-
thesis and lead to the discovery of more selective organocat-
alysts.
1
.64 (m, 2 H), 1.58–1.29 (m, 4 H), 0.92 (t, J = 7.0 Hz, 3 H) ppm.
1
3
C NMR (75 MHz, CDCl
3
): δ = 199.4, 140.7, 132.3, 130.1, 129.4,
7
5.7, 73.0, 34.4, 28.1, 22.8, 14.12 ppm. HPLC (Chiralpak AD-H,
hexane/iPrOH = 80:20, flow rate: 1.0 mL/min, λ = 254 nm): t
.7 (anti), 8.1 (anti), 10.5 (syn, minor), 11.7 min (syn, major).
R
=
6
Experimental Section
(
2S,3R)-1-(4-Methoxyphenyl)-2,3-dihydroxyheptan-1-one (7c):[22] 1
H
General: Unless otherwise stated, all reagents were purchased from
commercial sources and used as received. IR spectra were recorded
with a FTIR spectrometer. 1H NMR spectra were recorded at
3
NMR (300 MHz, CDCl ): δ = 7.97–7.80 (m, 2 H), 7.03–6.93 (m, 2
H), 4.94 (dd, J = 5.7, 1.7 Hz, 1 H), 3.98 (d, J = 5.7 Hz, 1 H), 3.89
s, 3 H), 1.89 (d, J = 9.4 Hz, 1 H), 1.77–1.62 (m, 2 H), 1.58–1.29 (m,
(
4
300 MHz in CDCl
3
. Data are reported as follows: chemical shifts
13
H), 0.93 (t, J = 7.1 Hz, 3 H) ppm. C NMR (75 MHz, CDCl
3
): δ
in parts per million (ppm) from tetramethylsilane as an internal
standard, integration, multiplicity (s singlet, d doublet, t triplet, q
quartet, dd double doublet, m multiplet, br broad), coupling con-
stants (in Hz) and assignment. 13C NMR spectra were recorded
at 100 MHz with complete proton decoupling. Chemical shifts are
reported in ppm relative to the residual solvent as an internal stan-
dard. HRMS were recorded with an electrospray ionization time-
of-flight (ESI-TOF) mass spectrometer. Optical rotations were
measured with a digital polarimeter at room temperature. The reac-
tions were monitored by using TLC on silica [alu-plates (0.2 mm)].
All reagents and solvents were purified and dried according to
common methods. All organic solutions were dried with anhydrous
magnesium sulfate. Reaction products were purified by flash
chromatography using silica gel 60 (240–400 mesh). HPLC analysis
was performed with an HPLC system equipped with chiral station-
ary phase columns (detection at 254 nm).
=
198.6, 164.4, 131.1, 126.6, 114.3, 75.1, 73.4, 55.7, 34.6, 28.2, 22.8,
14.2 ppm. HPLC (Chiralpak AS-H, hexane/iPrOH = 80:20, flow
rate: 0.5 mL/min, λ = 278 nm): t = 19.6 (anti), 25.1 (anti), 29.8
R
(
syn, major), 33.8 min (syn, minor).
2S,3R)-2,3-Dihydroxy-1,5-diphenylpentan-1-one
): δ = 7.81–7.72 (m, 2 H), 7.66–7.55 (m, 1
H), 7.52–7.40 (m, 2 H), 7.37–7.16 (m, 5 H), 4.98 (s, 1 H), 4.07–3.92
(
(7d):[7,8,9]
1H
NMR (300 MHz, CDCl
3
1
3
(
m, 2 H), 2.90–2.75 (m, 2 H), 2.19–1.99 (m, 2 H) ppm. C NMR
75 MHz, CDCl ): δ = 200.2, 141.4, 134.5, 134.2, 133.7, 129.2,
29.0, 128.7, 128.6, 128.4, 126.49, 126.2, 75.5, 72.3, 36.1, 32.1 ppm.
HPLC (Chiralpak AD-H, hexane/iPrOH = 80:20, flow rate:
.0 mL/min, λ = 254 nm): t = 12.1 (anti), 14.2 (anti), 17.9 (syn,
major), 22.6 min (syn, minor).
(
1
3
1
R
(7e):[7,9,22]
(2S,3R)-2,3-Dihydroxy-4-methyl-1-phenylpentan-1-one
H NMR (300 MHz, CDCl ): δ = 7.92–7.84 (m, 2 H), 7.67–7.58
1
3
(
m, 1 H), 7.57–7.47 (m, 2 H), 5.20 (dd, J = 5.0, 1.2 Hz, 1 H), 3.96
2
-Hydroxy Ketones: The 2-hydroxy ketones were prepared accord-
[21]
(d, J = 5.1 Hz, 1 H), 2.08–1.90 (m, 1 H), 1.13 (d, J = 6.7 Hz, 3 H),
1
2
ing to a previously described procedure. Iodobenzene diacetate
11.3 g, 35 mmol, 1.1 equiv.) was added during 15 min to a stirred
1
3
.04 (d, J = 6.7 Hz, 3 H) ppm. C NMR (75 MHz, CDCl
3
): δ =
(
00.8, 134.1, 133.8, 129.1, 128.6, 78.2, 73.8, 32.4, 19.4, 19.2 ppm.
solution of the corresponding methyl ketone (32 mmol, 1 equiv.)
and powdered potassium hydroxide (10 g, 180 mmol, 5.5 equiv.) in
methanol (20 mL) at 0 °C. The mixture was warmed to room tem-
perature, stirred for 3 h, and then evaporated to dryness under re-
duced pressure. The residue was shaken with water (20 mL) and
diethyl ether (20 mL). The ether solution was separated, dried with
magnesium sulfate and the solvents evaporated to dryness. The resi-
due was dissolved in a mixture of methanol (20 mL) and aqueous
hydrochloric acid (2 m, 20 mL) and then stirred overnight at room
temp. and then filtered. The solid product was recrystallized from
methanol or light petroleum ether.
HPLC (Chiralpak AD-H, hexane/iPrOH = 80:20, flow rate:
.0 mL/min, λ = 254 nm): t = 9.7 (anti), 11.4 (anti), 17.6 (syn,
minor), 18.6 min (syn, major).
1
R
2S,3R)-4-(Benzyloxy)-2,3-dihydroxy-1-phenylbutan-1-one (7f): 1
(
H
NMR (300 MHz, CDCl
H), 7.52–7.42 (m, 2 H), 7.40–7.22 (m, 5 H), 5.24 (s, 1 H), 4.58 (s,
3
): δ = 7.97–7.89 (m, 2 H), 7.65–7.56 (m, 1
2
3
=
H), 4.16 (dd, J = 9.2, 3.8 Hz, 1 H), 3.68 (dd, J = 9.2, 6.9 Hz, 1 H),
13
.62 (dd, J = 9.2, 6.1 Hz, 1 H) ppm. C NMR (75 MHz, CDCl
199.9, 137.9, 134.2, 133.7, 128.9, 128.9, 128.8, 128.6, 128.5, 127.9,
27.9, 127.8, 73.7, 73.2, 71.4, 71.0 ppm. HPLC (Chiralpak AD-H,
hexane/iPrOH = 80:20, flow rate: 1.0 mL/min, λ = 254 nm): t
13.4 (anti), 14.0 (anti), 16.2 (syn, major), 20.4 min (syn, minor).
3
): δ
1
General Procedures for the Aldol Reaction: Aldehyde (2 equiv.) was
added to a solution of catalyst (20–30 mol-%) and ketone (1 equiv.)
R
=
in CHCl
3
(2.5 mL) at room temp. or 0 °C for 60 h (see Table 3).
1
(
2S,3R)-4,4,4-Trichloro-2,3-dihydroxy-1-phenylbutan-1-one (7g): H
NMR (300 MHz, CDCl ): δ = 8.08–7.99 (m, 2 H), 7.74–7.65 (m, 1
H), 7.61–7.51 (m, 2 H), 5.73 (s, 1 H), 4.51–4.28 (m, 2 H), 3.73 (d,
The reaction mixture was stirred until TLC control showed disap-
pearance of the substrates (hexane/MTBE/dichloromethane 2:1:5)
and then the reaction mixture was dissolved in AcOEt (25 mL),
washed with water, saturated NaHSO
and brine, dried with MgSO and the solvents evaporated to dry-
ness. Standard purification method by column chromatography on
silica gel with hexane/MTBE/dichloromethane (2:1:5) as eluent af-
forded the desired aldol product.
3
13
J = 10.5 Hz, 1 H) ppm. C NMR (75 MHz, CDCl
3
): δ = 197.9,
3
(2ϫ 10 mL), water again
1
3
1
6
34.9, 132.3, 129.4, 129.1, 101.7, 80.7, 71.3 ppm. IR (neat): ν˜ =
384, 3361, 3063, 2967, 2939, 2847, 1689, 1598, 1580, 1448, 1410,
322, 1308, 1277, 1125, 981, 939, 898, 822, 771, 722, 693, 675,
4
–1
67 cm . HPLC (Chiralpak AD-H, hexane/iPrOH = 80:20, flow
rate: 1.0 mL/min, λ = 254 nm): t
(syn), 21.7 min (syn). HRMS (ESI): calcd. for C10
R
= 10.7 (anti), 11.8 (anti), 12.8
(
(
2S,3R)-2,3-Dihydroxy-1-phenylheptan-1-one (7a):[22] 1H NMR
300 MHz, CDCl ): δ = 7.92–7.86 (m, 2 H), 7.67–7.59 (m, 1 H), Na] 304.9515; found 304.9500.
H
9
Cl
3
O
3
[M +
+
3
Eur. J. Org. Chem. 2013, 6917–6923
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6921

S. Ba s´ , Ł. Wo z´ niak, J. Cygan, J. Mlynarski
FULL PAPER
(
(
2S,3R)-1-(Furan-2-yl)-2,3-dihydroxyheptan-1-one (7h):[15] 1H NMR
300 MHz, CDCl ): δ = 7.66 (dd, J = 1.7, 0.8 Hz, 1 H), 7.38 (dd,
135.3, 134.9, 129.5, 128.9, 128.8, 128.1, 127.4, 127.1, 125.9, 125.8,
121.5, 73.8, 73.8, 40.9 ppm. IR (neat): ν˜ = 3453, 3063, 3023, 2928,
2850, 1695, 1496, 1455, 1413, 1329, 1261, 1173, 1135, 1069, 1017,
3
J = 3.7, 0.8 Hz, 1 H), 6.62 (dd, J = 3.6, 1.7 Hz, 1 H), 4.78 (s, 1 H),
4
1
–
1
.11 (t, J = 6.0 Hz, 1 H), 3.78 (d, J = 4.5 Hz, 1 H), 2.37 (s, 1 H), 986, 871, 755, 743, 705 cm . HPLC (Chiralpak AD-H, hexane/
.80–1.68 (m, 2 H), 1.62–1.33 (m, 4 H), 0.96 (t, J = 7.1 Hz, 3 iPrOH = 80:20, flow rate: 1.0 mL/min, λ = 254 nm): t = 11.7 (syn,
minor), 12.3 (syn, major), 17.3 (anti), 18.7 min (anti). HRMS (ESI):
calcd. for C17
[M + Na]+ 347.0871; found 347.0810.
R
13
H) ppm. C NMR (75 MHz, CDCl
19.4, 112.9, 76.0, 72.9, 34.4, 28.1, 22.8, 14.2 ppm. HPLC (Chi-
ralpak AD-H, hexane/iPrOH = 80:20, flow rate: 1.0 mL/min, λ =
54 nm): t = 10.2 (anti), 11.2 (anti), 13.3 (syn, major), 15.9 min
syn, minor).
3
): δ = 188.7, 150.6, 147.2,
1
15 3 3
H F O
(
2S,3R)-1-[3,5-Bis(trifluoromethyl)phenyl]-2,3-dihydroxy-4-phen-
2
(
R
1
ylbutan-1-one (7n): H NMR (300 MHz, CDCl
3
): δ = 8.07 (s, 2 H),
7
.47–7.20 (m, 6 H), 4.90 (d, J = 1.3 Hz, 1 H), 4.17 (ddd, J = 8.7,
1
3
(
2S,3R)-4-(Benzyloxy)-1-(furan-2-yl)-2,3-dihydroxybutan-1-one (7i):
6.4, 1.3 Hz, 1 H), 3.12–2.95 (m, 2 H) ppm. C NMR (75 MHz,
CDCl ): δ = 197.9, 136.8, 135.1, 132.8, 132.4, 129.2, 129.2, 128.6,
1
H NMR (300 MHz, CDCl
.47–7.29 (m, 6 H), 6.60 (dd, J = 3.6, 1.7 Hz, 1 H), 4.95 (d, J =
.9 Hz, 1 H), 4.62 (s, 2 H), 4.35 (td, J = 6.2, 1.9 Hz, 1 H), 3.81–
3
): δ = 7.65 (dd, J = 1.7, 0.5 Hz, 1 H),
3
7
1
3
1
7
2
1
127.2, 126.9, 124.4, 120.8, 73.8, 73.73, 40.6 ppm. IR (neat): ν˜ =
3492, 3360, 3093, 3066, 3029, 2927, 2855, 1695, 1614, 1497, 1456,
13
.65 (m, 2 H) ppm. C NMR (75 MHz, CDCl
3
): δ = 187.9, 150.4, 1406, 1376, 1288, 1258, 1191, 1145, 1060, 914, 946, 783, 752, 701,
–
1
47.4, 137.9, 128.6, 128.5, 127.9, 127.9, 127.4, 119.8, 112.8, 73.9,
3.7, 71.4, 71.2 ppm. IR (neat): ν˜ = 3297, 3126, 3032, 2935, 2886, rate: 0.5 mL/min, λ = 206 nm): t
859, 1704, 1670, 1570, 1490, 1468, 1417, 1392, 1318, 1236, 1138, (syn, minor), 34.1 min (syn, major). HRMS (ESI): calcd. for
[M + Na]+ 415.0745; found 415.0658.
682 cm . HPLC (Chiralpak OD-H, hexane/iPrOH = 96:4, flow
R
= 11.7 (anti), 15.8 (anti), 30.5
–1
118, 1080, 1033, 985, 885, 860, 772, 758, 734, 696 cm . HPLC
Chiralpak AD-H, hexane/iPrOH = 80:20, flow rate: 1.0 mL/min,
λ = 254 nm): t = 15.6 (anti), 16.9 (anti), 19.1 (syn, major), 23.5 min
syn, minor). HRMS (ESI): calcd. for C15
[M + Na]+
18 14 6 3
C H F O
(
(
2S,3R)-2,3-Dihydroxy-1-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-
R
1
heptan-1-one (7o): H NMR (300 MHz, CDCl
3
3
3
): δ = 4.71 (dd, J =
.9, 2.0 Hz, 1 H), 4.21 (t, J = 1.9 Hz, 3 H), 4.17–4.07 (m, 2 H),
.92–3.83 (m, 1 H), 1.75–1.65 (m, 2 H), 1.50–1.29 (m, 5 H), 0.94
(
2
16 5
H O
99.0895; found 299.0873.
1
3
(
(
2S,3R)-4-(Benzyloxy)-1-(4-chlorophenyl)-2,3-dihydroxybutan-1-one
7j): H NMR (600 MHz, CDCl
(t, J = 7.0 Hz, 3 H) ppm. C NMR (75 MHz, CDCl
): δ = 7.89–7.84 (m, 2 H), 7.46– 79.6, 72.3, 62.0, 34.0, 27.8, 22.5, 13.9 ppm. IR (neat): ν˜ = 3331,
.41 (m, 2 H), 7.39–7.28 (m, 5 H), 5.19 (s, 1 H), 4.62–4.54 (m, 2 2955, 2872, 1706, 1648, 1510, 1487, 1440, 1408, 1330, 1309, 1202,
3
): δ = 195.4,
1
3
7
–
1
H), 4.16–4.10 (m, 1 H), 3.91 (s, 1 H), 3.66 (dd, J = 9.2, 6.9 Hz, 1
1161, 1092, 1003, 944, 915, 861, 811, 775, 689, 659 cm . HPLC
H), 3.62 (dd, J = 9.2, 5.8 Hz, 1 H), 2.32 (s, 1 H) ppm. 1 C NMR
3
(Chiralpak AD-H, hexane/iPrOH = 80:20, flow rate: 1.0 mL/min,
(
3 R
151 MHz, CDCl ): δ = 198.9, 140.7, 137.8, 132.1, 130.3, 129.4, λ = 254 nm): t = 5.4 (anti), 5.7 (anti), 7.8 (syn, major), 8.3 min
+
1
3
1
6
28.7, 128.1, 127.9, 73.7, 73.2, 71.4, 70.8 ppm. IR (neat): ν˜ = 3297,
16 4 4
(syn, minor). HRMS (ESI): calcd. for C14H F O [M + Na]
089, 3060, 3032, 2935, 2882, 1701, 1591, 1490, 1455, 1400, 1317,
255, 1214, 1134, 1096, 1029, 1014, 996, 983, 876, 867, 815, 740,
347.0882; found 347.0885.
(
2S,3R)-2,3-Dihydroxy-4-methyl-1-(2,3,5,6-tetrafluoro-4-methoxy-
–1
98 cm . HPLC (Chiralpak AD-H, hexane/iPrOH = 80:20, flow
= 13.9 (anti), 14.6 (anti), 15.4
syn, major), 16.3 min (syn, minor). HRMS (ESI): calcd. for
1
phenyl)pentan-1-one (7p): H NMR (300 MHz, CDCl
3
): δ = 4.88
rate: 1.0 mL/min, λ = 254 nm): t
(
R
(
d, J = 1.6 Hz, 1 H), 4.19 (t, J = 1.9 Hz, 3 H), 4.15–4.05 (m, 2 H),
3
6
.41 (dd, J = 8.9, 1.6 Hz, 1 H), 2.01–1.85 (m, 1 H), 1.03 (d, J =
.7 Hz, 6 H) ppm. C NMR (75 MHz, CDCl ): δ = 78.7, 78.5,
3
+
C
17
H17ClO
4
[M + Na] 243.0713; found 243.0710.
13
(
2S,3R)-4-(Benzyloxy)-2,3-dihydroxy-1-(4-trifluoromethylphenyl)-
62.7, 32.4, 19.7, 19.5 ppm. IR (neat): ν˜ = 3471, 2965, 2941, 2868,
1
butan-1-one (7k): H NMR (300 MHz, CDCl
3
): δ = 8.07–7.98 (m,
1708, 1650, 1511, 1491, 1440, 1412, 1314, 1203, 1141, 1097, 1068,
–
1
2
1
H), 7.79–7.69 (m, 2 H), 7.45–7.27 (m, 5 H), 5.23 (d, J = 1.9 Hz, 994, 802 cm . HPLC (Chiralpak AD-H, hexane/iPrOH = 80:20,
H), 4.57 (s, 2 H), 4.17–4.07 (m, 1 H), 3.75–3.58 (m, 2 H) ppm. flow rate: 1.0 mL/min, λ = 254 nm): t = 7.6 (anti), 9.2 (anti), 9.8
): δ = 199.9, 138.2, 137.3, 129.7, 129.3, (syn, minor), 11.3 min (syn, major). HRMS (ESI): calcd. for
R
1
3
C NMR (75 MHz, CDCl
3
1
7
1
9
29.2, 128.7, 128.6, 128.5, 128.4, 126.5, 126.5, 74.3, 74.2, 71.7,
1.2 ppm. IR (neat): ν˜ = 3331, 3063, 3032, 2929, 2874, 1708, 1615,
579, 1490, 1455, 1410, 1330, 1254, 1212, 1171, 1132, 1069, 1017,
C
13
H
14
F
4
O
4
[M + Na]+ 333.0726; found 333.0714.
(
2S,3R)-2,3-Dihydroxy-4,4-diphenyl-1-(2,3,5,6-tetrafluoro-4-meth-
1
oxyphenyl)lbutan-1-one (7q): H NMR (300 MHz, CDCl
3
): δ =
–
1
89, 874, 745, 699 cm . HPLC (Chiralpak AD-H, hexane/iPrOH
80:20, flow rate: 1.0 mL/min, λ = 254 nm): t = 9.9 (unseparated
anti), 11.5 (syn, major), 12.3 min (syn, minor). HRMS (ESI): calcd.
7
4
5
.44–7.14 (m, 10 H), 4.68–4.57 (m, 1 H), 4.54 (d, J = 4.0 Hz, 1 H),
=
R
.35 (d, J = 10.7 Hz, 1 H), 4.20 (t, J = 1.9 Hz, 3 H), 3.72 (d, J =
13
.7 Hz, 1 H), 1.89 (d, J = 6.3 Hz, 1 H) ppm. C NMR (75 MHz,
+
for C18
17 3 4
H F O [M + Na] 377.0977; found 377.0939.
3
CDCl ): δ = 195.4, 140.8, 140.5, 129.3, 129.1, 129.1, 128.6, 128.4,
(
2S,3R)-2,3-Dihydroxy-1-(4-trifluoromethylphenyl)butan-1-one (7l):
127.4, 127.3, 77.7, 74.5, 62.2, 55.1 ppm. IR (neat): ν˜ = 3482, 3084,
1
H NMR (300 MHz, CDCl
3
): δ = 8.12–7.97 (m, 2 H), 7.83–7.74 3062, 3030, 2959, 2928, 2850, 1709, 1648, 1598, 1511, 1491, 1453,
–1
(m, 2 H), 4.91 (d, J = 2.4 Hz, 1 H), 4.13 (m, 1 H), 1.39 (d, J =
1438, 1409, 1313, 1204, 1165 1124, 993, 812, 749, 707 cm . HPLC
13
6
1
2
8
8
1
.5 Hz, 3 H) ppm. C NMR (75 MHz, CDCl
3
): δ = 199.5, 136.9,
(Chiralpak AD-H, hexane/iPrOH = 80:20, flow rate: 1.0 mL/min,
R
29.0, 128.9, 125.9, 69.2, 68.8, 20.5 ppm. IR (neat): ν˜ = 3436, 2978, λ = 254 nm): t = 8.4 (syn, major), 15.7 (syn, minor), 17.5 (anti),
+
929, 1694, 1515, 1413, 1332 1269, 1173, 1137, 1069, 1011, 984,
18 4 4
18.6 min (anti). HRMS (ESI): calcd. for C23H F O [M + Na]
63, 847, 823 cm– . HPLC (Chiralpak OD-H, hexane/iPrOH =
1
457.1039; found 457.1020.
0:20, flow rate: 0.5 mL/min, λ = 254 nm): t
R
= 11.8 (syn, major),
(
2S,3R)-2,3-Dihydroxy-5-phenyl-1-(2,3,5,6-tetrafluoro-4-methoxy-
2.9 (syn, minor), 15.1 min (unseparated anti). HRMS (ESI): calcd.
1
phenyl)pentan-1-one (7r): H NMR (300 MHz, CDCl
.08 (m, 5 H), 4.67 (s, 1 H), 4.21 (t, J = 2.1 Hz, 3 H), 3.94–3.82
(m, 1 H), 3.78 (s, 1 H), 3.32 (s, 1 H), 2.88–2.65 (m, 2 H), 2.11–1.95
3
): δ = 7.35–
+
for C11
H
11
F
3
O
3
[M + Na] 271.0558; found 271.0493.
7
(
2S,3R)-2,3-Dihydroxy-4-phenyl-1-(4-trifluoromethylphenyl)butan-
1
13
1
7
2
-one (7m): H NMR (300 MHz, CDCl
.45–7.26 (m, 5 H), 4.92 (s, 1 H), 4.19–4.08 (m, 1 H), 3.12–2.95 (m,
H) ppm. 13C NMR (75 MHz, CDCl
): δ = 199.4, 137.2, 136.3,
3 3
): δ = 7.75–7.62 (m, 4 H), (m, 2 H) ppm. C NMR (75 MHz, CDCl ): δ = 195.3, 141.2,
128.6, 128.5, 126.2, 79.7, 71.7, 69.9, 62.2, 35.9, 32.0 ppm. IR (neat):
ν˜ = 3452, 3028, 2959, 2856, 1711, 1648, 1512, 1488, 1456, 1439,
3
6922
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6917–6923

Asymmetric syn-Aldol Reaction of α-Hydroxy Ketones
–
1
1
(
406, 1313, 1204, 1163, 1120, 1061, 1004, 749, 703 cm . HPLC
[7] B. M. Trost, H. Ito, E. R. Silcoff, J. Am. Chem. Soc. 2001, 123,
367.
3
Chiralpak AD-H, hexane/iPrOH = 80:20, flow rate: 1.0 mL/min,
[
8] N. Kumagi, S. Matsunaga, T. Kinoshita, S. Harada, S. Okada,
R
λ = 254 nm): t = 9.8 (syn, major), 11.2 (syn, minor), 17.3 (anti),
[M + Na]+
16 4 4
H F O
S. Sakamoto, K. Yamaguchi, M. Shibasaki, J. Am. Chem. Soc.
1
3
8.1 min (anti). HRMS (ESI): calcd. for C18
95.0882; found 395.0879.
2
003, 125, 2169.
[
9] N. Yoshikawa, N. Kumagai, S. Matsunaga, G. Moll, T. Ohsh-
ima, T. Suzuki, M. Shibasaki, J. Am. Chem. Soc. 2001, 123,
2466.
(
2S,3R)-4-(Benzyloxy)-2,3-dihydroxy-1-(2,3,5,6-tetrafluoro-4-
methoxyphenyl)butan-1-one (7s): H NMR (600 MHz, CDCl ): δ =
3
.38–7.29 (m, 5 H), 5.66 (s, 1 H), 4.55–4.45 (m, 2 H), 4.18 (dt, J = [10] W. Notz, B. List, J. Am. Chem. Soc. 2000, 122, 7386.
.0, 1.6 Hz, 1 H), 4.09–4.05 (m, 3 H), 3.70–3.61 (m, 2 H) ppm.
): δ = 128.8, 128.7, 128.7, 128.0, 127.9,
4.2, 73.9, 70.7, 67.9, 62.2 ppm. IR (neat): ν˜ = 3437, 3031, 2917,
870, 1729, 1651, 1496, 1455, 1418, 1312, 1201, 1137, 1028, 992,
48, 700 cm . HPLC (Chiralpak AD-H, hexane/iPrOH = 80:20,
= 8.6 (anti), 10.4 (anti),
.9 (syn, minor), 12.9 min (syn, major). HRMS (ESI): calcd. for
1
7
3
1
3
[11] For the formation of mixed linear/branched or linear products,
C
see: a) S. Samanta, J. Y. Liu, R. Dodda, C. G. Zhao, Org. Lett.
NMR (151 MHz, CDCl
3
2
005, 7, 5321; b) X. H. Chen, S. Luo, Z. Tang, L. F. Cun, A. Q.
7
2
7
Mi, Y. Z. Jiang, L. Z. Gong, Chem. Eur. J. 2007, 13, 689; c) Z.
Tang, Z. H. Yang, L. F. Cun, L. Z. Gong, A. Q. Mi, Y. Z. Ji-
ang, Org. Lett. 2004, 6, 2285.
–1
flow rate: 1.0 mL/min, λ = 254 nm): t
9
C
R
[
12] For the formation of syn/anti isomers, see: a) K. Sakthivel, W.
Notz, T. Bui, C. F. Barbas III, J. Am. Chem. Soc. 2001, 123,
5260; b) P. Dziedzic, W. B. Zou, J. Hafren, A. Cordova, Org.
Biomol. Chem. 2006, 4, 38; c) F.-C. Wu, C.-S. Da, Z.-X. Du,
Q.-P. Guo, W.-P. Li, L. Yi, Y.-N. Jia, X. Ma, J. Org. Chem.
+
18 16 4 5
H F O [M + Na] 411.0832; found 411.0830.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and copies of the HPLC
data as well as H NMR and C NMR spectra of all aldol prod-
ucts.
2009, 74, 4812.
1
13
[
13] For selected examples of syn-selective aldol reactions of hy-
droxy acetone, see: a) X. Wu, Z. Ma, Z. Ye, S. Qian, G. Zhao,
Adv. Synth. Catal. 2009, 351, 158; b) J. Li, S. Luo, J.-P. Cheng,
J. Org. Chem. 2009, 74, 1747; c) X.-Y. Xu, Y.-Z. Wang, L.-Z.
Gong, Org. Lett. 2005, 7, 5321; d) D. Sarkar, K. Harman, S.
Ghosh, A. D. Headley, Tetrahedron: Asymmetry 2011, 22,
Acknowledgments
The authors are grateful for financial support from the Foundation
for Polish Science TEAM programme co-financed by the European
Regional Development Fund. The research was carried out with
the equipment purchased through the financial support of the
European Regional Development Fund within the framework of
the Polish Innovation Economy Operational Program (contract
number POIG.02.01.00-12-023/08).
1051; e) Y. Liu, J. Wang, Q. Sun, R. Li, Tetrahedron Lett. 2011,
52, 3584; f) J. Paradowska, M. Pasternak, B. Gut, B. Gryzło,
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[14] S. Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem. Rev.
007, 107, 5471.
2
[
[
15] B. M. Trost, V. S. C. Yeh, Org. Lett. 2002, 4, 3513.
16] A list of catalysts that performed unsuccessfully in this study
is presented in the Supporting Information (p. S-2). All organo-
catalysts were used under the conditions described in the origi-
nal papers when hydroxyacetone was used as a donor.
[
1] R. Mahrwald (Ed.), Modern Aldol Reactions, Wiley-VCH,
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[18] T. Marcelli, H. Hiemstra, Synthesis 2010, 1229.
[19] Detailed information on the unsuccessful application of modi-
fied cinchona catalysts has been presented in the Supporting
Information (p. S-3/4).
[
[
2] B. Alcaide, P. Almendros, Eur. J. Org. Chem. 2002, 1595.
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Received: June 13, 2013
[
[
Published Online: September 13, 2013
Eur. J. Org. Chem. 2013, 6917–6923
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6923